N-Methylation of Amines with Methanol in Aqueous Solution Catalyzed by a Water-Soluble Metal-Ligand Bifunctional Dinuclear Iridium Catalyst

Article abstract of DOI:10.1021/acs.joc.9b03411

The N-methylation of amines with methanol in aqueous solution was proposed and accomplished by using a water-soluble metal-ligand bifunctional dinuclear iridium catalyst. In the presence of [(Cp*IrCl)₂(thbpym)][Cl]₂ (1 mol %), a range of desirable products were obtained in high yields under environmentally benign conditions. Notably, this research exhibited the potential of transition metal-catalyzed activation of methanol as a C1 source for the construction of the C-N bond in aqueous solution.

Full text of DOI:10.1021/acs.joc.9b03411

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Article
N-Methylation of Amines with Methanol in Aqueous Solution Catalyzed
by a Water-Soluble Metal-Ligand Bifunctional Dinuclear Iridium Catalyst
Chong Meng, Peng Liu, Nguyen Thanh Tung, Xingyou Han, and Feng Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03411 • Publication Date (Web): 02 Apr 2020
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N-Methylation of Amines with Methanol in
Aqueous Solution Catalyzed by a Water-Soluble
Metal-Ligand Bifunctional Dinuclear Iridium
Catalyst
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Chong Meng,†,§ Peng Liu,†,§ Nguyen Thanh Tung,† Xingyou Han,† and Feng Li*†,‡
* E-mail: fengli@njust.edu.cn.
†School of Chemical Engineering, Nanjing University of Science & Technology, Nanjing
210094, People’s Republic of China
‡State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024,
People’s Republic of China
[Cl]2
HO
Ir
OH
Ir
O
O
O O
S
S
Me
[(Cp*IrCl)2(thbpym)][Cl]2 (1 mol %)
KOH (1 equiv), 130 oC, 12 h
Cp*
Cl
N
N
N
N
Cl
R
NH2
R
N
H
Me OH
+
Cp*
Me
N
H
H2O
N
R-NH2
R
Me
HO
OH
or
R
Me
[(Cp*IrCl)2(thbpym)][Cl]2
R = aromatic group
R =aliphatic group
ABSTRACT:
The N-methylation of amines with methanol in aqueous solution was proposed and accomplished
by using a water-soluble metal-ligand bifunctional dinuclear iridium catalyst. In the presence of
[(Cp*IrCl)2(thbpym)][Cl]2 (1 mol%), a range of desirable products were obtained in high yields
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under environmentally benign conditions. Notably, this research exhibited the potential of
transition metal-catalyzed the activation of methanol as a C1 source for the construction of C-N
bond in aqueous solution.
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■ INTRODUCTION
The N-methylation of amines constitutes one of the most important and fundamental C-N bond-
forming reactions both on laboratory and industry scale.1 Conventionally, N-methylation of
amines are performed with methyl iodide, dimethyl sulfate, or diazomethane as a methylating
agent in the presence of at least a stoichiometric amount of base. However, these approaches
suffer from the use of highly toxic and hazardous methylating agents, low selectivity and the
generation of large amount of waste. In recent years, significant advance has been made in the
development of transition metal-catalyzed N-methylation of amines with methanol as a
methylating agent based on transition metal-catalyzed hydrogen autotransfer processes (or
hydrogen-borrowing strategy),2 using Ir,3 Ru,4 Mn,5 Fe6, Co7 and Re8 catalysts. In this procss,
methanol is first dehydrogenated to form formaldehyde and metal hydride species, followed by
the condensation between amines and the resulting formaldehyde resulted in the formation of
imine intermediates, which are hydrogenated by metal hydride species to afford desired N-
methylated amines. Such a strategy is highly attractive due to that methanol is an abundant and
renewable C1 source,9 and high atom efficiency and the formation of waters as the only by-
product. However, a relatively high energy is required for the dehydrogenation of methanol
compared with higher alcohols, such as ethanol (ΔH = +84 vs. +68 kJmol-1, respectively),10 thus
all reported procedures have to perform with a large excess of methanol as both N-methylating
agent and solvent at high temperature, despite highly volatile property of methanol.
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With increasing environmental awareness, significant efforts have been devoted to the
development of catalytic transformations in aqueous solution due to that water is cheap, safe and
environmentally benign compared with various organic solvents. Williams and co-workers
reported the N-alkylation of aromatic and aliphatic amines with alcohols in aqueous solution
catalyzed by [Cp*IrI2]2.11 Fujita, Yamaguchi and co-workers described the N-alkylation of
ammonia, and aromatic and aliphatic amines with alcohols in aqueous solution by water-soluble
iridium complexes [Cp*Ir(NH3)3].12 We also demonstrated the N-alkylation of poor nucleophilic
sulfonamides with alcohols and acceptorless dehydrogenative cyclization of o-aminobenzyl
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alcohols with ketones to quinolines in water catalyzed by a water-soluble Cp*Ir complex bearing
13a-b
a functional ligand [Cp*Ir(6,6’-(OH)2bpy)(H2O)][OTf]2
and [Cp*Ir(biimH2)(H2O)][OTf]2.13c
Despite these advances, the N-alkylation of amines with methanol in aqueous solution is
regarded to be an extremely challenging subject and remained unexplored to date. As a
continuing effort in the development of iridium catalyzed environmentally friendly reaction,13-14
we herein wish to report the first example of N-methylation of amines with methanol in aqueous
solution catalyzed by a water-soluble iridium complex.
■ RESULTS AND DISCUSSION
To explore the feasibility of reaction, the N-methylation of benzenesulfonamide (1a) was
selected as a model. In the presence of a water-soluble Cp*Ir complex (2 mol %), such as
cationic complexes (cat. 1-2) or complexes bearing three ammonia ligands (cat. 3), and one or
more aqua ligands (cat. 4-6), the model reaction was carried out in methanol/water (v/v = 1/3,
total volume: 1.2 mL) and KOH (1 equiv) at 130 oC for 12 h and the product 2a was obtained in
≤ 20% yield (Table 1, entries 1-6). When a Cp*Ir complex bearing a functional bipyridine ligand
[Cp*Ir(6,6’-(OH)2-2,2’-bpy)(H2O)][OTf]2 (cat. 7) was examined, the reaction gave the product
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2a in 84% yield, indicating that OH units in the ligand are crucially important for the activity of
catalysts (Table 1, entry 7). Furthermore, it was found that the yield of 2a could be enhanced to
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Table 1. The N-Methylation of Sulfonamides with Methanol under Various Conditions.a,b
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catal (x mol%)
base (y equiv)
MeOH/H2O (v/v)
O
S
O
O O
S
Me
NH2
N
H
130 oC, 12 h
1a
2a
MeOH/H2O (v/v)
Yield (%)b
Entry
x
y
Catal.
Base
1
2
3
4
5
6
cat.1
cat.2
cat.3
cat.4
cat.5
KOH
KOH
KOH
KOH
KOH
KOH
2
2
2
2
2
2
1.0
1.0
1.0
1.0
1.0
1.0
1/3
1/3
1/3
1/3
1/3
1/3
n.d.
<5
12
20
9
cat.6
cat.7
cat.8
cat.8
cat.8
cat.8
cat.8
cat.8
16
84
93 (87)c
7
KOH
KOH
KOH
KOH
Cs2CO3
KOH
KOH
KOH
KOH
2
1
1
1
1
1
1
1
1
1.0
1.0
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1:3
1/3
1/3
1/3
1/3
1/3
1/4
1/5
1/5
8
9
66
64
27
80d
82
71
10
11
12
13
14
15
cat.8
-
n.d.
2Cl-
[OTf]2
Cl-
Cl-
Ir Cl
N
Ir Cl
N
Ir
Ir
H2O
H2O
H3N
H3N
N
N
OH2
NH3
cat. 1
cat. 2
cat. 3
cat. 4
[Cl]2
[OTf]2
HO
[OTf]2
MeO
[OTf]2
HO
OH
Cl
N
N
N
Cp*
Cl
Ir H2O
Ir H2O
Ir H2O
OH
N
OMe
Ir
N
Ir
N
N
N
N
N
Cp*
HO
OH
cat. 5
cat. 6
cat. 7
cat. 8
a Reactions conditions: 2a (0.5 mmol), 1a (0.65 mmol, 1.3 equiv), catal (x mol %), H2O (1 mL), base
(y equiv), under air, 12 h. b Yield was determined based on the 1H NMR spectrum of the crude
reaction mixture with 1,3,5-trimethoxybenzene as the internal standard. c Isolated yield. d 120 oC.
93% when a dinuclear water-soluble iridium complex with 4,4’,6,6’-tetrahydroxy-2,2’-
bipyrimidine (thbpym) as a bridging ligand [(Cp*IrCl)2(thbpym)][Cl]215,16 (cat. 8) (1 mol %) was
used as an alternative catalyst (Table 1, entry 8). Next, cat. 8 was chosen as the catalyst for
further research. Attempts to reduce the amount of KOH and the use of Cs2CO3 instead of KOH,
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and decrease temperature of reaction and the ratio of methanol to water resulted in relatively low
yields (Table 1, entries 9-14). It was also found that no reaction occurred in the presence of
KOH alone (Table 1, entry 15).
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Encouraged by the promising result (Table 1, entry 8), the N-methylation of a range of
sulfonamides with methanol in aqueous solution was investigated, and these results are
summarized in Table 2. Reactions of benzenesulfonamides bearing a halogen atom, such as
fluorine, chlorine or bromine, gave corresponding products 2b-2g in 85-90% yields. Similarly,
more electron-withdrawing substituent, such as trifluoromethyl and trifluoromethoxy groups,
were tolerated and desired products 2h-2j were obtained in high yields. The N-methylation of
benzenesulfonamides bearing an electron-donating substituent, such as methyl or methoxy
group, proceeded smoothly to afford corresponding products 2k-2m in 91%-94% yields.
Furthermore, naphthalenesulfonamide was also converted into the desired product 2n in 90%
yield. This catalytic system was also suitable for aliphatic sulfonamides, giving corresponding
products 2o-2r in 89-92% yields.
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Table 2. The N-Methylation of a Variety of Sulfonamides with Methanol in Aqueous Solution.a
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7
8
cat. 8 (1 mol %)
KOH (1 equiv)
MeOH/H O (v/v = 1/3)
2
O
O
O
O
S
S
Me
R
NH
R
N
2
o
H
130 C, 12 h
1
2
9
b
Entry
1
Sulfonamide
F
Product
Yield (%)
90
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F
O
O
O
S
O
S
Me
Me
N
NH
2
2
H
1b
2b
O
S
O
O
O
S
NH
N
H
2
85
88
F
F
1c
2c
Cl
Cl
O
O
O
O
O
S
O
S
Me
Me
Me
N
NH
NH
NH
2
2
H
3
4
5
1d
2d
O
S
O
O
Cl
Cl
S
N
H
89
90
1e
2e
O
S
O
O
S
N
2
2
2
H
Cl
Br
Cl
Br
1f
2f
O
S
O
O
O
O
S
Me
Me
NH
NH
N
6
H
87
90
1g
2g
O
O
S
O
S
N
7
8
H
F C
3
F C
3
1h
2h
CF
CF
O
3
O
O
3
O
S
Me
Me
S
N
NH
2
2
H
85
89
1i
O
S
2i
O
O
O
S
NH
N
9
H
F CO
3
F CO
3
1j
2j
Me
Me
O
O
O
O
O
S
O
S
Me
Me
Me
N
NH
2
2
2
H
10
11
91
94
1k
O
S
2k
O
O
S
N
NH
H
Me
Me
1l
O
S
2l
O
O
S
NH
N
H
12
13
93
90
MeO
MeO
1m
2m
O
O
O
S
O
S
Me
N
NH
2
H
1n
2n
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Table 2. (Continued)
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6
7
8
b
Entry
14
Sulfonamide
Product
Yield (%)
O
O
O
O
92
S
Me
Me
S
N
NH
2
2
H
9
1o
2o
10
11
12
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O
S
O
O
O
S
NH
N
15
16
91
H
1p
2p
O
O
O
O
O
S
S
Me
Me
NH
N
2
2
89
90
H
1q
2q
O
S
O
O
S
17
Me
NH
Me
N
H
1r
2r
a
Reaction conditions: 1 (0.5 mmol), MeOH/H O (v/v =1/3, total volume: 1.2 mL), cat. 8
2
o
b
(1 mol %), KOH (1 equiv), 130 C, 12 h. Isolated yield.
To expand further the scope of reaction, the N-methylation of a series of aromatic and
aliphatic amines under similar conditions (MeOH/H2O, v/v = 1/1, total volume: 1.2 mL) was
then investigated (Table 3). Transformations of aniline gave the corresponding product 4a in
87% yield. For anilines bearing an electron-withdrawing substituent, desired products 4b-4e
were obtained in 77%-88% yields. Anilines bearing an electron-donating substituent were
converted to corresponding products 4f-4h in 79-86% yields. When aliphatic primary amines,
such as 1-phenylethanamine and amantadine, were used as substrates, N,N-dimethylated
products 4i and 4j were obtained in 81% and 84% yields, respectively, indicating aliphatic
amines are more nucleophilic than aromatic amines. In the case of secondary aliphatic amines,
such as 1,2,3,4-tetrahydroisoquinoline, 4-(3-(piperidin-4-yl)propyl)piperidine and piperazine,
desired products 4k-4m were obtained in 83-87% yields.
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Table 3. The N-Methylation of Various Aromatic Amines and Aliphatic Amines with Methanol
5
6
in Aqueous Solution.a
7
8
9
cat. 8 (1 mol %)
KOH (1 equiv)
MeOH/H2O (v/v = 1/1)
Me
N
H
N
or
R
NH2
R
Me
R
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
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30
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49
50
51
52
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56
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58
59
60
130 oC, 12 h
3
4
Yield (%)b
Entry
Aromatic or aliphatic Amines
NH2
Product
H
N
Me
1
2
87
3a
4a
H
N
NH2
Me
Me
80
88
F
F
3b
4b
H
N
NH2
3
Cl
Cl
3c
4c
H
N
NH2
Me
Me
4
5
82
77
Br
Br
3d
4d
H
N
NH2
F3CO
F3CO
3e
4e
H
N
NH2
NH2
Me
Me
6
7
8
84
79
86
Me
Me
3f
4f
H
N
Me
Cl
Me
Cl
3g
3h
4g
H
N
MeO
NH2
Me
MeO
Me
4h
Me
Me
NH2
N
9
81
84
Me
3i
4i
Me
Me
NH2
N
H
H
10
H
H
H
H
3j
4j
11
12
87
85
NH
N
Me
3k
4k
HN
NH
N
N
Me
Me
3l
4l
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Table 3. (Continued)
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6
7
8
b
Entry
Aromatic or aliphatic amines
Product
Me
Yield (%)
NH
HN
N
N
13
83
Me
9
3m
4m
a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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41
42
43
44
45
46
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50
51
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Reaction conditions: 3 (0.5 mmol), MeOH/H O (v/v = 1/1, total volume: 1.2 mL), cat. 8
2
o
b
(1 mol %), KOH (1 equiv), 130 C, 12 h. Isolated yield.
A plausible mechanism is proposed to account for the N-methylation of amines with methanol
in aqueous solution catalyzed by [(Cp*IrCl)2(thbpym)][Cl]2 (Scheme 1). The initial step of the
reaction involved the formation of an unsaturated species A by the reaction of cat. 8 with KOH.
Furthermore, the ligand accepted two protons in the step of the activation of methanol, resulting
in the generation of dimethoxidoiridium species B, which underwent β-hydrogen elimination to
afford iridium hydride species C and two molecular formaldehydes.17 Subsequently, the
condensation between the resulting two molecular formaldehydes and two molecular amines
gave two molecular unsaturated imines as intermediates. Accompanied by simultaneous transfer
of the hydride on iridium and the proton on the ligand of species C to the C=N bond of imine
intermediates, the desirable N-methylamines were released and the catalytic species A were
regenerated. A similar mechanism for the simultaneous delivery of hydride and proton to ketones
or imines has been proposed in metal-ligand bifunctional catalysts, such as Shvo’s catalyst18 and
Ru-TsDPEN systems.19
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Scheme 1. The Proposed Reaction Mechanism.
5
6
cat. 8
7
8
Base
-2HCl
9
2+
O
Ir
OH
10
11
12
13
14
15
16
17
18
19
20
21
22
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32
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Me
NH
N
N
N
N
Cp*
2 x CH3OH
2 x
R
Ir
Cp*
HO
O
A
2+
H
R
2+
HO
Ir
OH
N
O
Ir
OH
Ir
H
N
N
N
N
Cp*
MeO
Cp*
H
N
N
N
N
Cp*
H
Ir
H
OMe
Cp*
H
HO
OH
H
HO
O
H
N
R
C
B
O
H
2 x
H
2 x H2O
+
2+
HO
OH
Ir
N
N
Cp*
H
R
NH2
2 x
Ir
H
N
N
Cp*
HO
OH
=
vacant site
C
A series of labelling experiments with deuterated methanol were investigated to understand the
reaction mechanism (Scheme 2). The reaction of aniline (3a) was performed in CH3OD/H2O (v/v
= 1/1, total volume: 1.2 mL) for 12 h to afford N-methylaniline-d1 (5) in 82% yield, indicating
that the protic deuterium OD and hydridic proton from CH3 were selectively transferred to the
nitrogen and the carbon, respectively (Scheme 2, Eq.(1)). Furthermore, two parallel reactions of
3a with CH3OH and CD3OD were carried out to give a significant kinetic isotope effect (KIE)
(KH/KD = 3.76) (Scheme 2, Eq.(2)). Competitive reactions with a mixture of CH3OH and CD3OD
(v/v = 1/1) was also undertaken (Scheme 2, Eq.(3)). It was calculated that N-methyleneaniline
PhN=CH2 (75%) and deuterated methylidine-aniline-d2 PhN=CD2 (25%) were generated in the
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process of reaction. These results suggested that the C-H bond cleavage of methanol is
kinetically relevant.20
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Scheme 2. Labelling Experiments with Deuterated Methanol.
cat. 8 (1 mol %)
KOH (1 equiv)
CH3OD/H2O (v/v = 1/1)
D
N
NH2
NH2
NH2
CH3
(1)
(2)
130 oC, 12 h
5, 82% yield
1a
1a
H
N
D
N
cat. 8 (1 mol %)
KOH (1 equiv)
CH3
CD3
+
CH3OH/CD3OD
H2O, 130 oC, 8 h
2a
6
KH/KD = 3.76
H/D
H/D
N
N
CH3
CH2D
+
cat. 8 (1 mol %)
1a
KOH (1 equiv)/H2O
52%
23%
(3)
+
130 oC, 15 h
H/D
N
H/D
N
CH3OH
+
CHD2
CD3
+
CD3OD
21%
4%
To demonstrate the practical potential of this catalytic system, the large-scale of N-methylation
in aqueous solution was undertaken. Under established conditions (Table 1, entry 8), the
transformation of 1a (20 mmol) was performed to give the corresponding product 2a in 87%
yield (Scheme 3).
Scheme 3. Large-Scale Hydrogenation of 1a with Methanol in Aqueous Solution.
cat. 8 (1 mol %)
O
S
O
O O
KOH (1 equiv)
CH OH/H O (v/v= 1/1)
S
Me
3
2
NH
N
2
H
o
130 C, 12 h
1a (20 mmol)
2a, 87% yield
Furthermore, the synthesis of a biologically active molecular Loxapine (a drug used for
treating schizophrenia)21 was presented (Scheme 4). The reaction of 2-chloro-11-(1-
piperazinyl)dibenzo[b,f][1,4]oxazepine (7) with methanol were carried out in the presence of cat.
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8 (1 mol %)/KOH (1 equiv) at 130 oC for 12 h to afford the desirable product 8 in 73% yield.
Scheme 4. Synthesis of a Biologically Active Molecular.
H
Me
9
N
N
cat. 8 (1 mol %)
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KOH (1 equiv)
N
N
N
O
N
O
CH OH/H O (1/1)
3
2
o
130 C, 12 h
Cl
Cl
7
8, 73% yield
■ CONCLUSIONS
In summary, we have demonstrated that a water-soluble dinuclear Cp*Ir complex bearing
4,4’,6,6’-tetrahydroxy-2,2’-bipyrimidine as a bridging ligand is a highly effective catalyst for the
N-methylation of amines with methanol in aqueous solution. In the presence of
[(Cp*IrCl)2(thbpym)][Cl]2 (1 mol%), a range of desirable products were obtained in high yields
under environmentally benign conditions. The presence of OH units in the bpym ligand is
crucially important for the catalytic activity of the iridium complex. Notably, this research
exhibited the potential of transition metal-catalyzed the activation of methanol as a C1 source for
the construction of C-N bond in aqueous solution.
■ EXPERIMENTAL SECTION
General Experimental Details. Melting points were measured on a X-6 micro-melting
apparatus. Proton nuclear magnetic resonance (1H NMR) spectra were recorded at 500 MHz
using a 500 spectrometer. Chemical shifts are reported in delta (δ) units, parts per million (ppm)
downfield from tetramethylsilane or ppm relative to the center of the singlet at 7.26 ppm for
CDCl3 and 2.50 ppm for DMSO-d6. Coupling constants J values are reported in Hertz (Hz), and
the splitting patterns were designated as follows: s, singlet; d, doublet; t, triplet; m, multiplet; b,
broad. Carbon-13 nuclear magnetic resonance (13C NMR) spectra were recorded at 125 MHz
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using a 500 spectrometer. Chemical shifts are reported in delta (δ) units, ppm relative to the
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center of the triplet at 77.0 ppm for CDCl3 and 39.5 ppm for DMSO-d6. C NMR spectra were
7
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9
routinely run with broadband decoupling. Analytical thin-layer chromatography (TLC) was
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carried out using 0.2-mm commercial silica gel plates.
[Cp*Ir(Me2NCH2CH2NMe2)Cl]Cl (cat. 1),22 [Cp*Ir(bpy)Cl]Cl (cat. 2),23 [Cp*Ir(NH3)3][Cl]2
(cat. 3),11a [Cp*Ir(H2O)3][OTf]2 (cat. 4),24 [Cp*Ir(bpy)(H2O)][OTf]2 (cat. 5),25 [Cp*Ir(6,6'-
(OMe)2bpy)(H2O)][OTf]2 (cat. 6),26 [Cp*Ir(6,6'-(OH)2bpy)(H2O)][OTf]2 (cat. 7),27
[(Cp*IrCl)2(thbpym)][Cl]2 (cat. 8),15 were synthesized according the previous reports.
General procedure for the N-methylation of sulfonamides with methanol in aqueous
solution catalyzed by a water-soluble dinuclear Cp*Ir complex [(Cp*IrCl)2(thbpym)][Cl]2
(cat. 8). To an oven-dried, 25 mL Schlenk tube were added sulfonamides (0.5 mmol), cat. 8 (5.1
mg, 0.005 mmol, 1 mol %), KOH (28 mg, 0.5 mmol), MeOH/H2O (v/v = 1/3, total volume: 1.2
o
mL). The mixture of reaction was heated at 130 C in an oil bath for 12 h. The reaction mixture
was cooled to ambient temperature, concentrated in vacuo and purified by flash silica-gel column
chromatography to afford corresponding products 2a-2r.
N-methylbenzenesulfonamide (2a).28 The title compound was purified by flash silica-gel
column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Pale yellow oil; 87%
yield (74 mg); 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 7.4 Hz, 2H), 7.59 (t, J = 7.3 Hz, 1H),
7.52 (t, J = 7.9 Hz, 2H), 2.64 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 138.6, 132.7, 129.2,
127.2, 29.3.
2-Fluoro-N-methylbenzenesulfonamide (2b).29 The title compound was purified by flash
silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White solid;
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90% yield (85 mg); mp 39-40 C; H NMR (500 MHz, CDCl3) δ 7.91 (t, J = 7.6 Hz, 1H), 7.60
(q, J = 7.0 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.23 (t, J = 9.4 Hz, 1H), 4.98-4.29 (br s, 1H), 2.71
(s, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 158.9 (d, JC-F = 254.0 Hz), 135.2 (d, JC-F = 8.4 Hz),
130.9, 127.0, 124.7, 117.1 (d, JC-F = 21.5 Hz), 29.4.
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4-Fluoro-N-methylbenzenesulfonamide (2c).30 The title compound was purified by flash silica-
gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White solid; 85%
o
1
yield (80 mg); mp 75-76 C; H NMR (500 MHz, CDCl3) δ 7.90-7.86 (m, 2H), 7.19 (t, J = 8.5
Hz, 2H), 4.96-4.81 (br s, 1H), 2.65-2.63 (m, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 165.2 (d,
JC-F = 254.5 Hz), 134.9, 130.1 (d, JC-F = 9.3 Hz), 116.5 (d, JC-F = 22.6 Hz), 29.4.
2-Chloro-N-methylbenzenesulfonamide (2d).31 The title compound was purified by flash
silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White solid;
88% yield (90 mg); mp 37-38 oC; 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 7.9 Hz, 1H), 7.53-
13
7.51 (m, 2H), 7.44-7.40 (m, 1H), 5.58-4.27 (br s, 1H), 2.61 (s, 3H); C {1H} NMR (125 MHz,
CDCl3) δ 135.9, 134.0, 131.9, 131.7, 131.4, 127.4, 29.4.
3-Chloro-N-methylbenzenesulfonamide (2e).32 The title compound was purified by flash
silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White solid;
o
1
89% yield (92 mg); mp 45-46 C; H NMR (500 MHz, CDCl3) δ 7.84 (s, 1H), 7.74 (d, J = 7.3
Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 4.81-4.63 (br s, 1H), 2.65 (s, 3H); 13C
{1H} NMR (125 MHz, CDCl3) δ 140.7, 135.4, 132.9, 130.6, 127.4, 125.4, 29.4.
4-Chloro-N-methylbenzenesulfonamide (2f).32 The title compound was purified by flash silica-
gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White solid; 90%
yield (93 mg); mp 45-46 oC; 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.4 Hz, 2H), 7.50 (d, J =
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8.5 Hz, 2H), 2.68 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 139.3, 137.3, 129.5, 128.8, 29.3.
5
6
7
8
9
4-Bromo-N-methylbenzenesulfonamide(2g).33 The title compound was purified by flash silica-
gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Pale yellow solid;
87% yield (109 mg); mp 74-75 oC; 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 8.5 Hz, 2H), 7.61
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(d, J = 8.5 Hz, 2H), 5.12-5.08 (br s, 1H), 2.59 (s, 3H); C {1H} NMR (125 MHz, CDCl3) δ
137.9, 132.5, 128.9, 127.7, 29.2.
N-Methyl-4-(trifluoromethyl)benzenesulfonamide (2h).3c The title compound was purified by
flash silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White
solid; 90% yield (108 mg); mp 76-77 oC; 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 8.5 Hz, 2H),
7.80 (d, J = 8.5 Hz, 2H), 3.96-4.51 (br s, 1H), 2.70 (s, 1H); 13C {1H} NMR (125 MHz, CDCl3) δ
142.6,134.6 (d, JC-F = 34.5 Hz), 127.9, 126.5, 123.3 (q, JC-F = 273.5 Hz), 29.4.
N-Methyl-2-(trifluoromethyl)benzenesulfonamide (2i).29 The title compound was purified by
flash silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White
solid; 85% yield (102 mg); mp 97-98 oC; 1H NMR (500 MHz, CDCl3) δ 8.25-8.23 (m, 1H), 7.91-
7.88 (m, 1H), 7.76-7.69 (m, 2H), 4.61 (br s, 1H), 2.69 (d, J = 5.2 Hz, 3H); 13C {1H} NMR (125
MHz, CDCl3) δ 137.7, 132.9, 132.5, 128.7 (q, JC-F = 6.3 Hz), 127.7 (d, JC-F = 33.0 Hz), 123.2 (d,
JC-F = 273.4 Hz), 29.5.
N-Methyl-4-(trifluoromethoxy)benzenesulfonamide (2j).3c The title compound was purified
by flash silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Pale
yellow oil; 89% yield (114 mg); 1H NMR (500 MHz, CDCl3) δ 7.92 (d, J = 8.8 Hz, 2H), 7.34 (t,
J = 8.3 Hz, 2H), 5.00-4.80 (br s, 1H), 2.65 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 152.3 ,
137.4, 129.5, 121.1, 120.3 (q, JC-F = 259.5 Hz ), 29.3.
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N,2-Dimethylbenzenesulfonamide (2k).28 The title compound was purified by flash silica-gel
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column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White solid; 91% yield
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8
9
o
1
(84 mg); mp 70-71 C; H NMR (500 MHz, CDCl3) δ 7.94 (d, J = 8.3 Hz, 2H), 7.45 (t, J = 7.5
Hz, 1H), 7.33-7.29 (m, 2H), 4.54 (br s, 1H), 2.63 (s, 3H), 2.61 (s, 3H); 13C {1H} NMR (125
MHz, CDCl3) δ 137.2, 136.8, 132.9, 132.7, 129.8, 126.2, 29.1, 20.4.
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N,4-Dimethylbenzenesulfonamide (2l).33 The title compound was purified by flash silica-gel
column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White solid; 94% yield
(87 mg); mp 74-75 oC; 1H NMR (500 MHz, CDCl3) δ 7.75 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.0
13
Hz, 2H), 2.60 (s, 3H), 2.41 (s, 3H); C {1H} NMR (125 MHz, CDCl3) δ 143.6, 135.7, 129.8,
127.4, 29.3, 21.6.
4-Methoxy-N-methylbenzenesulfonamide (2m).28 The title compound was purified by flash
silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White solid;
o
1
93% yield (94 mg); mp 94-95 C; H NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.9 Hz, 2H), 6.97
(d, J = 8.9 Hz, 2H), 3.85 (s, 3H), 2.59 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 163.0,
130.3, 129.5, 114.4, 55.7, 29.3.
N-Methylnaphthalene-2-sulfonamide (2n).29 The title compound was purified by flash silica-
gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White solid; 90%
yield (100 mg); mp 105-106 oC; 1H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 7.94 (d, J = 8.8 Hz,
13
2H), 7.91-7.83 (m, 2H), 7.67-7.54 (m, 2H), 4.97 (br s, 1H), 2.66 (s, 3H); C {1H} NMR (125
MHz, CDCl3) δ 135.6, 134.9, 132.2, 129.6, 129.3, 128.9, 128.8, 128.0, 127.6, 122.4, 29.4.
N-Methyl-1-phenylmethanesulfonamide (2o).34 The title compound was purified by flash
silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White solid;
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92% yield (85 mg); mp 111-112 C; H NMR (500 MHz, CDCl3) δ 7.38 (s, 5H), 4.23 (s, 2H),
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6
2.67 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 130.7, 129.5, 129.0, 128.8, 57.7, 29.9.
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8
9
N,2-Dimethylpropane-2-sulfonamide (2p).35 The title compound was purified by flash silica-
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gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Pale yellow oil;
1
91% yield (69 mg); H NMR (500 MHz, CDCl3) δ 3.20 (br s, 1H), 2.88-2.82 (m, 3H), 1.21 (s,
9H); 13C {1H} NMR (125 MHz, CDCl3) δ 55.6, 31.6, 22.6.
N-Methylcyclopropanesulfonamide (2q).3c The title compound was purified by flash silica-gel
column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Pale yellow oil; 89%
yield (60 mg); 1H NMR (500 MHz, CDCl3) δ 2.79 (s, 3H), 2.40 (sep, J = 4.7 Hz, 1H), 1.16-1.09
(m, 2H), 1.01-0.94 (m, 2H); 13C {1H} NMR (125 MHz, CDCl3) δ 29.5, 28.6, 4.97.
N-Methylmethanesulfonamide (2r).3c The title compound was purified by flash silica-gel
column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Pale yellow oil; 90%
1
13
yield (49 mg); H NMR (500 MHz, CDCl3) δ 2.91 (s, 3H), 2.76 (s, 3H); C {1H} NMR (125
MHz, CDCl3) δ 38.4, 29.3.
General procedure for the N-methylation of aromatic or aliphatic amines with methanol in
aqueous solution catalyzed by
a
water-soluble dinuclear Cp*Ir complex
[(Cp*IrCl)2(thbpym)][Cl]2 (cat. 8). To an oven-dried, 25 mL Schlenk tube were added
aromatic or aliphatic amines (0.5 mmol), cat. 8 (5.1 mg, 0.005 mmol, 1 mol %), KOH (28 mg,
0.5 mmol), MeOH/H2O (v/v = 1:1, total volume: 1.2 mL). The mixture of reaction was heated at
o
130 C in an oil bath for 12 h. The reaction mixture was cooled to ambient temperature,
concentrated in vacuo and purified by flash silica-gel column chromatography to afford
corresponding products 4a-4m.
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N-Methylbenzenamine (4a).36 The title compound was purified by flash silica-gel column
chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Yellow oil; 87% yield (47
mg); 1H NMR (500 MHz, CDCl3) δ 7.27-7.20 (m, 2H), 6.75 (t, J = 7.4 Hz, 1H), 6.65 (d, J = 7.8
Hz, 2H), 3.71 (br s, 1H), 2.86 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 149.4, 129.3, 117.3,
112.5, 30.8.
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4-Fluoro-N-methylbenzenamine (4b).37 The title compound was purified by flash silica-gel
column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Yellow oil; 80% yield
1
(50 mg); H NMR (500 MHz, CDCl3) δ 6.92 (t, J = 8.7 Hz, 2H), 6.58-6.51 (m, 2H), 3.60 (br s,
13
1H), 2.81 (s, 3H, CH3); C {1H} NMR (125 MHz, CDCl3) δ 155.9 (d, JC-F = 234.3 Hz), 145.6,
115.4 (d, JC-F = 22.3 Hz), 113.0 (d, JC-F = 6.2 Hz), 31.1.
4-Chloro-N-methylbenzenamine (4c).38 The title compound was purified by flash silica-gel
column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Yellow oil; 88% yield
1
(62 mg); H NMR (500 MHz, CDCl3) δ 7.13 (d, J = 8.7Hz, 2H), 6.53 (d, J = 8.7 Hz, 2H), 3.72
(br s, 1H), 2.81 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 148.0, 129.1, 121.9, 113.6, 31.0.
4-Bromo-N-methylbenzenamine (4d).3c The title compound was purified by flash silica-gel
column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Yellow oil; 82% yield
1
(76 mg); H NMR (500 MHz, CDCl3) δ 7.24 (d, J = 8.8 Hz, 2H), 6.46 (d, J = 8.8 Hz, 2H), 3.70
(br s, 1H), 2.78 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 148.2, 131.7, 113.8, 108.6, 30.6.
Methyl-(4-trifluoromethoxy-phenyl)-amine (4e).3c The title compound was purified by flash
silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1);
Pale yellow oil; 77% yield (74 mg); 1HNMR (500 MHz, CDCl3) δ 7.04 (d, J =
8.6 Hz), 6.55 (d, J
=
8.6
Hz),
3.50
(br s,
1H),
2.81 (s, 3H); 13C
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{1H} NMR (125 MHz, CDCl3) δ 147.7, 140.4, 122.2, 120.6 (q, JC-F = 255.4 Hz), 112.6, 30.8.
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7
8
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N,4-Dimethylbenzenamine (4f).39 The title compound was purified by flash silica-gel column
chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Brown oil; 84% yield (51 mg);
1H NMR (500 MHz, CDCl3) δ 7.01 (d, J = 8.1 Hz, 2H), 6.55 (t, J = 8.2 Hz, 2H), 2.82 (s, 3H),
2.25 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 147.0, 129.6, 126.4, 112.5, 31.0, 20.3.
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4-Chloro-N,3-dimethylbenzenamine (4g).21 The title compound was purified by flash silica-gel
column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Yellow oil; 79% yield
1
(62 mg); H NMR (500 MHz, CDCl3) δ 7.01 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.44
(dd, J = 8.3 Hz and 2.4 Hz, 1H), 2.80 (s, 3H), 2.27 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ
147.5, 133.9, 130.3, 123.1, 111.6, 110.4, 29.9, 17.9.
3-Methoxy-N-methylbenzenamine (4h).40 The title compound was purified by flash silica-gel
column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Yellow oil; 86% yield
(59 mg); 1H NMR (500 MHz, CDCl3) δ 7.10-7.05 (m, 1H), 6.28-6.15 (m, 3H), 3.78 (s, 3H), 2.81
(s, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 160.7, 150.7, 129.8, 105.6, 102.2, 98.2, 54.9, 30.5.
N,N-dimethyl-1-phenylethanamine (4i).3c The title compound was purified by flash silica-gel
column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Pale yellow oil; 81%
yield (60 mg); mp 143-144 oC; 1H NMR (500 MHz, CDCl3) δ 7.32-7.27 (m, 4H), 7.26-7.21 (m,
1H), 3.23 (q, J = 6.8 Hz, 1H), 2.19 (s, 6H), 1.36 (d, J = 6.8 Hz, 3H); 13C {1H} NMR (125 MHz,
CDCl3) δ 143.9, 128.1, 127.4, 126.8, 65.9, 43.1, 20.1.
Adamantan-1-yl-dimethyl-amine (4j).41 The title compound was purified by flash silica-gel
column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Yellow oil; 84% yield
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(75 mg); 1H NMR (500 MHz, CDCl3) δ 2.18 (s, 6H), 1.99 (s, 3H), 1.61-1.55 (m, 9H), 1.53-1.48
(m, 3H); 13C {1H} NMR (125 MHz, CDCl3) δ 53.5, 38.0, 37.1, 36.9, 29.6.
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2-Methyl-1,2,3,4-tetrahydroisoquinoline (4k).3c The title compound was purified by flash
silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); White solid;
87% yield (64 mg); mp 121-122 oC; 1H NMR (500 MHz, CDCl3) δ 7.13-7.11 (m, 3H), 7.03-7.01
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(m, 1H), 3.58 (s, 2H), 2.93 (t, J = 6.0 Hz, 2H), 2.69 (t, J = 6.0 Hz, 2H), 2.46 (s, 3H); C {1H}
NMR (125 MHz, CDCl3) δ 134.9, 133.9, 128.7, 126.5, 126.2, 125.7, 58.1, 53.1, 46.3, 29.4.
1-Methyl-4-(3-(1-methylpiperidin-4-yl)propyl)piperidine (4l).3c The title compound was
purified by flash silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v =
1
100/1); Yellow oil; 85% yield (101 mg); H NMR (500 MHz, CDCl3) δ 2.68 (d, J = 11.6 Hz,
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4H), 2.10 (s, 6H), 1.73 (t, J = 11.4 Hz, 4H), 1.51 (d, J = 11.2 Hz, 4H), 1.20-1.00 (m, 12H); C
{1H} NMR (125 MHz, CDCl3) δ 56.0, 46.5, 36.7, 35.1, 32.4, 23.8.
1,4-Dimethylpiperazine (4m).3c The title compound was purified by flash silica-gel column
chromatography eluting with hexanes/ethyl acetate (v/v = 100/1); Colorless oil; 83% yield (47
mg); 1H NMR (500 MHz, CDCl3) δ 3.20-2.00 (m, 8H), 2.25-2.21 (m, 6H); 13C {1H} NMR (125
MHz, CDCl3) δ 55.2, 46.1.
Procedure for the N-methylation of 1a with CH3OD in aqueous solution catalyzed by a
water-soluble dinuclear Cp*Ir complex [(Cp*IrCl)2(thbpym)][Cl]2 (cat. 8) (Scheme 2,
(Eq.1)). To an oven-dried, 25 mL Schlenk tube were added 1a (0.5 mmol), cat. 8 (5.1 mg, 0.005
mmol, 1 mol %), KOH (28 mg, 0.5 mmol), CH3OD/H2O (v/v = 1/1, total volume: 1.2 mL). The
mixture of reaction was heated at 130 oC in an oil bath for 12 h. The reaction mixture was cooled
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to ambient temperature, concentrated in vacuo and purified by silica-gel flash column
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chromatography.
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PhNDCH3 (5).42 The title compound was purified by flash silica-gel column chromatography
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eluting with hexanes/ethyl acetate (v/v
=
100/1); Yellow oil; 82% yield (44 mg);
1H NMR (500 MHz, CDCl3) δ 7.24-7.20 (m, 2H), 6.74 (t, J = 7.4 Hz, 1H), 6.64 (d, J = 7.9 Hz,
2H), 2.85 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 149.2, 129.1, 117.1, 112.3, 30.6.
Kinetic Isotope Effect (KIE) Studies (Scheme 2, (Eq.2)): Parallel reactions for the N-
methylation were carried out using CH3OH/H2O = 1/1 (Total volume: 1.2 mL) and CD3OD/H2O
= 1/1 (Total volume: 1.2 mL) under identical conditions following the general procedure. And
the progress of the reaction was analysed by 1H NMR. All the reactions were repeated twice and
the average data were plotted as yield (%) vs time (h).
PhNDCD3 (6).42 The title compound was purified by flash silica-gel column chromatography
eluting with hexanes/ethyl acetate (v/v = 100/1); Yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.22-
7.18 (m, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.63 (d, J = 7.7 Hz, 2H); 13C {1H} NMR (125 MHz,
CDCl3) δ 149.2, 129.1, 117.2, 112.4, 29.6.
Competitive for the N-methylation of 1a: Reaction were carried out using CH3OH/CD3OD
(v/v = 1/1, total volume: 0.6 mL), H2O (0.6 mL) under identical conditions following the general
procedure. And the progress of the reaction was analysed by 1H NMR. The incorporation of zero,
1
one, two or three deuterium on the methyl of the product was determined by H NMR spectrum
of crude mixture according to the previous report.8
Procedure for large-scale N-methylation of amines with methanol in aqueous solution
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catalyzed by cat. 8 (Scheme 3). To an oven-dried, 250 mL Schlenk tube were added 1a (3.14
mg, 20 mmol), cat. 8 (204 mg, 0.2 mmol, 1 mol %), KOH (1.12 g, 20 mmol), MeOH/H2O = 1/1
(total volume: 30 mL). The mixture of reaction was heated at 130 oC in an oil bath for 12 h. The
reaction mixture was cooled to ambient temperature, concentrated in vacuo and purified by flash
silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v = 100/1) to afford the
corresponding product 2a (2.97 mg, 87% yield).
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Procedure for the synthesis of Loxapine (Scheme 4). To an oven-dried, 25 mL Schlenk tube
were added 2-chloro-11-(1-piperazinyl)dibenzo[b,f][1,4]oxazepine 7 (157 mg, 0.5 mmol), cat. 8
(5 mg, 0.005 mmol, 1 mol %), MeOH/H2O (v/v = 1/1, total volume = 1.2 mL). The mixture of
reaction was heated at 130 oC in an oil bath for 12 h. The reaction mixture was cooled to ambient
temperature, concentrated in vacuo and purified by flash silica-gel column chromatography to
afford the corresponding product 8.
2−Chloro−11−(4−methyl−1−piperazinyl)dibenz[b,f][1,4]oxazepine (8).43 The title compound
was purified by flash silica-gel column chromatography eluting with hexanes/ethyl acetate (v/v =
1
50/1); Yellow solid; 73% yield (120 mg); mp 109-110 °C; H NMR (500 MHz, CDCl3) δ 7.33
(dd, J = 8.7 Hz and 2.5 Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.14 (d, J = 8.5 Hz, 2H), 7.10-
7.05 (m, 2H), 6.99-6.94 (m, 1H), 3.53 (bs, 4H), 2.50 (bs, 4H), 2.33 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 159.1, 158.8, 151.7, 140.0, 132.4, 130.1, 128.9,
127.0, 125.7, 124.9, 124.4, 122.6, 120.0, 54.7, 47.2 (bs), 46.0.
■ ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.
1H NMR and 13C NMR spectra of the products (PDF)
■AUTHOR INFORMATION
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Corresponding Author
*E-mail: fengli@njust.edu.cn.
ORCID
Feng Li: 0000-0003-3288-4069
Author Contributions
§ C. M. and P. L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGEMENTS
Financial support from the National Natural Science Foundation of China (21272115), the
Natural Science Foundation of Jiangsu Province (BK20161494) and the State Key Laboratory of
Fine Chemicals (KF1704) is greatly appreciated.
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as the catalyst capable of reversible H2 storage using CO2 in aqueous media under mild
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temperatures and pressures, see: Hull, J. F.; Himeda, Y.; Wang, W.; Hashiguchi, B.; Periana, R.;
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