Bidentate geometry-constrained iminopyridyl nickel-catalyzed synthesis of amines or imines via borrowing hydrogen or dehydrogenative condensation

Article abstract of DOI:10.1016/j.tetlet.2020.152604

The efficient Ni-catalyzed N-alkylation of various anilines with alcohols via borrowing hydrogen is reported using a bidentate geometry-constrained iminopyridyl nickel complex as the catalyst. Substituted benzylic alcohols and short/long chain aliphatic alcohols could be applied as the alkylation sources to couple with aromatic and heteroaromatic amines to give a diverse set of N-alkylation outcomes in moderate to excellent yields. The nickel catalytic system was also suitable for aliphatic amines, selectively delivering the corresponding imines via an acceptorless dehydrogenative condensation strategy.

Full text of DOI:10.1016/j.tetlet.2020.152604

Journal Pre-proofs
Bidentate geometry-constrained iminopyridyl nickel-catalyzed synthesis of
amines or imines via borrowing hydrogen or dehydrogenative condensation
Yong Jiang, Miao Hu, Nan Sun, Baoxiang Hu, Zhenlu Shen, Xinquan Hu,
Liqun Jin
PII:
S0040-4039(20)31103-5
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152604
TETL 152604
To appear in:
Tetrahedron Letters
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Revised Date:
Accepted Date:
31 August 2020
20 October 2020
23 October 2020
Please cite this article as: Jiang, Y., Hu, M., Sun, N., Hu, B., Shen, Z., Hu, X., Jin, L., Bidentate geometry-
constrained iminopyridyl nickel-catalyzed synthesis of amines or imines via borrowing hydrogen or
dehydrogenative condensation, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152604
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Bidentate geometry-constrained iminopyridyl
nickel-catalyzed synthesis of amines or imines via borrowing
hydrogen or dehydrogenative condensation
Yong Jiang,a Miao Hu,a Nan Sun,a Baoxiang Hu,a Zhenlu Shen,a Xinquan Hua and
Liqun Jin*a,b aCollege of Chemical Engineering, Zhejiang University of Technology,
Hangzhou 310014, China
bState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, the Chinese Academy of Sciences, Lanzhou 730000, P. R.
China.
E-mail address: liqunjin@zjut.edu.cn
Abstract:
The efficient Ni-catalyzed N-alkylation of various anilines with alcohols via
borrowing hydrogen is reported using a bidentate geometry-constrained iminopyridyl
nickel complex as the catalyst. Substituted benzylic alcohols and short/long chain
aliphatic alcohols could be applied as the alkylation sources to couple with aromatic
and heteroaromatic amines to give a diverse set of N-alkylation outcomes in moderate
to excellent yields. The nickel catalytic system was also suitable for aliphatic amines,
selectively delivering the corresponding imines via an acceptorless dehydrogenative
condensation strategy.
Keywords: N-Alkylation; Amines; Imines; Iminopyridyl Nickel; Borrowing
Hydrogen; Dehydrogenative Condensation

Amines and imines are valuable organic compounds in synthetic chemistry. As
versatile intermediates or precursors, they are widely applied in the synthesis of
natural products, pharmaceuticals, pesticides, materials, and dyes [1]. Thus,
developing efficient methods for constructing C-N bonds to prepare amines and
imines is an important goal. The N-alkylation of amines is commonly utilized as an
important tool for the synthesis of substituted amines [2]. The nucleophilic
substitution of an amine with an alkyl halide is a typical method for N-alkylation [3],
although over-alkylation limits its applications [4]. Alternatively, other catalytic
approaches for the N-alkylation of amines have received great interest, such as
Buchwald−Hartwig amination [5], hydroamination of alkenes [6], reductive
amination of carbonyl compounds [7] and Fukuyama amine synthesis [8]. Since the
pioneering work reported independently by the groups of Grigg [9] and Watanabe
[10], significant progress has been achieved in applying alcohols as the alkyl source
due to their intrinsic advantages, such as ready availability, inexpensiveness, and low
toxicity, via homogeneous borrowing hydrogen (BH) catalysis [11]. The overall
process is generally recognized as consisting of the following three steps (Scheme 1):
(i) alcohol oxidation via acceptorless dehydrogenation by the metal catalyst to
generate [MH2]; (ii) imine formation via condensation between the amine and
carbonyl species; (iii) hydrogenation of the imine by [MH2] to release the target
N-alkylated product [12]. From the mechanistic cycle, it can be clearly seen that a
direct synthesis of imines could be realized via H2 liberation (iv) instead of imine
hydrogenation, which has been widely accepted as the concept of acceptorless
dehydrogenative condensation (ADC) [13]. In view of its potential versatility and
environmentally benign properties, imine synthesis through ADC catalysis from
amines and alcohols has received considerable attention [14].

R'
N
H
R
HO
R
[M]
[M]
H2
i
iv
i
iii
[MH2]
[MH2]
R'NH2
R'NH2
R'
R'
R
N
R
O
N
R
-H2O
ii
-H2O
ii
Scheme 1. Synthesis of amines and imines via the BH and ADC concepts.
In the field of N-alkylation, noble metal complexes, mainly Ru[15] and Ir [16],
have been predominantly applied as the catalysts of choice when using amines and
alcohols. In recent years, replacing these noble metal with nonprecious and/or
earth-abundant transition metals, such as Fe [17], Co [14g, 18], and Mn [14k, 19], has
received considerable interest by developing well-defined complexes [20]. Among 3d
metals, Ni has been relatively less applied in BH catalysis, especially in N-alkylation
reactions. To the best of our knowledge, only isolated examples of nickel-based
homogeneously catalyzed N-alkylation reactions have been reported by Banerjee [21],
Zhou [22], Adhikari [23], and Tang [24] in recent years. Although these reported
nickel catalytic systems are rather impressive, they have also suffered from some
obvious limitations. For example, a large excess of the alcohol (4 equiv. to amine)
needed to be utilized and long reaction times were necessary. These phenomena
strongly implied that the efficiency of these nickel catalyst systems could be
improved. Moreover, although aryl and heteroaryl amines were suitable substrates in
the reported examples, aliphatic amines were not discussed.
As previously mentioned, imines are commonly proposed as intermediates for
the N-alkylation of amines. The synthesis of imines directly from amines and alcohols
via ADC has also received significant attention. Recently, Fe [13i], Co [13f-h], and
Mn-catalyzed [13j-n] imine formation with amines and alcohols has been reported,
while nickel catalysis is less studied [25]. To this end, developing novel nickel

catalytic systems for the selective synthesis of N-alkyl amines or imines through BH
or ADC catalysis is still appealing.
Adhikari and co-workers revealed that the redox-active azo moiety present on
the ligand backbone played a crucial role in Ni-catalyzed N-alkylation [23]. Inspired
by their work, we envisioned that ligands with appropriate redox-active properties
should be investigated. The redox non-innocent iminopyridine scaffolds have been
applied as the preferable platform in 3d-metal catalysis due to their facile electronic
tunability that can result in unusual structures and reactivity [26]. In the past years, we
have developed a series of geometry-constrained iminopyridyl (CImPy) compounds
[27], which showed excellent catalytic efficiency and selectivity for hydride transfer
reactions, such as the hydroarylation of alkynes [28] and alkenes [29] as well as the
Markovnikov-selective hydrosilylation of alkynes [30]. Encouraged by these results,
we decided to examine CImPy compounds in this transformation due to its high steric
and electronic tunability and rigid environment, which can suppress the deactivation
of the catalyst to improve the catalyst efficiency [31]. Herein, we reported an efficient
Ni-catalyzed N-alkylation of aromatic amines with a wide substrate scope of alcohols
using the bidentate CImPy ligand. Meanwhile, a selective ADC of aliphatic amines
with alcohols affording imines is also established (Scheme 2).
R2 NH2
R1 OH
R1 OH
+
Ar
+
H2N
N
N
Ni
Ar
R1
+
N
R2
+
R1
H2O
H2
H O
+
2
N
H
Scheme 2. CImPy-Ni-catalyzed selective synthesis of amine and imine
derivatives from amines and alcohols.

Yield
(%)
R2
R3
R1
R1
N
N
Ni1
Ni2
H
H
H
H
H
73
74
R1
N
N
Me
Ar
Ar
R1
N
p-TsOH
R3
R2
Cl
Ni
N
R2
R3
Ni3
Ni4
Ni5
Ni6
Ni7
Ni8
H
H
H
H
methoxy
71
O
+
Cl
Toluene
Cl
Cl
R2
N,N-dimethyl 78
ArNH2
N
Ni
N
H
Me
Ph2CH
H
Me
Me
73
83
R2
R1
R1
H
HN
Ph
Me
N,N-dimethyl 77
N,N-dimethyl 74
NiCl2(DME)
EtOH
Ni1-Ni8
Ni1-Ni8
H
Scheme 3. Preparation of the ICmPy ligated nickel complexes.
Following the reported procedure, a series of CImPy ligated nickel complexes
were prepared [32]. Starting from tetrahydroquinolin-8-one, condensation reactions
were carried out with the substituted anilines in the presence of p-TsOH in toluene to
afford the target 8-aryl-imino-tetrahydroquinoline derivatives as yellowish oils in
moderate yields. The obtained imino compounds were then reacted with NiCl2(DME)
to afford their corresponding nickel complexes Ni1-Ni8 as green precipitates. These
nickel complexes were characterized using FT-IR spectroscopy, which indicated
effective coordination of the cationic nickel with the ligands as evidenced by the shift
of the ʋC=N stretching vibrations (1570-1610 cm-1). All efforts aimed at growing single
crystals of Ni1-Ni8 failed. However, analogous nickel complexes have been utilized
as homogeneous catalysts in ethylene polymerization by Sun’s group, for which
structural analysis showed that they were centrosymmetric dimers with two Cl atoms
as the bridges [32]. Therefore, we proposed that Ni1-Ni8 possessed the similar
dimeric structure as shown in Scheme 2 [33].
With these CImPy ligated nickel complexes in hand, we initially focused on
applying them in the Ni-catalyzed N-alkylation of amines with alcohols. The reactions

catalyzed by Ni1-Ni8 employing benzyl alcohol (1a, 2.0 mmol), aniline (2a, 1.0
mmol), base (1.5 mmol) and 5 mol% nickel complex in toluene were independently
conducted. As shown in Table 1, all tested CImPy ligated nickel complexes exhibited
different catalytic performance for aniline benzylation. When applying the ligand
without any substituents on the pyridine ring and phenyl imine, N-benzyl aniline (3a)
was obtained in 43% yield (Table 1, entry 1). Gratifyingly, an electron-donating
group on the aryl imine site markedly improved the transformation (Table 1, entries
2-4). Remarkably, the ligand with an N,N-dimethyl group on the aryl imine gave the
desired product in 94% yield (Table 1, entry 4). Nevertheless, changing the steric
properties of the aryl imine site did not improve the reaction and lower conversion
was observed (Table 1, entry 2 vs entries 5 and 6). Meanwhile, we also compared the
ligands with various substituents on the ortho-position of the pyridine ring, which
indicated that incorporating a phenyl or methyl group gave slightly lower yields of 3a
(Table 1, entry 4 vs entries 7 and 8). It was noted that most CImPy ligated nickel
complexes tested, except Ni1 and Ni5, exhibited high conversions but with varying
yields of 3a under identical reaction conditions. In these reactions, the imines were
detected using GC and GC-MS analysis. These results revealed that although benzyl
alcohol oxidation catalyzed by these nickel complexes occurred successfully,
hydrogenation of the imine to deliver the amine was greatly influenced by the various
CImPy ligands. Electron-rich ligands with a less hindered aryl imine site possibly
favour the imine hydrogenation step. Furthermore, 1,10-phenthroline, an efficient
ligand reported by Banerjee, was also examined under the same conditions [21],

which showed much lower conversion and yield (Table 1, entry 9). For activation of
the nickel precatalyst and -hydride elimination to generate nickel hydride, the base
also played a very important role [21]. Thus other bases were also screened and found
to be much less efficient than t-AmOK for the alkylation of aniline (Table 1, entries
10 and 11). In addition, reducing the catalyst loading or shortening the reaction time
had little effect on the conversion of aniline, but supressed the alkylation product
significantly (Table 1, entries 12 and 13). A lower amount of 1a resulted in good
conversion but only a moderate yield of 3a (Table 1, entry 14). To this end, the
optimal conditions for the N-alkylation of an amine was determined as amine (1
equiv.), alcohol (2 equiv.), t-AmOK (1.5 equiv.) and 5 mol% Ni4, at 140 oC in toluene
for 12 h.
Table 1. Performance of Ni1-Ni8 in the Ni-catalyzed N-alkylation of aniline with
benzyl alcohol.a

[Ni]
(10 mol%)
Ph
Ph
PhNH2
Ph
N
Ph
N
+
OH
Ph
1a
+
H
toluene, 140 oC
12 h
3a
2a
3a'
Yield (%)b
Conv. (%)b
Entry
Cat. (mol%)
Base (1.5 eq.)
3a
3a'
Ni1
Ni2
1
2
t-AmOK
t-AmOK
70
94
43
76
27
18
Ni3
Ni4
3
4
t-AmOK
t-AmOK
90
98
66
94 (90c)
24
4
Ni5
Ni6
5
6
t-AmOK
t-AmOK
78
92
48
30
22
70
Ni7
Ni8
7
8
t-AmOK
t-AmOK
95
96
84
88
11
8
NiCl2(DME)/
1.10-phenthroline
9
t-AmOK
64
41
23
Ni4
Ni4
Ni4
Ni4
10
11
12d
13e
t-AmONa
t-BuOK
81
54
91
93
20
25
72
68
61
29
19
25
t-AmOK
t-AmOK
14f
Ni4
t-AmOK
81
58
23
a Reagents and conditions: 1a (2.0 mmol), 2a (1.0 mmol), [Ni] (0.05 mmol, 10 mol% of Ni), base (1.5
mmol), 140 °C, toluene (4.0 mL), 12 h. b Conversions and yields were determined by GC with area
normalization. c Isolated yield in parenthesis. d 2.5 mol% Ni4 was utilized. e 6 h. f 1.4 equiv. of 1a was
utilized.
With the aforementioned optimal reaction conditions, we then investigated the
substrate tolerance of this Ni-catalyzed N-alkylation between benzyl alcohol and
various anilines. As shown in Table 2, aromatic amines with electron-donating
substituents reacted with benzyl alcohol to give their corresponding monoalkylated
amines in good to excellent isolated yields (3b−f). It was noted that sterically
hindered o-methoxyl aniline also proceeded efficiently (3f). Anilines with a weakly
electron-withdrawing group, such as F, resulted in an excellent yield of the alkylated
product (3g), however strongly electron-withdrawing groups, such as CN, NO2 and
the carbonyl group, were not well tolerated due to their reductive properties.
4-Chloroaniline gave the targeted product (3h) in 63% yield, in which the partially

dechlorinated product or reactant was also observed. Meanwhile, to illustrate the
synthetic utility, heteroaromatic amines were also examined. Gratifyingly, ortho- and
para-amino pyridines gave their corresponding alkylated amines in 85% (3k) and 53%
(3l) yield, respectively; substituted amino pyridines either with electron-donating or
electron-withdrawing groups were converted to the respective product in moderate to
good yields (3m-3p). Additionally, the N-alkylation protocol was also suitable for
amino pyrimidines (3q and 3r).
Table 2. Alkylation of various anilines with benzyl alcohol.a
[Ni4]
(5 mol%)
H
Ar
OH
H
N
H
+
N
t-AmOK, toluene
140 oC, 12 h
Ar
3b-3r
1a
2b-2r
OMe
MeO
N
H
N
N
H
OMe
N
H
N
H
H
3b
3c
3d
3e
3f
(86%)
(73%)
(85%)
(82%)
O
(80%)
F
Cl
N
N
N
N
H
N
N
O
H
H
H
H
3g
3h
3i
3j
3k
(84%)
(63%)
(78%)
MeO
(80%)
(85%)
F
Cl
N
N
N
H
N
H
N
N
H
N
H
N
N
H
N
3l
3m
3n
3o
3p
(53%)
(76%)
(82%)
(57%)
(48%)
N
N
N
N
N
N
H
H
3q
3r
(84%)
(65%)
a Reagents and conditions: 1a (2.0 mmol), 2 (1.0 mmol), Ni4 (0.05 mmol), t-AmOK (1.5 mmol),
140 °C, toluene (4.0 mL), 12 h. Isolated yields in parentheses.
Next, we turned our attention to examining the scope of the alcohols under the
optimized conditions (Table 3). We found that benzyl alcohols bearing electron-rich
functional groups, naphthalene, and nitrogen-containing heterocycles smoothly

reacted with aniline to afford the corresponding N-alkylated products (4b-4h) in
moderate to excellent yields. The application of a sterically hindered substrate
resulted in a lower yield of the alkylated product (4e). Notably, the secondary
alcohols also delivered the desired N-alkylated product in 81% yield (4i). Furthermore,
to demonstrate the general applicability of the catalytic system, more challenging
aliphatic alcohols were also evaluated. To our delight, both short-chain and
long-chain aliphatic alcohols successfully afforded the desired N-alkylated aniline
products in moderate to good yields (4j-4o).
Table 3. Alkylation of aniline with various alcohols.a
H(Ph)
[Ni4]
(5 mol%)
H
N
H
R
N
H
R
OH
+
t-AmOK, toluene
140 oC, 12 h
1b-1p
2a
4b-4p
H
N
N
N
H
N
H
H
MeO
4b
4c
4d
4e
(58%)
(78%)
(74%)
(56%)
N
H
N
H
N
H
N
H
N
4f
4g
4h
4i
(81%)
(92%)
(84%)
(56%)
H
N
N
N
H
N
6
H
H
4j
4k
4l
4m
(55%)
(53%)
(48%)
(55%)
N
N
H
10
8
H
4n
4o
(71%)
(57%)
a Reagent and conditions: 1 (2.0 mmol), 2a (1.0 mmol), Ni4 (0.05 mmol), t-AmOK (1.5 mmol), 140 °C,
toluene (4.0 mL), 12 h. Isolated yields in parentheses.
After exploring the scope of the aromatic amines and alcohols, we then tested

aliphatic amines. To the best of our knowledge, aliphatic amines have not been
discussed in previous reported homogeneous Ni-catalyzed N-alkylations [21-23].
Under identical conditions for the above N-alkylation of anilines with alcohols, the
dehydrogenative coupling of benzyl alcohol and octylamine was carried out. To our
surprise, imine compound 6a was isolated in 76% yield as the major product rather
than the expected amine. In fact, selective imine formation via the ADC of alcohols
and amines has been well demonstrated.13 However, no example has been reported
with a nickel catalyst, although imines are generally accepted as key intermediates in
the Ni-catalyzed N-alkylation of amines. Therefore, a variety of aliphatic amines were
screened under the optimal conditions. As shown in Table 4, linear and non-linear
aliphatic primary amines, including benzyl amine, underwent dehydrogenative
coupling with primary and secondary benzyl alcohols containing either
electron-donating or electron-withdrawing substituents to give the corresponding
imines in moderate to excellent yields (6a-6h). The synthesis of aliphatic imines is
intrinsically more challenging due to their relative instability. Encouragingly,
aliphatic alcohols reacted with aliphatic amines to form the corresponding imines in
moderate yields (6i), further demonstrating the practicality of our developed CImPy
nickel catalytic system.
Table 4. Dehydrogenative coupling of various alkyl amines with alcohols.a

H(Ph)
H(Ph)
[Ni4]
(5 mol%)
R2
H2N R2
+
R1
R1 OH
N
+
H2
t-AmOK, toluene
140 oC, 12 h
6a-6j
5a-5h
1
N
N
N
6
N
6a
6b
6f
6c
6g
6d
(76%)
(52%)
N
(86%)
N
(67%)
Ph
6
6
N
N
6
Ph
N
6
Cl
6hb
6e
6i
(62%)
(71%)
(74%)
(46%)
(73%)
a Reagents and conditions: 1 (2.0 mmol), 5 (1.0 mmol), Ni4 (0.05 mmol), t-AmOK (1.5 mmol), 140 °C,
b
toluene (4.0 mL), 12 h. Isolated yields in parentheses. Ni4 (0.1 mmol), other conditions were
identical.
(a) Kinetic profiles of the model reaction.
(b) The reaction of imine 3a' with anisyl alcohol
[Ni4]
, t-AmOK
Ph
Ph
[Ni4]
, t-AmOK
Ph
Ph
3a'
N
Ph
N
PhNH2
+
OH
Ph
1a
Ph
N
Ph
H
toluene, 140 o
12 h
C
+
OH
H
Ph
3a'
N
toluene, 140 o
12 h
C
3a
2a
3a
(74%)
4b
MeO
0.25
2a
3a'
3a
(c) Hydrogen detection
0.20
0.15
0.10
0.05
0.00
[Ni4]
, t-AmOK
Octylamine
+
H2
+
Ph
1a
OH
Ph
N
6
toluene, 140 o
12 h
C
6a
5a
0
20
40
60
80
100
120
Time (min)
Scheme 4. Mechanistic experiments.
To gain insights into the mechanism of this Ni-catalyzed N-alkylation of amines
with alcohols, a series of experiments were performed. First, the reaction employing
1a and 2a was monitored by GC under the optimal conditions (Scheme 4a). It can be
observed that along with the consumption of 2a, the target N-alkylated product 3a was
accumulated. Meanwhile, imine 3a’ was detected during the whole process. Moreover,
the reaction utilizing imine 3a' and benzyl alcohol was carried out under the optimal
reaction conditions, in which the N-alkylation product 3a was obtained in 76% yield

and 4-methoxybenzaldehyde was detected (Scheme 4b). These results indicated that
the imine is generated and quickly hydrogenated to the amine, and that the alcohol is
the hydride source. Furthermore, the reaction of benzyl alcohol and octylamine was
also performed, in which the Schlenk tube was connected to another one, which
contained diphenylacetylene and Pd/C in methanol. Reduction of diphenylacetylene to
(Z)-stilbene confirmed the evolution of hydrogen gas during imine formation (see
ESI). Based on these results, we believe that this nickel-catalyzed N-alkylation of
amine proceeds through a BH pathway.
In summary, we have successfully developed an efficient Ni-catalyzed
dehydrogenative coupling of amines and alcohols. The geometry-constrained
iminopyridyl ligand played an important role to improve the efficiency of this
transformation. The N-alkylation of various aromatic and heteroaromatic amines with
alcohols, including substituted benzyl alcohols and aliphatic alcohols, was established
in moderate to excellent yields. Under identical conditions, the dehydrogenative
coupling of various aliphatic amines with alcohols to selectively form imines was
demonstrated. Future work is ongoing in our laboratory towards obtaining additional
mechanistic insights and developing more efficient reaction systems using modified
ligands.
Acknowledgement
This work was supported by the National Natural Science Foundations of China
(21773210, 21972125, 21776260) and the Fundamental Research Funds for the
Provincial Universities of Zhejiang (RF-B2019005). We thank Dr. Dali Yang for the
XAFS analysis of Ni4.

Supplementary material
Supplementary data to this article can be found online at
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[33]
When the CImPy ligand contains a sterically hindered 2,6-disubstituted aryl imine moiety, a
monomeric nickel complex was obtained (ref 32a). For the tested ligand in this work, the
dimeric nickel structure is more likely. For Ni4, XAFS analysis indicated a dinuclear structure
as shown in Scheme 3 (see ESI for details).
Highlights
1. N-alkylaiton of various anilines with alcohols via borrowing hydrogen；
2. Acquiring imines via an acceptorless dehydrogenative condensation strategy

3. Bidentate geometry-constrained iminopyridyl nickel complex as the catalyst；
4. A diverse set of N-alkylation outcomes in moderate to excellent yields
H(Ph)
H(Ph)
H2N
+
R2 NH2
R'
+
(Het)Ar
R1 OH
R1 OH
N
N
Ni
H(Ph)
H(Ph)
R'
+
H2O
+
H2
(Het)Ar
R1
N
R2
R1: aryl, heteroaryl, alkyl; R2: aryl, alkyl
+
H2O
R1
N
H