lectivities as well as complete regioselectivity.6 Jørgensen
and co-workers catalyzed the same reaction successfully
under phase-transfer conditions with a chiral pyrrolidinium
salt in up to 95% ee.7 Very recently, Shibasaki and
co-workers disclosed a direct vinylogous Mannich reaction
of γ-butenolides catalyzed through a chiral lanthanum
complex.8
We have previously reported the first catalytic, enantiose-
lective, vinylogous Mukaiyama-Mannich reacion of vi-
nylketene silyl O,O-acetal 2 derived from an R,ꢀ-unsaturated
ester and imines 1.9 δ-Amino-R,ꢀ-unsaturated esters 3 were
obtained in typically high yields, complete γ-regioselectivity,
and good to very good enantioselectivities (Scheme 1). A
acetals 5 and imines. In a first step, we investigated various
dienolates 5 differing in the amine component in reactions
with imine 1a (Table 1). As reaction conditions we employed
our previously optimized protocol using 3 equiv of the
respective vinylketene silyl N,O-acetal 5, an alcoholic solvent
system containing equal amounts of 2-propanol, 2-methyl-
2-propanol, and 2-methyl-2-butanol with 1 equiv of water
and 10 mol % of phosphoric acid 4a. Whereas the N,N-
dimethyl-, N,N-diisopropylamide-, and pyrrolidide-based silyl
dienolates 5a-c, respectively, did not perform to our
expectations (entries 1-3), the piperidide- and morpholide-
derived vinylketene silyl N,O-acetals 5d and 5e proved to
be more suitable substrates and delivered the corresponding
vinylogous Mannich products 9a and 10a in good yields and
up to 78% ee within short reaction times of just 30 min at
-30 °C (entries 4 and 5).
Changing the Brønsted acid catalyst from our previously
optimized 3,3′-bismesityl-substituted phosphoric acid 4a to
the 3,3′-bistriphenylsilyl-substituted analogue 4b12c had a
dramatic effect on the enantioselectivity of the reaction. The
vinylogous Mannich product 9a was now obtained in 91%
yield and 90% ee whereas 10a was isolated in 80% yield
and 67% ee (entries 6 and 7). In both cases, the opposite
enantiomers were formed using the identical R-BINOL-
enantiomer as catalyst backbone. The same phenomenon had
been observed earlier by You et al. in the asymmetric transfer
hydrogenation of ꢀ,γ-alkynyl R-imino esters.17 On the basis
of these results, we selected the piperidide-based vinylketene
silyl N,O-acetal 5d and phosphoric acid 4b to study this
reaction further.
Scheme 1
.
Chiral Brønsted Acid-Catalyzed Vinylogous
Mukaiyama-Mannich Reaction
BINOL-based phosphoric acid 4a with 3,3′-mesityl groups
was employed as chiral Brønsted acid catalyst which led to
protonation of the imines and formed chiral contact ion pairs
in situ. This general strategy had been established indepen-
dently by the groups of Akiyama and Terada10,11 and was
subsequently applied to a broad range of mainly imine
addition reactions by various groups.12-16
The catalyst loading could be lowered to just 1 mol % by
simply extending the reaction time with no detrimental effects
on yield or enantioselectivity (Table 2). Thus, reaction of
imine 1b and vinylketene silyl N,O-acetal 5d with 1 mol %
of Brønsted acid 4b furnished vinylogous Mannich product
9b with 99% yield and 90% ee after 7 d at -30 °C even
slightly exceeding the results obtained with higher catalyst
loadings (compare entries 1 and 4).
We have now extended this process to vinylogous
Mukaiyama-Mannich reactions of vinylketene silyl N,O-
(6) Liu, T.-Y.; Cui, H.-L.; Long, J.; Li, B.-J.; Wu, Y.; Ding, L.-S.; Chen,
Y.-C. J. Am. Chem. Soc. 2007, 129, 1878.
Table 3 shows that the optimized protocol is broadly
applicable to aromatic and heteroaromatic aldimines 1b-o
which were converted into the vinylogous Mannich products
(7) Niess, B.; Jørgensen, K. A. Chem. Commun. 2007, 1620.
(8) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10,
2319.
(9) Sickert, M.; Schneider, C. Angew. Chem., Int. Ed. 2008, 47, 3631.
(10) (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566. (b) Yamanaka, M.; Itoh, J.; Fuchibe, K.; Akiyama,
T. J. Am. Chem. Soc. 2007, 129, 6756. (c) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356. (d) Uraguchi, D.; Sorimachi, K.; Terada, M.
J. Am. Chem. Soc. 2005, 127, 9360. See also: (e) Guo, Q.-X.; Liu, H.;
Guo, C.; Luo, S.-W.; Gu, Y.; Gong, L.-Z. J. Am. Chem. Soc. 2007, 129,
(14) Friedel-Crafts reactions with imines: (a) Uraguchi, D.; Sorimachi,
K.; Terada, M. J. Am. Chem. Soc. 2004, 126, 11804. (b) Terada, M.;
Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292. (c) Rowland, G. B.;
Rowland, E. B.; Liang, Y.; Perman, J.; Antilla, J. C. Org. Lett. 2007, 9,
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3790
.
(15) For select further applications with imines, see, e.g.: (a) Terada,
M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2006, 45, 2254.
(b) Rueping, M.; Sugiono, E.; Azap, C. Angew. Chem., Int. Ed. 2006, 45,
2617. (c) Chen, X.-H.; Xu, X.-Y.; Liu, H.; Cun, L.-F.; Gong, L.-Z. J. Am.
Chem. Soc. 2006, 128, 14802. (d) Seayad, J.; Seayad, A. M.; List, B. J. Am.
Chem. Soc. 2006, 128, 1086. (e) Rueping, M.; Antonchick, A. P.;
Brinkmann, C. Angew. Chem., Int. Ed. 2007, 46, 6903.
(11) Reviews: (a) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal.
2006, 348, 999. (b) Connon, S. J. Angew. Chem., Int. Ed. 2006, 45, 3909.
(c) Akiyama, T. Chem. ReV. 2007, 107, 5744, and references cited therein
.
(12) Reduction of imines with Hantzsch esters: (a) Rueping, M.; Sugiono,
E.; Azap, C.; Theissmann, T.; Bolte, M. Org. Lett. 2005, 7, 3781. (b)
Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem., Int. Ed. 2005, 44,
7424. (c) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2006, 128, 84. (d) Rueping, M.; Antonchick, A. P.; Theissmann,
T. Angew. Chem., Int. Ed. 2006, 45, 3683. (e) Hoffmann, S.; Nicoletti, M.;
List, B. J. Am. Chem. Soc. 2006, 128, 13074. (f) Li, G.; Liang, Y.; Antilla,
J. C. J. Am. Chem. Soc. 2007, 129, 5830. (g) Rueping, M.; Antonchick,
A. P. Angew. Chem., Int. Ed. 2007, 46, 4562. (h) Rueping, M.; Antonchick,
(16) For select other applications, see, e.g.: (a) Mayer, S.; List, B. Angew.
Chem., Int. Ed. 2006, 45, 4193. (b) Rueping, M.; Ieawsuwan, W.;
Antonchick, A. P.; Nachtsheim, B. J. Angew. Chem., Int. Ed. 2006, 46,
2097. (c) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla, J. C.
J. Am. Chem. Soc. 2007, 129, 12084. (d) Wang, X.; List, B. Angew. Chem.,
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T. Angew. Chem., Int. Ed. 2008, 47, 5661. (g) Rueping, M.; Theissmann,
T.; Kuenkel, A.; Koenigs, R. M. Angew. Chem., Int. Ed. 2008, 47, 6798.
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A. P. Angew. Chem., Int. Ed. 2008, 47, 5836
.
(13) Aza-Diels-Alder reactions with imines: (a) Itoh, J.; Fuchibe, K.;
Akiyama, T. Angew. Chem., Int. Ed. 2006, 45, 4796. (b) Akiyama, T.;
Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070
.
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