Direct reductive amination of aromatic aldehydes catalyzed by gold(i) complex under transfer hydrogenation conditions

Article abstract of DOI:10.1039/c1cc11201e

The direct reductive amination of aromatic aldehydes has been achieved with excellent isolated yields (89-96%) using readily accessible Ph ₃PAuCl/AgOTf catalyst along with ethyl Hantzsch ester as hydrogen source under mild reaction conditions.

Full text of DOI:10.1039/c1cc11201e

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 6605–6607
www.rsc.org/chemcomm
COMMUNICATION
Direct reductive amination of aromatic aldehydes catalyzed by gold(I)
complex under transfer hydrogenation conditionsw
Ming Zhang,a Hongwei Yang,a Yan Zhang,a Chengjian Zhu,*ab Wei Li,c Yixiang Cheng*a
and Hongwen Hua
Received 28th February 2011, Accepted 30th March 2011
DOI: 10.1039/c1cc11201e
The direct reductive amination of aromatic aldehydes has been
achieved with excellent isolated yields (89–96%) using readily
accessible Ph3PAuCl/AgOTf catalyst along with ethyl
Hantzsch ester as hydrogen source under mild reaction
conditions.
Table 1 Optimizing the reaction conditions of gold(I) complex
catalyzed one-pot reductive amination reactiona
The prevalence and importance of amines in natural products,
pharmaceuticals and agrochemicals have made the preparation
of functionalized amines necessary for over a century.1 Direct
reductive amination of carbonyl compounds, mostly aldehydes
or ketones, is one of the most powerful methods for the
synthesis of substituted amines.2 In addition, it would be
extremely valuable from a synthetic point of view if the
carbonyl compound is treated with the amine and a suitable
reducing agent in a one-pot reaction. Compared to a stepwise or
indirect reaction, the one-pot reaction is more advantageous,
since it avoids the isolation of the intermediary imine or
iminium. Typical direct reductive amination procedures
commonly use active borane3 or tin4 compounds, but these
methods have some drawbacks in one or another respect, such
as acidic conditions, poor stability and toxic byproducts. Other
homogeneous catalysts based on Pd5 and In6 have also shown
suitable performance for the direct reductive amination
reaction.
Entry Catalyst
Equiv. Solvent t/h Yield (%)b
1
2
Ph3PAuCl 5%
Ph3PAuCl + AgOTf 5%
DCM
DCM
DCM
DCM
DCM
DCM
THF
1
1
1
1
1
1
1
1
1
1
1
65
96
34
0
95
87
71
75
55
46
63
3
4
AgOTf
None
5%
—
5
6
7
8
9
10
11
Ph3PAuCl + AgOTf 1%
Ph3PAuCl + AgOTf 0.5%
Ph3PAuCl + AgOTf 1%
Ph3PAuCl + AgOTf 1%
Ph3PAuCl + AgOTf 1%
Ph3PAuCl + AgOTf 1%
Ph3PAuCl + AgOTf 1%
Toluene
MeCN
Hexane
MeOH
a
Reaction conditions: 1a (2 mmol), 2a (2 mmol), 3 (2.5 mmol) in DCM
b
(5 ml), rt. Isolated yields.
Herein we report the first example of a homogeneous gold(I)
complex catalysed direct reductive amination of various aromatic
aldehydes with ethyl Hantzsch ester as the hydrogen source.
Initially, the reaction of benzenamine (1a) and benzaldehyde
(2a) was carried out in dichloromethane (DCM) with
Ph3PAuCl as the catalyst and ethyl Hantzsch ester as the
hydrogen source at room temperature for 1 h, which led to the
desired product 4aa in 65% yield (Table 1, entry 1). The
reaction was considerably promoted by the addition of AgOTf
(entry 2), while using AgOTf only resulted in lower reactivity
(entry 3). No reaction was observed without using any catalyst
(entry 4). Ph3PAuOTf, generated in situ from Ph3PAuCl and
AgOTf, was found to be the best catalyst for this direct
reductive amination reaction. We were pleased to find that
there was no significant change in yield when the catalyst
amount was decreased to 1 mol% (entry 5). The reaction still
showed good results even with only 0.5 mol% catalyst in
DCM (entry 6). Besides, various other solvents such as THF,
toluene, MeCN, hexane and MeOH were also examined for
this reaction, but they showed lower catalytic activities
compared to dichloromethane (entry 5 versus entries 7–11).
Gold catalysts have gained much attention in organic
transformations, owing to their relativistic effects and soft
Lewis acidity.7 Reactions catalyzed by gold generally proceed
under mild conditions without exclusion of water and oxygen.
Cao and co-workers have shown that supported gold nano-
clusters are efficient heterogeneous catalysts for transfer
hydrogenation.8 In addition, Hantzsch ester 1,4-dihydropyridine
(HEH), which is a safe and easy-to-handle reagent, has been widely
used as a reducing agent in organic synthetic transformations.9
a State Key Laboratory of Coordination Chemistry, School of
Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, China. E-mail: cjzhu@nju.edu.cn;
Fax: +86-25-83317761; Tel: +86-25-83594886
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
c School of Pharmacy, Nanjing University of Chinese Medicine,
Nanjing 210046, China
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc11201e
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6605–6607 6605

View Article Online
Table 2 One-pot reductive amination of benzaldehyde with various
aromatic aminesa
Table 3 One-pot reductive amination of aromatic aldehydes and
ketones with anilinea
Yield/%b
Entry Substrate
t/h Product
Yield (%)b
Entry Substrate
t/h Product
1
1
95
1
1
96
2
3
4
5
6
7
8
1
95
90
94
93
92
89
2
0.5
1
92
93
95
95
93
93
92
93
94
1
3
1.5
1
4
0.5
5
1
2
6
0.5
2
7
2
3
3
91
91
8
0.5
9
a
Reaction conditions: 1a (2 mmol), 2 (2 mmol), 3 (2.5 mmol),
(PPh3)AuCl (0.02 mmol), AgOTf (0.02 mmol) in DCM (5 ml), rt.
9
2
b
Isolated yields.
10
0.5
With the optimized conditions in hand (1 mol% [(PPh3)AuCl]/
AgOTf in DCM), we then extended the scope to various
amines with benzaldehyde in this catalytic system. As shown
in Table 2, the results revealed that all the desired products
could be afforded in high yields (89–95%) within short
reaction times (1–3 h). We also found that the aromatic
amines with electron-donating substituents (entries 2 and 3)
showed similar reactivity with aniline. However, aromatic
amines with a strong electron-withdrawing group such as
p-nitrobenzenamine led to decreased activity (entry 9). All the
11
12
3
3
91
89
c
This journal is The Royal Society of Chemistry 2011
6606 Chem. Commun., 2011, 47, 6605–6607

View Article Online
Table 3 (continued )
In conclusion, we have demonstrated that the novel gold-
catalyzed reductive amination of aromatic aldehydes with
ethyl Hantzsch ester as the hydrogen source produces good
to excellent yields at room temperature. The reaction proceeds
with high efficiency to give the corresponding secondary
amines, which are extremely useful synthetic intermediates in
the construction of biologically important compounds.
Research is currently under way to elucidate the mechanism
and to apply the principle to other catalytic systems.
Entry Substrate
t/h Product
Yield/%b
13
14
6
95
0.5
12
92
87
We gratefully acknowledge the National Natural Science
Foundation of China (20774042, 20832001, 20972065) and the
National Basic Research Program of China (2007CB925103,
2010CB923303) for their financial support. Professor W. Li
thanks National Natural Science Foundation of China
(81072542) for the support.
15c
16c
3
3
94
90
Notes and references
1 For recent reviews, see: (a) J. F. Hartwig, Acc. Chem. Res., 2008,
41, 1534; (b) F. Collet, R. H. Dodd and P. Dauban,
Chem. Commun., 2009, 5061; (c) G. Guillena, D. J. Ramon and
M. Yus, Chem. Rev., 2010, 110, 1611.
17c
a
2 (a) R. P. Tripathi, S. S. Verma, J. Pandey and V. K. Tiwari, Curr.
Org. Chem., 2008, 12, 1093; (b) E. E. Boros, J. B. Thompson,
S. R. Katamreddy and A. J. Carpenter, J. Org. Chem., 2009, 74,
3587; (c) S. C. A. Sousa and A. C. Fernandes, Adv. Synth. Catal.,
2010, 352, 2218; (d) A. Kumar, S. Sharma and R. A. Maurya,
Adv. Synth. Catal., 2010, 352, 2227; (e) E. M. Dangerfield,
C. H. Plunkett, A. L. Win-Mason, B. L. Stocker and M. S. M.
Timmer, J. Org. Chem., 2010, 75, 5470; (f) C. Wang, A. Pettman,
J. Basca and J. L. Xiao, Angew. Chem., Int. Ed., 2010, 49, 7548.
3 (a) E. R. Burkhardt and B. M. Coleridge, Tetrahedron Lett., 2008,
49, 5152; (b) H. Alinezhad, M. Tajbakhsh, F. Salehian and
K. Fazli, Tetrahedron Lett., 2009, 50, 659; (c) W. Y. Liao,
Y. F. Chen, Y. X. Liu, H. G. Duan, J. L. Petersen and
X. D. Shi, Chem. Commun., 2009, 6436; (d) M. Tokizane,
K. Sato, Y. Sakami, Y. Imori, C. Matsuo, T. Ohta and Y. Ito,
Synthesis, 2010, 36; (e) P. V. Ramachandran, P. D. Gagare,
K. Sakavuyi and P. Clark, Tetrahedron Lett., 2010, 51, 3167.
4 (a) R. Apodaca and W. Xiao, Org. Lett., 2001, 3, 1745;
(b) H. Kato, I. Shibata, Y. Yasaka, S. Tsunoi, M. Yasuda and
A. Baba, Chem. Commun., 2006, 4189; (c) P. D. Pham, P. Bertus
and S. Legoupy, Chem. Commun., 2009, 6207.
5 (a) E. Byun, B. Hong, Castro, K. A. De castro, M. Lim and
H. Rhee, J. Org. Chem., 2007, 72, 9815; (b) B. Sreedhar,
P. S. Reddy and D. K. Debi, J. Org. Chem., 2009, 74, 8806.
6 (a) O. Y. Lee, K. L. Law, C. Y. Ho and D. Yang, J. Org. Chem.,
2008, 73, 8829; (b) O. Y. Lee, K. L. Law and D. Yang, Org. Lett.,
2009, 11, 3302.
7 (a) A. S. K. Hashmi, Gold Bull., 2004, 37, 51; (b) A. Arcadi and
S. D. Giuseppe, Curr. Org. Chem., 2004, 8, 795; (c) D. J. Gorin and
F. D. Toste, Nature, 2007, 446, 395.
8 (a) F. Z. Su, L. He, J. Ni, Y. Cao, H. Y. He and K. N. Fan, Chem.
Commun., 2008, 3531; (b) L. He, J. Ni, L. C. Wang, F. J. Yu,
Y. Cao, H. Y. He and K. N. Fan, Chem.–Eur. J., 2009, 15, 11833.
9 M. Rueping, E. Sugiono and F. R. Schoepke, Synlett, 2010, 852.
10 (a) T. C. Wabnitz, J. Q. Yu and J. B. Spencer, Synlett, 2003, 1070;
(b) T. C. Wabnitz, J. Q. Yu and J. B. Spencer, Chem.–Eur. J., 2004,
10, 484; (c) D. C. Rosenfeld, S. Shekhar, A. Takemiya,
M. Utsunomiya and J. F. Hartwig, Org. Lett., 2006, 8, 4179;
(d) A. S. K. Hashmi, Catal. Today, 2007, 122, 211.
11 (a) Z. Y. Han, H. Xiao, X. H. Chen and L. Z. Gong, J. Am. Chem.
Soc., 2009, 131, 9182; (b) X. Y. Liu and C. M. Che, Org. Lett.,
2009, 11, 4204; (c) M. Rueping, E. Merino and R. M. Koenigs,
Adv. Synth. Catal., 2010, 352, 2629.
Reaction conditions: 1 (2 mmol), 2a (2 mmol), 3 (2.5 mmol),
(PPh3)AuCl (0.02 mmol), AgOTf (0.02 mmol) in DCM (5 ml), rt.
b
c
Isolated yields. 50 1C.
o-substituted aromatic amines (entries 4, 6 and 8) displayed
lower reactivity.
Reactions of different aldehydes with aniline were then
examined. The results are summarized in Table 3. The alde-
hydes with various substituents all gave the expected products
in good to excellent yields (89–96%). The aromatic aldehydes
with electron-donating substituents could react efficiently in
excellent yields (entries 1–4) within a short time, while the
aromatic aldehydes with electron-withdrawing substituents
showed lower reactivity (entries 7, 9 and 11) for this reductive
amination reaction. Compared to the p-substituted aromatic
aldehydes, the o-substituted aromatic aldehydes afforded the
desired compounds in excellent yields within a shorter time,
except for o-nitrobenzaldehyde (entries 1–12). This result
clearly indicates that the electronic effect of o-substituents
has only a slight impact on the reaction. The phenomenon
described here was very different from the o-substituted
aromatic amines in Table 2. Heteroaromatic aldehydes such as
2-pyridinaldehyde and 2-furaldehyde could also react smoothly
under identical conditions (entries 13 and 14). Ketones have also
been investigated under the above optimized reaction conditions.
When aliphatic ketones were used, such as butanone, cyclo-
pentanone and cyclohexanone (entries 15–17), good yields were
obtained at higher reaction temperature.
The catalytic mechanism for this reaction is probably
through a proton-catalyzed hydride transfer process. The
catalyst Ph3PAuOTf is partially hydrolyzed with traces of
water, and provides the proton which can protonate the
imine.10 The resulting iminium can then be reduced by the
ethyl Hantzsch ester as the hydride source.11
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6605–6607 6607