pubs.acs.org/joc
the enantioselective addition of carbon nucleophiles (i.e., nitro-
Catalytic Enantioselective Mannich-Type Reaction
with β-Phenyl Sulfonyl Acetonitrile
alkanes, malonates, ketoesters) to azomethine derivatives.3
Nevertheless, the addition of alkylnitriles, a unique class of
carbon nucleophiles, represents an exception.4 From the syn-
thetic point of view, alkylnitriles constitute a versatile synthon
with wide functional potency and the same oxidation state as
carboxylic acids. There have been few attempts to catalytically
generate nucleophiles from alkylnitriles probably because of
its poor acidity (pKa 31.3 in DMSO, 28.9 in H2O).5 The use of
strong bases may cause undesirable reactions, whereas weak
bases fail deprotonation.6 The direct activation through co-
operative amine bases and soft Lewis acids has been, so far, the
most efficient procedure for the catalytic addition of acetonitrile
to imines.7 Here, we describe our attempts in developing an
effective method to overcome the above problems that consist of
the enantioselective addition of 2-(phenylsulfonyl)acetonitrile
(1)8 as a synthetic equivalent of acetonitrile to N-Boc-protected
imines (Scheme 1). It was argued that the presence of the
sulfonyl group would increase acidity enough to catalytically
allow the carbon nucleophile generation upon treatment with
mild bases under asymmetric conditions. The subsequent easy
removal of the sulfonyl moiety would render the corresponding
optically active β-amino nitriles.
ꢀ
Pedro B. Gonzalez, Rosa Lopez, and Claudio Palomo*
´
ꢀ
´
Departamento de Quımica Organica I, Facultad de Quımica,
´
Universidad del Paıs Vasco, Apdo. 1072, 20080 San Sebastian,
Spain
ꢀ
Received March 28, 2010
SCHEME 1. Addition of Formal Acetonitrile Anions to
N-Boc-Protected Imines
The organocatalytic addition of β-phenyl sulfonyl acetoni-
trile1to eitherN-Boc-protected R-amido sulfonesor imines
allowed the synthesis of enantioenriched R-unsubstituted
β-amino nitriles through a Mannich-type reaction.
We have recently disclosed a highly efficient method for
the enantioselective aza-Henry reaction of R-amido sulfones
and nitroalkanes employing commercially avavilable cinchone-
derived ammonium salts as phase transfer catalysts.9 By analogy
to this reaction, we decided to evaluate similar reaction condi-
tions in the addition of 2-(phenylsulfonyl)acetonitrile (1) to aryl
Chiral β-amino nitriles are interesting building blocks because
they are readily transformed into optically active β-amino acids
and 1,3-diamines useful for the preparation of optically active
ligands, peptides, and some natural products. Among the most
direct methods to prepare β-amino nitriles, the addition of
R-cyanoalkyl moieties to imines is very attractive since con-
comitant to the carbon-carbon bond formation up to two
contiguous stereocenters may be generated in a single operation.
However, very few enantioselective versions for this transfor-
mation have been reported.1,2 During the past decade, there
have been considerable advances in the catalytic generation and
(4) For a decarboxylative Mannich-type reaction, see: (a) Yin, L.; Kanai,
M.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 9610–9611. For Mannich
reactions involving cyanoacetates, see: (b) Paulsen, T. B.; Alemparte, C.;
Saaby, S.; Bella, M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 2896–
2899. (c) Santoro, S.; Paulsen, T. B.; Jørgensen, K. A. Chem. Commun. 2007,
5155–5157. For Mannich reactions invoving R-cyanoketones, see: (d) Nojiri,
A.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 5630–5631.
(e) Nojiri, A.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 3799–
3784.
(5) (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456–463. (b) Richard,
J. P.; Williamns, G.; Gao, J. J. Am. Chem. Soc. 1999, 121, 715–726.
(6) For exceptions, see the use of P(RNCH2CH2)3N: (a) Kisanga, P.;
McLeod, D.; D’Sa, B.; Verkade, J. J. Org. Chem. 1999, 64, 3090–3094.
(b) Matsukawa, S.; Kitzaki, E. Tetrahedron Lett. 2008, 49, 2982–2984.
(7) (a) Kumagai, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2004, 126, 13632–13633. (b) Kumagai, N.; Matsunaga, S.; Shibasaki, M.
(1) For addition to chiral imines, see: (a) Mukaiyama, T.; Michida, M.
Chem. Lett. 2007, 36, 1244–1245. (b) Nemoto, H.; Moriguchi, H.; Ma, R.;
Kawamura, T.; Kamiya, M.; Shibuya, M. Tetrahedron: Asymmetry 2007, 18,
383–389.
(2) A method for the catalytic and enantioselective synthesis of optically
active β-aminonitriles has been reported that consists of the asymmetric ring
opening of arylmethylated N-nosylazidirines with TMSCN: Minakata, S;
Murakami, Y.; Satake, M.; Hidaka, I.; Okada, Y.; Komatsu, M. Org.
Biomol. Chem. 2009, 7, 641–643.
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Tetrahedron 2007, 63, 8598–8608. (c) Aydin, J.; Conrad, C. S.; Szabo, K. J.
(3) (a) Friestad, G. K.; Mathies, A. K. Tetrahedron 2007, 63, 2541–2569.
(b) Vilaivan, T.; Bhanthumnavin, W.; Sritana-Anant, Y. Curr. Org. Chem.
2005, 9, 1315–1392. For metal-based asymmetric-catalyzed Mannich reac-
tions, see: (c) Kobayashi, S.; Veno, M. In Comprehensive Asymmetric Catalysis,
Supplement 1; Jacobsen, E., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin,
2004; pp 143-150. (d) Shibasaki, M.; Matsunaga, S. J. Organomet. Chem. 2006,
691, 2089–2100. For metal-free, see: (e) Verkade, J. M. M.; van Hermert, L. J. C.;
Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2008, 37, 29–41.
(f) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797–5815.
Org. Lett. 2008, 10, 5175–5178.
(8) For the use of other synthetic equivalents of acetonitrile, such as
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TMSCH2CN, see: (a) Palomo, C.; Aizpurua, J. M.; Lopez, M. C.; Lecea, B.
J. Chem. Soc., Perkin Trans. 1 1989, 1692–1694. (b) See ref 1.
(9) (a) Palomo, C.; Oiarbide, M.; Laso, A.; Lopez, R. J. Am. Chem. Soc.
2005, 127, 17622–17623. (b) Gomez-Bengoa, E.; Linden, A.; Lopez, R.;
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Mugica-Mendiola, I.; Oiarbide, M.; Palomo, C. J. Am. Chem. Soc. 2008, 130,
7955–7966. Also, see: Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.;
Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 7975–7978.
3920 J. Org. Chem. 2010, 75, 3920–3922
Published on Web 04/28/2010
DOI: 10.1021/jo1005872
r
2010 American Chemical Society