Enantioselective in Allylation

ORGANIC
LETTERS
Catalytic Enantioselective
Indium-Mediated Allylation of
Hydrazones
2005
Vol. 7, No. 13
2767-2770
Gregory R. Cook,* Robert Kargbo, and Bikash Maity

Department of Chemistry and Molecular Biology, North Dakota State UniVersity,
Fargo, North Dakota 58105-5516
gregory.cook@ndsu.edu
Received May 17, 2005
ABSTRACT
A facile and highly selective indium-mediated allylation of hydrazones utilizing BINOL ligands is described. Chiral (R)-3,3-bistrifluoromethylBINOL
afforded homoallylic amines in up to 97% ee with stoichiometric ligand. Employing only 10 mol % ligand afforded selectivity of up to 92% ee.
Over the past decade, allylindium complexes have emerged

as mild and effective reagents for the allylation of carbonyl
compounds.1 The application of chiral ligands to indiummediated allylations has been an arduous challenge due to
the low heterophilicity of the organoindium reagents. Enantioselective allylation of aldehydes utilizing allylindium was
reported by Loh and produced homoallylic alcohols in
moderate to good enantioselectivity using an excess of
cinchona alkaloids as chiral additives.2 Use of 2 equiv of a
cerium-pybox Lewis acid afforded ee up to 92% in one
example. Very recently, Singaram has reported the enantioselective allylation of aldehydes using excess chiral amino
alcohol additives with ee up to 93%.3 Herein, we report the
first enantioselectiVe indium-mediated allylation of hydrazones affording homoallylic amines in high selectivity
employing a catalytic amount of chiral additive.
(1) Reviews: (a) Araki, S.; Tsunehisa, H. In Main Group Metals in
Organic Synthesis; Yamamoto, H., Oshima, K., Eds.; Wiley: New York,
2004; Vol. 1, pp 323-386. (b) Nair, V.; Ros, S.; Jayan, C. N.; Pillai, B. S.
Tetrahedron 2004, 60, 1959. (c) Li, C. J.; Chan, T. H. Tetrahedron 1999,
55, 11149. (d) Ranu, B. C. Eur. J. Org. Chem. 2000, 2347. (e) Pae, A. N.;
Cho, Y. S. Curr. Org. Chem. 2002, 6, 715.
(2) (a) Loh, T.-P.; Zhou, J.-R. Tetrahedron Lett. 1999, 40, 9115. (b) Loh,
T.-P.; Zhou, J.-R.; Li, X.-R. Tetrahedron Lett. 1999, 40, 9333. (c) Loh,
T.-P.; Zhou, J.-R.; Yin, Z. Org. Lett. 1999, 1, 1855. (d) Loh, T.-P.; Lin,
M.-J.; Tan, K.-L. Tetrahedron Lett. 2003, 44, 507.
(3) Hirayama, L. C.; Gamsey, S.; Knueppel, D.; Steiner, D.; DeLaTorre,
K.; Singaram, B. Tetrahedron Lett. 2005, 46, 2315.
10.1021/ol051160o CCC: $30.25
Published on Web 05/28/2005
2005 American Chemical Society
A direct method for the preparation of chiral amines is

the addition of carbon nucleophiles to CdN bonds. However,
relative to carbonyls, imine derivatives are generally less
reactive, and the use of very strong organometallic reagents
is usually required for nucleophilic addition.4 Thus, enamine
formation and functional group tolerance are common
impediments in these processes. Several examples of indiummediated allylation of CdN bonds have been reported,5
affording an alternative to highly basic nucleophiles. Asymmetric variants have utilized chiral auxiliaries to effect a
diastereoselective addition. For example, chiral sulfinimine
derivatives,6 imines derived from amino acids7 and R-keto
(4) Reviews: (a) Kobayashi, S.; Ishitani, H. Chem. ReV. 1999, 99, 1069.
(b) Bloch, R. Chem. ReV. 1998, 98, 1407. (c) Enders, D.; Reinhold, U.
Tetrahedron: Asymmetry 1997, 8, 1895. (d) Denmark, S. E.; Nicaise, O.
J.-C. Chem. Commun. 1996, 999.
(5) (a) Beuchet, P.; Le Marrec, N.; Mosset, P. Tetrahedron Lett. 1992,
33, 5959. (b) Chan, T. H.; Lu, W. Tetrahedron Lett. 1998, 39, 8605. (c)
Lu, W.; Chan, T. H. J. Org. Chem. 2000, 65, 8589. (d) Kumar, H. M. S.;
Anjaneyulu, S.; Reddy, E. J.; Yadav, J. S. Tetrahedron Lett. 2000, 41, 9311.
(e) Lu, W.; Chan, T. H. J. Org. Chem. 2001, 66, 3467. See also: (f)
Prajapati, D.; Laskar, D. D.; Gogoi, B. J.; Devi, G. Tetrahedron Lett. 2003,
44, 6755. (g) Banik, B. K.; Ghatak, A.; Becker, F. F. J. Chem. Soc., Perkin
Trans. 1 2000, 2179. (h) Ghatak, A.; Becker, F. F.; Banik, B. K.
Heterocycles 2000, 53, 2769. (i) Skaanderup, P. R.; Madsen, R. J. Org.
Chem. 2003, 68, 2115.
(6) (a) Cooper, I. R.; Grigg, R.; MacLachlan, W. S.; Thornton-Pett, M.;
Sridharan, V. Chem. Commun. 2002, 1372. (b) Cooper, I. R.; Grigg, R.;
Hardie, M. J.; MacLachlan, W. S.; Sridharan, V.; Thomas, W. A.
Tetrahedron Lett. 2003, 44, 2283.
chiral sultams,8 have afforded relatively good diastereoselectivity and yield. Recently, we reported9 the highly
diastereoselective allylation of chiral hydrazones bearing an
oxazolidinone auxiliary introduced by Friestad.10 This offered
advantages in diastereoselectivity and reaction rate over the
fluoride-promoted allylsilane addition to chiral hydrazones
reported by Friestad, particularly for aliphatic aldehydederived hydrazones. To date, allylsilanes have been most
successful for stereoselective allylation of acylhydrazone
derivatives. Using CuCl and chiral ligands with allyltrimethoxysilane, Friestad has observed measurable but low
(9.7% ee) selectivity.11 The enantioselective allyation of
acylhydrazones using chirally modified allyl silanes has been
reported by Leighton,12 and high selectivity (85-97% ee)
was obtained in most cases. Chiral sulfoxide-promoted
allylation of hydrazones with allyltrichlorosilane has been
reported using an excess of the promoter in up to 93% ee.13
In addition, Kobayashi has demonstrated that chiral BINAP
oxides could promote this reaction using substoichiometric
amounts (20 mol %, 56% ee; 40 mol %, 69% ee).14 Chiral
bis-allylpalladium catalysts have also been employed in
enantioselective allylation of imines with allylsilanes and
allylstannanes with good to high ee (up to 94%).15
So far, the utility of allylindium in enantioselective
allylations has been very limited. Considering the excellent
success obtained in the addition of allylindium reagents
toward chiral hydrazones,9 we sought to develop the enantioselective variation of this reaction. We began by surveying
several chiral additives (Scheme 1) such as bisoxazoline
ligands, chiral amino alcohols, chiral diamine derivatives,
etc. with the benzaldehyde-derived achiral hydrazone 1a. The
reaction was carried out with 2 equiv of the chiral additive,
2 equiv of indium metal, and 3 equiv of allyl iodide. Most
resulted in very low selectivity or sluggish reactions.
However, similar to Lohs report, the use of 2 equiv of (-)cinchonidine afforded good enantioselectivity (80% ee).
Unfortunately, the yield was very poor. Addition of In(OTf)3
(7) (a) Basile, T.; Bocoum, A.; Savoia, D.; Umani-Ronchi, A.J. Org.
Chem. 1994, 59, 7766. (b) Loh, T.-P.; Ho, D. S.-C.; Xu, K.-C.; Sim, K.-Y.
Tetrahedron Lett. 1997, 38, 865. (c) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune, Y. J. Org. Chem. 2005, 70, 3464.
(8) (a) Lee, J. G.; Choi, K. I.; Pae, A. N.; Koh, H. Y.; Kang, Y.; Cho,
Y. S. J. Chem. Soc., Perkin Trans. 1 2002, 1314. (b) Miyabe, H.; Nishimura,
A.; Ueda, M.; Naito, T. Chem. Commun. 2002, 1454. (c) Miyabe, H.;
Yamaoka, Y.; Naito, T.; Takemoto, Y. J. Org. Chem. 2003, 68, 6745. (d)
Miyabe, H.; Yamaoka, Y.; Naito, T.; Takemoto, Y. J. Org. Chem. 2004,
69, 1415.
(9) Cook, G. R.; Maity, B.; Kargbo, R. Org. Lett. 2004, 6, 1741.
(10) Friestad, G. K.; Ding, H. Angew. Chem., Int. Ed. 2001, 40, 4491
and refs cited therein. Recently, Friestad and co-workers have improved
on the hydrazine cleavage method, improving the utility of these auxiliaries.
See: Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637.
(11) Ding, H.; Friestad, G. K. Synthesis 2004, 2216.
(12) (a) Berger, R.; Rabbat, P. M. A.; Leighton, J. L. J. Am. Chem. Soc.
2003, 125, 9596. (b) Berger, R.; Duff, K.; Leighton, J. L. J. Am. Chem.
Soc. 2004, 126, 5686.
(13) (a) Kobayashi, S.; Ogawa, C.; Konishi, H.; Sugiura, M. J. Am. Chem.
Soc. 2003, 125, 6610. (b) Fernandez, I.; Valdivia, V.; Gori, B.; Alcudia,
F.; A
lvarez, E.; Khiar, N. Org. Lett. 2005, 7, 1307.
(14) Ogawa, C.; Sugiura, M.; Kobayashi, S. Angew. Chem., Int. Ed. 2004,
43, 6491.
(15) (a) Fernandes, R. A.; Yamamoto, Y. J. Org. Chem. 2004, 69, 735.
(b) Bao, M.; Nakamura, H.; Yamamoto, Y. Tetrahedron Lett. 2000, 41,
131. (c) Nakamura, H.; Nakamura, K.; Yamamoto, Y. J. Am. Chem. Soc.
1998, 120, 0, 4242. (d) Nakamura, K.; Nakamura, H.; Yamamoto, Y. J.
Org. Chem. 1999, 64, 2614.
2768
Scheme 1
Lewis acid improved the reaction to 85% yield; however,

this was detrimental to the selectivity (29% ee). Chiral diols,
particularly (R)-BINOL, afforded modest yield and selectivity.16 This prompted us to investigate other BINOL derivatives to optimize the reaction. The 3,3-diiodoBINOL resulted
in an improvement in selectivity, and the 3,3-bistrifluoromethyl-BINOL17 (3) derivative performed the best, affording
a 72% yield of 2a in 70% ee. THF was the best solvent
examined; very low yields and selectivities were observed
in CH2Cl2 (20% yield, 7% ee), and no reaction was observed
in CH3CN. This may be attributed to the lack of generation
of the active allylindium reagent as evidenced by remaining
unreacted In(0). Water appeared to be detrimental to the
enantioselectivity, and optimal results were obtained with
the addition of 4 molecular sieves (45% ee without 4
MS). The concentration was also critical for success of the
reaction and was optimal at 0.17 M in substrate. When the
reaction was either diluted or concentrated by a factor of 2,
lower enantioselectivity was obtained (45 and 67% ee,
respectively). This is difficult to rationalize, but may be due
to varying disproportionation between organoindium species
of different oxidation states.12
After successful reactivity and selectivity were established
for the allylation of hydrazone 1a using excess ligand, the
stoichiometry of the chiral additive and the substrate scope
of the reaction were investigated. Results are summarized
in Table 1. We were gratified to find that the reaction of 1a
could be carried out with good selectivity employing only
10 mol % of the ligand, 1.1 equiv of In(0), and 1.5 equiv of
allyl iodide, giving 2a in 70% ee and 77% yield. Additionally, the stoichiometric reaction improved under these
conditions as well (84% ee). Para-substituted derivatives
performed even better, as demonstrated by substrates 1bd. The -donor substituents, Cl and OMe, afforded greater
(16) Recently, Loh has reported high selectivity using an In(OTf)3BINOL Lewis acid and allylstannanes: Teo, Y.-C.; Tan, K.-T.; Loh, T.-P.
Chem. Commun. 2005, 1318.
(17) Chong, J. M.; Shen, L.; Wu, T. R. Org. Lett. 2004, 6, 2701.
Org. Lett., Vol. 7, No. 13, 2005
Table 1. Enantioselective Allylation of Hydrazones
their optical purity could be increased by simple recrystallization. As demonstrated for 2c-e and 2j, a single recrystallization conveniently afforded enantiopure product. The
absolute configuration of 2a was determined by benzoylation
of the nitrogen and reductive cleavage of the hydrazine bond
to afford the known homoallylic benzamide.9
To gain more insight into the role of the BINOL ligands,
we examined several other analogues, and the results are
described in Table 2. It is apparent that electronic effects
Table 2. BINOL Derivatives for Enantioselective Allylation of

Hydrazone 1aa
a Reactions carried out with 2 equiv of chiral additive, 2 equiv of ln(0),

and 3 equiv of allyliodide. Ee was determined by HPLC.
a Allylindium/ligand complex was preformed at room temperature, and

reactions were carried out starting at 0 C and warming to room temperature.
See Supporting Information for details. Ee was determined by HPLC. Yield
and selectivities reported are averages of at least two experiments. b (S)3,3-BistrifluoromethylIBINOL was used, affording the enantiomer. c T )
-78 C to room temperature.
than 90% ee using 1 equiv of the chiral additives. Orthosubstituted substrates offered the highest enantioselectivity,
with the o-bromobenzaldehyde-derived 1e giving the best
overall yields and selectivity in both catalytic (85% ee) and
stoichiometric (97% ee) reactions. The o-Cl substrate 1f gave
an even higher level of enantioselectivity in the catalytic
reaction (91% ee), while the o-tolyl substrate 1g provided
92% ee with 10 mol % BINOL derivative. Surprisingly, this
substrate would not react with 100 mol % ligand, and the
starting material was recovered intact. Furthermore, o-trifluoromethyl- and 2,6-dimethyl-substituted substrates failed
to react under any conditions. Generally, isolated yields were
higher using a catalytic chiral additive. Even aliphatic and
cinnamyl derivatives 1j-l reacted to form the chiral homoallylic hydrazines in greater than 90% ee with 100 mol
% ligand. This was very rewarding considering that these
substrates suffer from competing achiral background reactions, as evidenced by the lower selectivity obtained with
catalytic ligand. However, in the case of 1j, starting the
reaction at a lower temperature significantly improved the
ee from 34 to 70%, suggesting that opportunity remains for
further optimization of the reaction conditions. As many of
the oxazolidinone-derived hydrazines were crystalline solids,
Org. Lett., Vol. 7, No. 13, 2005
rather than steric effects were most important for selectivity.

Changing the 3 and 3 substituents from CF3 to Me to TMS
(entries 3-5) resulted in a marked decrease in the enantioselectivity, while placing a Br in the 6 and 6 positions
(entry 6) led to high selectivity. Larger substituents with
electron-withdrawing groups in the 3 and 3 positions also
did not improve the selectivity. Generally, electron-efficient
BINOL derivatives performed better than those that were
electron-rich, suggesting that the acidity of the BINOL was
important. Presently, the nature of the BINOL-indium
complex is unknown. Preliminary NMR evidence suggests
that one of the BINOL protons may be deprotonated upon
interaction with allylindium,18 as evidenced by upfield shifts
of all the BINOL resonances (see Supporting Information).
It is not clear whether a chiral allylindium complex is
generated in the reaction or whether a chiral indium Lewis
acid is responsible for the catalytic reaction, and work is
currently underway to further characterize these intermediates.
In conclusion, we have demonstrated a facile and highly
enantioselective allylation of hydrazones utilizing BINOL
ligands. This represents the first successful example of the
use of catalytic amounts of a chiral additive in an addition
reaction with allylindium.19 Efforts are currently underway
(18) In(III) and In(I) allyls have been observed by NMR in the formation
of allylindium reagents. Chan, T. H.; Yang, Y. J. Am. Chem. Soc. 1999,
121, 3228.
(19) Chiral In(III) Lewis acids with allylstannanes may involve transmetalation to form allylindium in situ. Lu, J.; Hong, M.-L.; Ji, S.-J.; Loh,
T.-P. Chem. Commun. 2005, 1010.
2769
to further optimize the process and understand the role of

the BINOL in the reaction.
Acknowledgment. We are grateful to the National
Science Foundation (NSF-CHM-0316618), the ND-EPSCoR
Network in Catalysis program (NSF-EPS-0132289), and the
NDSU NIH Center for Protease Research (NCRR-P20RR15566) for financial support of this project. We also thank
2770
Pfizer for a Diversity Graduate Fellowship for Robert

Kargbo.
Supporting Information Available: Experimental procedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051160O
Org. Lett., Vol. 7, No. 13, 2005

Enantioselective in Allylation

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ORGANIC

Gregory R. Cook,* Robert Kargbo, and Bikash Maity

Over the past decade, allylindium complexes have emerged

2005 American Chemical Society

A direct method for the preparation of chiral amines is

Lewis acid improved the reaction to 85% yield; however,

Org. Lett., Vol. 7, No. 13, 2005

Table 1. Enantioselective Allylation of Hydrazones

Table 2. BINOL Derivatives for Enantioselective Allylation of

a Reactions carried out with 2 equiv of chiral additive, 2 equiv of ln(0),

a Allylindium/ligand complex was preformed at room temperature, and

rather than steric effects were most important for selectivity.

to further optimize the process and understand the role of

Pfizer for a Diversity Graduate Fellowship for Robert

Org. Lett., Vol. 7, No. 13, 2005

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