Air-tolerant direct reductive N-methylation of amines using formic acid via simple inorganic base catalysis

Article abstract of DOI:10.1016/j.cclet.2019.04.064

The construction of N-methyl amine moieties is an important reaction that has found numerous applications. Development of new methylation agents that are more environmentally benign than classical agents, such as iodomethane and methyl sulfate, is still highly desirable. Herein, we report a convenient protocol for direct reductive N-methylation of amines using formic acid as the methylation agent via simple inorganic base catalysis. The present protocol operates under transition-metal-free and air-tolerant conditions. Both the catalyst, K₂HPO₄, and the reductant, polymethylhydrosiloxane (PMHS), are cheap and easily separable from the crude reaction product mixture. Mechanistic investigations suggest that the reaction occur through the formation of an acetal intermediate followed by the C–N bond formation.

Full text of DOI:10.1016/j.cclet.2019.04.064

Accepted Manuscript
Title: Air-tolerant direct reductive N-methylation of amines
using formic acid via simple inorganic base catalysis
Authors: Yan Huang, Wei Deng, Bo-Lin Lin
PII:
DOI:
Reference:
S1001-8417(19)30235-9
https://doi.org/10.1016/j.cclet.2019.04.064
CCLET 4957
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
29 January 2019
22 March 2019
28 April 2019
Please cite this article as: Huang Y, Deng W, Lin B-Lin, Air-tolerant direct reductive
N-methylation of amines using formic acid via simple inorganic base catalysis, Chinese
Chemical Letters (2019), https://doi.org/10.1016/j.cclet.2019.04.064
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Communication
Air-tolerant direct reductive N-methylation of amines using formic acid via simple
inorganic base catalysis
Yan Huanga, Wei Denga,*, Bo-Lin Linb*
a School of Chemical and Environmental Engineering, Shanghai Institute of Technology, Shanghai 201418, China
b School of Technology and Physical Science, ShanghaiTech University, Shanghai 201210, China
 Corresponding authors.
E-mail addresses: linbl@shanghaitech.edu.cn (B. Lin), wdeng@shu.edu.cn (W. Deng)
Graphical Abstract
We report a convenient protocol for direct reductive N-methylation of amines using formic acid as the methylation agent via
simple inorganic base catalysis.
ARTICLE INFO
ABSTRACT
Article history:
The construction of N-methyl amine moieties is an important reaction that has found numerous
applications. Development of new methylation agents that are more environmentally benign
than classical agents, such as iodomethane and methyl sulfate, is still highly desirable. Herein,
we report a convenient protocol for direct reductive N-methylation of amines using formic acid
as the methylation agent via simple inorganic base catalysis. The present protocol operates under
transition-metal-free and air-tolerant conditions. Both the catalyst, K2HPO4, and the reductant,
polymethylhydrosiloxane (PMHS), are cheap and easily separable from the crude reaction
product mixture. Mechanistic investigations suggest that the reaction occur through the
formation of an acetal intermediate followed by the C-N bond formation.
Received 29 January 2019
Received in revised form 22 March 2019
Accepted 3 April 2019
Available online
Keywords:
Air-tolerant
N-Methylation
Formic acid
Simple inorganic bas
Transition-metal-free
N-Methylation of amines is one of the most important
synthetic reactions of fine chemicals, agricultural chemicals,
drugs and dyes [1],[2]. N-Methyl amines are a structural subunit
that can be found in many significant bioactive compounds and
drugs [3],[4]. In particular, the lipid solubility and permeability
in human bodies for pharmaceuticals can be improved upon the
methylation [5],[6]. In Fig. 1, some examples of important
bioactive compounds containing N-methyl subunit are shown.
Classical methods to install N-methyl group include direct
N-methylation using iodomethane or methyl sulfate and
Eschweiler-Clarke reaction, where formaldehyde serves as the
C1 source. Replacement of these toxic classical methylation
agents by safer alternatives has been long pursued. Formic acid,
methanol [7] and CO2 has recently emerged as new methylation
agents. Formic acid is a cheap, readily available chemical with
wide industrial applications, such as pesticide, medicine, printing
and dyeing [8], and emerging application as a hydrogen storage
chemical [9], [10]. Formic acid can be prepared from
hydrogenation [11]-[13] or electrochemical reduction [14] of
CO2. As such, methylation with formic acid as the C1 source is
often considered as an indirect utilization of CO2. However,
compared to the intense research efforts devoted to CO2 as the
methylation agent [15],[16], much less progress has been
achieved for the counterpart using formic acid.

Fig. 1. Several important compounds containing N-methyl moieties
in their structure.
Our study commenced with the methylation of N-
methylaniline with formic acid as C1 source. Nine different
hydrosilanes were screened for the reaction initially with a 10
mol% of K3PO4 as the catalyst and a 20 mol% of 18-crown-6 as
the additive (Table 1, entries 1-9). Most of the silanes led to the
desired product. Higher yields were observed for silanes with
less bulkiness or hydrosiloxanes. Encouragingly, PMHS is one of
the best among them (entry 8). Next, a few different inorganic
salts were further screen to improve the yield for the reaction
using PMHS as the reductant (entries 10-18). The yields vary
significantly with the basicity of the salts. To our delight, a 60%
yield was achieved with a moderate base, K2HPO4, as the
catalyst (entry 12), suggesting that it should be important to have
the just-right basicity to activate the hydrosilane. Various
reaction conditions, including the loading of the catalyst, reaction
temperature, reaction time and the solvent (Table S1-S4 in
Supporting information), were also screened. The optimized
conditions were identified as below: 4.6 equiv. of formic acid, 4
equiv. of PMHS, 10 mol% K2HPO4, 20 mol% 18-crown-6, 4 Å
Both homogeneous and heterogeneous catalyst have been
developed for the few known examples of N-methylation of
amines with formic acid as C1 resource. The first example was
reported in 2014. The employment of Pt/dppp [dppp =
bis(phenylphoshino) propane] led to catalytic methylation of
amines using phenylsilane as a reductant [17]. Later on, a further
example with Ru/triphos as the catalyst and methanesulfonic acid
as an additive was reported, in which an excess amount of formic
acid was used as both C1 resource and reductant [18]. A
heterogeneous catalytic system with Pt/C has been developed
using phenylsilane as the reductant [19]. Besides catalysts using
noble metals, copper acetate has also been shown as an effective
catalyst with phenylsilane as the reductant [20]. To date, Fu and
Shang et al. reported the only transition-metal-free protocol
using B(C6F5)3 as the catalyst and PMHS as the reductant under
air-free conditions [21]. PMHS is a waste product of silicon
industry [22]. Compared to other reductants [23][25], it is a
cheap, non-toxic, and aerobically stable reductant suitable for
large-scale production [26][27]. Therefore, it is of practical
significance to achieve the methylation reaction using PMHS
instead of phenyl silane.
o
molecular sieves as an additive, THF (2mL) as the solvent, 80 C
for 12 h.
Table 2
N-Methylation of various amines with formic acid to form tertiary
amines.a
Herein, we report that simple inorganic salt, K2HPO4, can also
catalyse the methylation of a range of amines using formic acid
as the C1 source and hydrosilanes, especially PMHS, as the
reductant under mild air-tolerant reaction conditions.
Mechanistic studies suggest that the reaction occur through an
acetal intermediate rather an amide intermediate.
Entry
1
Substrate
Product
Yield (%)b
61
Table 1
2
3
4
5
6
88
87
84
76
71
Catalytic N-methylation of N-methylaniline using formic acid. a
Entry
Catalyst
Silane
T (oC)
80
Yield
(%)b
27
1
2
K3PO4
K3PO4
PhSiH3
Bis(trimethylsiloxy)meth 80
ylsilane
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
KF
(CH3)2HSiOSiH(CH3)2
(C2H5)3SiH
Ph2SiH2
Ph3SiH
(C2H5O)3SiH
PMHS
(C2H5O)2CH3SiH
PMHS
PMHS
PMHS
PMHS
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
16
1
17
1
33
32
39
24
14
60
31
5
7
8
30
60
CsF
K2HPO4
KH2PO4
K2CO3
KOtBu
Cs2CO3
KOH
9
33
45
PMHS
PMHS
PMHS
PMHS
7
10
24
12
48
18
Na2HPO4
PMHS
a
11
12
55
45
Reaction conditions: N-methylaniline (0.25 mmol), silane (4
equiv.), catalyst (10 mol%), HCO2H(4.6 equiv.), 4Å MS (10 mg),
18-crown-6 (20 mol%), solvent (2.0 mL), 80 oC, 12 h.
b
Determined by GC analysis. Anisole was used as an internal
standard.

13
14
85
88
including 2-fluorobenzaldehyde (entry 7) and 3,5-bis (tert-butyl)
benzaldehyde (entry 8), were demonstrated. Unfortunately, the
present protocol is not yet applicable to primary aliphatic amines
due to the formation of tertiary amines via fast dialkylation with
the aldehyde. But by reacting aliphatic aldehyde with aniline, the
target product can be obtained (entries 9 and 10). This allows us
to prepare methylation products containing straight chains.
a
Reaction conditions: N-methylaniline (0.25 mmol), silane
(4equiv.), catalyst (10 mol%), HCO2H (4.6 equiv.), 4Å MS (10 mg),
18-crown-6 (20 mol%), solvent (2.0 mL), 80 oC, 12 h.
b The yields of the isolated products are reported.
Next, we studied the potential reaction mechanism for the
present catalytic system. Two possible pathways can be
envisioned (Scheme 2). In pathway (B), dehydrogenative
coupling between formic acid and hydrosilane occurs first to
afford silyl formate. Reduction of the formate can lead to the
corresponding acetal, which can react with amine for C-N bond
formation. Subsequent reduction generates the final product. In
pathway (B), dehydrative condensation between formic acid and
amine occurs first to form the corresponding formamide. Tandem
reductions of the amide and the corresponding imine then afford
the final product. Whether C-N bond formation takes place
before the reduction or not is the key difference among the
mechanisms. Since no reaction was observed for N,N'-formyl,
methylaniline under the present optimized catalytic conditions
(Eq 1), pathway (B) is clearly ruled out. We next carried out a
reaction between formic acid and PMHS in the absence of N-
methylaniline, which led to the formation of a mixture of silyl
formate and acetal as expected for pathway (A). The addition of
N-methylaniline to such a mixture resulted in the disappearance
of the acetal and the formation of the product (Figs. S3-S5 in
Supporting information). As such, path (A) is the preferred
reaction mechanism for the present catalytic system.
With the optimized conditions in hand, we next explored the
scope of secondary amines for the reaction (Table 2). In general,
good yields were obtained for aniline derivatives with various N-
substituted alkyl groups (entries 1-5). In particular, the good
tolerance of isopropyl and cyclohexyl indicates that the present
protocol has
a moderate tolerance of steric hindrance.
Encouragingly, several synthetically useful functional groups,
including olefinyl, chloro, bromo, nitro and cyano, were also
tolerated by the present method (entries 6, 8-13). Unfortunately,
for substrates with a strong electron-donating group, such as
methoxy, N-formylated product was observed instead of the
desired methylated one (Fig. S1 in Supporting information),
suggesting that the present protocol is sensitive to the basicity of
the amine. The significantly lower yield of diphenylamine
relative to N-benzyl aniline further suggests that such as basicity
should not too weak. As such, only the N-formylated product
was observed for aliphatic amines (Fig. S2 in Supporting
information) It should be noted that N-formylated amines are
desirable synthetic targets [28][30].
To test the scalability of the present methodology, a gram-
scale reaction was also carried out for N-methylaniline (Scheme
1). The obtained isolated yield is close to that of its smaller-scale
counterpart.
Table 3
Indirect N-methylation of primary amines using formic acid and
aldehyde. a
Entry
1
Substrate
Product
Yield (%)b
59
Scheme 1. A gram-scale reaction of N-methylaniline.
2
3
4
5
59
30
52
54
All our efforts to directly methylate primary amines with
present protocol failed. An in situ reductive amination with
aldehyde followed by trifluoroethylation with trifluoroacetic acid
leading to dialkylation of primary amines was reported recently
[31]. We applied the same strategy for primary amines and
successful achieved a 59% yield for the desired product using
aniline and benzaldehyde as model substrates (Table 3, entry 1).
Due to the limited commercial availability of primary aniline
derivatives, the scope of the present protocol was only probed
preliminarily. Under the assistance of benzaldehyde, it was found
that moderate yields can be obtained in general for substrates
with para-chloro, bromo, methoxy and trifluoromethyl groups,
showing a better tolerance of electronic properties than that for
the direct N-methylation of secondary amines (vide supra).
Encouragingly, trimethylaniline is also a suitable substrate (entry
6), indicating that the present protocol is fairlly sterically tolerant.
Further experiments prove that the assisting aldehyde can be
expanded to substrates other than benzaldehyde. Two examples,
6
7
43
42

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acid as the methylation agent and PMHS as the reduct-ant via simple
inorganic base catalysis. Both the catalyst and the reductant are
cheap and easily separable from the crude reaction product mixture,
providing a convenient new tool for syntheses of N-methylated
amines.
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We acknowledged the financial support by the National
Natural Science Foundation of China (No. U1532135).
References