Reductive monoalkylation of aromatic and aliphatic nitro compounds and the corresponding amines with nitriles

Article abstract of DOI:10.1021/ol047580f

(Chemical Equation Presented) 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.

Full text of DOI:10.1021/ol047580f

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
richard.hudson@utoledo.edu
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

nitrobenzene derivatives and for the corresponding anilines.
The progress of the reaction was monitored by GC-MS. Very
high yields or exclusive formation of secondary amine
products are shown for reaction with acetonitrile. The large
molar excess of acetonitrile used in the original example as
both reactant and solvent could be significantly reduced to
minimal concentrations required for formation of the second-
ary amine product at a reasonable rate, while substituting
the removed acetonitrile with methanol. Thus, when higher
alkyl analogues of acetonitrile (Table 2) were employed, use
of methanol as a co-solvent maintained the solubility of both
the nitro or amino arene and the alkyl nitrile.
For the cases shown in Tables 1 and 2 reduction of the
nitro group to the corresponding amine appeared to occur
rapidly in a preliminary step, as use of the amine directly
gave similar high ratios of secondary to tertiary products
(Table 3). This was in conformity with the analysis that
showed rapid formation of the amine in most cases,
especially for the nitroarenes with electron-donating activat-
ing groups. For small increases in the size and steric
encumberance of the alkyl group in the nitrile as well as the
presence of the ortho groups in the nitroarene or aniline, the
formation of the tertiary amine was reduced or eliminated
completely.
Table 1. Reductive N-Alkylation of Nitroarenes and Anilines
with Acetonitrile
1/2
3/4
time yield
entry
1
ratio
ratio
(h)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
nitrobenzene
p-nitrotoluene
o-nitrotoluene
m-nitrotoluene
p-methoxynitro-benzene 1:115
o-methoxynitro-benzene 1:102 100:0
1:89
1:102
1:100 100:0
1:100
85:15
90:10
1.5
1.2
2.3
1.4
0.4
2.5
1.4
1.2
1.3
0.8
0.7
2.2
1.6
78
76
83
85
93
96
90
95
94
86:14
86:14
aniline
1:71
1:79
1:79
1:78
1:90
1:90
1:90
88:12
81:19
100:0
88:12
70:30
100:0
91:9
p-toluidine
o-toluidine
m-toluidine
p-anisidine
o-anisidine
m-anisidine
100
100
98
86
that reductive N-monoalkylation with alkyl nitriles to form
the secondary amine in high yield might be developed more
generally.
Thus, the reaction was investigated for a number of simpler
substrates.14 Table 115 shows the results for a number of
Table 4 shows several examples using the procedure for
the formation of secondary amines starting from either
nitroalkanes or aminoalkanes. In these instances, the second-
ary amine products were always formed first, and in some
cases, it was relatively easy to discriminate kinetically
Table 2. Reductive N-Alkylation of Nitroarenes with Various Organic Nitriles
5/6
ratio
7/8
ratio
time
(h)
yield
(%)
entry
5
R′
CH3-
CH2CH2-
CH2(CH2)2-
CH3-
1
2
3
nitrobenzene
nitrobenzene
nitrobenzene
p-nitrotoluene
1:89a
1:8
1:8a
1:102a
1:8
1:8
1:100a
1:8
85:15
89:11
99:1
1.5
16.6
19.2
1.16
3.9
5.9
2.3
3.4
4.0
85
87
71
4
90:10
90:10
90:10
100:0
97:2b
100:0
86:14
95:5
76
5
6
7
p-nitrotoluene
p-nitrotoluene
o-nitrotoluene
CH2CH2-
CH2(CH2)2-
CH3-
100
100
83
100
100
85
8
9
o-nitrotoluene
o-nitrotoluene
m-nitrotoluene
CH2CH2-
CH2(CH2)2-
CH3-
1:8
1:100a
1:8
10
11
12
13
14
15
16
17
18
19
1.4
3.0
m-nitrotoluene
m-nitrotoluene
CH2CH2-
CH2(CH2)2-
CH3-
CH2CH2-
CH2(CH2)2-
CH2(CH2)4-
CH3-
89
1:8
97:3
3.3
0.4
4.0
4.5
29.0
2.5
3.1
100
93
99
100
75
96
p-methoxynitrobenzene
p-methoxynitrobenzene
p-methoxynitrobenzene
p-methoxynitrobenzene
o-methoxynitrobenzene
o-methoxynitrobenzene
o-methoxynitrobenzene
1:115a
1:8
86:14
90:10
90:10
71:0b
100:0
95:5
1:8
1:4
1:102a
1:8
CH2CH2-
CH2(CH2)2-
100
100
1:8
100:0
3.1
a In the absence of CH3OH, with CH3CN as the solvent. b Balance is starting material.
472
Org. Lett., Vol. 7, No. 3, 2005

Table 3. Reductive N-Alkylation of Aromatic Amines with Various Organic Nitriles
entry
9
R′
CH3-
CH2CH2-
CH2(CH2)2-
CH3-
CH2CH2-
CH2(CH2)2-
CH3-
CH2CH2-
CH2(CH2)2-
CH3-
CH2CH2-
CH2(CH2)2-
CH3-
CH2CH2-
CH2(CH2)2-
CH3-
CH2CH2-
CH2(CH2)2-
CH3-
CH2CH2-
CH2(CH2)2-
9/6 ratio
7/8 ratio
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
aniline
aniline
aniline
1:8
1:8
1:8
1:79a
1:8
1:8
1:79a
1:8
1:8
1:78a
1:8
1:8
1:90a
1:8
1:8
1:90a
1:8
1:8
1:90a
1:8
98:0b
94:6
97:3
81:19
90:10
95:5
100:0
97:3
4.3
6.7
8.6
1.2
4.2
5.5
1.3
2.8
4.5
1.2
2.4
2.5
0.7
2.5
3.9
2.2
3.1
3.5
1.6
3.0
4.5
83
100
100
95
100
100
94
100
100
100
100
100
100
99
100
98.0
100
100
86
p-toluidine
p-toluidine
p-toluidine
o-toluidine
o-toluidine
o-toluidine
m-toluidine
m-toluidine
m-toluidine
p-anisidine
p-anisidine
p-anisidine
o-anisidine
o-anisidine
o-anisidine
m-anisidine
m-anisidine
m-anisidine
98:2
88:12
88:12
96:4
70:30
83:17
90:10
100:0
92:8
98:2
91:9
94:6
99:1
100
100
1:8
a In the absence of CH3OH, with CH3CN as the solvent. b Balance is starting material.
between the formation of the secondary product and the
tertiary one. It was also possible to form asymmetric tertiary
products by forming the secondary amine first and then
subsequently forming the tertiary amine by addition of a
larger concentration of a nitrile with a smaller R group to
the medium. Thus, while the selective, high yield formation
of both aryl-alkyl and alkyl-alkyl secondary amines
occurred, this method was also applicable to the formation
of tertiary amines with three different alkyl substituents,
provided their total steric bulk was small.
In one example, cyclohexylamine was converted first to
N-propylcyclohexylamine in 78% yield with propionitrile
(8 equivalents, 2 h, rt). Subsequent addition of acetonitrile
(90 equivalents) at 60 °C for 28 h, gave a 70% yield of
N-ethyl-N-propylcyclohexylamine with less than 10% each
of N-propyl-, N,N-diethyl-, and N,N-dipropylcyclohexyl-
amines.
(12) Chen, P. Y.; Chen, M. C.; Chu, H. Y.; Chang, N. S.; Chuang, T. K.
Stud. Surf. Sci. Catal. 1986, 28, 73-7469.
(13) Fouchard, D. M. D.; Tillekeratne, L. M. V.; Hudson, R. A. Synthesis
2004, 17-18.
Table 4. Reductive N-Alkylation of Nitroalkanes and Aliphatic
Amines
(14) During the preparation of this manuscript, we became aware of an
analogous study of the reductive alkylation of amines with nitriles using a
direct catalytic hydrogenation procedure (Sajiki, H.; Ikawa, T.; Hirota, K.
Org. Lett. 2004, 6, 4977-4980) reporting many examples of selective
secondary amine formation using direct hydrogenation with hydrogen over
palladium or rhodium on carbon catalysts. The formation of the secondary
amine dominates for examples where aromatic amines are alkylated by
aliphatic nitriles and selective formation of secondary amines is less easily
controlled for alkylation of aliphatic amines with aliphatic nitriles. Reaction
rates using these conditions are much slower than those employing the
transfer hydrogenation procedure we used, though the net result in both
cases is the same. In some cases reported by Sajiki et al., the rate of the
hydrogenation reaction was shown to increase using ammonium acetate as
an additive. This procedure also improved the selective formation of the
secondary amine. In the report given here, the use of ammonium formate
as the hydrogen transfer source may also be consistent with an interesting
rate-accelerating effect due to added ammonium acetate that was observed
by Sajiki et al. yet remains to be explained.
10/6 11/12 time yield
entry
10
R′
ratio ratio
(h)
(%)
1
2
3
4
5
CH3(CH2)5NO2
CH3(CH2)5NO2
cyclohexylamine CH3-
CH3-
1:89a 4:96
2.3
NDc
CH2CH2- 1:8
70:30
0.3 51
0.4 39
1:80a 86:14
cyclohexylamine CH2CH2- 1:8
cyclohexylamine CH3(CH2)2 1:8
76:22b 1.0 77
85:6b
2.0 85
a In the absence of MeOH, with CH3CN as the solvent. b Balance is
(15) Yields reported in Tables 1-4 are based on weight of isolated
products; product ratios are based on GC-MS analysis of the isolated
products.
starting material. c ND ) not determined.
Org. Lett., Vol. 7, No. 3, 2005
473

The use of a transfer hydrogenation procedure appeared
to be much faster compared to direct reduction with hydrogen
over palladium or other types of catalysts. Indeed, there were
a number of reports of intramolecular nitrile-mediated
reductive alkylations that have been conducted with hydrogen
as a reductant at various pressures and over various types of
catalysts.16-20 Also, using active rhodium catalysts, Galan
et al.21 have demonstrated direct reductive coupling of
aliphatic nitriles to form the corresponding secondary amines
in high yield. In these instances, direct reduction of nitrile
led to the corresponding amine, which then reacted with
nitrile leading to a secondary amine product in a process
likely identical to that reported here. The products formed
in both those cases as well as here were consistent with the
intermediacy of an amidine22 reduced first to a geminal
diamine, from which ammonia was then eliminated to form
a Schiff’s base. A final reduction then led to the secondary
amine.
observations presented here. However, the hydrogenation
conditions employed for reductively alkylating nitriles with
amines, or nitro compounds that have to be first converted
to an amine, cannot in our case directly reduce the nitrile.
Thus, our conditions support nitro group but not nitrile
reduction. It is the apparent interaction of the nitrile with
the amine that leads to intermediates from which one of the
nitrogens must be eliminated and eventually reduced to yield
the observed secondary amine products.
The planar intermediates required for secondary amine
formation clearly would make it easier to form a secondary
rather than a tertiary product. In the carbon-nitrogen double-
bond character of the presumed intermediates formed during
reductive alkylation of the amine, the presence of a third
alkyl group in the formation of a tertiary product can clearly
become a steric problem. Whereas the secondary product
can still avoid steric difficulties, the carbon-nitrogen double-
bond intermediates formed on the way to the tertiary products
cannot. These steric effects are clearly more important for
the reductive alkylation of nitriles than in the analogous
nucleophilic substitution reactions.
This reductive coupling of nitriles to form secondary
amines represented a useful model for understanding the
(16) Somei, M.; Tsuchiya, M. Chem. Pharm. Bull. 1981, 29, 3145-
3157.
Supporting Information Available: Experimental pro-
(17) Sasai, H.; Yamada, Y.; Suzuki, T.; Shibasaki, M. Tetrahedron 1994,
50, 12313-12318.
1
cedures and H NMR and 13C NMR data for the products.
(18) Czeskis, B.; Clodfelter, D.; Wheeler, W. J. Label. Compd. Radio-
pharm. 2002, 45, 1143-1152.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(19) Makosza, M.; Stalewski, J.; Maslennikova, O. Synthesis 1997,
1131-1133.
(20) Zhou, L.; Zhang, Y. J. Chem. Soc., Perkin Trans. 1 1998, 2399-
2402.
OL047580F
(21) Galan, A.; Mendosa, J.; Prados, P.; Rojo, J.; Echavarren, A. M. J.
Org Chem. 1991, 56, 452-454.
(22) Zhang, J. Chang, H.-M.; Kane, R. R. Synlett 2001, 643-645.
474
Org. Lett., Vol. 7, No. 3, 2005