Mojtahedi et al.
431
Scheme 2.
and the results were compared with those available in the lit-
erature.2
CN
C6H5
Selected spectral data
HN
NH2
TMSCN
C6H5CHO +
(4-Methoxy-phenyl)-piperidin-1-yl-acetonitrile (3f)
.
Ph
Ph
MgBr2 OEt2
1
IR (neat, cm–1) ν: 2219, 1513, 1250. H NMR (80 MHz,
90%
d.e. = 50
CDCl3) δ: 1.22–1.50 (m, 6H), 2.25–2.50 (m, 4H), 3.65 (s,
3H), 4.61 (s, 1H), 6.77 (d, J = 8 Hz, 2H), 7.27 (d, J = 8 Hz,
2H). 13C NMR (20 MHz, CDCl3) δ: 23.7, 25.5, 50.4, 54.9,
61.9, 113.7, 115.5, 125.3, 128.7, 159.5. MS m/z: 230 (M+),
204, 146, 121, 84.
The procedure was further explored using acyclic amines.
Reactions between N-trimethylsilyldimethylamine (TMSNMe2),
diethylamine (HNEt2), or dibuthylamine (HNBu2) with
benzaldehyde (Table 1, entry 11) and TMSNMe2 with p-
methylbenzaldehyde (Table 1, entry 12) resulted in rapid
formation of products 3p (97%), 3q (88%), 3r (94%), and 3s
(91%), respectively. Use of aromatic amines was success-
fully examined by a reaction between benzaldehyde and ani-
line leading to 88% formation of 3t (Table 1, entry 13). Due
to the synthetic importance of N,N-dibenzyl protected α-
aminonitriles (17), the present procedure was employed to
attempt the preparation of these compounds. As an example,
the reaction between benzaldehyde and dibenzylamine in the
presence of TMSCN and MgBr2·OEt2 facilitated 90% forma-
tion of 3u (Table 1, entry 14).
To test the diastereoselectivity of the process, a test reac-
tion between (S)-1-phenylethylamine and benzaldehyde was
conducted under the same sets of conditions leading to for-
mation of 3v in 90% yield within a few minutes. NMR spec-
troscopy of the reaction mixture revealed the formation of
both possible products with a moderate diastereoselectivity
of 3:1 (Scheme 2).
In summary, we have demonstrated a highly efficient,
three-component conversion of aldehydes, amines, and
TMSCN to α-aminonitriles at room temperature using a cat-
alytic amount of MgBr2·OEt2 in the absence of any solvent.
The procedure is applicable to various aromatic and aliphatic
aldehydes and amines. The versatility of the reaction, pro-
duction of pure single compounds, easy procedure and work
up, and no use of solvent or extra additives are among other
benefits of the present method.
Piperidin-1-yl-thiophen-2-yl-acetonitrile (3h)
IR (neat, cm–1) ν: 3107, 2937, 2368, 1442. 1H NMR
(80 MHz, CDCl3) δ: 1.30–1.75 (m, 6H), 2.25–2.70 (m, 4H),
4.85 (s, 1H), 6.80–7.32 (m, 3H). 13C NMR (20 MHz,
CDCl3) δ: 23.7, 25.5, 50.7, 58.5, 114.7, 126.2, 126.5, 126.7,
137.8. MS m/z: 206 (M+), 122, 97, 84.
(4-Fluoro-phenyl)-piperidin-1-yl-acetonitrile (3i)
IR (neat, cm–1) ν: 2928, 2808, 2224, 1608. 1H NMR
(80 MHz, CDCl3) δ: 1.30–1.75 (m, 6H), 2.38–2.45 (m, 4H),
4.72 (s, 1H), 6.89–7.54 (m, 4H). 13C NMR (20 MHz,
CDCl3) δ: 23.6, 25.5, 50.6, 63.4, 115.3, 116.4, 129.1, 129.5,
214.8. MS m/z: 218 (M+), 217, 134, 123, 107.
4-Phenyl-2-piperidin-1-yl-butyronitrile (3m)
IR (neat, cm–1) ν: 3027, 2937, 2222, 1684. 1H NMR
(80 MHz, CDCl3) δ: 1.32–1.80 (m, 6H), 2.03 (t, J = 7 Hz,
2H), 2.20–2.82 (m, 6H), 3.40 (t, J = 8 Hz, 1H), 7.14–7.19
(m, 5H). 13C NMR (20 MHz, CDCl3) δ: 23.9, 25.6, 31.5,
32.2, 50.8, 57.1, 115.6, 126.1, 128.3, 139.8, 215.0. MS m/z:
228 (M+), 201, 123, 110.
Acknowledgments
The Ministry of Science, Research, and Technology of
Iran is gratefully acknowledged for partial financial support
of this work.
References
Experimental
1. (a) A. Strecker. Liebigs. Ann. Chem. 75, 27 (1850); (b) H.
Ishitani, S. Komiyama, Y. Hasegawa, and S. Kobayashi. J. Am.
Chem. Soc. 122, 762 (2000); (c) L. Yet. Angew. Chem. Int.
Ed. 40, 875 (2001).
2. (a) D. Enders and J.P. Shilvock. Chem. Soc. Rev. 29, 359
(2000); (b) M. North. Angew. Chem. Int. Ed. 43, 4126 (2004).
3. (a) D.B. Grotjahn, R.J. Albers, and J. Beckman. Synlett, 633
(2000); (b) G. Stork. Pure Appl. Chem. 61, 439 (1989);
(c) R.B. Woodward, F.E. Bader, H. Bickel, A.J. Frey, and R.W.
Kierstead. J. Am. Chem. Soc. 78, 2023 (1956); (d) R.B. Wood-
ward, F.E. Bader, H. Bickel, A.J. Frey, and R.W. Kierstead. J.
Am. Chem. Soc. 78, 2657 (1956).
General procedure
A mixture of aldehyde (2 mmol), amine (4 mmol), and
MgBr2·OEt2 (5 mol% in respect to aldehyde) was stirred at
room temperature for 5 min. TMSCN (2.4 mmol) was added
to this mixture and stirring continued for an appropriate
length of time until TLC showed completion of the reaction.
The product was extracted three times by 10 mL portions of
diethyl ether and the combined etheral phases were washed
with brine and dried over sodium sulphate. The solvent was
removed under reduced pressure and the product was puri-
fied by column chromatography over silica gel using an
EtOAc–hexane eluant, if necessary. The isolated yields of
the products were 88%–98%. All products were identified
by 1H NMR, 13C NMR, IR, and mass spectroscopic methods
4. (a) C.R. Hauser, H.M. Taylor, and T.G. Ledford. J. Am. Chem.
Soc. 82, 1786 (1960); (b) J.D. Albright. Tetrahedron, 39, 3207
(1983); (c) H.M. Taylor and C.R. Hauser. J. Am. Chem. Soc.
82, 1790 (1960).
2 Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository
of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 5013.
© 2006 NRC Canada