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org/acscatalysis Letter

Enantioselective Formal [4 + 3] Annulations to Access

Benzodiazepinones and Benzoxazepinones via NHC/Ir/Urea
Catalysis
Yang-Yang Li, Shuai Li, Tao Fan, Zi-Jing Zhang, Jin Song,* and Liu-Zhu Gong*
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ABSTRACT: A robust and scalable formal [4 + 3] annulation reaction

for the synthesis of optically pure 1,4-benzodiazepinones and 1,4-
benzoxazepinones has been established by a combined catalytic system
consisting of a chiral NHC, a chiral Ir/phosphine-olefin complex, and an
achiral urea, enabling the asymmetric synthesis of a selective inhibitor of
mitochondrial F1F0 ATP hydrolase.
KEYWORDS: N-heterocyclic carbene, iridium, multicatalysis, formal [4 + 3] annulations, 7-membered heterocycles

B oth 1,4-benzodiazepine and 1,4-benzoxazepine scaffolds

containing fused heterocycles are ubiquitous in natural
products, bioactive molecules, and pharmaceuticals (Scheme
benzodiazepine and 1,4-benzoxazepine scaffolds justifies a
continuation of the work on efficient synthetic methods,5 and
the catalytic enantioselective synthesis of these seven-
1a).1 Indeed, several of these seven-membered heterocycles membered heterocycles remains yet to be discovered.6
Chiral N-heterocyclic carbene (NHC) chemistry has
Scheme 1. Asymmetric Formal [4 + 3] Annulations via emerged as a unique and versatile synthetic toolbox to access
NHC/Ir/Urea Catalysis a range of enantioenriched heterocyclic systems in a
convergent manner.7 However, NHC-mediated synthetic
routes to access 1,4-benzodiazepine or 1,4-benzoxazepine
scaffolds in a highly enantioselective fashion remain underex-
plored.8 Over the recent years, NHC/metal asymmetric dual
catalysis9 has been recognized as a promising strategy for
accessing fundamentally new reactivity and can open up new
reaction pathways otherwise inaccessible for conventional
reactions.10 Recently, the Chi group11 and Scheidt group12
demonstrated elegant examples of asymmetric [4 + 2]
annulation reactions of NHC-activated salicylaldehydes and
isatoic anhydrides with reactive ketone substrates (Scheme
1b). The Ye group successfully applied salicylaldehydes as 1,4-
dipole synthons in the synthesis of racemic 1,4-benzoxazepi-
nones via NHC/copper-cocatalyzed [4 + 3] annulation
reactions.13 We envisaged that the successful coupling of
anthranilaldehydes with chiral metal complex mediated 1,3-
dipole electrophiles would provide direct access to the highly
valuable seven-membered heterocycles via an asymmetric [4 +
3] annulation reaction. In the past decades, vinyl aziridines14
have been commonly used as the three-atom component in the
have been identified as selective inhibitors of mitochondrial
F1F0 ATP hydrolase (I),2 as well as antihistaminic and Received: October 2, 2021
antianaphylactic agents (tarpane, II).3 Rocastine (III) shows Revised: October 30, 2021
potent antihistaminic activity, and more importantly, its optical Published: November 15, 2021
isomers with a stereodefined chiral Csp3 at C-2 show marked
differences in the antihistaminic potency.4 Consequently, the
interest associated with the pharmacological activities of 1,4-

© 2021 American Chemical Society https://doi.org/10.1021/acscatal.1c04541

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construction of a plentiful family of enantioenriched hetero- resulted in a slightly diminished yield (entry 6 vs 4). A survey
cycles.15 However, the development of efficient methodologies of triazolium precatalysts 4 showed no improvement in either
for the construction of seven-membered chiral skeletons is still yield or selectivity (entries 7 and 8). Subsequently, a brief
rather limited.16 Herein, we further advance the NHC/TM examination of the organic solvents was carried out (entries 9−
dual catalysis by demonstrating, for the first time, the NHC/ 11), and dichloromethane (DCM) was found to afford the
Ir/urea cocatalyzed highly enantioselective formal [4 + 3] desired product 3a with improved yield (80%) and
annulation reaction of anthranilaldehydes and salicylaldehydes enantioselectivity (97% ee) (entry 11). The control reactions
with vinyl aziridines, rapidly assembling enantioenriched carried out without urea A under the optimized reaction
seven-membered heterocycles (Scheme 1c). conditions further demonstrate its cocatalytic effect (entry 12).
The reaction of anthranilaldehyde 1a with vinyl aziridine 2 Under the optimized reaction conditions, the generality of
was initially treated with [Ir(COD)Cl]2] (2 mol %),15g,16b,17 the asymmetric formal [4 + 3] annulation for various
an achiral triazolium catalyst 4a, oxidant quinone (DQ),18 and substituted anthranilaldehydes was explored (Scheme 2).
a range of chiral ligands (L1-L3) in THF at 25 °C (entries 1−
3, Table 1). The use of the phosphine-olefin ligand19 L3 Scheme 2. Substrate Scopea

Table 1. Optimization of Reaction Conditionsa

entry L 4 solvent yield (%)b ee (%)c

1 L1 4a THF <5 a
2 L2 4a THF 56 55 Reactions were performed by using [Ir(COD)Cl]2 (2 mol %), L3 (8
3 L3 4a THF 71 71
mol %), 4b (20 mol %), A (10 mol %), 1 (0.1 mmol), 2 (0.2 mmol),
DQ (0.11 mmol), and Cs2CO3 (0.02 mmol) in CH2Cl2 (2.0 mL) at
4 L3 4b THF 57 91
25 °C. Isolated yields. The ee values were determined by HPLC.
5 L3 ent-4b THF 40 80
6d L3 4b THF 50 94
7d L3 4c THF 66 93 Anthranilaldehydes 1 with substituents at the meta position
8d L3 4d THF 66 83 to the carbonyl groups were well tolerated, and the desired
9d L3 4b CH3CN 58 68 products were obtained in great yields and enantioselectivities
10d L3 4b toluene 57 87 (3b and 3c). Substrates possessing a halogen substituent at 4-
11d L3 4b DCM 80 97 position of the benzene ring underwent the reaction smoothly
12 L3 4b DCM 67 91 to provide decent yields and excellent enantioselectivities (3d−
a
Reactions were performed by using [Ir(COD)Cl]2 (2 mol %), L (8 3f). Moreover, the presence of 5-substituent on 1 was also
mol %), 4 (20 mol %), 1a (0.1 mmol), 2 (0.2 mmol), DQ (0.11 allowed and the desired benzodiazepine derivatives (3g−3k)
mmol), and Cs2CO3 (0.02 mmol) in solvent (2.0 mL) at 25 °C. were obtained in satisfactory yields of 65−84% and with
b
Isolated yields after chromatography are shown. cThe ee values were excellent enantioselectivities (95−97% ee). The reactions of
determined by chiral high-performance liquid chromatography disubstituted anthranilaldehyde substrates also provided
(HPLC) analysis. dIn the presence of A (10 mol %). THF =
products 3l−3n in high yields (73−90%) and excellent levels
tetrahydrofuran. DCM = dichloromethane.
of stereoselectivity (91%−97% ee). In addition, 3-amino-2-
naphthaldehyde participated in a clean reaction to generate 3o
enabled the formation of 3a in 71% yield and with 71% ee in 80% yield and with 98% ee. The absolute configuration was
(entry 3). The introduction of a chiral triazolium catalyst 4b determined by single-crystal X-ray diffraction analysis of 3a.23
further enhanced the enantioselectivity to 91% ee (entry 4), Such NHC/Ir/urea catalytic system is also amenable to the
while its enantiomer ent-4b exerted a mismatched effect along enantioselective synthesis of 1,4-benzoxazepinones via the
with the chiral ligand L3 (entry 5). The addition of urea A, formal [4 + 3] annulation reaction between salicylaldehydes 5
which has shown cooperative catalytic reactivity with and vinyl aziridine 2 (see Table S1 in the SI for the detailed
NHC,11,20−22 provided improved enantioselectivity but condition optimizations). The salicylaldehyde 5a reacted
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smoothly with vinyl aziridine 2 to afford the desired product 6a Scheme 4. Synthetic Utilitya
in 87% yield and with 98% ee (Scheme 3). The generality of

Scheme 3. Scope of Salicylaldehydes 5a

a
Reactions were performed by using [Ir(COD)Cl]2 (2 mol %), L3 (8
mol %), 4b (10 mol %), A (10 mol %), 5 (0.1 mmol), 2 (0.15 mmol),
DQ (0.11 mmol), and Cs2CO3 (0.02 mmol) in CHCl3 (2.0 mL) at 25
°C. Yields of isolated products. The ee values were determined by
HPLC. a
Reagents and Conditions: (a) Pd(OAc)2, PhI, NEt3, CH3CN, 80 °C,
24 h. (b) Pd/C, H2 (1 atm), MeOH/DCM, 25 °C, 24 h. (c)
BH3•Me2S, THF, 80 °C, 36 h. (d) Red-Al, toluene, 25 °C, 12 h. (e)
1H-imidazole-5-carboxaldehyde, Na(OAc)3BH, HOAc, DCE, 25 °C,
this procedure for various salicylaldehydes was then explored. 48 h. (f) SmI2, THF, 25 °C, 4 h. (g) Pd/C, H2 (1 atm), MeOH/
The introduction of a methyl group and the variation of DCM, 25 °C, 24 h. (h) Grubbs II, methyl acrylate, DCM, 50 °C, 24 h.
substitution pattern were tolerated, and the products 6b−6e
were obtained in good yields and enantiomeric excesses. The The NHC/Ir/urea-catalyzed formal [4 + 3] annulation is
alternation of electron density of benzene ring by introducing readily scaled up. The reaction of salicylaldehyde 5a and vinyl
an electronically rich or deficient substituent exerted a aziridine 2 performed on one millimole-scale under standard
considerable effect on the reaction efficiency and stereo- conditions gave the benzoxazepinone 6a in 73% yield and with
selectivity, as indicated by the cases generating 6f−6m (78− 98% ee (Scheme 4b). The benzoxazepinone 6a can be
91% yields, 91−99% ee). Besides, both 4,5-(methylenebisoxy)- converted into various chiral molecules by easily operational
salicylaldehyde and 3-hydroxy-2-naphthaldehyde also delivered reaction conditions as shown in Scheme 4b. For example, the
good results (6n and 6o). exposure of 6a to SmI2 removed the N-Ts protecting group to
Further transformations successfully exemplified the syn- afford 13 in 83% yield and with 97% ee. Hydrogenation of the
thetic utility of the benzodiazepinones and benzoxazepinones C−C double bond in 6a catalyzed by Pd/C led to an alkyl-
obtained from this reaction (Scheme 4). The asymmetric substituted product 14. In addition, the vinyl moiety of 6a
formal [4 + 3] annulation reaction established was ultimately underwent cross-metathesis with methyl acrylate in the
applied to the asymmetric synthesis of a selective inhibitor of presence of the Grubbs II catalyst to generate 15 in 53%
mitochondrial F1F0 ATP hydrolase24 (Scheme 4a). Under the yield and with maintained ee values.
optimized reaction conditions, the annulation of anthranilalde- A preliminary mechanistic study was carried out to shed
hyde 1a and vinyl aziridine 2a gave 7 in 63% yield and with light on the reaction pathway and active catalytic species
97% ee. A Heck coupling reaction of 7 and iodobenzene (Table 2). In monitoring the reaction of salicylaldehyde 5a
provided the desired product 8 in 95% yield. Subsequent with vinyl aziridine 2 under the standard reaction conditions
hydrogenation of 8 over Pd/C, and followed by a reduction shown in Scheme 3, the rapid formation of O-allylation
process with borane-dimethyl sulfide, furnished 10 in decent product 16 accompanied by the disappearance of the starting
results (82% yield, 96% ee). A subsequent deprotection of the materials was observed in a few minutes, and the aldehyde 16
N-Ms group of 10 was accomplished with Red-Al in toluene, was then smoothly transformed to product 6a in the following
leading to a free amine 11 in 80% yield. Finally, a reductive 3 h. Accordingly, we speculated that the formal [4 + 3]
amination with the imidazolyl aldehyde24 afforded the selective annulation reaction might proceed through a relay catalytic
inhibitor of mitochondrial F1F0 ATP hydrolase 12 in 57% yield pathway. Thus, we carried out some control experiments to
and with 97% ee. investigate the stereocontrol elements in the iridium catalyzed
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Table 2. Mechanistic Studiesa

Figure 1. Proposed catalytic cycle.

ification of intermediate I with salicylaldehyde 5a gives adduct

16 as a key intermediate. Subsequently, the addition of NHC
to aldehyde 16 delivers the Breslow intermediate II, which is
oxidized by bisquinone (DQ) to afford the acyl azolium
intermediate III. The intermolecular lactamization of the
intermediate III finally leads to the formal [4 + 3] annulation
product 6a and regenerates the NHC catalyst.
a
In summary, we have established an efficient synthesis of
Yields of isolated products 16. The ee values were determined by highly enantioenriched 1,4-benzodiazepinones and 1,4-benzox-
HPLC.
azepinones by NHC/Ir/urea cocatalyzed formal [4 + 3]
annulation reaction. The integrated action of the chiral NHC,
the chiral Ir/phosphine-olefin complex, and the achiral urea
intermolecular allylic etherification reaction25,26 of salicylalde- enables excellent stereochemical control. The NHC catalyst
hyde 5a with aziridine 2, which is the initial step in the relay serves not only as a chiral ligand of the iridium to tune the
catalytic pathway (Table 2a). In the presence of [Ir(COD)Cl]2 catalytic performance but also as an organocatalyst of the
(2 mol %) and L3 (8 mol %), the aldehyde 16 was afforded asymmetric oxidative lactamization event. The achiral urea
with moderate enantioselectivity of 47% ee (entry 1, Table 2a). cocatalyst also works cooperatively with an iridium catalyst to
The stereoselectivity was improved to 64% ee upon the facilitate the control of stereoselectivity. The utility of this
addition of 10 mol % of NHC 4b (entry 2), suggesting that the methodology has been demonstrated in the context of catalytic
NHC could enhance the catalytic performance of the iridium asymmetric synthesis of a selective inhibitor of mitochondrial
species by serving as an activating ligand.27,28 As such, a hybrid F 1 F 0 ATP hydrolase and flexible modulation of the
[Ir(L3)(4b)] species10h,29 was prompted to form (detected by benzodiazepinone.
ESI-MS spectroscopy, see SI, Figure S1) and responsible for
the stereocontrol. Interestingly, the stereocontrol could be
further improved by adding catalytic amounts of urea A (entry
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*
ASSOCIATED CONTENT
sı Supporting Information
3), whereas the use of methylated urea B to supersede A under The Supporting Information is available free of charge at
the otherwise identical conditions gave results similar to those https://pubs.acs.org/doi/10.1021/acscatal.1c04541.
without urea additive (entry 4 vs 2), suggesting that the free
NH group of the urea A might get involved in noncovalent General information, experimental section, compound
interactions to benefit stereochemical control.11,20−22 Next, we characterization, and NMR spectra (PDF)
X-ray data for 3a (CIF)

■
performed the oxidation annulation of the chiral aldehyde
intermediate 16 with 94% ee under the catalysis of NHC 4b
(Table 2b), and the 1,4-benzoxazepinone 6a was obtained in AUTHOR INFORMATION
70% yield and 98% ee. The enhancement in enantioselectivity Corresponding Authors
(from 94% ee to 98% ee) can be explained by the kinetic Liu-Zhu Gong − Hefei National Laboratory for Physical
resolution process30 that exists in the chiral NHC-mediated Sciences at the Microscale and Department of Chemistry,
oxidative lactamization event (see Table S3 in SI). The similar University of Science and Technology of China, Hefei
results obtained from the one-pot reaction and the stepwise 230026, China; Center for Excellence in Molecular Synthesis
addition (6a in Scheme 3 vs Table 2b) lead to a conclusion of Chinese Academy of Sciences, Hefei 230026, China;
that the reaction proceeds through a relay catalytic pathway. orcid.org/0000-0001-6099-827X; Email: gonglz@
On the basis of the experimental results, a plausible catalytic ustc.edu.cn
cycle for the formal [4 + 3] annulation reaction is described in Jin Song − Institutes of Physical Science and Information
Figure 1. Initially, vinyl aziridine 2 coordinates with [Ir(I)]* Technology, Anhui University, Hefei 230601, China;
complex and undergoes oxidative addition to furnish the (η3- orcid.org/0000-0003-0449-1727; Email: jill@
allyl)iridium(III) species I. The asymmetric allylic ether- ahu.edu.cn
14391 https://doi.org/10.1021/acscatal.1c04541
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ACS Catalysis pubs.acs.org/acscatalysis Letter

Authors Pyrimidine-Fused Diazepinone Derivatives Bearing a Tertiary Stereo-

Yang-Yang Li − Hefei National Laboratory for Physical genic Center Enabled by Iridium-Catalysed Intramolecular Allylic
Sciences at the Microscale and Department of Chemistry, Substitution. Adv. Synth. Catal. 2021, 363, 3227.
University of Science and Technology of China, Hefei (7) For selected reviews, see: (a) Enders, D.; Niemeier, O.;
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Shuai Li − Hefei National Laboratory for Physical Sciences at Heterocyclic Carbenes as Organocatalysts. Angew. Chem., Int. Ed.
the Microscale and Department of Chemistry, University of 2007, 46, 2988. (c) Izquierdo, J.; Hutson, G. E.; Cohen, D. T.;
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Chem. Rev. 2015, 115, 9307. (j) Yetra, S. R.; Patra, A.; Biju, A. T.
ACKNOWLEDGMENTS Recent Advances in the N-Heterocyclic Carbene (NHC)-Organo-
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We are grateful to the National Natural Science Foundation of 1357. (k) Mondal, S.; Yetra, S. R.; Mukherjee, S.; Biju, A. T. NHC-
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