CÀC bond formation of soft Lewis basic substrates
under proton transfer conditions.11 A major drawback
to this strategy, however, is the tedious catalyst preparation.
A prototype catalyst required separate preparation of chiral
bisphosphine ligand/[Cu(CH3CN)4]PF6 (soft Lewis acid)
and LiOAr (hard Brønsted base) just before use. Mechanistic
studies revealed that {phosphine/Cu-OAr and LiPF6}, gen-
erated in equilibrium with {phosphine/CuPF6 and LiOAr},
also acts as a soft Lewis acid and a hard Brønsted base
cooperative catalyst.12 On the basis that a phosphine/Cu-base
fragment can deprotonate the pronucleophile, which is an
initial step to trigger proton transfer CÀC bond formation,
we focused on the use of the reaction intermediate as a
catalyst to simplify the catalytic system (Scheme 1). In the
reaction using nitroalkane 1 and thioamide 2, the intermedi-
ate is a chiral phosphine/Cu-thioamide enolate 4, in which
the Cu and thioamide enolate would function as a soft Lewis
acid and a hard Brønsted base, respectively. Nitroalkane 1
and the precatalyst comprising a chiral phosphine ligand/
mesitylcopper13 generated Cu-nitronate via irreversible de-
protonation with concomitant generation of mesitylene, and
the subsequent coordination of thioamide 2 delivered com-
plex 5. This is an entry point to the following catalytic cycle, in
which enantioselective CÀC bond formation through 5
generates the intermediate 4 that promotes proton exchange
with nitroalkane 1 to regenerate 5. By this catalytic cycle, the
entry to 4
Scheme 1. Catalyst Design and Application to the Reaction of
Nitroalkanes and R,β-Unsaturated Thioamides
aldehydes,6 and nitroalkenes.7 The analogous catalytic
asymmetric addition to R,β-unsaturated carboxylic acid
derivatives, however, is limited due to their low electro-
philicity, and to date, only one successful example using
R,β-unsaturated acylpyrazoles and nitromethane (1a) un-
der Ni complex/2,2,6,6-tetramethylpiperidine catalyst has
been reported.8 Our recent research focused on the use of
R,β-unsaturated thioamide 2 as a viable electrophile in the
carboxylic acid oxidation state that is chemoselectively
activated by a soft Lewis acid catalyst to overcome the
intrinsic low reactivity.9 In this context, we envisioned to
develop a catalytic asymmetric conjugate addition of
nitroalkanes 1 to R,β-unsaturated thioamides 2, promoted
by a soft Lewis acid/hard Brønsted base cooperative
catalyst.10 Divergent transformation of the thioamide
functionality of the product 3 highlights the synthetic
utility of the present protocol.
initiates an efficient proton transfer CÀC bond-forming
catalysis, and this methodology would be applicable to
other carbon pronucleophiles bearing an acidic proton. An
(R)-DTBM-Segphos/mesitylcopper precatalyst quickly
emerged as a suitable precatalyst for the reaction of nitro-
methane(1a) andN,N-dimethylthiocinnamide (2a), afford-
ing γ-nitrothioamide 3aa in 93% yield and 99% ee after 1 h
of stirring at room temperature in toluene (eq 1). Initially,
mesitylcopper deprotonated 1a with a concomitant
The soft Lewis acid/hard Brønsted base cooperative cata-
lyst offers a particularly effective strategy for stereoselective
(6) Recent selected examples: (a) Hojabri, L.; Hartikka, A.; Moghaddam,
F. M.; Arvidson, P. I. Adv. Synth. Catal. 2007, 349, 740. (b) Zu, L.; Xie,
H.; Li, H.; Wang, J.; Wang, W. Adv. Synth. Catal. 2007, 349, 2660.
(c) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307.
(d) Enders, D.; Wang, C.; Bats, J. W. Synlett 2009, 1777. (e) Gotoh,
H.; Okamura, D.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11,
4056. (f) Zhong, C.; Chen, Y.; Petersen, J. L.; Akhmedov, N. G.; Shi,
X. Angew. Chem., Int. Ed. 2009, 48, 1279. (g) Anwar, S.; Chang, H.-J.;
Chen, K. Org. Lett. 2011, 13, 2200. Examples using preformed silyl
nitronate as active nucleophile: (h) Ooi, T.; Doda, K.; Maruoka, K.
J. Am. Chem. Soc. 2003, 125, 9022.
(7) Rabalakos, C.; Wulff, W. D. J. Am. Chem. Soc. 2008, 130, 13524.
(8) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394.
(9) (a) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2010, 132, 10275. (b) Yanagida, Y.; Yazaki, R.; Kumagai, N.; Shibasaki,
M. Angew. Chem., Int. Ed. 2011, 50, 7910.
(10) Recent reviews on cooperative catalysis: (a) Ma, J.-A.; Cahard,
D. Angew. Chem., Int. Ed. 2004, 43, 4566. (b) Yamamoto, H.; Futatsugi,
K. Angew. Chem., Int. Ed. 2005, 44, 1924. (c) Ikariya, T.; Murata, K.;
Noyori, R. Org. Biomol. Chem. 2006, 4, 393. (d) Paull, D. H.; Abraham,
C. J.; Scerba, M. T.; Alden-Danforth, E.; Lectka, T. Acc. Chem. Res.
2008, 41, 655. (e) Lee, J.-K.; Kung, M. C.; Kung, H. H. Top. Catal. 2008,
49, 136. (f) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41,
222. (g) Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50,
4760.
(11) (a) Suzuki, Y.; Yazaki, R.; Kumagai, N.; Shibasaki, M. Angew.
Chem., Int. Ed. 2009, 48, 5026. (b) Yazaki, R.; Kumagai, N.; Shibasaki,
M. J. Am. Chem. Soc. 2010, 132, 5522. (c) Iwata, M.; Yazaki, R.; Chen,
I.-H.; Sureshkumar, D.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2011, 133, 5554.
(12) Yazaki, R.; Kumagai, N.; Shibasaki, M. Chem. ;Asian J. 2011,
6, 1778.
(13) Tsuda, T.; Yazawa, T.; Watanabe, K.; Fujii, T.; Saegusa, T.
J. Org. Chem. 1981, 46, 192.
(14) Experiments were conducted with mesitylcopper prepared from
the reported procedure (ref 13). Mesitylcopper is commercially available
from Strem Chemicals Inc., and purchased mesitylcopper exhibited
comparable catalytic performance in the present reaction: the reaction
of 1b and 2a (Table 2, entry 1) under otherwise identical conditions, 3ba
was obtained in 89% yield syn/anti = 80/20, 99% ee (syn).
Org. Lett., Vol. 14, No. 1, 2012
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