Highly enantioselective direct conjugate addition of ketones to nitroalkenes promoted by a chiral primary amine-thiourea catalyst

Article abstract of DOI:10.1021/ja0620890

Primary amine-thiourea derivative 1 is an active and highly enantioselective catalyst for the conjugate addition of ketones to nitroalkenes. Broad substrate scope is described, with nitroalkenes bearing either aromatic or aliphatic substituents and a wide

Full text of DOI:10.1021/ja0620890

Published on Web 05/12/2006
Highly Enantioselective Direct Conjugate Addition of Ketones to Nitroalkenes
Promoted by A Chiral Primary Amine-Thiourea Catalyst
Hongbing Huang and Eric N. Jacobsen*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford Street,
Cambridge, Massachusetts 02138
Received March 27, 2006; E-mail: jacobsen@chemistry.harvard.edu
The importance of nitroalkanes in organic synthesis is tied to
their propensity to undergo facile R-alkylation reactions and
interconversions to other important organic functional groups.1
Conjugate addition of carbon-centered nucleophiles to nitroalkenes
represents a direct and most appealing approach to chiral nitroal-
kanes, and development of asymmetric catalysts for such processes
has been the focus of important recent research effort.2 Among the
variants of this strategy, direct Michael addition of carbonyl
compounds to nitroalkenes offers a particularly attractive approach,
affording versatile difunctional products in an atom-economical
manner (eq 1). Impressive progress has been made recently in the
development of bifunctional organic catalysts for the enantiose-
lective addition of malonate derivatives3 or simple aldehydes and
ketones to nitroalkenes.4 Nonetheless, identification of new catalyst
systems with broad substrate scope with respect to both nucleophilic
and electrophilic reacting partners remains an important challenge.
Herein, we describe a new catalyst (1) for asymmetric conjugate
additions of ketones to nitroalkenes. The notable features of this
system include high enantioselectivities across a broad range of
substrates, as well as high diastereo- and regioselectivities resulting
directly from the unusual structural features of the catalyst.5
after 48 h. Further increase of the concentration to 5 M allowed
generation of Michael adduct 3a in 83% yield and 99% ee using
only a small excess of acetophenone (1.1 equiv).
With optimized conditions established for the model reaction of
acetophenone with nitrostyrene, we explored the scope of useful
nitroalkene substrates using acetone as a more challenging reacting
partner.4b-f Although reaction of acetone with nitrostyrene afforded
the desired Michael adduct 4a in 99% ee, yield was compromised
due to formation of bisalkylation byproduct (40% yield). However,
this side reaction was suppressed completely and without erosion
of enantioselectivity by the addition of catalytic amounts of weak
acids, such as benzoic acid. Under these conditions, a wide range
of aromatic and heteroaromatic nitroalkenes underwent reaction with
acetone in high yields and enantioselectivities (Table 1, entries a-e).
Table 1. Enantioselective Addition of Acetone to Nitroalkenes
entry
R
yield (%)a
ee (%)b
a
b
c
d
Ph
93
88
87
88
94
70
78
81
99
99
97
99
96
98
95
94
4-MeOC6H4
4-MeC6H4
2-furyl
2-thienyl
Me
e
fc
gc
hc
Inspired by the proven ability of thiourea derivatives to serve as
effective general acid catalysts in asymmetric addition reactions,6
we undertook a systematic investigation of members of this
compound class as potential catalysts for the model reaction of
acetophenone with nitrostyrene (Scheme 1). In particular, we
n-Bu
i-Bu
a Isolated yield of purified 4. b Determined by HPLC analysis (see
Supporting Information). c Results obtained using 15 mol % of 1 and 2
mol % of PhCO2H.
Scheme 1. Model Reaction11
Perhaps more significant, nitroalkenes bearing aliphatic â-substit-
uents proved to be viable electrophilic reacting partners in the
presence of added benzoic acid.9 Highly reactive 1-(E)-nitropropene
provided the Michael adduct with excellent enantioselectivity (98%
ee, entry f). Nitroalkenes bearing more sterically demanding
aliphatic substituents underwent reaction in high enantiomeric
excesses along with improved yields (entries g and h).
performed an extensive screen of chiral thiourea frameworks
incorporating additional amine functionality for cooperative enamine
generation, and this led to the identification of primary amine 1 as
a promising catalyst.7,8 Among the standard reaction parameters,
solvent choice and reagent concentration proved particularly
important. While reactions carried out in highly polar and/or protic
solvents were impractically slow, those run in nonpolar solvents,
such as toluene or CH2Cl2, proceeded with useful rates along with
high enantioselectivity (up to 99% ee). Reactions carried out at
[2a]0 ) 0.3 M in dichloromethane required use of 2-fold excess
acetophenone and stalled at 40% conversion after 96 h. However,
at higher concentration (2 M), complete conversion was achieved
Catalyst 1 displayed a marked bias toward activation of ethyl
ketones, allowing regio- and diastereoselective formation of a
variety of branched products bearing contiguous tertiary stereo-
centers (5a-e, Chart 1). Methyl ethyl ketone underwent reaction
with nitrostyrene with modest 2:1 regioselectivity, favoring branched
product 5a over its chromatographically separable regioisomer, with
both generated with high enantioselectivities (97 and 95% ee,
respectively). Furthermore, the branched product 5a was generated
with high (15:1) selectivity favoring the anti diastereomer.12 Higher
n-alkyl ethyl ketones afforded Michael adducts with complete
regioselectivity, high enantiomeric excess (98-99% ee), and
diastereoselectivity favoring the anti isomers (11-20:1 dr). No
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10.1021/ja0620890 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Chart 1. Diastereo- and/or Regioselective Asymmetric Additions
of Ketones to Nitroalkenesa
analysis of racemic and enantiomerically enriched products. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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(3) For organocatalytic conjugate additions of 1,3-dicarbonyl compounds to
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Soc. 2003, 125, 12672-12673. (b) Li, H.; Wang, Y.; Tang, L.; Deng, L.
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(4) (a) Tsogoeva, S. B.; Yalalov, D. A.; Hateley, M. J.; Weckbecker, C.;
Huthmacher, K. Eur. J. Org. Chem. 2005, 4995-5000. (b) Andrey, O.;
Alexakis, A.; Tomassini, A.; Bernardinelli, G. AdV. Synth. Catal. 2004,
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Tanaka, F.; Barbas, C. F., III. Synthesis 2004, 1509-1521. (d) Ishii, T.;
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9558-9559. (e) Mitchell, C. E. T.; Cobb, A. J. A.; Ley, S. V. Synlett
2005, 611-614. (f) Enders, D.; Seki, A. Synlett 2002, 26-28. (g) List,
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W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369-1371. (i)
Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed.
2005, 44, 4212-4215.
(5) During the final stages of preparation of this manuscript, a different primary
amine-thiourea catalyst system was reported for analogous ketone-
nitroalkene Michael reactions: Tsogoeva, S. B.; Wei, S. Chem. Commun.
2006, 1451-1453.
(6) For recent reviews, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2006, 45, 1520-1543. (b) Connon, S. J. Chem.sEur. J. 2006,
Early View (DOI: 10.1002/chem.200501076).
(7) For examples of asymmetric catalysis based on the primary amine
functionality, see: (a) Pizzarello, S.; Weber, A. L. Science 2004, 303,
1151. (b) Tanaka, F.; Thayumanavan, R.; Mase, N.; Barbas, C. F., III.
Tetrahedron Lett. 2004, 45, 325-328. (c) Amedjkouh, M. Tetrahedron:
Asymmetry 2005, 16, 1411-1414. (d) Bassan, A.; Zou, W.; Reyes, E.;
Himo, F.; Co´rdova, A. Angew. Chem., Int. Ed. 2005, 44, 7028-7032 and
references therein.
(8) Results obtained with representative catalyst structures are provided as
Supporting Information.
(9) To our knowledge, these represent the first examples of highly enanti-
oselective asymmetric addition of ketones to aliphatic nitroolefins. For
earlier efforts, see ref 4g.
a rr ) regioisomer ratio. Method A: 20 mol % of 1, 2 mol % of PhCO2H,
1.5-5.0 equiv of ketone. Method B: 10 mol % of 1, 1.5 equiv of ketone.
Method C: 20 mol % of 1, 2.0 equiv of ketone.
soluble byproducts were detected, and the moderate product yields
(50-65%) appear to reflect formation of small amounts of insoluble
polymeric materials. The observed sense of relative stereoinduction
stands in contrast to results obtained with secondary amine catalysts,
which lead to selective formation of the syn diastereomers.4,13 As
might be anticipated from the results leading to 5a-e, additions of
methyl propyl ketone provided linear products (5f, 5h) with modest
(4:1) regioselectivity and excellent enantioselectivity, while the more
sterically demanding methyl isopropyl ketone afforded linear
products (5g, 5i) exclusively. However, branched products (5j, 5k)
were obtained with methoxyacetone as the Michael donor.
(10) Added benzoic acid leads to increased product yield, but does not affect
the enantioselectivity of these reactions. Therefore, it is likely not involved
in the ee-determining conjugate addition step, but rather only in minimizing
byproduct formation by accelerating the delicate balance of imine and
enamine formation and imine hydrolysis steps in the desired catalytic
pathway. No beneficial effect of added acid was observed for certain
substrate combinations (see Chart 1).
A bifunctional mechanism involving enamine catalysis is clearly
indicated in Michael reactions promoted by catalyst 1. The observed
anti diastereoselectivity suggests participation of a Z-enamine
intermediate (Figure 1), given the complementary diastereoselec-
(11) The absolute configuration of 3a was established by comparison of the
rotation value with published data: Seebach, D.; Lyapkalo, I. M.;
Dahinden, R. HelV. Chim. Acta 1999, 82, 1829-1842.
(12) The relative configuration was assigned by comparison with published
data: Yamamoto, Y.; Nishii, S. J. Org. Chem. 1988, 53, 3597-3603.
(13) Alexakis et al. have reported an anti-selective Michael addition using
R-hydroxyacetone, but only this particular substrate afforded anti product.
Other substituted ketones afforded syn Michael adducts. See ref 4b and
(a) Andrey, O.; Alexakis, A.; Bernardinelli, G. Org. Lett. 2003, 5, 2559-
2561. (b) Andrey, O.; Alexakis, A. G. Org. Lett. 2002, 4, 3611-3614.
(14) Consistent with this hypothesis, cyclic ketones capable only of forming
E-enamines afford syn products. See also ref 5.
Figure 1. Proposed intermediates in Michael reactions catalyzed by 1. (A)
Favored Z-enamine. (B) Disfavored E-enamine.
(15) The precise mode of nitroalkene binding to the thiourea is not known.
Ground state structures determined both experimentally (Etter, M. C.;
Urbanczyk-Lipkowska, Z.; Zia-Ebrahimi, M.; Panunto, T. W. J. Am. Chem.
Soc. 1990, 112, 8415-8426) and computationally (Zuend, S.; Jacobsen,
E. N., unpublished) point to an in-plane arrangement with each thiourea
hydrogen bound to one oxygen of the nitro group as most stable. However,
modeling studies suggest that an out-of-plane binding geometry, wherein
only one of the nitro group oxygens is engaged by the thiourea, may be
required for intramolecular reaction with the enamine.
tivity obtained in analogous reactions involving E-enamines gener-
ated from secondary amine catalysts.14,15 The utility of bifunctional
primary amine catalysts in other valuable organic transformations
is under active investigation.16
Acknowledgment. This work was supported by the NIGMS
(16) For example, aldehydes participate in highly enantioselective additions
to nitroalkenes with primary amine-thiourea catalysts closely related to
1: Lalonde, M. P.; Chen, Y.; Jacobsen, E. N. work in progress.
through GM-43214 and P50 GM069721.
Supporting Information Available: Catalysts screening studies,
experimental procedures, analytical data, and chiral chromatographic
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