Heterogeneous catalysts have attracted much attention because of their simple separation
from products and their inherently reusable nature. In particular, metal nanoparticle
(NP)-immobilized heterogeneous catalysts are of great interest because of their high
reactivity, unique selectivity, and robustness.[1 ] Our laboratory has developed polymer-immobilized metal NPs as heterogeneous catalysts,
which have displayed promising reactivity tolerance, such as aerobic oxidation,[2 ] tandem oxidative processes for ester or amide formation,[3 ] and asymmetric C–C bond-forming reactions.[4 ] Recently, we reported a highly active polysilane-supported Rh/Pt bimetallic NP heterogeneous
catalyst for arene hydrogenation.[5 ] During the course of the hydrogenation of aniline catalyzed by the Rh/Pt NP-immobilized
catalyst, we found that the reaction afforded not only cyclohexylamine, but also dicyclohexylamine
in moderate yield. Inspired by this finding, we were fascinated by the possibility
of a new methodology to obtain highly desirable alkylamines.
Amines are important and useful compounds for chemical synthesis.[6 ] In particular, alkylamines are widely found in fine chemicals, pharmaceuticals,
agrochemicals, and natural products. Reductive amination is a more reliable method
to obtain alkylamines than the nucleophilic substitution of alkyl halides with primary
amines, which sometimes suffers from overalkylation and coproduction of large amounts
of useless inorganic salts.[7 ]
Scheme 1 Previous related work and present work
N-Alkylated cyclohexylamine derivatives exhibit significant bioactivities, acting
as, for example, anticonvulsants, kinase inhibitors, antidiabetics, and antiviral
compounds.[8 ] Recently, synthesis of N-alkylated cyclohexylamine derivatives through hydrogenation
of phenol in the presence of amines was reported (Scheme [1a ]).[9 ] By contrast, synthesis of N -cyclohexylaniline derivatives catalyzed by Pd/C, starting from nitroarenes, which
are available in a wider range than phenol derivatives, was also reported (Scheme
[1b ]).[10 ] In these reactions, ketone or imine derivatives generated in situ through arene
hydrogenation are utilized to react with amines. However, reductive cross-amination
between externally added alkylamines and nitroarenes has not been reported because
it was assumed that alkylamines were dehydrogenated to afford imines in the proposed
reaction mechanism.[9 ] Conversely, no dehydrogenation of an alkylamine was found with our Rh/Pt NP-immobilized
catalyst in preliminary studies, suggesting that a partially reduced intermediate
in the course of aniline hydrogenation reacted directly during dicyclohexylamine formation
(Scheme [1c ]). In this context, we targeted hydrogenation of aniline and nitroarene derivatives
in the presence of alkylamines to afford N-alkylated cyclohexylamine derivatives through
reductive cross-amination by direct utilization of imine intermediates that were generated
through partial arene hydrogenation. In this reaction, reductive cross-amination would
occur before dicyclohexylamine formation because amines interacting with the surface
of the catalyst might trap unstable imine intermediates that are produced, immediately
on the catalyst. Herein, we describe a highly selective reductive cross-amination
using aniline derivatives and primary alkylamines catalyzed by metal NP-immobilized
catalysts under mild conditions. To our knowledge, this is the first example of reductive
cross-amination of alkylamines with aniline derivatives for the synthesis of N-alkylated
cyclohexylamine derivatives.
We commenced our study by investigating the reductive cross-amination with solvent
screening using n -octylamine (1a ) and 2 equivalents of aniline (2a ) in the presence of a heterogeneous catalyst. For the catalyst, we used Rh/Pt bimetallic
NPs immobilized on a nanocomposite support of dimethylpolysilane and alumina (DMPSi/Al2 O3 -Rh/Pt), which was used in our previous report. Initially, polar solvents were examined.
While THF gave a moderate yield, EtOH afforded the product in good yield (Table [1 ], entries 1 and 2). Meanwhile, almost none of the desired reaction products were
obtained in DMF, which suffered from a low conversion of aniline, probably because
of the strong interaction of DMF with the metal NPs (entry 3). Relatively polar solvents
such as EtOAc and CPME gave moderate yields (entries 4 and 5). By contrast, hexane,
which is a nonpolar solvent, afforded the desired product in the best yield (entry
6).
Table 1 Effect of Solvents
Entry
Solvent
Conv. (%)a
3aa (%)a
4 (%)a,b
1
THF
77
66
2
2
EtOH
90
81
4
3
DMF
25
<1
<1
4
EtOAc
69
60
<1
5
CPME
49
50
<1
6
hexane
88
82
3
a Determined by GC analysis.
b Calculated based on used aniline.
Reaction conditions were further optimized in hexane. A slightly larger amount of
aniline gave the desired product in excellent yield (Table [2 ], entry 2). The catalyst loading was then lowered to 0.5 mol%, affording a lower
yield (entry 3). We found that this transformation proceeded smoothly even when conducted
in neat solvent (entry 4). In all cases, only a small amount of dicyclohexylamine
4 was generated as a by-product, indicating that the desired reaction would proceed
through the expected pathway.
Table 2 Optimization of Reaction Conditions
Entry
x (mol%)
Y (equiv)
Conv. (%)a
3aa (%)a
4 (%)a,b
1
0.75
2.0
92
82
4
2
0.75
2.5
>99
92
6
3
0.5
2.5
67
71
<1
4c
0.75
2.5
94
91
7
a Determined by GC analysis.
b Calculated based on used aniline.
c Reaction was conducted in neat solvent.
Recovery and reuse of DMPSi/Al2 O3 -Rh/Pt were then investigated. The catalyst was recovered by simple filtration of
the reaction mixture and dried in vacuo at room temperature after washing with acetone
and water. High yields were maintained for five runs (Table [3 ]).
Table 3 Recovery and Reuse of DMPSi/Al2 O3 -Rh/Pt
Run
1
2
3
4
5
Yield (%)
92
>99
92
90
90
The generality of this transformation was tested under neat conditions. Various primary
amines were reacted with aniline (2a ). n -Hexylamine (1b ) gave a quantitative yield (Table [4 ], entry 2). In the case of 3-phenylpropylamine (1c ), the product was obtained in excellent yield without further reduction of the phenyl
ring (entry 3). 3-Methoxypropylamine (1d ) and mono-Boc-protected diamine (1e ) were also acceptable (entries 4 and 5). Even tert -amine-containing substrate (1f ), which is assumed to strongly interact with the catalyst, afforded the product in
quantitative yield (entry 6). The reductive cross-amination of N -methylaniline (2b ) with n -octylamine (1a ) also proceeded smoothly (entry 7). Furthermore, the desired product was obtained
in good yield in the reaction with nitrobenzene (2c ) (entry 8).
Here, we assume the mechanism of this reaction is as follows: Initially, partial hydrogenation
of aniline by the catalyst affords an enamine, which gives an imine intermediate by
isomerization. This imine is either trapped by a nucleophile or undergoes further
hydrogenation to form cyclohexylamine. The trapping of the imine between an alkylamine
and generated cyclohexylamine is competitive; an alkylamine affords the desired product
while cyclohexylamine gives dicyclohexylamine as a by-product (Scheme [2 ]). Considering the results of the mechanistic study in the previous report,[5 ] it is assumed that the alkylamine is strongly adsorbed on the surface of the catalyst,
which facilitates the rapid trapping of the imine intermediate generated on the surface
of the catalyst by the alkylamine, leading to a high selectivity for the desired product
over the by-product. To confirm this hypothesis, a mechanistic study was initiated.
Table 4 Substrate Scope of Reductive Cross-Amination[11 ]
[12 ]
Entry
Amine
Electrophile source
Product (cy = cyclohexyl)
Yield (%)a
1
n -octylamine (1a )
aniline (2a )
3aa
93b
2
n -hexylamine (1b )
aniline (2a )
3ba
>99
3c
3-phenylpropylamine (1c )
aniline (2a )
3ca
92
4d
3-methoxypropylamine (1d )
aniline (2a )
3da
97
5
tert -butyl N -(6-aminohexyl)carbamate (1e )
aniline (2a )
3ea
85
6
N ,N ′-dimethyl-1,6-hexanediamine (1f )
aniline (2a )
3fa
>99
7
n -octylamine (1a )
N -methylaniline (2b )
3aa
89
8
n -octylamine (1a )
nitrobenzene (2c )
3aa
87
a Isolated yield.
b Determined by GC analysis.
c 72 h.
d 38 h.
Scheme 2 Assumed reaction mechanism
To begin, reaction profiles were recorded to confirm adsorption of a primary amine
to the catalyst surface by varying the amount of n -octylamine. A larger amount of n -octylamine (1.2 or 2.4 mmol) diminished the rate of the aniline hydrogenation compared
with that obtained with a smaller amount of n -octylamine (0.6 mmol) (Scheme [3 ]). These results indicate that n -octylamine is adsorbed on the surface of the catalyst and prevents the adsorption
of aniline, which suppresses aniline hydrogenation. By contrast, when the rate of
the product formation is compared, less n -octylamine gives the fastest reaction rate; in other words, a larger amount of n -octylamine, which suppresses aniline hydrogenation, and does not accelerate the reaction,
suggesting that the aniline hydrogenation is the rate-determining step of this reaction.
Furthermore, it was clearly observed that dicyclohexylamine started to form immediately
after the complete consumption of the alkylamine when 0.6 mmol of the alkylamine was
used (Scheme [4 ]). These results indicate that the alkylamine adsorbed on the surface of the catalyst
prevented the dicyclohexylamine formation by trapping the imine intermediate immediately,
leading to the high selectivity of the product.
Scheme 3 Profile of conversion of aniline
Scheme 4 Reaction profile
In summary, we have achieved a highly selective reductive cross-amination using aniline
derivatives and primary alkylamines catalyzed by heterogeneous bimetallic NPs under
mild conditions. Various primary alkylamines, such as simple alkyl amines, phenyl
ring-containing amine, and tert -amine-containing amine afforded the desired products in high yields. In addition,
the reaction was applicable to N -alkylanilines and even nitroarenes. Furthermore, the catalyst was successfully recovered
and reused by simple filtration while maintaining its high activity. In this reaction,
imine intermediates generated during the course of partial hydrogenation of aniline
derivatives reacted with primary alkylamines directly. In all cases, the desired cross-aminated
products were selectively obtained before dicyclohexylamine derivatives, which could
be generated through self-amination of aniline derivatives. It is assumed that primary
alkylamines adsorbed on the surface of the catalyst trapped unstable imine intermediates
immediately, which would lead to the highly selective transformation to give the desired
products, while suppressing dicyclohexylamine formation. Further investigations on
reductive cross-amination toward useful compounds such as drug precursors are ongoing.
