Copper(II)-Catalyzed Selective Reductive Methylation of Amines with Formic Acid: An Option for Indirect Utilization of CO2

Article abstract of DOI:10.1021/acs.orglett.7b00551

A copper-catalyzed protocol for reductive methylation of amines and imine with formic acid as a C1 source and phenylsilane as a reductant is reported for the first time, affording the corresponding methylamines in good to excellent yields under mild conditions. This protocol offers an alternative method for indirect utilization of CO₂, as formic acid can be readily obtained from hydrogenation of CO₂.

Full text of DOI:10.1021/acs.orglett.7b00551

Letter
pubs.acs.org/OrgLett
Copper(II)-Catalyzed Selective Reductive Methylation of Amines with
Formic Acid: An Option for Indirect Utilization of CO2
Chang Qiao,† Xiao-Fang Liu,† Xi Liu,† and Liang-Nian He*,†,‡
†State Key Laboratory and Institute of Elemento-Organic Chemistry and ‡Collaborative Innovation Center of Chemical Science and
Engineering, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A copper-catalyzed protocol for reductive
methylation of amines and imine with formic acid as a C1
source and phenylsilane as a reductant is reported for the first
time, affording the corresponding methylamines in good to
excellent yields under mild conditions. This protocol offers an
alternative method for indirect utilization of CO2, as formic
acid can be readily obtained from hydrogenation of CO2.
Scheme 1. Reductive N-Alkylation of Amines with
Carboxylic Acid
ethyl-substituted amines have found wide applications in
pharmaceuticals, agrochemicals, dyes, and materials.1
M
Thus, the methylation of amines is of high interest in both
academia and industry.2 Recently, methodologies for N-
3
methylation of amines using CO2 as methylating agent has
been flourished due to its abundant, cheap, and nontoxic
characters. As an easily available C1 source, formic acid can be
prepared from CO2 through catalytic hydrogenation.4 In this
perspective, methylation with formic acid as C1 synthon can be
considered as indirect utilization of CO2, thus providing an
alternative synthetic method and promising field for CO2
chemistry.
Seminal work on N-methylation of amines with formic acid
as C1 source and hydrosilane as a reductant was reported in
2014 by utilizing Pt/dppp [dppp = bis(phenylphoshino)-
propane] at room temperature.5 Soon after, a broad range of
alkylated secondary and tertiary amines has been obtained by
N-alkylation of amines with carboxylic acid using similar
platinum/diphosphine-based catalyst in the range of room
temperature to 120 °C.6,7 Since then, other metal catalysts
including Ru,8 Rh,9 Ir,10 and heterogeneous Pt/C11 have
successfully been developed to promote this C−N bond
formation reaction employing hydrosilane as reductant.
Notably, borane i.e. B(C6F5)3 serving as an metal-free catalyst
has also been demonstrated to be effective.12 Furthermore, the
Ru/triphos [triphos = 1,1,1-tris(diphenylphosphinomethyl)-
ethane] system is also proven efficient for N-alkylation of
amines with different kinds of carboxylic acids as alkylating
agents and H2 (60 bar) as reductant at 160 °C.13 On the other
hand, it should be noted that Eschweiler−Clarke reaction
(reductive amination using excess formaldehyde as C1 source
and formic acid as reductant) has been reported to obtain N-
methylamines,14 which is quite different from the above-
mentioned reaction with formic acid as C1 source and
hydrosilane or hydrogen molecule as reductant.
with complicated ligands. Thus, the development of easily
available and cost-effective catalysts especially based on non-
noble metal under mild conditions is highly desirable but still
remains a challenge. Herein, we report Cu(OAc)2 as a robust
catalyst for efficient N-methylation of amines/imine with
formic acid as renewable C1 building block and phenylsilane
as reductant at 80 °C.15 Copper salts with oxygen/fluoride-
containing anion show good selectivity toward methylamines,
while copper halides (halogen = Cl, Br, I) exhibit high
exclusivity for formamides. To the best of our knowledge, this is
the first example that non-noble metal catalyst is applied to N-
methylation of amines using formic acid and hydrosilane.
Our study commenced with the methylation of N-methylani-
line (1a) with formic acid as C1 source and phenylsilane as
reductant at 80 °C as listed in Table 1. In the absence of any
catalyst, N-methylformanilide (2a) was obtained in 32% yield
(entry 1). Cu(OAc)2 showed excellent activity and exclusive
formation toward N,N-dimethylaniline (3a) (entry 2), while
Despite the achievements in this field as shown in Scheme 1,
Received: February 25, 2017
most of the reported catalysts are mainly based on noble metals
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00551
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Letter
a
With the optimal conditions in hand, we evaluated the scope
of this newly established Cu-catalyzed N-methylation protocol.
As shown in Scheme 2, the reaction of para-substituted N-
Table 1. Screening of Various Non-noble Metal Salts
Scheme 2. N-Methylation of Various Amines with Formic
Acid and PhSiH3*
b
b
entry
catalyst
Cu(OAc)2
conv (%) yield of 2a (%) yield of 3a (%)
1
2
3
4
5
6
7
8
32
>99
50
32
0
0
c
99 (97)
Fe(OAc)2
Co(OAc)2
Ni(OAc)2
Zn(OAc)2
Cu(NO3)2·2.5H2O
CuSO4·5H2O
Cu(acac)2
Cu(OTf)2
CuF2
50
48
73
99
73
58
19
0
0
48
0
76
2
>99
97
0
22
>99
>99
>99
>99
75
40
d
9
76
10
11
12
13
14
15
99
0
99
CuCl2
74
83
70
66
0
0
CuCl
83
0
CuBr
70
0
0
CuI
66
e
c
16
Cu(OAc)2
>99
99 (98)
a
Unless otherwise specified, all the reactions were performed with 1a
(0.5 mmol), HCOOH (1.5 equiv), PhSiH3 (3.0 equiv), catalyst (5 mol
b
%), nBu2O (1.0 mL), 80 °C, 12 h, argon atmosphere. Determined by
c
GC using 1,3,5-trimethoxybenzene as an internal standard. Isolated
yield of 3a. acac = acetyl acetonate. Open air in 10 mL flask.
d
e
*
Reaction conditions: secondary amine (0.5 mmol), HCOOH (1.5
equiv), PhSiH3 (3.0 equiv), Cu(OAc)2 (5 mol %, 4.6 mg), nBu2O (1.0
mL), 80 °C, 8 h. Primary amine (0.2 mmol), HCOOH (2.5 equiv),
PhSiH3 (6.0 equiv), Cu(OAc)2 (5 mol %, 1.9 mg), nBu2O (1.0 mL),
other metal acetates including Fe(OAc)2, Co(OAc)2, Ni-
(OAc)2, and Zn(OAc)2 could only result in the formation of
formamide 2a (entries 3−6), indicating the obvious superiority
of copper salt for this N-methylation reaction, which may be
attributed to the compatibility of the newly formed copper
hydride with acidic system. Subsequently, the influence of
anions were evaluated, and only the ones containing oxygen,
including Cu(NO3)2·2.5H2O, CuSO4·5H2O, Cu(acac)2, and
Cu(OTf)2 (entries 7−10), could promote the N-methylation.
CuF2 also allowed the reaction to afford quantitative yield of 3a
successfully (entry 11). This may be because the oxygen-16 or
fluoride-containing3f,17 anion could activate the hydrosilane via
the interaction of oxygen or fluoride with silicon. This is in
sharp contrast with that of CuCl2 or CuX (X = Cl, Br, I), which
only led to the formation of 2a with high selectivity. It may be
explained that halide has no facilitation for copper hydride
generation, thus forbidding the following-up reduction and
terminating the reaction at formamide 2a (entries 7−10 vs 12−
15). Even at 60 °C, Cu(OAc)2 could still give 84% yield of 3a
and was more active than Cu(OTf)2 (OTf = trifluorometha-
nesulfonate) and CuF2 (Table S3). Notably, this protocol was
air-tolerant (entry 16).
Miscellaneous parameters were intensively screened on the
reaction outcome. Among the hydrosilanes tested in Table S5,
only phenylsilane allowed this reaction to proceed smoothly
(Table S5, entry 2), being consistent with reducing ability of
hydrosilanes tested.12a,18 Non- and low-polar solvents such as
toluene and ethers were favorable solvents for this methylation
reaction (Table S4, entries 1−4) compared with polar solvents
such as DMF (N,N-dimethylformamide) and acetonitrile
(Table S4, entries 5 and 6). Such a solvent effect may be
attributed to the relative stability of the copper hydride species
in ether and arene solvent.19 In addition, the N-methylation
reaction was completed within 8 h (Figure S1).
a
b
80 °C, 16 h. Isolated yield. Yield was determined by 1H NMR using
1,3,5-trimethoxybenzene as an internal standard.
methylanilines proceeded smoothly to deliver N,N-dimethylani-
line derivatives in high to excellent yields (3b−d). However, N-
methyl-4-nitroaniline was unreactive with almost full recovery
of the substrate, probably due to the strong electron-
withdrawing effect. N-Ethyl-, N-isopropyl-, and N-benzylani-
lines were successfully methylated with formic acid (3f−h), but
the amine with bulky group showed lower reactivity (3g)
ascribed to the steric hindrance. N-Substituted anilines with
alkenyl or hydroxyl were transformed into the corresponding
methylated products with the sensitive group intact, showing
good functional group compatibility (3i,j). This protocol was
also applicable to aliphatic amines such as piperidine and
morpholine (3k,l). In addition, primary amines worked in a
fashion similar to that for secondary amines, resulting in the
dominant formation of dimethylated products by increasing the
amount of hydrosilane and doubling the reaction time (3m−p).
However, monomethylated byproducts were inevitably present,
which led to low yield of dimethylated products (see the
Supporting Information (SI)). Notably, imine benzylidene
phenylamine is a suitable substrate for this Cu-catalyzed
methylation protocol to afford the corresponding N-methylated
amine in 82% yield (Scheme S1). Furthermore, a gram-scale
experiment of 1a (10 mmol, 1.0707 g) results in 86% isolated
yield of 3a, which shows the practicality of this methodology on
a gram scale (see the SI).
Several control experiments were conducted as shown in
Scheme 3 to probe the reaction mechanism. Initially, N-
methylformanilide (2a) was tested under the optimized
reaction conditions, and only 9% yield of N,N-dimethylaniline
B
DOI: 10.1021/acs.orglett.7b00551
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Letter
the presence of hydrosilane to furnish the methylation product
G through reductive amination. On the other hand, D is
reduced by hydrosilane to regenerate the copper hydride B to
finish the catalytic cycle. This path is deemed as the major one
because a nearly quantitative yield of N,N-dimethylaniline (3a)
was obtained when paraformaldehyde was employed (Scheme
3, eq 3). Path II explains the formation of formamide H, which
follows by a conventional amide reduction process.21,22 Though
a low yield of N,N-dimethylaniline (3a) was obtained with N-
methylformanilide (2a) (Scheme 3, eq 1), this route cannot be
excluded. With copper halide (excluding CuF2) as catalyst, only
formamide H was obtained in high selectivity. This may be
because the presence of halide seems to be disfavorable for the
formation of the copper hydride B, thus suppressing
subsequent reduction and rendering the reaction terminated
at formamide 2a.
Scheme 3. Control Experiments
In conclusion, we have established the first non-noble-metal-
catalyzed methylation of amines with formic acid using
phenylsilane as a reducing agent. Primary amines, secondary
amines, as well as imine are suitable substrates and give
corresponding methylamines in 37−98% yields under relatively
mild conditions. Formic acid, which can be easily obtained by
hydrogenation of CO2, is employed as a sustainable methylating
agent in this protocol, providing a new option for indirect
utilization of CO2. Therefore, this copper-catalyzed protocol
represents an environmentally friendly, readily operational, and
highly efficient example for methylation of amines.
(3a) was obtained (eq 1). Then, methanol was used as C1
source to replace formic acid under otherwise identical
conditions, and no N-methylated product 3a was detected at
all (eq 2). When paraformaldehyde was employed, the desired
product 3a was obtained in 91% yield (eq 3), indicating that
formaldehyde could be a possible intermediate. We then
verified the feasibility of the reduction of formic acid to
formaldehyde, and the reaction of formic acid and phenylsilane
in the absence of N-methylaniline was conducted (Figure S2).
It revealed that formic acid could be reduced to the silyl acetal
and methoxide under our reaction conditions (eq 4).20
Therefore, formaldehyde might be present in the reaction
mixture as a transient species.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00551.
Based on the above experimental results and previous reports
on reductive alkylation of amines with carboxylic acid and
hydrosilane,5,6,8−13 two possible reaction pathways for this
copper acetate catalyzed methylation of amines with formic
acid are proposed as shown in Scheme 4. In path I,
Experimental procedures; characterization of all products
(PDF)
AUTHOR INFORMATION
■
Scheme 4. Proposed Mechanism
Corresponding Author
*E-mail: heln@nankai.edu.cn.
ORCID
Liang-Nian He: 0000-0002-6067-5937
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Key
Research and Development Program (2016YFA0602900),
National Natural Science Foundation of China (21472103,
21421001, 21421062, 21672119), the Natural Science
Foundation of Tianjin Municipality (16JCZDJC39900),
Specialized Research Fund for the Doctoral Program of Higher
Education (project 20130031110013), MOE Innovation Team
(IRT13022) of China, and the Foundation of State Key
Laboratory of Coal Conversion (Grant No. J16-17-902-2).
dehydrogenative coupling between formic acid and hydrosilane
leads to formoxysilane A. In parallel, the copper hydride species
B is initially generated by metathesis between copper acetate
and hydrosilane in which oxygen of acetate interacts with
silicon of hydrosilane and promotes hydride transfer to copper.
Two such species (A and B) could readily deliver the silyl
acetal C, which is further converted into formaldehyde E with
release of the copper ether D. Then, E reacts with the amine in
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