One-Pot Transfer Hydrogenation Reductive Amination of Aldehydes and Ketones by Iridium Complexes “on Water”

Article abstract of DOI:10.1002/ejoc.202001097

An efficient and practical one-pot transfer hydrogenation reductive amination of aldehydes and ketones with amines has been developed by using iridium complexes as catalysts and formic acid as hydrogen source in aqueous solution, providing an environmentally friendly methodology for the construction of a wide range of functionalized amine compounds in excellent yields (≈ 80 %-95 %). This effective methodology can be scaled up to gram scale with 0.1 mol-% catalyst loading and also be employed in the synthesis of medical substances such as Meclizine.

Full text of DOI:10.1002/ejoc.202001097

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: One-Pot Transfer Hydrogenation Reductive Amination of
Aldehydes and Ketones by Iridium Complexes “on Water”
Authors: Lu Ouyang, Yanping Xia, Jianhua Liao, and Renshi Luo
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Link to VoR: https://doi.org/10.1002/ejoc.202001097
01/2020

10.1002/ejoc.202001097
European Journal of Organic Chemistry
COMMUNICATION
One-Pot Transfer Hydrogenation Reductive Amination of
Aldehydes and Ketones by Iridium Complexes “on Water”
Lu Ouyang, Yanping Xia, Jianhua Liao, and Renshi Luo*
L. Ouyang, Y. Xia, J. Liao, Dr. R. Luo
School of Pharmacy, Gannan Medical University, Ganzhou, 341000, Jiangxi Province, P. R. China
E-mail: luorenshi@163.com
Supporting information for this article is given via a link at the end of the document.
Abstract: An efficient and practical one-pot transfer hydrogenation
reductive amination of aldehydes and ketones with amines has been
developed by using iridium complexes as catalysts and formic acid
as hydrogen source in aqueous, providing an environmentally
friendly methodology for the construction of a wide range of
functionalized amine compounds in excellent yields (80%~95%).
This effective methodology can be scaled up to the grams with 0.1
mol% catalyst loading and also be employed in the synthesis of
medical substance such as Meclizine.
type of iridium catalyst applied in the research of organic
synthesis reactions still have important theoretical guidance and
practical value.
Recently, we have strong interest in the design and synthesis
of bis-nitrogen iridium complexes and their catalytic reactions.
As our continuous effort in the development of iridium
complexes-catalyzed organic transformation reactions, we
developed
the
pH-dependent
chemoselective
transfer
hydrogenation of α, β-unsaturated aldehydes[27] and selective
hydroxylation and alkoxylation of silanes[28] (Scheme 1a).In our
previous work, we found Tang’s catalysts can efficiently catalyze
the decomposition of formic acid to release carbon dioxide and
hydrogen. In this catalytic system, formic acid can be used as a
hydrogen source to generate active hydrogen in situ to realize
the reduction of unsaturated compounds. There are two reaction
processes for the reductive amination of carbonyl compounds
and amines. Firstly, the amines react with the aldehydes and
ketones to obtain imines. Then the imines are reduced to
achieve reductive amination. According to preliminary research
of our group and the reductive amination processes of carbonyls
and amines, we envisaged using formic acid as the hydrogen
source to generate active hydrogen in situ, realizing the one-pot
The construction of C-N bond plays a paramount role in organic
chemistry, providing wide application in the area of bioactive
molecules, pharmaceuticals agents and natural products and
multifunctional materials.[1] Therefore, the research on the
formation of C-N bond has always been a research hotspot.
There are many means to achieve this transformation. For
example, the reduction of imines, [2] the reductive amination of
[3]
aldehydes,
amines,
the borrowing hydrogenation of alcohols and
[4]
[5]
the reduction of amides,
halogenated hydrocarbons
the addition of amines and alkynes, [8] etc.
the coupling of
[6]
and boric acids[7] to amines, and
Among the above-mentioned common synthetic methods,
reductive amination is the most direct and efficient method for
the construction C-N bond.[9] Studies show that more than a
quarter of reactions for the C-N bond formation were proceeded
via reductive amination in the field of medicament synthesis.[10]
Until now, homogeneous transition metal catalysts such as
[12]
Rh,[11] Ir,
Ru,[13] Co[14] and Fe[15] employed in reduction
amination have been reported. In order to improve the recycling
of the catalysts, there are also reports of the heterogeneous
metal catalysts such as Ru, [16] Ir, [17] Pd, [18] Pt, [19], Mn [20] and Au.
[21]
Besides, metal-free reduction amination of aldehydes was
also reported.[22] Therefore, reductive amination has been the
chemist’s most common tools for the preparation of C-N bond
transformation.
The half-sandwich IrIII complexes, which coordinate with Cp-
type ligand, which have the features of controllability, flexility,
stability and ease to synthesize, [23] had been the most attractive
and powerful catalysts for efficient assembly of new chemical
bonds.[24] For example, Xiao[25a] and others[25b~e] reported the
iridium complexs-catalyzed transfer hydrogenation reductive
amination of carbonyl compounds with amines. Although
outstanding research results had been made in the field of half-
sandwich IrIII catalysts,[25, 26] further design and synthesis of this
Scheme 1. Transfer hydrogenation and reductive amination of iridium
complexes.
reductive amination of aldehydes and ketones. Herein, we
reported transfer hydrogenation reductive amination of
aldehydes and ketones via one-pot two-step procedure of
various carbonyl compounds to synthesize functionalized
amines in high yield under mild condition (Scheme 1b).
1
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10.1002/ejoc.202001097
European Journal of Organic Chemistry
COMMUNICATION
Compared with conventional method, one-pot two-step
procedure method of carbonyl compounds with amine avoids the
isolation of unstable imine intermediates, which has important
value in terms of synthetic chemistry.[29]
reaction solvent, the reaction can be completely converted in a
shorter time (Table 1, entry 18).
Table 1 Optimization of the reaction conditions. [a]
Entry
1
2[c]
3[d]
4
Catalyst
TC-1
TC-1
TC-1
TC-1
TC-2
TC-3
TC-4
TC-5
TC-6
TC-1
TC-1
TC-1
TC-1
TC-1
TC-1
TC-1
TC-1
TC-1
Hydrogen donor
HCOONa
HCOOH/HCOONa
HCOOH/NEt3
HCOOH
Solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
toluene
THF
Yield (%)[b]
68
56
66
86
5
HCOOH
80
6
HCOOH
79
7
HCOOH
83
8
HCOOH
74
9
HCOOH
81
10
11
12
13
14
15
16
17
18[e]
HCOOH
55
Scheme 2. Substrate scope of aldehydes and amines for reductive amination.
Standard conditions: a solution of 1 (0.5 mmol), 2 (0.6 mmol), TC-1 (0.005
mmol) and HCOOH (10 equiv) in H2O (2 mL) at room temperature under air for
12 h. Yield of isolated product.
HCOOH
86
HCOOH
1,4-dioxane
DCM
78
HCOOH
65
HCOOH
Et2O
77
HCOOH
acetone
DMF
83
With the optimized reaction conditions in hand, the scope of
transfer hydrogenation reductive amination of different
aldehydes and amines was investigated by using Tang’s catalyst
on water (Scheme 2). To our delight, a range of aldehydes and
amines, including aliphatic and aromatic aldehydes, aliphatic
and aromatic amines, primary and secondary amines, could be
compatible with this catalytic system, delivering the
corresponding products in excellent yields under the standard
reaction conditions. It is worth mentioning that aromatic
aldehydes possessing halogen group could also undergo the
reaction smoothly in high yields (3ba, 3ca), in particular for the
ortho position with steric hindrance on aromatic ring of aldehyde
(3da). Furthermore, this reductive amination process could also
be applied to heteroaromatic aldehydes such as furan, pyridine
and aliphatic aldehydes, providing the desired products (3ea,
3fa, 3ga) in high yields. Different kinds of amines were also
proceeded for this strategy, which found the halogen substituted
anilines and N-methylaniline conducted efficiently (3ha-3ka). In
HCOOH
78
HCOOH
H2O
95
HCOOH
H2O
95(93)
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), solvent (2 mL), catalyst
(0.005 mmol), hydrogen donor (10 equiv) at room temperature under air for 12
h. [b] Determined by GC-MS using dodecane as the internal standard. The
number in the parentheses was isolated yield. [c] The reaction was carried out
with 5.0 equiv of HCOOH, 2.0 equiv of HCOONa. [d] The reaction was carried
out with 5.0 equiv of HCOOH, 2.0 equiv of Et3N. [e] The reaction was
conducted for 6 h.
We began our studies by employing benzaldehyde (1a) and
aniline (2a) as the template reaction for the optimization of the
reaction conditions (Table 1). When the reaction was carried out
with TC-1 as the catalyst and HCOONa as the hydrogen donor
in methanol at room temperature for 12 h, moderate yield of the
desired product 3aa was detected by GC-MS analysis (entry 1).
Interestingly, we found that the use of different hydrogen
sources, such as HCOOH/HCOONa, HCOOH/NEt3 led to
moderate yield of 3aa (Table 1, entries 2 and 3). When HCOOH
was used as the hydrogen source, the reaction could proceed
smoothly and afforded the desired product 3aa in 86% yield
(Table 1, entry 4). Further screening of other Tang’s catalyst
with different substituted functional group found that TC-1 was
the best choice for this reductive amination (Table 1, entries 5-9).
In order to further improve the catalytic efficiency, a range of
solvents were checked, which showed that hydrophilic organic
solvents exhibited good catalytic activity, giving 3aa in excellent
yield (Table 1, entries 10-17). It’s well known water is a green
and friendly reaction solvent to environment. When water was
chosen as reaction solvent under the standard condition, 3aa
was obtained in the yield of 95%. In addition, with water as the
addition,
the
cyclic
secondary
amines
such
as
tetrahydroisoquinoline and indoline, did not affect the formation
of the desired products absolutely, leading to the corresponding
amines in good yield (3la, 3ma). Meanwhile, this catalytic
system was also applicable for the reductive amination of
different substituted N-phenyl piperazines under standard
conditions, obtaining the corresponding amines in 90%-94%
yields (3na-3ra).
Due to the excellent catalytic ability of this catalytic system for
aldehydes and amines, various ketones with amines were also
tested through Ir-catalyzed transfer hydrogenation reductive
amination under standard conditions. According to the test
results, the catalytic system was also compatible with various
ketones. Ketones with the electron-donating group (EDGs) or
2
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10.1002/ejoc.202001097
European Journal of Organic Chemistry
COMMUNICATION
electron-withdrawing group (EWGs) on aromatic ring all
undergoes smoothly under this catalytic symstem (Scheme 3).
For example, using acetophenones substituted with EDGs such
as methoxyl or methyl group as the substrates, desired amines
products were achieved in high catalytic efficiency (3ab, 3af).
Meanwhile, substrates substituted with EWGs such as CN, NO2,
and CF3 were practicable under standard condition in good yield
(3ac-3ae). Interestingly, when heteroaromatic ketones were
employed as the substrates with aniline under the standard
condition, the corresponding products 3ah, 3ai, 3aj could also
be afforded in good yields. To further explore the practicability of
this reductive amination, various aliphatic ketones, such as
cyclopropyl methyl ketone, phenylacetone, 2-norbornanone, 5-
fluoro-1-indanone, (4-pyridyl)acetone (3ak-3am, 3ap), were also
subjected to the reaction. Fortunately, high yields were also
obtained, which indicated execellent substrates tolerance.
Besides, the reductive amination of cyclic ketones with aniline
were also studied under aboving optimized conditions. Results
showed that the corresponding amine (3an, 3ao) were isolated
in high yield.
Scheme 4. Large scale experiment and synthesis of Meclizine.
On the basic of experimental results and previous reports, we
proposed a reaction mechanism as showed in Scheme 5. As we
know, imines were obtained from carbonyl compounds and
amines through dehydration condensation and subsequently
reductive amination of imines happened. Details as follows,
Firstly, int-I was transformed into int-II in the presence of the
formate ion [31]. Decarboxylation of int-II was happened and
produced the active int-III. Then, imines were trapped by int-III
and generated a four-membered transition intermediate int-IV [32]
The desired products were achieved via the ligand exchange of
int-IV, and int-I was released for the next catalytic cycles.
.
Scheme 5. Proposed mechanism for the transformation.
In summary, we have successfully developed a practical
reductive amination between aldehydes/ketones and amines.
The broad substrate scope, simple operation, good functional
group tolerance and excellent yield are the attractive features of
this transformation. Moreover, the using of water as reaction
medium makes this methodology for the synthesis of various
amines eco-friendly. In addition, the catalytic efficiency is high
with the TOF up to 1000. The synthesis of Meclizine
demonstrates this useful method has great potential synthetic
applications. Ongoing studies are focused on further exploring
the asymmetric hydrogenation and the results will be reported in
due course.
Scheme 3. Substrate scope of ketones and amines for reductive amination.
Standard conditions:
a solution of 1 (0.5 mmol), 2 (0.6 mmol), TC-1
(0.005mmol) and HCOOH (10 equiv) in H2O (2 mL) at room temperature under
air for 12 h. Yield of isolated product.
Encouraged by the above results, we next focused on the
practical synthetic applications of this reductive amination. A
scale-up experiment (1a, 50 mmol) and (2a, 60 mmol) was
carried out under above established conditions with 0.1 mol%
TC-1 loading, giving 3aa in the yield of 90% (Scheme 4a).
Acknowledgements
Meclizine is a blocker of H1 histamine receptors by reducing
the vasodilating and spasmogenic effect of histamine [30]. We
envisage applying above effective methodology to the synthesis
of this medical molecule. To our delight, Meclizine was afforded
in the yield of 88% by this one-pot reductive amination (Scheme
4b).
The authors thank the National Natural Science Foundation of
China (21961002, 21962004, and 21562004), Jiangxi provincial
department of science and technology (20192BAB203004),
Fundamental Research Funds for Gannan Medical University
(QD201810), and the COVID-19 emergency project of Gannan
Medical University (YJ202027) for financial support.
3
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10.1002/ejoc.202001097
European Journal of Organic Chemistry
COMMUNICATION
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Keywords: reductive amination • transfer hydrogenation •
aldehydes and ketones • amines • iridium complexes
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European Journal of Organic Chemistry
COMMUNICATION
Reductive amination (key topic)
This is a practical reductive amination between aldehydes/ketones and amines for the construction of a variety of amine compounds
in excellent yields. Moreover, the attractive features of this transformation are simple operation, good functional group tolerance and
high catalytic efficiency. In addition, this useful method can be applied to the synthesis of Meclizine demonstrates.
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