Iron-catalyzed N-alkylation of aromatic amines via borrowing hydrogen strategy

Article abstract of DOI:10.1080/00958972.2021.1881066

Earth-abundant transition metals could be used as a noble metal replacement in catalysis not only for different catalytic reactivity but environmentally benign methodology. We report here on the iron-catalyzed synthesis of N-alkylated amines via borrowing hydrogen strategy and differently functionalized aniline derivatives are alkylated in good yields.

Full text of DOI:10.1080/00958972.2021.1881066

Journal of Coordination Chemistry
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Iron-catalyzed N-alkylation of aromatic amines via
borrowing hydrogen strategy
Hui Chen, Qingfu Wang, Tingting Liu, Haitao Chen, Duo Zhou & Fengbo Qu
To cite this article: Hui Chen, Qingfu Wang, Tingting Liu, Haitao Chen, Duo Zhou & Fengbo Qu
(2021) Iron-catalyzed N-alkylation of aromatic amines via borrowing hydrogen strategy, Journal of
Coordination Chemistry, 74:4-6, 877-884, DOI: 10.1080/00958972.2021.1881066
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JOURNAL OF COORDINATION CHEMISTRY
2021, VOL. 74, NOS. 4–6, 877–884
https://doi.org/10.1080/00958972.2021.1881066
Iron-catalyzed N-alkylation of aromatic amines
via borrowing hydrogen strategy
Hui Chena, Qingfu Wangb, Tingting Liua , Haitao Chena, Duo Zhoua and
Fengbo Qua
b
aInstitute of Chemistry, Henan Academy of Sciences, Zhengzhou, P. R. China; Technology Center,
China Tobacco Henan Industrial Co., Ltd, Zhengzhou, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 20 July 2020
Accepted 19 November 2020
Earth-abundant transition metals could be used as a noble metal
replacement in catalysis not only for different catalytic reactivity
but environmentally benign methodology. We report here on the
iron-catalyzed synthesis of N-alkylated amines via borrowing
hydrogen strategy and differently functionalized aniline deriva-
tives are alkylated in good yields.
KEYWORDS
Iron; N-alkylation;
borrowing hydrogen; aniline
derivatives
1. Introduction
The efficient formation of carbon–nitrogen bonds is of importance for synthesis of a
plethora of organic compounds, which could be applied in pharmaceuticals and fine
chemicals [1, 2]. There are numbers of methods available for synthesis of amines due
CONTACT Tingting Liu
ltt0720@163.com
Institute of Chemistry, Henan Academy of Sciences, Zhengzhou,
450002, P. R. China.
Supplemental data for this article is available online at https://doi.org/10.1080/00958972.2021.1881066.
ß 2021 Informa UK Limited, trading as Taylor & Francis Group

878
H. CHEN ET AL.
Scheme 1. Selected non-noble metal complex catalysts.
to their importance, such as hydroaminations, Ullmann reactions, Buchwald–Hartwig
reaction, etc. [3–5]. Most of these methods require catalysts or additives with specific
(noble metal) complexes. These methods proved their efficiency in numerous exam-
ples, but they often suffer from the co-production of considerable amounts of waste
or side products. Sustainable, atom-economical and environmentally benign borrowing
hydrogen methodologies have operational simplicity and generation of water as the
only byproduct and have been widely used in C-C and C-N bond construction [6–8].
Through borrowing hydrogen strategy, alcohols and amines are directly reacted by
acceptorless dehydrogenative coupling which is one of the most promising, green syn-
thesis pathways for preparation of N-alkylated amines [9,10]. Alcohols are not only
readily available by a variety of industrial processes but can be obtained renewably
via catalytic conversion of lignocellulosic biomass or fermentation . Direct N-alkylation
of amines with primary alcohols with ruthenium(II) [11, 12], rhodium(I) [13], iridium(III)
[14, 15], and osmium(II) [16] has been documented through a borrowing hydrogen
strategy. Due to the economic and ecological benefits as well as excellent reactivity, it
is desired to apply non-noble metal catalysis in organic synthesis. In this regard,
manganese(I), cobalt(II), and nickel(II) have achieved progress in N-alkylation of aro-
matic amines [17–23]. Recently, Hanson and co-workers reported a Co(II) catalyst bear-
ing a bis(phosphino)-amine (PNP) ligand that could be used to catalyze N-alkylation of
amines [24]. Kempe and co-workers introduced PN5P ligand-stabilized Co(II) complexes
for catalytic applications, highly active for alkylation of aromatic amines [25]. The mild
reaction conditions allow synthesis of unsymmetrically alkylated diamines and the
selective monoalkylation of (hetero)aromatic amines. The groups of Feringa and Barta,
Zhao, and Wills reported N-alkylation of amines with primary and secondary alcohols
€
to give substituted amines by utilizing Fe catalysts based on Knolker’s complex featur-
ing functionalized cyclopentadienone or hydroxycyclo-pentadienyl ligands [26–29].
They also reported a Mn-catalyzed N-alkylation. An air-stable [Mn(I)(CO)2Br] complex
stabilized by a tridentate PNHP ligand and activated in situ by a base, catalyzed the N-
alkylation of amines with alcohols very efficiently [30]. Kempe and co-workers intro-
duced a Mn(I) pincer complex, active for dehydrogenative coupling of alcohols and
amines to form imines selectively [18]. Intrigued by these recent discoveries, we
describe herein the efficient coupling of alcohols and amines catalyzed by Fe(II) associ-
ate with an NNN ligand (Scheme 1).

JOURNAL OF COORDINATION CHEMISTRY
879
2. Experimental
2.1. General considerations
1
1
Solvents were dried and distilled prior to use by literature methods. H and 13Cf Hg
NMR spectra were recorded on a Bruker DRX-400 spectrometer and all chemical shift
values refer to dTMS ¼ 0.00 ppm, CDCl3 (d (1H), 7.26 ppm; d (13C), 77.16 ppm) and
DMSO-d6 (d (1H), 2.50 ppm; d (13C), 39.52 ppm). TLC analysis was performed by using
glass plates coated with 0.2 mm silica gel. Flash column chromatography was per-
formed on silica gel (200–300 meshes). All chemical reagents were purchased from
commercial sources and used as received unless otherwise indicated: 2,6-dibromopyri-
dine, benzene-1,2-diamine, 3,5-dimethyl-1H-pyrazole, 4,5-dimethylbenzene-1,2-diamine,
N,N’-(4,5-diamino-1,2-phenylene)bis(4-methylbenzenesulfonamide),
phenylmethanol,
aniline, p-toluidine, 2-chloroaniline, 4-fluoroaniline, naphthalen-1-amine, (4-chlorophe-
nyl)methanol, 2-phenylethanol, and heptan-1-ol.
2.2. General procedure for iron-catalyzed N-alkylation of aromatic amines (3)
Synthesis of N-benzylaniline (3a): Under a nitrogen atmosphere, a mixture of benzyl
alcohol 1a (216 mg, 2.0 mmol), aniline 2a (186 mg, 2 mmol), tBuOK (168 mg, 1.5 mmol),
FeCl2 (5 mg, 0.04 mmol) and L1 (12 mg, 0.04 mmol) was stirred at 110 ꢀC for 36 h. After
cooling to ambient temperature, the mixture was filtered through a short pad of celite
and rinsed with 10 mL CH2Cl2. The combined filtrate was concentrated under reduced
pressure, and the resulting residue was purified by column chromatography on silica
gel (eluent: petroleum ether (60-90 ꢀC)/ethyl acetate: 20:1, v/v) to afford 3a as a white
solid (340 mg, 93%) which was further analyzed by NMR.
1
N-benzylaniline (3a): H NMR (400 MHz, CDCl3) d 7.41 (d, J ¼ 2.7 Hz, 4 H), 7.36-7.30
(m, 1 H), 7.24 (dd, J ¼ 10.8, 4.5 Hz, 2 H), 6.80 (t, J ¼ 7.0 Hz, 1 H), 6.67 (d, J ¼ 7.5 Hz, 2 H),
1
4.33 (s, 2 H), 4.00 (s, 1 H). 13Cf Hg NMR (100 MHz, CDCl3) d 148.2, 139.5, 129.3, 128.6,
127.5, 127.2, 117.5, 112.8, 48.2.
1
N-benzyl-4-methylaniline (3 b): H NMR (400 MHz, CDCl3) d 7.44-7.35 (m, 4 H), 7.30 (t,
J ¼ 14.8 Hz, 1 H), 7.04 (d, J ¼ 7.9 Hz, 2 H), 6.61 (d, J ¼ 8.2 Hz, 2 H), 4.35 (s, 2 H), 3.93 (s,
1
1 H), 2.29 (s, 3 H). 13Cf Hg NMR (100 MHz, CDCl3) d 146.04, 139.8, 129.9, 128.7, 127.6,
127.3, 126.8, 113.10, 48.7, 20.5.
1
N-benzyl-2-chloroaniline (3c): H NMR (400 MHz, CDCl3) d 7.42-7.38 (m, 4 H), 7.37-7.29
(m, 2 H), 7.16-7.10 (m, 1 H), 6.68 (t, J ¼ 7.4 Hz, 2 H), 4.79 (s, 1 H), 4.44 (s, 2 H). 13Cf Hg
1
NMR (100 MHz, CDCl3) d 144.0, 138.9, 129.2, 128.8, 127.9, 127.5, 127.4, 119.2, 117.5,
111.6, 48.0.
N-benzyl-4-fluoroaniline (3d): 1H NMR (400 MHz, Acetone-d6) d 7.39 (d, J ¼ 7.4 Hz,
2 H), 7.31 (dd, J ¼ 9.8, 4.9 Hz, 2 H), 7.23 (t, J ¼ 5.7 Hz, 1 H), 6.86 (ddd, J ¼ 12.6, 6.4, 2.9 Hz,
2 H), 6.63 (dt, J ¼ 8.6, 4.2 Hz, 2 H), 5.40 (s, 1 H), 4.32 (s, 2 H). 13Cf Hg NMR (100 MHz,
1
acetone-d6) d 206.2, 157.3, 155.0, 146.4, 141.0, 129.2, 128.1, 127.6, 116.1, 115.9, 114.2,
114.2, 48.7.
N-benzylnaphthalen-1-amine (3e): 1H NMR (400 MHz, CDCl3) d 7.80 (dd, J ¼ 10.5,
8.9 Hz, 2 H), 7.48-7.38 (m, 4 H), 7.35 (t, J ¼ 7.7 Hz, 2 H), 7.32-7.20 (m, 3 H), 6.64 (d,

880
H. CHEN ET AL.
1
J ¼ 7.3 Hz, 1 H), 4.48 (s, 2 H). 13Cf Hg NMR (100 MHz, CDCl3) d 143.0, 139.0, 134.4, 128.9,
128.0, 127.6, 126.7, 125.9, 125.0, 123.6, 120.1, 118.1, 105.3, 48.9.
N-(4-chlorobenzyl)aniline (3f): 1H NMR (400 MHz, CDCl3) d 7.31 (s, 4 H), 7.18 (t,
J ¼ 7.9 Hz, 2 H), 6.73 (t, J ¼ 7.3 Hz, 1 H), 6.61 (d, J ¼ 8.0 Hz, 2 H), 4.32 (s, 2 H), 4.06 (s, 1 H).
1
13Cf Hg NMR (100 MHz, CDCl3) d 148.0, 138.1, 133.0, 129.4, 128.9, 128.8, 117.9,
113.0, 47.8.
1
N-phenethylaniline (3 g): H NMR (400 MHz, CDCl3) d 7.39 (dd, J ¼ 13.7, 6.5 Hz, 2 H),
7.27 (dd, J ¼ 18.1, 7.5 Hz, 5 H), 6.79 (t, J ¼ 7.2 Hz, 1 H), 6.69 (d, J ¼ 7.9 Hz, 2 H), 3.63 (s,
1 H), 3.46 (d, J ¼ 7.0 Hz, 2 H), 2.97 (d, J ¼ 6.9 Hz, 2 H). 13Cf Hg NMR (100 MHz, CDCl3) d
1
148.1, 139.4, 129.4, 128.9, 128.7, 126.5, 117.6, 113.1, 45.1, 35.6.
N-heptylaniline (3 h): 1H NMR (400 MHz, CDCl3) d 7.22 (t, J ¼ 7.7 Hz, 2 H), 6.74 (t,
J ¼ 7.3 Hz, 1 H), 6.65 (d, J ¼ 8.2 Hz, 2 H), 3.63 (s, 1 H), 3.14 (t, J ¼ 7.1 Hz, 2 H), 1.69 ꢁ 1.64
(m, 2 H), 1.40-1.31 (m, 8 H), 0.95 (t, J ¼ 6.4 Hz, 3 H). 13Cf Hg NMR (100 MHz, CDCl3) d
1
148.7, 129.3, 117.1, 112.8, 44.1, 31.9, 29.7, 29.3, 27.3, 22.7, 14.2.
1
N-benzylideneaniline (4a): H NMR (400 MHz, CDCl3) d 8.48 (s, 1 H), 7.96 (d, J ¼ 3.8 Hz,
2 H), 7.51 (dd, J ¼ 3.8, 0.7 Hz, 3 H), 7.37-7.47 (m, 2 H), 7.28 (td, J ¼ 7.3, 1.7 Hz, 3 H).
1
13Cf Hg NMR (100 MHz, CDCl3) d 160.4, 152.1, 136.3, 131.4, 129.2, 128.9, 128.8,
126.0, 121.0.
3. Results and discussion
First, FeX2 and L1-L3 were screened for acceptorless dehydrogenative coupling of ben-
zyl alcohol with aniline in toluene (2 mL) at 110 ꢀC, and the results are summarized in
Table 1. When FeCl2, FeBr2 and FeI2 were used as pre-catalysts, an obvious catalyst
effect was observed on the alkylation efficiency and selectivity with the order FeCl2 >
FeBr2 > FeI2 (entries 1-3); the size of the anion has a big influence on reaction effi-
ciency, higher conversion with small Cl-. The functional group on L1-L3 also has an
influence on the alkylation reaction with H > CH3 > NHTs, indicating the electronic
effect of ligand affects the reaction efficiency (entries 1, 4 and 5). The reaction effi-
ciency was remarkably decreased with tBuONa and K2CO3 as the base, reaching 20%
and 18% conversion for 2a and poor selectivity for 3a/4a. Using KOH, 99% conversion
was achieved for 2 with a 74/26 selectivity for the target N-alkylation product 3a and
N-alkylation/dehydrogenation product 4a (Table 1, entries 6-8). Reaction efficiency was
improved by strong and bulky base. Under the closed system and high temperature
conditions, the reaction could not efficiently occur (Table 1, entries 9 and 10).
Lowering the base loading of tBuOK to 0.75 equiv., the N-alkylation has a comparable
efficiency with that of 1 equiv., while not for 0.5 and 0.4 equiv. tBuOK which reduced
the conversion of 2a with deteriorated selectivities of 3a/4a. Lowering the catalyst
and ligand loading to 1.0 mol %, the reaction efficiency was decreased with 90% yield
and 90/10 selectivity (entries 11-14).
Under optimal conditions, benzyl alcohol (1a) was employed to react with various
anilines to prepare diverse secondary amines in Table 2. Benzyl alcohol (1a) reacted
with p-toluidine (2b) to form N-benzyl-4-methylaniline 3b in 90% yield, exhibiting
lower reactivity than aniline (2a). 3-Chloroaniline (2c) also efficiently reacted with 1a,
producing the desired products in 88% yields. Both 4-fluoroaniline (2d) and

JOURNAL OF COORDINATION CHEMISTRY
881
Table 1. Screening of reaction conditions.
Base
(equiv.)
Yield (%)a
(3a:4a)
Entry
Cat.
Conv. (2a) (%)a
1
2
3
4
FeCl2þL1
FeBr2þL1
FeI2þL1
1
1
1
1
1
1
1
1
1
>99
78
57
67
56
20
18
>99
23
65
97:3
46:54
67:33
82:18
73:27
2:98
FeCl2þL2
FeCl2þL3
FeCl2þL1
FeCl2þL1
FeCl2þL1
FeCl2þL1
FeCl2þL1
FeCl21L1
FeCl2þL1
FeCl2þL1
FeCl2þL1
5
6b
7c
8d
9e
10f
11
12
13
14g
3:97
74:26
52:48
77:23
97:3
97:3
72:28
90:10
1
0.75
0.5
0.4
0.75
>99
95
93
90
Conditions: 2 mmol 1 and 2, tBuOK, 0.1 MPa N2, toluene, reflux 36 h. 2 mol% FeX2 [FeX2:L (molar ratio) ¼ 1:1].
aDetermined by GC analysis.
btBuONa.
cK2CO3.
dKOH.
e25-mL sealed tube.
fXylene, reflux.
g1 mol% FeX2 [FeX2:L (molar ratio) ¼ 1:1].
Scheme 2. Proposed mechanism.
naphthalen-1-amine (2e) could effectively react with 1a to form secondary amines 3d
(91%) and 3e (93%), respectively.
Next, the protocol was extended to diverse alcohols in Table 3. 4-Chlorobenzyl alco-
hol (1b) worked well with aniline to afford the target product N-phenyl(4-

882
H. CHEN ET AL.
Table 2. Scope of anilines.
Conditions: 2 mmol 1 and 2, 0.75 equiv. tBuOK, 0.1 MPa N2, toluene, reflux 36 h. 2 mol% FeCl2, 2 mol% L1.
Table 3. Scope of primary alcohols.
Conditions: 2 mmol 1 and 2, 0.75 equiv. tBuOK, 2 mol% FeCl2, 2 mol% L1, 0.1 MPa N2, toluene, reflux 36 h.
chlorobenzyl)amine (3f) in 90% yield. Aliphatic secondary alcohols 2-phenylethanol
(1c) and heptan-1-ol (1d) reacted with aniline (2a) less efficiently, giving 3g and 3h in
80-82% yields.
A simplified mechanism is proposed in Scheme 2. The FeCl2(II) with L1 promotes
oxidation of the primary alcohols to the corresponding aldehyde by generation of an
iron hydride species. Then, the base mediated condensation of the in situ formed

JOURNAL OF COORDINATION CHEMISTRY
883
aldehyde and amine to form the imine intermediate. Subsequent transfer hydrogen-
ation of the resultant imine with the iron hydride species yields the secondary amine.
4. Conclusion
Direct synthesis of secondary amines from N-alkylation of primary amines with alco-
hols occurs with FeCl2 and L1 through a borrowing hydrogen strategy. The catalyst
system exhibited very high catalytic activity towards an array of amine and alcohol
substrates. The present protocol provides a green method to access higher-
order amines.
Acknowledgment
We are grateful to the National Natural Science Foundation of China (22001060), Henan Youth
Support Talent Project (2021HYTP005), Scientific Research and Development Project of Henan
Academy of Sciences (200403001, 200503001, 200603035, 200603041, 200603108) and
Outstanding Youth Training Program of Henan Academy of Sciences (190403004) for support of
this research.
Disclosure statement
The authors declare no competing financial interest.
ORCID
Tingting Liu
http://orcid.org/0000-0002-0156-3054
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