A general method for N-methylation of amines and nitro compounds with dimethylsulfoxide

Article abstract of DOI:10.1002/chem.201303802

DMSO methylates a broad range of amines in the presence of formic acid, providing a novel, green and practical method for amine methylation. The protocol also allows the one-pot transformation of aromatic nitro compounds into dimethylated amines in the presence of a simple iron catalyst. Not just a solvent: DMSO methylates a broad range of amines in the presence of formic acid, providing a novel, green and practical method for amine methylation. The protocol also allows the one-pot transformation of aromatic nitro compounds into dimethylated amines in the presence of a simple iron catalyst. Copyright

Full text of DOI:10.1002/chem.201303802

DOI: 10.1002/chem.201303802
Communication
&
Synthetic Methods
A General Method for N-Methylation of Amines and Nitro
Compounds with Dimethylsulfoxide
[a]
[a]
[a]
[a]
[a]
[a, b]
Xue Jiang, Chao Wang,* Yawen Wei, Dong Xue, Zhaotie Liu, and Jianliang Xiao*
Chem. Eur. J. 2014, 20, 58 – 63
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Communication
Abstract: DMSO methylates a broad range of amines in
the presence of formic acid, providing a novel, green and
practical method for amine methylation. The protocol also
allows the one-pot transformation of aromatic nitro com-
pounds into dimethylated amines in the presence of
a simple iron catalyst.
Scheme 1. Dimethylation of amines and direct transformation of nitro group
into dimethyl amine by iron catalysis.
amines directly in the presence of a simple iron catalyst with-
out ligand (Scheme 1).
[
13]
Methylation of amines is a general transformation in organic
During our study of reductive amination reactions,
we
[
1]
synthesis as well as in biological processes. Methylated
amines are found in dyes, natural products, pharmaceuticals
found that p-anisidine could be methylated to afford N’,N-di-
methyl-p-anisidine 1a in DMSO (3 mL) in the presence of
8 equivalents of formic acid with 31% isolated yield in 12 h at
1508C [Eq. (1)]. Examination of solvent effect revealed that the
reaction only proceeded in DMSO. In all the other solvents
tested (e.g., dimethylformamide, acetonitrile, toluene, isopro-
panol, dioxane) or in pure formic acid, N-(4-methoxyphenyl)-
formamide was observed as the only product, which resulted
[
2]
and bulk and fine chemicals. Common methods for prepara-
tion of methylated amines include nucleophilic attack of meth-
ylating reagents, for example, MeI or dimethyl sulfate, or meth-
ylation with formaldehyde in the presence of a reducing re-
[
3]
[4]
agent, for example, formic acid, metal hydrides or hydrogen
[
5]
gas. However, most of the methylating reagents are toxic or
carcinogenic and have issues of over methylation or limited
substrate scope. N-Methylation in industry is normally carried
out by catalytic hydrogenative alkylation with formaldehyde at
[14]
from the reaction of p-anisidine with formic acid. The yield
of 1a could be improved to 66% by addition of equimolar
amount of triethylamine to formic acid. By keeping the ratio of
formic acid and triethylamine to 1:1 while increasing the
amount of formic acid and triethylamine, the yield increased
steadily, reaching 91% with 20 equivalents of formic acid. De-
creasing the volume of DMSO to 2 or 1 mL does not affect the
yield of the reaction.
[
5c]
relative high pressure. The use of dimethyl carbonate and
methanol as methylating reagents in the presence of catalysts
[
6]
has emerged as green alternatives for amine methylation.
[
7]
[8]
[9]
Very recently, Cantat, Beller, Klankermayer and their co-
workers reported that CO could act as a methylating reagent
2
with Zn or Ru catalysts with hydrosilane or hydrogen gas as re-
ducing reagents.
Dimethyl sulfoxide (DMSO) is a byproduct of the wood in-
dustry. It is a cheap, versatile solvent with low toxicity and is
widely used in organic synthesis and the pharmaceutical indus-
try. It has even been used as a medicine or presented as a com-
ponent in some medicines. It is a relatively stable molecule
and hence its applications as reactant in organic reactions are
[
10]
few. Methylation of aromatic hydrocarbons with DMSO was
[
11]
reported early in 1966 through a carbanion intermediate.
Although the reaction mechanism was not clear initially, we
decided to examine the generality of this new methylation
protocol. The substrate scope turned out to be very broad.
Table 1 summarises the results obtained from different primary
amines. Aromatic amines with different substituents on their
phenyl rings were firstly examined. Good to excellent yields
were generally obtained (Table 1, 1a–q). Electron-deficient sub-
stituents tend to slow down or alter the selectivity of the reac-
tion. Substrate with a p-trifluoromethyl group afforded 63%
yield of 1h (Table 1) after a long time of 48 h. A mixture of
mono- and dimethylated products was observed for p-cyano-
aniline in 48 h with almost full conversion. Interestingly, only
monomethylated product was obtained for the trichloro-sub-
stituted aniline (Table 1, 1n). Pyridine could be tolerated under
the reaction conditions (1o). When two amino groups were
presented, both of them were methylated (Table 1, 1p and q).
This allows the synthesis of Wurster’s blue in high yield
Using the Fenton reagent, methyl radical was found to be gen-
erated from DMSO and exploited for the C5 carbon methyla-
[12]
tion of deoxycytosine nucleotide in biological studies. Apart
from these studies, we are not aware of any further examples
of methylation reactions with DMSO. Herein we would like to
disclose that DMSO is a versatile methylation reagent for
amines under catalyst-free conditions (Scheme 1). Moreover, ar-
omatic nitro compounds could be transformed into dimethyl
[a] X. Jiang, Prof. Dr. C. Wang, Y. Wei, Prof. Dr. D. Xue, Prof. Dr. Z. Liu,
Prof. Dr. J. Xiao
Key Laboratory of Applied Surface and Colloid
Chemistry of Ministry of Education
Department of Chemistry & Chemical Engineering
Shaanxi Normal University, Xi’an, 710062 (China)
E-mail: c.wang@snnu.edu.cn
[15]
[b] Prof. Dr. J. Xiao
(
Table 1, 1q), which has found biomedical application.
Various secondary amines, which could be easily obtained
Department of Chemistry, University of Liverpool
Liverpool, L69 7ZD (UK)
E-mail: j.xiao@liv.ac.uk
[15]
from our previously reported reductive amination reaction,
were then tested as substrates. The results are presented in
Table 2. Secondary amines prepared from aromatic amines and
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303802.
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Communication
[
a]
[a]
Table 1. Methylation of primary amines in DMSO.
Table 2. Methylation of secondary amines in DMSO.
[a] Reaction conditions: 1 mmol amine, 20 mmol HCOOH, 20 mmol Et
3
N,
3
mL DMSO, 1508C, isolated yields. [b] Yields were determined by
1
H NMR with 1,3,5-trimethoxybenzene as internal standard.
aromatic ketones reacted well with yields ranging from 83–
98% in 12 h (Table 2, 2a–h). Good yields were obtained for
amines synthesised from aliphatic ketones and aromatic
amines (Table 2, 2i–n) as well as substrates derived from alde-
hydes and aromatic amines (Table 2, 1b and 2o–r). However,
only moderate yields were obtained for secondary amines
bearing two alkyl groups (Table 2, 2s–w).
Nitrogen-containing heterocyles are an important class of
compounds in organic chemistry. Indolines and tetrahydroqui-
nolines were chosen as substrates to test the viability of this
protocol for methylation of nitrogen-containing heterocyles
[
3
a] Reaction conditions: 1 mmol amine, 20 mmol HCOOH, 20 mmol Et
mL DMSO, 1508C,12 h, isolated yields.
3
N,
(Table 3). Delightfully, indolines were smoothly converted to N-
methylated indolines with acceptable yields (Table 3, 3a–e).
Tetrahydroquinolines bearing both aromatic and aliphatic sub-
stituents gave good to excellent yields (Table 3, 3 f–p). A fur-
ther example is seen in the synthesis of Galipinine, an alkaloid
used against fever, which could be obtained with 82% yield
from its corresponding tetrahydroquinoline precursor 6g
(Scheme 2). The latter was conveniently accessed from 5g
using our previously reported aqueous asymmetric transfer hy-
drogenation system. Only a slight loss of enantiomeric excess
[16]
was observed on going from 6g to 3q (Scheme 2).
route avoids the use of toxic NaBH(CN)3.
This
[
17]
As formic acid is a reducing reagent, nitro compounds
might be directly transformed into dimethylated amines
through amine intermediates. Indeed, dimethylated 1a was
Scheme 2. Synthesis of Galipinine.
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Communication
[
a]
[a]
Table 3. Methylation of heterocyles in DMSO.
Table 4. One-pot methylation of aromatic nitro compounds.
[
b]
R
Product
Yield [%]
1
2
3
4
5
6
7
8
9
0
4-OMe
4-H
1a
1b
1c
1d
1e
7a
7b
7c
7d
7e
83
70
73
81
80
62
75
89
80
71
4-CH
4-Cl
4-Br
4-I
3
4-SCH
3
4-tert-Butyl
3-Cl
3-I
1
[
a] Reaction conditions: 1 mmol amine, FeCl
2 2
·7H O (0.02 mmol), 26 mmol
HCOOH, 21 mmol Et N, 3 mL DMSO, 1508C, 12 h. [b] Isolated yields.
3
formamide intermediate by formic acid. Indeed, in the reaction
of p-anisidine, N-(4-methoxyphenyl)-formamide 8 was ob-
served. Compound 8 was then separately synthesised and sub-
jected to the reaction conditions of methylation [Eq. (2)]. Di-
methylated product 1a was formed, however, at a slower rate
compared with starting from p-anisidine, suggesting that the
formamide is not involved in the process of methylation.
Isotope labelling was then pursued, leading to more insight
[
3
a] Reaction conditions: 1 mmol amine, 20 mmol HCOOH, 20 mmol Et
mL DMSO, 1508C,12 h, isolated yields. [b] Yields were determined by
3
N,
1
H NMR with 1,3,5-trimethoxybenzene as internal standard. [c] The reac-
tion time was 24 h.
formed in 38% yield in 12 h, when 1-methoxy-4-nitrobenzene
13
(
1 mmol) was subjected to the standard reaction conditions.
into the mechanism. Thus, when C labelled formic acid was
The yield could be improved to 47% by using a larger amount
used to methylate p-anisidine under the standard reaction con-
13
of formic acid (26 mmol) and NEt (21 mmol). Under these con-
ditions, no C labelled methylation product was observed,
showing that the methyl groups in the product are not from
3
ditions, the starting material was fully consumed in 12 h, but
uncharacterised side products were formed. Beller and co-
workers have shown that aromatic nitro compounds can be re-
duced under iron catalysis with formic acid as hydrogen
formic acid [Eq. (3)]. Furthermore, when [D ]DMSO was used
6
instead of DMSO, four of the six protons from the ÀNMe
2
group of 1a were replaced by deuterium atoms [Eq. (4)]. When
DCOOH was used instead of HCOOH, two of the six protons
were replaced by deuterium atoms [Eq. (5)]. Full deuteration
[
18]
source. Inspired by this finding, catalytic amount (2 mol%)
of various iron salts, for example, Fe (CO) , Fe(BF ) ·6H O,
3
12
4 2
2
Fe(OAc) , together with the tetraphos ligand tris[(2-diphenyl-
happened only when [D ]DMSO and DCOOH was used
2
6
phosphino)-ethyl]phosphine (PP ) were added to the above re-
[Eq. (6)]. The same deuterium labelling results were observed
when starting from 8, supporting the non-involvement of
formamide in the methylation. Still further, when starting from
3
action. The yields were indeed improved, to over 80% for all
the iron catalysts tested. Surprisingly, in the absence of the PP3
ligand, similar yields were observed. For example, with 2 mol%
of FeCl ·7H O, 1-methoxyl-4-nitrobenzene was converted to 1a
monomethylated p-anisidine using [D ]DMSO or DCOOH, the
6
deuteration pattern shown in Equations (7) and (8) was ob-
2
2
with 83% yield. With this result in hand, a range of aromatic
nitro compounds were examined using the cheap and easily
available FeCl ·7H O as catalyst. As can be seen from Table 4,
2
2
satisfactory yields were obtained for substrates with various
substituents, including even a methylthio group. It is worth
noting that the reduction of nitro groups with formic acid
under catalyst-free or iron catalysis without ligands is unprece-
dented in the literature, to the best of our knowledge.
The mechanism of the methylation reaction was then stud-
ied. First, both formic acid and DMSO were shown to be essen-
tial for the methylation reaction; in the absence of either com-
ponent, no methylation took place. As formamides can be
easily formed from amines and formic acid, we initially thought
that the methylation might proceed via the reduction of a
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though it was not characterised by spectroscopic means. In
this mechanism, the methyl group is transferred as a methylene
from DMSO to the product; of the three protons on the
methyl group of product, two come from DMSO and one from
formic acid, which fits well with the deuterium labelling experi-
ments. The formamide intermediate observed is probably in
equilibrium with the amine substrate under the reaction condi-
tion. This explains why slower reaction was observed when
starting from 8. Triethylamine may play a role in tuning the
acidity of the system, thus insure that free amine substrate is
available to participate in the nucleophilic attack of 9.
served. Together, these experiments clearly show that the N-
methyl groups arise from DMSO instead of HCOOH; but for
each methyl group, two protons come from DMSO and one
from the CÀH hydrogen of HCOOH. It is worth noting that
these labelling studies provide a convenient method to access
Concerning the mechanism of methylation of nitro com-
pounds, we believe that the nitro compound is first reduced
to an amine and this is then followed by the pathway shown
in Scheme 3. Support for this proposition is found in the ex-
periment that replacing DMSO with DMF in the iron-catalysed
methylation of 1-methoxyl-4-nitrobenzene afforded only 75%
of 8 and 8% of p-anisidine as products; 1a was not observed.
In conclusion, a new amine methylation protocol has been
developed with very broad substrate scope. The cheap and
low-toxic DMSO has been identified as the methylating re-
agent under catalyst-free conditions. Aromatic nitro com-
pounds could be directly transformed into dimethylated
amines in the presence of a cheap iron catalyst for the first
time. The method provides a simple and convenient way to
[3d]
methylated amines with various level of deuterium labelling.
[10]
Based on the above mechanistic studies and the literature,
we propose a mechanism for this new methylation reaction. It
is known that DMSO can react with anhydrides to form an
acylated intermediate, which could undergo Pummerer rear-
[
19]
rangement to afford intermediate 9. Alternatively, 9 could
be formed by protonation and dehydration under acidic condi-
[
10]
tions. We believe that the intermediate 9 is also involved in
this reaction. DMSO might be acylated by formic acid or by
the formic acid anhydride that is formed in-situ, or protonated
by formic acid, which will all lead to the formation of 9
(Scheme 3). The presence of 9 is supported by the Friedel–
13
synthesise deuterium or C labelled methyl amines. Mechanis-
tic studies suggest that the methylation involves the transfer
of a methylene group from DMSO to an amine and the reduc-
tion of the resulting imine by formic acid.
Experimental Section
General procedure for methylation of amine: Amine (1 mmol),
HCOOH (99%, 20 mmol), triethylamine (20 mmol) and a magnetic
stir bar were placed in a pressure tube. The mixture was bubbled
with argon for 15 min, and then stirred at 1508C for 12–48 h.
Caution! Pressure build-up during the reaction. Suitable pressure
vessel must be chosen when scaling-up the reaction.
After being cooled to room temperature, the reaction was basified
with NaOH solution, and the resulting solution was extracted with
CH Cl (3ꢁ10 mL). The organic layers were washed with brine and
Scheme 3. Proposed mechanism for methylation of amines.
2
2
dried over Na SO . CH Cl was then removed under reduced pres-
2
4
2
2
sure and the product was purified by flash chromatography using
petroleum ether and ethyl acetate as eluent.
Crafts reaction shown in Equation (9), in which 9 is intercepted
[
20]
by 1,3,5-trimethoxybenzene. Under our conditions, 9 could
[20f]
be intercepted by an amine to form intermediate 10.
The
Acknowledgements
elimination of methane thiol from 10 results in the imine inter-
mediate 11, which could be reduced by formic acid, affording
the methylated amine product. The smell in the reaction tube
after the reaction supports the presence of methane thiol, al-
We are grateful for the financial support of the National Sci-
ence Foundation of China (21103102), Program for Changjiang
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Scholars and Innovative Research Team in University (IRT 1070),
the Cheung Kong Scholar Programme, the Fundamental Re-
search Funds for the Central Universities (GK261001095), and
the Program for Key Science and Technology Innovative Team
of Shaanxi Province (2012KCT-21 and 2013KCT-17).
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Published online on December 10, 2013
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