Short Articles
Table 1. Optimization of conditionsa)
[Fe]: 10 mol%
Selective Direct N-Alkylation of
Amines with Alcohols using Iron(III)
Phthalocyanine Chloride under
Solvent-Free Conditions
NH2
H
N
base: 2.0 mmol
+
+
H2O
Microwave, 130 °C
neat, 12 h
HO
1a: 1.0 mmol
2a: 4.0 mmol
3aa
Entry
[Fe]
Base
Yield/%b)
1
2
3
4
5
6
7
8
9
10
11
12
13d)
14e)
15f)
FeIIICl3
tBuOK
59
38
7
11
5
FeIICl2
tBuOK
tBuONa
KOH
FeIIICl3
FeIIICl3
Maki Minakawa,* Masataka Okubo
and Motoi Kawatsura*
,
FeIIICl3
K2CO3
Cs2CO3
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
FeIIICl3
9
[FeIII(acac)3]
FeIIIF3
58
60
27
91
31
21
48
51
66
Department of Chemistry, College of
Humanities and Science, Nihon University,
Sakurajosui, Setagaya-ku, Tokyo 156-8550
[FeII(C5H5)2]
[FeIII(Pc)]Clc)
[FeII(Pc)]c)
M. Minakawa
E-mail: minakawa@chs.nihon-u.ac.jp
Received: June 23, 2015; Accepted: August 26, 2015;
Web Released: September 4, 2015
[FeIII(Pc)]Clc)
[FeIII(Pc)]Clc)
[FeIII(Pc)]Clc)
a) Reaction conditions: 1a (1.0 mmol), 2a (4.0 mmol), Fe
catalyst (10 mol %, based on aniline), and base (2.0 mmol) in
solvent-free conditions under microwave irradiation at 130 °C
for 12 h under N2 atmosphere. b) Isolated yield. c) Pc:
phthalocyaninato. d) Without microwave irradiation (oil bath).
Direct N-alkylation of amines with alcohols in the
presence of iron(III) phthalocyanine chloride as a catalyst in
solvent-free conditions under microwave irradiation afforded
the corresponding N-alkylamines in moderate to high yield
with excellent selectivity.
t
e) 0.5 mmol of BuOK was used. f) Reaction time: 6 h.
Direct N-alkylation of amines with alcohols is an attractive
and environmentally friendly alternative to conventional meth-
odology, such as alkylation of amine with alkyl halides. The
conventional procedure is problematic due to overalkylation
and the toxic nature of alkylating reagents.1 The direct N-
alkylation of amines with alcohols is less hazardous and more
atom economical because the only by-product is water. In the
reaction a generally accepted mechanism, a so-called borrow-
ing-hydrogen methodology,2 involves dehydrogenation of
alcohols to provide carbonyl compounds, which are converted
to imines, and the subsequent reduction of imines by transition
metal hydrides to give N-alkylamines. The most common
metals used for the catalytic N-alkylation of amines with
alcohols are Ru3 and Ir.4 Recently, catalysts derived from other
metals, such as Au,5 Ag,6 Cu,7 Ni,8 Rh,9 Pd,10 and Fe11 have
also been explored. However, Fe-catalyzed N-alkylation of
amines with alcohols has remained a challenging topic.11 In
this paper, we described the selective and efficient N-alkylation
of amines with alcohols using iron catalysis in solvent-free
conditions under microwave irradiation. This reaction em-
ployed [FeIII(Pc)]Cl (Pc: phthalocyaninato), an inexpensive
commercial compound that is typically used as an industrial
additive for ink and rubber manufacturing. The [FeIII(Pc)]Cl
showed good catalytic activity for the direct N-alkylation of
amines with alcohols.
product 3aa in 38% yield (Entry 2). The reaction with different
bases (tBuONa, KOH, K2CO3, or Cs2CO3) in the presence of
FeCl3 resulted in lower yield of the desired product (Entries
t
3-6). Therefore, we selected BuOK as a base for further
evaluation. After screening several Fe catalysts, it was found
that the N-alkylation of aniline (1a) with benzyl alcohol (2a)
using [FeIII(Pc)]Cl (10 mol %) as a catalyst afforded the desired
product 3aa in 91% yield (Entry 10). The N-alkylation with
10 mol % of [FeII(Pc)] gave 3aa in 31% yield under similar
conditions (Entry 11). The reaction was ineffective in the
absence of Fe catalyst (Entry 12).12 Although Singh et al.
reported an efficient N-alkylation of amines with alcohols using
[FeII(Pc)] catalyst for preparation of benzoimidazoles, benzo-
thiozoles, and benzoxazoles, the [FeIII(Pc)]Cl was more
effective than [FeII(Pc)] under our conditions in the N-alkyla-
tion of aniline (1a) with benzyl alcohols (2a).11b A slower reac-
tion was observed without microwave irradiation (Entry 13).
The reaction with 0.5 mmol of tBuOK under similar conditions
gave 51% of 3aa (Entry 14). Although the efficient N-
t
alkylation of amine with a catalytic amount of BuOK was
t
reported,6c,13 an excess amount of BuOK was needed in our
reaction conditions. The reaction for 6 h under similar condi-
tions afforded a reduced yield (66%) of 3aa (Entry 15).
We next examined the Fe-catalyzed N-alkylation of various
amines 1b-1n with benzyl alcohol (2a) under the optimized
reaction conditions (Table 2). The formation of N-alkylamines
from 4-methylaniline (1b), 3-methylaniline (1c), and 2-meth-
ylaniline (1d), with 2a carried out under similar conditions
to give N-benzyl-4-methylaniline (3ba; 80%), N-benzyl-3-
methylaniline (3ca; 84%), and N-benzyl-2-methylaniline (3da;
59%), respectively (Entries 1-3). The reaction of 4-meth-
In initial studies, we tested several iron-catalyzed reaction
conditions for the direct N-alkylation of aniline with benzyl
alcohol (Table 1). The N-alkylation of aniline (1a) with benzyl
t
alcohol (2a) using FeCl3 (10 mol %) and BuOK as a base in
solvent-free conditions under microwave irradiation at 130 °C
for 12 h gave N-benzylaniline (3aa) in 59% isolated yield
(Entry 1). The N-alkylation using FeCl2 afforded the desired
© 2015 The Chemical Society of Japan