Acs Chemrev 7b00064

Review
pubs.acs.org/CR
Imino Esters in Organic Synthesis: Recent Advances

Bagher Eftekhari-Sis*, and Maryam Zirak
Department of Chemistry, University of Maragheh, Maragheh 55181-83111, Iran
Department of Chemistry, Payame Noor University, Tehran 19395-3697, Iran
ABSTRACT: -Imino esters are useful precursors for the synthesis of a variety of types
of natural and unnatural -amino acid derivatives, with a wide range of biological
activities. Due to the adjacent ester group, -imino esters are more reactive relative to
other types of imines and undergo dierent kinds of reactions, including organometallics
addition, metal catalyzed vinylation and alkynylation, aza-Henry, aza-Morita-Baylis-
Hillman, imino-ene, Mannich-type, and cycloaddition reactions, as well as hydro-
genation and reduction. This review discusses the mechanism, scope, and applications of
the reactions of -imino esters and related compounds in organic synthesis, covering the
literature from the last 12 years.
CONTENTS 9.3. FriedelCrafts Reactions of Furans, Pyrroles,

and Thiophenes AT
1. Introduction B 9.4. Intramolecular FriedelCrafts Reaction AT
2. Synthesis of -Imino Esters C 9.5. Discussion, Synthetic Utility, and the Future AT
3. Organometallics Addition D 10. Aza-Morita-Baylis-Hillman Reaction AT
3.1. Grignard Reagents D 11. Aza-Henry Reaction AU
3.2. Organolithium Reagents H 12. Mannich Reaction AV
3.3. Organoboron Reagents H 12.1. Reaction with Enolizable Ketones and
3.4. Organoaluminum Reagents Q Aldehydes AV
3.5. Organozinc Reagents Q 12.2. Reaction with Silyl Enol Ethers BA
3.6. Organotin Reagents V 12.3. Reaction with Esters BB
3.7. Organosilicon Reagents V 12.4. Reaction with -Dicarbonyl and Related
3.8. Organotitanium Reagents W Compounds BC
3.9. Discussion, Synthetic Utility, and the Future W 12.5. Reaction with 2-Alkyl Azaarenes BF
4. Metal-Catalyzed Additions W 12.6. Reaction with Diazo Compounds BG
4.1. In-Mediated Allylation W 12.7. Vinylogous Mannich Reaction BI
4.2. Ag-Catalyzed Alkynylation AA 12.8. -Imino Ester as Nucleophile in Mannich
4.3. Cu-Catalyzed Alkynylation AB Reaction BJ
4.4. Zn-Catalyzed Alkynylation AD 12.9. Discussion, Synthetic Utility, and the Future BK
4.5. Rh-Catalyzed Alkynylation and Arylation AE 13. Michael Addition BK
4.6. Ru-Catalyzed Reductive Allylation AF 14. Reduction BK
4.7. Ni-Catalyzed Vinylation AF 14.1. Catalytic Hydrogenation BK
4.8. Discussion, Synthetic Utility, and the Future AF 14.2. Transfer Hydrogenation BM
5. Umpolung Reactions AG 14.3. Group III and IV-Hydride Donors BN
5.1. Grignard Reagents AG 14.4. Discussion, Synthetic Utility, and the Future BO
5.2. Organoaluminum Reagents AI 15. [2 + 1] Aziridinations BO
5.3. Discussion, Synthetic Utility, and the Future AL 16. [2 + 2] Cycloadditions BP
6. Triuoromethylation AL 17. [3 + 2] Cycloadditions and Cyclizations BR
7. Acylation AM 18. [4 + 2] Cycloadditions BS
8. Addition of Nitrogen, Oxygen, and Sulfur Nucle- 18.1. Synthesis of Tetrahydropyridines and Piper-
ophiles AN idines BS
9. FriedelCrafts Reactions AO 18.2. Synthesis of Quinolines and Tetrahydroqui-
9.1. FriedelCrafts Reactions of Indoles AO nolines BU
9.2. FriedelCrafts Reactions of Phenols, Ani-
soles, and Anilines AS
Received: January 24, 2017
XXXX American Chemical Society A DOI: 10.1021/acs.chemrev.7b00064

Chem. Rev. XXXX, XXX, XXXXXX
Chemical Reviews Review
18.3. Synthesis of Tetrahydropyrimidines and keto esters (Mannich-type reaction) and nitroalkanes (aza-
Dihydroquinazolines BX Henry reaction), and aza-Morita-Baylis-Hillman reaction, cyclo-
18.4. Discussion, Synthetic Utility, and the Future BX addition reactions such as [2 + 1] aziridination, [2 + 2], [3 + 2]
19. Ene Reaction BX and [4 + 2] cycloadditions, ene reaction, hydrogenation and
20. Aza-Cope and Electrocyclic Reactions BY reduction, and also a variety of sequences of some dierent kinds
21. Oxidative Cyclizations CA of reactions, leading to compounds that are inaccessible using
22. Radical Addition CB other precursors. There are so many published papers in the eld
23. Miscellaneous Reactions CC of -imino esters, and also there is growing number of published
24. Concluding Remarks CD papers on -imino esters in organic synthesis. However, there are
Author Information CF some reviews on the limited aspects or selected reactions of the
Corresponding Author CF related compounds in the literature;914 the necessity of a
ORCID CF comprehensive review article, covering all types of reactions of -
Notes CF imino esters is of interest in view of synthetic and medicinal
Biographies CF scientists. Because using -imino esters in synthesis has a long
Acknowledgments CG history, and there are some old reviews about the imines, the
Abbreviations CG present work covers the period from the 2005 to the end of 2016.
References CG Since the main purpose of this review is to show the synthetic
utility of -imino esters, not only simple -imino esters such as
glyoxalate and pyruvate imines are reviewed but also -imino
1. INTRODUCTION ketones, -oximino esters, and -hydrazono esters are included.
Opening by Weiners remarkable work on imino ene reaction in However, most reactions, in which -imino esters and -imino
1982, -imino esters have been known in synthetic organic ketones were in situ generated and took part in the synthesis of
chemistry for many years.14 -Imino esters are practical heterocyclic compounds, were surveyed in our recent reviews,5,6
precursors to a variety of types of substituted -amino acid in this paper, these reactions are excluded. Figure 1 shows all
derivatives and have appreciated a conspicuous place in natural possible structures of the -imino esters and related compounds
product synthesis, pharmaceutical research, and the study of that are reviewed in this paper. Because, very recently a review
biological systems. Also, some unnatural amino acids with a wide was published about the isatin imines in the stereoselective
range of biological activities were prepared using -imino esters. synthesis,15 this scaold is also excluded.
Moreover, -imino esters, either presynthesized or in situ The reactivity portrait of -imino esters is illustrated in Figure
generated, play an important role in heterocyclic chemistry.5,6 2, indicating three distinct electrophilic positions of these
Several derivatives of -imino esters have shown strong aldose scaolds. Therefore, three modes of nucleophilic addition to -
reductases inhibitory activity.7,8 imino esters took place. Addition to carbon of imine moiety
As a consequence of the adjacent electron withdrawing ester (path a) is well documented in the literature. Nucleophilic
functionality, -imino esters are more reactive relative to other addition to the carbonyl of ester functional group (path b) is also
types of imines and utilized in a number of organic trans- feasible but has not been reported frequently. In the third mode,
formations, including nucleophilic addition of organometallics, nitrogen of imine is attacked by certain types of nucleophiles
enolic components and active methylene compounds such as - (path c), which are called umpolung and is very rare.
Figure 1. Structures of reviewed -imino esters.

B DOI: 10.1021/acs.chemrev.7b00064
solution of ethyl glyoxalate and TsNCO in toluene for 2 days, in

80%, measured by 1H NMR. Le Goc et al.21 reported this
reaction catalyzed with AlCl3 in reuxing dry benzene for 34 h,
to synthesize dierent alkyl esters of N-tosyl -iminoacetates in
9095% yields. In(OTf)3 catalyzed in situ formation of -imino
ester by similar methodology was also reported by Frost et al.22
(Scheme 1, b). The synthesis of -imino esters was achieved by
nitrosobenzene mediated oxidative decarboxylation of malonate
Figure 2. Reactivity portrait of -imino esters.
and -ketoester derivatives. Treatment of diphenyl malonates
with 1 equiv of a base, including LDA or NaHMDS, in THF at
78 or 0 C for 30 min, followed by dropwise addition of a
solution of nitrosobenzene (1.05 equiv) in THF and stirring at
2. SYNTHESIS OF -IMINO ESTERS 78 C for 530 min, furnished the corresponding -imino
-Imino esters can be prepared either prior to use or in situ. esters in 8397% yields. Reaction with 2-methyl benzoylacetates
However, -imino esters are generally synthesized through using NaHMDS as base resulted in pyruvate derived imines in
condensation of -oxoesters with an amine in the presence of an high yields. Also, 1,3-diketones were subjected to oxidative
acid catalyst with azeotropic removal of water, or using a deacylation, to furnish corresponding -imino ketones in 83
dehydrating agent, commonly a MS (Scheme 1, a),1618 and 84% yields (Scheme 1, c).23 A similar approach was reported for
other ecient reports exist for preparing -imino esters in the the synthesis of methyl 2-hydroxyimino-3-phenylpropionate in
literature. [2 + 2] cycloaddition of glyoxalate with isocyanate led 92% yield, by reacting dimethyl 2-benzylmalonate with methyl
to -imino ester by CO2 release. Holmes19 and Lu20 reported the nitrite (1.05 equiv) in the presence of NaOMe (1 equiv) in dry
in situ generation of N-tosyl -iminoacetate by reuxing a MeOH at 0 C for 12 h. 24 Transesterication of 2-
Scheme 1. Synthesis of -Imino Esters
C DOI: 10.1021/acs.chemrev.7b00064
Scheme 2. Grignard Addition to -Imino Esters in the Presence or Absence of ZnCl2a
a 1
R = i-Pr, 8-Ph-menthyl; R2 = Et, i-Pr, c-Pr, t-Bu, n-Oct, Bn, o-BrBn, PhCH2CH2, allyl, 3-thienyl; X = Cl, Br, I; condition A, 1: 7399%, 2: 0%;
condition B, 1: 038%, 2: 090%; R* = 8-Ph-menthyl; 4: n = 4, m = 1, 74%, > 99/1 dr; n = 5, m = 2, 50%, 98/2 dr.
(trimethylsilyl)ethyl -imino esters was reported to synthesize Scheme 3. Grignard Addition to ,-Alkynyl--imino Estera
variety of uorinated -imino esters. Reactions were performed
by stirring a solution of silylated -imino ester, TBAF (1.5
equiv), and an electrophile (RX, 2 equiv) in THF at room
temperature for 124 h, giving corresponding -imino esters in
2095% yields. Starting 2-(trimethylsilyl)ethyl -imino esters
were prepared by alkoxycarbonylation of imidoyl chloride with
trimethylsilyl ethanol in the presence of a palladium catalyst
(Scheme 1, d).25 Rhodium(II) catalyzed reaction of -
diazoesters with organic azides is another useful method for
the preparation of -imino esters. By slowly adding an -diazo
ester to a solution of an azide (1 equiv) in DCM in the presence
of 1 mol % Rh2(OAc)4 at room temperature and stirring for an
additional 24 h at the same temperature under nitrogen
atmosphere, -imino esters were obtained in 3197% yields
(Scheme 1, e).26,27 Similar methodology was used for the
construction of cyclic -imino esters by Cu(I) catalyzed
intramolecular interception of azides with diazo moiety in 1,3-
diazidoisopropyl diazoacetates (Scheme 1, f).28,29 Moreover, an
ecient synthesis of -imino esters was developed by Hu et al.30
through slowly adding a solution of -diazoacetate in DCM to a
solution of an aniline (1 equiv), Rh2(OAc)4 (1 mol %), and
DEAD (1.1 equiv) in DCM under argon atmosphere and reux
conditions, over 1 h, resulting -imino esters in 5095% yields a 1
(Scheme 1, g). R = Ph, TMS; R* = 8-Ph-menthyl; R2 = Me, Et, i-Pr, n-Bu, i-Bu, c-
Hex, n-Oct, Bn, p-MeOBn, PhCH2CH2, allylCH2, vinyl, TMSCH2,
Cl(CH2)4, 1,3-dioxan-2-yl-(CH2)2; 3597%, > 99/1 dr.
3. ORGANOMETALLICS ADDITION
3.1. Grignard Reagents
Ishihara et al.31 described selective Grignard addition to N-PMP- ZnCl2, addition occurred at the carbon of imine. Also, one-pot
protected -imino esters in the presence or absence of Zn2+. intramolecular tandem C-alkyl additionN-alkylation of -imino
Addition with RMgX (3.3 equiv) in the presence of ZnCl2 (1.1 ester with alkylzinc(II)ate reagents was conducted by stirring a
equiv) in THF at 78 C proceeded via alkylzinc(II)ate solution of 4-chlorobutylMgBr or 5-chloropentylMgBr in the
(R3Zn), in situ generated from RMgX and ZnCl2, to give C- presence of ZnCl2 in THF at 78 C for 1 h, followed by
adducts 1 in 8399% yields, selectively. Reaction with 1.1 equiv treatment with TBAI in DMF, to give piperidine-2-carboxylate 4
of RMgX without using ZnCl2 led to corresponding N-adducts 2 (m = 1) or azepane-2-carboxylate 4 (m = 2) in 74% or 50% yield,
in 090% yields, along with formation of C-adducts 1 as respectively. One-pot addition of PhMgBr in the presence of
byproducts. However, by increasing the amount of RMgX (1.5 ZnCl2, followed by treatment with chloroacetyl chloride and
equiv), the yields of the N-adducts 2 were improved. In the case then DBU at room temperature for 25 h, instead of routine acidic
of allylMgCl and 3-thienylMgI in the presence or absence of workup, aorded -lactam 5 in 87% yield (Scheme 2).
D DOI: 10.1021/acs.chemrev.7b00064
Scheme 4. Synthesis of ()--Conhydrine 15a and (+)--Conhydrine 15b via Grignard Addition to -Imino Amide 11
Scheme 5. Synthesis of [1,4]Oxazino[4,3-a]azepine-1,6(9H)- In some cases, the Li+ cation improved the yields of products,
diones 19 by Means of Grignard Addition when added to the reaction medium as LiCl (1.1 equiv) as an
additive or using TMSCH2Li in place of TMSCH2MgCl. The
excellent diastereoselectivity was attributed to the bulky chiral 8-
phenylmenthyl moiety, which promoted the addition of in situ
generated zinc(II)ate complex [R-
(TMSCH2)2Zn][MgX]+[MgCl2]2 from the si-face (7), ex-
clusively. Reduction of 8-phenylmenthyl 2-ethyl-2-(p-methox-
yphenylamino)-4-phenylbut-3-ynoate 6 with LiAlH4 in THF at
0 C gave -alkynyl--amino alcohol 8 in 95% yield, which was
transformed into 2-alkynyl aziridine 9 via Mitsunobu reaction
using Ph3P and di(iso-propyl) azodicarboxylate in THF at 0 C
and then room temperature for 24 h in 94% yield with 99% ee
(Scheme 3).32
The Grignard addition of vinylMgBr to N-tert-butanesulnyl
protected -imino ester of phenylglyoxalate was also performed
in the presence of a catalytic amount of Me2Zn in THF at 78 or
100 C, which underwent desulnylation using HCl in MeOH
to give corresponding -amino esters in 5470% yields.33 Also,
N-(diethoxyphosphoryl)diuoroacetyl protected imine of meth-
yl triuoropyruvate underwent Grignard addition with MeMgBr,
PhMgBr, and BnMgBr in anhydrous Et2O at 78 C for 1 h to
produce corresponding C-adducts in 76%, 60%, and 63% yields,
respectively.34
Vicario et al.35 described the synthesis of ()--conhydrine
15a and (+)--conhydrine 15b, two bioactive -hydroxyalkyl-
substituted piperidines. By condensation of morpholinone 10
with benzylamine in the presence of anhydrous Na2SO4 in Et2O
Also, the Grignard addition to ,-alkynyl--imino esters was at room temperature, -imino amide 11a was obtained in 73%
conducted using RMgCl (1.1 equiv) in the presence of ZnCl2 yield, which underwent Grignard addition with allylMgCl in
(1.1 equiv) and TMSCH2MgCl (2.2 equiv) in THF at 78 C, THF at 78 C to give -amino amide 12a in 79% yield, with 98/
for 5 min, to give C-adducts 6 in 3597% yields, with >99/1 dr. 2 dr. -Amino amide 12a was converted to ketoamide 13 by
E DOI: 10.1021/acs.chemrev.7b00064
Scheme 6. Grignard Addition to Iminium Salts, in Situ Generated by Oxidation of Amino Ketene Silyl Acetalesa
a
21: R = Me, Et, n-Pr, i-Pr, c-Pr, c-Hex, allylCH2, TMSCH2, Bn, BnCH2, 4-MeOC6H4O(CH2)6, 4-XC6H4 (X = H, Cl, Me, MeO); X = Cl, Br; 24
75%. 22: R1 = Me, Et, n-Pr, i-Pr, c-Pr, c-Hex, t-Bu, vinyl, ethynyl, Bn, 4-XC6H4 (X = H, Me, MeO), 2-thienyl; R2 = PhCC, 4-XC6H4 (X = H, Cl,
Me, MeO), 1-naphthyl; X = Cl, Br; 1695%. 24: R = Et, n-Pr, i-Pr, c-Hex, n-Oct, allyl, allylCH2, TMSCH2, 1,3-dioxan-2-yl(CH2)2, BnO(CH2)4,
vinyl, PhCC, Ph, 2-thienyl; 2986%. 2627: n = 1, 2; m = 0, 1, 2; 26: 4777%; 27: 483%.
Scheme 7. Addition of Organolithiums to -Imino Ester 30a Scheme 8. Cu(I) Catalyzed Addition of Alkylborane Reagents
to -Imino Estersa
a
R = n-Bu, Ph, PhCC; 6274%.
reaction with EtLi at 78 to 0 C, followed by subjecting with

acryloyl chloride in the presence of Et3N in THF at room
temperature in 80% yield for the second step. By ring closing
metathesis using second generation Grubbs catalyst, dihydropyr-
idinone 14 was obtained in 75% yield, which was transformed
into ()--conhydrine 15a in further three steps. Also, Grignard
addition was used in the synthesis of (+)--conhydrine, in which
-imino amide 11b, generated from reaction of morpholinone 10
with allylamine in the presence of anhydrous Na2SO4 in Et2O at
room temperature in 60% yield, was reacted with allylMgCl in
THF at 78 C, in 66% yield, with 90/10 dr. Obtained -amino
amide 11b was converted to (+)--conhydrine 15b in further
steps through 12b (Scheme 4). a
Fustero et al.36 reported the synthesis of some nitrogen- 32: R1 = n-Bu, c-Hex, CH2OPh, XC6H4 (X = H, 4-Cl, 4-Br, 3-Me, 4-
Me, 4-t-Bu, 4-MeO), 3,4-(MeO)2C6H3, 1-naphthyl, 2-thienyl; R2 = H,
bridged heterocycles 19 by means of Grignard addition to cyclic
Me; R3 = H, R1R3 = (CH2)4; Ar = XC6H4 (X = H, 4-Cl, 4-Br, 3-Me,
-imino esters, imino lactones 16. By treatment of Grignard 4-Me, 2-MeO, 4-MeO, 4-NO2, 4-CO2Et), 1-naphthyl; 3785%. 33: R5
reagent (2 equiv) with a solution of imino lactones 16 in toluene = H, Me; 5962%. 34: Ar = XC6H4 (X = 4-Br, 3-Me, 4-Me, 2-MeO, 4-
in the presence of BF3OEt2 (2 equiv) at 78 C for 4 h, addition MeO); 4453%, 2133% ee.
products 17 were obtained in 2965% yields, which were
converted to acrylamides 18 by reacting with acryloyl chloride
(1.5 equiv) in the presence of Et3N (2 equiv) in DCM at 0 C for catalyst (5 mol %) in DCM under reux conditions for 2 h, nal
2 h. By ring closing metathesis using Grubbs second generation heterocyclic systems 19 were obtained. Reaction of but-3-en-1-yl
F DOI: 10.1021/acs.chemrev.7b00064
Scheme 9. Proposed Reaction Mechanism for Cu(I) Catalyzed Addition of Alkylborane Reagents to -Imino Esters
Scheme 10. Pd(II) Catalyzed Three-Component Coupling of Scheme 11. Proposed Reaction Mechanism of Pd(II)
Boronic Acids and Allenes with -Imino Estersa Catalyzed Homoallylation of -Imino Esters
a
41: R1 = 1-Octenyl, XC6H4 (X = 3-Br, 4-MeO, 4-CN, 4-CO2Me, 4-
Ac), -styryl; R2 = n-Hex, c-Hex, 2-Et-Hex, MeOCH2OCH2CH2; Ar =
4-XC6H4 (X = H, MeO); Ligand = P(o-Tol)3, HP(t-Bu)3BF4, 2-
Dicyclohexylphosphino-2,6-dimethoxybiphenyl; 3682%, 2/125/1
dr. 42: R1 = XC6H4 (X = 3-Br, 4-MeO, 4-CO2Me); rst step: 7678%; iminium salt 29. Grignard reagents attacked to 29 to give nal
second step: 90100%. desired addition products 21 (Scheme 6, a). The same research
group in 2011 reported a similar methodology using N,N-
dibromodimethylhydantoin (DBDMH) as oxidant, by stirring a
substituted imino lactone 16a with MeMgBr, led to (4R,10aS)- solution of equimolar amounts of DBDMH and amino ketene
tetrahydro-1H-[1,4]oxazino[4,3-a]azepine-1,6(9H)-dione 19a, silyl acetal 20b with RMgX (2 equiv) in the presence of BF3OEt2
while the diastereoisomeric compound (4R,10aR)-19b (n = 2) (1 equiv) in EtCN under argon atmosphere for 5 min at 0 or 78
was formed by starting from addition of but-3-enylMgBr to C and then for 1 h at room temperature, leading to addition
methyl substituted imino lactone 16b (Scheme 5). products 22 in 1695% yields (Scheme 6, b).38 Also, the
The Grignard addition to -alkoxycarbonyl iminium salts 29 in Grignard addition to the iminium salts generated by the
situ generated by oxidation of amino ketene silyl acetales 20 was oxidation of cyclic amino ketene silyl acetals 23 derived from
reported by Shimizu et al.37 Treatment of 1-ethoxy-2- pipecolic acid was developed to synthesize -quaternary amino
dibenzylamino-1-trimethylsiloxyethylene 20a with 2 equiv of ester derivatives 24. Reactions were carried out by addition of
Grignard reagent in the presence of DDQ (1 equiv) in DME- amino ketene silyl acetal 23 and Grignard reagent (2 equiv) to a
DCM under an atmosphere of argon at 55 C, then at room solution of NBS (1.1 equiv) as oxidant in EtCN under an argon
temperature for 15 h, aorded -amino esters 21 in 2475% atmosphere at 60 C for 10 min, to furnish -quaternary amino
yields. Reaction with t-BuMgBr did not occur. In the proposed esters 24 in 2986% yields (Scheme 6, c). In addition, vinylation,
reaction mechanism, N,O-acetal 28 was formed by reaction of allylation, and homoallylation of N-allylated and homoalylated
ketene silyl acetal 20a with DDQ, which transformed into cyclic amino ketene silyl acetals 25 were studied under similar
G DOI: 10.1021/acs.chemrev.7b00064
Scheme 12. Addition of Allylboronic Acid Esters to -Imino Scheme 14. Proposed Reaction Mechanism for -Addition of
Acida Allylboronate to -Hydrazono Ester
a 1
R = H, Me, n-Pr; R2 = H, Me; 49: 5188%; 50: 6993%, 94 to temperature, -amino esters 31 were obtained in 6274% yields
>98% ee. (Scheme 7).34
3.3. Organoboron Reagents
Copper(I) catalyzed addition of alkylborane reagents to -imino
reaction conditions, resulting in the formation of desired
esters was reported by Zeng et al.40 Reactions were carried out by
addition products 26 in 4777% yields, which underwent ring
heating a solution of equimolar amounts of alkenes and 9-BBN in
closing metathesis using Grubbs rst, Grubbs second, or
THF at 60 C for 1 h to prepare the alkylborane, followed by
Hoveyda-Grubbs second generation catalysts (4 mol %) in
cooling the reaction mixture to room temperature, then addition
toluene under reux conditions for 418 h to aord
of Cs2CO3 (10 mol %) and CuCN (6.7 mol %), and stirring at 25
corresponding N-bridged bicyclic compounds 27 in low to
C for 30 min. Subsequently, -imino ester (0.67 equiv) in dry
high yields (Scheme 6, d).39
toluene and H2O (0.67 equiv) were added, and the obtained
3.2. Organolithium Reagents mixture was stirred at 70 C for another 24 h. This stepwise
One report on the addition of organolithium reagents to -imino reductive coupling method was successfully applied to a wide
ester was published in the literature. By stirring a solution of range of -imino esters and a variety of inactive alkenes, to give
equimolar amounts of organolithiums, such as n-BuLi, PhC addition adducts 32 in 3785% yields. Using alkenes with bromo
CLi, and PhLi, and N-(diethoxyphosphoryl)diuoroacetyl substitution, 4-bromo-1-butene and 4-bromo-2-methyl-1-bu-
protected imine 30 derived from methyl triuoropyruvate in tene, piperidine-2-carboxylates 33 were obtained via a stepwise
anhydrous THF at 78 C for 2 h, followed by warming to room reductive coupling/cyclization process in 5962% yields. Also,
Scheme 13. Addition of Allylboronate to -Hydrazono Estersa
a
51: R1 = Me, Et, Bn; Ar = 4-XC6H4 (X = H, OH, OMe, NMe2, NO2); Y = (CH2)2, (CH2)3, (CMe2)2; 79% to Quant., 7490% ee. 52: R2 = H, R3 =
Me; 19%, 7% ee, syn/anti = 96/4; R2 = Me, R3 = H; 25%, 14% ee, syn/anti = 1/99. 53: R4 = Me, Et, n-Bu, i-amyl; 76-Quant., 8788% ee, syn/anti =
< 1/>99.
H DOI: 10.1021/acs.chemrev.7b00064
Scheme 15. Born-Mediated Carbon Radical Addition to - Scheme 17. Addition of Alkynyltriuoroborates to -Imino
Hydrazono and -Imino Esters and -Oximino Acida Estersa
a
R = n-Pr, c-Pr, t-Bu, CH2SPh, TMS, 4-XC6H4 (X = H, F, Me, n-Bu,
MeO, Ph), 2-Me-4-MeOC6H3, 6-MeOnaphthalen-2-yl; Ar = 4-XC6H4
(X = Br, I, MeO), 2-Me-4-MeOC6H3; 5595%.
Scheme 18. Pd-Catalyzed Addition of Arylboronic Acids to N-

Aryl -Imino Estersa
a 1
a Ar = XC6H4 (X = H, 4-Cl, 4-Br, 4-Me, 4-OMe, 4-NO2, 3-CO2Et);
57: R = i-Pr, t-Bu, c-Hex; 7590%. 58: R1 = H, Me, OH, OMe; R = i- Ar2 = XC6H4 (X = H, 4-F, 3-Cl, 4-Cl, 4-OH, 3-Me, 4-Me, 4-CF3, 2-
Pr, t-Bu, c-Hex; 6096%. 59: R = i-Pr, t-Bu, c-Hex, n-Oct, 1- MeO, 3-MeO, 4-MeO, 4-Ph), 1-naphthyl, 2-thienyl, 3-thienyl, 3-furyl;
adamantyl; L3: 4583%, R/S = 40/601/99; L4: 4782%, R/S = 58/ 1493%, 5799% ee.
42 to >99/1.
Scheme 16. Addition of Alkenyltriuoroborates to -Imino OH. The -complex 38, formed by coordination of -imino ester
Estersa to alkylcopper species 37 with assistance of Lewis acid 9-BBN
OH, was transformed into N-copper intermediate 39 by
intramolecular migratory insertion or nucleophilic addition.
Protonation of 39 aorded the desired product 32, along with
regeneration of Cu(I) for the next catalytic cycle. In the second
pathway (path b), in the absence of copper catalyst, the imine
moiety was coordinated to alkyl-9-BBN 35 through the nitrogen
atom (40), which underwent nucleophilic addition and then
protonation to produce 32 (Scheme 9).
Highly branched homoallylic -amino esters were prepared via
Pd(II) catalyzed three-component coupling of boronic acids and
allenes with ethyl iminoacetate. Reactions were conducted by
addition a solution of allene (5 equiv) and ethyl N-(4-
methoxyphenyl)iminoacetate (1 equiv) in anhydrous THF to a
mixture of boronic acid (2 equiv), Pd(OAc)2 (0.1 equiv), H[P(t-
Bu)3]BF4 (0.1 equiv), and CsF (4 equiv), and stirring at room
temperature under argon atmosphere for 24 h, to give -amino
esters 41 in 5182% yields, with 2/125/1 dr.41 Also, a similar
a 1 methodology was reported by the same authors, using dierent
R = H, Me; R2 = H, Me, t-Bu, n-Hex, Ph; R3 = H, Me, Ph; Ar = 4-
XC6H4 (X = Cl, I, MeO, NO2); 090%. Pd(II) catalysts and phosphine ligands, resulting the desired
products 41 in 3676% yields, with 5/118/1 dr.42 The
synthetic utility of the homoallylic amino esters 41 to synthesize
the enantioselectivity of the reductive coupling of styrene with - tetrahydropyridines 42 was investigated by N-allylation using
imino esters was investigated using Cu(OTf)2 (10 mol %) and a allyl bromide (6 equiv) in the presence of K2CO3 (3 equiv) in
chiral ligand L1 (15 mol %), in which the addition adducts 34 anhydrous DMF at 120 C for 7.5 h, followed by ring closing
were obtained in 4453% yields, with 2133% ee (Scheme 8). metathesis (RCM) using Grubbs second generation catalyst
Two possible pathways were described for the reaction (0.050.1 equiv) in DCM under reux conditions for 3.55 h
mechanism. In path (a), alkyl-9-BBN 35, generated through (Scheme 10). In the proposed reaction mechanism, intermediate
hydroboration of alkene, was activated by Cs2CO3 to form 43 was generated by transmetalation and migratory insertion,
alkylborate 36, which underwent water assisted boron-Cu(I) which converted to (aryl) (allyl)Pd(II)L complex 44 via
transmetalation, leading to alkylcopper species 37 and 9-BBN transmetalation with another ArB(OH)2 molecule. By coordi-
I DOI: 10.1021/acs.chemrev.7b00064
Scheme 19. Addition of Arylboronic Acids to N-Tosyl - 52 via -addition in low yields and enentioselectivity, but with
Imino Estersa excellent diastereoselectivity, syn/anti ratios of 96/4 and 1/99,
respectively. Also, the addition of -substituted allylboronates
was investigated, in which the reactions were conducted using
ZnF2 (5 mol %) and chiral diamine L2 (12 mol %) at 20 C for
48 h. Only -addition products 53 with anti selectivity were
obtained in 76% to quantitative yields, with 8788% ee (Scheme
13). In the assumed reaction pathway, -substituted allylboro-
nate reacted with ZnF2 through -addition via a six-membered
chairlike transition state 54 to aord (Z)-crotylzinc species 55,
which underwent second -addition toward hydrazono ester
stereoselectively, via transition state 56, which led to crotylated
product 53 with anti selectivity, by means of hydrolysis (Scheme
14). Same research group reported two examples of the addition
of allylboronate to -N-acylhydrazono esters using InI (5 mol %)
as catalyst in the presence of i-PrOH (5 equiv) in DCM at 0 C
for 1272 h, to give corresponding products in 9598% yields,
with excellent anti selectivity through (Z)-crotylindium species
and via transition state like 56.45 -Allylation of an example of -
imino esters was also reported using cinnamyl boric acid.46
Born-mediated carbon radical addition to an -hydrazono
ester was accomplished by stirring a solution of 1530 equiv of
alkyl iodide with -hydrazono ester in DCM in the presence of
Et3B (2.5 equiv) at 20 C for 15 min to give alkylated products 57
in 7590% yields, with 11/1 to >30/1 ratio of alkylated/
ethylated products (Scheme 15, a). In the absence of alkyl iodide,
the ethylated product was obtained in 82% yield, via addition of
Et3B.47 Also, the same research group reported the born-
mediated alkyl radical addition to cyclic -imino esters. Reaction
a
of cyclic -imino esters was conducted in THF/DCM using 10
Ar1 = XC6H4 (X = H, 4-Cl, 4-Br, 4-Me, 4-OMe, 4-NO2, 3-CO2Et); 15 equiv of alkyl iodide in the presence of Et3B as radical
Ar2 = XC6H4 (X = H, 4-F, 3-Cl, 4-Cl, 4-OH, 3-Me, 4-Me, 4-CF3, 2-
generator, and Yb(OTf)3 (1 equiv) or n-Bu3SnH (3 equiv) at
MeO, 3-MeO, 4-MeO, 4-Ph), 1-naphthyl, 2-thienyl, 3-thienyl, 3-furyl;
1493%, 5799% ee. 78 or +20 C for 560 min resulted alkylated products 58 in
6096% yields, along with generation of ethylated products, via
addition of Et radicals, generated from Et3B (Scheme 15, b).
nation of imine with nitrogen atom to Pd, followed by Moreover other cyclic -imino esters were studied under various
nucleophilic allyl transfer to imine, intermediate 45 was formed, reaction conditions, including in the presence or absence of
which underwent allene insertion to give (allyl) (amido)Pd(II)L Lewis acids or n-Bu3SnH as additives, leading to corresponding
complex 46. By transmetalation of 46 with another ArB(OH)2 alkylated products. However, ethyl addition products were
molecule, the nal product 41 was produced through hydrolysis obtained, when alkyl iodides were not used at all. For the
of 47, with regeneration of catalytically active complex 44 generation of Et radical and subsequent alkyl radical formation,
(Scheme 11). reactions should be performed under air atmosphere.48 Jang et
Diastereoselective amidoallylation of glyoxylic acid was al.49 developed an enantioselective alkyl radical addition to
reported to synthesize ,-unsaturated amino acids 49 via in glyoxylic acid oxime in the presence of Cinchona alkaloid derived
situ generation of -imino acid by treatment of (R)-tert- chiral ammonium salts of hypophosphorous acid, L3 and L4.
butanesulnamide with glyoxylic acid in the presence of 3 Reactions were carried out by in situ generation of -oximino
MS in DCM for 42 h at room temperature, followed by addition acid by stirring a solution of glyoxylic acid with equivalent
of allylboronic acid pinacol ester and stirring at the same amount of BnONH2HCl in the presence of L3 or L4 (2 equiv)
temperature for 23 h. Nucleophilic addition occurred at -carbon in DCM/water mixture at room temperature for 1 h under argon
via transition state 48, to give ,-unsaturated -amino acids 49 in atmosphere, followed by addition of alkyl halide (5 equiv) and
5188% yields, which were hydrolyzed to -amino acids 50 Et3B (0.5 equiv) with air bubbling to the reaction mixture at
using aqueous HCl at 90 C for 4 h or HCl in dioxane/iso- room temperature over 4 h, yielding alkylated products 59 in
propanol mixture at room temperature for 1 h, in 6993% yields, 4583%, with formation of ethylated products in 737% yields
with 94 to >98% ee (Scheme 12).43 (Scheme 15, c).
Asymmetric allylation of -hydrazono esters was described by The synthesis of -alkenyl--amino esters 63 was achieved by
Kobayashi et al.44 Treatment of hydrazono ester with Yb(III) catalyzed addition of alkenyltriuoroborates 60a to the
allylboronate (1.2 equiv) in the presence of catalytic amounts imine double bond of -imino esters. Various Lewis acids, such as
of ZnF2 (10 mol %) and chiral diamine L2 (12 mol %) in a Sc(OTf)3, Cu(OTf)2, InBr3, MnCl2, AgOTf, and Yb(OTf)3,
mixture of water/acetone (3/5), at 0 C for 24 h, aorded the were screened for the addition of -styrenyltriuoroborate 60a to
allylated products 51 in 79% to quantitative yields, with 7490% the PMP-protected -imino ester of ethyl glyoxalate, and
ee. In the absence of water, the reaction did not aord the desire Yb(OTf)3 in DCM was selected due to the high yield of the
product. Reactions with (E)- and (Z)-crotylbronates proceeded product. The scope of the reaction was investigated by addition
very slowly (about 110 h), to produce corresponding products of 60a (1.2 equiv) to a solution of -imino ester (0.5 mmol) and
J DOI: 10.1021/acs.chemrev.7b00064
Scheme 20. CH Oxidative Cross-Coupling of N-Aryl Glycine Esters with Arylboronic Acidsa
a 1
R = 4-F, 4-Cl, 3-Br, 4-Br, 4-Me, 4-MeO, 4-CF3, 3,4-Me2; R2 = Me, Et, t-Bu, Bn; Ar = XC6H4 (X = 4-F, 4-Cl, 4-Br, 4-I, 4-Me, 2-MeO, 3-MeO, 4-
MeO, 4-CF3, 4-Ac, 4-CO2Et), 3,5-Me2C6H3, 3,4-(OCH2O)C6H3, 2-naphthyl, 3-thienyl; 2081%, 6696% ee.
Scheme 21. Addition of Arylboronic Acids to N-tert- Scheme 22. Addition of Arylboronic Acid to in Situ Generated
Butanesulnyl Protected -Imino Estersa N-Sulfonyl -Imino Estera
a
R = Me, n-Pr, 4-XC6H4 (X = H, F, Br, Me, t-Bu, MeO, NO2), 3,4,6-(i-
Pr)3C6H2, 2-naphthyl, 2-thienyl; Ar = XC6H4 (X = H, 4-F, 2-Cl, 3-Cl,
4-Cl, 4-Br, 2-Me, 4-Me, 4-MeO, 4-CF3), 9-phenanthryl, 2,2,4,6,7-
pentamethyl-2,3-dihydrobenzofuran-5-yl; 3087%, > 99/1 er.
uoroborane 60b, which underwent complexation with nitrogen

a
of imine moiety to form nitrogenboron complex 61. By
Ar = XC6H4 (X = H, 2-Me, 3-Me, 4-Me, 4-OMe, 3-NO2, 4-CF3), 1- migration of alkenyl group from the boron to the carbon of
naphthyl, 2-naphthyl; 5790%, 87.396.9% ee. imine, intermediate 62 was formed, which was transformed into
nal products 63 by protonation during aqueous workup
Yb(OTf) 3 (10 mol %) in DCM and stirring under N2 (Scheme 16).50
atmosphere at room temperature for 2 h. The corresponding In another work, Stefani et al.51 developed the Yb(III)
addition products 63 were obtained in 2190% yields. However, catalyzed addition of potassium alkynyltriuoroborate salts 64 to
a variety of substituted alkenyltriuoroborates 60a worked well -imino esters to give -alkynyl -amino esters 65. Reactions
in the addition reaction, and in the case of -styrenyltriuor- were carried out by stirring a solution of -imino esters, 64 (1.2
oborates, reaction did not occur. The proposed reaction equiv), and Yb(OTf)3 (10 mol %) in DCM at room temperature
mechanism involves the generation of electrophilic alkenyldi- for 0.52 h, and adducts 65 were obtained in 5595% isolated
K DOI: 10.1021/acs.chemrev.7b00064
Scheme 23. Rhodium-Catalyzed Addition of Arylboronic Scheme 25. 1,4-Addition of Arylboronic Acids to ,-
Acids to Cyclic -Imino Ester 79a Unsaturated -Imino Esters 87
a 1
R = Et, t-Bu, Bn; R2 = H, 6-F, 6-Cl, 6-Me, 7-Me, 8-Me, 6-MeO, 5,6-
(OCH2O); Ar = 4-XC6H4 (X = H, F, Cl, Br, Me, MeO, CF3), 3,4-
(OCH2O)C6H3, 3,4,5-(MeO)3C6H2, 2-naphthyl; 8499%, 8397%
ee.
Scheme 24. Addition of Arylboronic Acid to Cyclic -Imino

Esters 81 and 83a
a 1
Ar = XC6H4 (X = H, 3-F, 4-Cl, 2-Br, 2-Me, 3-Me, 4-Me), 2-thienyl;
Ar2 = XC6H4 (4-F, 4-Cl, 2-Me, 3-Me, 4-Me, 3-MeO, 4-MeO, 4-BnO,
4-i-Pr, 4-t-Bu, 4-CF3), 3,4-(OCH2O)C6H3, 1-naphthyl, 2-naphthyl;
5599%, 7596% ee.
esters were obtained in 3081% or 5390% yields, respec-

tively.52
Enantioselective preparation of arylglycine derivatives 66 was
reported by Zeng et al.53 via Pd-catalyzed addition of arylboronic
acids to N-aryl -imino esters. Various Pd(II) salts in the
presence of a variety of chiral ligands were investigated, and
Pd(OAc)2 in the presence of (4S,4S)-4,4-diisopropyl-2,2-
bis(oxazoline) L5 led to signicant improvement in the yield and
enantioselectivity. The scope of the reaction was investigated by
heating a solution of Pd(OAc)2 (0.1 equiv) and ligand L5 (0.1
equiv) in CH3NO2 at 50 C under an atmosphere of argon for 1
h, followed by additions of -imino ester (0.1 mmol, 1 equiv) and
arylboronic acid (1 equiv) and heating at the same temperature
under argon atmosphere for 2448 h, giving arylated -amino
esters 66 in 1493% yields, with 5799% ee. Not only
a phenylboronic acids with dierent electron donating and
82: R3 = H, 5-F, 5-Cl, 5-Me, 5-t-Bu, 5-MeO, 6,7-(CH)4; Ar = XC6H4 electron withdrawing substitutions worked well, but also
(X = H, 3-Cl, 4-Cl, 3-Me, 4-Me, 2-MeO, 3-MeO, 4-MeO), 1-naphthyl,
2-naphthyl; 3596%, 8599% ee. 84: X = O, NMe, NBn, NPMP; R =
heterocyclic boronic acids, such as 2-thienyl, 3-thienyl, and 3-
H, 6-Cl, 7-Cl, 6-Me, 6-t-Bu; Ar = XC6H4 (X = H, 2-F, 4-F, 3-Br, 2-Me, furyl, are good substrate for this transformation (Scheme 18).
3-Me, 4-Me, 3-MeO, 4-MeO), 3,4-Me2C6H3, 1-naphthyl, 2-naphthyl, Reaction did not occur in the case of 2-pyridylboronic acid.
3-thienyl; 3399%, 9599.9% ee. Also, Pd(II)-catalyzed, one-pot enantioselective synthesis of
arylglycine derivatives 67 from ethyl glyoxylate, p-toluenesul-
fonyl isocyanate and arylboronic acids was reported by Lu et al.20
yields (Scheme 17). Also, the Stefanis group developed the Reactions were carried out by reuxing a solution of equimolar
synthesis of similar -unsaturated -amino esters via Yb(III) amount of Ts-NCO and ethyl glyoxylate in the presence of
catalyzed three component reaction between aniline, ethyl Pd(TFA)2 (5 mol %) and (S)-4-benzyl-2-(pyridin-2-yl)-4,5-
glyoxalate, and alkenyltriuoroborates or alkynyltriuoroborate, dihydrooxazole ligand L6 (6 mol %) in toluene for 3 h, followed
in the presence of Na2SO4 in DCM at room temperature. The by addition of phenylboronic acid (2 equiv) and reuxing for
corresponding -alkenyl -amino esters or -alkynyl -amino another 24 h. About 8 chiral ligands were investigated, and ligand
L DOI: 10.1021/acs.chemrev.7b00064
Scheme 26. Unusual 1,2-Aryl Shift in Pd-Catalyzed Reaction of Arylboronic Acids with -Imino Estersa
a
Ar1 = XC6H4 (X = H, 4-Cl, 4-Br, 4-Me, 4-MeO, 4-NO2, 3-CO2Et); Ar2 = XC6H4 (X = H, 4-F, 3-Cl, 4-Cl, 3-Me, 4-Me, 2-MeO, 3-MeO, 4-MeO, 4-
CF3, 3-NO2, 4-Ph, 4-Ac), 3-F-4-BnOC6H3, 3-MeO-4-MO2CC6H3, 3,4-(OCH2O)C6H3, 1-naphthyl, phenanthrene-9-yl, 2-thienyl, 3-thienyl,
benzothiophene-2-yl; 1894%.
Scheme 27. Addition of Triallylaluminum to Chiral Glyoxylic Oxime Ethers 100
L6 was selected for the highest enantioselectivity. The proposed followed by hydrolysis of 71, addition adducts 67 were obtained
reaction mechanism involves the combination of Pd(TFA)2 and in 2373% yields, with 6481% ee (Scheme 19).
chiral ligand L6 to generate palladium species 68, which was Enantioselective CH oxidative cross-coupling of N-aryl
transformed into palladium species 69 via transmetalation with glycine esters with arylboronic acids was described for the
arylboronic acid. Then, the in situ generated -imino ester from preparation of aryl glycinate derivatives 72. Reactions were
[2 + 2] cycloaddition of Ts-NCO with ethyl glyoxylate, followed carried out by heating N-aryl glycine esters with arylboronic acid
by [2 + 2] cycloreversion and releasing CO2 (Scheme 1, b), (1.2 equiv) in the presence of Pd(OAc)2 (10 mol %), (S,S)-
coordinated to 69 to give intermediate 70a or 70b. By addition of iPrBox L5 (10 mol %), and 2,2,6,6-tetramethylpiperidine-1-
the aryl group to imine moiety in a highly selective manner, oxoammonium tetra-uoroborate (T+BF4, 1.1 equiv) in DCE
M DOI: 10.1021/acs.chemrev.7b00064
Scheme 28. Zr-Catalyzed Addition of Dialkylzinc Reagents to Scheme 30. Ti(IV)-Bifunctional Salene Catalyzed Addition of
-Imino Estersa Et2Zn to -Imino Estersa
a
a 1
115: R1 = 4-MeOC6H4, Ph2CH; R2 = Me, Et; additive = CF3CH2OH,
R = n-Pr, i-Pr, i-Bu, c-Hex, 4-pentenyl, PhCH2CH2, XC6H4 (X = H, BnOH, Ph(Me)CHOH, Ph2CHOH; 1974%, 2475% ee. 116: R2 =
3-Cl, 2-Br, 4-Br, 4-I, 2-Me, 4-MeO, 4-CF3), 1-naphthyl, 2-naphthyl, 2- Me, Et; 235%.
furly, N-Me-indol-3-yl, N-Boc-indol-3-yl, N-Me-imidazol-2-yl; R2 =
Me, Et, t-Bu, Bn; R3 = Me, Et; Ar = 2-XC6H4 (X = MeO, PhO), 2,4-
(MeO)2C6H3; 3498%, 8297% ee.
which underwent nucleophilic addition with aryl palladium
species 74, formed by transmetalation of Pd-(S,S)-i-PrBox
under argon atmosphere at 60 C for 16 h, aording aryl complex 73 with arylboronic acid. The stereochemistry outcome
glycinates 72 in 2081% yields, with 6696% ee. N-Aryl glycine of the reaction was attributed to the coordination of -imino
esters possessing electron withdrawing substituent aorded the ester to Pd complex through the nitrogen atom, which led to the
best results; however, reaction with electron-donating sub- addition of aryl from si-face of the imine (transition state 75) to
stituted arylboronic acids aorded the products 72 in high yields. yield intermediate 76. By acetolysis of 76, the nal desired
The proposed reaction mechanism involves the oxidation of N- products 72 were obtained, along with regeneration of Pd-
aryl glycine esters with T+BF4 to in situ generate -imino ester, complex 73, for further catalytic cycles (Scheme 20).54
Scheme 29. Synthetic Utility of Addition of Dialkylzinc to -Imino Esters
N DOI: 10.1021/acs.chemrev.7b00064
Scheme 31. Reformatsky Reaction of Iminoacetates with tert- Scheme 33. Addition of Organozinc Reagents to (S)-N-
Butyl Bromozinc Acetatea Sulnyl -Imino Estera
a
Ar = PMP, 2-HOCH2C6H4, 3,5-Br2-4-HOC6H2, 4-Br-1-naphthyl,
quinolin-5-yl, benzopyrazol-5-yl, 6591%.
a
126: R = XC6H4CH2 (X = H, 3-Cl, 4-Cl, 4-Br, 2-Me, 3-Me, 3-CF3, 4-
Also, a cationic palladium-complex L7 catalyzed addition of vinyl), 2,4- and 3,4-Cl2C6H3, 1-naphthyl; 6094%, 90/1097/3 dr.
arylboronic acids to N-tert-butanesulnyl protected -imino 127: Ar = 4-XC6H4 (X = H, Cl, Br); 8593%, syn/anti = > 99/1, 99%
esters was developed to synthesize optically active aryl glycine ee.
derivatives 77. Reactions were conducted by heating a solution of
ethyl ((RS)-N-tert-butanesulnyl) iminoacetate and arylboronic
acid (2 equiv) in the presence of L7 (5 mol %) in dioxane at 60 %) in dioxane at 60 C under an atmosphere of N2, for 312 h, to
C for 24 h, and the corresponding adducts 77 were obtained in give addition adducts 80 in 8499% yields, with 8397% ee
5790% yields, with 87.396.9% de. However, various (Scheme 23).
substituted phenyl- and also - and -naphthylboronic acids Xu et al.58 reported Rh-catalyzed addition of arylboronic acid
worked well in the reaction conditions; 4-pyridylboronic acid was to ethyl benzo[d]isothiazole-3-carboxylate 1,1-dioxide 81.
not good substrate for this transformation (Scheme 21).55 Reactions were carried out by stirring a solution of 81 and
Manolikakes et al.56 developed a Pd-catalyzed synthesis of aryl arylboronic acid (2 equiv) in the presence of [Rh(COE)2Cl]2 (3
glycinates 78 via three-component reaction between sulfona- mol %), chiral ligand L9 (3.3 mol %), and KF (1 equiv) in toluene
mides, ethyl glyoxalate, and arylboronic acids. Reactions were at room temperature or 60 C, for 35 h, and corresponding
performed by subjecting sulfonamides with ethyl glyoxalate (1.2 products 82 were obtained in 3596% yields, with 8599% ee.
equiv) and arylboronic acid (2.3 equiv) in the presence of In the proposed transition state, after coordination of chiral
Pd(TFA)2 (10 mol %) and (S,S)-iPrBox L5 (15 mol %) in ligand L9 and transmetalation, in the in situ generated Rh
CH3NO2 at 40 C for 64 h, leading to aryl glycinates 78 in 30 complex 85 the aryl group is positioned trans to the alkene
87% yields, with more than 99/1 er (Scheme 22). ligand. To minimize unfavorable steric interactions between the
Rhodium-catalyzed asymmetric addition of arylboronic acids 1-naphthylmethyl group on the alkene moiety and benzene ring
to cyclic N-sulfonyl ketimines was developed for construction of of imine 81, the sulfonyl moiety was coordinated to the Rh, in
,-diaryl--amino acid derivatives. Nishimura and Takechi57 such a way that the benzene ring of imine oriented away from 1-
applied addition to benzo[e][1,2,3]oxathiazine-4-carboxylate naphthylmethyl group 85. Thus, the migratory insertion of aryl
2,2-dioxide 79, by heating a solution of 79, arylboronic acid (2 occurred at si-face of the imine, to form the (R)-products 82
equiv), K3PO4 (1 equiv) and [Rh(OH)((S,S)-Bn-tfb*)]2 (3 mol (Scheme 24, a). In another work by the same research group,
Scheme 32. Addition of Allylzinc Bromide to -Imino Estersa
a 1
R = PMP, (S)-PhCH(Me), (R)-phegyl-OMe; R2 = Et, t-Bu, Bn, TMS(CH2)2; R3 = H, Me, Ph, CO2Et, CO2t-Bu; 122: 5099%; 123: 7595%.
O DOI: 10.1021/acs.chemrev.7b00064
Scheme 34. Migratory Addition of N-tert-Butanesulnyl Scheme 36. Zinc-Mediated Addition of Alkyl Iodides to
Iminoacetate with Organozinc Reagentsa Glyoxylic Oxime Ethersa
a
R = i-Pr, s-Bu, t-Bu, c-Pent, c-Hex; X = OBn: 4296%; X = NPh2:
6395%.
Scheme 37. Nucleophilic [2 + 1] Cycloaddition of -

Ketoimines 138 with Bis(iodozincio)methanea
a
X = I; R = Et, n-Bu, c-Hex, n-C10H21, BnO2C(CH2)3; Cat. =
Ni(acac)2 (10 mol %); 7392%, 60/4068/32 dr. X = Br, R = XBn
(X = H, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 4-Br, 2-Me, 4-Me, 3-CN, 4-CN,
3-CF3, 4-CF3, 4-CO2Et); Cat. = none, 4175%, 89/1198/2 dr (S,S/
S,R).
Scheme 35. BF3OEt2-Catalyzed Addition of Organozinc to -

Oxime Estersa
a 1
R = Ph, PMP, 2-naphthyl; R2 = Ph, Ts; E = H, TMS, Ac; 9299%.
Reactions were conducted by stirring a solution of 87 and

arylboronic acid (3 equiv) in the presence of [Rh(acac)(C2H4)2]
a 1
R = Et, i-Pr, n-Bu, t-Bu, allyl, Ph(CH2)2; R2 = Me, i-Pr, n-Bu,
(5 mol % Rh) and chiral (R)-briphos ligand (12.5 mol %) in
MeO2CCH2; 2385%. toluene at 25 C for 2050 h to give -enamino esters 88 in 55
99% yields and 7596% ee. A variety of substituted arylboronic
acid and ,-unsaturated imino esters 87 were investigated and
rhodium-catalyzed asymmetric arylation of benzoxazinones and worked well in the reaction. Authors provided transition states 89
quinoxalinones 83 with arylboroxines was performed by stirring a and 90 to indicate the stereochemistry of the products, by DFT
solution of 83 and arylboroxines (1.2 equiv) in the presence of computation, in which the transition state 89 is preferred due to
[Rh(COE)2Cl]2 (1.5 mol %), chiral ligand L9 (3.3 mol %), and the minimal steric repulsion. Aryl-Rh species, generated by
anhydrous K3PO4 (1 equiv) in anhydrous dioxane at room transmetalation, attacked to carboncarbon double bond of ,-
temperature under an argon atmosphere for 30 min, followed by unsaturated imino esters 87 through si-face to give (S)-
addition of MeOH (4 equiv) and heating at 60 C for 212 h. stereoisomers as the major enantiomer (Scheme 25).
Arylation products 84 were obtained in 3399% yields and 95 Zeng and co-workers61 reported an unusual 1,2-aryl shift in
99.9% ee. Reaction with -styrylboroxine aorded the Pd-catalyzed reaction of arylboronic acids with -imino esters. By
corresponding product in 28% yield and 95% ee. The treatment of -imino esters with an equal amount of arylboronic
stereoselectivity outcome was attributed to the formation of acid in the presence of Pd(TFA)2 (5 mol %) and bipyridine
arylrhodium species, in which the aryl group positioned trans to ligand L10 (5 mol %) in CH3NO2 at 110 C, under argon
the double bond of chiral ligand L9, and to avoid the steric atmosphere for 48 h, ethoxycarbonylation of arylboronic acids
repulsion with naphthyl group on double bond, the imine moiety occurred to obtain corresponding aryl esters 91 in 1894%
was coordinated by Rh via re-face (86) to aord (R)-products in yields. However, the reaction between -styrylboronic acid and
excellent enantioselectivity (Scheme 24, b).59 N-(4-methoxyphenyl)--imino ester did not occur. Several
Asymmetric 1,4-addition of arylboronic acids to ,- control experiments were applied to propose the mechanism.
unsaturated imino esters 87 was reported by Lee and Kim.60 By heating the addition product of p-tolylboronic acid and N-(4-
P DOI: 10.1021/acs.chemrev.7b00064
Scheme 38. Copper-Catalyzed Asymmetric Conjugate additional 10 min at the same temperature. Reactions proceeded
Addition of Et2Zn to ,-Unsaturated -Imino Estersa smoothly and gave the corresponding addition products 101 in
7589% yields, with up to >99% ee. Due to the dierent nature
of chiral glyoxylic oxime ethers 100, dierent stereoselectivity
was observed. For example, in 100a and 100c the sulfonyl moiety
chelated with an Al atom (102 and 104), which led to high
diastereoselectivity (82% and >99% dr, respectively). While in
the case of 100b, low diastereoselectivity was shown, which could
be attributed to the existence of equilibrium between s-cis 103
and s-trans 100b conformers in the transition state, due to the
week coordination of -oxime ether groups occurred to Al. Used
glyoxylic oxime ethers 100 were prepared by subjecting O-
benzylhydroxylamine hydrochloride with glyoxylic acid (2 equiv)
in water at ambient temperature, for 2 h, to give glyoxylic oxime
ether 99, followed by activation of the carboxylic acid group by
conversion to acyl chloride through reuxing in SOCl2 under N2
atmosphere for 2 h, which was transformed into nal 100 by
treatment with a chiral amine or alcohol in the presence of NaH
(1.5 equiv) in THF at 0 C for 2 h, in 7690% yields (Scheme
27).62
3.5. Organozinc Reagents
Hoveyda et al.63 described Zr-catalyzed addition of dialkylzinc
reagents to -imino esters. Reactions were conducted by
addition of dialkylzinc reagent (4 equiv) to a solution of -
imino esters, Zr(Oi-Pr)4HOi-Pr (510 mol %) and amino
acidbased chiral ligands L11 or L12 (510 mol %) in toluene
under N2 atmosphere, at 15 C for 24 h. The eect of the
various alkoxy groups on -imino esters, such as OMe, OEt,
OBn, and Ot-Bu, was investigated in the addition of Me2Zn, and
a -quaternary amino esters 105 were obtained in 3486% yields,
R = Me, Et; Ar1 = 4-XC6H4 (X = Me, MeO, NO2); Ar2 = 4-XC6H4
(X = Me, NO2); 8389%, 88/1294/6 er. with 9496% ee. The scope of the Zr-catalyzed addition of
Me2Zn to a range of aryl substituted -imino methyl esters was
applied under similar conditions, in which -amino esters 105
methoxyphenyl)--imino ester in the presence of Pd(TFA)2 (5 were produced in 9198% yields, with 8896% ee. Also, the
mol %) and L10 (5 mol %) in CH3NO2 at 110 C, for 48 h, addition of Me2Zn to some heterocyclic substituted -imino
corresponding ethoxycarbonylation product, ethyl p-methylben- esters, such as 2-furyl- and N-Me and N-Boc-protected 3-indolyl-
zoate, was formed only in low yield (<5%), while, a similar 2-[N-(2-methoxyphenyl)]iminoacetate, were investigated, and
reaction in the presence of additional p-tolylboronic acid (20 mol the addition adducts 105 were obtained in 9398% yields, with
%) led to ethyl p-methylbenzoate in 85% yield. Therefore, the 9197% ee. The presence of a competitive chelating group, such
existence of the addition product as an intermediate was as N-methylimidazole-substituted -imino ester, diminished the
approved. Also, in the reaction of phenylboronic acid with N- asymmetric induction, in which products were obtained in >98%
(4-methoxyphenyl)--imino ester, under the reaction condi- conversion, but with low enantioselectivity (12% ee). Also, the
tions, in addition to ethyl benzoate, 4-methoxy-N-(2-nitroethyl)- addition of the Et2Zn reagent to -imino esters was investigated
aniline 98 was formed in 28% yield, indicating the releasing of (4- under similar conditions, providing corresponding -quaternary
methoxyphenyl)methyleneamine. A possible reaction mecha- amino esters 105 in 5075% yields and 9196% ee. However, in
nism is outlined in Scheme 26. By coordination of N-aryl-- the case of CF3-substituted -imino esters, the C-addition adduct
imino ester to the palladium species 92, in situ generated by was obtained in very low yield. Addition of Me2Zn using chiral
transmetalation with arylboronic acid, followed by migratory ligand L12, led to corresponding -amino esters 105 in 3885%
addition of aryl to the imine moiety of the N-aryl--imino ester yields, with 8293% ee. The stereochemical outcome of the
(93), intermediate 94 was generated, which transformed into addition reaction was attributed to the formation of complex
addition adduct 95 upon protonation. Subsequently, the Pd 106, in which addition occurred from si-face, leading (R)-
complex 92, acting as Lewis acid, activated the ester carbonyl stereoisomers (Scheme 28). The utility of this reaction for the
group, which underwent 1,2-aryl migration with assistance of construction of N-heterocycles was investigated. Addition of
lone pairs of electron on the nitrogen atom (intermediate 96). By Me2Zn (4 equiv) to dimethyl 2-[(2-methoxyphenyl)imino]-
cleavage of C(sp2)C(sp3) bond on intermediate 97, the nal pentanedioate 107 in the presence of Zr(Oi-Pr)4HOi-Pr (10
ethoxycarbonylation product 91 was obtained, along with mol %) and chiral ligand L12 (10 mol %) led to pyrrolidine-2-
generation of (4-methoxyphenyl)methyleneamine species. one 108 in 63% yield, with 79% ee. The reaction proceeded by
3.4. Organoaluminum Reagents alkylation of -imino ester 107 and concomitant cyclization of
Diastereoselective allylation of various chiral glyoxylic oxime the resulting metal amide with neighboring ester moiety. N-
ethers 100 with triallylaluminum was reported by addition of Allylation of -amino ester 109, obtained from methylation of 4-
triallylaluminum (22.2 equiv) in a solution of chiral 100 in pentenyl substitute -imino ester, followed by ring closing
DCM at 78 C, over period of 20 min, followed by stirring an metathesis using catalyst 111, furnished azacene-2-carboxylate
Q DOI: 10.1021/acs.chemrev.7b00064
Scheme 39. Addition of -Silyloxyallylstannanes 148 to -Imino Estersa
a 1
R = Me, Et, i-Pr; R2 = Me, i-Pr, n-Bu; (E)-allylstannanes: 2164%, syn/anti = 72/2856/44; (Z)-allylstannanes: 4362%, syn/anti = 5/9544/56.
Scheme 40. [3 + 2]-Type Cycloaddition of Allenylstannane alcohol group (113) to a leaving group (OMs) using MsCl (1.5
158 and -Imino Estera equiv) in the presence of Et3N (2 equiv) in DCM and then
treatment with K2CO3 (3 equiv) in DMF at 22 C for 12 h,
resulted in aziridine 114 in 74% yield, with 94% ee (Scheme 29).
Kozlowski et al.64 developed the asymmetric addition of Et2Zn
to -imino esters in the presence of Ti(Oi-Pr)4-bifunctional
salens complex (10 mol %) and an additive (0.5 equiv) in toluene
at 40 C, to give -amino esters 115 in 1974% yields, with
2475% ee. Various additives were investigated, from which
alcohols represented good enantioselectivities. The transition
state of the addition (117) is shown in Scheme 30. In the case of
N-PMP-protected -imino esters, in addition to C-addition
adducts 115, imidazolidine-2-carboxylates 116 were obtained in
223% yields, via nucleophilic addition of generated amide
anion to another molecule of -imino ester, followed by
intramolecular cyclization. The synthesis of imidazolidin-4-one
derivatives 116 were described via domino reaction of -imino
esters and dialkylzinc. By addition of a solution of R2Zn (1.2
equiv) in toluene to a solution of -imino ester in toluene at
room temperature and stirring for 18 h, imidazolidin-4-ones 116
a
were obtained in 5885% yields. Chiral ligands did not improve
Ar = XC6H4 (X = H, 4-Cl, 3-Me, 4-CF3, 4-NO2), 3,5-(CF3)2C6H3, the enantioselectivity in the formation of 116.65
3,4,5-F3C6H2; 3480%, 7493% ee. N-Arylated racemic aspartates 118 were prepared via
Reformatsky reaction of iminoacetates with tert-butyl bromozinc
110 in 81% yield, with 86% ee. Reduction of methyl 2-[(2- acetate (1.12.2 equiv) in anhydrous THF at 0 or 20 C under
methoxyphenyl)amino]-2-phenylpropanoate 112 using LiAlH4 N2 atmosphere within 2 h, in 6591% yields. Used -imino
(2 equiv) in THF at 0 to 22 C for 4 h, followed by conversion of esters were obtained by subjecting ethyl glyoxalate with aniline
R DOI: 10.1021/acs.chemrev.7b00064
Scheme 41. Addition of Allylstannanes to -Imino Esters and Scheme 43. [3 + 2] Cycloaddition of Allenylsilanes 169 with
-Oximino Estersa -Imino Estera
a
170: R = Me, n-Pr, i-Pr, c-Hex; Si = Si(i-Pr)3, SiPh3, Si(t-Bu)Ph2, Si(t-
Bu)Me2; 4692%, 7185% ee. 171: R = Me, n-Pr, c-Hex; 8998%,
7185% ee.
CO2R) were also investigated, in which corresponding t-butyl

a
ester aorded the addition product 122 in 86% yield, while the
163: R = Me, Et, i-Pr, n-Bu, Bn; 7987%, 8087% ee. 165: X = CH2, ethyl ester gave the -methylene -lactam 124 through a tandem
CO; Y = NPh, NTs, SO2; 9094%, 91 to >99% dr.
additionring-closing process. Additionally, peruoroalkylated
-imino esters 121b were subjected to addition with allylzinc
Scheme 42. Addition of AllylTMS to -Imino Estera reagents that gave corresponding products 122 in 9099%
yields. By ring closing metathesis of obtained 2-allyl-3,3-diuoro-
2-(amino)hex-5-enoates 122 using second generation Grubbs
catalyst [(IHMes) (PCy3)Cl2RuCHPh] in reuxing DCM,
cyclohex-3-en carboxylates 123 were produced in 7595% yield.
An excellent diastereoselectivity (>98%) was observed in the
addition of allylzinc bromide reagents to N-(R)-PhCH-
(CH2OMe) ((R)-phegly-OMe) protected -imino esters,
which was attributed to the six-membered cyclic transition
state 125, arising from chelation of the imine nitrogen and the
oxygen in the chiral auxiliary to the Zn, and addition the allylic
moiety through -position from the less-hindered side of the
imine, the side opposite the phenyl group (si-face). Used -imino
a
Lewis acid: BF3OEt2, X = TBDMS: 38% (85/15 dr); X = H: 40% esters 121 were prepared by synthesis of imidoyl chlorides 120a
(84/16 dr). SnCl4, X = TBDMS: 72% (77/23 dr). from reaction of the corresponding carboxylic acids 119 with an
amine in the presence of Et3N and PPh3 in CCl4 under reux
derivatives in the presence of a water absorbent in DCM or THF conditions for 3 h, which were transformed into imidoyl iodides
or by azeotropic removal of water in reuxing benzene (Scheme 120b by reacting with NaI (3 equiv) in dry acetone at room
31). When an insucient amount of tert-butyl bromozinc acetate temperature. By stirring a solution of imidoly iodides 120b with
was used, imidazolidin-4-one (Like 116) was generated, via corresponding alcohols (1.2 equiv) in toluene/DMF (10/1: v/v)
nucleophilic addition of formed N-centered anion of N-arylated in the presence of palladium catalyst ([Pd2(dba)3]CHCl3, 4
aspartate to second molecule of -imino ester, followed by mol %) and K2CO3 (2 equiv) under an atmosphere of CO (1
cyclization.66 atm.) at room temperature for 24 days, -imino esters 121a
Cyclohex-3-en carboxylate derivatives 123 were synthesized in were prepared in 2070% yields. Peruoroalkylated -imino
two steps starting from 3,3-diuoro-2-(imino)hex-5-enoate 121. esters 121b were prepared by transesterication of trimethylsi-
Treatment of -imino esters 121 with allylzinc bromide (1.5 lylethyl -imino esters 121a with 3-(peruorooctyl)propyl
equiv) in THF under inert atmosphere at 40 C for 10 min, iodide in the presence of TBAF in THF during 2 h (Scheme
aorded the addition adducts 122 in 9199% yields. In another 32).67,68 Zinc-mediated addition of allyl bromide to -imino
method, allylzinc reagents were prepared in situ and attacked to esters, followed by ring closing metathesis, was also reported for
-imino esters 121, by stirring zinc powder (1.8 equiv) and allyl the synthesis of a number of pyridine derivatives.69
bromide (1.4 equiv) with -imino esters in THF/saturated Synthesis of chiral N-tert-butanesulnyl -amino acid
NH4Cl (1/4: v/v) biphasic solution at room temperature for 1 h, derivatives 126 was reported by addition of organozinc reagents
in which -amino esters 122 were produced in 5086% yields. to N-tert-butylsulnyl iminoacetate. Reactions were conducted
Allylzinc reagent derived from 2-(bromomethyl)acrylates (R3 = by stirring a solution of (S)-N-tert-butylsulnyl iminoacetate with
S DOI: 10.1021/acs.chemrev.7b00064
Scheme 44. Intramolecular Addition of Allyl- and Propargylsilanes to -Imino Lactone
Scheme 45. Addition of Propargyl-SiCl3, Allenyl-SiCl3, and Allyl-SiCl3 to -Hydrazono Estera
a 1
R = H, Me, 4-XC6H4 (X = H, Br, Me, MeO), 2-naphthyl; R2 = Me, Et; 1893%, 3698% ee.
RZnXMgCl2LiCl (1.5 equiv) in THF at 78 C for 20 min, to Wei et al.73 reported a migratory addition of N-tert-
furnish desired products 126 in 6094% yields, with 90/1097/ butanesulnyl iminoacetate with organozinc reagents. First, the
3 dr (Scheme 33, a).70 Zinc-mediated addition of cinnamyl reaction of ethyl N-tert-butanesulnyl iminoacetate with
bromide to (S)-N-sulnyl -imino ester was also reported, in alkylzinc iodide (2.5 equiv) were investigated in the presence
which the corresponding -addition products 127 were obtained of a variety of catalysts (10 mol %) in THF at 78 C to room
temperature for 12 h, in which Ni(acac)2 exhibited high yields
as only syn stereoisomer in 8593% yields. Reactions were
(6692%) with 60/4068/32 dr. Using substituted benzylzinc
performed using 2 equiv of Zn in THF at room temperature for 2
bromide the reactions proceeded suciently without using any
h (Scheme 33, b).71 Moreover, the addition of substituted catalyst, and reactions were performed by stirring a solution of
benzylzinc reagent (BnZnClMgCl2) to -imino ester, derived ethyl N-tert-butanesulnyl iminoacetate and benzylzinc bromide
from triuoromethylpyruvate, was accomplished in THF at 10 (2.5 equiv) in dry THF under an argon atmosphere at 20 C to
to 0 C, to give the corresponding addition products in 7095% room temperature for 12 h, resulting in the (S)-ethyl 3,3-
yields.72 dimethyl-2-((S or R)-phenylmethylsulnamido)butanoates 128
T DOI: 10.1021/acs.chemrev.7b00064
Scheme 46. Addition of Organotitanium Reagents to -Imino Estersa
a
190: R = Me, i-Pr, t-Bu, c-Hex, Ph; 8396%; 192: R = Me, i-Pr, c-Hex; 8498%; 194: n = 1, 2, 3, 4; 6987%.
in 4175% yields, with 89/1198/2 dr (S,S/S,R). In the corresponding product 128 was obtained, demonstrating the
proposed reaction mechanism, a small amount of benzyl radical, radical existence in the mechanism of the reaction (Scheme 34).
generated during the preparation of benzylzinc reagent from Another report on the similar methodology was reported by the
reaction of benzyl bromide with zinc dust, attacked to the imine same research group, in which N-tert-butanesulnyl iminoacetate
moiety to release a more stable t-Bu radical. By addition of t-Bu was subjected to a variety of alkylzinc iodides and bromides (2
radical to imine moiety, the intermediate 129 was generated, equiv) in the presence of Ni(acac)2 (10 mol %) in THF at 20
which was transformed into intermediate 130 by releasing C to room temperature, to give the corresponding migratory
another t-Bu radical to initiated further reaction cycle. The t-Bu addition products in 4792% yields. Imines other than
radical attacked stereospecically through the anti position to the iminoacetate and other substituted sulnyl moieties did not
t-Bu on the sulfoxide moiety of the starting iminoacetate, to aord the desired products.74
generate the rst chiral center. The NSO functionality of BF3OEt2-catalyzed organozinc species addition to -oxime
the intermediate 130 underwent addition of the benzylzinc esters was developed to give addition adducts 134. A variety of
reagent via intermediates 131 and 132, followed by hydrolysis to reaction conditions were investigated, from which reaction with
nal products 128, as two diastereoisomers. Using the 24 equiv of dialkylzinc or trialkylzincate in DCM in the
commercially available Et2Zn reagent, the migration-addition presence of BF3OEt2 (1 equiv) under N2 atmosphere at 0 C or
reaction did not occur; however, by addition of Ni(acac)2, which reux for 24 h was selected as the optimum conditions. Reactions
catalyzed generating the Et radical from Et2Zn reagent, the were performed with dierent types of -oxime esters, and
U DOI: 10.1021/acs.chemrev.7b00064
products 134 were obtained in 2385% yields. Treatment of 0.4515 h at the same temperature. Reactions with (E)-
benzyl ether-oxime of 5-bromo-2-oxopentanoate 135 with allylstannanes 148a gave syn-allylated products, whereas anti
Et3ZnMgBr (2 equiv) under similar reaction conditions isomers were produced from (Z)-counterparts 148b. Additions
furnished methyl 1-(benzyloxy)-2-ethylpyrrolidine-2-carboxy- occurred via cyclic transition states 152, in which nitrogen and
late 136 in 77% yield, by addition of Et to CN double bond oxygen atoms of the imino ester moiety were chelated with the
of oxime, followed by intramolecular addition of amide anion to Sn atom. The stereochemistry was assigned by conversion of
bromoalkyl moiety (Scheme 35).75 major products 149b, obtained from (Z)-isomers, to oxazolidi-
Zinc-mediated addition of alkyl iodides to glyoxylic oxime nones 151 through desilylation using TBAF in THF at 0 C for
ethers and hydrazones was reported by adding saturated NH4Cl 0.51 h, to give the amino alcohols 150, with the subsequent
aqueous solution to a mixture of -oximino or hydrazino esters treatment with Cl3COCOCl in the presence of DMAP and Et3N
with RI (5 equiv) and Zn (7 equiv) in MeOH at room in DCM. This strategy was applied for the synthesis of
temperature and stirring at the same temperature for 0.251 h, to sphingosine 157, an important mammalian lipid in signal
give products 137 in 4296% or 6395% yields, respectively. transduction and cellular regulation, starting by diastereoser-
The reactions proceeded through the radical pathway based on a ective allylation of -imino ester with -silyloxyallylstannane 153,
single-electron transfer from zinc, as shown in Scheme 36.76 Also, followed by reduction of ester moiety of 154 with LiAlH4 in Et2O
diethylzinc-mediated radical addition to -imino esters was under reux condition along with removal of the TMS group. By
investigated in the presence of phenylorganotellurium com- acetylation of obtained 155 using Ac2O in pyridine, followed by
pounds as radical precursors.77 removing the PMP group using CAN, triacetate 156 was
The synthesis of 2-aminocyclopropanol 139 was achieved by obtained, which was converted to erythro-sphingosine 157 in
nucleophilic [2 + 1] cycloaddition of -ketoimines 138 with further steps (Scheme 39).80
bis(iodozincio)methane. Reactions were carried out by dropwise Synthesis of chiral dehydroproline esters 160 was achieved by
addition of dizinc reagent (2 equiv) to a solution of 138 in THF Akiyama et al.81,82 via enantioselective [3 + 2]-type cycloaddition
at 25 C. After 30 min, a quenching reagent, such as water, acetic of allenylstannane 158 and -imino ester, followed by Stille
anhydride, and chlorotrimethylsilane, was added dropwise, and coupling reaction. Reactions were carried out by heating a
the resulting mixture was stirred for another 30 min to give 2- solution of N-tosyl -iminoacetate and allenyl(tributyl)stannane
aminocyclopropanol derivatives 139 in 9299% yields. Reac- 158 (1.2 equiv) in toluene in the presence of [Cu(MeCN)4]-
tions with O-methyl oxime and tosylhydrazone did not occur and ClO4 (10 mol %) and (R)-TolBINAP (10 mol %) at 80 C for 1 h
the starting materials were completely recovered. The reactions to give stannyldehydroproline ester 159, which were treated with
proceeded via double coordination of 138 to bis(iodozincio)- Pd(PPh3)4 (10 mol %) and aryl bromides (1.2 equiv) under
methane in a face-to-face fashion (140), leading to cis isomers reux conditions for 5 h in a one-pot manner, leading to 4-
139, as shown in Scheme 37.78 aryldehydroproline-2-carboxylates 160 in 3480% yields, with
Copper-catalyzed asymmetric conjugate addition of Et2Zn to 7493% ee. The stannyldehydroproline ester 159 was prepared
,-unsaturated -imino esters 141 was reported by Palacios and via the propargylationcyclization mechanism, by copper(I)-
Vicario.79 By stirring a solution of Cu-(CH3CN)4PF6 (5 mol %) catalyzed addition of 158 to -imino ester, to generate a -
and phosphoramidite ligand L13 (10 mol %) in toluene at room carbocation intermediate 161, which underwent CSn bond
temperature for 1 h, copper-phosphoramidite complex was cleavage, resulting in formation of stannylamide intermediate
obtained, which by cooling to 40 C and addition of ,- 162. Then cyclization of 162 to stannyldehydroproline ester 159
unsaturated imines 141 and Et2Zn (1.5 equiv) at the same occurred via copper(I)-alkyne -complex (Scheme 40).
temperature, corresponding 1,4-addition products 142 were (R)-L14-(AuCl)2-catalyzed enantioselective addition of allyl-
obtained in 8389% yields, with 88/1294/6 enantioselectiv- stannanes to -imino esters was reported to give allylated -
ities. Proposed catalytic cycle involves the alkyl transfer between amino acid derivatives 163 in 7987% yields, with 8087% ee.
Et2Zn and copper to generate intermediate 143, followed by Reactions were conducted using allyltributyltin in the presence of
formation of the -complex 144 between the soft Cu species and (R)-L14-(AuCl)2 (5 mol %) and AgOTf (10 mol %) in DCM at
the double bond of the 141, where the imino ester moiety was 40 C for 3 h (Scheme 41, a).83 In this context, Chen et al.84
chelated with the hard Lewis acid EtZnX via nitrogen and oxygen reported a diastereoselective allylation of camphor derived
of carbonyl. The exclusive formation of Z-enamine was attributed glyoxylic oxime ethers 164 using allyltributyltin in the presence
to the coordination of both copper and zinc with the of Sn(OTf)2 to aord homoallylic amines 165 in 9094% yields,
counteranion in species 144. Capturing a second molecule of with 91to >99% dr. Reactions were applied using 2 equiv of
Et2Zn by the Cu species with simultaneous release of one of the allyltributyltin in the presence of Sn(OTf)2 (1 equiv) in CH3CN
phosphoramidite ligand molecules L13 generated a highly at 40 C for 1 h. The absolute stereochemistry of the newly
nucleophilic Cu/Zn cluster 145, which underwent an oxidative formed stereocenter was deduced as (S) using single crystal X-ray
addition of the organocopper reagent to the double bond, leading crystallography (Scheme 41, b).
to the -complex 146. Finally, reductive elimination with 3.7. Organosilicon Reagents
concomitant formation of the CC bond gave the 147, which
was quenched with water to yield -dehydro -amino ester 142 Allylation of -imino ester 166, derived from triuoropyruvate,
(Scheme 38). was investigated using allyltrimethylsilane (3 equiv) in the
presence of Lewis acids in DCM at room temperature. No
3.6. Organotin Reagents reaction occurred when a catalytic amount of Yb(OTf)3 (0.1
Addition of -silyloxyallylstannanes 148 to -imino esters was equiv) was used. BF 3 OEt 2 (2 equiv) resulted in the
studied in the presence of trimethylsilyl triate. Reactions were corresponding allylated amino ester 167 (X = TBDMS) in
carried out by addition of -silyloxyallylstannanes 148 (0.84 38% yield (85:15 dr) along with desilylated product 167 (X = H)
equiv) to a solution of -imino esters and TMSOTf (1.35 equiv) in 40% yield (84:16 dr). Reaction in the presence of SnCl4 (1.25
in DCM under an atmosphere of argon at 78 C and stirring for equiv) led to the expected allylated product 167 in 72% yield,
V DOI: 10.1021/acs.chemrev.7b00064
with 77:23 dr. The stereochemistry assignment of the 167 was 190 by subjecting with Me3OBF4 (1.1 equiv) in DCM under
achieved by cyclization to morpholinones 168 through argon atmosphere at ambient temperature for 2 h, followed by
conditions depicted in Scheme 42.85 addition of KF (10 equiv) in the presence of water in DCM and
Akiyama et al.86 reported enantioselective [3 + 2] cyclo- stirring at the same temperature for additional 0.753 h. The
addition reaction of 1-alkyl-substituted allenylsilanes 169 with 2 yields were 5192%, for the last two steps. The formation of 3,4-
equiv of -imino ester by means of [Cu(MeCN)4]BF4 or dehydroprolines 190 was rationalized by formation of vinyl
[Cu(MeCN)4]PF6 (10 mol %) and (R)-DM-SEGPHOS L15 aminosulfoxonium salts 188a, followed by F induced double
(11 mol %) catalytic system in reuxing benzene under N2 bond isomerization via deprotonationprotonation sequences
atmosphere for 124 h to synthesize silyl-substituted (189) and then cyclization to 190. A similar procedure was
dehydroproline derivatives 170 in 4692% yields, with 71 applied using -methyl vinyl sulfoximine 187 (R2 = Me), leading
85% ee. Ring opening of silyl-substituted dehydroprolines 170 to 4-methylene prolines 192, by deprotonation at the -methyl
with aqueous HI solution at room temperature for 23 h led to group (191). Also, the aminoalkylation of cyclic sulfonimidoyl-
desilylated -amino ketones 171 in 8998% yields, with 7185% substituted allyl titanium complexes 193a was performed under
ee, without loss in enantioselectivity (Scheme 43). similar conditions to give vinyl sulfoximines 194a. However,
Intramolecular addition of allyl- and propargylsilanes to imino mono(allyl)titanium complexes 193b resulted in the formation
lactone, a cyclic -imino ester, was conducted in acidic of enantiomers 194b in 6987% yields. By treatment of
conditions to furnish the corresponding spirocyclic -amino sulfoximine 194b (n = 2) with Me3OBF4, followed by addition
esters. Allylsilanes 173, prepared by cross metathesis reaction of saturated NH4Cl, cyclic -chloro-,-dehydro amino ester 195
between imino lactone 172 and allyl-TMS using second- was obtained in 64% yields, which was transformed into
generation Grubbs catalyst (10 mol %) in DCM at 40 C, hexahydro-1H-isoindole-1-carboxylate derivative 196 in 93%
underwent intramolecular cyclization in the presence of TFA (5 yield, by subjecting with DBU in DCM at room temperature for
equiv) in DCM at room temperature, to give spirocyclic 30 min (Scheme 46).90
compounds 174a and 174b in 89% and 71% yields, respectively. 3.9. Discussion, Synthetic Utility, and the Future
Four diastereoisomers were expected, from which major ones are Addition of organometallics, including Grignard, organo-lithium,
indicated. The chairlike transition state 175 for cyclization of aluminum, born, zinc, tin, and silicon reagents, to -imino esters
173b to major stereoisomer 174b is depicted in Scheme 44, in mostly occurs at carbon of imine moiety and is one of the most
which the allylsilane, preferred the quasi-equatorial position, important approaches for the construction of various types of
attacked to imine moiety through re-face opposite the bulky substituted -amino acid derivatives. However, asymmetric
phenyl group in a quasi-axial fashion. By cyclocondensation of induction is shown in the newly formed stereocenter, by
propargylsilane substituted -keto ester 176 with (R)-phenyl- conducting addition to a chiral -imino ester or reaction in the
glycinol in CF3CH2OH, the imino lactone 177 was obtained, presence of a chiral catalyst. Addition of these types of
which underwent cyclization in the presence of acidic reagents. organometallics aorded corresponding -alkyl, allyl, allenyl,
Treatment with TFA led to the expected spirocyclic allene 178 in vinyl, alkynyl, and aryl substituted -amino acid derivatives,
27% yield (>95/5 dr), along with generation of imine 179 in 35% which were converted to various natural and unnatural important
yield, via ene reaction with inverse electron demand. Some other products, such as aspartates, -amino--hydroxy acid and alcohol
Lewis and Brnsted acids were investigated, and neat formic acid derivatives, carbocyclic compounds, such as cyclopropane, spiro-
resulted in the formation of products 178 and 179 in a 92/8 ratio. cyclopentane, spiro-cyclohexane and cyclohexene derivatives,
Further reactions on obtained products were performed to and heterocyclic compounds, especially aza-heterocycles, such as
synthesize a variety of carbocyclic and heterocyclic com- aziridine, azetidinone, pyrrolidine, piperidine, tetrahydropyr-
pounds.87 idine, azepane, imidazole, morpholine and some 6 to 8
Allenylation and propargylation of -hydrazono ester was membered N-bridged fused heterocycles. However, the addition
reported using propargyltrichlorosilane and allenyltrichlorosi- of Grignard, organoboron, and organozinc reagents were studied
lane, respectively. Allenylation was carried out by addition of suciently, and future works on the synthetic utility of the
propargyltrichlorosilane (1.5 equiv) to a solution of -hydrazono addition of these organometallics to synthesize other types of
ester in DMF at 0 C for 24 h, to give the addition product 180 in heterocyclic compounds and also natural products can be
87% yield. By treatment of -hydrazono ester with allenyltri- expected. Meanwhile, the addition of organotin and organo-
chlorosilane (1.5 equiv) in the presence of EtN(i-Pr)2 (1.5 equiv) silicon reagents is limited to allylation and allenylation reactions,
in DMF at 10 C for 24 h, propargylated product 181 was using other types of these organometallics are of interest.
obtained in 76% yield. Supposed cyclic transition states 182 and Although, the additions of organoaluminum reagents to -imino
183 for selective allenylation and propargylation of -hydrazono esters at a carbon atom of imine moiety are rare, the addition of
ester is shown in Scheme 45, a.88 Also allylation was performed organoaluminum reagents mostly occurs at nitrogen via
by treatment of -keto ester N-benzoylhydrazone with allyl-SiCl3 umpolung, which will be discussed in section 5.2. Also, addition
(5 equiv) in the presence of bis-sulfoxide/N-oxide (R,R)-L16 (3 of all of these organometallics to -imino esters using dierent
equiv) and 2-methyl-2-butene (7 equiv) in anhydrous DCM at types of chiral catalysts, leading to new chiral -amino acids, is
50 C for 48 h, giving N-benzoylhydrazine derivatives 184 in needed in view of the synthetic and medicinal communities.
1893% yields, with 3698% ee (Scheme 45, b).89
3.8. Organotitanium Reagents 4. METAL-CATALYZED ADDITIONS
Treatment of in situ generated sulfonimidoyl-substituted 4.1. In-Mediated Allylation
bis(allyl)titanium(IV) complexes 186 with N-tert-butanesulfonyl Barbier-type In-mediated addition of -substituted allyl
-imino ester (1.2 equiv) in THF at 78 C for 6 h and then at bromides, such as cinnamyl bromide, crotyl bromide, and
room temperature for 15 h aorded functionalized vinyl cyclohex-1-en-3-yl bromide, to -imino esters was developed by
sulfoximines 187, which were converted to 3,4-dehydroprolines Babu et al.91 to give ,-unsaturated ,-disubstituted N-aryl -
W DOI: 10.1021/acs.chemrev.7b00064
Scheme 47. In-Mediated Addition of -Substituted Allyl Scheme 48. In-Mediated Synthesis of Aspartic Acid
Bromides to -Imino Esters and -Hydrazono Estersa Derivatives by Allylation of -Imino Estersa
a
197: R = 4-XC6H4 (X = H, Cl, Br, Me, MeO), 3,4-Cl2C6H3, 3,4-
Me2C6H3; R1 = H, R2 = Me, Ph; 4071%, syn/anti = 98/2. R = NHBz; a
203: R = Me, Et; Ar = 4-XC6H4 (X = H, Cl, Br, Me, Ph, Ac, CO2Et),
R1 = H, R2 = Me, Ph; 6571%, syn/anti = 75/25. R = 4-XC6H4 (X = 3,4-Cl2C6H3, 3,4-Me2C6H3, 3,5-Cl2C6H3, 3-Me-4-BrC6H3, 1-naphthyl;
Br, MeO), 3,4-Cl2C6H3, NHBz; R1 = Me, R2 = Me2CCHCH2CH2; 4896%, syn/anti = > 95/5; 205: R1 = H, Me; NR2R3 = NHBz,
5580, syn/anti = 90/10. 198: Ar = 4-XC6H4 (X = Cl, Br), 3,4- phthalimido; 4681%, syn/anti = 70/3090/10; 206: R1 = H; R2 = H,
Cl2C6H3; 4550%, anti/syn = 98/2. 202: R2 = Me, Ph; Ar = 4-XC6H4 F, Et, n-Pr, n-Hex; R1 = R2 = Me, F; R3 = Et, t-Bu; Ar = 4-XC6H4 (X =
(X = H, Br, Me, MeO), 3,4-Me2C6H3; 6095%. Cl, OMe, Ph); 3585%; 207: Ar = 4-XC6H4 (X = OMe, Ph); 67
72%.
amino esters. Reactions were carried out by stirring a mixture of
-imino esters and allyl bromide (2.5 equiv) in the presence of In
(1.5 equiv) in THF/water (50/50: v/v) solvent at room corresponding products 197 (R = NHBz) were obtained in 71%
temperature for 1224 h. Reaction with E-cinnamyl bromide (syn/anti = 75/25), 65% (syn/anti = 75/25), and 80% (syn/anti
or E-crotyl bromide led to corresponding products 197 in 50 = 90/10) yields, respectively. A number of products were
71% and 4061% yields, with 98/2 diastereoselectivity with converted to tetrahydropyridine derivatives 202 by N-allylation
majority of syn products, respectively. Using cylcohexen-3-yl to 201 using allyl bromide (6 equiv) in the presence of K2CO3 (3
bromide with Z geometry, reactions were conducted in equiv) and NaI (0.1 equiv) in CH3CN under reux conditions
anhydrous THF and addition products 198 were obtained in for 2448 h in 6490% yields, followed by RCM using Grubbs
4550% yields, with 98/2 anti selectivity. The syn-selectivity in second generation catalyst (0.050.1 equiv) in DCM at room
the case of E-allyl bromides was attributed to the in situ temperature overnight in 6095% yields (Scheme 47).
formation of allyl indium species and complexation through N The synthesis of aspartic acid derivatives 203 and 205206
and O atoms of -imino ester (transition state 199), in which the was reported by the same research group, using In-mediated
more bulky group (Ph or Me) positioned equatorially. Whereas, addition of (E)-4-bromocrotonate to -imino esters. Reactions
in the case of cyclohexen-3-yl bromide, the methylene of were performed by addition of In powder (2 equiv) to a solution
cyclohexane stayed on the axial position (transition state 200), of -imino ester and (E)-4-bromocrotonate (3 equiv) in EtOH
aording anti isomers as the major products. Also, reaction of and stirring at 30 C for 6 h, producing N-aryl -vinyl aspartic
geranyl bromide with -imino esters was investigated in DMF, to acid esters 203 in 4896% yields and syn/anti ratio of >95/5.
furnish geranylation products 197 in 5561% yields, with a syn/ Also, -hydrazono esters worked well in the similar reaction to
anti ratio of 90/10. Moreover, the addition of cinnamyl bromide, aord corresponding products 205 in 4681% yields, with 70/
crotyl bromide, and geranyl bromide to -hydrazono ester was 3090/10 dr. Reactions occurred via -addition and transition
performed, under the similar reaction conditions, in which state 204, leading to syn isomers as major products. Additionally,
X DOI: 10.1021/acs.chemrev.7b00064
Scheme 49. In-Mediated Allylation of (R)-Phenylglycinol Scheme 50. InCl3/Al(0) Induced Allylation of -Imino
Methyl Ether Based -Imino Estera Estersa
a
213: R1 = R2 = Me; R3 = H; Ar = PMP; 57%. R1 = Me, Ph; R2 = R3 =
H; Ar = PMP, 3,4-Cl2C6H3; 6068%, syn/anti = 60/4090/10. R1 =
a
209a: R1 = Et, allyl, propargyl, Bn, CH2CH2TMS, R2 = H, Me, H; R2R3 = (CH2)3; Ar = PMP; 70%, anti/syn = 65/35. 214: R = H,
CO2Et, 4598%, 18/1 to >20/1 dr. 209b: R3 = Me, Ph, CO2Et, 60 Me; 2558%, 98/2 dr. 215: Y = Bz, Ts; 2058%. 216: Ar = 4-XC6H4
92%, 7.4/1 to >20/1 dr. (X = Br, MeO), 3,4-Me2C6H3; 3858%.
the reaction of -imino esters with -bromo esters (3 equiv) was equiv of allyl bromides and 2 equiv of In powder in THF at room
investigated in the presence of In powder (2 equiv) in DMF or temperature for 1972 h, and nal desired -addition products
THF at 3080 C for 324 h, to aord aspartic acid derivatives 209 were obtained in 4598% yields, with anti/syn ratio of up to
206 in 3585% yields. Reaction with ,-disubstituted and - >20/1. The high diastereoselectivity of the reaction was related
monosubstituted -bromo esters occurred as well as unsub- to chair like transition state 210 formed by chelation of In with
stituted -bromo esters. Also, the addition of -bromo - nitrogen and methoxy group of imine moiety, and oxygen of
butyrolactone to -imino ester under similar reaction conditions carbonyl of ester, in which the substitution on allylindium species
furnished the corresponding addition products 207 in 6772% positioned equatorially. The addition of allylindium to imine in
yields, with moderate diastereoselectivity (Scheme 48).92 such a transition state occurred at the si-face of imine. Addition
Soengas and Estevez reported In-mediated allylation and product 209b (R3 = Ph) was converted to morpholine derivatives
Reformatsky reaction of glyoxalate oxime ethers by sonication 211, by deprotection of methyl ether moiety using BBr3 in DCM
of a solution of oxime with allyl bromide and ethyl 2- at 78 to 25 C in 78% yield, followed by lactonization in the
bromoalkanoate (1.5 equiv) in the presence of indium powder presence of NaOH in EtOH/water at room temperature in 60%
(1 equiv) in THF, respectively. Allylation occurred in high yields yield. Aziridine 212 was produced through reduction of ester
(7289%). Indium-mediated Reformatsky addition of bro- moiety of 209a (R1 = Et, R2 = H) using DIBAL-H in DCM at
moesters aorded corresponding addition products in 8188% 78 C to room temperature in 96%, followed by intramolecular
yields, with syn/anti ratio of 2/13/1.93 aziridination using MsCl in the presence of Et3N in DCM at
Also, Kang et al.94 reported the Barbier-type allylation of PMP- room temperature in 93% yield (Scheme 49).95
protected -iminoacetate by addition of allyl bromide derivatives Allylation of -imino esters was reported using a catalytic
(2 equiv) to a mixture of -iminoacetate, In powder (1.2 equiv), amount of InCl3 in combination with Al0. By treatment of -
and AcOH (6 equiv) in THF/saturated aqueous NH4Cl (1/1: v/ imino esters with allyl bromides (2 equiv) in the presence of
v) at room temperature and stirring for 5 h to give -addition InCl3 (34 mol %) and Al powder (1.5 equiv) in anhydrous
products in 7988% yields. THF at room temperature for 410 h, -addition products 213
In-mediated allylation of (R)-phenylglycinol methyl ether were obtained in 5770% yields. (E)-Cinnamyl and (E)-crotyl
based imines of triuoropyruvate 208 was reported to highly bromide aorded the products with syn selectivity (syn/anti =
diastereoselective synthesis of quaternary -triuoromethyl - 60/4090/10), while reaction of cyclohexen-3-yl bromide with
amino acid derivatives 209. Reactions were performed using 2.2 (Z) stereochemistry resulted in formation of the product with
Y DOI: 10.1021/acs.chemrev.7b00064
Scheme 51. Pd/In Mediated Catalytic Allylation of Chiral N- Scheme 52. Pd-Catalyzed In-Mediated Allylation of -
Sulnyl -Imino Estersa Hydrazono Ester 223
Diastereoselective Pd/In mediated catalytic allylation of chiral

N-sulnyl -imino esters was described by Grigg et al.98 By
charging a suspension of chiral -imino ester, aryl iodide (1.5
equiv), indium metal powder (1.5 equiv), Pd(OAc)2 (10 mol %),
tri(2-furyl)phosphine (20 mol %), CuI (20 mol %), and
piperidine (1 equiv) in DMF with allene gas (0.5 bar) and
heating at 40 C for 24 h, 2-arylallyl -amino acid esters 219 were
obtained in 4992% yields. In the plausible reaction mechanism,
electrophilic -allyl palladium species 217, generated by
oxidative addition of Pd with ArI, followed by allene insertion,
underwent transmetalation with In to generate nucleophilic 1-
allyl indium species 218, which attacked the imine moiety.
Reaction with (S)-sulnimines aorded the (S) stereochemistry
(S,S)-219, while (R)-sulnimines led to (R) stereochemistry of
the newly formed stereocenter (R,R)-219. This stereochemistry
outcome of the reaction was attributed to the formation of
a
219: Ar = XC6H4 (X = H, 4-Me, 4-CF3, 3-MeO), 3,4-Cl2C6H3, 3,5- transition states 220 by chelation of N and O atoms of the imino
(CF3)2C6H3, 6-Cl-pyridin-2-yl, pyrazin-2-yl; (S)-sulnimines: 5292% ester moiety with In along with coordination of the O atom of
(S,S); (R)-sulnimines: 4980% (R,R). 222: X = O, NSO2Ph, CH2O, sulnyl moiety to In atom, in which esters moiety located in the
C(O)NMe; (S)-sulnimines: 2864% (1R,2S,3S); (R)-sulnimines: axial position, and si-face and re-face addition occurred to form
3264% (1S,2R,3R). (S) and (R)-stereochemistry of new stereocenter, respectively.
Treatment of bifunctional aryl iodide/allenes 221 with this
catalytic system furnished cyclizationallylation products 222 in
anti selectivity (syn/anti = 35/65). The allylation of chiral N-tert- 2864% yields, with excellent stereoselectivity (Scheme 51).
butylsulnyl imino ester was also tested, in which the allylated One example of the Pd-catalyzed In-mediated allylation of the
products 214 were obtained with excellent diastereoselectivity, as -hydrazono ester 223 was reported, in which treatment of 223
S- and R-sulnimine provided S and R stereochemistry at the new with allyl acetate (1.2 equiv) in the presence of InI (1.2 equiv)
chiral center, respectively (Scheme 50, a; see also ref 95)96 Also, and Pd(PPh3)4 (5 mol %) in a 1/1 mixture of THF/water at
the addition of allyl bromide to N-benzoyl and N-tosyl room temperature, aorded allylated product 224 in 80% yield,
hydrazones of ethyl glyoxalate was investigated under similar with 80/20 dr. Proposed reaction mechanism involves the
conditions, in which corresponding adducts 215 were obtained generation of -allylpalladium species 225 followed by trans-
in 58% and 20% yields, respectively. Moreover, the addition of metalation via formation of Pd(II)In(I) coordinative bond
propargyl bromide to -imino esters was applied using a 226, to form nucleophilic allylindium species 227, which
combination of InCl3 and Al0, in which ethyl 2-(arylamino)pent- underwent addition to -hydrazono ester (Scheme 52).99
4-ynoates 216 were formed in 3858% yields (Scheme 50, b). 2-Aminomethyl-2-ethoxycarbonyl-1,3-butadienes 229 were
However, the most likely proposed reaction mechanism involves achieved through the reaction of -imino esters with organo-
the Al-induced generation of In0 and then in situ conversion to indium reagent, in situ generated from indium and 1,3-dibromo-
allylic indium species, followed by addition to -imino esters, but 2-butyne 228. Treatment of -imino ester with 1.5 equiv of 228
the authors proposed the activation of Al surface by In(III), and In (3 equiv) in the presence of MgSO4 (1 equiv) in EtOH at
generating allylic aluminum reagent, which attacked to imine room temperature for 6 h furnished amino-dienes 229 in 65
moiety.97 77% yields. The obtained diene 229 underwent DielsAlder
Z DOI: 10.1021/acs.chemrev.7b00064
Scheme 53. In-Mediated Addition of 1,3-Dibromo-2-butyne 228 to -Imino Estera
a
R = PMP, BnO; 6577%.
Scheme 54. Ag-Catalyzed Alkynylation of -Imino Estera Scheme 55. Cu-Catalyzed Alkynylation of -Imino Estera
a
Ar = 4-XC6H4 (X = H, Me, t-Bu, n-Pent, MeO), 2,5-(MeO)2C6H3,
3,4-(OCH2O)C6H3, 6-MeO-naphthalen-2-yl; 6093%, 93/7 dr.
a
cycloaddition with various dienophiles, to give corresponding R = c-Pr, n-Hex, Bn, PhCH2CH2, TMS, TMSCH2; 5592%, 4891%
cycloadducts 230232 in 6283% yields (Scheme 53).100,101 ee.
4.2. Ag-Catalyzed Alkynylation
Rueping et al.102 reported the alkynylation of PMP-protected -
iminoacetate using dual catalytic system, combining an were obtained in 6093% yields, with high diastereoselectivity
enantioselective Brnsted acid and metal-catalysts. Various chiral (more than 93/7 dr). Two parallel catalytic cycles I and II were
binol hydrogen phosphates and metal salts were investigated for proposed for the reaction mechanism, in which chiral Brnsted
the addition of terminal alkynes to -imino esters and using 2 acid activated the -imino ester electrophilic species to form
equiv of alkynes in the presence of AgOAc (5 mol %), and chiral chiral ion pair intermediate 235, which underwent addition with
binol hydrogen phosphate L17 (10 mol %) in toluene at 30 C Ag+ salt activated nucleophilic alkyne 234 (Scheme 54). Also,
was selected as the optimum reaction conditions, in which Ag-catalyzed addition of -imino esters with alkynes (2 equiv)
corresponding alkyne substituted -amino ester derivatives 233 was described using AgOTf (10 mol %) in hexane at room
AA DOI: 10.1021/acs.chemrev.7b00064
Scheme 56. Cu-Catalyzed Aerobic Cross-Dehydrogenative temperature for 1 h, followed by cooling to 10 C and addition
Coupling of N-Aryl Glycine Esters with Terminal Alkynesa of -imino ester, alkyne (2 equiv), and p-anisidine (10 mol %)
and stirring at the same temperature for 3648 h, to furnish ,-
alkynyl -amino esters 236 in 5592% yields, with 4891% ee.
The proposed reaction mechanism involves the chelation of -
imino ester with N and O atoms with Cu(I) (pybox) complex
(237), followed by formation of soft metal-alkyne -complex
(238), which underwent intramolecular deprotonation by N
atom of -imino ester moiety as a weak base, and alkyne transfer
to give complex 239. Subsequent decomplexation of 239
a 1
resulted in the formation of nal product 236 along with
R = Et, i-Pr, i-Bu; R2 = c-Pr, n-Bu, n-Hex, n-Oct, CH2CH2OBn, regeneration of Cu(I) (pybox) complex Cu-L18 (Scheme
CH2CH2OTBS, XC6H4 (X = H, 4-Cl, 4-Br, 3-Me, 4-Me, 4-MeO); Ar 55).104 Also, the synthesis of ,-alkynyl -amino esters was
= 4-XC6H4 (X = Br, Me, MeO), 2,4-Me2C6H3; 3080%, 84/1693.5/
6.5 er.
achieved in 6180% yields, with 6674% ee, via three-
component reaction of p-anisidine, ethyl glyoxalate (1.04
equiv), and a terminal alkyne (2 equiv) using CuOTf0.5C6H6
temperature for 0.51 h to give ,-alkynyl -amino ester (10 mol %), and pybox L18 (10 mol %) in dry DCM at room
derivatives in 7993% yields.103 temperature.105 Moreover, Cu-catalyzed alkynylation of -imino
4.3. Cu-Catalyzed Alkynylation esters was reported using other chiral pybox ligands via either
The synthesis of ,-alkynyl -amino esters 236 was achieved by two- or three-components fashion.106108
addition of terminal alkynes to -imino esters in the presence of a Liu et al.109 reported copper-catalyzed enantioselective
chiral Cu(I) complex, CuPF6/bis(oxazolidine)pyridine (pybox) alkynylation of -imino esters by aerobic cross-dehydrogenative
L18. Reactions were carried out by in situ generation of a chiral coupling of N-aryl glycine esters with terminal alkynes. Reactions
Cu(I) complex Cu-L18 by stirring a solution of pybox L18 (10 were carried out by in situ generation of -imino esters by
mol %) and CuOTf0.5C6H6 (10 mol %) in DCM at room treating N-aryl glycine esters with O2 (1 atm) in the presence of
Scheme 57. CuBr2-Catalyzed Alkynylation of -Iminium Carboxylates and Their Synthetic Utility
a
245: R = n-Bu, CH2OMe, (CH2)3OMe, (CH2)3Cl, (CH2)3CO2Me, Ph, Ferrocenyl; X = O, NPh, benzo; 3574%.
AB DOI: 10.1021/acs.chemrev.7b00064
Scheme 58. Zn-Catalyzed Alkynylation of -Imino Estersa Scheme 59. Rh-Catalyzed Alkynylation of -Imino Estera
a
252: R1 = F; R2 = c-Pr, t-Bu, n-Hex, cyclohexen-1-yl, CH2CH2Ph,
TMS, OTBDMS, XC6H4 (X = 3-Cl, 4-n-Pr, 4-MeO, 4-CO2Et), 6-
MeO-naphthalen-2-yl; 8495%, 91.999.6% ee.112 252: R1 = F, Cl,
Br, CF3; R2 = c-Pr, BnOCH2, Ph, 6-MeO-naphthalen-2-yl; 7695%,
8996% ee. 254: R = c-Pr, n-Hex, cyclohexen-1-yl, TMS, XC6H4 (X =
H, 3-Cl, 4-MeO, 4-CO2Et); Ar = XC6H4 (X = H, 4-Br, 3-Me, 4-CF3, 4-
MeO), 2-naphthyl; 8498%, 8699% ee.111 253: R1 = Me, Et; R2 = c- a
255: R = XC6H4 (X = H, 4-Br, 2-Me, 4-Me, 4-CF3, 4-MeO, 4-CHO,
Pr, cyclohexenyl, PhCH2CH2, (i-Pr)3Si, XC6H4 (X = H, 4-F, 2-Cl, 4- 4-NHFmoc), 3-thienyl, N-Boc-indol-5-yl; Cond. = Rh-complex L21
Cl, 4-Br, 4-Me, 2-MeO, 3-MeO, 4-MeO), 1-naphthyl, 9-anthryl; Ar = (2.5 mol %), toluene, rt, 12 h, 8499%, 9095% ee;114 Cond. = Rh-
XC6H4 (X = 2-MeO, 4-MeO), 2,4-Br2-6-MeO-C6H2; 7697%, 86 complex L22 (0.5 mol %), toluene, rt, 12 h, 8497%, 8895% ee.115 R
93% ee.113 = c-Pr, cyclohexenyl, CH 2 CH 2 Ph, CH 2 CH 2 NO 2 , CH(OEt) 2 ,
CH2OTBS, CH2NHCbz, C(Me)2OH, TMS; Cond. = Rh-complex
L21 (5.0 mol %), 4 MS, toluene, 0 C, 48 h, 8297%, 8296%
Cu(OTf)2 (10 mol %) and pybox L18 (10 mol %) in toluene at ee;114 Cond. = Rh-complex L21 (2.5 mol %), 4 MS, toluene, 0 C,
40 C for 2 h, followed by the addition of a terminal alkyne (2 48 h, 8698%, 8091% ee.115 257: R = c-Pr, CH2CH2Ph, XC6H4 (X =
equiv) under N2 atmosphere overnight. The ,-alkynyl -amino 2-Me, 4-Me, 4-CF3, 4-MeO); 9099%, 7887% ee.115
esters 240 were obtained in 3080% yields, with 84/1693.5/
6.5 er. No product was formed for N-alkyl or N-acyl glycine esters
(Scheme 56).
Yamamoto and Hayashi110 reported CuBr2-catalyzed alkyny- 245 in 2968% yields. In the absence of a dienophile, reaction
lation of -iminium carboxylates, in a three-component reaction aorded pyrrole-2-carboxylate 243 in 39% yield, through
by stirring a solution of an equimolar amount of N-benzylallyl- iridium-catalyzed isomerization of exocyclic diene 242. Rh-
amine, ethyl glyoxalate, and terminal alkynes in the presence of catalyzed intramolecular [4 + 2] and [5 + 2] cycloadditions of
CuBr2 (10 mol %) and 4 MS in toluene at room temperature glycinate-tethered dienyne 246 and cyclopropylenyne 247,
under an atmosphere of argon for 24 h, to give glycinate tethered prepared form CuBr2-catalyzed reaction of ethyl glyoxalate and
1,6-enynes 241, which was converted to tricyclic pyrrole-2- 1-hexyne with N-benzylhexa-2,4-dienylamine and N-benzyl-3-
carboxylates 245 in 3574% yields, when heated with a
cyclopropylprop-2-enylamine, respectively, were also investi-
dienophile, such as N-phenylmaleimide, maleic anhydride, or
gated. Irradiation of 246 in the presence of Rh(acac)(CO)2 (5
naphthoquinone (1.1 equiv) in toluene in the presence of
[IrCl(cod)]2 (3 mol %) and AcOH (12 mol %), under reux mol %) in toluene at 120 C for 0.5 h, aorded [4 + 2]
conditions for 24 h, under argon atmosphere. Reactions cycloaddition product, cyclohexadiene 248 and its isomer 249, in
proceeded via domino cycloisomerization/DielsAlder cyclo- 64% yield, with a 249/248 ratio of 64/36. Seven membered ring
addition, followed by in situ dehydrogenative aromatization of products 250 and 251 were obtained in 33% combined yield with
244 via CH activation on the 3,4-dehydroproline ring with Ir the ratio of 63/37, by heating cyclopropylenyne 247 in the
species. Also, the same reaction was conducted using microwave presence of RhCl(PPh)3 (5 mol %) and AgOTf (5 mol %) in
irradiation at 150 C for 0.5 h, leading to corresponding products toluene at 120 C for 0.5 h, under MW irradiation (Scheme 57).
AC DOI: 10.1021/acs.chemrev.7b00064
Scheme 60. Proposed Reaction Mechanism for Rh-Catalyzed Alkynylation of -Imino Ester
Scheme 61. Hydrogen-Mediated Reductive Coupling of 1,3- Scheme 62. Rh(III)-Catalyzed Aromatic CH Bond Addition
Enynes and 1,3-Diynes with -Imino Estersa to -Imino Estera
a
R = H, 4-Me, 5-Me, 4-MeO, 4-Ac; DG = pyrrolidine-1-yl-CO-, 1-
oxidotetrahydrothiophen-1-ylidene-carbamoyl, pyrazol-1-yl, 1-Bn-
1,2,3-triazol-4-yl, PhNN-, 3,5-Me2C6H3NN-; 4776%, 94/6 to
>99/1 dr.
4.4. Zn-Catalyzed Alkynylation

Enantioselective Zn/BINOL-catalyzed alkynylation of -uo-
roalkyl -imino esters and -aryl -imino esters was reported by
a
264: R1 = n-Pent, CH2OTBS, CH2CH2OTBS, CH2NHBoc, Ph, 2- Zhang et al.111,112 A variety of chiral BINOL ligands in
furyl, 2-indolyl, 2-naphthyl; R2 = t-Bu, p-tolyl, mesityl; 6699%. 265: combination with Me2Zn were explored for the reaction.
R1 = Me, CH2OTBS, CH2NHBoc; R2 = t-Bu (Reaction did not Treatment of -uoroalkyl -imino esters with terminal alkynes
occur), p-tolyl, mesityl, 2,4,6-(i-Pr)3C6H2; Ar = Ph, 2-furyl; 7896%. (1.7 equiv) in the presence of Me2Zn (1.2 equiv) and BINOL
L19 (5 mol %) in toluene at room temperature for 1970 h
furnished quaternary -triuoromethyl -amino esters 252 in
8395% yields, with more than 89% ee (Scheme 58, a).
However, addition to -aryl -imino esters was applied under
AD DOI: 10.1021/acs.chemrev.7b00064
Scheme 63. Ru(II)-Catalyzed Regioselective Reductive 4.5. Rh-Catalyzed Alkynylation and Arylation
Allylation of -Imino Estersa Mashima et al.114 described Rh-catalyzed enantioselective
alkynylation of benzyloxycarbonyl (Cbz) protected -triuor-
omethyl -imino ester. Reactions with aryl substituted alkynes
were conducted by treatment of RhPhebox catalyst L21 (2.5
mol %) with aryl-substituted alkynes (1.5 equiv) in toluene under
an atmosphere of argon, followed by addition of -imino ester
and stirring at room temperature for 12 h, to give corresponding
alkynylated products 255 in 8499% yields, with 9095% ee. In
the case of alkyl substituted alkynes, reactions were performed by
stirring a solution of RhPhebox complex L21 (5 mol %) and
alkyl-substituted alkynes (3 equiv) in the presence of 4 MS in
toluene under argon atmosphere at 30 C for 3 h, followed by
cooling to 0 C and addition of -imino ester and stirring at the
same temperature for 48 h, to furnish products 255 in 8297%
yields, with 8296% ee. By reduction of the product 255 (R =
CH2NHCbz) using H2 (1 atm.) over 10% Pd/C in MeOH at
room temperature for 24 h, followed by treatment with phthaloyl
dichloride in the presence of DMAP in CHCl3 at 0 C and then
under reux conditions for 48 h, piperidine-2-one 256 was
obtained in 68% yield (Scheme 59, a). Proposed reaction
mechanism involves the formation of (acetato-2O,O)-
(alkynyl)(phebox)Rh(III) complex 260 from reaction of
(aqua)(diacetato)(phebox)Rh(III) complex 258 with alkyne
via -complex 259, followed by reaction with -imino ester to
give (amido)Rh(III) complex 261, which transformed into
complex 262 by coordination of another alkyne molecule. By
a 1
R = H, Ph; R2 = H, Me, Ph, CH2CH2CHCMe2; R3 = H, Me;
proton transfer from alkyne to amide group via transition state
R1R3 = (CH2)2; Ar = XC6H4 (X = H, 4-Cl, 4-Br, 4-Me, 4-MeO, 4- 263, the nal product 255 was produced, along with regeneration
NO2, 3-CO2Et), 3-pyridyl, 1-naphthyl; 3395%, syn/anti = 1/13/1. of complex 260 (Scheme 60). Also, (trimethylsilylethyl)Rh(III)
complex L22 catalyzed the addition of aryl- and alkyl-substituted
Scheme 64. Ni-Catalyzed Addition of Styrenes to Cyclic - alkyne to -imino ester, to give corresponding products 255 in
Imino Estersa 8497% (8895% ee) and 8698% (8091% ee) yields,
respectively. Moreover, the addition of terminal alkynes to cyclic
N-sulfonyl -imino ester 81 was studied using various Rh
complexes as catalysts, in which (trimethylsilylethynyl)Rh(III)
complex L23 (5.0 mol %) in the presence of 4 MS in toluene at
70 C for 24 h aorded addition products 257 in 9099% yields,
with 7887% ee (Scheme 59, b).115
Hydrogen-mediated reductive coupling of 1,3-enynes and 1,3-
diynes with N-(sulnyl)imino esters was reported to provide 2-
aminohexa-3,5-dienoates 264 and 2-aminohex-3-en-5-ynoates
265, respectively. Reactions were carried out by addition of
Rh(COD)2OTf (5 mol %) and BIPHEP (5 mol %) to a solution
of -iminoacetate and 1,3-enyne or 1,3-diyne (2 equiv) in DCM
at ambient temperature and stirring under H2 (1 atm), to give
corresponding products 264 or 265 in 6699% or 7896%
yields, respectively. In the case of 1,3-diynes, reaction with ethyl
(N-tert-butanesulnyl) iminoacetate did not occur. Remarkably,
2-aminohex-3-en-5-ynoates 265 were obtained as single
a 1
R = H, 5-F, 5-Cl, 7-Cl, 5-Me, 5-t-Bu, 5-CF3, 5-MeO, 5-OCF3, 7- regioisomers, as coupling occurred exclusively at the aromatic
OCF3, 6-Cl-7-F, 6,7-CHCHCHCH; R2 = Me, Et, i-Pr, n-Bu; R3 terminus of the conjugated diyne. Plausible catalytic cycle was
= H, 4-Cl, 4-Br, 3-Me, 4-Me, 4-t-Bu, 3-MeO, 2,4-Me2, 2,4,6-Me3; 35 illustrated in Scheme 61. By coordination of Rh(I) with alkyne
83%, 8899% ee. moiety, Rh(I)-alkyne -complex 266a was formed, could be as
metallacyclopropene form 266b, which attacked to -imino
esters to generate Rh(III) intermediate 267. The hydrogenolytic
similar reaction conditions using L20, to give corresponding cleavage of the metallacyclic intermediate 267 by hydrogen
quaternary -amino esters 254 in 8498% yields, with 8799% activation via -bond metathesis aorded the nal product
ee (Scheme 58, c). Also, Me2Zn-catalyzed addition of terminal through intermediate 268 along with regeneration of Rh(I)
1,3-diynes to -uoromethyl -imino esters using L19 (10 mol species (Scheme 61).116
%) as a chiral ligand in toluene at 0 C for 48 h was developed to Rh(III)-catalyzed CH bond addition of aromatic com-
prepare 2-(triuoromethyl)hexa-3,5-diynoates 253 in 7697% pounds to the N-peruorobutanesulnyl -imino ester was
yields, with 8693% ee (Scheme 58, b).113 reported by Ellman et al.117,118 Treatment of -imino ester with
AE DOI: 10.1021/acs.chemrev.7b00064
Scheme 65. Umpolung Three-Component Coupling of -Imino Ester, Grignard Reagents, and Electrophilesa
a 2
R = Et, n-Pent; 280: 8485%; 281a: R3 = Ph, PhCH2CH2, PhCHCH-, 4-NO2C6H4CHCH-; 4890%, > 20/1 dr; 281b: 52%, > 20/1 dr;
282: 6772%, 1.3/11.4/1 dr; 283: R1 = Me, Et, i-Pr, t-Bu, Bn; Ar1 = XC6H4 (X = H, 4-Cl, 2-Me, 4-MeO), N-Bn-indol-2-yl; Ar2 = Ph, PMP; 58
87%; 284: R4 = Et, Bn, t-BuO2CCH2; 4872%; 286: R = Me, Et; Ar = Ph, 2-thienyl; n = 1, 2; 4566%.
arenes (1.52 equiv) in the presence of [Cp*RhCl2]2 (10 mol Reactions were performed using 2 equiv of styrene derivatives in
%) and AgB(C6F5)4 (40 mol %) in DCE under an atmosphere of the presence of Ni(ClO4)26H2O (10 mol %) and (S)-BINAP
N2 at 50 C for 24 h, aorded arylglycinates 269 in 4776% L24 (12 mol %) in DCM at 100 C for 2472 h. Reactions with
yields, with 94/6 to >99/1 dr. Electron decient as well as various substituted cyclic N-sulfonyl -imino esters 81 with
electron rich arenes worked well in the reaction. The styrene aorded corresponding -addition products 278 in 69
stereochemical outcome of the reaction was attributed to the 83% yields, with 9299% ee. Moreover, addition of dierent
formation of enantiomeric rhodacycles 270a and 270b through substituted styrenes was also investigated, giving corresponding
CH activation of arenes and chelation of directing group (DG) products 278 in 3574% yields, with 8899% ee. Reaction with
with Rh(III), followed by coordination of N-sulnyl -imino electron-withdrawing, 4-Cl, 4-Br, and 3-MeO, substituted
ester to Rh via O atom of sulnyl moiety to generate intermediate styrenes aorded lower yields of products, 35%, 40%, and 55%
271, in which C4F9 oriented away from the reaction center yields, respectively (Scheme 64).
(Scheme 62). 4.8. Discussion, Synthetic Utility, and the Future
4.6. Ru-Catalyzed Reductive Allylation Metal-catalyzed additions to -imino esters involve In-mediated
Ruthenium(II)-catalyzed regioselective reductive coupling of - and Ru-catalyzed allylation, Ag, Cu, Zn, and Rh-catalyzed
imino esters with dienes was reported by Zeng et al.119 to alkynylation, and a few reports on the arylation and vinylation.
synthesize -branched allylic -amino ester derivatives 272. In-mediated allylation of -imino esters were performed using
Reactions were conducted using 4 equiv of dienes in the presence allyl bromides, to aord allyl substituted -amino acid
of i-PrOH (2 equiv) and RuHCl(CO)(PPh3)3 (10 mol %), in derivatives, which were excellent synthetic intermediate to
toluene under argon atmosphere at 130 C for 24 h. The scope of synthesize aspartates, and a number of heterocyclic compounds,
the reaction was examined using various N-aryl substituted - such as aziridine, tetrahydropyridine, morpholinone, benzofuran,
imino esters and also a variety of dienes, leading to corresponding benzothiophene, and indole derivatives. Allyl acetate was also
allylic -amino esters 272 in 3395% yields. In most cases used as an allylation reagent in the presences of In metal. Mostly,
coupling occurred at -carbon of dienes, while s-cis-1,3-hexadiene in situ generation of allyl indium species and chair like transition
aorded the ,-unsaturated -amino ester in 65% yield. No state, formed by chelation of In with nitrogen of imine moiety,
reaction occurred, in the case of, 2,4-dimethyl-2,3-hexadiene, a and oxygen of carbonyl of ester, led to the chiral -amino esters
disubstituted alkene. Cyclohexadiene showed low reactivity, and via -addition. However, the In-mediated allylation of -imino
the corresponding product was obtained in 33% yield. In the esters has been extensively studied; the allenylation and
proposed reaction mechanism, addition of ruthenium hydride to alkylation of -imino esters using propargyl bromide and -
diene gave -allylruthenium complex 273, which was isomerized bromo esters would be expected, for future research, respectively.
to primary -allyl haptomer 274, and then transformed into nal ,-Alkynyl -amino acid derivatives were synthesized via Ag, Cu,
products 272, by reaction with -imino esters via allylation and Zn, and Rh-catalyzed alkynylation of -imino esters using
then protonation through transition states 275 and 276, along terminal alkynes. Reaction in the presence of chiral ligands
with regeneration of RuH species via -hydride elimination of resulted in the formation of enantioenriched -amino esters.
alkoxy ruthenium intermediate 277 with liberation of acetone Synthesis of carbocyclic and heterocyclic compounds, such as
(Scheme 63). cyclohexene, cycloheptene derivatives, and piperidin-2-one are
some of the synthetic utility of the metal-catalyzed alkynylation
4.7. Ni-Catalyzed Vinylation of -imino esters. Addition of alkynes to -imino esters in the
Jia et al.120 reported an enantioselective addition of styrenes to presence of other metal catalysts and also using dierent chiral
cyclic N-sulfonyl -imino esters 81 using the complex of ligands, providing excellent enantioselectivity, are some of the
Ni(ClO4)2 with chiral phosphine ligand L24 as a catalyst. future prospects of this reaction. In fact, there are a few reports on
AF DOI: 10.1021/acs.chemrev.7b00064
the Rh, Ru, and Ni-catalyzed arylation, allylation, and vinylation Scheme 67. Umpolung Coupling of -Imino Esters, Grignard
of -imino esters, in the literature, the study of arylation with Reagents, and Cinnamyl Acetatea
various electron donating and electron withdrawing substituted
aromatic and also heteroaromatic compounds using these metal
catalysts in the presence of chiral ligands, as well as reductive
coupling with 1,3-dienes, 1,3-diynes and 1-en-3-ynes is of
interest.
5. UMPOLUNG REACTIONS
5.1. Grignard Reagents
Three-component coupling of -imino ester, Grignard reagent,
and an electrophilic component, such as water, aldehyde, imine,
Scheme 66. Umpolung N,N-Dialkylation and N,N,C-

Trialkylation of O-Acyl -Oxyimino Estersa
a
287: R = Me; 0%; R = n-Pr, i-Pr, t-Bu, c-Hex, Bn; 1279%. 288: R =
Me, c-Hex, Bn, vinyl, Ph, 2-thienyl; 3164%.
R = Et, n-Pent, TMSCH2CH2, CH2CH-(CH2)n (n = 2, 3, 4); R2 =

a 1
alkyl halide, and acyl cyanide, was reported via umpolung Ph; Ar1 = 4-XC6H4 (X = H, F, Cl, Me, MeO), 2-naphthyl, 2-thienyl;
addition. The proposed reaction mechanism involves the in situ Ar2 = 4-XC6H4 (X = H, MeO, Me2N), 3,4-Me2C6H3; 7289%, 74
generation of tetra-substituted enolate 279 via N-alkylation of - 92% ee.123 R1 = Et; R2 = H, n-Pr, Ph, PMP; Ar1 = Ph, Ar2 = PMP; 70
imino ester with RMgBr, which attacked an electrophile to give 82%, 5264% ee.124
nal products 280284. Reactions were performed under
dierent conditions due to the used electrophile. Subjecting - 4872% yields. Chloro-substituted alkylMgBr under similar
imino ester with EtMgBr (1.5 equiv) or n-pentylMgBr (1 equiv) reaction conditions resulted in the formation of cyclic -amino
in THF at 78 C under N2 atmosphere, followed by warming to esters 286 in 4566% yields, via tandem N-alkylation-intra-
room temperature, stirring for 45 min, and then quenching with molecular -alkylation of 285 (Scheme 65).121
saturated NaHCO3 solution, aorded -amino esters 280 in 84% The synthesis of -N,N-dialkylamino and -alkyl--N,N-
or 85% yields, respectively. By treatment of -imino ester with dialkylamino esters 287288 was achieved by N,N-dialkylation
RMgX (1.51.7 equiv) in THF at 78 C under N2 atmosphere, and N,N,C-trialkylation of O-acyl -oxyimino esters via
and then stirring at room temperature for 45 min, followed by umpolung addition of Grignard reagents. Various solvents in
cooling to 78 C and addition of an aldehyde (25 equiv) and the presence of a variety of additives were explored to obtain
stirring for 4 h at the same temperature, aminoalcohols 281a optimum conditions. Dialkylation was conducted by addition of
were obtained in 4890% yields, with >20/1 dr. Reaction with EtMgBr (2.2 equiv) to a solution of -oximino ester in toluene at
imine was carried out under similar conditions, to give ,- 78 C under an argon atmosphere for 30 min, followed by
diamino ester 281b in 52% yield and >20/1 dr. Reaction of - addition of benzoic acid (0.75 equiv) and warming the mixture to
imino ester with RMgBr (2 equiv) and trans--nitrostyrene (3 30 C for 5 min, and then addition of RMgBr (1.75 equiv) and
equiv) in THF at 78 C for 1 h led to conjugated addition stirring for 30 min, at the same temperature, to furnish the
products 282 in 6777% yields and 1.3/11.4/1 dr. Addition of corresponding N-ethyl-N-alkyl--amino esters 287 in 1279%
pyruvonitrile (5 equiv) to a solution of -imino ester and RMgBr yields. Reaction with MeMgBr did not give the corresponding
(1.5 equiv) in THF at ambient temperature for 1 h furnished - product. However, t-BuMgBr aorded the corresponding
acetyl--amino esters 283 in 5887% yields. By subjecting a dialkylated product in low yield (12%). N,N,C-Trialkylation
solution of -imino ester and EtMgBr (2 equiv) in THF with was applied as above, followed by oxidation of N,N-dialkylated
alkyl halide (2.5 equiv) in DMF at room temperature for 2 h, products using a solution of DBDMH (0.6 equiv) in DCM for 15
corresponding -alkylated -amino esters 284 were obtained in min, to in situ generate -iminium salts, which underwent
AG DOI: 10.1021/acs.chemrev.7b00064
Scheme 68. Tandem N-Alkylation/Vinylogous Aldol Reaction of ,-Alkenyl -Imino Estersa
R = Et, i-Bu, n-Oct, CH2CH-(CH2)2, Cl(CH2)4, 1,3-dioxan-2-yl(CH2)2, 1,3-dioxolan-2-yl(CH2)3; R2 = 4-XC6H4 (X = H, Cl, MeO), 2-thienyl, 2-
a 1
pyridyl, PhCHCH-, PhCC-; Ar1 = Ph, 2,6-Me2C6H3, 2-thienyl; Ar2 = H, 4-XC6H4 (X = H, F, MeO), 2-thienyl; 296: 2581%, 297: 037%. R =
Me, t-Bu; Ar = Ph, 2-thienyl; 300+301: 8598%, 300/301 = 26/7486/14. R = Ph, (E)-PhCHCH-; Ar = Ph, 2-thienyl; 303: 4971%, 64/36
93/7 dr.
nucleophilic addition by another RMgBr (2 equiv) during 15 dihydro-3-amino-2H-pyran-2-ones 299, which partially under-
min, giving trialkylated products 288 in 3159% yields (Scheme went desulfenylation to 300 and 301 via anti-elimination during
66). In the proposed reaction mechanism, N-alkylation followed purication by chromatography using deactivated silica gel.
by removing acyloxy moiety aorded the corresponding -N- Reaction of ,-alkenyl -imino ester 302 bearing a phenyl-
alkylimino ester which underwent further N-alkylation.122 dimethylsilyl group on its alkene part was also investigated, in
Asymmetric synthesis of -allyl--aryl -amino acids 289 was which after the vinylogous aldol reaction, the Peterson
reported via a three-component umpolung coupling of -imino olenation proceeded faster than the intramolecular cyclization,
esters, Grignard reagents, and cinnamyl acetate through to aord dienamines 303 in 4971% yields (Scheme 68).125
intermediate 290. Reactions were carried out by adding a Umpolung N-addition to ,-alkynyl -imino esters 304
mixture of [3-C3H5PdCl]2 (7.5 mol % of Pd), ligand L24 or L25 followed by regioselective acylation was developed by Shimizu et
(5 mol %), and cinnamyl acetate (1 equiv) in THF to a solution al.126 Reactions were carried out by addition of acyl chloride (5
of -imino ester and RMgBr (1.6 equiv) in THF at 78 C under equiv) to a solution of ,-alkynyl -imino esters 304 and RMgBr
argon atmosphere, followed by warming to room temperature (1.1 equiv) in THF at 78 C under argon atmosphere, followed
and stirring for 45 min. The N-alkylation/-allylation products by warming to room temperature during 30 min, to give N-
289 were obtained in 7289% yields, with 7492% ee.123 Also, alkylation/-acylation products 305 in 32% to quantitative
similar methodology was reported using various allyl acetates, by yields. Due to the steric hindrance, acyl chlorides having
the same research group, in which 1,3-disubstituted allyl acetates branched aliphatic groups such as pivaloyl chloride gave no
did not aord the desired products. By ring closing metathesis of product. Interestingly, in the presence of Lewis acids, tandem N-
N-alkylation/-cinnamylation products 291, obtained from 3- alkylation/-acylation products 306 were obtained. Reactions
buten-1-ylMgBr and 4-penten-1-ylMgBr, using Grubbs catalyst were performed by addition of RMgBr (1.1 equiv) to a solution
(5 mol %) in toluene under MW irradiation at 115 C for 1 h, of ,-alkynyl -imino esters 304 and MgBr2 (2 equiv) in THF at
tetrahydro-1H-azepine-2-carboxylate and hexahydroazocine-2- 78 C under an atmosphere of argon, followed by addition of
carboxylate 292 were obtained in 95% yield, respectively. acyl chloride (2 equiv) and warming the obtained mixture to
Removing of the PMP group using CAN (3 equiv) in room temperature during 30 min. Aromatic acyl chlorides
CH3CN/water mixture for 30 min, in 59% yield (293), followed aorded the desired products 306 in 6386% yields, while
by iodine-induced cyclization using NIS in DCM for 1 h, aorded reaction with aliphatic acyl chlorides did not occur. However,
pyrrolizidine 294 in 67% yield (Scheme 67).124 using acyl chlorides (5 equiv) in the presence of BF3OEt2 (2
The synthesis of dihydro-3-amino-2H-pyran-2-one derivatives equiv) in toluene led to the formation of N-alkylation/-
296 and 299 was achieved by tandem N-alkylation/vinylogous acylation products 306 in the case of both aromatic and aliphatic
aldol reaction of ,-alkenyl -imino esters 295 and 298. By acyl chlorides in 1354% yields. This can be attributed to the
treatment of 295 with RMgBr (1.1 equiv) in THF at 78 C for 5 lower Lewis acidity of MgBr2 in comparison to BF3OEt2, which
min, and then at 40 C for 25 min under an atmosphere of argon, led to slow formation of acylium ions form acyl chlorides. It is
followed by addition of aldehydes (5 equiv) and heating under noteworthy that silyl substituted imino esters gave -adducts
reux conditions, dihydro-3-amino-2H-pyran-2-ones 296 were 305, exclusively in 8386% yields. The proposed reaction
obtained in 2581% yields. In addition to 296, N-alkylation mechanism involves the umpolung addition of RMgBr to -
products 297 were produced in 037% yields, as by products. imino ester (307), to in situ generate magnesium enolate 308,
Also ,-alkenyl -imino esters 298 bearing sulfenyl groups were which attacked acyl chloride at the -position under basic
subjected to the similar reaction, leading to corresponding conditions, while under Lewis acidic conditions, the enolate 308
AH DOI: 10.1021/acs.chemrev.7b00064
Scheme 69. Umpolung N-Addition/Acylation of ,-Alkynyl -Imino Estersa
a
305: R1 = XC6H4 (X = H, 3-F, 4-Cl), 2-thienyl, 1-cyclohexenyl, TIPS, TES; R2 = Me, Et, Bn; R3 = Me, Et, i-Pr, allyl, Ph, 2-furyl, 2-thienyl, OEt;
32%-quant.; R3 = t-Bu, No reaction. 306: R1 = XC6H4 (X = H, 3-F, 4-Cl), 2-thienyl, 1-cyclohexenyl; R3 = Me, Et, allyl, Ph, 2-furyl, 2-thienyl;
condition A: 086%; condition B: 1354%. 312: R1 = XC6H4 (X = H, 3-F, 4-Cl), 1-cyclohexenyl, TIPS; 3973%.
attacked to acylium ion, derived from acyl chloride with a Lewis substituted dihydroquinoxalin-2-ones 315. Reactions were
acid, at the -position through orbital control. Also, tandem N,C- carried out under argon atmosphere by stirring a solution of 4-
diethylation of ,-alkynyl -imino esters 304 was conducted by acetyl-3-oxo-3,4-dihydroquinoxalin-2-carboxylate 313 and
one-pot N-alkylation/oxidation/C-alkylation sequences. By TMSCl (3 equiv) in EtCN at 78 C for 10 min, followed by
treatment of -imino esters 304 with EtMgBr (3 equiv) in slowly addition of R1MgBr (1.5 equiv) for 30 min, then oxidation
THF at 78 C and then at room temperature for 20 min under process by treatment with NCS (2.4 equiv) at 78 C for 10 min,
an argon atmosphere, followed by subjecting with DBDMH (1.5 and then addition of R2MgBr (3 equiv) and stirring for 30 min at
equiv) at room temperature for 10 min, to give -bromo amine 78 C, leading to nal N,C-dialkylated products 315 in 40
310 through transition state 309, the iminium salt 311 was in situ 75% yields, along with deprotection of acetyl moiety. Synthetic
generated. By cooling the mixture to 78 C, addition of EtMgBr utility of the obtained products 315, owning N-homoallyl C-
(3 equiv) and then warming to room temperature during 1 h, vinyl, allyl and homoallyl substituents, for the construction of
N,C-diethyl products 312 were obtained in 3973% yields tricyclic compounds was investigated via ring closing metathesis
(Scheme 69). using HoveydaGrubbs second-generation catalyst. Reactions
Synthesis of multisubstituted dihydroquinoxalin-2-ones 314 were conducted using 4 mol % of catalyst in toluene at room
and 315 was described using an umpolung addition of 3- temperature, to furnish tricyclic products 316 in 7084% yields
(Scheme 70).127
oxoquinoxaline-2-carboxylates 313, a cyclic -imino estesr. By
treating a solution of 3-oxo-3,4-dihydroquinoxaline-2-carbox- 5.2. Organoaluminum Reagents
ylates 313 with EtMgBr (3 equiv) in EtCN at 78 C for 25 min Highly diastereoselective tandem N-alkylation-Mannich reaction
and then at room temperature for 5 min under an argon of -imino esters was reported via umpolung addition of ethyl
atmosphere, N-alkylated products 314 were obtained in 1590% aluminum reagent to -imino ester followed by oxidation to
yields, with deprotection of N-acyl groups. Reaction with t- iminium ion and then Mannich reaction with lithium enolate or
BuMgBr did not occur. N-Alkylation/oxidation/C-alkylation ketene silyl acetales. By subjecting a PMP-protected -imino
sequences were also performed for construction of multi- ester with equimolar amounts of Et2AlCl, EtAlCl2, and benzoyl
AI DOI: 10.1021/acs.chemrev.7b00064
Scheme 70. Umpolung Addition to 3-Oxoquinoxaline-2- peroxide (BPO) in DME at room temperature for 10 min,
carboxylates, a Cyclic -Imino Estesra followed by addition of lithium enolate (1.5 equiv prepared in
THF) and stirring at 78 C for 10 min, Mannich adducts 317
were obtained in 2995% yields, with excellent diastereose-
lectivity. Reaction of N-naphthyl -iminoacetate with lithium
enolate of methyl ester and reaction of N-(o-methoxyphenyl) -
iminoacetate with lithium enolate of t-Bu ester gave no
corresponding Mannich adducts. As shown in a plausible
reaction mechanism, umpolung addition of Et-Al reagents to
-imino esters generated the aluminum enolate 319, which
transformed into iminium ion 321 by oxidation with BPO,
followed by removing of benzoate group (320). The in situ
generated iminium ion 321 underwent addition with lithium
enolate to give nal Mannich adducts. Obtained excellent
diastereoselectivity was attributed to the formation of the seven-
membered transition states 322a and 322b through the chelation
of lithium ion of (E) and (Z)-enolate with ester moiety,
respectively, in which (E)-enolates aorded syn isomers 318,
wheras the (Z) counterparts led to the formation of anti isomers
318. Also, a similar reaction was applied using ketene silyl
acetales (1.8 equiv) to give Mannich adducts 318 in 2095%
yields, with excellent diastereoselectivity, similar to those lithium
enolates (Scheme 71).128
a
314: R1 = Me, Et, n-Pr, i-Pr, n-Bu, n-Hex, allylCH2, 1,3-dioxane-2- Synthesis of ,-unsaturated quaternary -amino acid
yl(CH2)2, Ph; Y = Boc, Bz, Ac, Cbz, Ts, CONMe2; 1590%; 315: R1 derivatives was developed through umpolung addition and
= Et, n-Pr, allylCH2, R2 = Me, Et, n-Pr, i-Pr, 1,3-dioxane-2-yl(CH2)2, Claisen rearrangement of allyl -imino esters. Reacting allyl 2-(4-
vinyl, allyl, allylCH2; 4075%; 316: n = 0, 1, 2; 7084%. methoxyphenylimino)acetates with equimolar amounts of
Et2AlCl and EtAlCl2 in DME at 40 C for 624 h resulted in
the formation of quaternary -amino acid, which converted to
Scheme 71. Umpolung N-Alkylation-Mannich Reaction of -Imino Estersa
a
317: R1 = XC6H4 (X = H, 4-Cl, 2-MeO, 3-MeO, 4-MeO), 1-naphthyl, c-Hex; R2 = H, Me; R3 = Me, Et, i-Pr, t-Bu; 2992%. 318: R1 = XC6H4 (X =
H, 4-Cl, 3-MeO, 4-MeO), c-Hex; R2 = H, R3 = Me or R2 = Me, R3 = H; M = Li, 8495%, M = TMS, TBS, 2095%; (E)-enolate syn/anti = > 99/
1; (Z)-enolate syn/anti = < 1/99.
AJ DOI: 10.1021/acs.chemrev.7b00064
Scheme 72. Umpolung Addition/Claisen Rearrangement of Allyl -Imino Estersa
a
323: R = c-Hex, XC6H4 (X = H, 3-F, 4-F, 4-Cl, 3-MeO), 2-thienyl; 3079%. 324: R1 = Me, R2 = H, 62%, E/Z = 59/41; R1 = H, R2 = Me, 73%.
Scheme 73. Synthesis of Indolin-3-one by Umpolung the corresponding methyl esters 323 by treatment with CH2N2
Additiona in Et2O at 0 C for 10 min, in 3079% overall yields. In the case
of strongly electron-donating substituted 2-aryl iminoacetate,
allyl 2-(4-methoxyphenyl)-2-((4-methoxyphenyl)imino)acetate,
the reaction gave no product, in which hydrolyzed N-ethyl-4-
methoxybenzenamine is obtained as a byproduct. However, in
the case of 2-thienyl substituted -imino ester, the Claisen
rearrangement product is generated in 30% yield, along with the
corresponding N-ethylated adduct as a byproduct. Also, the
bulky t-Bu derivative gave no adduct. Moreover, substituted allyl
moieties were studied, in which methallyl and 2-butenyl esters
aorded desired products 324 in 73% and 63% yields,
respectively, while reaction with crotyl -imino ester did not
give the Claisen rearrangement product, and only N-ethylated
product was obtained in 26% yield. The proposed reaction
mechanism involves the umpolung ethylation of -imino esters,
activated by coordination to EtAlCl2 as a strong Lewis acid 325,
with Et2AlCl, to generate aluminum enolate 326, which
underwent Claisen rearrangement, followed by methylation
with CH2N2. The diastereoselectivity of the reaction of 2-butenyl
ester was determined as E/Z = 59/41 that can be attributed to the
formation of two enolates 326. The (Z)-enolate proceeded via a
six-membered chairlike transition state with Me in a quasi-
equatorial position 327a, to aord the (E)-alkene 324, while the
(E)-counterpart led to conformation 327b, with a quasi-axial Me
substituent, resulting in the formation of (Z)-alkene 324
a
329: R = 4-XC6H4 (X = H, Cl, MeO), 2-thienyl, (E)-PhCHCH, (Scheme 72).129
PhCC, CO2Et; Y = OMe, OPh, SEt, Sp-tolyl; 1867%. 331: Ar = 4- Indolin-3-one derivatives 329 were synthesized by umpolung
XC6H4 (X = H, Cl, Me, MeO); 5776%. addition of (TMS)2AlCl to N-(2-alkoxycarbonylphenyl)--
imino esters 328, followed by desilylation. Reactions were
carried out by addition of (TMS)2AlClOEt2 (1.3 equiv) to a
AK DOI: 10.1021/acs.chemrev.7b00064
solution of -imino ester 328 in EtCN at 20 C under an argon Scheme 74. Triuoromethylation of -Imino Ketonesa
atmosphere and stirring at room temperature for 2 h, with
subsequent quenching the reaction using saturated KF solution
in water, to give indolin-3-ones 329 in 1867% yields. In the
proposed reaction mechanism, intermediate 330a was generated
by addition of (TMS)2AlCl to the nitrogen of -imino ester,
which was tautomerized to aluminum enolate 330b. However,
the intermediate 330a could also be generated by addition of
TMS to carbon of imine moiety, followed by 1,2-aza-Brook
rearrangement. Aluminum enolate 330b underwent Dieckmann
condensation to produce indolin-3-ones 329. A similar approach
was developed for the synthesis of indolin-3-one imines 331 by
umpolung ethylation/cyclization/acetylation sequences. Traet-
ment of N-(2-cyanophenyl)--imino esters 328b with Et2AlCl (3
equiv) and EtAlCl2 (1 equiv) in EtCN at room temperature for 2
h, followed by subjecting with Ac2O (4 equiv) in the presence of
DMAP (1 equiv) and Et3N (4 equiv) at room temperature for 1.5
h, furnished indolin-3-one imines 331 in 5776% yields
(Scheme 73).130
5.3. Discussion, Synthetic Utility, and the Future
Due to the adjacent ester functionality with electron withdrawing
nature, polarity inversion at the imine bond of -imino esters
occurs and umpolung additions are exhibited, in which the
nitrogen of imine is attacked by a limited number of
organometallic compounds, including Grignard reagents and
organoaluminums under specic conditions. The addition of
Grignard reagents in the presence of ZnCl2 or other Lewis acid
catalysts mostly takes place at the carbon of imine moiety, while
-imino esters underwent umpolung addition with Grignard
reagents, in the absence of any Lewis acid, in most cases. The
umpolung addition to -imino esters is of interest because of
formation of N-alkyl substituted -amino acid derivatives. By a
333: R = i-Pr, t-Bu; Ar = 4-XC6H4 (X = H, 4-CF3, 4-MeO, 4-NO2),
umpolung/C-alkylation sequences of -imino esters, the syn- 7-Et-benzofuran-2-yl; 6990%; R* = (S)-PhCH(Me), Ar = 4-XC6H4
thesis of N,C-dialkyl -amino acids was achieved. However, the (X = H, 4-MeO); 7578%, 6/4 dr.131 R = i-Pr, t-Bu; Ar = 4-XC6H4 (X
umpolung addition of Grignard reagents to -imino esters was = H, 4-MeO, 4-NO2), benzofuran-2-yl, 7-Et-benzofuran-2-yl; 7594%,
extensively studied, in which the synthesis of various N-alkyl 3071% ee.132 336: R = t-Bu, c-Hex; Ar = 4-XC6H4 (X = H, 4-Br, 4-
CF3, 4-MeO, 4-NO2), 3,4-(MeO)2C6H3, 3,4-(OCH2O)C6H3; 30
substituted -amino acids and also a variety of types of
65%.135
heterocyclic compounds, such as piperidine, azepane, azocane,
pyrrolizidine, and other 6, 7, and 8-membered N-bridged fused
Scheme 75. Triuoromethylation of (1R)-Camphorquinone
heterocycles, and pyran-2-one derivatives was reported, the
3-Iminesa
umpolung/C-alkylation/intramolecular cyclization sequences to
give new N-heterocycles, is of interest for future works. Also,
umpolung addition of organoaluminum reagents to -imino
esters followed by oxidation and then Mannich reaction or
intramolecular acylation was studied, aording aspartate or
indolin-3-one scaolds, respectively. Actually, by umpolung
addition/oxidation, a new -carboxy iminium was generated,
which could undergo many types of reactions and could be a
research subject of synthetic and medicinal chemists.
6. TRIFLUOROMETHYLATION
Mloston et al.131 described the regioselective triuoromethyla-
tion of -imino ketones, derived from arylglyoxals, by subjecting
-imino ketones with (triuoromethyl)trimethylsilane
(CF3SiMe3, 1.1 equiv) in the presence of a catalytic amount of
CsF in anhydrous DME at room temperature to yield O-silylated
-imino alcohols 332, which were transformed into -amino--
triuoromethyl alcohols 333 by reduction with NaBH4 (6 equiv)
in EtOH at room temperature for 12 h along with desilylation, in a
6990% yields, for two steps. The triuoromethylation of - 340: R = Me, Et, i-Pr, t-Bu, c-Hex, (R)-PhCH(Me), Ph, PMP; 65
imino ketones, bearing a chiral auxiliary moiety, was also studied, 88%; 341: R = Me, Ph; 7376%.
in which -amino alcohols 333 were obtained in 7578% yields,
AL DOI: 10.1021/acs.chemrev.7b00064
Scheme 76. Chemoselective Addition of CF3SiMe3 to the desilylation along with reduction of imine moiety to aord amino
Imine Bond of N-(tert-Butyl)-aiminoketonesa alcohol 341 in 7376% yields (Scheme 75).136
Chemoselective addition of CF3SiMe3 to the imine group of
N-(tert-butyl)-aiminoketones, derived from arylglyoxals was
achieved under acidic conditions. By treatment of potassium
hydrogenuoride (KHF2; 2.5 equiv) with -imino ketones in the
presence of DMF in dry MeCN under an atmosphere of argon,
followed by addition of TFA (3.75 equiv) at 10 C for 5 min,
and then addition of CF3SiMe3 (2.5 equiv), and storing the
mixture at 15 C for 30 days, 1-aryl-2-(tert-butylamino)-3,3,3-
triuoropropan-1-ones 342 were obtained in 1970% yields,
a
along with the formation of CO triuoromethylated
Ar = 4-XC6H4 (X = H, 4-Br, 4-MeO), 3,4-(MeO)2C6H3, 3,4- compounds as minor byproducts. The preferred triuoromethy-
(OCH2O)C6H3, 7-Et-benzofuran-2-yl; 342: 1970%; 343: 6884%, lation of the CN bond is attributed to the higher reactivity of
threo/erythro = 90/1096/4. the iminium salts, in situ generated by protonation of the
nitrogen atom of imine under acidic conditions, rather than the
CO moiety. In the case of -imino ketones bearing electron-
with 6/4 dr. Obijalska et al.132 reported the enantioselective withdrawing substituted aryls, such as 4-NO2 and 4-CF3 groups,
addition of CF3SiMe3 (1.4 equiv) to -imino ketone in the the corresponding products were obtained in low yields, which
presence of chiral catalyst CD-(8S,9R)-L26 (15 mol %) and were not isolated in pure form. However, the addition to CO
K2CO3 (15 mol %) in toluene at 40 C for 5 h, to give O- aorded the major products. Reduction of obtained -
silylated -imino alcohols 332, which were subjected to (triuoromethyl)--amino ketones 342 using LiAlH4 (2 equiv)
reduction with NaBH4 as above, without further purication in in dry THF at 10 C and then room temperature for 12 h,
7594% yields, with 3071% ee. Other chiral catalysts were aorded 1-aryl-2-(tert-butylamino)-3,3,3-triuoropropan-1-ols
investigated in the presence of a variety of additives, and CD- 343 in 6884% yields, with 90/1096/4 dr (Scheme 76).137
(8S,9R)-L26 (15 mol %) in the presence of K2CO3 was selected As mentioned above only triuoromethylation of -imino
as the optimum condition due to the high enantioselectivity ketones was studied, in which addition took place at the ketone
(Scheme 74, a). By desilylation of O-silylated -imino alcohols moiety to give -imino alcohols, which were transformed into -
using TBAF (1.5 equiv) in THF at 0 C for 3 h, followed by amino alcohols and many types of heterocyclic compounds via
oxidation using m-CPBA (1.1 equiv) in DCM in an ice bath for 2 further reactions. Therefore, opening the triuoromethylation of
h, oxaziridines 334 were obtained in 6883% yields and >9/1 dr -imino esters is deeply felt. Also enantioselective triuorome-
(Scheme 74, b).133 The synthesis of a number of three-, ve-, and thylation of -imino esters and ketones using chiral catalysts is of
six-membered heterocycles were also developed starting from interest.
obtained -amino alcohols.134 Also, Obijalska et al.135 described
diuoromethylation of -imino ketones of arylglyoxals, by 7. ACYLATION
stirring a solution of -imino ketones and CF2HSiMe3 (2
equiv) under argon atmosphere either in the presence of a Takemoto et al.138 have reported N-heterocyclic carbene
catalytic amount of CsF in anhydrous DMF at room temperature (NHC)-catalyzed acylation of -imino esers, to synthesize -
for 24 h or in the presence of t-BuOK (2 equiv) in anhydrous amino--keto esters. Reactions were carried out by stirring a
THF at 78 C for 4 h. Reduction of obtained (diuoromethyl)-
imino alcohols 335 with NaBH4 in EtOH at room temperature Scheme 77. NHC-Catalyzed Acylation of -Imino Esersa
for 12 h aorded -(diuoromethyl)--amino alcohols 336 in
3065% yields, for two steps (Scheme 74, c). Only in the case of
t-Bu and c-hexyl substituted -imino ketones, the desired
products were obtained, while reactions with imino ketones,
possessing i-pr, 1-phenylethyl, or methoxy substituents, did not
occurr. However, triuoromethylation of these substrates with
CF3SiMe3 aorded the higher yields of the products that can be
attributed to the more reactivity of CF3SiMe3 than CF2HSiMe3
toward electrophiles.
Stereoselective triuoromethylation of (1R)-camphorquinone
3-imines 337 was reported by addition of CF3SiMe3 (1.1 equiv)
to a solution of imine 337 and a catalytic amount of CsF in
anhydrous DME at room temperature for 1 h, followed by
hydrolysis using a 5 M solution of HCl in EtOH under reux
conditions for 15 h, giving (1R,2S)-2-hydroxy-2-
(triuoromethyl)bornan-3-one 339 in 7585% yields, via
desilylation along with hydrolysis of imine moiety of 338.
Selective desilylation was conducted using NaBH4 (5 equiv) in
EtOH or MeOH in an ice bath, followed by reuxing for 18 h, to
furnish imino alcohols 340 in 6588% yields. Heating of TMS- a
R = Me, Ph(CH2)2, BnOCH2, BocNHCH2, XC6H4 (X = 2-Cl, 3-Cl,
protected imino alcohols 338 with diisobutyl aluminum hydride 4-Cl, 4-Me, 4-MeO, 4-NO2, 4-CN, 4-CO2Me), 2-furyl, 3-thienyl; 39
(DIBAL-H, 2.5 equiv) in reuxing THF for 30 min led to 73%.
AM DOI: 10.1021/acs.chemrev.7b00064
solution of an aldehyde with 1.1 equiv of -imino ester in the Scheme 79. Addition of Alcohols, Amines, and Thiols to -
presence of NHC precatalyst 345a (20 mol %) and K2CO3 (20 Imino Estersa
mol %) in THF at room temperature for 24 h. Various
substituted aromatic aldehydes worked well in the reaction,
aording corresponding acylated products 344 in 3973%
yields. Reaction with aliphatic aldehydes also proceeded well, to
give the desired products 344 in 5262% yields. Aldehyde
possessing -alkyl substitution did not furnish the product. A
plausible reaction mechanism involves the in situ formation of
carbene catalyst 345b by deprotonation of triazolium salt 345a in
the presence of K2CO3, which attacked the aldehyde to generate
Breslow intermediate 346. By reaction of intermediate 346 with
-imino ester, tetrahedral intermediate 347 was generated, which
converted to the nal desired product through intermediate 348
by intramolecular proton transfer, followed by releasing the
carben 345b for further catalytic cycles (Scheme 77).
8. ADDITION OF NITROGEN, OXYGEN, AND SULFUR

NUCLEOPHILES
Synthesis of -amido -amino ester derivatives was reported by
Zeng et al.139 By subjecting -imino ester with an amide (1.5
Scheme 78. Amidation of -Imino Estersa
a
353: Ar = 4-XC6H4 (X = F, Me); 9697%. 354: R = CH2, (CH2)2, o-
benzo; 9295%. 356: R = Me, Et; Ar = Ph, 4-tolyl; 98%. 357: R =
HO2CCH2, MeO2CCH2, 4-ClC6H4; Ar = Ph, 4-tolyl; 8190%. 358a:
Ar1 = 2-pyridyl, pyrazin-2-yl; Ar = 4-tolyl; 7582%. 358b: Ar = Ph, 4-
a 1
R = i-Pr, c-Hex, XC6H4 (X = H, 4-Cl, 4-Br, 4-Me, 4-MeO, 4-NO2, 3- tolyl; 7880%.
CO2Et); R2 = Me, 4-XC6H4 (X = H, Cl, Me, MeO, NO2), 1-naphthyl,
2-pyridyl, 2-thienyl, 2-furyl, OBn, acryloyl; 3198%.
Unprotected -imino triuoropyruvates were reacted with
MeOH by stirring a solution of -imino ester in anhydrous
MeOH at room temperature for 10 h, to aord MeO-addition
equiv) in the presence of Cu(OTf)2 (20 mol %) and PPh3 (20 product 352 in 99% yield. By subjecting -imino ester with an
mol %) in toluene at 25 C under argon atmosphere for 636 h, equivalent amount of thiophenols in Et2O at room temperature
amidation products 349 were obtained in 3198% yields. for 10 h, thiolated products 353 were obtained in 9697% yields.
Reaction with Brnsted acid aorded the desired product in low Treatment of -imino ester with thiols bearing carboxylic acid
yield, and no product was obtained in the absence of Cu(II) salts. functional group, thioglycolic, 3-mercapto propionic, or 2-
Various ligands and Cu(II) salts were studied, from which mercaptobenzoic acid, in Et2O or THF at room temperature for
Cu(OTf)2 in the presence of PPh3 was selected for the best 8 h, gave thiazolidone, thiazinanone, or benzothiazine 354, in
results. Reactions with dierent substituted N-aryl -imino esters 92%, 92%, and 95% yields, respectively. Reactions proceeded by
proceeded well, and the amidation products 349 were obtained nucleophilic addition of thiols to imine moiety, followed by
in high yields. On the contrary, signicant substituent eect was intramolecular lactam formation. Benzoxazine 355 was obtained
observed for the benzamide derivatives, as electron donation in 60% yield, by subjecting -imino ester with salicylaldehyde at
substituted benzamide, 4-MeOC6H4CONH2, aorded the room temperature for 10 h, followed by addition of benzene and
related product 349 in 80% yield, while addition of electron- TsOHH2O (4 mol %) and reuxing for 2 h. [3 + 2]
with d rawin g substit uted ben zam id es, such a s 4- cycloaddition of -imino triuoropyruvates with nitrile oxide, in
NO2C6H4CONH2, led to amidation product in 31% yield. situ generated from 4-chloro-N-hydroxybenzenecarboximidoyl
Cu(II)-catalyzed one-pot cascade intramolecular amidation/ chloride and Et3N in Et2O at 30 C and then room temperature
dehydrogenation of N-(2-aminophenyl) protected -imino ester for 3 h, was also investigated, leading to the corresponding
350 was investigated to give N-protected benzimidazole-2- dihydro-1,2,4-oxadiazole in 90% yields (Scheme 79, a). Used -
carboxylate 351 in 87% yield (Scheme 78). imino triuoropyruvates were prepared in 80% yield, by aza-
AN DOI: 10.1021/acs.chemrev.7b00064
Scheme 80. FriedelCrafts Reaction of Indoles with -Imino Esters, Derived from Ethyl Glyoxalatea
a
Cond. = L2710H2O (1030 mol %), toluene, 60 C to 80 C, 2148 h; R = H, 5-Br, 6-Br, 5-Me, 5-MeO, 5-CO2Me; 1399%, 1488% ee.143
Cond. = (S)-L17 (10 mol %), 5 MS, toluene, 50 C, 1.5 h; R = H, 5-F, 5-Br, 6-Br, 5-Me, 5-MeO, 6-OBn; 8593%, 5787% ee.144 Cond. = L28
(10 mol %), ZnEt2 (20 mol %), THF, rt, 12 h; R = H, 4-F, 5-F, 6-F, 4-Cl, 5-Cl, 6-Cl, 4-Br, 5-Br, 6-Br, 2-Me, 5-Me, 6-Me, 7-Me, 4-Ph, 4-MeO, 5-
MeO, 4-OBoc, 4-OAc, 6-CO2Me, 5-NO2; 4188%, 12 to >99% ee.145
Wittig reaction of triuoropyruvates with Ph3PNH in L27. Treatment of -imino ester with indole (1.5 equiv) in the
anhydrous Et2O at 0 C and then at room temperature.140,141 presence of 10 mol % of L2710H2O in toluene at 60 C
Also, the addition of alcohols, amines, and thiols to N-benzoyl - furnished -(3-indolyl) -amino ester derivatives 359 in 13
imino esters, derived from trichloropyruvates, was described by 99% yields, with 1488% ee (Scheme 80). It is noteworthy that
the same research group. Treatment of -imino ester with the inclusion of water in the chiral acid complex L27 plays an
alcohols, MeOH, or EtOH, at room temperature overnight, important role in the enantioselectivity, as using acid catalyst
aorded corresponding addition products 356 in 98% yields. L27nH2O in the presence of a water adsorbent (4 MS) led to a
Reactions with thiols were performed in Et2O at room poor enantioselectivity (1%).143 Similar methodology was
temperature for 2 h to overnight, leading to corresponding developed by You et al.144 using chiral Lewis acid (S)-L17 (10
thiolated products 357 in 8190% yields. The addition of mol %) in the presence of 5 MS in toluene at 50 C.
amines, such as imidazole, 2-aminopyridine, 2-aminopyrazine, Reactions performed using 2 equiv of indole under an
and morpholine, was conducted in Et2O at room temperature, atmosphere of argon to give (3-indolyl)glycine derivatives 359
overnight to give products 358 in 7580% yields (Scheme 79, in 8593% yields, with 5787% ee. Also, three-component
b).142 FriedelCrafts reaction of indole, alkyl glyoxalate, and anilines
Examples of the addition of N, O, and S nucleophiles to - was investigated using (S)-L17, in which FriedelCrafts
imino esters are rare, and corresponding addition products could products 359 were obtained in 8592% yields, with 3473%
be utilized in the heterocycles synthesis. ee. In another work, Trosts dinuclear complex 360 was reported
for asymmetric FriedelCrafts reaction of indole with N-PMP
9. FRIEDELCRAFTS REACTIONS protected -iminoacetate to aord 3-indolylglycine derivatives.
Reactions were conducted using 10 mol % of L28 in the presence
9.1. FriedelCrafts Reactions of Indoles of 20 mol % of Et2Zn in THF at room temperature for 12 h,
Enantioselective aza-FriedelCrafts reaction of indoles with - giving 3-indolylglycines 359 in 4188% yields, with 12 to >99%
imino esters was reported using the chiral Brnsted acid catalyst ee. In the proposed reaction mechanism, indole was coordinated
AO DOI: 10.1021/acs.chemrev.7b00064
Scheme 81. FriedelCrafts Reaction of Indoles with -Imino Scheme 82. FriedelCrafts Reaction of Indoles with Sulnyl
Esters, Derived from Arylglyoxalate and Triuoropyruvatea -Imino Estera
a
364: R1 = H, 6-Cl, 6-Br, 6-Me, 7-Me, 5-MeO; R2 = H, Me; R3 = H,
Me; Ar = XC6H4 (X = H, 4-Br, 4-Me, 3-MeO, 4-MeO); X = Boc, Cbz;
5899%, 1199% ee. 365: R1 = 5-F, 6-F, 5-Cl, 6-Cl, 5-Br, 5-Me, 7-Me,
5-MeO, 5-CO2Me; R3 = H, Me; 2299%, 54/4698/2 er.
to the zinc atom by deprotonation and release of an ethane

molecule (intermediate 361), followed by activation of imine
moiety by chelation with another zinc atom to generate
intermediate 362, in which indole attacked preferentially to si-
face of the imine moiety to give intermediate 363. By proton
transfer between intermediate 363 and the incoming indole, the
desired product 359 was obtained by regeneration of
a 1
intermediate 361, for further catalytic cycles (Scheme 80).145 R = H, Me; R2 = H, Me, Ph, 2-BrC6H4, PhCC; R3 = H, 5-F, 6-
Liu et al.146 developed a catalyst and solvent-free method for the F, 5-Cl, 4-Br, 5-Br, 5-Me, 5-MeO; 7690%, 9598% de.
three-component FriedelCrafts reaction of indoles with -
imino esters, in situ generated from ethyl glyoxalate and aniline 798/2 er. As mentioned above, N-Me-indole led to low yield
derivatives, in good to high yields. A similar approach was (22%) with poor enantioselectivity (54/46 er; Scheme 81, b).150
developed by Jiang and Huang147 using MgSO4 in toluene at Cu(OTf)2-catalyzed highly diastereoselective FriedelCrafts
room temperature, leading to 3-indolylglycine derivatives in 26 reaction of indoles with a chiral N-tert-butanesulnylimino ester
to >99% yields. Moreover, Ghandi and Taheri148 reported the was reported for the preparation of 3-indolyl glycinates 366.
similar three-component reaction in water without using any Treatment of indoles with N-tert-butanesulnylimino ester in the
catalyst. presence of 10 mol % of Cu(OTf)2 in dry DCM at room
Hu et al.149 developed a chiral Lewis acidcatalyzed temperature for 2030 min, aorded desired products 366 in
enantioselective FriedelCrafts reaction of indoles with - 7690% yields, with 9598% de. Reactions proceeded via
imino esters, derived from arylglyoxalates. Reactions were carried transition state 367, in which Cu2+ was chelated with nitrogen of
out in toluene using 5 mol % of chiral phosphoric acid L29 in the imine and oxygen of ester moieties, leading to the addition of
presence of 4 MS at 5 C for 24 h, to aord quaternary - indole from si-face of the imine due to the steric repulsion of tert-
amino esters 364 in 8899% yields, with 8199% ee. butyl group on re-face of the imine (Scheme 82, a).151 Hiemstra
Substitution at the indole 2-position did not signicantly aect et al.152 reported the FriedelCrafts reaction of N-sulfenyl -
the yield and ee of the product. When, N-Me-indole was used, the imino esters with indole (1.1 equiv) in the presence of chiral
corresponding product was obtained only in low yield (58%), phosphoric acid (R)-L29 or (R)-L31 (2 mol %) and MS in
and ee (11%), indicating the critical role of the free NH of benzene or DCM at room temperature, to give indolyl glycinates
indole in interaction with phosphoric acid (Scheme 81, a). The 368 in 8797% yields, with 7988% ee (Scheme 82, b).
stereochemistry of the major enantiomers were determined as Synthesis of (3-indolyl)glycine derivatives 369 was achieved in
(R) by X-ray crystallography. The similar methodology was used 5485% yields, by three component reaction of equimolar
for arylation of N-Boc protected triuoropyruvate imine via amounts of indole, ethyl glyoxalate, and substituted anilines in
FriedelCrafts reaction, catalyzed with chiral phosphoric acid the presence of MS in DCM at ambient temperature for 624 h.
L30 (6 mol %) in toluene at 78 C for 3 h, giving -indolyl-- When the reactions were conducted in the presence of Sc(OTf)3
triuoromethyl--amino esters 365 in 6599% yields, with 93/ at 50 C, a mixture of products 369, 370 and 374 with majority
AP DOI: 10.1021/acs.chemrev.7b00064
Scheme 83. Three Component FriedelCrafts Reaction of Indole, Ethyl Glyoxalate, and Anilinesa
R = H, OMe; R2 = H, Cl, OMe; R3 = H, OMe; 369: 3598%; In the presence of Sc(OTf)3: 50 C, 3598%, 369/374/370: 95/2/3100/0/0.
a 1
Room temperature: 7595%, 369/374/370: 35/65/00/0/100; 369/375/371: 0/0/100.
Scheme 84. FriedelCrafts Reaction of Indoles with a Cyclic Scheme 85. FriedelCrafts Alkylation of Indoles with Cyclic
-Imino Estera -Imino Esters 81a
a 1
R = H, F, Cl, Me, CF3, MeO; R2 = H, 6-Cl, 5-Br, 2-Me, 7-Me, 4-
MeO, 5-MeO; R3 = H, Me, allyl, Bn; 6798%, 83 to >99% ee.
by coordination to Sc(III) (372) underwent elimination of

aniline to generate ethyl 2-(3H-indol-3-ylidene)acetate 373,
which was transformed into compounds 374 via nucleophilic
addition of aniline moiety of another molecule of (3-indolyl)-
glycine 369 through the para position. However, in the case of
a
R = H, 5-Br, 6-Br, 5-Me, 6-Me, 7-Me, 5-MeO, 6-MeO; 8299%, 94 2,4-dimethoxyaniline derivative, addition occurred at the 5-
to >99% ee. position, activated by two MeO groups (375). By Sc(III)-
induced eliminating amine moiety, the nal products 370 or 371
of (3-indolyl)glycines 369 were obtained. Subjecting (3- were obtained along with regeneration of ethyl 2-(3H-indol-3-
indolyl)glycines 369 with Sc(OTf)3 at room temperature ylidene)acetate 373 (Scheme 83).153
aorded the rearrangement products 370; however, three- Maruoka el al.154 reported a highly enantioselective addition of
component reaction under this conditions was also provided indoles to a cyclic -imino ester 376 via FriedelCrafts reaction
compounds 370 as the major products. In the case of para using chiral phosphoric acid (S)-L32 as catalyst. Various chiral
substituted anilines, compounds 371 were obtained. In the binol derivatives were investigated as Lewis acid catalyst, from
suggested reaction mechanism, (3-indolyl)glycine 369 activated which (S)-L32 was selected for the best obtained ee. Reactions
AQ DOI: 10.1021/acs.chemrev.7b00064
Scheme 86. FriedelCrafts Alkylation of 3-Substituted Scheme 89. FriedelCrafts Alkylation of Electron-Rich
Indoles with ,-Unsaturated -Imino Esters 381a Arenes with N-tert-Butansulfonyl -Imino Estera
a 1
R = H, 4-Me, 5-Me, 6-Me, 7-Me, 4-BnO, 5-BnO, 6-BnO; R2 = Me,
a
Et, NHBoc; Ar = XC6H4 (X = H, 3-Cl, 4-Cl, 3-Br, 4-Br, 2-Me, 4-Me, 4- Ar = 4-MeC6 H4 , 2,4-(MeO) 2 C6 H3 , 3,4-(MeO) 2 C6 H3, 2,3,4-
i-Pr, 4-CF3, 3-MeO, 4-MeO, 3-NO2, 4-NO2), 2-F-5-BrC6H3, 1- (MeO)3C6H2, 2-Cl-4,6-(MeO)2C6H2, 2-MeO-1-naphthyl, 4-MeO-1-
naphthyl, 2-thienyl, 2-furyl; 3093%, 92 > 99% ee. naphthyl, 4-MeSC6H4, 2,4-(MeS)2C6H3; 6089%, 6896% ee.
Scheme 87. FriedelCrafts Reaction between Phenols and Scheme 90. FriedelCrafts Reaction of Anilines with -
Enantiopure -Imino Glyoxylatea Hydrazono Estersa
a 1
R = 3,4-(CHCHCHCH), 5,6-(CHCHCHCH), 4-
MeO-5,6-(CHCHCHCH), 3,5-(MeO)2, 4,5-(CH2OCH2), 5-
NH2; R2 = Me, CH2OH; 5879%, 77/3393/7 dr.
Scheme 88. In(OTf)3-Catalyzed FriedelCrafts Reaction of

Electron-Rich Arenes with (R)-N-tert-Butanesulnylimino R = H, 3-Me, 3-OMe, 3-SMe; R2 = R3 = Me, Et; R2R3 = (CH2)4;
a 1
Estera R2 = Me, R1R3 = 2-(CH2)3, 2-(CH2)4; 5492%, 8795% ee.
were performed using 1.2 equiv of indole in the presence of 5 mol

% of (S)-L32 in toluene at 78 C for 328 h, giving
corresponding indolyl glycinates 377 in 8299% yields, with 94
to >99% ee. The absolute conguration of the major enantiomer
was determined as (R) using single crystal X-ray crystallography.
One example of the addition of pyrrole to the cyclic -imino ester
was also studied, leading to related pyrrolyl glycinate derivative in
99% yield, with 75% ee. In the suggested model for the transition
state of the addition, both indole and -imino ester were
activated by hydrogen bonding with chiral phosphoric acid (S)-
L32, in which indole was oriented in such a way as to approach
the -imino ester through the si-face (transition state 378). In the
case of N-Me-indole, the corresponding FriedelCrafts adduct
was obtained only in trace amount, indicating the critical role of
the NH of indole in the H bond with chiral phosphoric acid to
formation of product (Scheme 84). Camphorsulfonic acid-
catalyzed similar FriedelCrafts reaction of indoles with cyclic -
a
Ar = 2,4-(MeO)2C6H3, 2,3,4-, 2,4,5-, 2,4,6-(MeO)3C6H2, 3-Me-2,4- imino ester was also reported in THF at room temperature for
(MeO)2C6H2, 2-Me-4,6-(MeO)2C6H2, 2-Cl-4,6-(MeO)2C6H2, 2-OH- 848 h, in 5098% yields.155
3,4-(OCH2O)C6H2, 6-Me-2,3,4-(MeO)3C6H, 2-OH-, 4-OH-, 2-MeO-, Synthesis of chiral indolyl cyclic -amino esters 379 bearing
4-MeO-, 2,4-(MeO)2-1-naphthyl; 6091%, 70 to >99% dr. tetrasubstituted -stereogenic center was developed by an
AR DOI: 10.1021/acs.chemrev.7b00064
Scheme 91. FriedelCrafts Alkylation of Heteroarenes with FriedelCrafts reaction under similar reaction conditions, to give
-Imino Estersa corresponding pyrrolyl and 4-(N,N-dimethylamino)phenyl
substituted cyclic -amino esters in 90% (98% ee) and 62%
(81% ee) yields, respectively. Proposed asymmetric induction
model 380 is depicted in Scheme 85, in which -imino ester 81,
activated as electrophilic species by coordination to chiral Cu(II)
complex through N and O atoms, underwent nucleophilic
addition with indole through the re-face to form (R)-enantiomer
379 as the major product.156
Hu et al.157 developed a chiral phosphoric acid L29 catalyzed
enantioselective FriedelCrafts alkylation of 3-substituted
indoles at C2 with ,-unsaturated -imino esters 381. Reactions
were carried out with 3 equiv of indoles in the presence of chiral
L29 (10 mol %) in toluene/DCM at room temperature for 72 h,
resulting in FriedelCrafts adducts 382 in 3087% yields, with
92 to >99% ee. Various -aryl substituted ,-unsaturated -
imino esters 381 and unsubstituted and electron-donating
substituted 3-alkyl indoles worked well in the reaction, while 5-
Cl-3-Me-indole aorded the corresponding product in low yield
(<10%). When 3-unsubstittued indole was subjected with 381,
corresponding C3 FriedelCrafts alkylation adduct was obtained
in 90% yields, as a racemic mixture (0% ee; Scheme 86).
a
391: R = H, Me, OMe; 6891%. 392: X = O, NH, S; 4092%. 394: 9.2. FriedelCrafts Reactions of Phenols, Anisoles, and
R1 = H, Me, Et, Ph, Ph(Et)CH, Ph, Bn, 4-MeOBn, 2,4-Cl2Bn; R2 = H, Anilines
Me, MeO, EtO, n-decyl; 1095%. Enantiopure substituted phenol or naphthol glycinates 383 were
synthesized in 5879% yields, with 77/3393/7 dr, from
Scheme 92. BF3OEt2-Catalyzed Intramolecular Friedel FriedelCrafts reaction between phenols or naphthols with
Crafts Reaction of 2-(N-Arylcarbamoyl)-2-iminoacetatesa enantiopure -imino glyoxylate in the absence of any acid
catalyst. Reactions were carried out by stirring a solution of
equimolar amounts of ethyl glyoxalate and a chiral secondary
amine in the presence of Na2SO4 in toluene for 2 h, to generate -
imino ester, followed by addition of an equimolar amount of a
phenol derivative and stirring at 15 C for 310 h. No product
was obtained in reaction with 2-methoxynaphthalene, indicating
the critical role of OH to promote a cyclic transition state 384, in
which the addition to imine moiety was achieved from the si-face.
2-Naphthylthiol was also studied in the similar reaction, which
gave the corresponding product in 73% yield, 84/16 dr (Scheme
87).158
In(OTf)3-catalyzed diastereoselective FriedelCrafts reaction
of electron-rich arenes with (R)-N-tert-butanesulnylimino ester
was developed by Xu et al.159 Traetment of glyoxalate imine with
1.5 equiv of arenes in the presence of In(OTf)3 (30 mol %) in dry
DCM at room temperature for 0.58 h, aorded -arylglycinates
a 1 385 in 6091% yields, with 70 to >99% dr. By increasing the
R = H, 5-F, 5-Cl, 5-Br, 5-I, 5-Me, 7- Me, 5-MeO, 7-MeO, 4,6-Me2,
4,7-Me2, 6,7-(CH)4; R2 = Me, Ph, Bn; R1R2 = 7-(CH2)2; 7392%;
amount of In(OTf)3 to 1 equiv dialkylation product 386 was
R1 = 4- or 6-Cl, 4- or 6-Br, 4- or 6-Me; R2 = Bn; 7292%, 4-/6- = 61/ obtained in 43% yield, when 1,3-dimethoxybenzene was reacted
3971/29. with (R)-N-tert-butanesulnylimino ester. The stereochemistry
outcome of the reaction was attributed to the formation of ve-
membered transition state 387, in which the arene addition
enantioselective FriedelCrafts alkylation of indoles with cyclic occurred through re-face of the imine (Scheme 88). In addition,
-imino esters 81 in 6797% yields, with 83 to >99% ee. 2-methylfuran and 2-methylthiophene are investigated under the
Reactions were conducted using equimolar amounts of indole reaction conditions; leading to the corresponding FriedelCrafts
and -imino esters 80 in the presence of Cu(OTf)2 (10 mol %) alkylated products at C-5 in 90% (90% ee) and 74% (79% ee)
and chiral bisoxazoline ligand L33 (12 mol %) in DCM at room yields, respectively.
temperature for 12 h. Dierent salts of Cu(II) in the presence of a Enders et al.160 have reported an enantioselective synthesis of
variety of types of chiral bisoxazolines were investigated that L33 arylglycines 388 via FriedelCrafts alkylation of electron-rich
aorded the desired products 379 in high yields and excellent arenes with glyoxylate imine. A number of chiral binol-derived
enantioselectivity. Reactions with N-alkyl substituted indoles phosphoric acids were investigated as organocatalyst in the
proceeded well to aord corresponding indolyl -amino esters reaction of N-tert-butansulfonyl -imino ester with 1,3-
379 in 6794% yields, with more than 99% ee. In addition, dimethoxybenzene, and N-triyl phosphoramide Brnsted acid
pyrrole and N,N-dimethylaniline were also investigated in the L34 aorded the desired product 388 in high yield, and high
AS DOI: 10.1021/acs.chemrev.7b00064
enantioselectivity. Reactions were conducted by stirring a -ethoxycarbonyl--bromo-N-phenylacetamides with sodium

solution of -imino ester and an arene (1.1 equiv) in the azide by azidation and denitrogenation.
presence of L34 (1 mol %) in toluene at 22 C for 12 days 9.5. Discussion, Synthetic Utility, and the Future
under argon atmosphere to give FriedelCrafts products 388 in FriedelCrafts reaction was extensively developed for the
6289% yields, with 8196 ee. Also, thioanisole derivatives were synthesis of -aryl substituted -amino acids via aminoalkylation
examined in the reaction at room temperature, which aorded of electron-rich aromatic compounds with -imino esters. Using
the corresponding -aryl -amino esters 388 in 6068% yields, -imino esters possessing chiral auxiliary or conducting the
with 6870% ee (Scheme 89). reaction in the presence of chiral catalysts aords enantioen-
Enantioselective FriedelCrafts reaction of various substi- riched -aryl glycinate derivatives, which are found in natural
tuted anilines as electron-rich arenes with -hydrazono esters products and also exhibit various biological activities. However,
was reported by Leighton.161 Reactions were performed using indole was suciently studied in the FriedelCrafts reaction
strained silacycle reagent (S,S)-L35 (1.5 equiv) in toluene at 20 with -imino esters, and there are a few reports on the Friedel
C for 2248 h, to furnish arylglycinate derivatives 389 in 54 Crafts aminoalkylation of electron-rich aromatic and hetero-
92% yields, with 8795% ee. Also, several heteroarenes, such as aromatic compounds, such as phenols, anisoles, anilines, furans,
pyrrole, thiophene, and indole, were investigated, leading to - pyrroles, and thiophenes with -imino esters. Therefore, the
heteroarylglycinates in 7491% yields, and 8889% ee. The FriedelCrafts reaction of these aromatics as well as other
obtained enantioselectivity was attributed to the formation of aromatic compounds bearing weak electron donating substitu-
complex 390 by reaction of silane L35 with hydrazono ester by ents is of interest. Also, the development of new ecient chiral
isomerization of CN bond from trans in the hydrazone to cis catalysts to aord excellent enantioselectivity is an important
in the complex 390, in which the Ph group on silane restricted the ongoing research eld in the FriedelCrafts aminoalkylation
access to the back (re) face of the silane-activated hydrazone with -imino esters. Moreover, FriedelCrafts aminoalkylation
(Scheme 90). followed by further reactions and intramolecular cyclization with
9.3. FriedelCrafts Reactions of Furans, Pyrroles, and appropriate substituents on aromatic core and also intra-
Thiophenes molecular FriedelCrafts reaction can be the future researches
to produce novel heterocyclic systems.
Larionov and Meijere162 reported a few number of Friedel
Crafts alkylation of furan derivatives with 2-cyclopropyl-(N-Boc- 10. AZA-MORITA-BAYLIS-HILLMAN REACTION
imino)acetate in the presence of BF3OEt2 in DCM at room
temperature. Reactions were completed in a short time (30 min), Asymmetric aza-Morita-Baylis-Hillman reaction of -imino
and 2-furyl -amino esters 391 were obtained in 6891% yields esters, derived from ethyl glyoxalate, with methyl vinyl ketone
(Scheme 91, a). Moreover, Gautun et al.163 described the
synthesis of several hetaryl -mino esters by diastereoselective Scheme 93. Aza-Morita-Baylis-Hillman Reaction of -Imino
FriedelCrafts alkylation of pyrrole, thiophene, furan, and indole Estersa
with N-sulnylimino esters, in the presence of TMSOTf (1
equiv) in dry DCM under an argon atmosphere. Reactions were
performed using 12 equiv of heteroarenes at 78 C, leading to
desired products 392 in 5692% yields, while thiophene
underwent alkylation at higher temperature (20 C), in 40%
yield. When, 2 equiv of -imino ester was subjected with pyrrole
in the presence of TMSOTf (2 equiv), dialkylated product 393
was obtained in 77% yield (Scheme 91, b). FeCl3-catalyzed
alkylation of thiophene derivatives was also reported via Friedel
Crafts reaction with N-PMP protected -imino acetate.
Reactions were performed using 2 equiv of thiophenes in the
presence of 10 mol % of FeCl36H2O in nitromethane at room a
temperature for 4120 h, which resulted in formation of 3- R = Me, Et; Ar = XC6H4 (X = H, 4-F, 4-Cl, 4-Br, 3-Me, 4-Me, 3-CF3,
4-MeO), 4-Cl-2-MeOC6H3; 5399%, 6697% ee.
thienylglycine derivatives 394 in 1095% yield. Reaction with
electron-withdrawing substituent (3-bromothiophene) did not Scheme 94. Aza-MBH Reaction of -Imino Esters Catalyzed
occur (Scheme 91, c).164 There are other reports on the Friedel with DABCO or PPh3a
Crafts alkylation of electron-rich arenes and heteroarenes with -
imino esters in the literature.34,165
9.4. Intramolecular FriedelCrafts Reaction
BF3OEt2-catalyzed intramolecular FriedelCrafts reaction was
described by Yu et al.166 to synthesize 3-aminooxindole
derivatives 397. Treatment of 2-(N-arylcarbamoyl)-2-iminoace-
tates 395 with 2 equiv of BF3OEt2 in anhydrous CH3CN at 80
C for 1.5 h, aorded 3-aminooxindoles 397 in 7292% yields.
meta-Substituted 2-(N-arylcarbamoyl)-2-iminoacetates aorded
two regioisomers, with majority of 4-substituted oxindole
a
derivatives. Proposed intramolecular FriedelCrafts occurred R = Me, Et; Ar = XC6H4 (X = H, 4-Cl, 4-Br, 3-Me, 4-Me, 3-CF3), 4-
via intermediates 396, which is shown in Scheme 92. Used 2-(N- Cl-2-MeC6H3; Base = DABCO, 399: 3485%; Base = PPh3, 400: 51
arylcarbamoyl)-2-iminoacetates were prepared from reaction of 82%.
AT DOI: 10.1021/acs.chemrev.7b00064
Scheme 95. Aza-MBH Reaction of ,-Unsaturated 11. AZA-HENRY REACTION

Aldehydes with -Imino Estersa Chiral Brnsted acid catalyzed asymmetric direct aza-Henry
reaction of N-PMP protected -iminoacetate was developed for
Scheme 96. Aza-Henry Reaction of N-PMP Protected -

Imino Estersa
a 1
R = Me, Et, n-Pr, i-Pr; R2 = H, Me; R3 = Et, i-Pr; 3968%, E/Z = 4/
116/1, 9199% ee (for E-isomer).
and ethyl vinyl ketone was investigated using bifunctional chiral

phosphine Lewis bases (R)-L36. Reactions were carried out by
stirring a solution of -imino esters and vinyl ketones (1.5 equiv)
in the presence of (R)-L36 (10 mol %) and 4 MS in anhydrous
Et2O at 10 C under an atmosphere of argon during 4860 h,
to aord ethyl 2-arylamino-3-propionylbut-3-enoates 398 in 53
99% yields, with 6697% ee. Reaction of N-PMP protected
imine of ethyl glyoxalate with methyl vinyl ketone in the presence
of isomeric organocatalyst (S)-L36 under the similar reaction
condition, furnished MBH-adduct 398 in 80% yield, with
opposite enantioselectivity (93% ee; Scheme 93).167
Shi et al.168 developed aza-MBH reaction of -imino esters
with ethyl or methyl vinyl ketones using DABCO and PPh3 as
base. Reactions were conducted using 1.5 equiv of vinyl ketone in
the presence of DABCO or PPh3 (30 mol %) and 4 MS in
CH3CN at room temperature under an argon atmosphere for 2
4 days to give ethyl 3-methyl-4-oxo-2-(phenylamino)-2-
alkenoates 399 or ethyl 3-methylene-4-oxo-2-(phenylamino)-
alkanoate 400 in 3485% or 5182% yields, respectively. By a 1
subjecting MBH-adducts 400 with bases such as DBU or K2CO3, R = Me, Et; R2 = Me, Et, n-Bu, Bn, 4-BrBn, 4-MeOBn, 2-
thienylCH2, Ph(CH2)3, 4-MeC6H4; 5793%, anti/syn = 2/113/1,
disordered BH-adducts 399 were obtained, illustrating that BH-
92/896/4 ee for anti-isomer.
adducts 400, in situ generated via BABCO-induced MBH
reaction, underwent isomerization by deprotonationprotona-
Scheme 97. Synthesis of Pyrrolidin-2-one from -Imino Ester
tion in the presence of DABCO (Scheme 94).
by Conjugate Addition/Aza-Henry/Lactamization Sequences
A highly enantioselective aza-MBH reaction of ,-unsatu-
rated aldehydes with glyoxalate derived -imino esters was
reported by stirring a solution of -imino esters and aldehydes (5
equiv) in the presence of (S)-proline L37 (30 mol %) and
imidazole (1 equiv) in DMF at 4 C for 23 h. The aza-MBH
adducts 401 were obtained in 3968% yields, with 9199% ee
for E-isomer. The E/Z ratio of the alkene moiety was obtained as
4/116/1 (Scheme 95).169
Aza-Morita-Baylis-Hillman reaction of -imino esters is one of
the most remarkable approaches to generate highly function-
alized products bearing ester, amine, carboncarbon double
bond and ketone or aldehyde groups, which could be an
important synthetic intermediate to prepare interesting novel
heterocycles, thought to be inaccessible by formerly known
methodologies. A few numbers of aza-Morita-Baylis-Hillman
reactions of -imino esters were reported until now, and it could
be a main research subject of synthetic and heterocyclic
communities. Chiral phosphine and amine catalysts lead to the synthesis of -nitro--amino esters. Reactions were
asymmetric induction in the newly formed stereocenter. performed using 10 equiv of nitroalkanes in the presence of
However, using chiral auxiliary substituted -imino esters, can H8-L29 (10 mol %) in benzene at 30 C for 12166 h, to give -
aord Baylis-Hillman adducts with excellent enantioselectivity. nitro--amino esters 402 in 5793% yields, with anti/syn ratio of
AU DOI: 10.1021/acs.chemrev.7b00064
Scheme 98. 3-Pyrrolidinecarboxylic Acid Catalyzed Mannich Reaction of Enolizable Carbonyls with -Imino Estersa
a
L38: R1 = H; R2 = Me, i-Pr, n-Bu, t-Bu, n-Pent, 2-octen-1-yl; R3 = Et, i-Pr, t-Bu, allyl; 5792%, anti/syn = 86/1499/1, 77 to >99% ee (anti
isomers); L39: R1 = H; R2 = Me, i-Pr, n-Bu, t-Bu, n-Pent, 2-octen-1-yl, allyl, Bn; R3 = Et, i-Pr, t-Bu, allyl; 6088%, anti/syn = 93/799/1, 6399% ee
(anti isomers); R1 = Me, Et, n-Pr; R2 = Me, Et, allyl, (CH2)3Cl, (CH2)2CO2Et, (CH2)2CN; R1R2 = (CH2)4, (CH2)5, (CH2)6, (CH2)2OCH2,
(CH2)2SCH2, (CH2)2C(OCH2CH2O)CH2; R3 = Et, i-Pr, t-Bu, allyl; 6596%, anti/syn = 90/10 to >99/1, 18 to >99% ee (anti isomers); R1 = Me,
Et, CH2OH, CH2OBn; R2 = OH, OMe, OBn, SMe, N3; R3 = Et; 4191%, anti/syn = 50/5083/17, 8090% ee (anti isomers).
2/113/1 and 92/896/4 ee for the anti isomer. A variety of intermediates to prepare some valuable products and hetero-
binol-derived chiral phosphoric acids was investigated in cyclic motifs, as one example of the synthesis of pyrrolidine was
dierent solvents, and H8-L29 in benzene was selected for the reported. Exploring the reaction in regard with used chiral
best obtained results. In the proposed reaction mechanism chiral catalysts, and scope of the reaction is also expected.
phosphoric acid H8-L29 accelerated the nitroalkane/nitronate
equilibrium, which attacked to -imino ester, activated by 12. MANNICH REACTION
protonation, via intermediate 403, in which phosphoric acid
acted simultaneously as a Brnsted acid and as a Lewis base 12.1. Reaction with Enolizable Ketones and Aldehydes
(transition state 404, Scheme 96).170 Enantioselective aza-Henry Barbas et al.173175 described the Mannich reaction of a variety of
reaction of N-PMP protected iminoacetate with 2-nitro- enolizable carbonyl compounds with N-PMP protected -
propionates was studied using Cu(OTf)2 in the presence of iminoacetates using several chiral pyrrolidine derivatives, from
chiral ligands and bases, in which a combination of quinine which (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid (L38) and
cinchona alkaloid and (R)-Ph-BOX-Cu(OTf)2 exhibited high (R)-3-pyrrolidinecarboxylic acid (L39) exhibited a high anti
yields and enantioselectivity.171 selectivity of the Mannich reaction. By treatment of -imino
Synthesis of densely functionalized pyrrolidin-2-one 406 was esters with aldehydes (24 equiv) in the presence of either L38
achieved by conjugate addition/aza-Henry/lactamization se- (130 mol %) or L39 (5 mol %) in anhydrous DMSO at room
quences. Conjugate addition of Et2Zn (1.1 equiv) to nitro- temperature for 0.548 h, corresponding Mannich adducts 407
acrylate in the presence of Cu(OTf)2 (5 mol %) in THF at 78 were obtained in 5792% yields, with 86/14 to >99/1 dr, and 77
C to room temperature for 1.5 h, led to the formation of to >99% ee for anti isomers with (2S,3R) stereochemistry.
nitronate, which was treated with N-PMP protected -imino Mannich reaction of -imino esters with acyclic ketones (10
ester (2 equiv) and TFA (3.5 equiv) in THF in one pot manner at equiv) was conducted using 10 mol % of L39 in i-PrOH at room
78 C for 1 h, and then at room temperature for 16 h. By temperature for 596 h, resulting in the formation of Mannich
nucleophilic addition of nitronate to -imino ester, aza-Henry adducts in 6891% yields, with 9/1 to >99/1 anti selectivity and
product 405 was in situ generated, which was cyclized to nal up to 98% ee. Cyclic ketones underwent anti selective Mannich
pyrrolidin-2-one 406 in 69% yield. Also, methoxy acetal of reaction using 310 mol % of L39, leading to desired products in
glyoxal imine was investigated, giving corresponding pyrrolidine- 6596% yields, with excellent diastereoselectivity (anti/syn =
2-one in 63% yield under similar reaction conditions (Scheme 95/5 to >99/1) and up to 99% ee for anti isomers. In addition, -
97).172 hydroxy, alkoxy, methylthio, and azide substituted ketones were
The synthesis of -nitro--amino esters was achieved by aza- studied under similar reaction conditions, which gave the
Henry reaction of -imino esters. A chiral Brnsted acid Mannich adducts in 4191% yields, with a weak diastereose-
catalyzed enantioselective reaction was reported, leading to lectivity, and good to high enantioselectivity. The transition
enantioenriched aza-Henry adducts. Unexpectedly, reports on states of the reactions were depicted in Scheme 98. In the case of
the aza-Henry reaction of -imino esters are rare, and this catalyst L38, due to the unfavorable steric interactions between
reaction can attract considerable attention in future, because the the 5-methyl group and the enamine in conformation 408, S-
aza-Henry adducts with dierent functional groups, including trans conformation 409 of enamine was major conformer in
ester, amine and nitro groups, will be interesting synthetic equilibrium. Formation of hydrogen bond between 3-carboxylic
AV DOI: 10.1021/acs.chemrev.7b00064
Scheme 99. L-Proline/Quinidine Thiourea L40 Catalyzed 413, whereas the enamine was too far from imine to produce the
Mannich Reaction of Enolizable Carbonyls with -Imino products (Scheme 98).
Estersa Mannich reaction of -iminoacetate with unmodied
aldehydes or ketones catalyzed by modularly designed organo-
catalysts (MDOs), in situ self-assembled from L-proline and
quinidine thiourea L40, was reported by Zhao et al.176 Reactions
were carried out by mixing carbonyl compounds (1.2 equiv) with
imine in the presence of L-proline (5 mol %) and quinidine
thiourea L40 (5.0 mol %) under neat condition at room
temperature, for <560 min. The Mannich adducts 407 were
obtained in 7098% yields, with syn/anti ratio of 75/25 to >99/
1, and up to >99% ee. The syn selectivity was illustrated by in situ
generation of E-enamine from condensation of L-proline of
MDO with aldehyde, along with hydrogen-bonding -imino
ester to thiourea moiety of quinidine (transition state 414),
leading to the re-face approach of enamine to the si-face of the
imine moiety (Scheme 99).
Also, stereoselective synthesis of -amino ketones was
reported by the Mannich reaction of enolizable aldehydes and
ketones with ethyl glyoxalate imine. Reactions were catalyzed
with (R)-3-triuoromethanesulfonamidopyrrolidine, (R)-L41,
and aorded the Mannich products 407 in 5695% yields,
with 4/1 to >20/1 anti selectivity. Reactions were carried out by
a 1
R = H, Me; R2 = H, Me, n-Pr, i-Pr, n-Pent, n-Hept, n-Decyl, Bn; stirring a solution of -imino ester and aldehyde or ketone (3
R1R2 = (CH2)4, (CH2)2OCH2; 7098%, syn/anti = 75/25 to >99/ equiv) in the presence of (R)-L41 (5 mol %) in DMF at 400
1, 70 to >99% ee. or 20 C for 124 h or 272 h, respectively. The stereochemistry
outcome of the reaction was attributed to the stabilization of
acid of enamine 409 and nitrogen atom of imine caused transition state with hydrogen bond, in which the addition
transition state 410, in which the si-face of enamine attacked to occurred via six-membered cyclic transition state involving a
the si-face of imine moiety, leading to anti selectivity of the three-centered hydrogen bond 415, leading to anti isomers as the
Mannich reaction. Two conformations of the in situ generated major products (Scheme 100).177 Additionally, (S)-L41 and
enamines 411 and 412 may have similar free energies in the case (3R,4R)-L42 were studied for catalysis of the similar anti-
of catalyst L39. Because of the formation of hydrogen bond of selective Mannich reaction of ethyl glyoxalate imine.178180 anti-
carboxylic acid group with imine, the conformation 412 resulted Mannich reaction of aldehydes with N-PMP protected ethyl
in formation of anti-Mannich-adducts through transition state glyoxalate imine was also studied using pyrrolidine-based
Scheme 100. 3-NHTf-Pyrrolidine Catalyzed Mannich Reaction of Enolizable Carbonyls with -Imino Estersa
a
Cond. = (R)-L41 (5 mol %), DMF, 4020 C, 172 h; R1 = R2 = H: R3 = Et, i-Pr, 9-nonenyl, Bn; R1 = H: R2 = Me, R3 = Me, Ph; R2R3 =
(CH2)4, (CH2)5; R3 = H: R1 = Et, R2 = Me, R1R2 = (CH2)4, (CH2)5, (CH2)2OCH2, (CH2)2SCH2; 5695%, anti/syn = 4/1 to >20/1, 60 to >99%
ee for anti-isomer. Cond. = L43a (R = Me, TBDMS, TBDPS, 0.010.5 mol %), EtOAc, 0 C, 174 h; R1 = H: R2 = Me, i-Pr, n-Pent, 9-nonenyl, Bn;
6790%, anti/syn = 87/1396/4, 9499% ee for anti-isomers. Cond. = catalyst L43a (15 mol %), EtOAc, rt, 128 h; R2 H: R1 = Me, Et, R2 =
Et, R1R2 = (CH2)4, (CH2)5, (CH2)2OCH2, (CH2)2C[O(CH2)2O]CH2; 5292%, anti/syn = 75/2599/1, 8398% ee for anti-isomers.
AW DOI: 10.1021/acs.chemrev.7b00064
Table 1. Reported Organocatalyst for the Mannich Reaction of Enolizable Aldehydes and Ketones with -Imino Esters
Scheme 101. Mannich Reaction of -Azido Ketones or - selectivity and 8398% ee for the major isomers. The
Phthalimidoacetone with -Imino Estersa stereochemistry of the reaction was attributed to the formation
of enamine 416a, which exists as two forms in equilibrium. Due
to the formation of the H-bond between the NHTf moiety of the
catalyst and the N atom of the -imino ester and also steric
hindrance of the alkoxy group, the reactions proceeded via
transition state 417, which led to the anti isomer as major
products (Scheme 100).181 The same research group has
reported the anti-selective Mannich reaction of aldehydes and
ketones with N-PMP -iminoacetate using similar pyrrolidine-
based catalyst L43b supported on polystyrene and its
homogeneous model L43c. Reactions with aldehydes were
conducted using 1.5 equiv of aldehyde in DMF at 0 C for 4 h,
while ketones (1.2 equiv) were subjected with -imino esters in
DMF at 25 C for 424 h. The Mannich-adducts were obtained
in 6490% (anti/syn = 84/1695/5) and 4892% (anti/syn =
74/26 to >95/5), in the case of aldehydes and ketones,
respectively.182
Other pyrrolidine based organocatalysts were extensively
a reported for the Mannich reaction of aldehydes and ketones with
423: R = Me, Ph; 8796%, syn/anti = 88/1291/9; 424: solvent =
DMSO, DMF, NMP; 8695%, 6491% ee.
-imino esters, which were summarized in Table 1, along with
the reaction conditions, yields, stereoselectivity of the Mannich
reactions, and possible transition state. As depicted in Table 1,
organocatalysts L43a. By treatment of aldehydes (1.5 equiv) with L39, L44, and L45 (entries 13) aorded anti isomers as the
-imino ester in the presence of chiral pyrrolidines L43a (0.01 major products.183189 However, sulfonamide derivatives of L-
0.5 mol %) in EtOAc at 0 C for 174 h, Mannich adducts 407 proline L46 (entries 4,5)190192 and (S)-2-(tetrazol-5-yl)-
(R3 = H) were obtained in 6790% yields, with 87/1396/4 pyrrolidine L47 (entry 6)190 led to the syn selectivity of the
anti/syn selectivity and 9499% ee for anti isomers. In addition, Mannich reaction. L-Proline was also extensively used for the
various cyclic and acyclic ketones were investigated using 15 Mannich reaction of -imino esters, in-which the syn selectivity
mol % of catalysts at room temperature in 128 h, leading to was mainly observed.193198 (S)-Pipecolic acid L48-catalyzed
Mannich adducts in 5292% yields, with 75/2599/1 anti/syn Mannich reaction of -imino esters was developed by Barbas et
AX DOI: 10.1021/acs.chemrev.7b00064
Scheme 102. Mannich Reaction of Aldehydes with Cyclic -Imino Ester 376a
a
R = Et, n-Bu, n-Hex, CH2c-Hex, Bn; L-proline: 6272%, syn/anti = > 20/1, 99% ee; (S)-L52: 5979%, anti/syn = > 20/1, 99% ee.
Scheme 103. Proline-Catalyzed Mannich Reaction of amino--oxoesters by the Mannich reaction of -imino esters in
Enolizable Ketones with Cyclic -Imino Ester 431a the literature.212216
(S)-2-(Tetrazol-5-yl)pyrrolidine L47-catalyzed three-compo-
nent Mannich reaction of -azido ketones or -phthalimidoa-
cetone with ethyl glyoxalate and p-anisidine was reported to
synthesize -azido--amino--oxoester 423 or -phthalimido--
amino--oxoester 424, respectively. Reactions were carried out
by stirring a solution of equimolar amounts of glyoxalate and p-
anisidine with 1.5 equiv of -substituted ketones in the presence
of L47 (30 mol %) in solvent at room temperature for 0.572 h.
Reactions with -azido ketones were conducted in DMSO to
give 1,2-azidoamines 423 in 8796% yields, with a syn/anti ratio
of 88/1291/9 and up to 99% ee for each stereoisomer. Reaction
with -phthalimidoacetone was investigated in dierent solvents,
such as DMSO, DMF, and NMP, at 4 C or room temperature,
to give 1,4-diamine derivative 424 in 8695% yields, with 64
91% ee (Scheme 101).217
In 2012, Maruoka et al.218 described a highly diastereo- and
enantioselective Mannich reaction of aldehydes with cyclic -
a
432: R = Me, Ph; R1 = H, Me, Et, allyl, CH2CHC(Me)2, Bn, OH;
R1 = Me, Et, n-Hex, CHC(Me)2; R1R2 = (CH2)3, (CH2)4, imino ester in the presence of either L-proline or axially chiral
(CH2)5; 3091%, anti/syn = 10/1 to >20/1, 80 to >99% ee. 433: R1 = aminosulfonamide (S)-L52. By treatment of cyclic -imino ester
Me; R2 = Me, Et; R1R2 = (CH2)4; 9098%. 376 with aldehydes (5 equiv) in the presence of L-proline (20
mol %) and benzoic acid (10 mol %) in CH3CN at 0 C for 5 h,
al.,199 and obtained results are shown in Table 1, entry 7. Mannich adducts 425 were obtained, which were in situ
However, the Mannich adducts were obtained with moderated converted to -lactone 426 through reduction with NaBH4 in
syn selectivity. Dziedzic and Cordova200 developed the anti- MeOH, in 6272% yields, with >20/1 syn/anti ratio and 99% ee.
Mannich reaction of -iminoacetate catalyzed with -amino acid, However, reactions with (S)-L52 were performed using 3 equiv
(R)-3-amino-4-methylpentanoic acid L49 (entry 8). Reactions of aldehydes and (S)-L52 (5 mol %) in DMAc at 45 C for 5 h,
were performed using 10 equiv of cyclic ketones in the presence followed by reduction with NaBH4 in MeOH, resulting in the
of L49 (30 mol %) and seawater in DMSO at room temperature formation of -lactone 425 in 5979% yields, with >20/1 anti/
for 16 h, to furnish corresponding Mannich adducts in 2070%, syn ratio and 99% ee. The transition states of the Mannich
with 1/2 to >19/1 anti/syn ratio. Reaction with an acyclic ketone reactions were depicted in Scheme 102. In the case of reactions
(3-pentanone) aorded the Mannich-adduct only in low yield, catalyzed with L-proline, the re-face of the S-trans-enamine
even with an extended reaction time (72 h). Other organo- attacked the re-face of imine moiety (transition state 427) to give
catalysts, such as (S)-alanine,201 Ot-Bu-L-threonine,202,203 Mannich adducts 425 in syn selectivity, while in the reactions
polymer-supported threonine derivative, 204 bifunctional with (S)-L52, the si-face of the in situ generated enamine
aminethiourea catalyst L50 (entry 9),205 and binaphthyl- approached the re-face of imine moiety (transition state 428), to
based secondary amines L51 (entry 10)206211 were also used for aord anti-selective Mannich adducts. By subjecting the
diastereoselective and enantioselective Mannich reaction of ethyl Mannich adduct, in situ obtained from reaction of 3-phenyl-
-iminoacetate. There are other reports on the construction of - propionaldehyde and cyclic -imino ester 376 in the presence of
AY DOI: 10.1021/acs.chemrev.7b00064
Scheme 104. Mannich Reaction of Cyclic N-Sulfonyl -Imino Ester 81 with Ketonesa
a 1
R = H, 4-F, 5-F, 5-Cl, 7-Cl, 5-Me, 6-Me, 5-t-Bu, 5-MeO, 5-CF3, 5-OCF3, 5,6-(CH); R2 = Me, Et; 435: R3 = Me, Ph; 6099%, 8099% ee. 436: n =
1, 2; 7399%, 14/1 to >99/1 dr, 9599% ee.
Scheme 105. Mannich Reaction between Allylic Ketones and stirring a solution of 431 and a ketone (36 equiv) in the presence
Cyclic -Imino Ester 81a of L-proline (30 mol %) in anhydrous DMSO at room
temperature for 24 h, giving Mannich adducts 432 in 3091%
yields, with 10/1 to >20/1 anti/syn ratio and 80 to >99% ee.
However, reaction with cyclopentanone aorded the product in
low yields, other cyclic ketones, such as cyclohexanone and
cycloheptanone worked well in the reaction. Variety types of
acyclic ketones were also investigated, which resulted to Mannich
adducts 432 in good to high yields, with high to excellent
diastereoselectivity and enantioselectivity. The synthesis of -
amino--oxoacids 433 was achieved in 9098% yields, by
hydrogenolysis of obtained Mannich adducts 432 using
concentrated aqueous HBF4 (1 equiv) and 20% (w/w)
Pd(OH)2/C in EtOH/H2O at 40 C under H2 (40 bar). The
anti selectivity of the reaction could be attributed to the
formation of transition state 434, in which the hydrogen bonding
of carboxylic acid of proline with nitrogen atom of imine moiety
led to the nucleophilic addition of the re-face of enamine to the
re-face of imine (Scheme 103).
Highly diastero- and enantioselective direct Mannich reaction
a 1
R = n-Hex, Bn, XC6H4 (X = H, 2-F, 4-F, 3-Cl, 4-Cl, 4-Br, 3-Me, 4-
of cyclic N-sulfonyl ketimines 81 with ketones catalyzed with
Me, 3-MeO, 4-MeO, 4-CF3, 4-CN), 1-naphthyl, 2-naphthyl, 2-thienyl, amino sulfonohydrazide L53 was developed by Wang et al.220
-styrenyl; R2 = H, 5-F, 6-F, 5-Cl, 7-Cl, 5-Me, 5-MeO, 5-CF3; 45 Reactions were performed using equimolar amounts of cyclic -
99%, 1.5/120/1 dr, 7796% ee. imino ester 81 and ketones in the presence of 5 mol % of both
L53 and TFA in toluene at room temperature for 30 h. Reactions
L-proline, with benzyl amine, followed by reductive elimination with acyclic ketones, such as acetone and acetophenone,
of OH group (429) with Et3SiH in the presence of BF3OEt2 in proceeded in 6099% yields, with 8099% ee. However, cyclic
DCM, -lactam syn-430 was obtained in 77% yield, with 99% ee ketones aorded Mannich products 436 in 7399% yields, with
(Scheme 102). 14/1 to >99/1 dr and 9599% ee. The synthetic utility of the
Proline-catalyzed highly enantioselective and anti-selective obtained Mannich adducts 435 was investigated by reduction of
Mannich reaction of enolizable ketones with a cyclic -imino 435a, obtained from acetone, using NaBH4 in MeOH at 0 C
ester, 5,5-disubstituted-5,6-dihydro-1,4-oxazin-2-one 431, was then room temperature, to diols 438a and 438b in 24% and 71%
developed by Glorius et al.219 Reactions were conducted by yields, respectively. Diol 438b was transformed into spirote-
AZ DOI: 10.1021/acs.chemrev.7b00064
Scheme 106. ZnF2/L2-Catalyzed Mannich-Type Reaction of reaction was exhibited by conversion of Mannich product 441a
-Hydrazono Esters with Silyl Enol Ethersa to spirobenzosultam derivative 442, via reduction with NaBH4 in
MeOH at 0 C, in 76% yield, with 97% ee. In addition,
pyrrolo[1,2-b]isothiazole 5,5-dioxide 444 was obtained through
hydroboration/oxidation of the alkene moiety to 443, followed
by subsequent Mitsunobu cyclization in 81% yield, with 93% ee,
for the last step (Scheme 105).221
12.2. Reaction with Silyl Enol Ethers
The synthesis of -hydrazino--oxoesters 445 was achieved by
the Mannich-type reaction of -hydrazono esters with silyl enol
ethers catalyzed with ZnF2-chiral diamine ligand L2. Reactions
were carried out by stirring a solution of -hydrazono esters and
silyl enol ethers (3 equiv) in the presence of ZnF2 (100 mol %),
TfOH, or NaOTf (1 mol %) and diamine L2a or L2c (1020
mol %) in water/THF (1/9: v/v) at 0 C for 8420 h, to give
Mannich adducts 445 in 3091% yields. (Z)-Enols aorded the
syn Mannich adducts with 5494% dr and 8691% ee, whereas
(E)-enols led to anti-selective Mannich reaction with 4674% dr
and 8591% ee. Also, reactions were studied in water by
treatment of -hydrazono ester with silyl enol ether of
acetophenones (3 equiv) in the presence of ZnF2 (100 mol %)
and chiral diamine ligands L2b (10 mol %) at 0 C for 2072 h,
producing corresponding Mannich adducts 445 in 3594%
yields, with 9196% ee. Reactions of substituted silyl enol ethers
in water were performed using 10 mol % of ZnF2 in the presence
of L2c (510 mol %) and CTAB (2 mol %) at 0 C for 40155
h, in which (Z)-enols aorded syn adducts in 6087% yields,
with 8092% dr, and 9698% ee, and (E)-enol of 3-pentanone
furnished the anti adduct in 75% yield, with 74% dr, and 82% ee.
The investigation of various counterions of Zn2+ salts revealed
that both Zn2+ and F ions were essential, and ZnF2 played a
bifunctional role by activation of -hydrazono ester through
chelation with Zn2+ and activation of silyl enol ether moiety with
a
L2a, TfOH (1 mol %), water/THF (1/9: V/V): R1 = H, Me; R2 = H; F ions. The chiral diamine ligands L2 aected the stereo-
R3 = i-Pr, 4-XC6H4 (X = H, Cl, Me, MeO); 3091%, Z-enol syn/ chemistry of the reaction. The proposed reaction mechanism
anti = 90/1096/4, 8891% ee. L2c, NaOTf (1 mol %), water/THF involves the activation of hydrazono ester with in situ formed
(1/9: V/V): R1 = H, Me; R2 = H, Me; R3 = Et, St-Bu; 2298%, Z-enol ZnF2-diamine chiral complex 446 as Lewis acid and activation of
syn/anti = 77/2397/3, E-enol syn/anti = 13/8727/73. L2b, silyl enol ether with F ions to generate intermediate 447. By
No additive, water: R1 = R2 = H; R3 = 4-XC6H4 (X = H, Cl, Me, nucleophilic addition to the imine moiety, zinc amide 448 was
MeO); 9194%, 9195% ee. L2c, CTAB (2 mol %), water: R1 = H,
Me, Et; R2 = H, Me; R3 = Et, Ph, PMP; 6087%, Z-enol syn/anti =
generated along with formation of TMSF. Hydrolysis of 448 gave
90/1096/4, E-enol syn/anti = 13/87, 9298% ee (for major the Mannich adduct by releasing Zn(OH)F-diamine chiral
isomer). complex 449 which was reacted with TMSF for regenerating
ZnF2-diamine chiral complex 446 for further runs (Scheme
106).222 One example of the Mannich reaction of silyl ketene
trahydrofuran 440 in two steps, by protection of sulfonamide acetal with -hydrazono ester catalyzed with chiral neo-
moiety with BnBr in CH3CN in the presence of K2CO3 at 60 C, pentoxychlorosilane was also reported.223
in 96% yield (439), followed by intramolecular cyclization using Mannich addition of silyl enol ethers to iminium salts 454, in
TFA in DCM at 0 C, in 67% yield. The excellent stereo- situ generated by the oxidation of amino ketene silyl acetales, was
selectivity of the reaction was illustrated by transition state 437, reported by Shimizu et al.224 Reactions were performed using 2
formed between in situ generated enamine and cyclic -imino equiv of silyl enol ethers and DDQ (1 equiv) in the presence or
ester by hydrogen bonding with both nitrogen and oxygen atoms absence of Lewis acids, such as BF3OEt2 or Et2AlCl (2 equiv) in
of the imino ester (Scheme 104). DME, DMF, or DCM at 55 C to room temperature for 12.5
The Mannich reaction between allylic ketones and cyclic - 18 h. A variety of silyl enol ethers, derived from ketones, esters,
imino ester 81 was reported using saccharide-derived chiral and thioesters, and also amino ketene silyl acetales were
tertiary amino-thiourea catalyst L-54. Reactions were carried out investigated, and corresponding Mannich adducts 450 were
using 1.1 equiv of allylic aryl ketones in the presence of L54 (5 obtained in 1381% yields, with moderate diastereoselectivity.
mol %) in THF at room temperature for 524 h, giving the In addition, Mannich reaction of in situ generated iminium ion
Mannich adducts 441 in 8199% yields, with 6/1 to >20/1 dr, 454 was studied using equivalent amount of enamine in the
and 8796% ee. Reaction with two examples of allylic aliphatic presence of 1.1 equiv of DDQ in EtCN at 0 C to room
ketones were also investigated, in which corresponding Mannich temperature for 10 h, in which desired products 451 were
adducts 441 were obtained in moderate yield (4564%), and obtained in 6383% yields, with moderate diastereoselectivity.
week diastereoselectivity (1.5/12.5/1). Synthetic utility of this In the presence of Lewis acids, such as BF3OEt2 and AlCl3,
BA DOI: 10.1021/acs.chemrev.7b00064
Scheme 107. Mannich Addition of Silyl Enol Ethers to Iminium Salts 454a
a
450: R = Me, allyl, Bn; RR = (CH2)4, (CH2)5, (CH2)2O(CH2)2; R1 = H, Me, BnO; R2 = H, Me; R3 = t-Bu, Ph, OMe, OEt, Ot-Bu, Set; Si = TMS,
DMS, TIPS, TBS; additive = none, BF3OEt2, Et2AlCl, solvent = DME, DMF, DCM; 1381%, anti/syn = 8/9290/10. 451: n = 1, 2; X = bond,
CH2, O; 6383%, 33/6737/63 dr.
reactions proceeded in low yields with no improvement in ether to give nal desired products 450, along with regeneration
diastereoselectivity. The proposed reaction mechanism involves of the hafnium catalyst, by traping MeO group with TMS
the generation of iminium salt 454, via reaction of amino ketene (Scheme 108).
silyl acetales with DDQ through one-electron transfer (452) or 12.3. Reaction with Esters
an ionic intermediate (453), which underwent nucleophilic
addition with silyl enol ethers via one of the transition states 455a The Mannich reaction/Dieckmann condensation sequence was
reported by Shimizu et al.130 to synthesize tetrahydro-4-
or 455b, formed by chelation with Si-metal in an anti-periplanar
quinolone derivatives 458. Addition of a solution of N-(2-
fashion (Scheme 107).
methoxycarbonylphenyl)--imino ester 457 in EtCN to a
Sakai et al.225 have reported the Hf(OTf)4-catalyzed Mannich-
solution of 2-(trimethylsilyl)acetate (1.5 equiv) in DME in the
type reaction of ketene silyl acetals or enol silyl ethers with N,O- presence of LDA (2 equiv) at 60 C under argon atmosphere,
acetals, derived from ethyl glyoxalate. Reactions were carried out and then gradually warming to room temperature over 7 h,
by stirring a solution of N,O-acetals and ketene silyl acetals (1.2 followed by quenching the reaction using saturated KF in water,
equiv) in the presence of 10 mol % of Hf(OTf)4 in DCM at room gave tetrahydro-4-quinolones 458 in 1259% yields, with syn/
temperature for 0.5 h. Reactions with silyl enol ether derived anti ratio of 70/30100/0. Reactions proceeded by Mannich
from propiophenone led to Mannich adducts 450a in 7992% addition of 2-(trimethylsilyl)acetate to the imine moiety of -
yields, with anti/syn ratio of 61/3964/36. Ketene silyl acetal imino ester 457 in the presence of LDA (459) and then 1,3-aza-
aorded aspartate derivatives 450b in 7599% yields. N,O- Brook rearrangement (460) to give lithium enolate 461, which
Acetal having a bis(trimethylsilyl)amino group furnished N- underwent Dieckmann condensation to N-TMS-tetrahydro-4-
unsubstituted aspartic acid derivatives in 5270% yields, after a quinolone 462. By desylilation using KF, the nal desired
standard aqueous workup. In the proposed reaction mechanism, products 458 were obtained (Scheme 109).
iminium salt 454 was formed by coordinating oxygen of acetal to Rh(I)-catalyzed tandem conjugate addition-Mannich cycliza-
hafnium triate 456 and then elimination of the MeO group of tion reactions was reported for the construction of tetrahy-
acetal, which underwent nucleophilic addition with silyl enol droquinoline-2,3-dicarboxylate 464. Treatment of (E)-methyl 3-
BB DOI: 10.1021/acs.chemrev.7b00064
Scheme 108. Hf(OTf)4-Catalyzed Mannich-Type Reaction of Scheme 109. Synthesis of Tetrahydro-4-quinolone

Silyl Enol Ethers with N,O-Acetalsa Derivatives 458 via Mannich/Dieckmann Sequencea
a
R = Ph, 4-ClC6H4, 2-thienyl, (E)-4-XC6H4CHCH (X = H, Cl,
MeO), (E)-2,4-Cl2C6H4CHCH, PhCC; 1259%, syn/anti = 70/
30100/0.
Scheme 110. Rh(I)-Catalyzed Tandem Conjugate Addition-

Mannich Cyclization of -Imino Ester 463
a
NR2 = piperidine, morpholine, N(allyl)2; R1 = H, Me; R2 = H, Me;
450a: 7992%, anti/syn = 61/3964/36. 450b: 7599%. 450c: 52
70%.
[2-((E)-(2-ethoxy-2-oxoethylidene)amino)-5-methylphenyl]-
acrylate 463 with PhB(OH)2 (2.5 equiv) in the presence of
[Rh(OH)(cod)2]2 (2 mol %) and K3PO4 (2 equiv) in 1,4-
dioxane at 80 C for 1 h furnished tetrahydroquinoline-2,3-
dicarboxylate 464 in 33% yields. By transmetalation of
hydroxorhodium(I) with arylboronic acid, the organorhodium-
(I) species is generated, which attacked to 463 through conjugate
addition to form (oxa--allyl)rhodium(I) intermediate 465. By
intramolecular cyclization of 465 via nucleophilic addition to the
imine group, N-rhodium(I) species 466 was generated, which
was protonated with arylboronic acid to releases the product 464
(via intermediate 467) along with metaboric acid and
organorhodium(I) species to promote the next catalytic cycle.
This protonation mechanism was provided, because the reaction
was complete in the absence of proton source (Scheme 110).226
12.4. Reaction with -Dicarbonyl and Related Compounds
Decarboxylative Mannich reaction of -keto acids with optically
active N-tert-butanesulnyl -imino esters was reported using
La(OTf)3 or Y(OTf)3 as catalyst. Reactions were conducted by
stirring a solution of -imino ester with aromatic or aliphatic -
keto acid (1.2 equiv) in the presence of La(OTf)3 (3 mol %) or
Y(OTf)3 (5 mol %) and 5 MS in toluene at 20 C for 524 h,
respectively. Corresponding -amino--oxoesters 468 were imino ester to give salt 471, which was transformed into
obtained in 6189% yields, with 94/6 to >99/1 dr. In the substituted -keto acid 472 along with regenerating salt 469, by
proposed reaction mechanism, by displacement of La(OTf)3 displacement with -keto acid. Final Mannich adducts 468 were
with -keto acid, salt 469 was formed, which attacked the - obtained by decarboxylation of 472. The excellent diastereose-
BC DOI: 10.1021/acs.chemrev.7b00064
Scheme 111. Decarboxylative Mannich Reaction of -Keto Scheme 113. Visible Light Catalysis Assisted Mannich
Acids with N-tert-Butanesulnyl -Imino Estersa Reaction of -Keto Esters with -Amino Estersa
R = R2 = Me, R1R2 = (CH2)3; R3 = Me, Et, i-Pr, t-Bu, Bn; R4 = Me,

a 1
Et, Bn; 4591%, 1/11/3 dr.
a 1
lectivity of the reaction was attributed to the chairlike transition
R = n-Pr, i-Pr, t-Bu, n-undecyl, Bn, XC6H4 (X = H, 4-F, 2-Cl, 4-Cl, 4- state 470, formed by coordination of La salt 469, with -imino
Br, 4-MeO, 3-NO2, 4-NO2), 2-furyl, 2-thienyl; R2 = Et, i-Pr, Bn; 61
ester through nitrogen and oxygen atoms of imino ester and
89%, 94/6 to >99/1 dr.
sulnyl moieties (Scheme 111).227
IPrAuCl-catalyzed Mannich addition of 1,3-dicarbonyl com-
Scheme 112. Mannich Reaction of 1,3-Dicarbonyl
pounds with N-tosyl -imino ester, derived from ethyl glyoxalate,
Compounds with -Imino Esters, Derived from Ethyl
was reported by stirring a solution of 1,3-dicarbonyls 473 with -
Glyoxalatea
imino ester (1.2 equiv) in the presence of 5 mol % of IPrAuCl in
DCM at room temperature under an atmosphere of N2.
Reactions proceeded in 1224 h, and Mannich adducts 474
were obtained in 5389% yields, with 61/3984/16 dr. Some
limited examples of the similar reaction were reported using
Lewis acid catalyst in combination with chiral ligands, leading to
stereoselective Mannich adducts (Scheme 112, a).228 Reaction of
ethyl 2-methylacetoacetate with N-tosyl -iminoacetate in the
presence of [(i-Prtrisox)Cu](ClO4)2 or [(i-Pr-BOX)Cu]-
(ClO4)2 (10 mol %) in acetone/Et2O mixture at 28 C for
36 h furnished the corresponding Mannich adduct 474 in 84%
yields, with 90% or 84% ee, respectively.229 In this context,
Sodeoka et al.230 described the asymmetric addition of -keto
acetate to N-PMP protected -iminoacetate using chiral
palladium complex L56 (5 mol %) in THF at room temperature,
to give the Mannich adducts 474 and 476 in 6370% yields, with
74/2677/23 dr and 8999% ee for major isomer. Also, three-
component reaction of ethyl glyoxalate with anilines and -
ketoester 475 was investigated, leading to Mannich adducts 476
in 6185% yields, with 70/3095/5 dr and 9698% and 86
96% ee for major and minor isomers, respectively (Scheme 112,
b).
a
474: R1 = Me; R2 = H, Me; R1R2 = (CH2)3, (CH2)4; R3 = Me, t-
Bu, OEt, Oi-Pr, Ot-Bu; 5389%, 61/3984/16 dr. 476: Ar = XC6H4 Visible light catalysis assisted synthesis of succinate derivatives
(X = 3-Cl, 4-MeO); 6185%, 70/3095/5 dr, 9698% ee (major 474 was reported via cross-coupling reaction of -keto esters
isomer), 8696% ee (minor isomers). with -amino esters using Ru(bpy)3(PF6)2 and Co(dmgH)2pyCl
as a photosensitizer and a catalyst, respectively. By 450 nm blue
LED irradiation of a solution of -amino ester and -keto ester
473 (2 equiv) in the presence of Ru(bpy)3(PF6)2 (10 mol %) and
BD DOI: 10.1021/acs.chemrev.7b00064
Scheme 114. Mannich Reaction of -Dicarbonyl Compounds Scheme 115. Mannich Reaction of Malonates with N-PMP
with -Chloroglycine Estera Protected -Imino Estera
a 1
R = Me, Et; R2 = Et, n-Pr, i-Pr, n-Bu, allyl, Bn, Ph, Cl; 2580%, 22
98% ee.
Scheme 116. Mannich Reaction of -Cyanoacetates with N-

Boc -Iminoacetatea
a 1
R = Me, XC6H4 (X = H, 4-F, 4-Cl, 4-MeO, 4-NO2, 3-CF3); R2 = Me,
Ph, 4-ClC6H4, OEt, Oi-Pr, Ot-Bu, OCH(Ph)2; 3295%, 5198% ee.
Co(dmgH)2pyCl (5 mol %) in anhydrous CH3CN at room

temperature, the desired products 474 were obtained in 4591%
yields, with 1/11/3 dr. The proposed reaction mechanism
involves the formation of -imino ester, as a reaction
intermediate, by two steps single electron transfer (SET). An
electron transfer from -amino ester to excited state Ru-
(bpy)32+*, in situ generated upon visible light irradiation of
Ru(bpy)32+, led to an amine radical cation 477 and reduced
Ru(bpy)3+, which was oxidized by Co(dmgH)2pyCl (CoIII) to
regenerate Ru(bpy)32+ along with formation of the reduced CoII.
The CoII species underwent reduction to highly active CoI
species through an electron and/or proton transfer from amine
radical cation 477, resulting in the formation of iminium ion or a
R = Me, Et, n-Pr, i-Pr, t-Bu, Bn; Ar = XC6H4 (X = H, 4-Cl, 2-Br, 3-
imine, which was captured by -keto ester 473 to give the cross- Me, 4-MeO), 3,4-(MeO)2C6H3, 2-naphthyl, 2-thienyl; 8999%, 18/
coupling product 474. On the other hand the CoI species was 8289/11 dr, 1197% ee.
converted to CoIII through reaction with protons delivered by the
substrates to produce CoIIIH hydride, followed by protonation,
and then H2 elimination (Scheme 113).231
Asymmetric Mannich synthesis of -amino esters 478 was succinates 478 in 3288% yields, with 5196% ee. Considering
developed using -chloroglycine ester as a practical imino ester that no reactions occurred in the absence of thiourea catalyst L57
precursor. Reactions were performed using 2 equiv of - either with or without adding Et3N, the proposed reaction
dicarbonyl compounds as Mannich donors in the presence of mechanism is depicted in Scheme 114, in which by Cl anion
chiral catalyst L57 (10 mol %), Et3N (25 mol %) and 4 MS in abstraction form -chloroglycine ester by thiourea L57, a
DCM under N2 atmosphere, at 78 C and then 30 C for 36 thiourea-bound acyliminium/chloride intermediate 479 was
h. Reactions with -diketones aorded corresponding Mannich generated. Reacting tertiary amine moiety with diketone
adducts 478 in 4095% yields, with 8698% ee. However, generated amine-bond enolate 480, which attacked to the nearby
reactions with -keto esters resulted in formation of -amino iminium ion in an enantioselective manner.232
BE DOI: 10.1021/acs.chemrev.7b00064
Scheme 117. Mannich-Elimination Cascade Reaction of N- Scheme 119. Mannich Reaction of 2-Alkyl Azaarenes with -
Boc -Imino Esters with -Keto-2-pyridylsulfones 489a Imino Estera
a
R = RCO [R = Et, c-Pr, 4-XC6H4 (X = H, F, Br, Ph), 2-thienyl],
CN, CO2Me; 3598%.
Scheme 118. Mannich Addition of -Keto Phosphonates 489

to N-Tosyl -Imino Estera
a 1
R = H, 6-F, 8-Cl, 6-Br, 6-Me, 6-EtO; R = H, Me; R2 = H, 3-Me, 4-
R = Me, n-Pr, t-Bu, Bn, Ph, 2-naphthyl, OEt, R2 = Me, R1R2 =
a 1
Me, 6-Me; 5583%.
(CH2)3; 44 to >98%, 1/110/1 dr, 4384% ee (major isomer).
486. Reactions were carried out by addition of sulfone 486 to a
solution of -imino ester (10 equiv) and Et3N (1 equiv) in
Asymmetric Mannich reaction of malonates with N-PMP
DMSO and stirring at 80 C for 25 h, under an atmosphere of
protected -imino ester, derived from ethyl glyoxalate, was
N2. Reactions proceeded through Mannich reaction to give
developed by Kobayashi et al.233 using chiral zirconium complex.
intermediate 487, which underwent elimination of 2-pyridylsul-
Reactions were carried out by slow addition of -imino ester to a
fonyl moiety to nal desired products 488 in 3598% yields, with
solution of malonate derivatives (1.2 equiv) and chiral Zr
excellent E selectivity (Scheme 117).235
complex, in situ prepared from Zr(Ot-Bu)4 (510 mol %) and
Chiral Lewis acid catalyzed asymmetric Mannich addition of -
BINOL derivative L58 (5.511 mol %), in the presence of 3
keto phosphonates 489 to N-tosyl -imino ester was reported to
MS in THF or toluene at 20 C for 18 h. Dierent BINOL
synthesize optically active phosphonate functionalized -amino
derivatives were investigated and desired Mannich adducts 481
acid derivatives 490. Reactions were performed by in situ
were obtained in 2580% yields, with 2298% ee. The proposed
generation of chiral Lewis acid, Cu(OTf)2-(S)-t-Bu-DiMe-BOX,
catalytic cycle was started by generation of the active zirconium
by stirring 10 mol % of both Cu(OTf) 2 and 2,2-
enolate 483 through interaction of malonate with the Zr catalyst
isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] L1b under vac-
in a bidentate fashion (482), followed by activation of -imino
uum for 2 h, followed by addition of dry DCM and stirring under
ester by coordination to Zr, to give intermediate 484, in which
N2 atmosphere for 0.5 h. Then, by addition of -imino ester (1.2
enolate attacked the imine moiety to give nal Mannich products
equiv), -keto phosphonate 489 and Et3N (10 mol %), and
481 along with regeneration of the chiral Zr complex, for further
stirring at room temperature for 96 h, under N2 atmosphere,
cycles (Scheme 115).
Mannich adducts 490 were obtained in 44 to >98% yields, with
Moreover, -substituted -cyanoacetates were subjected to
1/110/1 dr and 4384% ee for major isomer. The proposed
Mannich reaction with N-Boc -iminoacetate (1.21.5 equiv) in
transition state (491) of the reaction is depicted in Scheme 118,
the presence of (DHQD)2PYR L59 (5 mol %) in DCM at 78
in which -keto phosphonate 489 coordinated to the Cu(II)
C, to give -amino--cyanosuccinate derivatives 485 in 89
center in a bidentate fashion, and due to the steric repulsion
99% yields, with 80/2089/11 dr and 9197% ee. Interestingly,
between t-Bu group of the chiral bisoxazoline ligand L1b and the
ortho-substituted bromocyanoester led to corresponding Man-
N-tosyl moiety of the -imino ester, addition occurred trough re-
nich adduct in 95% yield, with anomalous diastereoselectivity
face of the -enol phosphonate 489 to the re-face of the imine,
(18/82% dr) and very low ee. By performing reaction in toluene,
that accounted the diastereo- and enantioselectivity of the
diastereo- and enantioselectivity were improved to 85/1598/2
reaction.236
dr and 98% ee (Scheme 116).234
Synthesis of -oxo-,-dehydro--amino esters 488 was 12.5. Reaction with 2-Alkyl Azaarenes
achieved via an Et3N-mediated Mannich-elimination cascade A Brnsted acid promoted Csp3H functionalization of 2-alkyl
process from N-Boc -imino esters with -keto-2-pyridylsulfones azaarenes with -imino ester, derived from triuoropyruvate, was
BF DOI: 10.1021/acs.chemrev.7b00064
Scheme 120. Three-Component Mannich-Type Reaction of Diazo Compounds, Phosphoramidate, and -Imino Estersa
a 1
R = n-Bu, XC6H4 (X = H, 4-F, 3-Cl, 4-Cl, 4-Br, 4-MeO), PhCO; R2 = H, CO2Me, CO2Et; R3 = Me, Et, i-Pr, t-Bu; Ar = 2,6-Me2C6H3; 4573%,
60/40 to >99/1 dr (syn selectivity), 7998% ee.
Scheme 121. Mannich-Type Reaction of -Imino Esters with 3-Diazooxindole and Indolea
a 1
R = Me, Bn; R2 = H, 5-Br, 6-Br, 7-Me, 5-MeO, 5-NO2; R3 = Bn, Boc; R4 = H, 5-F, 6-F, 6-Cl, 5-Me, Ar = 4-XC6H4 (X = H, F, Cl, Br, Me), 3,4-
Cl2C6H3, 3,5-Cl2C6H3; 4994%, > 95/5 dr, 4998% ee.
described by heating a solution of -imino ester with 2 equiv of were performed using 1.2 equiv of both diazo compound, a
an alkyl azaarene in 1,4-dioxane in the presence of TfOH (20 mol phosphoramidate in the presence of Rh2(OAc)4 (2 mol %), chiral
%) at 100 C for 12 h. Reactions proceeded by protonation of Brnsted acid (S)-L17 (2.5 mol %) and 4 MS in toluene at
nitrogen of azaarene to ion 493, which caused an increase in the room temperature, and 2,3-diaminosuccinates 496 were
acidity of CH of alkyl group, triggering the cleavage of the CH obtained in 4573% yields, with syn selectivity (60/40 to
bond to generate enamine intermediate 494. Enamine 494 >99/1 dr) and 7998% ee. The proposed reaction mechanism
attacked the activated -imino ester to give Mannich addition involves the Rh-catalyzed insertion of diazo compounds with
products 495, which underwent in situ deprotection to nal phosphoramidate to generate phosphoramidate ammonium
adducts 492 in 5583% yields (Scheme 119).237
ylide 497, which attacked the Brnsted acid induced activated
12.6. Reaction with Diazo Compounds -imino esters 498 via transition state 499 to give desired
The synthesis of 2,3-diaminosuccinic acid derivatives 496 was products 496 (Scheme 120).238
achieved by three-component Mannich-type reaction of diazo Mannich-type reaction of -imino esters, derived from
compounds, phosphoramidate, and -imino esters. Reactions arylamines and ethyl glyoxalate, with a zwitterionic intermediate,
BG DOI: 10.1021/acs.chemrev.7b00064
Scheme 122. Mannich Reaction of -Imino Ester with 3-Diazooxindole and Benzyl Alcohol or Diazoketone and Watera
a
506: R1 = Me, Bn, Bz; R2 = H, 5-F, 5-Cl, 6-Cl, 5-Br, 6-Br, 5-Me; Ar = XC6H4 (X = H, 2-Br, 4-Br, 2-Me, 4-MeO), 2-naphthyl, 2-thienyl, PhCH
CH-, PhCC-; 5086%, > 20/1 dr, 68/3298/2 er. 507: R = i-butenyl, c-Hex, trans-styryl, XC6H4 (X = H, 3-Br, 4-Br, 4-Me, 4-MeO), 2-naphthyl;
Ar = 4-XC6H4 (X = H, Cl, Br, Me), X2C6H3 (X = 3,4-F2, 3,4-Cl2, 3,5-Cl2); 5888%, anti/syn = 66/3489/11, 8596% ee (for anti isomer).
Scheme 123. Vinylogous Mannich Reaction of -Imino Esters with 2-Siloxyfurana
a
Ar = XC6H4 (X = H, 3-Cl, 4-Br, 4-I, 4-t-Bu, 3-MeO, 4-CF3), 2-naphthyl; NaHCO3 workup: anti: 5178%, 8191% ee, anti/syn = 72/2593/7;
AcOH workup: anti: 7295%, 8794% ee, anti/syn = 89/11 to >98/2. Ar = 2-BrC6H4; NaHCO3 workup: syn: 87%, 32% ee, anti/syn = < 2/98;
AcOH workup: syn: 87%, 32% ee, anti/syn = < 2/98.
generated from a 3-diazooxindole 500 and indole, was reported -amino esters 501 in 4994% yields, with >95/5 dr and 49
by Xing et al.239 in a four component fashion. Reactions were 98% ee. Reactions proceeded by generation of zwitterionic
carried out by slow addition of a solution of 3-diazooxindole 500 intermediates 502a and 502b, from reaction of 3-diazooxindole
and indole (1.1 equiv) in xylene to a mixture of arylamine (1.1 500 and indole, followed by dematalation of 502b into enol 503,
equiv) and ethyl glyoxalate (1.2 equiv) in the presence of which attacked the in situ generated -imino ester, activated by
Rh2(OAc)4 (2 mol %) and chiral Lewis acid (S)-L29 (5 mol %), chiral phosphoric acid 504, to give nal Mannich adducts 501.
and 4 MS in xylene over 1 h at 25 C, to give -tetrasubstituted The stereochemistry outcome of the reaction was attributed to
BH DOI: 10.1021/acs.chemrev.7b00064
Scheme 124. Vinylogous Mannich-Type Reaction of Dioxinone-Derived Silyl Dienolate with N-tert-Butanesulnyl -Imino Estera
a
R = Me, Et, t-Bu, Bn; 512a: 5086%, 92/895/5 dr; 512b: 4083%, 13/8718/82 dr; 513: 4289%, 96.5/3.5 to >99/1 dr.
Scheme 125. Vinylogous Mannich Reaction of Benzhydryl- alcohol (1.5 equiv), and 3-diazooxindole 500 (1.5 equiv) in the
Protected -Imino Ester with Substituted 2-Vinyloxirane presence of Rh2(OAc)2 (1 mol %), chiral BINOL derived
phosphoric acid derivative L30 (10 mol %), and 4 MS in DCM
at 0 C for 1 h, under argon atmosphere. The desired Mannich
adducts 506 were obtained in 5086% yields, with >20/1 dr and
68/3298/2 er (Scheme 122, a).240 Same research group
developed highly enantioselective synthesis of chiral -hydroxy-
-amino acid derivatives 507 via a four-component reaction of a
diazoketone, water, an aniline, and ethyl glyoxylate in the
presence of Rh2(OAc)4 and a chiral Brnsted acid L29. Reactions
were performed with a 1.2/1.0/1.2 ratio of -diazoketone/
aniline/ethyl glyoxalate in the presence of water, Rh2(OAc)4 (2
mol %) and chiral Brnsted acid (S)-L29 (5 mol %) in DCE at
10 C, to give -hydroxy--amino acids 507 in 5888% yields,
with anti/syn ratio of 66/3489/11 and 8596% ee for the anti
isomer (Scheme 122, b).241
12.7. Vinylogous Mannich Reaction
Ag-catalyzed diastereo- and enantioselective vinylogous Man-
nich reaction of -imino esters was developed by Hoveyda et
al.242 Treatment of 2-siloxyfuran with -imino esters in the
presence of chiral ligand L60 (10 mol %), AgOAc (11 mol %),
and i-PrOH (1 equiv) in THF at 78 C for 15 h, under an
atmosphere of N2, followed by workup using aqueous NaHCO3
furnished vinylogous Mannich adducts 508 in >98% conversion,
as two stereoisomers, with majority of anti isomers in 5176%
yields, with 8191% ee. anti/syn ratios were determined as 72/
2593/7. Acidic workup using AcOH in MeOH, was improved
the formation of transition state 505, in which the aryl group of the yields of anti isomers (7295% yields) and diastereose-
the imine moiety was oriented toward the empty pocket of the lectivity. Reactions with -imino ester, derived from ortho-
L29 catalyst, and due to the formation of hydrogen bond bromophenylglyoxalate and also 4-methyl-2-siloxyfuran led to
between Lewis basic phosphoryl oxygen atom and the acidic C corresponding syn isomers as major products in 87% and 94%
H proton at the C3 position of the indole ring in the zwitterionic yields, with low enantioselectivity, respectively. The stereo-
intermediate 502b, the Bn-group on indole was positioned away chemistry outcome of the reaction was attributed to the
from the ester group (Scheme 121). formation of the 1:1 Ag/ligand complex, followed by
A similar methodology was reported for the construction of coordination of -imino ester to Ag in a bidentate fashion
chiral -alkoxy C-tetrasubstituted -amino esters 506 via through nitrogen of imine and oxygen of ortho-methoxy group, in
Mannich reaction between N-benzhydryl--imino ester, benzyl such way to minimize the steric hindrance with tert-butyl bulky
BI DOI: 10.1021/acs.chemrev.7b00064
Scheme 126. Reductive Mannich Reaction of N-Tosyl -Imino Ester with Aldiminesa
a
R = Ph, c-Hex; Ar = XC6H4 (X = H, 2-MeO, 4-MeO, 4-Me2N, 2-MeS), 2,4-(MeO)2C6H3; 1785%, syn/anti = 89/11 to >99/1; R = PhCC,
TMSCC; Ar = PMP; 4455%, anti/syn = 93/7 to >99/1.
substituent on ligand to form endo catalyst-substrate complex of silyl dienolate and also oxygen of sulnyl and nitrogen of imine
509, in which the aryl group of -imino ester is situated trans to moiety (516), which led to re-face addition to give R-
the Si group of 2-siloxyfuran, which was activated by amide conguration in the newly formed chiral center. However, the
terminus for addition. In the case of the ortho-substituted aryl larger anion, TfO, inhibited the approach of OTMS to Ag+,
group and 4-Me-2-siloxyfuran, due to the steric interactions, resulting in the -selectivity (Scheme 124).
reactions proceeded via exo catalyst-substrate complex 510, 1,2-Dihydropyridine 518 was synthesized by vinylogous
leading to the syn isomer with low to moderate enantioselectivity Mannich reaction of a benzhydryl-protected -imino ester with
(Scheme 123). substituted 2-vinyloxirane 517. Reactions were performed using
A highly regio- and diastereoselective vinylogous Mannich- Sc(OTf)3 (15 mol %) in the presence of 5 MS in THF at 0 C
type reaction of dioxinone-derived silyl dienolate 511 with chiral and then at 50 C for 2 h, giving 1,2-dihydropyridine 518 in 63%
(R)-N-tert-butanesulnyl imino ester was reported by Liu et yield. In the proposed reaction mechanism, intermediate 520 is
al.243 Reactions were carried out by addition of silyl dienolate 511 generated by ring opening of the epoxide followed by a 1,2-
(1.5 equiv) to a solution of -imino ester in the presence of Lewis hydride shift and a subsequent enolization of complex 519,
acid (10 mol %) in DCM at 78 C under argon atmosphere and formed by coordination of vinyloxirane 517 to Sc(OTf)3. By
stirring for 2460 h at the same temperature. When Zn(OTf)2 vinylogous Mannich reaction of intermediate 520 with -imino
was used as Lewis acid catalyst, -addition products 512a were ester, (E)-amino-,-unsaturated aldehyde 521 was formed,
obtained in 5086% yields, with 92/895/5 dr, and SR,CR which isomerized into the (Z)-isomer 523 via dienolate
conguration of major diastereomers. Using AgOTf, correspond- intermediate 522, under the inuence of Sc(OTf)3. 1,2-
ing -adducts 512b were obtained in 4083% yields, with invers Dihydropyridine 518 was obtained by cyclization of the (Z)-
diastereoselectivity (13/8718/82 dr, with majority of SR,CS). amino-,-unsaturated aldehyde 523 to the hemiaminal 524,
By conducting the reactions using Ag(TFA) or AgOAc, - followed by elimination of a water molecule (Scheme 125).244
adducts 513 were obtained as major products in 4289% yields,
12.8. -Imino Ester as Nucleophile in Mannich Reaction
with 96.5/3.5 to >99/1 dr (SR,CR). Reaction with (S)-N-tert-
butanesulnyl imino ester in the presence of Ag(TFA) aorded ,-Diamino esters 525 were synthesized by diastereoselective
corresponding -adduct 513 in 82% yield, with 97/3 dr (SS,CS). reductive Mannich reaction of N-tosylimine derived from ethyl
In the transition state of the Zn(OTf)2-catalyzed vinylogous glyoxylate with various aldimines in 1785% yields. Reactions
Mannich reaction, the -imino ester moiety was coordinated to were carried out by addition of -imino ester (2 equiv) to a
Zn2+ via nitrogen and oxygen atoms in bidentate fashion, leading solution of aldimine and TiI4 (3 equiv) in CH3CN at 40 C and
to the addition from re-face of imine, to give the (R) then stirring at 40 to 10 C for 23 h. In the cases of
conguration of the newly formed stereocenter (514). In aldimines derived from benzaldehyde and cyclohexane carbalde-
contrast, in the case of Ag(OTf), Ag+ was chelated with nitrogen hyde, the corresponding diamino esters 525 were obtained with
and oxygen atoms of imino ester and also oxygen atom of sulnyl excellent syn selectivity (syn/anti = 89/11 to >99/1). While
moiety in a tridentate fashion, which caused addition to imine via aldimines possessing carboncarbon triple bonds aorded anti
si-face (515). In the case of AcO and TFA counterions of Ag adducts 525, predominantly (anti/syn = 93/7 to >99/1).
salts, they play a critical role by interacting with the Si of TMS Proposed reaction mechanism involves the generation of enolate
group to enhance the coordination between Ag+ and the oxygen species 526 by addition of iodide anion with imine (route a) or
BJ DOI: 10.1021/acs.chemrev.7b00064
ester (route b) moieties of -imino ester, followed by reaction Scheme 127. MukaiyamaMichael Addition of Silylketene
with the other iodide anion. The Mannich addition of enolate Acetals to N-Tosyl ,-Unsaturated -Imino Estersa
526 to aldimine occurred via a six-membered cyclic transition
state 527 or an acyclic counterpart 528, leading to syn-selectivity.
The anti-selectivity outcome of the reaction in the case of alkyne
substituted aldimines, attributed to the addition of enolate 526 to
aldimine via chair like transition state 529, in which due to the
less hindrance of triple bond, the (E)-imine isomerized to the (Z)
ones, and alkyne moiety positioned equatorially in the transition
state (Scheme 126).245
12.9. Discussion, Synthetic Utility, and the Future
Mannich reaction of enolizable carbonyl compounds, including
aldehydes and ketones, with -imino esters was vastly studied
using variety types of chiral catalysts, aording -amino--
oxoesters with good to excellent enantio- and diastereoselectiv-
ity. Synthetic utility of this reaction was also investigated, and
various heterocyclic systems, such as tetrahydrofuran-2-one, a
R = Me, Et, i-Pr; Ar = XC6H4 (X = H, 2-Cl, 3-Cl, 4-Cl, 4-Me, 2-MeO,
spiro-tetrahydrofuran, pyrrolidine-2-one, and pyrrolo[1,2-b]- 3-MeO, 4-MeO, 2-NO2, 3-NO2, 4-NO2), 2-furyl; Cat. = None, Time =
isothiazole, were synthesized. However, due to the notable 2024 h: 5699%, Z/E = 85/1599/1; Cat. = Cu(OTf)2, Time =
functional groups, including amine, ester and ketone or aldehyde 2090 min: 8099%, Z/E = 14/861/99.
groups, the corresponding Mannich adducts can also be utilized
in the synthesis of other valuable products, in the future works. stabilizing the primitive positive charge at the acetal carbon with
Mannich type reaction of -imino esters with silyl enol ethers was the primitive negative charge on the nitrogen atom, which is
also investigated in the presence of chiral catalyst, exhibiting high possible in the s-cis conformation. On the other hand, in the
to excellent enantio- and diastereoselectivity. There are a few presence of Cu(OTf)2, nitrogen of imine coordinated to Cu(II)
reports on the Mannich type reaction of esters with -imino ions, rendering the substrate more electrophilic, and the reaction
esters, in the literature, which were applied to construction of occurred through an acyclic transition state 533 with the
tetrahydroquinoline derivatives. -Ketoesters, as well as unsaturated imine having the s-trans conformation (Scheme
malonates and cyanoacetates were also investigated in the 127).246 In the meantime, conjugate addition of alkyl zinc
Mannich type reaction with -imino esters, leading to 3-acyl, 3- (Scheme 38) and PhB(OH)2 (Scheme 110) was described in the
carboxy and 3-cyano-aspartates, respectively. However, some related sections, beforehand.
future works are needed to explore the scope of these reactions Michael addition is one of the most important carboncarbon
and investigating dierent kinds of chiral catalysts, to achieve bond forming reactions, and ,-unsaturated -imino esters
excellent stereoselectivity. Also, the application of corresponding underwent this reaction with various carbon nucleophiles. Only
Mannich adducts in organic synthesis can be of interest. few reports are on the Michael addition to ,-unsaturated -
Moreover, Mannich type reaction of -ketosulfone and imino esters in the literature (see also Scheme 38), furnishing
phosphonate were developed. One example of the Mannich enamino esters. Addition of other nucleophiles in the presence of
type reaction of alkyl azaarenes was studied to prepare arylmethyl chiral catalysts to aord enantioenriched products needs to be
substituted -amino acid derivatives, which can be extended to studied.
other types of alkyl aromatics and heteroaromatics, in the future
researches. In addition, some valuable -tetrasubstituted - 14. REDUCTION
amino ester, -hydroxy--amino ester, and ,-diamino ester 14.1. Catalytic Hydrogenation
scaolds were prepared via Mannich type reaction of diazo-
compounds with -imino esters in stereoselective manner using Rh-catalyzed asymmetric hydrogenation of -imino esters was
chiral catalysts. Using various types of diazo compounds and developed for enantioselective synthesis of glycine derivatives
chiral catalysts would be expected in ongoing researches in the 534. Four dierent chiral ligands were investigated, and
eld. Also, vinylogous Mannich reaction was studied; giving allyl (S,S,R,R)-tangphos L61 was selected for excellent conversion
substituted -amino acid derivatives, which were transformed and enantioselectivity. Reactions were carried out by heating a
into dihydropyridine motifs. mixture -imino ester and [Rh((S,S,R,R)tangphos) (cod)]BF4
(1 mol %) in DCM at 50 C under a pressure of H2 (50 atm) in
an autoclave for 24 h, and corresponding -amino esters 534
13. MICHAEL ADDITION were obtained in 84 to >99% conversion with 8495% ee, with a
MukaiyamaMichael addition of silylketene acetals with N- majority of (S) conguration (Scheme 128).247 Hydrogenation
tosylimines derived from ,-unsaturated -keto esters was of -imino ester to the corresponding glycinate derivative was
reported to synthesize N-tosyl ,-dehydroamino esters. also reported using [Ir(COD)Cl]2 (0.5 mo%) in the presence of
Reaction with 2.4 equiv of ,-unsaturated -imino esters 530 chiral phosphinephosphoramidite ligand (R,R)-L62 (1.1 mol %)
in DCM at room temperature for 2024 h aorded the conjugate and KI (5 mol %) in DCM at room temperature for 24 h, under
addition products 531 in 5699% yields, with 85/1599/1 dr, H2 pressure of 20 bar, in 96% yield, with 86% ee.248
with a majority of (Z)-isomer. While (E)-isomers were obtained Iron-catalyzed biomimetic reduction of one example of -
when reactions were carried in the presence of Cu(OTf)2 (10 imino ester with H2 in the presence of phenanthridine (PD,
mol %) in DCM at room temperature for 2090 min. The yields 536a) was reported by Beller et al.249 In this context the same
were 8099% with 14/861/99 dr. Noncatalyzed reaction took research group reported the asymmetric reduction of benzox-
place through a cyclic DielsAlder-like transition state 532 by azinones 376, cyclic -imino esters, via a relay iron/chiral
BK DOI: 10.1021/acs.chemrev.7b00064
Scheme 128. Rh-Catalyzed Asymmetric Hydrogenation of - Scheme 130. Rh-Catalyzed Hydrogenation of Arylglyoxal
Imino Estersa Imines to -Amino Alcoholsa
a
Ar = 4-XC6H4 (X = H, Cl, Br, MeO), 7-X-benzofuran-2-yl (X = H,
Et); 3173%, 9799% ee.
a 1
R = c-Hex, XC6H4 (X = H, 2-F, 3-F, 4-F, 4-Cl, 4-Br, 4-Me, 2-MeO, Scheme 131. Chiral Phosphoric Acid Catalyzed Transfer
3-MeO, 4-MeO, 3-NO2), 1-naphthyl, 2-naphthyl; R2 = Me, Et; Hydrogenation of -Imino Esters with DHPa
84>99% conversion, 8495% ee.
Scheme 129. Iron-Catalyzed Biomimetic Hydrogenation of

Cyclic -Imino Estersa
a 1
R = Me, n-Hex, PhCH2CH2, 4-XC6H4 (X = H, Cl, Br, Me, MeO,
CF3), 3,5-F2C6H3; R2 = Et; R3 = Ph, PMP; 8598%, 9498% ee.252 R1
= c-Hex, XC6H4 (X = H, 4-F, 4-Cl, 4-Br, 3-Me, 4-Me, 4-MeO), 2-
naphthyl, 2-thienyl; R2 = Me, Et, i-Pr, t-Bu, Bn; R3 = PMP; 4695%,
3398% ee.253 R1 = XC6H4 (X = H, 3-Br, 4-Br, 4-Me, 3-MeO, 4-
MeO); R2 = Me; R3 = Cbz; 8996%, 9094% ee.149
were obtained in 7596% yields, with up to 98/2 er. The

proposed mechanism for the hydrogenation reaction of 376 is
depicted in Scheme 129, in which chiral Brnsted acid-induced
asymmetric hydrogen transfer to 376 occurred from dihydro-
phenanthridine (DHPD, 536b), in situ generated from PD 536a
in the presence of a catalytic amount of Fe3(CO)12 and H2. The
enantioselectivity of the hydrogenation is attributed to the
formation of transition state 537, in which the chiral Brnsted
acid L34 controlled the possible hydride transfer process.250
RhCl[(R,R)-TsDPEN](C5Me5)-catalyzed synthesis of -
amino alcohols through reduction of -imino ketones, derived
a 1
from arylglyoxals, was reported by Zaidlewicz et al.251 Reduction
R = H, 7-F, 7-Cl, 5-Me, 6-Me, 7-Me, 7-MeO, 7,8-(CH)4; R2 = Et, i- performed using the HCO2H/Et3N system, by stirring a solution
Pr, n-Bu, Bn, Ph(CH2)2, i-Pr(CH2)3, Cl(CH2)3, MeO(CH2)3, of -imino ketones with HCO2H (5.8 equiv) and Et3N (0.6
vinyl(CH2)3, 4-XC6H4 (X = H, F, t-Bu, MeO), 3,4-Me2C6H3, 3,4-
(CH2CH2O)C6H3; 7596%, 91/998/2 ee.
equiv) in the presence of Rh-catalyst (0.5 mol %) in DMF under
N2 atmosphere at room temperature for 24 h. Reduction
occurred at both ketone and imine moieties to give
Brnsted acid catalysis. By mixing benzoxazinone derivatives 376 corresponding -amino alcohols 538 in 3090% conversion
with PD 536a (20 mol %), tris(4-methoxyphenyl)phosphine (4 and 3148% isolated yields, with 9799% ee, with a majority of
mol %), Fe3(CO)12 (4 mol %), and chiral phosphoric acids (S)- (S)-enantiomer. Reaction with nitro-substituted arylglyoxal
L34 (4 mol %) in mesitylene for 15 min, under argon atmosphere imine did not occur. Reduction of imines of benzofuran-2-yl
in an autoclave, followed by purging with H2 (50 bar) and then glyoxals proceeded in 5773% yields, with 98% ee, in which (R)-
heating at 65 C for 4896 h, chiral dihydrobenzoxazinones 535 enantiomers were obtained as major isomers (Scheme 130).
BL DOI: 10.1021/acs.chemrev.7b00064
Scheme 132. Chiral Brnsted Acid Catalyzed Transfer Scheme 135. Reduction of Chiral N-Phosphinyl -Imino
Hydrogenation of Cyclic -Imino Esters Using DHPa Esters 544 Using L-Selectridea
a
R = Me, Et; Ar = XC6H4 (X = H, 3-F, 4-F, 4-Cl, 4-Br, 2-Me, 3-Me, 4-
Ph), 3,5-Cl2C6H3, 2-naphthyl; 8898%, 96/499/1 dr.
Scheme 136. Reduction of -(Phenylselenyl)--imino Esters

with NaBH3CNa
a
Ar = 4-XC6H4 (X = H, Br, MeO, 4-BrPh), 3,4-Me2C6H3, 2-thienyl;
8192%, 90 to >99% ee.
Scheme 133. Transfer Hydrogenation of ,-Alkynyl -Imino

Esters with DHPa a 1
R = H, Me; R2 = Me, Et, n-Pr, i-Pr, Bn; R3 = Bn, (R)-PhCH(Me);
546: 4755%, 547: 4167%.
using dihydropyridine (DHP) in the presence of (S)-L63 (5 mol

%) in toluene at 50 C for 1822 h, leading to -amino acid
a
Ar = XC6H4 (X = H, 3-F, 4-Cl, 3-Me, 4-Me), 1-naphthyl; 2764%, derivatives 534 in 8598% yields, with 9499% ee (Scheme
8396% ee. 132). You and co-workers253 reported a similar transfer
hydrogenation in the presence of 1 mol % of (S)-L17 in Et2O
Scheme 134. Asymmetric Transfer Hydrogenation of -Imino at room temperature for 48 h, to give the desired products 534 in
Esters and Ketones with Benzothiazolinesa 4695% yields, with 8498% ee. Reaction with methyl ester of
-imino esters resulted in low enantioselectivity (33%). Also,
(S)-L17 catalyzed reduction of N-Cbz protected -imino esters
with DHP was reported, aording -amino esters in 8998%
yields, with 9094% ee (Scheme 131).149 Moreover, molecular
iodine catalyzed transfer hydrogenation of -imino esters with
DHP was reported by Akiyama et al.255
In addition, chiral Brnsted acid catalyzed transfer hydro-
genation of cyclic -imino esters using DHP was reported by
stirring a solution of benzoxazinones 376 and 1.2 equiv of DHP
in the presence of chiral phosphoric acid L17 (1 mol %) in
CHCl3 at room temperature. The corresponding cyclic aryl-
substituted amino acid derivatives 535 were obtained in 8192%
yields, with 90 to >99% ee. Dihydrobenzoxazinones 535 were
opened to linear amino acid amides 540 by subjecting with
a pyridine-2-ol (3 equiv) and benzylamine (5 equiv) in THF at
534: R = c-Hex, XC6H4 (X = H, 3-F, 4-F, 4-Cl, 4-Me, 4-MeO), 2-
naphthyl; Ar = 4-XC6H4 (X = H, Cl, MeO); 7799%, 9399% ee. room temperature for 12 h, without racemization. In the
542: Ar1 = 4-XC6H4 (X = F, Cl, Br, MeO); Ar2 = Ph; Ar1 = Ar2 = proposed reaction mechanism, transition state 540 was formed,
XC6H4 (X = H, 3-F, 4-F, 3-Cl, 4-Cl, 4-Br, 3-Me, 4-Me), 3,4-Cl2C6H3, which favored the hydride transfer form less hindered si-face of
2-naphthyl; 6197%, 9096% ee. the imine moiety (Scheme 132).256 There is another similar
report on the hydrogenation of benzoxazinone with DHP in the
presence of chiral phosphoric acid, in the literature.257
14.2. Transfer Hydrogenation Asymmetric transfer hydrogenation of ,-alkynyl -imino
Chiral phosphoric acid catalyzed transfer hydrogenation of - esters with DHP was reported by You et al.258 Treatment of ,-
imino esters was reported by dierent research groups.149,252254 alkynyl -imino esters 304 with 2.2 equiv of DHP in the presence
Antilla et al.252 described the hydrogenation of -imino esters of chiral Brnsted acid L17 (1 mol %) in Et2O at room
BM DOI: 10.1021/acs.chemrev.7b00064
Scheme 137. Regioselective Reduction of ,-Unsaturated -Imino Esters 141 with NaBH4a
a
R = Me, 4-MeC6H4, 4-NO2C6H4, 2-furyl, CO2Et; Ar = 4-XC6H4 (X = Me, MeO, NO2); 548: 6479%, 549: 8189%, 550: 8290.
Scheme 138. Hydrosilylation of -Imino Estersa genation of -imino ketones, derived from benzile derivatives,
using 1.5 equiv of 2-naphthylbenzothiazoline in the presence of
chiral Brnsted acid L34 (10 mol %) in toluene at 30 C for 2.5
4 h, to give corresponding -amino ketones 452 in 6197%
yields, with 9096% ee (Scheme 134, b).
14.3. Group III and IV-Hydride Donors
Enantioselective reduction of -imino esters, derived from
arylglyoxalate, with catecholborane was developed by Enders et
al.263 for the preparation of glycinate derivatives 534. Treatment
of N-PMP protected -imino esters with 1.6 equiv of
catecholborane in the presence of chiral BINOL-derived
phosphoric acid L34 (10 mol %) in toluene at 22 C for 24
h, resulted in the formation of -amino esters 534 in 8199%,
with 5796% ee. Lithium tri-sec-butyl(hydrido)borate (L-
Selectride) was reported for the reduction of chiral N-phosphinyl
-imino esters 544, by Han et al.264 Reactions were conducted
using 2 equiv of L-Selectride in THF at 78 C under argon
a
534: Ar = XC6H4 (X = H, 3-F, 4-F, 2-Cl, 4-Cl, 2-Br, 4-Br, 3-Me, 4- atmosphere for 8 h, to aord corresponding -amino esters 545
Me, 4-MeO); 7197%, 5193% ee. 552: Ar = 4-XC6H4 (X = H, F, in 8898% yields, with 96/499/1 dr. Used -imino esters 544
Me, CF3); 6874%, 9497% ee. were prepared in 2659% yields, by subjecting phosphinyl amide
543 with -ketoester (2 equiv) in the presence of TiCl4 (100 mol
temperature, furnished trans-alkenyl -amino esters 541 in 27 %) and Et3N (400 mol %) in DCM at room temperature for 12 h
64% yields, with 8396% ee. Interestingly, reduction occurred at (Scheme 135).
both the alkyne and imine moieties. No product was obtained in Aziridine-2-carboxylate derivatives 547 were constructed by
the case of alkyl substituted ,-alkynyl -imino esters. Further reduction of -(phenylselenyl)--imino esters with NaBH3CN
studies revealed that the carboncarbon triple bond was rst (1 equiv) in the presence of AcOH (1 equiv) in EtOH under
reduced to in situ generate alkenyl -imino esters, which argon atmosphere at 0 C for 1 h, followed by cyclization of
underwent next hydrogenation at imine moiety to give nal obtained -(phenylselanyl)--amino esters 546 by treatment
desired products 541 (Scheme 133). with either Me3OBF4 (2.1 equiv) in DCM at room temperature
Moreover, benzothiazoline (BTZ) was reported as a reducing for 12 h or NBS (1.1 equiv) at CH3CN at room temperature for 5
agent for the reduction of -imino esters, through transfer min. Reductions proceeded in 4755% yields, and cylization
hydrogenation.259262 In this context Zhu and Akiyama260 with Me3OBF4 or NBS aorded aziridine-2-carboxylates 547 in
reported the asymmetric transfer hydrogenation of -imino 4161% or 4567% yields, respectively. Reduction of (R)-
esters by heating with 1.6 equiv of benzothiazoline in the phenylethyl protected -imino ester led to two diastereomers in
presence of chiral phosphoric acid L34 (1 mol %) in mesitylene 1/1 ratio (Scheme 136).265
at 50 C for 2230 h, under N2 atmosphere. Various 2- Regioselective reduction of ,-unsaturated -imino esters
arylsubstituted benzothiazolines, including phenyl, o-, m-, and p- 141 was developed by Palacios et al.266 By treatment of ,-
hydroxyphenyl, and 6-hydroxynaphthalen-2-yl-benzothiazolines, unsaturated -imino esters 141 with NaBH4 (2 equiv) in THF at
were studied, and nal desired glyciantes 534 were obtained in 78 C for 12 h, reduction occurred via 1,4-addition to give (Z)-
7799% yields, with 9399% ee (Scheme 134, a). Guo et al.262 -dehydroamino esters 548 in 6479% yields. Reaction of ,-
developed a regioselective and enantioselective transfer hydro- unsaturated -imino esters 141 with NaBH4 (2 equiv) in the
BN DOI: 10.1021/acs.chemrev.7b00064
Scheme 139. Synthesis of Aziridines via Aza-Darzen Reaction of -Imino Esters with Diazo Compoundsa
a
554: R = Me, Et, t-Bu; Ar = XC6H4 (X = H, 4-Cl, 3-Me, 4-Me, 3-MeO), 2-naphthyl; 7492%, 8498% ee. 556: Ar = XC6H4 (X = H, 4-Cl, 3-Me, 4-
Me, 3-MeO), 2-naphthyl; 5166%, > 20/1 dr. 557: R = OEt, XC6H4 (X = H, 4-F, 3-Cl, 4-Br, 3-Me, 4-Ph, 4-MeO), 2-naphthyl; 4778%, 11/119/1
dr.
presence of TFA in CH3CN at 0 C for 3 h resulted in reduction 14.4. Discussion, Synthetic Utility, and the Future
at imine moiety to give ,-unsaturated -amino esters 549 in Reduction of imine bonds of -imino esters is one of the most
8189% yields. When reaction conducted at 30 C in THF, - important approaches to -amino acid derivatives. Catalytic
amino esters 550 were obtained in 8290% yields, in which hydrogenation, transfer hydrogenation and reduction with group
reduction occurred at both imine and carboncarbon double III and IV hydride donors are most commonly used methods for
bonds. (Z)--Dehydroamino esters 548 and ,-unsaturated - the reduction of -imino esters. Using chiral ligands or catalysts
amino esters 549 were also converted to -amino esters 550 by during reduction, enantioenriched -amino esters were obtained.
subjecting with NaBH4 in THF at 30 C and H2 in the presence Reduction of -imino esters was vastly investigated in the
of PdC in MeOH, respectively. When ,-unsaturated -imino presence of chiral catalysts, and corresponding -amino esters
ester 141b, derived from glutamate, treated with NaBH4 in THF were obtained in high to excellent enantioselectivity. Reduction
at 25 C, lactam 551 was produced in 73% yield, via reduction of of -imino ketones occurred either at imine moiety to give -
both imine and carboncarbon double bonds, followed by amino ketones or at both imine and ketone moiety to give -
intramolecular cyclization. Used ,-unsaturated -imino esters amino alcohols. The synthesis of aziridine-2-carboxylate and
141 were prepared through an aza-Wittig reaction of pyrrolidine-2-one are some of the synthetic utility of the
phosphazenes with ,-unsaturated -ketoesters in 8295% reduction of -imino esters. However, the reduction of -
imino esters were appropriately studied, the development of new
yields (Scheme 137).
chiral catalysts and methodologies for mild and enantioselective
Highly enantioselective Lewis base organocatalyzed hydro-
reduction of these compounds are of interest. Also, the utility of
silylation of -imino esters was reported by Zhang et al.267 By this reaction for the construction of natural products and also
subjecting -imino esters with Cl3SiH (2 equiv) in the presence heterocyclic compounds would be expected.
of Lewis base L64 (10 mol %) and pentanoic acid (0.5 mol %) as
an additive in dry DCM at 40 C for 61127 h, corresponding 15. [2 + 1] AZIRIDINATIONS
-amino esters 534 were obtained in 7197% yields, with 51
93% ee, with a majority of (R)-conguration. Reduction of a Chiral Brnsted acid-catalyzed asymmetric aziridination of N-
Boc--imino esters of arylglyoxalates with -diazoacyl oxazoli-
cyclic -imino ester led to the desired product in 90% yield, with
dinones 553 was reported by Maruoka et al.275 Reactions were
15% ee (Scheme 138, a). There are other reports on the performed with N-Boc -imino ester and -diazoacyl oxazolidi-
reduction of some limited examples of -imino esters using nones 553 (1.3 equiv) in the presence of 5 mol % of chiral
Cl3SiH in the literature.268,269 Additionally, Et3SiH (1.5 equiv) Brnsted acid (S)-L66 (5 mol %) in toluene at 40 C for 45 h,
was used for the enantioselective reduction of -imino esters in leading to aziridine-2-carboxylate derivatives 554 in 7492%
the presence of chiral oxorhenium complex L65 (5 mol %) in yields, with 8498% ee (Scheme 139, a). The same research
CHCl3 at room temperature, to give corresponding aryl group described asymmetric aziridination between N--diazo-
glycinates 552 in 6874% yields, with 9497% ee (Scheme acetyl camphorsultam 555 and N-Boc -imino esters (1.2 equiv)
138, b).270 There are other reports on the reduction of -imino in the presence of Brnsted acid Tf2NH (20 mol %) in toluene at
esters and also reductive amination of -keto esters to produce 78 C for 1520 min, to give aziridine-2-carboxylates 556 in
corresponding -amino esters in the literature.271274 5166% yields, with >20/1 dr (Scheme 139, b).276 Also, aza-
BO DOI: 10.1021/acs.chemrev.7b00064
Scheme 140. Aza-CoreyChaykovsky Aziridination of N-tert- diastereoselective aziridination of -imino esters using chiral
Butanesulnyl -Imino Estersa catalysts can be ongoing research in the viewpoint of medicinal
and synthetic chemistry.
16. [2 + 2] CYCLOADDITIONS
A highly diastereoselective synthesis of trans--lactams was
reported by dropwise addition of ketene acetal (1.2 equiv) to a
Scheme 141. Synthesis of -Lactams via [2 + 2] Cycloaddition

of -Imino Estera
a
558: R = Me, Et, i-Pr, c-Pr, c-Hex, PhCH2CH2, CF3, i-propenyl, Ph,
4-ClC6H4, 3,4-(MeO)2C6H3, 2-MeO-5-CF3C6H3, 2-furyl, 2-thienyl;
2492%, 4/1 to >97/3 dr. 559: R1 = H, OMe, CF3; X = O, S; PG =
MOM, PMB; 5188%.
Darzen synthesis of aziridine-2,3-dicarboxylates was developed

by subjecting an -imino ester with -diazo acetate in the
presence of TfOH in EtCN at 78 C.277 A similar approach was
developed for the construction of 2-(triuoromethyl)aziridine-2-
carboxylates in 6295% yields, by stirring a solution of -imino
esters, derived from triuoropyruvates, with diazomethane (10
equiv) in Et2O at room temperature, overnight, followed by
treatment with TFA in reuxing toluene or CHCl3 for 335 h.278
Moreover, the synthesis of triuoromethyl substituent bearing
aziridines was achieved by in situ generation of triuoromethyl
diazomethane from reaction of 2,2,2-triuoroethyl amine
hydrochloride (3 equiv) with NaNO2 (3.6 equiv) in DCM/ a
R = Me, Et, i-Pr, Bn, CH2SMe, CH2CH2Cl, OPh; 7191%, anti/syn
water (30/1: v/v) at 0 C for 1 h, followed by addition of -imino = 28/188/1.
ketones, derived from aryl glyoxals, and BF3OEt2 (1.8 equiv) at
78 C for 0.51.5 h. The triuoromethyl aziridines 557 were
obtained in 4778% yields, with 11/119/1 dr (Scheme 139, c). solution of PMP-protected -imine esters in DCM in the
Also, an example of -imino esters was studied under similar presence of 10 mol % of phosphonium uoride precatalyst at
reaction conditions, to give the corresponding 3-triuoromethy- 78 C and then stirring at room temperature overnight. -
laziridine-2-carboxylate in 60% yield.279 Lactams 560 were obtained in 7191% yields, with anti/syn ratio
Aza-CoreyChaykovsky aziridination of N-tert-butanesulnyl of 28/188/1, via [2 + 2] cycloaddition reaction. Reactions
-imino esters was developed for the construction of aziridine-2- proceeded by activation of ketene acetal through deprotection of
carboxylates by Marsini et al.280 by subjecting a solution of - silyl moiety by nucleophilic addition of oride to silane, followed
imino esters in toluene with trimethylsulfoxonium iodide (2 by reaction with -imino ester to give intermediate 561, which
equiv) in DMSO in the presence of 2 equiv of NaH or KOt-Bu, at were cyclized to nal -lactam 560, along with generation of
0 C, aording aziridine-2-carboxylate derivatives 558 in 24 phosphonium phenoxide, which continued the subsequent
92% yields, with 4/1 to >97/3 dr. Reaction with ethyl glyoxalate catalytic cycles as catalyst. The high diastereoselectivity of the
imine did not occur. Reactions with -imino esters bearing ortho- reaction was attributed to Lewis acidity of phosphonium
O-MOM and ortho-S-PMB substituents aorded corresponding phenoxide, which organized the transition state in such a way
aziridine-2-carboxylates 558 in 5387% yields, with >97/3 dr, that the trans isomer is favored (Scheme 141).281
which were cyclized to corresponding dihydrobenzofurans and Lectka et al.282 developed the synthesis of -lactams by
thiophene 559 by treatment with HCl in EtOH at C, via addition of substituted-acetyl chlorides to a suspension of
deprotection of MOM, PMB, and sulnyl groups along with In(OTf)3 (10 mol %), benzoylquinine (BQ) L68 (10 mol %),
chloride induced ring opening, followed by subjecting with NaI and proton sponge L67 (1 equiv) in toluene at 78 C, followed
in the presence of K2CO3 in CH3CN at 60 C, in 5388% and by adding a solution of N-tosyl -imino ester (1 equiv) in toluene
51% yields, respectively (Scheme 140). at the same temperature during 1 h, and then warming to room
Aziridines, the smallest saturated azaheterocycles, possess temperature over 16 h. -Lactams 562 were obtained in 9198%
many interesting chemical properties. [2 + 1] Aziridination of - yields, with 9/160/1 dr, and 9698% ee, for syn isomer. In the
imino esters, including aza-Darzen and aza-Corey-Chaykovsky absence of In(III), the products 562 were obtained in 4565%
reactions, are commonly used to synthesize aziridine-2- yields. The proposed reaction mechanism involves the formation
carboxylate derivatives. Due to the importance of aziridine-2- of a nonmetal-coordinated zwitterionic enolate 564 by the
carboxylates in natural products and pharmaceuticals synthesis, reaction of complex In(III) 563 with phenylketene, in situ
development of [2 + 1] aziridination of -imino esters with generated from acetyl chloride, followed by coordination of -
dierent substitutions is of interest. Also, enantio- and imino ester to the In-metal through nitrogen and oxygen atoms,
BP DOI: 10.1021/acs.chemrev.7b00064
Scheme 142. In-Catalyzed Synthesis of -Lacatms via [2 + 2] Scheme 145. Proposed Mechanism for the [2 + 2]
Cycloaddition of -Imino Estersa Cycloaddition of Sulfonylchlorides with N-Tosyl -
Iminoacetate
to give intermediate 565, which was transformed to desired nal

products 562 via intermediate 566 by transacylation followed by
regeneration of catalyst (Scheme 142). Also, BQ was reported as
a catalyst for the [2 + 2] cycloaddition reaction between -imino
ester and in situ generated ketenes for the construction of -
lactam core of carbapenems.283 There are other reports on the
synthesis of -lacatms via [2 + 2] cycloaddition of -imino
esters.284
-Lactam derivatives 569 were synthesized by [2 + 2]
a
R = Br, Ph, Bn, CH2OPh, OPh, OAc, OBn, vinyl; 9198%, syn/anti = Staudinger reaction between -imino esters and ketene 568, in
9/160/1, 9698% ee (syn isomer). situ prepared from (E)-methyl 2-diazo-3-oxo-5-phenylpent-4-
enoate 567 via Wol rearrangement. Reactions were carried out
Scheme 143. Synthesis of -Lactam by Staudinger Reaction of by stirring a solution of -imino ester with 567 (1.2 equiv) in the
-Imino Estersa presence of Rh2(OAc)4 (1 mol %) in DCM at 40 C for 1 h, to
give -lactams 569 in 8197% yields, with 1.4/1 to >20/1 dr
(anti/syn). Used -imino esters were prepared by rhodium(II)-
catalyzed reactions of -diazoesters and organic azides in DCM
at 40 C for 24 h (Scheme 143).26
Quinine-catalyzed [2 + 2] cycloaddition of sulfonyl chlorides
with N-tosyl -iminoacetate was described to synthesize -
sultams 570, which underwent ring opening to sulfonamide and
sulfone derivatives. Reactions were conducted in a one-pot
manner, by slowly adding -imino ester to a solution of sulfonyl
chloride (2 equiv) in DCM in the presence of quinine (10 mol
a
R = 1-(TBSO)-vinyl, Ac, 4-XC6H4 (X = H, MeO, NO2); Ar = 4- %) and DIPEA (2.5 equiv) at 80 C, over a period of 10 h, and
XC6H4 (X = MeO, NO2); 8197%, anti/syn = 1.4/1 to >20/1. then stirring for additional 10 h, at the same temperature,
followed by addition of n-octylamine (2 equiv) and warming to
room temperature and stirring for 1 h, to give ethyl 3-
Scheme 144. Synthesis of -Sultams by [2 + 2] Cycloaddition of Sulfonylchlorides with N-Tosyl -Iminoacetatea
a
R = Et, n-Pr, Bn; 4055%, 11/117/1 dr, 7886% ee.
BQ DOI: 10.1021/acs.chemrev.7b00064
octylsulfamoyl-2-(p-toluenesulfonylamino)alkanoates 571 in Scheme 147. Cycloaddition Reaction of Methyl Glyoxalate

4055% yields, with 11/117/1 dr (anti/syn), and 7886% Oxime with Cyclopentadinea
ee. To study the synthetic utility of obtained products, aziridine
572 was synthesized in 74% yield, by reduction of 571 (R = n-Pr)
with LiAlH4 in THF to corresponding alcohol in 82% yield,
followed by cyclization using Mitsunobu condition. Moreover,
ring opening of -sultam 570 was performed using PhMgBr (3
equiv) in Et2O at 0 C to room temperarture for 14 h, leading to
-amino sulfone 573 in 75% yield, regioselectively, in which the
ester moiety remained unchanged (Scheme 144). According to
the fact that no sulfene (like ketene) is generated at 80 C, the
a
authors proposed a mechanism as outlined in Scheme 146. By Acid = TFA, HClO4, BF3, AlCl3, ZnI2; 965%, 580/579 = 42/58
addition of DIPEA to imine moiety, zwitterionic aminal 80/20.
intermediate 574 was generated, which attacked the sulfonyl
chloride to form sulfonamide 575. Deprotonation of inter- monosubstituted alkenes aorded the desired products 578 in
mediate 575 at -position to the SO2 group led to zwitterionic good yields. Ethyl methacrylate furnished isoxazolidine-3,5-
carbanion 576, which underwent cyclization to desired -sultam dicarboxylate 578 in 53% yield, with 7/1 dr. The N-
570, along with regeneration of DIPEA (Scheme 145).285 boranonitrone 577 was reported as the reaction intermediate,
-Lactam skeletons, are found in the structure of many natural formed by acting of BF3 on O-TBDMS protected oxime. Starting
products and a class of drugs for the treatment of bacterial O-TBDMS -oximino esters were prepared by subjecting chloral
infections. [2 + 2] Cycloaddition reaction of -imino esters is hydrate with hydroxyammonium sulfate in the presence of
one of the most important approaches to 2-azetidinon-4- MgCl2 in EtOH to give glyoxylate oxime, followed by silylation
carboxylates, which can be utilized in the synthesis of novel with TBDMSCl in the presence of imidazole in DMF at room
pharmaceuticals. Also, by varying the substituents of -imino temperature for 46 h (Scheme 146).286
esters, new -lactams would be expected, with interesting Acid-catalyzed cycloaddition reaction of methyl glyoxalate
biological activities. Enantio- and diastereoselective construction oxime with cyclopentadine was developed, in which both [4 + 2]
of -lactams is achieved by using chiral catalysts or chiral auxiliary and [3 + 2] cycloadditions occurred. Dependent on the used
bearing substituted -imino esters, which can be interested acids and temperature, in all cases the [3 + 2] cycloaddition
research elds for future works. Also, one report for the preparing reaction took place mostly, and isoxazolidine-3-carboxylate 580
-sultams was reported, and utilized in the synthesis of various was obtained in 965% yields (Scheme 147).287
compounds, such as -amino acid and aziridine derivatives, and Highly enantioselective Ag-cinchona-derived amino phos-
further studies are of interest. phine catalyzed [3 + 2] cyclization of cyclic -imino esters with
isocyanoacetate was reported by Zhao et al.288 By treatment of
17. [3 + 2] CYCLOADDITIONS AND CYCLIZATIONS Ag2O (10 mol %) with L69 (20 mol %) in anhydrous THF at
The synthesis of isoxazolidine-3-carboxylate derivatives 578 was room temperature for 5 min, followed by addition of cyclic -
achieved by [3 + 2] cycloaddition reaction of O-TBDMS oxime, imino ester 367 and isocyanoacetate (2 equiv) and stirring at
20 C for 24 h, directly linked oxazole-imidazoline derivatives
Scheme 146. Synthesis of Isoxazolidine-3-carboxylate by [3 + 581a were obtained in 6199% yields, with 9199% ee, via
2] Cycloaddition of -Oximino Estera double [3 + 2] cyclization reactions at both imine and ester
moieties. Me-substitution at imine moiety of cyclic -imino ester
led to corresponding [3 + 2] cycloadducts 581b in 69% yield,
with low ee (37% ee). When reactions were performed using
isocyanoacetate as the limiting reagent, mono [3 + 2] cyclization
occurred at only imine moiety, and 4-oxo-3a,4-dihydro-3H-
benzo[b]imidazo[1,5-d][1,4]oxazine-3-carboxylates 582 were
obtained in 8496% yields, with 9397% ee. Also, the three-
component reaction with two dierent isocyanoacetates was
investigated by sequentially adding isocyanoacetates, in which
rst cyclization occurred at imine moiety by rst isocyanoacetate,
followed by reaction at ester group by addition of second
isocyanoacetate, to give corresponding linked oxazole-imidazo-
line 583 in 67% yields, with 97% ee (Scheme 148).
Tomita zipper-cyclization of the cyclic N-sulfonyl -imino
esters 81 with ynones 584 was reported to provide functionalized
a 1
cyclopentanone-fused benzosultams 585. Reactions were carried
R = H, Me, Et; R2 = Et, n-Bu, (CH2)4OMe, Ph, CO2Et; R3 = H; out in DCE using 2 equiv of ynones 584 in the presence of 20
R2R3 = (CH2)3; 2879%. mol % of each Ph3P and AcOH, at room temperature for 39 h,
resulted in formation of fused benzosultams 585 in 7895%
derived from ethyl glyoxalate, with dierent alkenes, in 2879% yields, with the E/Z ratio of 1.3/111.1/1. The proposed
yields. Reactions were conducted by heating a solution of oxime reaction mechanism involves the 1,4-addition of Ph3P to ynone
with an alkene (10 equiv) in the presence of BF3OEt2 (2.2 584 to generate the zwitterion intermediate 586a, which
equiv) in DCE at 60 C for 222 h. However, 1,1-disubstituted underwent [1,3]-proton shift in the presence of proton source
alkenes led to the corresponding isoxazolidine in low yields, (AcOH) to give intermediate 586b. Intermediate 586b was
BR DOI: 10.1021/acs.chemrev.7b00064
Scheme 148. Enantioselective [3 + 2] Cyclization of Cyclic -Imino Esters with Isocyanoacetatea
a
581a: R1 = H, 6-Cl, 7-Br, 8-Br, 6-Me, 6-Ph, 6-MeO, 8-MeO; R3 = Me, Et, i-Pr, t-Bu, Ph; 6199%, 9199% ee; 582: R1 = H, 6-Cl, 7-Br, 6-Me, 6-Ph,
8-MeO; R3 = Me, Ph; 8496%, 9397% ee.
Scheme 149. Tomita Zipper-Cyclization of Cyclic N-Sulfonyl shift, followed by regenerating the PPh3 molecule for further
-Imino Esters with Ynonesa catalytic cycles (Scheme 149).289
A variety of ve membered heterocyclic compounds could be
synthesized by [3 + 2] cycloaddition and cyclization reactions. [3
+ 2] cycloaddition of alkenes with nitrones, in situ generated
form -oximino esters, was reported, leading to isoxazolidine-3-
carboxylates. Imidazoline-, fused imidazoline- and fused
pyrrolidine-carboxylates were also prepared by [3 + 2]
cyclization reactions of dierent types of -imino esters.
However, these types of reactions are common in the synthesis
of various types of ve membered heterocycles, there is a few
reports in the literature, and further researches in the led would
be expected. Moreover, opening studies on the enantio- and
diastereoselective [3 + 2] cycloaddition and cyclization of -
imino ester is deeply felt.
18. [4 + 2] CYCLOADDITIONS
18.1. Synthesis of Tetrahydropyridines and Piperidines
Asymmetric aza-DielsAlder reaction between ethyl glyoxylate
imine with aryl-substituted 2-silyloxy-1,3-butadienes 589 was
reported to synthesize tetrahydropyridines 590. Reactions were
performed using 1.2 equiv of diene 589 in the presence of 5 mol
% of a BINOL-derived phosphoric acid L70, in THF at 22 C
for 48 h, leading to tetrahydropyridine derivatives 590 in 18
99% yields, with 6597% de and up to 87% ee, for major
diastereo-isomer. Reactions with electron-withdrawing substi-
tuted aryls such as 4-NO2C6H4 and 2-ClC6H4 aorded low yields
of products. Cleavage of TIPS moiety using TBAF (1 equiv) in
a 1
R = H, Me, Et; R2 = H, Cl, Me, MeO; Ar = 4-XC6H4 (X = H, F, Me, THF at room temperature for 5 min, aorded corresponding
MeO, MeOCH2O); 7895%, E/Z = 1.3/111.1/1. piperidin-4-ones 591 in 8081% yields, with 7685% de and
7187% ee (Scheme 150).290
Gautun et al.291 developed aza-DielsAlder reaction between
converted to phosphorus ylide 588 by nucleophilic addition to N-tert-butanesulnyl -imino ester and 2 equiv of dierent
the imine moiety of -imino ester 81, to provide intermediate dienes promoted by BF3OEt2 (1 equiv) in dry DCM under an
587, followed by intramolecular cyclization. Final desired argon atmosphere. Reaction with Danishefskys diene conducted
products 585 were obtained by AcOH-assisted [1,2]-proton at 78 C for 15 h, aording tetrahydropyridine-4-ones 592ad
BS DOI: 10.1021/acs.chemrev.7b00064
Scheme 150. Synthesis of Tetrahydropyridines via Aza-Diels case of the reaction of N-aryloyl -hydrazono esters with 2,3-
Alder Reaction of Ethyl Glyoxalate Iminea dimethyl-1,3-butadiene in addition to [4 + 2] cycloaddition, [3 +
2] cycloaddition reactions occurred and corresponding
pyrazolidines 596 were obtained as byproducts in moderate
yields. Cycloaddition of N-benzoyl -hydrazono ester with
cyclopentadiene, exclusively aorded corresponding pyrazoli-
dine 597 in 78% yield, with >20/1 dr and 98% ee. The proposed
reaction mechanism involves the generation of silane
hydrazone complex 598 followed by addition of diene to give
allyl cation intermediate 599, which could be collapse to give [3 +
2] cycloadducts (route a) or [4 + 2] cycloadducts (route b)
(Scheme 152). Also, three-component aza-DielsAlder reac-
tions of in situ generated -imino esters with variety of dienes
were reported in the literature.294296
Chiral phosphoric acid catalyzed enantioselective invers-
electron demand aza-DielsAlder reaction of 1-azadienes, N-
aryl ,-unsaturated -imino esters 141, with enecarbamates was
reported by Masson et al.297 Reactions were carried out using 2
equiv of enecarbamates in the presence of BINOL-derived chiral
phosphoric acid L30 (10 mol %) in DCM at room temperature,
a to give tetrahydropyridine-2-carboxylate derivatives 600 in 61
590: Ar = XC6H4 (X = H, 2-Cl, 4-Cl, 3-Br, 4-Br, 4-Me, 4-MeO, 4-
NO2), 3,4-(OCH2O)C6H3, 3,5-(MeO)2C6H3, 1-naphthyl, 2-naphthyl, 82% yields, with 7095% ee. The stereochemistry outcome of
2-furyl; 1899%, 6597% de, up to 87% ee. 591: Ar = 4-BrC6H4, 1- the reaction was attributed to the formation of transition state
naphthyl; 8081%, 7685% de, 7187% ee. 601 by bifunctional catalysis, in which OH group of phosphoric
acid acted as Brnsted acid to activate the 1-azadiene and the
in 73% yield, with 83/17 dr (syn/anti). Cyclopentadiene phosphoryl oxygen atom activated the enecarbamates as a Lewis
furnished corresponding bicyclic tetrahydropyridine derivative base, leading to the endo selectivity of the aza-DielsAlder
593 in 47% yield, with exo/endo ratio of 9/1, at 50 C for 19 h. reaction by addition from the si-face of the azadiene, to aord
Reactions with 2-methyl- or 2,3-dimethyl-1,3-butadienes at 0 C (4S,5R,6R)-cycloadducts (Scheme 153).
for 12 h gave tetrahydropyridines 594 in 19 or 42% yields, Enantioselective synthesis of 4,6-bis(1H-indole-3-yl)-piper-
respectively (Scheme 151). In another work, the same research idine-2-carboxylates 603 was achieved by [2 + 2 + 2] cyclization
group reported the aza-DielsAlder reaction of various dienes of 3-vinylindoles 602 with ethyl glyoxalate derived -imino
with optically active N-sulnyl -imino esters in the presence of esters. Reactions were carried out by addition of 3-vinylindole
BF3OEt2 or TMSOTf (1 equiv) in DCM at dierent derivative 602 (12 equiv) and chiral phosphoric acid L17 (10
temperatures to provide desired cycloadducts in 764% mol %) to a solution of -imino ester in DCM and stirring at
yields.292 room temperature for 1 h, to furnish bisindolyl-piperidine-2-
[4 + 2] cycloaddition of N-pivaloyl -hydrazono esters with carboxylates 603 in 2164% yields, with 75 to >99% ee. In the
substituted 1,3-butadienes was described by Leighton et al.293 plausible reaction mechanism, by addition of 3-vinylindole 602
using 1.5 equiv of (R,R)-silan L35, in toluene or CHCl3 at 23 C to -imino ester through -position of vinyl moiety, followed by
for 24 h, to give the corresponding tetrahydropyridines 595 in proton-shift, intermediate 604 was generated, which underwent
7099% yields, with 8598% ee. Reaction catalyzed with (S,S)- a similar addition path with a second molecule of 3-vinylindole
silan L35 led to the another enantiomer with 8186% ee. In the 602 to alkylidene moiety to give intermediate 605. The nal
Scheme 151. Aza-DielsAlder Reaction between N-tert-Butanesulnyl -Imino Ester and Dienes
BT DOI: 10.1021/acs.chemrev.7b00064
Scheme 152. [4 + 2] Cycloaddition of N-Pivaloyl -Hydrazono Esters with Dienesa
a
R = XC6H4 (X = 2-MeO, 4-MeO, 4-NO2); R1 = R2 = Me; 4575%, 595/596 = 1/1.81.8/1. R = t-Bu; R1 = Me, PhCH2CH2, PMBOCH2CH2, Ph,
4-BrC6H4; R2 = H; R1 = R2 = Me; 595: 6699%, 8198% ee. 597: 78%, > 20/1 dr, 98% ee.
Scheme 153. Invers-Electron Demand Aza-DielsAlder alkyne, and aniline was also investigated to give corresponding
Reaction of 1-Azadienes, N-Aryl ,-Unsaturated -Imino quinolone-2-carboxylates 606 in 7183% yields (Scheme
Estera 155).299 In addition, a iodine-catalyzed three component
reaction of aniline, ethyl glyoxalate, and an alkyne was developed,
in which corresponding quinoline-2-carboxylates were obtained
in 4582% yields, via aza-DielsAlder reaction of in situ
generated imine with alkyne, followed by air-assisted aromatiza-
tion.300
Regio- and stereoselective cycloaddition of N-PMP sub-
stituted -imino acetate with 1-substituted and 1,4-disubstituted
1,3-dienes was described in the presence of BF3OEt2, in which
tetrahydroquinoline derivatives were produced through non-
concerted mechanism. Reaction of ethyl glyoxalate imine with 1-
MeO-1,3-butadiene (1.3 equiv) or 1-OTBS-1,3-butadiene (0.7
equiv) in dry toluene using BF3OEt2 (10 mol %) at 78 C for 5
min and then at room temperature for 45 or 15 min aorded
corresponding 4-vinyl substituted-1,2,3,4-tetrahydroquinoline-
2-carboxylates 607 in 44% or 55% yield, respectively. Reaction
with symmetrical 1,4-disubstituted 1,3-butadines was also
studied under similar reaction conditions using 0.51.1 equiv
of dienes and BF3OEt2 (11.15 equiv) for 13 h. Reaction with
1,4-dimethyl and 1,4-diacetoxy-1,3-butadiene led to 4-vinyl-
1,2,3,4-tetrahydroquinoline-2-carboxylates 608 in 45% and 22%
yield, respectively. In the case of 1,4-di(OTBS)-1,3-butadiene,
a 1
R = Me, Et, n-Pr, i-Pr, t-Bu; R2 = Me, n-Pr; R3 = Et, t-Bu, Bn, 4-BrBn, dihydroquinoline-2-carboxylate 609 was obtained in 30% yield,
4-CF3Bn, C6F5CH2, uoren-9-yl; Ar1 = XC6H4 (X = H, 3-Cl, 4-Cl, 3- via cycloaddition followed by oxidation of corresponding
Br, 4-Me, 4-MeO, 4-NO2), 2-furyl, 2-thienyl; Ar2 = XC6H4 (X = H, 4- tetrahydroquinoline derivative 608. Reaction of 1,4-diphenyl-
Cl, 4-Br, 4-Me, 2-MeO, 4-MeO); 6182%, 7095% ee. 1,3-butadine aorded the ethyl 6-methoxy-3-phenyl-4-(-
styryl)-1,2,3,4-tetrahydroquinoline-2-carboxylate 611 in 41%
yield, with dierent stereochemistry. Reactions proceeded
desired piperidine derivatives 603 were produced by intra- through an ionic mechanism, in which the diene attacked the
molecular cyclization along with proton transfer. Free NH group BF3-induced activated imine moiety, in such way that major part
on the indole is necessary, as reaction with N-Me-indole did not of the diene oriented away from the ester group, to generate the
occur (Scheme 154).298 cationic intermediate 610a. By rotation around the formed CC
18.2. Synthesis of Quinolines and Tetrahydroquinolines bond to 610b, followed by cyclization through addition with
Copper-catalyzed synthesis of quinoline-2-carboxylate deriva- aromatic ring, nal tetrahydroquinoline derivatives 608 were
tives 606 was developed through sequential intermolecular produced. In the case of 1,4-diphenyl-1,3-butadiene the
addition of alkynes onto imines and subsequent intramolecular electronically favored interaction of the iminium nitrogen with
ring closure by arylation. Reactions were conducted using 20 mol the approaching aromatic group led to the preference depicted in
% of Cu(OTf)2 in DCM at room temperature for 16 h, to aord the formation of cationic intermediate 612a, which resulted
quinoline-2-carboxylates 606 in 5292% yields. The proposed dierent stereochemistry of the nal product (Scheme 156).301
reaction mechanism involves the Cu2+ catalyzed alkynylation of Asymmetric Povarov reaction between -imino ester and N-
-imino ester, to generate alkynyl -amino esters 240, which protected pyrroline derivatives was developed using 4 mol % of
underwent Cu2+-induced cyclization to the nal desired product chiral urea catalyst L71 and 2 mol % of ortho-nitrobenzene-
606. Three-component reaction between ethyl glyoxalate, an sulfonic acid (NBSA) as the Brnsted acid in toluene at 60 C
BU DOI: 10.1021/acs.chemrev.7b00064
Scheme 154. [2 + 2 + 2] Cyclization of 3-Vinylindoles with Ethyl Glyoxalate Iminesa
a
R = H, 6-F, 5-Br, 7-Me, 5-MeO, 5-Br-7-Me; Ar = XC6H4 (X = H, Br, MeO), 3,5-Me2C6H3; 2164%, 75 to >99% ee.
Scheme 155. Aza-DielsAlder Reaction of -Imino Esters 619 aorded nal fused tetrahydroquinolines 614 with
with Alkynea regeneration of the gold catalyst (Scheme 158).303
BF3OEt2-catalyzed cycloaddition of glyoxalate derived -
imino esters with alkenes was developed by Palacios et al.304
Reaction of an equimolar amount of styrene or indene with N-(3-
pyridyl) protected -imino ester using 1.2 equiv of BF3OEt2 in
CHCl 3 at room temperature for 35 h aorded the
corresponding 1,2,3,4-tetrahydro-1,5-naphthyridine-2-carboxy-
lates 620 and 621 in 60% or 68% isolated yield, respectively.
Reactions with strained alkenes, such as norbornene and
dicyclopentadiene, gave the corresponding [4 + 2] cycloadducts
622 and 624 in 55% and 65% yields, along with the azetidine
derivatives 623 and 624 via [2 + 2] cycloaddition reaction, in
15% and 14% yields, respectively. Treatment of norbornadiene
a 1
R = Me, MeO, BnO; R2 = XC6H4 (X = H, 2-F, 4-F, 4-Cl, 3-Me, 4- with N-(3-pyridyl) protected -imino ester under the similar
Me, 4-t-Bu, 4-MeO, 4-Ac, 4-HCC); 5292%. reaction conditions furnished the [4 + 2], [2 + 2] and [2 + 2 + 2]
cycloadducts 626a, 627, and 628a in 12%, 54%, and 16% yields,
in the presence of 5 MS, giving 2,3,4-trisubstituted respectively. [2 + 2 + 2] cycloaddition took place through
tetrahydroquinolines 613 in 3280% yields, with 7/39/1 dr transition state 630. In the case of N-(4-nitrophenyl) protected
and 84/1695/5 er (Scheme 157). Large scale synthesis of -imino acetates, reactions aorded the [2 + 2 + 2] cycloadducts
tetrahydroquinoline-2-carboxylates 613 was also investigated by 628b in 45% yield, with formation of [4 + 2] cycloadducts 626a
in situ generation of -iminoacetate by reacting 4-bromoaniline and -amino--lactones 629 via ionic mechanism, BurgiDunitz
with ethyl glyoxalate in toluene at 0 C for 30 min, followed by approach 631, as minor products (Scheme 159). Moreover, the
subjecting with N-protected pyrrolines, chiral urea catalyst L71, a construction of tetrahydroquinoline derivatives via BF3OEt2
Brnsted acid (such as NBSA or PTSA), and 5 MS at 60 C catalyzed Povarov reactions of arylglyoxal and glyoxalate imines,
for 2 h.302 derived from 12-aminodehydroabietic, with cyclopentadiene and
Gold-catalyzed tandem Povarov-type/FriedelCraft reaction ethyl vinyl ethere was reported.305
of uorinated -imino esters with 2-disubstituted furans was Synthesis of one example of the cyclopropane-fused
reported to synthesize uorinated tetrahydrofuran-fused tetrahy- tetrahydroquinoline, 6-methoxy-1a,2,3,7b-tetrahydro-1H-
droquinolines 614. Reactions were performed using 2 equiv of cyclopropa[c]quinoline-1a,2-dicarboxylate 633, was succeeded
furan derivatives in the presence of gold catalyst (5 mol %) in by Sc(OTf)3-catalyzed Povarov cycloaddition between N-PMP
DCM at room temperature, overnight under N2 atmosphere. -imino ester and cyclopropene, in situ generated from
Fused tetrahydroquinolines 614 were obtained in 5185% enoldiazoacetate 632. Reactions were carried out by subjecting
yields, with moderate diastereoselectivity. The plausible reaction enoldiazoacetate 632 (1.2 equiv) with 1 mol % Rh2(OAc)4 in
mechanism involves the generation of cationic intermediate 616 DCM at 0 C for 30 min and then 10 min at room temperature,
by addition of gold activated -imino ester 615 with furan at the followed by addition of -iminoacetate and Sc(OTf)3 (5 mol %)
5-position. By nucleophilic addition of the ortho position of the and stirring at 0 C for 2 h, to give cyclopropa[c]quinoline-
aromatic ring, tricyclic intermediate 617 was formed, which was dicarboxylate 633 in 45% yield, with >20/1 ratio of anti/syn. In
transformed into intermediate 618 via 1,3-proton shift, with the plausible reaction mechanism, metal enol carbene 634 was
subsequent coordination of the gold salt with the enol ether generated by dirhodium(II) catalyzed N2 extrusion from
moiety. FriedelCrafts addition of second molecule of furan to enoldiazoacetate 632, followed by intramolecular cyclization to
BV DOI: 10.1021/acs.chemrev.7b00064
Scheme 156. BF3OEt2-Catalyzed Cycloaddition of N-PMP -Imino Ester with Alkenesa
a
607: R = Me, OTBS; 4455%. 608: R = Me, OAc; 2245%.
Scheme 157. Povarov Reaction between -Imino Ester and N- aromatic addition to generate intermediate 638, followed by
Protected Pyrrolinesa aromatization (Scheme 160).306
Also, 3-uoro-4-triuoroquinoline-2-carboxylate 639 was
prepared in 64% yield, by reaction of pentauoropropen-2-ol
with -imino ester in DCM at 30 C for 0.5 h and then 2.5 h at 0
C, followed by reuxing in toluene for 7 h, with subsequent
addition of TFA and heating under reux conditions for further 8
h. Reactions proceeded by uncatalyzed Mannich addition of
pentauoropropen-2-ol to imine group (640) to generate
intermediate 641, which underwent intramolecular Friedel
Crafts cyclization to tetrahydroquinoline 643 via 642 at higher
temperature. TFA-assisted aromatization of 643 to 639 was
conducted by dehydration and dehydrouorination (Scheme
161).307
Quinoline moiety of uncialamycin, a natural product isolated
from a streptomycete, was synthesized by intramolecular aza-
DielsAlder reaction promoted with BF3OEt2/DDQ. Reactions
a
R = Boc, Fmoc, Cbz; 3280%, 7/39/1 dr, 84/1695/5 er. were performed using allyl or propargyl imino esters 644a or
644b in the presence of DDQ (2 or 1 equiv) and BF3OEt2 (1
form cyclopropene 635, which attacked the Sc(III)-activated equiv) in DCM at room temperature for 1 h, to give fused
imine 636 via Mannich reaction, to provide intermediate 637. quinoline-lactone derivatives 645 in 1572% or 564% yields,
Final product was obtained by intramolecular electrophilic respectively (Scheme 162).308
BW DOI: 10.1021/acs.chemrev.7b00064
Scheme 158. Gold-Catalyzed Tandem Povarov-Type/ alkenes were reported in the literature, to generate benzo-
FriedelCraft Reaction of -Imino Esters with Furansa heterocycles, such as quinoline, tetrahydroquinoline, and also
naphthyridine derivatives. Using either N-heterocycles sub-
stituted -imino esters or a variety of types of alkenes, such as
cycloalkenes and cyclic or acyclic enamines and enol ethers, etc.
in Povarov reaction, the synthesis of new fused heterocyclic
compounds would be expected. However, Povarov type
cycloaddition of two molecules of -imino esters aorded
corresponding dihydroquinazoline-2,4-dicarboxylates, which can
be extended by using either two dierent types of -imino esters
or one -imino ester with another simple imine derivative. Also,
intramolecular aza-DielsAlder reaction of -imino esters is
another important research area for the preparation of cores of
many natural products, exhibiting interesting biological activities,
which can be investigated in the future.
19. ENE REACTION

Tobey et al.310 reported the ene reaction between alkenes and -
imino esters, derived from ethyl glyoxalate. Reactions were
performed using diethyl phosphate (1.0 equiv) as Lewis acid
catalyst in DCM at room temperature for 48 h, to give imino-ene
products 648 in 2591% yields. -Methylstyrene and methyl-
idene cyclopentane worked well in the reaction, while cyclo-
hexenyl substrate aorded the moderate yields of products. The
acyclic and monosubstitutes alkenes were poorer substrates,
a 1
giving corresponding imino-ene adducts 648 in trace to 25%
R = H, 4-Me, 4-MeO, 4-CF3, 2,3-(CH)4; R2 = Me, Et, Ph, 2-thienyl; yields (Scheme 164, a). Moreover, In(OTf)3-catalyzed ene
R3 = H, Me; RF = CF3, ClCF2, PhCF2, PhCHCHCF2; 5185%. addition to -imino esters was developed by Frost et al.22 to
synthesize -allyl -amino ester derivatives. Reactions were
18.3. Synthesis of Tetrahydropyrimidines and carried out by in situ generation of -imino ester from reaction of
Dihydroquinazolines ethyl glyoxalate with an equimolar amount of p-toluenesulfonyl
isocyanate in the presence of In(OTf)3 (5.0 mol %) in
Tetrahydropyrimidine derivatives 646 were synthesized by
benzotriuoride under heating at 110 C for 2428 h, followed
Zn(OTf)2-catalyzed [4 + 2] cycloaddition of 1-azadiene, 3-
by cooling the mixture to room temperature and addition of an
[(tert-butyldimethylsilyl)oxy]-2-[(4-methoxyphenyl)imino]but-
alkene (0.5 equiv) and stirring at the same temperature for 618
3-enoate, with various aldimines. Reactions were conducted in
h, to give ene products 649 in 5588% yields. However, -
DCM using 1.2 equiv of aldimine in the presence of 10 mol % of
methylstyrene and methylidene cycloalkanes worked well in the
Zn(OTf)2 at 0 C under a N2 atmosphere for 3648 h, to
imino-ene reaction, and cyclohexene did not produce the ene
provide tetrahydropyrimidines 646 in 7291% yields (Scheme
adduct. -Imino esters were activated by In(OTf)3 via chelation
163, a).26 In addition, CuBr2-catalyzed synthesis of quinazoline
through N and O atoms (Scheme 164, b).
derivatives 647 was developed by Li et al.309 Reactions
Ni-catalyzed enantioselective ene reaction between -
proceeded by aza-DielsAlder cycloaddition between two
methylstyrene derivatives and cyclic N-sulfonyl -imino esters
molecules of -imino esters using 10 mol % of CuBr2 in toluene
81 was reported by treatment of 81 with -methylstyrenes (3
under reux conditions for 5 days, and 3,4-dihydroquinazoline-
equiv) in the presence of Ni(ClO4)2 (10 mol %) and chiral ligand
2,4-dicarboxylates 647 were obtained in 5279% yields (Scheme
L72 (12 mol %) in DCM at 100 C of oil bath temperature for
163, b).
2040 h, to give corresponding imino-ene adducts 650 in 70
18.4. Discussion, Synthetic Utility, and the Future 92% yields, with 8895% ee (Scheme 165).231
Six membered N-heterocycles are found in many natural A derivative of 4,6-diaminopiperidine-2-carboxylate 651 was
products and pharmaceuticals, with a wide range of biological prepared via tandem aza-ene type reaction/cyclization cascade
activities. Aza-DielsAlder reaction is one of the most important between N-Boc protected -imino ester, derived from ethyl
methods to construction of various types of six membered glyoxalate, and N-Cbz enecarbamate. The reaction was
heterocyclic compounds. Aza-DielsAlder reaction of -imino conducted using N-Cbz enecarbamate (2.1 equiv) in the
esters with various types of dienes was properly studied, giving presence of chiral binaphthol-derived phosphoric acid catalyst
tetrahydropyridine-2-carboxylate derivatives. Also, invers-elec- (R)-L73 (2 mol %) in DCM at 0 C for 5 h, to aord 4,6-
tron demand aza-DielsAlder reaction of ,-unsaturated - diaminopiperidine-2-carboxylate 651 in 84% yield, and a trans/
imino esters with dienophilic components was also reported to cis ratio of 88/12. The ee of the trans isomer was determined as
synthesize tetrahydropyridines. However, there are many reports 98%. In the proposed reaction mechanism, acid-catalyzed imino-
relating to aza-DielsAlder reaction of both -imino esters and ene reaction of -imino ester with N-Cbz enecarbamate gave
,-unsaturated -imino esters in the literature, the investigation active imine intermediate 652, which was converted to nal
of these reactions using new substituted -imino esters and/or in piperidine-2-carboxylate 651 by second imino-ene reaction with
the presence of chiral catalysts to generate enantioenriched another molecule of N-Cbz enecarbamate, to form ,-diamino
tetrahydropyridines are of interest. Additionally, a number of imine 653, followed by subsequent cyclization. The high
Povarov reactions of N-aryl -imino esters with alkynes and enantioselectivity and diastereoselectivity was attributed to that
BX DOI: 10.1021/acs.chemrev.7b00064
Scheme 159. Synthesis of 1,5-Naphthyridine-2-carboxylates via Cycloadditions of N-(3-Pyridyl) -Imino Estera
(R)-L73 preferentially directed attack of both the initial -imino stirring a solution of ,-unsaturated ketones with -imino ester
ester and intermediate 652 onto the si-face, leading to a 4,6-trans (1.5 equiv) and AlCl3 (1 equiv) in DCE at room temperature for
relationship (Scheme 166).311 172 h, and the desire products 655 were obtained in 2787%
Imino-ene reactions of -imino esters are of interest, because yields. Reactions proceeded by nucleophilic addition of nitrogen
highly substituted -allyl--amino acids are produced. However, of -imino ester to AlCl3 activated carbonyl group of ,-
the imino-ene reaction is the rst reported reaction of -imino unsaturated ketones to generate intermediate 654, which
esters; it needs to be explored by varying the alkenes, and underwent [3,3] sigmatropic rearrangement to produce
conducting the reaction using either -imino esters bearing chiral allylglycine amides 655 (Scheme 167).
auxiliary substituents or chiral catalysts to achieve enantioen- Waters et al.313 developed domino 2-aza-Cope/[3 + 2] dipolar
riched -allyl--amino acid derivatives. The products with cycloaddition sequence for the synthesis of highly functionalized
dierent useful functional groups, including carboncarbon pyrrolidines. Reactions were carried out by heating a solution of
double bond, amine and carboxylate groups, can be important equimolar amounts of a homoallylic amine and ethyl glyoxylate
synthetic intermediates to prepare natural products, and also in the presence of 4 MS in toluene under reux conditions for
novel heterocyclic systems; as one example of the synthetic utility 23 h to generate -imino esters 656, which underwent in situ
of this reaction to give highly substituted piperidines has been aza-Cope rearrangement to imine 657, followed by addition of a
reported.
dipolarophile (1.5 equiv), AgOAc (1.5 equiv) and Et3N (2 equiv)
to the reaction mixture and stirring at room temperature for 6 h.
20. AZA-COPE AND ELECTROCYCLIC REACTIONS Various 2-arylsubstituted homoallyl amines and activated
AlCl3-catalyzed tandem nucleophilic addition/oxy-2-azonia- alkenes, such as N-phenyl maleimide, dimethyl maleate, and
Cope rearrangement was reported by Wang et al.312 to prepare dimethyl fumarate, were investigated, and nal pyrrolidines 658
allylglycine amide derivatives. Reactions were performed by were obtained in 2997% yields (Scheme 168).
BY DOI: 10.1021/acs.chemrev.7b00064
Scheme 160. Sc(III)-Catalyzed Povarov Cycloaddition between N-PMP -Imino Ester and Cyclopropene
Scheme 161. Synthesis of Quinoline-2-carboxylate by Reaction of Pentauoropropen-2-ol with -Imino Ester
Scheme 162. Intramolecular Aza-DielsAlder Reaction of Allyl or Propargyl Imino Esters
a
Approach a: R1 = H, F, Cl, Me, MeO, CF3; R2 = H, n-Pr, CH2OBn, Ph; 1572%. Approach b: R1 = H, MeO; R2 = H, n-Pr, CH2OBn, Ph; 564%.
Azasilalactone 663 was synthesized in 48% yield by Claisen hydroxypyrroles were formed, which were isolated as their
rearrangement of silane 662, generated by silylene 660 transfer acylated derivatives 665 by in situ acylation using related
to 3-phenylallyl -imino ester by treatment with 1,1-di-tert-butyl- anhydride at room temperature for 8 h, in 1575% yields. Also, a
2,2-dimethylsilirane 659 in the presence of AgOTs (10 mol %) in similar reaction was investigated with -oximino esters, resulting
toluene at 20 C. Reactions occurred by generation of 661 via in corresponding 3-acyloxypyrrole derivatives 665 in 2773%
addition of nitrogen of imine to the in situ generated silylene 660, yields. In all cases, acylation occurred at both hydroxyl and
followed by 6-electrocyclization to give silane 662, which unsubstituted C-4 of electron rich pyrroles. The proposed
underwent [3,3] sigmatropic rearrangement though a chairlike reaction mechanism involves the protonation of the carbonyl
transition state (Scheme 169).314 group to generate cation intermediate 664, which underwent 4-
The synthesis of 3-hydroxypyrrole derivatives 665 was electrocyclization to give 3-hydroxypyrroles (Scheme 170).315
achieved by aza-Nazarov reaction of 1-azapenta-1,4-dien-3- Due to its ability to construction of complex molecules from
ones. By slow addition of -hydrazono ketones to a solution of simple starting materials, aza-Cope reaction is of interest and
1.32.8 equiv of TfOH in DCM at 78 C, followed by stirring studied in the synthesis of natural products, pharmaceuticals, and
for 10 min at the same temperature, the corresponding 3- heterocyclic compounds. Nevertheless, a few reports on the aza-
BZ DOI: 10.1021/acs.chemrev.7b00064
Scheme 163. Synthesis of Pyrimidine and Quinazoline via [4 + Scheme 165. Ene Reaction between -Methylstyrenes and
2] Cycloaddition of -Imino Estersa Cyclic -Imino Estersa
a
R = H, 5-F, 5-Cl, 5-Me, 5-t-Bu, 5-MeO, 7-OCF3, 6-Cl-7-F; Ar =
XC6H4 (X = H, 4-Br, 3-Me, 4-Me, 4-Et, 3-MeO), 2-naphthyl; 7092%,
8895% ee.
a
646: Ar = XC6H4 (X = 2-Cl, 4-Br, 4-Me, 4-MeO, 4-NO2), 2-
naphthyl; 7291%. 647: R = 3-Cl, 4-Cl, 4-Br, 3-Me, 4-Me, 4-MeO; synthesis of 2-oxo-3-iminopyrrole derivatives. Reactions were
5279%.
carried out by treatment of ortho-allylanilines 666a with 2 equiv
of -imino esters in the presence of Cu(OAc)2 (3 equiv), MnO2
Scheme 164. Acid-Catalyzed Imino-Ene Reaction of -Imino (1 equiv) as oxidant, and KHCO3 (1 equiv) in reuxing toluene
Estersa at 135 C for 24 h, under argon atmosphere, to give 4-
(dihydroindol-2-yl)-2-oxo-3-iminopyrrole-5-carboxylates 667a
in 2173% yields. N-Tosyl-(2,2-dimethyl)-pent-4-enylamine
666b was also studied under the reaction conditions, providing
corresponding pyrrolidine substituted 2-oxo-3-iminopyrrole-5-
carboxylate 667b in 49% yield. The proposed reaction
mechanism involves the generation of the -aminoalkyl radical
669 through aminocupraion of alkene and subsequent CCu(II)
homolysis (668). Then alkyl radical 669 attacked the imino ester
to generate the nitrogen radical intermediate 670, which
converted to enamine 671b by oxidation with either Cu(II) or
MnO2 to imine 671a, followed by tautomerization. Enamine
671b was transformed into nal desired products 667a by
nucleophilic addition to another -imino ester to generate 672
and subsequent tautomerization/intramolecular cyclization to
673, followed by oxidation (Scheme 171).316
3,8-Dioxo-1,4-diazaspiro[4.5]deca-1,6,9-triene-2-carboxylate
derivatives 675 were prepared in 4090% yields, via oxidative
cyclization of 2-(N-phenylcarbamoyl)-2-iminoacetates 674,
using TBAI (1.2 equiv) and tert-butyl hydroperoxide (TBHP,
1.9 equiv) in DCE at 80 C, under an oxygen atmosphere. The
proposed reaction mechanism involves the iodine mediated
generation of the t-BuO radical, which abstracted a hydrogen
atom from 2-(N-phenylcarbamoyl)-2-iminoacetates 674, to give
iminyl radical 677, which underwent ipso-5-exo cyclization to
a
648: R1 = H, Et, Ph; R2 = H, Me; R3 = H, Me; R1R3 = (CH2)3, aord radical 678. Under an atmosphere of oxygen, radical 678
(CH2)4; 2591%. 649: X = None, NTs, (CH2)2; 5588%. was captured by O2 to generate peroxy radical 679, aording nal
produts 675. When reactions were conducted under an argon
Cope reaction with -imino esters are found in the literature, and atmosphere, in addition to 675, quinoxalin-2-ones 676 were
the application of this reaction to build new structures is of obtained in 2868% yields, through intramolecular ortho-
interest. However, the synthesis of -allyl--amino acid attacking cyclization of iminyl radical 677 or 1,2-migration of the
derivatives and also poly substituted pyrrolidines was reported. iminyl moiety (678) to form radical 680, followed by oxidation
In addition, electrocyclic and other pericyclic reactions were and subsequent deprotonation (Scheme 172, a).317 By photo-
rarely reported, in which interesting heterocycles were prepared. catalytic oxidative cyclization of ethyl 2-(N-arylcarbamoyl)-2-
Therefore, the development of this kind of reaction can be chloroiminoacetates 681, under an argon atmosphere, quinox-
interesting to the viewpoint of synthetic and medicinal chemists. alin-2-ones 676 were obtained. Reactions were performed by UV
irradiation of 681 in the presence of Na2CO3 (2 equiv) either in
21. OXIDATIVE CYCLIZATIONS the presence or absence of Ru(phen)3Cl2 (2 mol %) in CH3CN
Cu(OAc)2-promoted cascade carboamination/oxidative cycliza- or DMF, at room temperature for 1224 h, to furnish
tion of -imino esters with alkenes was developed for the quinoxalin-2-one derivatives 676 in 2097% or 1489% yields,
CA DOI: 10.1021/acs.chemrev.7b00064
Scheme 166. Tandem Aza-Ene Type Reaction/Cyclization Cascade between -Imino Ester and N-Cbz Enecarbamate
Scheme 167. AlCl3-Catalyzed Tandem Nucleophilic Scheme 169. Claisen Rearrangement of Silane, Generated by
Addition/Oxy-2-azonia-Cope Rearrangement of -Imino Silylene Transfer to -Imino Ester
Estersa
a 1
R = Me, n-Pent, CH2OPh; R2 = H, Me; R3 = H, Me; R4 = n-Pr, c-Pr,
n-Bu, i-Bu, n-Hex, Bn, (CH2)2CO2Et, (CH2)3OMe, OMe, OEt; 27 Scheme 170. Aza-Nazarov Reaction of 1-Azapenta-1,4-dien-3-
87%. onesa
Scheme 168. Domino 2-Aza-Cope/[3 + 2] Dipolar

Cycloaddition Sequencea
a 1
R = N(Ph)Me, OMe, OBn; R2 = Me, Et, Ph; Ar = XC6H4 (X = H, 4-
Cl, 2-Br, 4-NO2), 3-thienyl, -styryl; 1575%.
22. RADICAL ADDITION

Mn-mediated addition of alkyl iodides to -hydrazono esters was
developed for the synthesis of quaternary -amino acide
derivatives. Subjecting -hydrazono ester with 5 equiv of alkyl
a
Ar = 4-XC6H4 (X = H, MeO, CF3), 2-furyl, 3-pyridyl; 658a: 3697%; iodide in the presence of Mn2(CO)10 (1.1 equiv) and InCl3 (2.2
658b: X = H, Y = CO2Me; 2986%; Y = H, X = CO2Me; 5297%. equiv) in DCM, and irradiation, led to the alkyl adducts 682 in
3869% yields. NN bond cleavage to the corresponding -
amino ester derivatives 683 was performed using SmI2/MeOH
in THF, followed by benzoylation in the presence of Et3N in 76
respectively. Reactions proceeded by a similar mechanism via 98% yields. Radical addition to chiral -hydrazono ester of
iminyl radical 677, as above (Scheme 172, b).318 methyl pyruvate was also investigated under similar reaction
CB DOI: 10.1021/acs.chemrev.7b00064
Scheme 171. Cu(II) Promoted Cascade Carboamination/Oxidative Cyclization of -Imino Esters with Alkenesa
a 1
R = H, 4-F, 4-Cl, 4-Br, 4-Me, 4-MeO, 4-NO2, 3-CO2Et, 4-CO2Et; R2 = Me, p-tolyl; Ar = XC6H4 (X = 4-F, 4-Cl, 4-Br, 4-Me, 4-MeO, 4-NHAc, 3-
CO2Et); 2173%.
conditions, giving corresponding adducts 684 in 6685% yields, described by Shi el al.321 Reactions were performed by stirring a
with 70/3092/8 dr. Reactions proceeded by alkyl radical solution of -imino ester and methyl vinyl ketone (MVK, 1.5
generation via photolysis of Mn2(CO)10 in the presence of alkyl equiv) in CH3CN in the presence of Ph2PMe (30 mol %), and 4
iodides, followed by addition to imine moiety (685) and then H MS at 20 C for 24 h, under aza-MoritaBaylisHillman
atom abstraction from solvent molecule (Scheme 173).319 reaction conditions, and unexpectedly, ethyl 4-oxo-1,3-diaryl-5-
Nucleophilic addition of alkyl radicals to glyoxalate oxime (arylamino)imidazolidine-2-carboxylates 688 were obtained in
ether was developed to prepare -substituted -amino esters 2981% yield, instead of BaylisHillman adducts. Interestingly,
686. Photochemical decarboxylation of acids using a 100-W no reaction occurred in the absence of MVK. The proposed
high-pressure mercury lamp under argon atmosphere in the reaction mechanism involves the addition of Ph2PMe Lewis base
presence of equivalent amounts of phenanthrene (Phen) and to the carbonyl group of the -imino ester (689), followed by
1,4-dicyanobenzene (DCB) in aqueous CH3CN solution for 6 h intramolecular epoxidation to give intermediate 690, which
generated the alkyl radical, which in situ attacked the imine underwent ring opening with aniline, in situ formed by hydrolysis
moiety. Reactions with an equivalent amount of -oximino ester of -imino ester with moisture, generating intermediate 691 by
led to products 686 in 3257% yields, while 4070% yields of removing Ph2PMe. Intramolecular proton transfer provided
products 686 were obtained when 2 equiv of the -oximino ester aminal 692, which attacked another intermediate 690 to give bis-
was used. A plausible reaction mechanism is illustrated in Scheme aminal 694, by removing Ph2PMe with subsequent proton
174. Protonation of glyoxalate oxime ether with carboxylic acid transferring via 693. Deprotonating 694 to 695 with
aorded the carboxylate anion, which underwent decarbox- intermediates, generated in the dimerization cycle of MVK,
ylation with the photogenerated cation radical of phen+ to followed by cyclization resulted in nal imidazolidin-4-ones 688.
produce the alkyl radical (R). The addition of the radical to Compound 694 was also obtained as a byproduct of the reaction,
protonated -oximino ester generated the cation radical 687, which was converted to nal imidazolidin-4-one 688 when
converting to the nal product via electron transfer with the subjected with MVK in the presence of Ph2PMe under reaction
anion radical of DCB.320 Moreover, B, Zn, and Cu mediated
conditions in quantitative yield. Treatment of 694 with other
radical addition to -imino esters were described in Schemes 15,
bases, including K2CO3, DBU, DABCO, and NaH, without using
36, and 171, respectively.
MVK, did not aord the desired product, arming the proposed
mechanism (Scheme 175).
23. MISCELLANEOUS REACTIONS Phosphite-induced heterocyclization of (N-hetarylimino)-
An unexpected phosphine-catalyzed annulation of -imino esters triuoropyruvates 696 was developed for the preparation of
to give polysubstituted oxoimidazolidine derivatives 688 was fused imidazoles 697. Reactions were carried out by stirring a
CC DOI: 10.1021/acs.chemrev.7b00064
Scheme 172. Oxidative Cyclization of 2-(N-Phenylcarbamoyl)-2-iminoacetatesa
a
675: R1 = H, 3-Cl, 3-Br, 2-Me, 3-Me, 2-MeO, 3-MeO, 2,5-Me2, 3,5-Me2, 2,3-(CH)4; R2 = Me, Ph, Bn; 4090%. 676: 6-Br, 6-I, 6-Me, 6-MeO; 27
46%; 5-Cl/7-Cl = 42/20, 5-Me/7-Me = 40/20. 675: 1060%.317 676: R1 = 4-X (X = H, F, Cl, Br, I, Me, OMe, CF3, Ph), 3-X (X = Cl, Br, Me, OMe,
CF3); R2 = Me, Et, Bn, Ph; R1R2 = 6-(CH2)3; Ru(II) presence: 1297%, Ru(II) absence: 1488%.318
solution of equimolar amounts of -imino carboxylate 696 with dig cyclization to provide azetidine 703. In the case of more bulky
triethyl phosphite in Et2O at 0 C for 24 h, leading to tert-butyl isocyanide, corresponding azitidine 703 was obtained
corresponding fused imidazoles 697 in 7587% yields. In the in 9% yield, with formation of ethyl 3-(tert-butylamino)-2-(4-
plausible reaction mechanism, by cheletropic 1,4-cycloaddition methoxyphenylamino)-3-oxopropanoate 704 in 34% yield, via
of N-hetarylimino esters 696 with phosphite followed by 707 by addition of water to nitrilium amine intermediate 705
recyclization of unstable cyclic phosphorane 698, zwitterionic during the workup process (Scheme 178).325
intermediate 699 was generated, which underwent migration of
F to intermediate 700, that cyclized to nal fused imidazole 24. CONCLUDING REMARKS
derivatives 697 by elimination of (EtO) 3 PF 2 (Scheme In this review, we describe recent advances that have been made
176).322,323 in the use of -imino esters and related compounds, including -
exo-Imidazolidin-2-one dienes 701 were synthesized by hydrazono and -oximino esters, -imino ketones, -imino
subjecting -imino ketones with isocyanates (2.5 equiv) in the amide, and unsaturated -imino esters, in organic synthesis. The
presence of Et3N (3 equiv) and Li2CO3 (7.2 equiv) in anhydrous chemistry of these compounds serves as a versatile tool in
toluene at room temperature under N2 for 1224 h in the dark, synthesis of dierent types of -amino acid derivatives, which
in 6185% yields, which underwent DielsAlder reaction with have been wieldy used in the construction of natural products
alkenes, such as N-phenyl maleimide, methyl vinyl ketone, and and also biologically active compounds.
acrolein, to give the corresponding cycloadducts 702 in 8795% Due to the adjacent electron withdrawing ester functionality,
yields (Scheme 177).324 -imino esters were utilized in various types of organic
Two examples of the addition of isocyanides (3 equiv) to N- transformations, in which other types of imines either did not
PMP protected -iminoacetate were reported using 20 mol % of take part or participated with low reactivity. In this review, rst
BF3OEt2 as catalyst in dry THF at room temperature for 24 h. In the methods for synthesis of -imino esters were described and
the case of cyclohexyl isocyanide, azetidine-2-carboxylate 703 then their utility in organic synthesis was surveyed considering
was obtained in 34% yield, through addition of isocyanide to the the types of nucleophile and reaction names. Addition of most
Lewis acid activated imine to generate nitrilium amine organometallic reagents and also metal catalyzed additions
intermediate 705. Addition of a second molecule of isocyanide occurred at the imine moiety, while in some cases, especially
gave nitrilium imine intermediate 706, which underwent 4-exo- Grignard and organoaluminum reagents, addition could take
CD DOI: 10.1021/acs.chemrev.7b00064
Scheme 173. Mn-Mediated Addition of Alkyl Iodides to - Scheme 174. Nucleophilic Addition of Alkyl Radicals to
Hydrazono Estersa Glyoxalate Oxime Ethera
a
R = t-Bu, n-Pent, c-Hex, i-Pr(BocNH)CH, Bn(BocNH)CH, N-Boc-
pyrrolidine-2-yl; 3270%.
place at the nitrogen of the imine via umpolung. Most other

reactions followed the addition at the imine moiety, exceptionally
triuoromethylation of -imino ketones, which occurred at the
ketone group. Also, reductions took place either in imine or both
imine and carbonyl, according to the reducing agents. Cyclo-
addition reactions were also suitably investigated for the
construction of heterocyclic compounds bearing an ester
substituent.
a
R = Et, i-Pr, i-Bu, n-Pent, n-dodecyl, TMSO(CH2)2, TBSO(CH2)4, However, some reactions, such as addition of Grignard,
682: 3868%, 683: 7998%; R = Et, i-Pr, 684: 6685%, 70/3092/8 organoboron, and organozinc reagents, metal catalyzed
dr. alkynylation, FriedelCrafts reaction, Mannich reaction, reduc-
tion, and [4 + 2] cycloadditions were properly studied; it is
Scheme 175. Unexpected Phosphine-Catalyzed Annulation of -Imino Estersa
a
Ar = XC6H4 (X = H, 3-F, 4-F, 4-Cl, 3-Br, 3-Me, 3-CF3, 4-CF3); 2981%.
CE DOI: 10.1021/acs.chemrev.7b00064
Scheme 176. Phosphite-Induced Heterocyclization of (N- Scheme 177. Synthesis of exo-Imidazolidin-2-one Dienes
Hetarylimino) Triuoropyruvatesa from -Imino Ketonesa
a
701: R1 = CH2CH2Cl, XC6H4 (X = H, 3-Cl, 4-Cl, 3-Me, 4-Me, 4-
MeO); Ar = XC6H4 (X = H, 3-Cl, 4-Cl, 3-Me, 4-Me, 4-MeO); 61
85%. 702a: R1 = CH2CH2Cl, Ph; Ar = Ph, 3-MeC6H4; 8790%. 702b:
a 1
R1 = Ph, 4-ClC6H4; R2 = H, Me; 9295%.
R = H, Me; R2 = H, Me; R3 = H, Me; 7587%.
Scheme 178. Addition of Isocyanides to N-PMP Protected -Iminoacetatea
a
R = t-Bu: 703, 9%, 704, 34%; R = c-Hex: 703, 34%.
worthwhile to investigate other types of reactions in light of AUTHOR INFORMATION

synthetic and medicinal chemistry. Meanwhile, the study of the Corresponding Author
mentioned reactions with dierent substrate scope could be of *E-mail: eftekharisis@maragheh.ac.ir; eftekhari.sis@gmail.com.
interest. Also, the investigation of the reactions of -imino esters
ORCID
in the presence of chiral catalysts or using -imino esters bearing
chiral auxiliary groups, to give enantioenriched derivatives of - Bagher Eftekhari-Sis: 0000-0001-8998-8040
amino acids and heterocycles, can be some of the future Notes
prospects of the reactions of -imino esters. The reactions The authors declare no competing nancial interest.
summarized in this review demonstrate that -imino esters and Biographies
related compounds have many competencies in the synthesis of
Bagher Eftekhari-Sis obtained his B.Sc. in Applied Chemistry from
-amino acid derivatives and heterocyclic compounds. However,
University of Tabriz in 2004 and M.Sc. in Organic Chemistry from
the examples represent only a few of the reactions of -imino Sharif University of Technology with Prof. Mohammed M. Hashemi in
esters that can be envisaged. Therefore, expansion of the scope of 2006. Also, he received his Ph.D. under the supervision of Prof.
the reactions of these compounds will require greater eorts. Mohammed M. Hashemi in 2009 and then joined the Chemistry
CF DOI: 10.1021/acs.chemrev.7b00064
Department of the University of Maragheh. His research eld involves TBHP, tert-butyl hydroperoxide
the synthetic utility of dicarbonyl compounds, especially in synthesis of TBS, tributylsilyl
heterocycles, supported catalyst, polymeric, and nanomaterials and their TFA, triuoroacetic acid and triuoroacetate
applications in sensors and biosensors. TfOH, triuoromethanesulfonic acid or triic acid
Maryam Zirak received her B.Sc. in Pure Chemistry and M.Sc. in THF, tetrahydrofuran
Organic Chemistry from University of Tabriz. She obtained her Ph.D. in TIPS, tri-iso-propylsilyl
2010 from University of Tabriz on the topic of pyrone based TMS, trimethylsilyl
heterocycles and their applications in Medicinal Chemistry under the Ts, tosyl
advisement of Prof. Aziz Shahrisa. Then she joined the Chemistry
Department of the Payame Noor University of Mahabad-West REFERENCES
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CP DOI: 10.1021/acs.chemrev.7b00064

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What are some common reactions involving α-imino esters discussed in the review?

What are some common reactions involving α-imino esters discussed in the review?

What are some examples of metal-catalyzed additions to α-imino esters mentioned?

What are some examples of metal-catalyzed additions to α-imino esters mentioned?

Review

Imino Esters in Organic Synthesis: Recent Advances

Department of Chemistry, University of Maragheh, Maragheh 55181-83111, Iran

Department of Chemistry, Payame Noor University, Tehran 19395-3697, Iran

CONTENTS 9.3. FriedelCrafts Reactions of Furans, Pyrroles,

XXXX American Chemical Society A DOI: 10.1021/acs.chemrev.7b00064

Figure 1. Structures of reviewed -imino esters.

solution of ethyl glyoxalate and TsNCO in toluene for 2 days, in

Scheme 1. Synthesis of -Imino Esters

Scheme 2. Grignard Addition to -Imino Esters in the Presence or Absence of ZnCl2a

reaction with EtLi at 78 to 0 C, followed by subjecting with

Scheme 13. Addition of Allylboronate to -Hydrazono Estersa

Scheme 18. Pd-Catalyzed Addition of Arylboronic Acids to N-

uoroborane 60b, which underwent complexation with nitrogen

Scheme 24. Addition of Arylboronic Acid to Cyclic -Imino

esters were obtained in 3081% or 5390% yields, respec-

Scheme 27. Addition of Triallylaluminum to Chiral Glyoxylic Oxime Ethers 100

Scheme 29. Synthetic Utility of Addition of Dialkylzinc to -Imino Esters

Scheme 32. Addition of Allylzinc Bromide to -Imino Estersa

Scheme 37. Nucleophilic [2 + 1] Cycloaddition of -

Scheme 35. BF3OEt2-Catalyzed Addition of Organozinc to -

Reactions were conducted by stirring a solution of 87 and

Scheme 39. Addition of -Silyloxyallylstannanes 148 to -Imino Estersa

CO2R) were also investigated, in which corresponding t-butyl

Scheme 44. Intramolecular Addition of Allyl- and Propargylsilanes to -Imino Lactone

Scheme 45. Addition of Propargyl-SiCl3, Allenyl-SiCl3, and Allyl-SiCl3 to -Hydrazono Estera

Scheme 46. Addition of Organotitanium Reagents to -Imino Estersa

Diastereoselective Pd/In mediated catalytic allylation of chiral

Scheme 53. In-Mediated Addition of 1,3-Dibromo-2-butyne 228 to -Imino Estera

4.4. Zn-Catalyzed Alkynylation

Scheme 66. Umpolung N,N-Dialkylation and N,N,C-

R = Et, n-Pent, TMSCH2CH2, CH2CH-(CH2)n (n = 2, 3, 4); R2 =

Scheme 68. Tandem N-Alkylation/Vinylogous Aldol Reaction of ,-Alkenyl -Imino Estersa

Scheme 69. Umpolung N-Addition/Acylation of ,-Alkynyl -Imino Estersa

Scheme 71. Umpolung N-Alkylation-Mannich Reaction of -Imino Estersa

Scheme 72. Umpolung Addition/Claisen Rearrangement of Allyl -Imino Estersa

8. ADDITION OF NITROGEN, OXYGEN, AND SULFUR

Scheme 78. Amidation of -Imino Estersa

to the zinc atom by deprotonation and release of an ethane

Room temperature: 7595%, 369/374/370: 35/65/00/0/100; 369/375/371: 0/0/100.

by coordination to Sc(III) (372) underwent elimination of

Scheme 88. In(OTf)3-Catalyzed FriedelCrafts Reaction of

Estera R2 = Me, R1R3 = 2-(CH2)3, 2-(CH2)4; 5492%, 8795% ee.

were performed using 1.2 equiv of indole in the presence of 5 mol

enantioselectivity. Reactions were conducted by stirring a -ethoxycarbonyl--bromo-N-phenylacetamides with sodium

Scheme 95. Aza-MBH Reaction of ,-Unsaturated 11. AZA-HENRY REACTION

Scheme 96. Aza-Henry Reaction of N-PMP Protected -

and ethyl vinyl ketone was investigated using bifunctional chiral

Scheme 108. Hf(OTf)4-Catalyzed Mannich-Type Reaction of Scheme 109. Synthesis of Tetrahydro-4-quinolone

Scheme 110. Rh(I)-Catalyzed Tandem Conjugate Addition-

R = R2 = Me, R1R2 = (CH2)3; R3 = Me, Et, i-Pr, t-Bu, Bn; R4 = Me,

Et, Bn; 4591%, 1/11/3 dr.

Scheme 116. Mannich Reaction of -Cyanoacetates with N-

Co(dmgH)2pyCl (5 mol %) in anhydrous CH3CN at room

Scheme 118. Mannich Addition of -Keto Phosphonates 489