Table 2 Basic character of the S-3CR manifold
This work was supported by the Spanish by the Spanish
Ministerio de Ciencia e Innovacion and the European
´
Regional Development Fund (CTQ2005-09074-C02-02 and
CTQ2008-06806-C02-02), the Spanish MSC ISCIII (RETICS
´
RD06/0020/1046) and Fundacion Instituto Canario de
´ ´
Investigacion del Cancer (FICIC-REDESFAC). F.C. A
thanks CSIC for a predoctoral JAE grant.
Notes and references
Entry
R
Catalyst
Yield (%)a
z General procedure. To a stirred (250 rpm) salt-saturated aqueous
solution (brine) (7 ml) is sequentially added acetyl cyanide (1.4 mmol),
N,N-dimethylcylclohexylamine (0.035 mmol), carbonyl compound 2a
(0.70 mmol) and aniline (0.70 mmol) (dropwise) to form a biphasic
system. The stirring rate is increased to 1200 rpm and after a few
minutes, the biphasic system breaks into small drops. After 5 h (1 h for
aldehydes), the reaction is quenched by addition of dichloromethane
and the organic materials are recovered in dichloromethane. Concen-
tration and flash chromatography (ethyl acetate–hexanes: 20 : 80)
yields pure compound 3a: oil, 1H NMR (400 MHz, CDCl3): d = 0.91
(t, 3J(H,H) = 7 Hz, 3H), 1.07 (t, 3J(H,H) = 7.5 Hz, 3H), 1.29–1.39
(m, 4H), 1.45–1.58 (m, 2H), 1.82–2.08 (m, 2H), 3.5 (bs, NH), 6.86–6.95
(m, 3H), 7.21–7.28 (m, 2H); 13C NMR (100 MHz, CDCl3) d = 8.0,
13.9, 22.4, 23.6, 30, 31.6, 36.6, 57.3, 117.1, 120.3, 121.1, 129.3 (ꢁ3C),
143.8; IR (CHCl3, cmꢂ1): 3431 (NH), 2230,5 (CN); Anal. Calcd. for
C15H22N2: C, 78.21; H, 9.63; N, 12.16. Found: C, 78.02; H, 9.79; N,
12.06.
1
2
3
4
5
Me
nPr
nPr
Me
Ph
N,N-diisopropylethylamine
N,N-dimethylcyclohexylamine
Pyridine
None
N,N-dimethylcyclohexylamine
85
69
12
r10
r10
a
Yields of analytically pure products.
1 S. Strecker, Ann. Chem. Pharm., 1850, 75, 27.
2 For recent general reviews on the synthesis of a-amino acids:
(a) C. Najera and J. M. Sansano, Chem. Rev., 2007, 107,
´
4584; (b) A. Perdih and M. S. Dolenc, Curr. Org. Chem., 2007,
11, 801.
3 M. Shibasaki, M. Kanai and T. Mita, The Catalytic Asymmetric
Strecker Reaction, in Organic Reactions, ed. L. Overman,
Hoboken, NJ, 2008, vol. 70, pp. 1–119.
Scheme 1 A mechanistic proposal. (LB = Lewis base).
4 (a) J. S. Connon, Angew. Chem., Int. Ed., 2008, 47, 1176 and
references cited therein; (b) C. Spino, Angew. Chem., Int. Ed., 2004,
43, 1764.
5 (a) A. Baeza, C. Najera and J. M. Sansano, Synthesis, 2007, 1230;
(b) for an iron-catalyzed solvent-free process see: N. H. Khan,
S. Agrawal, R. I. Kureshy, S. H. R. Abdi, S. Singh, E. Suresh and
R. V. Jasra, Tetrahedron Lett., 2008, 49, 640.
6 (a) G. K. S. Prakash, T. Mathew, C. Panja, S. Alconcel, H. Vaghoo,
C. Do and G. A. Olah, Proc. Natl. Acad. Sci. U. S. A., 2007, 104,
3703; (b) G. K. S. Prakash, C. Panja, C. Do, T. Mathew and
G. A. Olah, Synlett, 2007, 2395.
7 A. Heydari, S. Khaksar and M. Tajbakhsh, Tetrahedron Lett.,
2009, 50, 77.
catalyst: while pyridine roughly catalyzes the reaction (12%),
the more basic N,N-dimethylcyclohexylamine affords product
3a with moderate-to-good efficiency (69%) (Table 2, entries 2
and 3). Observe that in the absence of catalyst, the manifold
still generates a background amount of a-amino nitrile 3a
(r10%) (entry 4). If we compare the yields in the absence of
catalyst (acetyl cyanide) and that obtained with pyridine
(butyryl cyanide), both are in the same range; that is, they
represent the background yield for the non-catalyzed S-3CR.
Finally, benzoyl cyanide, lacking a-protons, drastically reduces
the efficiency of the manifold to the background level (r10%)
(entry 5).
8 G. K. S. Prakash, T. E. Thomas, I. Bychinskaya, A. G. Prakash,
C. Panja, H. Vaghoo and G. A. Olah, Green Chem., 2008, 10, 1105.
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10 (a) S. Lundgren, E. Wingstrand and C. Moberg, Adv. Synth.
A mechanistic proposal accounting for the experimental
results is outlined in Scheme 1. The ketone (aldehyde) reacts
with the primary amine to give the corresponding ketimine
(aldimine). To be chemically efficient, this reaction requires a
dehydrating agent to shift the equilibrium towards the imine
product. Herein, the own manifold realizes this task removing
the water generated in the condensation from the organic
phase (drop) to the bulk water, shifting the ketone–imine
equilibrium toward the imine side. This counterintuitive
physicochemical behaviour is very remarkable and it offers a
powerful manner to perform ‘‘dry’’ organic chemistry in
water. Next, the imine reacts with the cyanide anion generated
in the Lewis base-catalyzed dimerization of acetyl cyanide to
give the corresponding amide intermediate, which in turn is
neutralized by the Lewis base conjugated acid to give the
a-amino nitrile derivative 3 with regeneration of the Lewis
base to reinitiate the cycle.
Catal., 2007, 349, 364 and references cited therein; (b) S. Hunig
¨
and R. Schaller, Angew. Chem., Int. Ed. Engl., 1982, 21, 36.
11 (a) S. Chandra Pan and B. List, Chem.–Asian J., 2008, 3, 430 and
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M. Mihara, T. Takeuchi and M. Takemoto, Tetrahedron Lett.,
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Org. Lett., 2003, 5, 2679; (f) M. Scholl, C.-K. Lim and G. C. Fu,
J. Org. Chem., 1995, 60, 6229.
12 On water refers to the reactions performed with sparingly soluble
or insoluble reactants in water. S. Narayan, J. Muldoon,
M. G. Finn, V. V. Fokin, H. C. Kolb and K. B. Sharpless, Angew.
Chem., Int. Ed., 2005, 44, 3275.
13 A. Chanda and V. V. Fokin, Chem. Rev., 2009, 109, 725.
14 F. G. Moore and G. L. Richmond, Acc. Chem. Res., 2008, 41, 739.
15 (a) Z.-L. Shen, S.-J. Ji and T.-P. Loh, Tetrahedron, 2008, 64,
8159; (b) S. Kobayashi and T. Busujima, Chem. Commun., 1998,
981.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 6839–6841 | 6841