Transition metal-free methylation of amines with formaldehyde as the reductant and methyl source

Article abstract of DOI:10.2533/chimia.2015.345

A simple transition metal-free procedure using formaldehyde for the N,N-dimethylation and N-methylation of primary and secondary anilines is reported. The reaction showed limitations on sterically hindered and electron-withdrawing anilines, but is successful on amines with electron-donating substituents. Formaldehyde acts as both the reducing agent and the carbon source in the reaction.

Full text of DOI:10.2533/chimia.2015.345

CatalytiC aCtivation of Small moleCuleS
CHIMIA 2015, 69, No. 6 345
doi:10.2533/chimia.2015.345
Chimia 69 (2015) 345–347 © Schweizerische Chemische Gesellschaft
Transition Metal-free Methylation of
Amines with Formaldehyde as the
Reductant and Methyl Source
a
b
a
b
Nikki Y. T. Man , Wanfang Li , Scott G. Stewart , and Xiao-Feng Wu*
Abstract:Asimpletransitionmetal-freeprocedureusingformaldehydefortheN,N-dimethylationandN-methylation
of primary and secondary anilines is reported. The reaction showed limitations on sterically hindered and electron-
withdrawing anilines, but is successful on amines with electron-donating substituents. Formaldehyde acts as
both the reducing agent and the carbon source in the reaction.
Keywords: Anilines · Eschweiler-Clarke reaction · Formaldehyde · Metal-free · N-methylation
N-Methylation of amines in organic catalysts. N-Methylation utilising CO as however, with a reduced amount of 2, the
2
synthesis is a simple yet important reac- the C1 source has also recently been re- conversion was as high as under the origi-
[
10]
[11]
tion due to its significance in the bulk and ported by the Cantat, Klankermayer,
nal conditions and the yield is comparable
fine chemical industries because these Leitner and Beller groups.[13] Although ( Ta ble 1, entry 3). Th e reaction was also
[12]
amines are widely used as intermediates in these reactions are efficient and green, in performed under different temperatures
the preparation of products such as dyes, an effort to provide an alternative proce- ( Ta ble 1, entries 5–7).
[
1]
pharmaceuticals and agrochemicals. Not dure without the use of metals or catalysts,
only important in industry, N-methylated the N-methylation of amines under other ( Ta ble 1, entries 8–13) which led to lower
compounds are also prevalent in naturally mild conditions was investigated. conversions and yields. Different organic
occurring and synthetic biologically active Formaldehyde is an excellent C1 bases were also tested ( Ta ble 1, entries
A variety of inorganic bases was tested
compounds such as N-methylated peptides building block that is inexpensive, readi- 14–17) which led to Et N as the best can-
3
and amino acids;[ the methylation of the ly available and has been used in a varie- didate since the reaction produced the least
2,3]
nitrogen atoms regulate biological func- ty of different organic transformations.[
14]
amount of by-product. Th e equivalence
tions and is therefore considered one of the Dissolved in water under 200 °C, for- of base was then altered to see its effects
most important chemical modifications in maldyde exists predominantly as its hy- on the reaction ( Ta ble 1, entries 18–22).
natural science.[
3]
drated geminal diol, methandiol. Under Although the conversion of substrate 1 is
[15]
Many general methodologies utilised basic conditions, methandiol converts into nearly quantitative, the yield is not; this is
for the methylation of amines in the labo- formic acid by proton exchange.[ Under due to the formation of by-products 3 and
ratory require the use of activated methyl this environment, the presence of both for- 4, which comes from the Mannich reaction
compounds,[ which are quite undesir- mic acid and formaldehyde can initiate a of the starting material with formaldehyde
able due to their high toxicity, as well as classic Eschweiler-Clarke reaction which and methanol (Scheme 1).[ Comparisons
the generation of by-products and waste allows the preparation of tertiary amines with K CO showed that the reaction does
16]
4]
17]
2
3
in the form of their organic and inorgan- from secondary and primary amines.
ic salts. Other common procedures for the Th eadvantageoftheclassicEschweiler-
not succeed when there is a high equiva-
lence of this base. In an attempt to reduce
methylation of amines require harsh con- Clarke reaction is that it is a one-pot reac- the amount of the by-products formed in
ditions such as the use of different met- tion that does not require the addition of the reaction, a higher equivalence of Et N
3
al hydrides[ and metal or zeolite
5,6]
[7]
[8,9]
metal catalysts and CO source. Herein, was used which led to a slightly improved
2
we report a transition metal-free methyl- yield, and no by-product ( Ta ble 1, entry
ation procedure which uses formaldehyde 24).
as both the reducing agent as well as the
source of carbon.
Length of the reaction time was varied
( Ta ble 1, entries 25–28), and 1,4-dioxane
Initially, the reaction conditions were was tested as an alternative solvent ( Ta ble
optimised using N-methylaniline (1) as the 1, entry 29). Th e optimised yield of 76%
standard substrate ( Ta ble 1). Upon heating
a mixture of 1, formaldehyde (37 % w/w, comparable to the original conditions, the
0 equiv.), K CO (0.2 equiv.) at 130 °C optimised conditions led to a minimal
was achieved ( Ta ble 1, entry 28). Although
1
2
3
under an argon atmosphere in toluene, the amount of by-product and a lower equiva-
b
*
Correspondence: Prof. X. Wu
conversion of 1 was greater than 99% with lence of formaldehyde is required.
Tel.: +49 381 1281 343
a yield of the dimethylated product (3) of
74% ( Ta ble 1, entry 1). Next, the reaction
was performed with different equivalents this methylation protocol was performed.
of 1 ( Ta ble 1, entries 2–4). Unfortunately, Unfortunately, the substrate scope turned
As the reaction provided a moderate
E-mail: xiao-feng.wu@catalysis.de
School of Chemistry and Biochemistry
The University of Western Australia
5 Stirling Hwy, Crawley WA 6009, Australia
Leibniz-Institut für Katalyse e.V. an der Universität
Rostock, Albert-Einstein-Str. 29a
a
yield, an examination of the generality of
3
b
the variation of the amount of substrate out to be fairly limited. Non-substituted ar-
18059 Rostock, Germany
did not improve the yield of the reaction; yl amines were first examined ( Ta ble 2, en-

346 CHIMIA 2015, 69, No. 6
CatalytiC aCtivation of Small moleCuleS
Table 1. Optimization of the reductive methylation of N-methylaniline (1)
non-methylated counterparts at 13% and
5
7%, respectively.
Sterically hindered amines were ex-
H
N
amined next. 2,4,6- Tr i-tert-butylaniline
N
H
O
and N,N- diphenylaniline did not undergo
methylation, and the slightly less steri-
cally-hindered 2,6-dimethylaniline pro-
duced trace amounts of the monomethyl-
ated product and no dimethylated product.
Saturated cyclic amines such as piperidine
and 1-adamantylamine did not undergo
methylation and the starting materials were
decomposed in the reaction. Azepane and
base
toluene
+
H
1
2
3
a
Entry 2 (equiv.) Base (equiv.) T[ °C] Ti me [h] Conversion [%] 3 Yield [%]
1
2
3
4
5
6
7
8
9
10
4
8
16
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
K CO (0.2)
130
130
130
130
r.t.
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
2
> 99
35
74
47
72
1.6
2.2
5.2
69
0
2
3
K CO (0.2)
2
3
2
,6-tetramethylpiperidine, however, were
K CO (0.2)
> 99
88
2
3
successfully methylated at 92% and 89%
K CO (0.2)
yields, respectively ( Ta ble 2, entries 6,7).
Saturated linear amines N-methyl-1,3-
propanediamine and ethylenediamine did
not undergo methylation and the starting
materials were decomposed in the reaction.
Subsequently, electronic effects were
studied with anilines with a variety of sub-
stituents and substitution patterns.Anilines
with strongly deactivating electron with-
drawing substituents such as nitroanilines,
aminobenzonitriles and 3-amino-4-trifluo-
romethylaniline did not undergo methyla-
tion. 2-Fluoroaniline and 2-bromoaniline
did not undergo methylation, however,
trace amounts of the mono- and dimeth-
2
3
K CO (0.2)
18
2
3
K CO (0.2)
70
42
2
3
K CO (0.2)
110
130
130
130
130
130
94
2
3
K S O (0.2)
0
2
2
8
t
BuOK (0.2)
Na CO (0.2)
85
52
54
59
57
58
56
40
75
18
11
16
46
61
64
1.7
71
22
40
53
76
31
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
88
2
3
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
NaOH (0.2)
Cs CO (0.2)
86
99
2
3
NaHCO (0.2) 130
> 99
98
3
DBU (1.0)
130
130
130
DIPEA (1.0)
52
ylated product of 4-chloroaniline were
detected in GC-MS. 4-Bromoaniline was
methylated, however, the reaction only
Et N (1.0)
91
3
pyridine (1.0) 130
98
produced a negliable yield of 0.5% ( Ta ble
2, entry 8).
Et N (0.1)
130
130
130
130
130
130
130
130
130
130
130
130
> 99
> 99
> 99
98
3
Anilines with electron-donating groups
fared better in the methylation reaction.
4-Methoxy-N,N-dimethylaniline was iso-
Et N (0.4)
3
Et N (0.8)
3
1
lated at 87% ( Ta ble 2, entry 9), and N -
Et N (1.0)
3
1
methyl-N -phenylethane-1,2-diamine was
Et N (1.5)
98
3
isolated at 60% yield ( Ta ble 2, entry 10).
K CO (1.5)
2
3-(Methylamino)-1-phenyl-1-propanol
was transformed into an imine under the
given conditions.
2
3
Et N (5.0)
97
3
Et N (5.0)
77
3
Th ree indoles (1H-indole-2-
Et N (5.0)
4
88
acetonitrile, tryptamine and 5-aminoin-
dole) as well as 2,4-diaminotoluene were
also examined without successful methyl-
ation and starting materials were decom-
posed in the reaction.
3
Et N (5.0)
8
90
3
Et N (5.0)
16
16
99
3
b
2
9
Et N (5.0)
30
3
Although the reaction showed limi-
tations on compounds that are sterically
hindered and carry electron-withdrawing
groups, this procedure is quite successful
on amines in electron-donating environ-
ments. Formaldehyde is used as both the
reducing and methylating reagent in this
reaction and future work involving the use
a
b
Determined by GC using n-hexadecane as an internal standard. 1,4-Dioxane used as solvent.
H
N
CH OH
N
N
N
O
3
CH O
2
1
3
4
13
of C labelled formaldehyde solution may
lead to its applications in fluorescent tag-
ging for biological evaluations.
[
17]
Scheme 1. Literature Mannich reaction of N-methylaniline with formaldehyde and methanol.
Acknowledgments
tries 1–5) and the results show that the fur- the yield of the reaction as exemplified by
We thank the general support from Prof.
ther away the N-atom is from the aryl ring, the original reaction with N-methylaniline Matthias Beller.
the higher the yield. Th e presence of an
at 76% and N-methylbenzylaniline ( Ta ble
N-methylgroupontheaminealsoincreases 2, entry 3) at 99%, compared to their
Received: April 16, 2015

CatalytiC aCtivation of Small moleCuleS
CHIMIA 2015, 69, No. 6 347
Table 2. Methylation of different amines with formaldehyde.
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6
90
92
5
753.
7
8
89
0.5
b
9
87
b
1
0
60
a
b
Determined by GC using n-hexadecane as an internal standard. Isolated yields.