Highly Selective Reductive Cross-Amination between Aniline or Nitroarene Derivatives and Alkylamines Catalyzed by Polysilane-Immobilized Rh/Pt Bimetallic Nanoparticles

Article abstract of DOI:10.1055/s-0037-1611341

Reductive cross-amination between imine intermediates generated through partial hydrogenation of aniline or nitroarene derivatives and alkylamines is an ideal method for obtaining N-alkylated cyclohexylamine derivatives; however, no such transformations have hitherto been established. Here, we report a highly selective reductive cross-amination using aniline derivatives and alkylamines catalyzed by heterogeneous Rh/Pt bimetallic nanoparticles under mild conditions. The catalyst was recovered and reused for five runs, keeping high activity. In this reaction, imine intermediates generated during the course of partial hydrogenation of aniline derivatives were trapped immediately by strongly interacting primary alkylamines with the catalyst, which caused a highly selective transformation to give the desired products, while suppressing dicyclohexylamine formation.

Full text of DOI:10.1055/s-0037-1611341

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2019, 30, A–F
letter
A
en
Synlett
A. Suzuki et al.
Letter
Highly Selective Reductive Cross-Amination between Aniline or
Nitroarene Derivatives and Alkylamines Catalyzed by Polysilane-
Immobilized Rh/Pt Bimetallic Nanoparticles
H
Aya Suzuki1
NH2
N
Hiroyuki Miyamura
Shū Kobayashi*
0
0
0
0-0
0
0
2-
8
2
3
5-4
3
6
8
H2
H
Department of Chemistry, School of Science, The University of
Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
N
N
R
NH2
NH
R
R
NH2
H
Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue
H
NH3
H
H
H2N
R
R
NH2
NH2
NPs
2
H N
R
Received: 23.08.20018
Accepted after revision: 17.10.2018
Published online: 18.01.2019
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 chemi-
DOI: 10.1055/s-0037-1611341; Art ID: st-2018-b0543-l
License terms:
6
Abstract Reductive cross-amination between imine intermediates
generated through partial hydrogenation of aniline or nitroarene deriv-
atives and alkylamines is an ideal method for obtaining N-alkylated cy-
clohexylamine derivatives; however, no such transformations have hith-
erto been established. Here, we report a highly selective reductive
cross-amination using aniline derivatives and alkylamines catalyzed by
heterogeneous Rh/Pt bimetallic nanoparticles under mild conditions.
The catalyst was recovered and reused for five runs, keeping high activ-
ity. In this reaction, imine intermediates generated during the course of
partial hydrogenation of aniline derivatives were trapped immediately
by strongly interacting primary alkylamines with the catalyst, which
caused a highly selective transformation to give the desired products,
while suppressing dicyclohexylamine formation.
cal synthesis. In particular, alkylamines are widely found
in fine chemicals, pharmaceuticals, agrochemicals, and nat-
ural products. Reductive amination is a more reliable meth-
od 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
N-Alkylated cyclohexylamine derivatives exhibit signifi-
cant bioactivities, acting as, for example, anticonvulsants,
8
kinase inhibitors, antidiabetics, and antiviral compounds.
Recently, synthesis of N-alkylated cyclohexylamine deriva-
tives through hydrogenation of phenol in the presence of
Key words reductive amination, arene hydrogenation, heteroge-
neous catalyst, metal nanoparticle
9
amines was reported (Scheme 1a). By contrast, synthesis of
N-cyclohexylaniline derivatives catalyzed by Pd/C, starting
from nitroarenes, which are available in a wider range than
1
0
Heterogeneous catalysts have attracted much attention
because of their simple separation from products and their
inherently reusable nature. In particular, metal nanoparti-
cle (NP)-immobilized heterogeneous catalysts are of great
interest because of their high reactivity, unique selectivity,
phenol derivatives, was also reported (Scheme 1b). In
these reactions, ketone or imine derivatives generated in
situ through arene hydrogenation are utilized to react with
amines. However, reductive cross-amination between ex-
ternally added alkylamines and nitroarenes has not been
reported because it was assumed that alkylamines were de-
hydrogenated to afford imines in the proposed reaction
1
and robustness. Our laboratory has developed polymer-
immobilized metal NPs as heterogeneous catalysts, which
have displayed promising reactivity tolerance, such as aero-
9
mechanism. Conversely, no dehydrogenation of an alkyl-
2
bic oxidation, tandem oxidative processes for ester or am-
amine 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
3
ide formation, and asymmetric C–C bond-forming reac-
4
tions. Recently, we reported a highly active polysilane-sup-
ported Rh/Pt bimetallic NP heterogeneous catalyst for arene
5
hydrogenation. During the course of the hydrogenation of
aniline catalyzed by the Rh/Pt NP-immobilized catalyst, we
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

B
Synlett
A. Suzuki et al.
Letter
(
(
a) Li and Vaccaro (2015)
H
OH
O
N
H2
ArNH2
Ar
b) Corma (2013)
difficult
to use
R
NH2
R
NH
–
H2
H2
H
NO2
NH2
NH2
NH
N
H2
H2
ArNH2
Ar
–
(
c) This work
H
N
NO2
NH2
NH2
NH
H2
H2
Alkyl-NH2
Alkyl
Scheme 1 Previous related work and present work
nitroarene derivatives in the presence of alkylamines to af-
ford N-alkylated cyclohexylamine derivatives through re-
ductive cross-amination by direct utilization of imine inter-
mediates that were generated through partial arene hydro-
genation. In this reaction, reductive cross-amination would
occur before dicyclohexylamine formation because amines
interacting with the surface of the catalyst might trap un-
stable imine intermediates that are produced, immediately
on the catalyst. Herein, we describe a highly selective re-
ductive cross-amination using aniline derivatives and pri-
mary alkylamines catalyzed by metal NP-immobilized cata-
lysts 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.
metallic NPs immobilized on a nanocomposite support of
dimethylpolysilane and alumina (DMPSi/Al O -Rh/Pt),
2
3
which was used in our previous report. Initially, polar sol-
vents 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 inter-
action of DMF with the metal NPs (entry 3). Relatively polar
solvents such as EtOAc and CPME gave moderate yields (en-
tries 4 and 5). By contrast, hexane, which is a nonpolar sol-
vent, afforded the desired product in the best yield (entry 6).
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,
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 bi-
Table 1 Effect of Solvents
H
H
N
NH2
Rh/Pt–DMPSi/Al2O3 (0.75 mol% as Rh)
N
C8H17NH2
+
C8H17
+
H2 (1 atm), 50 °C
solvent (2.4 M), 24 h
1a
2a
2.0 equiv)
3aa
4
(
Entry
Solvent
Conv. (%)a
3aa (%)a
4 (%)a,b
1
2
3
4
5
THF
77
90
25
69
49
88
66
81
<1
60
50
82
2
4
EtOH
DMF
<1
<1
<1
3
EtOAc
CPME
hexane
6
a
Determined by GC analysis.
Calculated based on used aniline.
b
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

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Synlett
A. Suzuki et al.
Letter
Table 2 Optimization of Reaction Conditions
H
H
N
NH2
Rh/Pt–DMPSi/Al2O3 (x mol% as Rh)
N
C8H17NH2
C8H17
+
+
H2 (1 atm), 50 °C
hexane (2.4 M), 24 h
1a
2a
3aa
4
(
Y equiv)
Entry
x (mol%)
Y (equiv)
Conv. (%)a
3aa (%)a
4 (%)a,b
1
2
3
0.75
0.75
0.5
2.0
2.5
2.5
2.5
92
>99
67
82
92
71
91
4
6
<1
7
4c
0.75
94
a
Determined by GC analysis.
Calculated based on used aniline.
Reaction was conducted in neat solvent.
b
c
Table 3 Recovery and Reuse of DMPSi/Al O -Rh/Pt
2
3
H
H
N
NH2
Rh/Pt–DMPSi/Al2O3 (0.75 mol% as Rh)
N
C8H17NH2
+
C8H17
+
H2 (1 atm), 50 °C
hexane (2.4 M), 24 h
1a
2a
3aa
4
(
2.5 equiv)
Run
1
2
3
4
5
Yield (%)
92
>99
92
90
90
only a small amount of dicyclohexylamine 4 was generated
as a by-product, indicating that the desired reaction would
proceed through the expected pathway.
amine and generated cyclohexylamine is competitive; an
alkylamine affords the desired product while cyclohexyl-
amine gives dicyclohexylamine as a by-product (Scheme 2).
Considering the results of the mechanistic study in the pre-
Recovery and reuse of DMPSi/Al O -Rh/Pt were then in-
2
3
5
vestigated. The catalyst was recovered by simple filtration
of the reaction mixture and dried in vacuo at room tem-
perature after washing with acetone and water. High yields
were maintained for five runs (Table 3).
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
vious report, 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.
To begin, reaction profiles were recorded to confirm ad-
sorption of a primary amine to the catalyst surface by vary-
ing the amount of n-octylamine. A larger amount of n-oc-
tylamine (1.2 or 2.4 mmol) diminished the rate of the ani-
line 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 ani-
line, 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, sug-
gesting that the aniline hydrogenation is the rate-determin-
ing step of this reaction. Furthermore, it was clearly ob-
served 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
(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-Methoxypropyl-
amine (1d) and mono-Boc-protected diamine (1e) were
also acceptable (entries 4 and 5). Even tert-amine-contain-
ing 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 (en-
try 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 interme-
diate by isomerization. This imine is either trapped by a nu-
cleophile or undergoes further hydrogenation to form cy-
clohexylamine. The trapping of the imine between an alkyl-
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

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A. Suzuki et al.
Letter
Table 4 Substrate Scope of Reductive Cross-Amination11,12
Rh/Pt–DMPSi/Al2O3
H
NH2
(0.75 mol% as Rh)
N
R1
1
R NH2 +
H2 (1 atm), 50 °C, 24 h
1
2
3
Entry
1
Amine
Electrophile source
Product (cy = cyclohexyl)
Yield (%)a
93b
H
N
n-octylamine (1a)
aniline (2a)
Cy
C H
8
17
3
aa
H
N
2
n-hexylamine (1b)
aniline (2a)
aniline (2a)
Cy
C H
>99
92
6
13
3
ba
H
N
Ph
3c
3-phenylpropylamine (1c)
Cy
3
3
ca
H
N
OMe
4d
5
3-methoxypropylamine (1d)
aniline (2a)
aniline (2a)
aniline (2a)
97
85
Cy
3
3
da
H
N
NHBoc
tert-butyl N-(6-aminohexyl)carbamate (1e)
N,N′-dimethyl-1,6-hexanediamine (1f)
Cy
6
3
ea
H
N
NMe2
6
7
Cy
>99
3
3
fa
H
N
n-octylamine (1a)
n-octylamine (1a)
N-methylaniline (2b)
nitrobenzene (2c)
Cy
C H
89
87
8
17
17
3
aa
H
N
8
Cy
C H
8
3
aa
a
Isolated yield.
b
c
Determined by GC analysis.
2 h.
7
3
d
8 h.
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.
In summary, we have achieved a highly selective reduc-
tive cross-amination using aniline derivatives and primary
H
NH2
N
H2
H
N
N
R
NH2
NH2
NH
R
R
H
H
NH3
H
H
H2N
R
R
NH2
NH2
NPs
2
H N
R
Scheme 2 Assumed reaction mechanism
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

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A. Suzuki et al.
Letter
Rh/Pt–DMPSi/Al2O3
(0.75 mol% as Rh)
Funding Information
H
N
NH2
C8H17NH2
+
C8H17
This work was partially supported by a Grant-in-Aid for Science Re-
search from the Japan Society for the Promotion of Science (JSPS), the
Global COE Program, The University of Tokyo, Ministry of Education,
Culture, Sports, Science and Technology (MEXT), Japan, and the Japan
Science and Technology Agency (JST). A. S. thanks the JSPS fellowship
for Japanese Junior Scientist.()
H2 (1 atm), 50 °C
hexane (2.4 M)
1a
2a
(3.0 mmol)
3aa
(
x mmol)
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611341.
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
References and Notes
Scheme 3 Profile of conversion of aniline
(
1) Ding, K.; Uozumi, Y. Handbook of Asymmetric Heterogeneous
Catalysis; Wiley-VCH: Weinheim, 2008.
(2) Kobayashi, S.; Miyamura, H. Aldrichimica Acta 2013, 46, 17.
alkylamines catalyzed by heterogeneous bimetallic NPs un-
der 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 cata-
lyst was successfully recovered and reused by simple filtra-
tion 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-aminat-
ed products were selectively obtained before dicyclohexyl-
amine 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 de-
sired products, while suppressing dicyclohexylamine for-
mation. Further investigations on reductive cross-amina-
tion toward useful compounds such as drug precursors are
ongoing.
(
(
3) Miyamura, H.; Kobayashi, S. Acc. Chem. Res. 2014, 47, 1054.
4) (a) Yasukawa, T.; Suzuki, A.; Miyamura, H.; Nishino, K.;
Kobayashi, S. J. Am. Chem. Soc. 2015, 137, 6616. (b) Miyamura,
H.; Suzuki, A.; Yasukawa, T.; Kobayashi, S. Adv. Synth. Catal.
2015, 357, 3815.
(5) Miyamura, H.; Suzuki, A.; Yasukawa, T.; Kobayashi, S. J. Am.
Chem. Soc. 2018, 140, 11325.
(6) (a) Nugent, T. C. Chiral Amine Synthesis: Methods, Developments
and Applications; Wiley: Hoboken, 2010. (b) Ricci, A. Modern
Amination Methods; Wiley: Hoboken, 2008. (c) Breuer, M.;
Ditrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.; Stürmer, R.;
Zelinski, T. Angew. Chem. Int. Ed. 2004, 43, 788.
(
7) (a) Yin, Z.; Zeng, H.; Wu, J.; Zheng, S.; Zhang, G. ACS Catal. 2016,
6, 6546. (b) Kim, I.; Itagaki, S.; Jin, X.; Yamaguchi, K.; Mizuno, N.
Catal. Sci. Technol. 2013, 3, 2397. (c) Lorentz-Petersen, L. L. R.;
Jensen, P.; Madsen, R. Synthesis 2009, 4110. (d) Hollmann, D.;
Bahn, S.; Tillack, A.; Beller, M. Chem. Commun. 2008, 3199.
(e) Hollmann, D.; Bähn, S.; Tillack, A.; Beller, M. Angew. Chem.
Int. Ed. 2007, 46, 8291. (f) Tillack, A.; Hollmann, D.; Michalik, D.;
Beller, M. Tetrahedron Lett. 2006, 47, 8881.
(
8) (a) Song, W.-H.; Liu, M.-M.; Zhong, D.-W.; Zhu, Y.-l.; Bosscher,
M.; Zhou, L.; Ye, D.-Y.; Yuan, Z.-H. Bioorg. Med. Chem. Lett. 2013,
23, 4528. (b) Chen, T.; Takrouri, K.; Hee-Hwang, S.; Rana, S.;
Rh/Pt-DMPSi/Al2O3
(0.75 mol% as Rh)
H
N
H
N
NH2
NH2
C8H17NH2
+
C8H17
+
+
H2 (1 atm), 50 °C
hexane (2.4 M)
1
a
2a
(3.0 mmol)
3aa
4
5
(
0.6 mmol)
Scheme 4 Reaction profile
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F

F
Synlett
A. Suzuki et al.
Letter
Yefidoff-Freedman, R.; Halperin, J.; Natarajan, A.; Morisseau, C.;
Hammock, B.; Chorev, M.; Aktas, B. H. J. Med. Chem. 2013, 56,
(100 °C), Int. T (50 °C), Int. T (0 min), Rate (5 °C/min), Fin. T
(100 °C), Fin. T (10 min): tR = 30.068 (N-n-octylcyclohexyl-
amine), 19.304 (decane internal standard) min.
9457.
(
9) (a) Jumde, V. R.; Petricci, E.; Petrucci, C.; Santillo, N.; Taddei, M.;
Vaccaro, L. Org. Lett. 2015, 17, 3990. (b) Chen, Z.; Zeng, H.; Gong,
H.; Wang, H.; Li, C.-J. Chem. Sci. 2015, 6, 4174. (c) Chen, Z.; Zeng,
H.; Girard, S. A.; Wang, F.; Chen, N.; Li, C.-J. Angew. Chem. Int. Ed.
(12) Rh-Pt/(DMPSi-Al O ) (81.2 mg, 0.75 mol% as Rh), 3-methoxy-
2
3
propylamine (1d) (176.7 mg, 1.2 mmol) and aniline (2a) (279.4
mg, 3.0 mmol) were placed in a Caroucel® tube. The atmosphere
was exchanged to H using balloon and pump. After the reaction
2
2
2
015, 54, 14487. (d) Li, J.-S.; Qiu, Z.; Li, C.-J. Adv. Synth. Catal.
017, 359, 3648.
mixture was stirred at 50 °C for 38 h, the reaction was quenched
by the addition of CH Cl (5 mL). The catalyst was filtered off
2
2
(
10) Rubio-Marques, P.; Leyva-Perez, A.; Corma, A. Chem. Commun.
013, 8160.
11) Rh-Pt/(DMPSi-Al O ) (33.4 mg, 0.75 mol% as Rh), n-octylamine
and the filtrate was concentrated. The desired product was iso-
2
lated from the crude mixture by column chromatography (hex-
1
(
ane/EtOAc/Et N = 3:2:0.1). Yield: 97%; H NMR (600 MHz,
2
3
3
(
1a) (51.7 mg, 0.4 mmol) and aniline (2a) (74.0 mg, 0.8 mmol)
CDCl ): δ = 3.44 (t, J = 6.2 Hz, 2 H), 3.32 (s, 3 H), 2.71 (t, J =
6.9 Hz, 2 H), 2.44–2.39 (m, 1 H), 1.87 (d, J = 13.0 Hz, 2 H), 1.77–
3
®
were placed in
a
Caroucel tube. The atmosphere was
exchanged to H2 using a balloon and pump. The reaction
mixture was stirred at 50 °C for 24 h, then the reaction was
quenched by the addition of EtOAc (5 mL) and the reaction
mixture was analyzed by GC using decane as internal standard.
Yield: 93%; GC flow rate (157.5 kPa, He), Inject (50 °C), Detect
1.70 (m, 4 H), 1.63–1.59 (m, 1 H), 1.42 (br, 1 H), 1.29–1.21 (m,
2 H), 1.19–1.14 (m, 1 H), 1.09–1.03 (m, 2 H). C NMR (100 MHz,
13
CDCl ): δ = 71.4, 58.6, 56.9, 44.3, 33.6, 30.4, 26.2, 25.1. IR (neat):
3
3579, 3312, 2928, 2853, 1672, 1454, 1375, 1304, 1255,
–1
+
+
1195 cm . HRMS (DART): m/z [M+H] calcd for C10H22NO :
72.17014; found: 172.16781.
1
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–F