Initially, we examined 10% Pd/C-catalyzed N-ethylation
of aniline (1), aromatic amine, with MeCN under various
conditions. Amazingly, mono-N-ethylaniline (2a) was ob-
tained at ambient temperature and under hydrogen pressure
in MeCN as a solvent although the formation of a minimal
amount of overalkylated N,N-diethylaniline (3a) was ob-
served (Table 1, entry 1). The effect of MeOH as a solvent
Table 2. Reductive Mono-N-alkylation of Aniline Using
Various Nitriles
additive time
(1 equiv) (h)
entry
RCN
1/2/3a
1
2
3
4
5
6
7
8
9
MeCNb
EtCN
PrCN
25
29
42
19
0:100 (85)c: 0
2:98:0
5:95:0
Table 1. Reductive Mono-N-alkylation of Aniline Using
MeCN
dist. PrCN
iPrCN
0:99:1
24 100:0:0
28
48
49
dist. iPrCN
BuCN
0:100 (88)c:0
0:100 (89)c:0
5:95:0
81:19:0
0:100 (80)c:0
72:28:0
entry
MeCN (equiv)
solvent
time (h)
1/2a/3aa
0:98:2
0:89:11
0:100 (85)c:0
8:92:0
dist.iBuCN
dist. tBuCN
56
1
2
3
4
38b
5
2
24
24
25
24
10d dist. tBuCN
NH4OAc 24
MeOH
MeOH
MeOH
11
dist. Me(CH2)10CN
72
48
12d dist. Me(CH2)10CN
0:100: 0
1.5
13
14
15
16
17
dist. CyCN
HO(CH2)2CN
(CH2CN)2
(MeO)2CH(CH2)2CN
BnCN
NH4OAc 24
0:100 (quant)c: 0
0:100 (81)c: 0
0:100 (86)c ,f: 0
0:100: 0
a Determined by 1H NMR. b MeCN was used as a solvent. c Isolated
yield.
53
27
24
27
1:99:0
a Determined by 1H NMR. b 2 equiv of MeCN was used. c Isolated yield.
d 20 wt % of 10% Pd/C was used. e Cy ) cyclohexyl. f N-(3-Cyanopropyl)-
aniline was isolated as a sole product.
is essential for this reaction, and the use of only 2 equiv of
MeCN versus aniline gave a thoroughly selective result as
shown in Table 1, entry 3.
It is well-known that the hydrogenation of nitriles under
relatively vigorous hydrogenation conditions over platinum
metal catalysts is favorable for the formation of symmetrical
secondary and tertiary amines.11 While it is quite expected
that the hydrogenation of nitriles in the presence of amines
can produce unsymmetrical amines,12 only a few examples
of selective mono-N-alkylation of amines have been reported
in the literature because nitriles are not so reactive under
hydrogenation conditions and the regulation of the selective
reaction is very difficult.11,13 Such conventional procedures
are all limited to the substrate and require large excess
amount of amines and elevated hydrogen pressure and/or
higher temperature.14
The Pd/C-catalyzed reductive mono-N-alkylation of aniline
(1) using various nitriles is summarized in Table 2. The
present mono-N-alkylation system could be applied to a
variety of primary, secondary, and tertiary nitriles while the
use of 5 equiv of nitriles gave better results except only
i
i
t
MeCN (entry 1). When PrCN, PrCN, BuCN, BuCN, Me-
(CH2)10CN, or cyclohexanecarbonitrile was used as an
alkylating reagent, the alkylation was incomplete (see entries
3 and 5). This drawback can be overcome by the use of
distilled reagents (entries 4, 6, 8, 10, 12, and 13, see the
Supporting Information). If the yield was still lower (entries
9 and 11), the multiplication of 10% Pd/C (20 wt %) and/or
the addition of 1.0 equiv of NH4OAc as an additive gave
complete results (entries 10, 12, and 13). N-Alkylation of
aniline (1) with nitriles bearing alcohol and acetal proceeded
to give the corresponding mono-N-alkylated anilines (2) in
excellent yields (entries 14 and 16). For the alkylation using
succinonitrile under the same conditions, N-(3-cyanopropyl)-
aniline was isolated as the sole product (entry 15).
We next examined the mono-N-alkylation of other aro-
matic amines (4). Mono-N-alkylation of aniline derivatives
with MeCN bearing electron-donating (OMe, NHCOMe) and
electron-withdrawing (Ph, F, CO2H, CF3) substituents at the
aromatic ring smoothly and selectively proceeded to give
the corresponding mono-N-alkylated aniline derivatives (5)
in nearly quantitative yields (Table 3, entries 1-6). Although
the reaction of 4-trifluoromethylaniline with MeCN did not
give a satisfactory result (entry 7), the addition of 1.0 equiv
of NH4OAc is very efficient for the selective mono-N-
alkylation of 4-trifluoromethylaniline (entry 8). Other aro-
(11) (a) Rylander, P. N. Hydrogenation Methods; Academic Press:
London, 1985; pp 94-103. (b) Nishimura, S. Handbook of Heterogeneous
Catalytic Hydrogenation for Organic Synthesis; Wiley-Interscience: New
York, 2001; pp 270-285.
(12) Kindler, K.; Hesse, F. Arch. Pharm. (Weinheim, Ger.) 1933, 271,
439-445.
(13) (a) Rylander, P. N.; Hasbrouck, L.; Karpenko, I. Ann. New York
Acad. Sci. 1973, 214, 100-109. (b) Fu¨lo¨p, F.; Huber, I.; Berna´th, G.;
Ho¨enig, H.; Seufer-Wasserthal, P. Synthesis 1991, 43-46. (c) Rosowsky,
A.; Mota, C. E.; Wright, J. E.; Queener, S. F. J. Med. Chem. 1994, 37,
4522-4528. (d) Gavagan, J. E.; Fager, S. K.; Fallon, R. D.; Folsom, P.
W.; Herkes, F. E.; Eisenberg, A.; Hann, E. C.; DiCosimo, R. J. Org. Chem.
1998, 63, 4792-4801. (e) Graffner-Nordberg, M.; Kolmodin, K.; Aqvist,
J.; Queener, S. F.; Hallberg, A. J. Med. Chem. 2001, 44, 2391-2402. (f)
Gangjee, A.; Adair, O. O.; Queener, S. F. J. Med. Chem. 2003, 46, 5074-
5082. (g) Ananthan, S.; Kezar, H. S.; Saini, S. K.; Khare, N. K.; Davis, P.;
Dersch, C. M.; Porreca, F.; Rothman, R. B. Bioorg. Med. Chem. Lett. 2003,
13, 529-532.
(14) Recently, an attractive example of mono-N-alkylation of primary
amines using cyanohydrin and Pd/C accompanied by cyclization was
investigated; see: Vink, M. K. S.; Schortinghuis, C. A.; Mackova-
Zabelinskaja, A.; Fechter, M.; Po¨chlauer, P.; Marianne, A.; Castelijns, C.
F.; van Maarseveen, J. H.; Hiemstra, H.; Griengl, H.; Schoemaker, H. E.;
Rutjes, F. P. J. T. AdV. Synth. Catal. 2003, 345, 483-487.
4978
Org. Lett., Vol. 6, No. 26, 2004