One-pot, solvent-free synthesis of α-aminonitriles under catalysis by magnesium bromide ethyl etherate

Article abstract of DOI:10.1139/V06-024

A three-component, efficient, and facile procedure has been developed for the synthesis of α-aminonitriles from aldehydes, amines, and trimethylsilyl cyanide using a catalytic amount of magnesium bromide ethyl etherate in the absence of solvent. Rapid formation of products is observed at room temperature in a one-pot procedure under very mild conditions giving excellent yields of the title compounds.

Full text of DOI:10.1139/V06-024

429
One-pot, solvent-free synthesis of ␣-aminonitriles
under catalysis by magnesium bromide ethyl
etherate
Mohammad M. Mojtahedi, M. Saeed Abaee, and Hassan Abbasi
Abstract: A three-component, efficient, and facile procedure has been developed for the synthesis of α-aminonitriles
from aldehydes, amines, and trimethylsilyl cyanide using a catalytic amount of magnesium bromide ethyl etherate in
the absence of solvent. Rapid formation of products is observed at room temperature in a one-pot procedure under very
mild conditions giving excellent yields of the title compounds.
Key words: catalyzed Strecker’s reaction, α-aminonitriles, magnesium bromide, solvent-free.
Résumé : On a développé une méthode simple et efficace pour réaliser la synthèse de α-aminonitriles par réaction mo-
notope d’aldéhydes, d’amines et de cyanure de triméthylsilyle, en présence d’une quantité catalytique du complexe bro-
mure de magnésium/éthérate d’éthyle, en l’absence de solvant. La formation rapide de produits se produit à la
température ambiante, dans des conditions très douces et conduit aux composés mentionnés dans le titre avec
d’excellents rendements.
Mots clés : réaction de Strecker catalysée, α-aminonitriles, bromure de magnésium, sans solvant.
[Traduit par la Rédaction] Mojtahedi et al. 432
Introduction
Scheme 1.
A three-component combination of aldehydes, amines, and
“cyanide”, known as Strecker’s reaction (1), facilitates the
formation of α-aminonitriles (2), which are equivalent
synthones to imminium moieties (3) and acyl anions (4).
These compounds are very versatile intermediates for the
synthesis of α-amino acids (5, 4b), 1,2-diamines (6), amides
(7), and various nitrogen-containing heterocycles such as
thiadiazoles and imidazoles (8). Recent progress such as the
development of one-pot procedures for aminative cyanation
of carbonyl compounds (9), use of Lewis acidic conditions
(10), and employment of new cyanating reagents, especially
trimethylsilyl cyanide (TMSCN) (11, 1a), have contributed
outstanding elaborations (12) to the classical version of the
Strecker’s reaction (13). However, use of expensive reagents
and strong acidic conditions, long reaction times, deactiva-
tion and decomposition of the catalytic systems under the re-
action circumstances, and production of toxic disposals are
still among the deficiencies of many of these methods. Thus,
development of efficient, clean, and catalytic reactions for
the synthesis of the title structures are still in demand.
In recent years, magnesium bromide ethyl etherate
(MgBr2·OEt2) has found many applications as a mild Lewis
acid (14) because of its ease of preparation, oxophilic na-
ture, and coordinating ability for bidentate chelation (15)
CN
TMSCN
RCHO
+
R'2NH
.
MgBr2 OEt2
R'2N
R
1
2
3a-3v
that makes various chelation-controlled organic transforma-
tions easier. Our experiences with the use of such reaction
conditions (16) prompted us to look for a mild medium for
the synthesis of the title compounds. We would like to intro-
duce here an efficient, three-component combination of al-
dehydes with various amines and TMSCN at room
temperature for the synthesis of α-aminonitriles using a cat-
alytic amount of MgBr2·OEt2 (Scheme 1).
Results and discussion
Initial experiments were carried out by subjecting a
benzaldehyde, pyrrolidine (piperidine), and MgBr2·OEt2
mixture to reaction with TMSCN at room temperature in the
absence of solvent (Table 1). Complete disappearance of the
aldehyde and rapid formation of the product were monitored
by TLC. Various amounts of the Lewis acid were used to op-
timize the reaction conditions. A catalytic quantity of
MgBr2·OEt2 (5 mol%) proved to be effective for the com-
plete conversion of starting materials to the desired product
(3a or 3b) in 5 min (Table 1, entry 1). Use of smaller
amounts of the catalyst down to 1 mol% only prolonged the
reaction time up to 45 min, leading to nearly quantitative
formation of 3a (or 3b). Similar reactions using various aro-
matic aldehydes bearing electron-withdrawing and electron-
releasing groups with cyclic amines were conducted under
the same conditions. Consequently, more than 90% yields of
Received 30 December 2005. Published on the NRC Research
Press Web site at http://canjchem.nrc.ca on 31 March 2006.
M.M. Mojtahedi,1 M.S. Abaee, and H. Abbasi. Chemistry
and Chemical Engineering Research Center of Iran,
P.O. Box 14335-186, Tehran, Iran.
1Corresponding author (e-mail: mojtahedi@ccerci.ac.ir).
Can. J. Chem. 84: 429–432 (2006)
doi:10.1139/V06-024
© 2006 NRC Canada

430
Can. J. Chem. Vol. 84, 2006
Table 1. Room-temperature MgBr2·OEt2-catalyzed synthesis of α-aminonitriles.
a
Entry
Aldehyde
Amine
Product
Yield (%)
CN
1
C6H5CHO
Pyrrolidine
Piperidine
3a: n = 1
94
93
N
C6H5
3b: n = 2
(CH2)n
CN
2
3
(p-Me)C6H4CHO
Pyrrolidine
Piperidine
3c: n = 1
3d: n = 2
94
94
N
C6H4(Me-p)
(CH2)n
CN
(p-OMe)C6H4CHO
Pyrrolidine
Piperidine
3e: n = 2
3f: n = 2
93
96
N
C6H4(OMe-p)
(CH2)n
CN
S
4
2-Thiophen-CHO
Pyrrolidine
Piperidine
3g: n = 2
3h: n = 2
91
93
N
(CH2)n
CN
5
6
7
(p-X)C6H4CHO
Piperidine
Morpholine
HNEt2
3i: X = F
3j: X = Cl
98
93
N
C6H4(X-p)
CN
(p-Cl)C6H4CHO
(p-CO2Me)C6H4CHO
3k
3l
94
96
N
C6H4(Cl-p)
O
CN
N
C6H4(CO2Me-p)
CN
N
8
C6H5CH2CH2CHO
Piperidine
3m
92
CH2CH2C6H5
CH2CH2CH3
CN
N
9
CH3CH2CH2CHO
CH3CH2CH2CHO
HNEt2
3n
3o
88
91
CN
10
Pyrrolidine
N
CH2CH2CH3
CN
R
N
R
C6H5
11
C6H5CHO
TMSNMe2
HNEt2
3p: R = Me
3q: R = Et
3r : R = Bu
97
88
94
HNBu2
CN
CN
12
13
14
(p-Me)C6H4 CHO
C6H5CHO
TMSNMe2
Aniline
3s
91
88
90
N
C6H4(Me-p)
H5C6
3t
C6H5
N
H
CN
C6H5CH2
C6H5CHO
HN(CH2C6H5)2
3u
N
C6H5
CH2C6H5
aIsolated yields.
products 3c–3l were all easily obtained in less than 10 min
(Table 1, entries 2–7). The methodology proved to be
equally effective for the smooth conversion of aliphatic al-
dehydes into α-aminonitriles when 3-phenyl-propionalde-
hyde or butyraldehyde were subjected to the reaction condi-
tions (Table 1, entries 8–10).
© 2006 NRC Canada

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

432
5. (a) A.J. Davies, M.S. Ashwood, and I.F. Cottrell. Synth.
Can. J. Chem. Vol. 84, 2006
Takamura, Y. Hamashima, H. Usuda, M. Kanai, and M.
Shibasaki. Chem. Pharm. Bull. 48, 1586 (2000); (d) M.
Chavarot, J.J. Byrne, P.Y. Chavant, and Y. Vallee. Tetrahe-
dron: Asymmetry, 12, 1147 (2001); (e) K. Mai and G. Patil.
Tetrahedron Lett. 25, 4583 (1984).
Commun. 30, 1095 (2000); (b) W.H.J. Boesten, J.P.G.
Seerden, B. Lange, H.J.A. Dielemans, H.L.M. Elsenberg, B.
Kaptein, H.N. Kellogg, and Q.B. Broxtermann. Org. Lett. 3,
1121 (2001); (c) Y.M. Shafran, V.A. Bakulev, and V.S.
Mokrushin. Russ. Chem. Rev. 58, 148 (1989).
12. (a) J.T. Su, P. Vachal, and E.N. Jacobsen. Adv. Synth. Catal.
343, 197 (2001); (b) F.A. Davis, S. Lee, H. Zhang, and D.L.
Fanelli. J. Org. Chem. 65, 8704 (2000); (c) F.A. Davis, P.S.
Portonovo, R.E. Reddy, and Y.H. Chiu. J. Org. Chem. 61, 440
(1996); (d) M.S. Sigman and E.N. Jacobsen. J. Am. Chem.
Soc. 120, 4901 (1998); (e) G. Jenner, R.B. Salem, J.C. Kim,
and K. Matsumoto. Tetrahedron Lett. 44, 447 (2003); ( f ) P.P.
Sun, C.T. Qian, L.M. Wang, and R.F. Chen. Synth. Commun.
32, 2973 (2002).
6. E. Leclerc, P. Mangency, and V. Henryon. Tetrahedron: Asym-
metry, 11, 3471 (2000).
7. (a) D. Enders, A.S. Amaya, and F. Pierre. New J. Chem. 23,
261 (1999); (b) T.H. Chuang, C.C. Yang, C.J. Chang, and J.M.
Fang. Synlett, 733 (1990).
8. (a) L.M. Weinstock, P. Davis, B. Handelsman, and R. Tull. J.
Org. Chem. 32, 2823 (1967); (b) W.L. Matier, D.A. Owens,
W.T. Comer, D. Deitchman, H.C. Fergusen, R.J. Seidehamel,
and J.R. Young. J. Med. Chem. 16, 901 (1973); (c) J.P.
Leblanc and H.W. Gibson. J. Org. Chem. 59, 1072 (1994);
(d) J.A. Gonzalez-Vera, M.T. Garcia-Lopez, and R. Herranz. J.
Org. Chem. 70, 3660 (2005).
9. (a) J.S. Yadav, B.V.S. Reddy, B. Eshwaraiah, and M. Srinivas.
Tetrahedron, 60, 1767 (2004); (b) W.Y. Chen and J. Lu.
Synlett, 2293 (2005); (c) D.E. Fuerst and E.N. Jacobsen. J.
Am. Chem. Soc. 127, 8964 (2005); (d) E. Takahashi, H.
Fujisawa, T. Yanai, and T. Mukaiyama. Chem. Lett. 34, 604
(2005).
10. (a) S.K. De and R.A. Gibbs. Tetrahedron Lett. 45, 7407
(2004); (b) L. Royer, S.K. De, and R.A. Gibbs. Tetrahedron
Lett. 46, 4595 (2005); (c) M. Suginome, A. Yamamoto, and Y.
Ito. Chem. Commun. (Cambridge), 1392 (2002); (d) L.
Bernardi, B.F. Bonini, E. Capit, G. Dessole, M. Fochi, M.
Comes-Franchini, and A. Ricci. Synlett, 1778 (2003); (e) N.
Azizi and M.R. Saidi. Synth. Commun. 34, 1207 (2004);
( f ) R. Yousefi, N. Azizi, and M.R. Saidi. J Organomet. Chem.
690, 76 (2005); (g) B.C. Ranu, S.S. Dey, and A. Hajra. Tetra-
hedron, 58, 2529 (2002); (h) S.K. De. J. Mol. Catal. A: Chem.
225, 169 (2005); (i) S.K. De and R.A. Gibbs. Synth. Commun.
35, 961 (2005); ( j) E. Takahashi, H. Fujisawa, T. Yanai, and T.
Mukaiyama. Chem. Lett. 34, 318 (2005); (k) S.K. De. Synth.
Commun. 35, 653 (2005); (l) S.K. De. Synth. Commun. 35,
1577 (2005).
13. J.M. Fang, C.C. Yang, and Y.W. Wang. J. Org. Chem. 54, 481
(1989).
14. (a) C. Malanga and S. Mannucci. Tetrahedron Lett. 42, 2023
(2001); (b) S. Yamada, S. Yaguchi, and K. Matsuda. Tetrahe-
dron Lett. 43, 647 (2002); (c) S.K. Tipparaju, S.K. Mandal, S.
Sur, V.G. Puranik, and A. Sarkar. Chem. Commun. (Cam-
bridge), 1924 (2002); (d) B.Z. Zheng, M. Yamauchi, H. Dei, S.
Kusaka, K. Matsui, and O. Yonemitsu. Tetrahedron Lett. 41,
6441 (2000); (e) A. Vakalopoulos and H.M. Hoffmann. Org.
Lett. 2, 1447 (2000); ( f ) T. Onoda, R. Shirai, and S. Iwasaki.
Tetrahedron Lett. 38, 1443 (1997); (g) P. Lupattelli, C.
Bonini, L. Caruso, and A. Gambacorta. J. Org. Chem. 68,
3360 (2003); (h) S.K. Tipparaju, V.G. Puranik, and A. Sarkar,
Org. Biomol. Chem. 1, 1720 (2003); (i) D.E. Ward, M.J.
Hrapchak, and M. Sales. Org. Lett. 2, 57 (2000); ( j) T. Abe,
C. Sato, H. Ushirogochi, K. Sato, T. Takasaki, T. Isoda, A.
Mihira, I. Yamamura, K. Hayashi, T. Kumagai, S. Tamai, M.
Shiro, A.M. Venkatesan, and T.S. Mansour. J. Org. Chem. 69,
5850 (2004); (k) H. Fujisava, Y. Saski, and T. Mukaiyama.
Chem. Lett. 30, 190 (2001).
15. S.K. Tipparaju. Synlett, 912 (2004).
16. (a) D.E. Ward and M.S. Abaee. Org. Lett. 2, 3937 (2000);
(b) M.S. Abaee, R. Sharifi, and M.M. Mojtahedi. Org. Lett. 7,
5893 (2005); (c) M.S. Abaee, M.M. Mojtahedi, M.M. Zahedi,
and R. Sharifi. Heteroatom Chem. In press.
11. (a) A.S. El-Ahl. Synth. Commun. 33, 989 (2003); (b) M.
Takamura, Y. Hamashima, H. Usuda, M. Kanai, and M.
Shibasaki. Angew. Chem. Int. Ed. 39, 1650 (2000); (c) M.
17. (a) P. Sun, C. Qian, L. Wang, and R. Chen. Synth. Commun.
32, 2973 (2002); (b) R. Martinez, D.J. Ramon, and M. Yus.
Tetrahedron Lett. 46, 8471 (2005).
© 2006 NRC Canada