N-Alkylation of amines with alcohols catalyzed by a Cp*Ir complex

Article abstract of DOI:10.1016/S0040-4039(03)00371-X

A new effective catalytic system consisting of [Cp*IrCl₂]₂/K₂CO₃ (Cp=pentamethylcyclopentadienyl) for the N-alkylation of primary amines with alcohols has been developed. As an example, the reaction of aniline with benzyl alcohol in the presence of [Cp*IrCl₂]₂ (5.0 mol%Ir) and K₂CO₃ (5.0 mol%) in toluene at 110°C for 17 h gave benzylaniline in an isolated yield of 88%.

Full text of DOI:10.1016/S0040-4039(03)00371-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2687–2690
N-Alkylation of amines with alcohols catalyzed by a
Cp*Ir complex
a,
b
b
b,
Ken-ichi Fujita, * Zhenzi Li, Naohiro Ozeki and Ryohei Yamaguchi *
a
Department of Natural Resources, Graduate School of Global Environmental Studies, Kyoto University, Kyoto 606-8501, Japan
b
Graduate School of Human and Environmental Studies, Kyoto University, Kyoto 606-8501, Japan
Received 16 December 2002; revised 3 February 2003; accepted 6 February 2003
Abstract—A new effective catalytic system consisting of [Cp*IrCl ] /K CO (Cp*=pentamethylcyclopentadienyl) for the N-alkyl-
2
2
2
3
ation of primary amines with alcohols has been developed. As an example, the reaction of aniline with benzyl alcohol in the
presence of [Cp*IrCl ] (5.0 mol%Ir) and K CO (5.0 mol%) in toluene at 110°C for 17 h gave benzylaniline in an isolated yield
2
2
2
3
of 88%. © 2003 Elsevier Science Ltd. All rights reserved.
5
b
The alkylation of primary amines to secondary or
tertiary amines is one of the most fundamental and
important reactions in synthetic organic chemistry. The
N-alkylation with alkyl halides is a well-known
N-heterocyclization of amino alcohols,
which
prompted us to study N-alkylation of amines with
alcohols. In this paper, we wish to report a Cp*Ir
complex-catalyzed N-alkylation of primary amines with
alcohols.
1
method, but use of alkyl halides is undesirable from an
environmental point of view, and it generates wasteful
salts as byproducts. The reductive amination of alde-
hydes and ketones is another well-known method,
which has been developed as the most useful tool in the
First, we investigated Cp*Ir-catalyzed N-alkylation of
aniline with benzyl alcohol under various conditions.
The reactions were performed in the presence of several
catalysts and base (K CO ) in toluene as a solvent. The
2
synthesis of various amines. However, this method
2
3
requires the use of strong reducing reagents or danger-
ous hydrogen gas and is not always selective for mono-
alkylation of primary amines.
results are summarized in Table 1. In each reaction,
Table 1. Catalytic N-alkylation of aniline with benzyl
a
alcohol under various conditions
The N-alkylation of amines with alcohols is an attrac-
tive method because (1) it does not generate harmful
byproducts (only H O as byproduct); (2) alcohols are
2
more readily available than corresponding halides or
carbonyl compounds in many cases. Although some
catalytic systems for N-alkylation of amines with alco-
3
hols have been studied with ruthenium and rhodium
Yield (%)b
Entry
1
Catalyst
Temp. (°C) Time (h)
4
catalysts, most of these systems require high reaction
temperature (>150°C), and applicable amines and alco-
hols are very restricted. During the course of our
investigation on the chemistry of pentamethylcyclopen-
tadienyl (Cp*) iridium complexes, we found a catalytic
activity of [Cp*IrCl ] toward hydrogen-transfer reac-
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl
[Cp*IrHCl]2 110
110
110
90
17
17
17
40
17
17
17
100
30
52
81
55
3
c
2
3
4
5
6
7
5
]
90
2
2
2
2
6
[IrCl(cod)]2
110
110
tions between organic molecules, and reported Oppe-
5a
[Cp*RhCl
2
]
2
43
nauer-type oxidation of alcohols
and oxidative
a
The reaction was carried out with aniline (1.0 mmol), benzyl alcohol
(1.0 mmol), catalyst (5.0 mol%metal), and K CO (0.050 mmol) in
Keywords: iridium catalyst; N-alkylation; hydrogen transfer; amine;
2
3
alcohol.
toluene (0.5 mL).
Determined by GC.
The reaction was carried out without K CO .
2 3
b
c
*
Corresponding author. Tel.: +81-75-753-6827; fax: +81-75-753-6634;
e-mail: fujitak@kagaku.mbox.media.kyoto-u.ac.jp
0
040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00371-X

2
688
K. Fujita et al. / Tetrahedron Letters 44 (2003) 2687–2690
mono-alkylated benzylaniline was formed as a single
product; no formation of di-alkylated dibenzylaniline
was observed. Benzylaniline was formed quantitatively
when the reaction was performed at 110°C for 17 h in
the presence of [Cp*IrCl ] (5.0 mol%Ir) and K CO
Table 2. Cp*Ir catalyzed N-alkylation of anilines with
a
various primary and secondary alcohols
2
2
2
3
(
5.0 mol%) (entry 1). The yield of benzylaniline consid-
erably decreased when the reaction was performed in
the absence of K CO3 (entry 2). The reaction also
2
proceeded at lower temperature (90°C), but longer reac-
tion time was necessary to obtain a satisfactory result
(
entries 3 and 4). Other iridium catalysts [Cp*IrHCl]2,
[
IrCl(cod)] (cod=1,5-cyclooctadiene), or rhodium cat-
2
alyst [Cp*RhCl ] , showed lower activity than
2
2
[
Cp*IrCl ] (entries 5–7).
2 2
Results obtained from N-alkylation of anilines with
various primary and secondary alcohols are summa-
7
rized in Table 2. The present N-alkylation system
could be applied to a variety of primary and secondary
alcohols. N-Alkylation of aniline with benzyl alcohols
bearing electron-donating (Me, OMe) and electron-
withdrawing (Cl, NO ) substituents at the aromatic ring
2
proceeded to give benzylaniline derivatives in good to
excellent yields (entries 2–7). Other primary alcohols,
b-phenethyl alcohol or 1-octanol were also applicable
8
to this reaction (entries 8 and 9). When the reaction of
aniline with 1-octanol was performed using an excess
amount of 1-octanol (2.6 equiv.) for 40 h, the di-alkyl-
ated product was obtained in a yield of 36% as well as
the mono-alkylated product (63%) (entry 10), indicating
that the second alkylation is sufficiently slow. The
reaction of aniline with secondary alcohols proceeded
in good to excellent yields (entries 11–13). The reaction
of substituted anilines with benzyl alcohol also pro-
ceeded satisfactorily (entries 14 and 15).
We next examined the N-alkylation of other primary
7
amines. The results are summarized in Table 3. N-
alkylation of benzylamine with several primary and
secondary alcohol proceeded in good yields (entries
8
1
–6). When the reaction of benzylamine with 1-octanol
was performed using an excess amount of 1-octanol
2.6 equiv.) for 40 h, dioctylbenzylamine was obtained
(
as a major product (80%) (entry 4), indicating that
di-alkylation of benzylamine is easier than that of ani-
line. Other primary amines, such as b-phenethyl- and
octylamine were also alkylated by the present catalytic
system (entries 7–9).
N-Alkylation of secondary amines was also examined.
Reactions of N-methylaniline and N-methylbenzyl-
amine with benzyl alcohol proceeded to give corre-
sponding tertiary amines in good yields (Eq. (1)).
Although the mechanism for the present reaction is not
completely clear yet, a possible mechanism is shown in
Scheme 1. The first step of the reaction would involve
catalytic oxidation of an alcohol to the corresponding
(
1)

K. Fujita et al. / Tetrahedron Letters 44 (2003) 2687–2690
2689
Table 3. Cp*Ir catalyzed N-alkylation of primary amines
carbonyl compound B, with the generation of a hydrido
iridium species C. We have already revealed the cata-
lytic activity of [Cp*IrCl ] toward oxidation of pri-
a
with various alcohols
2
2
mary and secondary alcohols to the corresponding
5a
carbonyl compounds. The carbonyl intermediate B
would readily react with primary amine to afford an
imine D. Then addition of the hydrido iridium C to a
CꢀN bond of D would occur to give an amido iridium
species E. The species E would react with an alcohol to
give product and regenerate the catalytically active
alkoxo iridium complex A. The base (K CO ) would
2
3
stimulate the first oxidation step as we have already
5a
reported.
In summary, we have developed a new effective cata-
lytic system for N-alkylation of primary amines with
alcohols, which is applicable to a wide variety of
amines and alcohols. It should be noted that the
present N-alkylation proceeds with high selectivity for
mono-alkylation under milder condition (90–110°C)
compared 3 to the known catalytic systems with
4
ruthenium and rhodium catalysts, which are applica-
ble to a limited kind of amines and alcohols and/or
require high reaction temperature (>150°C).
Acknowledgements
This work was supported in part by Grants-in-Aid for
Scientific Research from the Japan Society for the
Promotion of Science (No. 14550806). We thank Mr. T.
Fujii for his valuable technical assistance.
References
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Scheme 1.

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K. Fujita et al. / Tetrahedron Letters 44 (2003) 2687–2690
7. Typical procedure: In a heavy-walled glass reactor under
chromatography. The products were identified by NMR
an atmosphere of argon were suspended [Cp*IrCl ] (0.025
analysis.
2
2
mmol) and K CO (0.050 mmol) in toluene (0.5 mL). Then
8. N-Methylation by methanol was unsuccessful. N-Methyla-
tion by methanol is known to be considerably difficult.
Huh, K.-T.; Tsuji, Y.; Kobayashi, M.; Okuda, F.; Watan-
abe, Y. Chem. Lett. 1988, 449.
2
3
amine (1.0 mmol) and alcohol (1.0 mmol) were added, and
the mixture was stirred at 110°C for 17 h in the sealed
reactor. The products were isolated by silica gel column