Reductive: N -methylation of quinolines with paraformaldehyde and H2 for sustainable synthesis of N -methyl tetrahydroquinolines

Article abstract of DOI:10.1039/c8cc10309g

A new and straightforward method was developed for the synthesis of N-methyl-1,2,3,4-tetrahydroquinolines by one-pot reductive N-methylation of quinolines with paraformaldehyde and H₂ over Pd/C catalyst. A series of functional MTHQs, including (±)-galipinine and (±)-angustrureine were successfully synthesized in good to excellent yields by applying this simple catalyst system.

Full text of DOI:10.1039/c8cc10309g

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Reductive N-methylation of Quinolines with Paraformaldehyde
and H for Sustainable Synthesis of N-methyl
2
Tetrahydroquinolines
Received 00th January 20xx,
Accepted 00th January 20xx
Hongli Wang, Yongji Huang, Qi Jiang, Xingchao Dai and Feng Shi*a
a
a
a
a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new and straightforward method was developed for the
Due to their significance, extensive efforts have been paid to
synthesis of N-methyl-1,2,3,4-tetrahydroquinolines by one-pot develop effective synthetic methodologies for the preparation
reductive N-methylation of quinolines with paraformaldehyde and of MTHQs over the past few decades. Traditionally, THQs are
2
H over Pd/C catalyst. A series of functional MTHQs, including (±)- usually employed as starting materials for the synthesis of
9
-
2
Galipinine and (±)-Angustrureine were successfully synthesized in MTHQs with a variety of methylating agents, such as MeX, CO ,
1
4
15,16
17,18
19
good to excellent yields by applying this simple catalyst system.
dimethylcarbonate (DMC),
HCOOH,
HCHO, and
others.20 Although a number of above methods have been
established, there is still room for the development of facile,
straightforward procedures toward MTHQs.
1
,2,3,4-Tetrahydroquinolines (THQs) derivatives are valuable
backbones in natural alkaloids and are widely utilized in fine
chemicals, pharmaceuticals, agrochemicals, dyes, fragrances,
It is well-known that the reduction of quinolines is one of the
1
,2
and hydrogen-storage materials. Among these, the N-methyl
substituted ones are especially attractive and powerful motifs
of biologically active molecules and pharmaceuticals because
the incorporation of methyl group into molecules is of
significant importance to regulate their biological and
2, 21
most commonly used approaches to synthesize THQs.
Thus,
direct N-methylation of readily available quinolines offers a
straightforward and promising approach to access MTHQs in
term of its simplicity and high step efficiency. To date, however,
only a few catalytic systems dealing with N-methylation of
quinolones have been reported. In 2009, Perumal and co-
3
,4
pharmaceutical
activities.
For
example,
N-
methyltetrahydroquinoline (MTHQ) motif is observable in many
natural alkaloids such as angustureine, galipeine, galipinine and
cuspareine, which displayed excellent antiplasmodial and
workers demonstrated that reaction of quinoline and CH
3
I with
Hantzsch dihydropyridine ester could be used for the synthesis
22
of MTHQs. Recently, Han and co-workers developed a nice
method for the N-methylation of quinolines with CO /H as
methylating agent using a homogeneous Ru/triphos catalyst
5
-8
cytotoxic activity (Scheme 1).
2
2
2
3
system.
Compared with the homogeneous catalysts,
OH
N
N
heterogeneous counterparts can be more facilely separated
and recycled. Till now, only one example of N-methylation of
quinoline with methanol was reported using zinc as a reductant
Me
Me
OMe
(-)-Angustrureine
(-)-Galipeine
o
24
in the presence of Pd/C catalyst at 150 C. However, the
employment of zinc as a reductant and rigorous reaction
conditions significantly reduced the appeal of this method in
industrial applications. Therefore, the development of
straightforward, facile, cost-effective heterogeneous catalyst
system for the N-methylation of quinolines under mild
conditions is highly demanded. Herein, we describe the first
OMe
OMe
O
O
N
N
Me
Me
(-)-Galipinine
(-)-Cuspareine
Scheme 1 Several examples of pharmaceuticals containing a MTHQ motif.
examples
of
N-methylation
of
quinolines
with
paraformaldehyde and H
2
in the presence of a simple Pd/C
a. State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou730000, China.
University of Chinese Academy of Sciences, No. 19A, Yuquanlu, Beijing 100049,
catalyst (Scheme 2). Two main steps were involved in the
reaction. The first step is the catalytic hydrogenation of
quinoline to THQ, and the second step is the reductive N-
b.
P.R. China.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
2
5
methylation of THQ to N-methyl MTHQ. The Pd/C catalyst is
This journal is © The Royal Society of Chemistry 20xx
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crucial to realize the whole reaction. The one-pot reductive N- quinoline with 96% yield for N-methyltetrahydroqVuieiwnAorltiicnleeOwnlianes
methylation of quinolines avoids the synthesis of THQ, so it is maintained when it was used at the 3rd rDuOnI:(1e0n.1t0ry399/C).8TChCu1s0,30th9iGs
simpler and more economic.
catalyst exhibits nice reusability. Meanwhile, the Pd loadings of
Pd/C before and after recycling were tested by ICP-AES. The
results suggested that the Pd loadings decreased from 2.46 wt%
st
to 2.38 wt% after the 1 run, then it maintained stable after the
rd
2
run (2.12 wt%, Table S1).
Table 1 Reaction condition optimization for reductive N-methylation of quinoline with
a
HCHO/H
2
Cat. H2 (1.0 MPa)
+
(HCHO)n
solvent, 100 oC, 12 h
N
N
1a
2a
3a
b
Entry
Cat.
Pd/TiO
Pd/TiO
Pd/TiO
Pd/TiO
Pd/C
Solvent
1,4-dioxane
toluene
MeOH
EA
Conv. (%)
Yield (%)
1
2
3
4
5
6
7
2
2
2
2
52
55
43
89
99
80
n.r.
99
41
43
34
85
97
69
--
EA
EA
EA
EA
EA
EA
EA
2
Pd/γ-Al O
3
Pd/SiO
Pd/C
Pd/C
Pd/C
Pd/C
2
Scheme 2 Reductive N-methylation of quinolines to MTHQs.
8
9
c
98
98(96)
d
e
e
99(99)
82
87
1
0f
1g
69
77
We began our exploration with reductive N-methylation of
1
quinoline with paraformaldehyde and H
2
as the model reaction
(Table 1). The catalysts used here were prepared by a
a
Reaction conditions: quinoline 1a (1.0 mmol), paraformaldehyde 2a (1.2 mmol),
o
b
deposition−precipitation method and followed by reduction catalyst (40 mg ), H
2
(1.0 Mpa), solvent (4.0 mL), 100 C, 12 h. Determined by GC-
c
2 2
H H (0.4 MPa).
(0.7 MPa). d
FID using biphenyl as the internal standard material.
with hydrazine hydrate solution. Prompted by our reductive N-
monomethylation of nitroarene and formaldehyde using
e
f
g
The catalyst was recovered and reused at the 3rd run. (0.2 MPa). 9 h.
2
6
2
Pd/TiO as catalyst, the reductive N-methylation reaction was
The supported Pd catalysts were characterized by XPS, XRD,
TEM and N adsorption−desorption instruments to reveal their
2
structures. Firstly, the XPS studies of the catalysts were
performed to determine the chemical state of Pd nanoparticles.
As shown in Fig. 1a and Fig. S1, weak peaks of Pd 3d5/2 were
initially investigated with quinoline and the paraformaldehyde
in the presence of 40 mg 2 wt% Pd/TiO
2
under 1.0 MPa H
2
in
o
1
,4-dioxane at 100 C. To our delight, 52% conversion with 41%
yield for N-methyl-1,2,3,4-tetrahydroquinoline was obtained
entry 1). The influence of the solvent on the reactivity and
(
found in Pd/TiO
fresh Pd/C, which might be attributed to the low Pd content on
the catalyst surface. The Pd 3d5/2 signals of Pd/TiO , Pd/Al
and Pd/SiO appeared at 335.0, 335.3, and 335.9 eV,
respectively. These results suggested that metallic Pd was
mainly formed on the surface of Pd/TiO , Pd/Al , and Pd/SiO
Besides, the N1s spectra at 400.1 eV and the Pd 3d5/2 signals at
36.3 eV, which were usually assigned to N-coordinated
2 2 3 2
, Pd/Al O , and Pd/SiO but not observable in
selectivity of this reaction was further evaluated (entries 2−4).
It was discovered that EA was the optimal choice and much
higher conversion (89%) of quinoline and 85% yield to N-
methyltetrahydroquinoline were obtained when EA was used as
the solvent. Following, the catalytic performance of nano-Pd
catalysts with different supports was tested (entries 5−7).
Clearly, Pd/C exhibits the best catalytic performance, achieving
2
2 3
O ,
2
2
2
O
3
2
.
3
9
(
9% conversion with 97% yield towards the desired product.
entry 5). The excellent performance of this catalyst might be
attributed to the π-π interaction between π electron of active
2
9
metallic Pd, can be observed after recycling of the Pd/C
catalyst (Fig. S1-2). Therefore, we speculated that the N-
coordinated Pd might be the active species in-situ generated
during the reaction.
Moreover, the XRD patterns of the catalysts are shown in Fig.
2
b and Fig. S3. The Pd/C and Pd/SiO catalyst shows diffraction
peaks at 40.1°, 46.7°, 68.1°, and 82.1°, which can be ascribed to
the diffraction peaks of Pd(111), Pd(200), Pd(220), Pd(311).
However, neither palladium oxide nor metallic palladium
2
7,28
carbon and aromatic ring of quinolone.
If other catalysts
including Pd/γ-Al , and Pd/SiO were employed, lower
O
2 3
2
conversion or no conversion of quinoline was observed.
Interestingly, 99% conversion with 98% yield to methylated
2
product was still observed if reducing the H
MPa, affording the desired product in 89% isolated yield (entry
). However, conversion decreased from 99% to 82% if further
reducing of the H pressure to 0.2 MPa (entry 10). Furthermore,
2
pressure to 0.4
9
2 2 3
diffraction pattern was detectable in Pd/TiO and Pd/γ-Al O
2
catalysts (Fig. S3). So, the Pd species in these catalysts were
amorphous or highly dispersed. Compared with fresh Pd/C, the
intensity of the diffraction peaks of reused samples increases
somewhat, indicating a slight increase in the crystalline order.
reducing the reaction time led to a lower conversion and yield
to desired product (entry 11). Notably, this catalyst is easily
recoverable by simple filtration, and it can be reused directly
without further treatment. To our delight, a 99% conversion of
2
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producing the desired product in 88% yield (3a). Reductive N-
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DOI: 10.1039/C8CC10309G
methylation of electron rich methyl- and -methoxy substituted
quinolines proceeded smoothly to provide the corresponding
products in 72-84% yields (3b−3f). Electron-deficient
nitroarenes bearing fluoride and ester groups also proceeded
well, affording their corresponding products in 82% and 77%
yields, respectively (3g−3h). In addition, the fused-ring acridine
was also successfully converted to the corresponding N-
methylated product in 81% yield (3i). Gratifyingly,
Fig. 1 XPS spectra of fresh and reused Pd/C (a). XRD patterns of fresh and reused benzoquinoline led to the corresponding product in decent
Pd/C (b).
yield, too (3j). Only 8% GC yield of N-methylpiperidine was
observed when pyridine was used as substrate. Therefore, this
TEM and HAADF-STEM images of Pd/C before and after being
catalyst can not be applied in the reductive N-methylation of
used for 3 times, and their corresponding particle size
pyridine.
distributions are shown in Fig. 2. The TEM and HAADF-STEM
results revealed that the Pd nanoparticles are homogeneously
Table 2 Results of the N-monomethylation of quinolinesa
dispersed on carbon surface and possess an average diameter
of 1.0−2.5 nm and 1.0-3.0 nm in fresh and used Pd/C,
respectively. The slight increase in nanoparticle size does not
influence the catalytic performance remarkably. Compared
Pd/C, H2
R
+
(HCHO)n
R
N
N
Me
b
Entry
1
Substrates
Products
Yield (%)
with Pd/C, much bigger Pd nanoparticles were found on SiO
Fig. S4). The poor activity of Pd/SiO might be attributed to the
bigger Pd nanoparticle size, and more importantly, the weak
interaction between nan-Pd and the SiO The
adsorption−desorption tests (Fig. S5) showed that the BET
surface areas of the Pd/C, Pd/TiO , Pd/γ-Al , and Pd/SiO
2
(
2
89 (88%)c
N
N
3
a
Me
2
.
N
2
Me
Me
2d
3e
72
84
N
2
O
2 3
2
N
2
-1
3b Me
Me
were 198.49, 59.16, 146.66, 270.95 m g , respectively. Based
on the FT-IR analysis and Boehm titration results, lactone group,
which is 0.62 mmol/g, and carboxylic group, which is 0.27
mmol/g, were detectable on the carbon surface (Fig. S6).
Me
N
N
3
c
Me
Me
Me
4
5d
6
N
75
81
80
82
77
N
3d
Me
N
N
Me
3
Me
Me
e
MeO
MeO
N
N
3f
Me
F
F
7
N
N
3
g
Me
MeO2C
MeO2C
8
9
N
N
3h
Me
Fig.2 TEM (a, c) and HAADF-STEM (b, d) images of the fresh Pd/C (a, b), reused Pd/C (c,
d).
N
81
68
N
Me 3i
With these optimized conditions in hand, we proceeded to
examine the substrate scope of the Pd/C catalyst for the
reductive N-methylation reaction. As shown in Table 2, the
quinolines with both electron-withdrawing and electron-
donating groups on the phenyl ring were well tolerated under MPa), Ethyl acetate (4.0 mL), 100 C, 12 h. Isolated yields. Catalyst was
the current conditions. Importantly, the catalyst could be
reused for this reaction for at least three catalytic cycles
1
0e
N
N
3
j
Me
a
2
Quinolines (1.0 mmol), paraformaldehyde (1.2 mmol), Pd/C (40 mg), H (0.4
o
b
c
d
H
2 2
(0.4 MPa), 120 oC. Pd/C (80 mg), H
e
recovered and reused at the third run.
o
(0.4 MPa), 120 C, 24 h.
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H. Schönherr and T. Cernak, Angew. Chem. Int. EVdie.w,A2rt0ic1le3O,n5lin2e,
4
5
In addition, this reaction was easily performed with a gram-
scale and N-methyl tetrahydroquinoline was obtained in 81%
yield when 10 mmol (1.290 g) quinoline was used as the starting
material (Scheme 3). This result demonstrates the scalability of
this reaction.
1
2256-12267.
DOI: 10.1039/C8CC10309G
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+
(HCHO)n
EA, 100 oC, 12 h
N
N
Me
1.290 g
0.360 g
1.183 g, 81% yield
Scheme 3 The scaled-up reaction for synthesis of N-methyl tetrahydroquinoline
To demonstrate synthetic application, a concise and efficient
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0
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1
3 T. Toyao, S. M. A. H. Siddiki, Y. Morita, T. Kamachi, A. S.
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1
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EA, 100 oC, 12 h
N
R
N
R
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O
O
N
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1
N
Me
Me
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5
a ( +_ ) Galipinine
Yield: 74%
5b ( +_ ) Angustrureine
Yield: 83%
1
Scheme 4 Synthesis of THQ alkaloids (±)-Galipinine and (±)-Angustrureine
2
2
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2
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Financial supports from the NSFC (21802147, 21633013,
1745106), National Key Research and Development Program
2
2
2
9
of China (2017YFA0403100) and Key Research Program of
2
Frontier Sciences of CAS (QYZDJ-SSW-SLH051) are gratefully 28 D. Zhu, H. Jiang, L. Zhang, X. Zheng, H. Fu, M. Yuan, H. Chen
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acknowledged.
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0 G. Diaz-Muñoz, R. G. Isidorio, I. L. Miranda, G. N. de Souza Dias
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Conflicts of interest
There are no conflicts to declare.
Notes and references
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