ORGANIC
LETTERS
2005
Vol. 7, No. 3
471-474
Reductive Monoalkylation of Aromatic
and Aliphatic Nitro Compounds and the
Corresponding Amines with Nitriles
Ruel Nacario,† Shailaja Kotakonda,† David M. D. Fouchard,†,1
L. M. Viranga Tillekeratne,†,‡ and Richard A. Hudson*,†,‡
Department of Medicinal & Biological Chemistry, College of Pharmacy, and
Department of Chemistry, College of Arts & Sciences, UniVersity of Toledo,
Toledo, Ohio 43606
Received November 24, 2004
ABSTRACT
A simple, selective, rapid, and efficient procedure for the synthesis of secondary amines from the reductive alkylation of either aliphatic or
aromatic nitro compounds and the corresponding amines is reported. Ammonium formate is used as the hydrogen source and Pd/C as the
hydrogen transfer catalyst. The reaction is carried out at room temperature. The rate differences for the preferential formation of secondary
over tertiary products are due to both steric and electronic factors.
Control over the synthesis of secondary amines is a problem
of long standing in organic chemistry.2 The problem of
overalkylation has been solved in many instances either by
the use of an excess of primary amine,3 by special protecting
groups,4 or by special zeolyte5 or other catalysts, including
phase-transfer catalysts.6-12 However, improvements in the
efficiency of secondary amine formation have usually come
at considerable cost. Thus, improved selective methods of
secondary amine synthesis continue to be sought.
The present investigation began with the observation that
aminobenzimidazole formation in a reduction reaction ac-
companying an imidazole cyclization reaction was compli-
cated by a troublesome reductive N-ethylation of the isolated
nitro group (Scheme 1).13 In this instance, the undesired
product was formed in 75% yield without any attempt to
optimize. While the N-ethylation reaction could be avoided
by substitution of the acetonitrile with acetic acid, the total
absence of the tertiary diethylamine in this example suggested
† College of Arts & Sciences.
‡ College of Pharmacy.
(1) Current address: Department of Chemistry and Biochemistry,
Montana State University (Gaines Hall, # 328), Bozeman, MT 59715.
(2) Salvatore, R. N.; Yoon, C. W.; Jung, K. W. Tetrahedron 2001, 57,
7785-7811.
(3) Mitsunobu, O. ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 6, p 65.
(4) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999; pp 494-632.
(5) Siswanto, C.; Rathman, J. F. J. Colloid Interface Sci. 1997, 196, 99-
102.
Scheme 1
(6) Hayden, L.; Sauter, G.; Ore, F.; Pasillas, P.; Hoover, J.; Lindsay,
G.; Henry, R. J. Appl. Phys. 1990, 68, 456-465.
(7) Bhattacharyya, A. K.; Nandi, D. K. Ind. Eng. Chem. Prod. Res. DeV.
1975, 14, 162-167.
(8) Narayanan, S.; Prabhu Prasad, B. J. Mol. Catal. A: Chem. 1995, 96,
57-64.
(9) Narayanan, S.; Kumari, V. D.; Rao, A. S. Appl. Catal., A 1994, 111,
133-142.
(10) Brown, A. B.; Reid, E. E. J. Am. Chem. Soc. 1924, 46, 1836-
1839.
(11) Bayer, A. C.; Pittman, C. U.; Wang, L.; Alley, E. Ger. Offen. DE
4,013,613, 1990.
10.1021/ol047580f CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/07/2005