Kinetic resolutions of azomethine imines via copper-catalyzed [3 + 2] cycloadditions

Article abstract of DOI:10.1021/ja052876h

An effective method has been developed for the kinetic resolution of racemic azomethine imines via [3 + 2] cycloadditions with alkynes catalyzed by a chiral copper complex. Efficient kinetic resolution is observed for a variety of N1 and C5 substituents o

Full text of DOI:10.1021/ja052876h

Published on Web 07/21/2005
Kinetic Resolutions of Azomethine Imines via Copper-Catalyzed [3 + 2]
Cycloadditions
Andre´s Sua´rez, C. Wade Downey, and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received May 2, 2005; E-mail: gcf@mit.edu
The kinetic resolution of racemic mixtures is a powerful method
for preparing enantiomerically enriched compounds,1,2 complement-
ing approaches such as asymmetric synthesis and classical resolu-
tion. Of course, the use of a chiral catalyst, rather than a
stoichiometric reagent, to effect the kinetic resolution can be
advantageous from the standpoint of considerations such as cost
and efficiency. To date, there are only scattered examples of kinetic
resolutions that capitalize on a 1,3-dipolar cycloaddition as the key
enantiomer-differentiating step;3 to the best of our knowledge, none
of these methods exploits a chiral catalyst.
We recently described the development of a new copper-
catalyzed reaction, the asymmetric [3 + 2] cycloaddition of
azomethine imines with terminal alkynes (eq 1),4 a process that
likely involves reaction of the dipole with a copper acetylide
generated in situ.5 Our initial investigation focused on couplings
of achiral azomethine imines with alkynes to furnish bicyclic
pyrazolidinone derivatives, a family of molecules with interesting
bioactivity.6 More recently, we decided to explore the use of copper/
phosphaferrocene-oxazoline catalysts for the kinetic resolution of
racemic mixtures of azomethine imines; the resulting highly
enantioenriched dipoles could then be reacted with nucleophiles
or dipolarophiles to afford a wide array of useful monocyclic and
bicyclic pyrazolidinones.7,8
(s > 10),10 with ethyl propiolate and 4-(trifluoromethyl)phenyl-
acetylene being the most effective among those that we have
explored to date (entries 1 and 3).
Next, we turned our attention to defining the scope of this new
kinetic resolution process. As illustrated in Table 2, good selectivity
factors are obtained for azomethine imines that possess a wide
variety of N1 substituents. Thus, highly enantioenriched dipoles
can be generated that bear aryl (entry 1), heteroaryl (entries 2 and
3), alkenyl (entry 4), and cycloalkyl (entry 5) groups.11
We have also examined the scope of this kinetic resolution with
respect to substitution at the other two positions of the heterocycle
(C4 and C5). Unfortunately, C4-substituted (e.g., cyclohexyl)
azomethine imines do not undergo kinetic resolution with useful
selectivity (s < 2). On the other hand, a variety of C5-substituted
dipoles can be effectively resolved by CuI/3 (Table 3). Thus, the 5
position can bear not only an aryl (entries 1 and 2) but also a
heteroaryl (entry 3) or a branched alkyl (entries 4 and 5) group;
the presence of an unbranched alkyl substituent leads to low
selectivity (s < 5). As indicated in Table 3, in certain instances,
we employ an amide- rather than an ester-substituted alkyne as the
dipolarophile since side reactions are occasionally observed during
cycloadditions of ethyl propiolate.12
Table 1. Kinetic Resolutions of Azomethine Imines: Dependence
of the Selectivity Factor on the Structure of the Alkyne
For our initial studies, we chose to investigate the kinetic
resolution of azomethine imine 2 (eq 2). We were pleased to
discover that, under the conditions that we had previously described
(eq 1), CuI/1-catalyzed cycloaddition with ethyl propiolate leads
to effective kinetic resolution of the dipole (eq 2; s ) selectivity
factor ) [rate of fast-reacting enantiomer/rate of slow-reacting
enantiomer]). Upon surveying other ligands, we determined that
phosphaferrocene-oxazoline 3 furnishes a selectivity factor higher
than that of 1 and allows the use of a lower catalyst loading (eq 2).
We have examined the influence of the alkyne on the selectivity
factor for these kinetic resolutions of azomethine imines (Table
1).9 A variety of electron-poor alkynes provide useful selectivities
a The selectivity factors are the average of two experiments.
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10.1021/ja052876h CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Kinetic Resolutions of Azomethine Imines: Variation of
the N1 Substituent
a variety of N1 and C5 substituents on the dipole, thereby furnishing
an array of useful enantioenriched azomethine imines. Additional
investigations of copper-catalyzed cycloadditions are underway.
Acknowledgment. Support has been provided by the NIH
(National Institute of General Medical Sciences: R01-GM66960),
the Spanish Ministry of Education and Science (postdoctoral
fellowship to A.S.), Merck Research Laboratories, and Novartis.
Funding for the MIT Department of Chemistry Instrumentation
Facility has been furnished in part by NSF CHE-9808061 and NSF
DBI-9729592.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
a The selectivity factors are the average of two experiments. b Solvent:
CHCl3.
(1) For reviews of kinetic resolution, see: (a) Kagan, H. B.; Fiaud, J. C. Top.
Stereochem. 1988, 18, 249-330. (b) Keith, J. M.; Larrow, J. F.; Jacobsen,
E. N. AdV. Synth. Catal. 2001, 1, 5-26. (c) Robinson, D. E. J. E.; Bull,
S. D. Tetrahedron: Asymmetry 2003, 14, 1407-1446.
(2) For two classic examples of metal-catalyzed kinetic resolution, see: (a)
Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; Wiley-VCH: New York, 2000; Chapter 6A. (b) Jacobsen, E. N.
Acc. Chem. Res. 2000, 33, 421-431.
The highly enantioenriched dipoles that are produced in these
kinetic resolutions serve as precursors to useful families of
compounds, such as monocyclic and bicyclic pyrazolidinones. A
few examples are provided in eq 3-5.13
(3) For a review, see: Cardona, F.; Goti, A.; Brandi, A. Eur. J. Org. Chem.
2001, 2999-3011.
(4) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 10778-10779.
(5) For related examples of copper-catalyzed [3 + 2] cycloadditions of
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Chem. Commun. 1972, 466-467. (b) Miura, M.; Enna, M.; Okuro, K.;
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(9) Notes: (a) Use of CHCl3 (but not THF or EtOAc) leads to a comparable
selectivity factor. (b) CuCl and CuBr can also be used. (c) The selectivity
factor is not highly temperature-dependent.
In summary, we have developed an effective method for the
kinetic resolution of racemic azomethine imines via copper-
catalyzed [3 + 2] cycloadditions with alkynes. The process tolerates
Table 3. Kinetic Resolutions of Azomethine Imines: Variation of
the C5 Substituent
(10) For a kinetic resolution that proceeds with a selectivity factor of 10, starting
material of 90% ee can be obtained at 62% conversion.
(11) If R (Table 2) is an acyclic alkyl group (e.g., i-Bu), the dipole decomposes
to a small extent during the cycloaddition, thereby precluding a reliable
determination of the selectivity factor.
(12) Through X-ray crystallography, we have determined the absolute con-
figuration of the recovered dipole from entry 2 of Table 3. The other
configurations are assigned by analogy.
(13) For precedent for: (a) Reduction with NaBH4: Greenwald, R. B.; Taylor,
E. C. J. Am. Chem. Soc. 1968, 90, 5273-5274. (b) Addition of a Grignard
reagent: Dorn, H.; Graubaum, H. J. Prakt. Chem. 1976, 318, 253-260.
Rutjes, F. P. J. T.; Udding, J. H.; Hiemstra, H.; Speckamp, W. N.
Heterocycles 1992, 33, 81-85 (the diastereoselectivity was not reported
in either paper). (c) Thermal cycloaddition with dimethyl acetylenedicar-
boxylate: Turk, C.; Svete, J.; Stanovnik, B.; Golic, L.; Golic-Grdadolnik,
S.; Golobic, A.; Selic, L. HelV. Chim. Acta 2001, 84, 146-156. (d)
Hydrolysis: Dorn, H.; Otto, A. Chem. Ber. 1968, 101, 3287-3301.
a The selectivity factors are the average of two experiments. b Reaction
temperature: 0 °C. c 2% Cul/2.2% 3. d Yield of the pyrazolidinone after
reduction of the dipole.
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