N-methylation of nitrogen-containing heterocycles with dimethyl carbonate

Article abstract of DOI:10.1080/00397910500278578

Reactivity of dimethyl carbonate, the environmentally friendly reagent, as methylating agent for nitrogen-containing heterocyclic compounds has been studied. Reactions of imidazole, pyrazole, pyrrole, morpholine, and piperazine with dimethyl carbonate to afford N-methylated products were reported. The reactions were carried out with neither catalyst nor solvent at a temperature range of 110-170°C under atmospheric pressure. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500278578

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N‐Methylation of
Nitrogen‐Containing
Heterocycles with Dimethyl
Carbonate
a
a
Samedy Ouk , Sophie Thiébaud , Elisabeth
a
b
Borredon & Bernard Chabaud
a
Laboratoire de Chimie Agro‐industrielle, Toulouse,
France
b
SNPE, Centre de recherche Le Bouchet Research
Center, Vert‐le‐Petit, France
Version of record first published: 21 Aug 2006.
To cite this article: Samedy Ouk, Sophie Thiébaud, Elisabeth Borredon & Bernard
Chabaud (2005): N‐Methylation of Nitrogen‐Containing Heterocycles with Dimethyl
Carbonate, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:23, 3021-3026
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Synthetic Communications , 35: 3021–3026, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500278578
N-Methylation of Nitrogen-Containing
Heterocycles with Dimethyl Carbonate
Samedy Ouk, Sophie Thi e´ baud, and Elisabeth Borredon
Laboratoire de Chimie Agro-industrielle, Toulouse, France
Bernard Chabaud
SNPE, Centre de recherche Le Bouchet Research Center, Vert-le-Petit,
France
Abstract: Reactivity of dimethyl carbonate, the environmentally friendly reagent, as
methylating agent for nitrogen-containing heterocyclic compounds has been studied.
Reactions of imidazole, pyrazole, pyrrole, morpholine, and piperazine with dimethyl
carbonate to afford N-methylated products were reported. The reactions were carried
out with neither catalyst nor solvent at a temperature range of 110–1708C under
atmospheric pressure.
Keywords: Dimethyl carbonate, imidazole, methylation, morpholine, NH-containing
heterocycles, piperazine, pyrazole, pyrrole
N-Methylation of NH-containing heterocyclic compounds is an important
[
1,2]
reaction in organic synthesis. Conventionally, methyl halides
dimethyl sulfate
or
were used as methylating agents. Those processes
[3,4]
involve not only the use of highly toxic reagents but also generate a stoichio-
metric amount of salt to be disposed of. In view of these disadvantages, an
environmentally benign reagent with an efficient process that is easy to
scale up is very desirable.
Received in Poland May 30, 2005
Address correspondence to Sophie Thi e´ baud, Laboratoire de Chimie Agro-
industrielle, UMR 31010 INRA/INP-ENSIACET 118 route de Narbonne, 31077,
Toulouse cedex 4, France. Tel.: þ33-5-62-88-57-20; Fax: þ33-5-62-88-57-30.
E-mail: Sophie.ThiebaudRoux@ensiacet.fr
3
021

3022
S. Ouk et al.
Recently, dimethyl carbonate (DMC) was reported to be a potential
[
5–7]
harmless and versatile methylating reagent.
containing heterocycles, the reaction of indoles,
In the N-methylation of NH-
[8,9]
[10]
[11]
xanthine,
with DMC have been reported. All those
reactions were carried out in the presence of a catalyst, which is an organic
uracils,
[11]
[12]
thiamine,
and imidazoles
[10–12]
or inorganic base. In some cases a phase-transfer catalyst was employed.
We report herein a simple process for N-methylation of various aromatic
and nonaromatic NH-containing heterocyclic compounds with DMC in the
absence of either a catalyst or a solvent, except for the N-methylation of pyrrole.
RESULTS AND DISCUSSION
The reactions were carried out under atmospheric pressure at a temperature
ranging from 1108C to 1708C depending upon nature of substrate. DMC, a
low-boiling-point reagent (bp ¼ 908C) was loaded progressively into the
preheated reactor containing another substrate. During the reaction, a low-
boiling-point by-product, methanol, and the excess of DMC were immediately
distilled from the reaction medium. The reactor was therefore equipped with a
suitable distillation column enabling a good separation of methanol from
[
13]
dimethyl carbonate.
Table 1 shows that the N-methylation of imidazole at 1708C leads to
quantitative yield of N-methylimidazole. For the N-methylation of pyrazole,
a better yield of N-methylpyrazole was obtained at 1408C because on one
hand, when this reaction was operated at a higher temperature, the DMC
concentration in the liquid phase is nearly null as a result of operation at
atmospheric pressure. On the other hand, at lower temperature, the rate of
N-methylation is too slow and the formation of by-products increases. At
the same time, the N-methylation of nonaromatic NH-containing heterocyclic
morpholine and piperazine with DMC takes place in the absence of
catalyst even at 1108C to yield 67% and 29% of N-methylmorpholine and
1
-methylpiperazine respectively. In the case of morpholine, the selectivity
toward N-methylation was 81% and the main by-product was N,N-carbonyl-
dimorpholine whereas in the case of piperazine selectivity was only 60% and
the main by-product was 1,4-dimethylpiperazine.
However, no reaction takes place when pyrrole was allowed to react with
DMC at 1208C in the absence of a catalyst. The low basicity of pyrrole would
certainly explain its nonreactivity. When a catalytic amount of tetrabutyl-
ammonium bromide (TBAB) was added, the reaction occurred and led
mainly to methyl-1-pyrrolecaboxylate and 1-methylpyrrole. After 24 h of
reaction at 1208C total conversion of pyrrole was attained and the reaction
yielded 36% and 51% of 1-methylpyrrole and methyl-1-pyrrolecaboxylate
respectively. This poor selectivity toward N-methylation is probably due to
[
14]
low reaction temperature.
We also observed that when this reaction was
carried out at 1108C, the selectivity of N-methylation drops from 36% to

N-Methylation of Heterocycles
3023
Table 1. Effect of reaction conditions on yield and on MHSVb of the reaction of
heterocycles N-methylation with dimethyl carbonate
Physical
properties
Reaction conditions and results
b
bp
(8C)
T
MHSV
21
Time
(h)
Conversion
(%)
Yield
(%)
a
Substrates
pKa
(8C)
(h
)
2
1
2
55
86
04
7.0
2.5
170
140
140
0.2
9
8
8
100
74
98
69
0.2
0.2
c
85
43/39
218
140
0.2
8
60
57
d
1
1
1
31
29
46
24.0
5.7
120
110
110
0.1
0.4
0.2
24
100
82
36
67
29
10
10
4.2
48
a
pK
a
of protonated form.
Molar hourly space velocity per mole of NH-containing substrate.
b
c
Molar ratio 1,3-dimethylpyrazole/1,5-dimethylpyrazole.
d
Reaction was carried out in the presence of a catalytic amount of tetrabutylammo-
nium bromide (8% molar).
only 4% whereas that of N-methoxycarbonylation increases from 51% to
9
2%. However, at 1108C the conversion rate of pyrrole is divided by two.
As the reactions of imidazole, pyrazole, morpholine, and piperazine with
DMC take place without a catalyst, we suggest that the electronic loan pair on
nitrogen would be basic enough to react directly with DMC through B -2
Al
mechanism resulting N-methylated product (Scheme 1) or through B -2,
Ac
resulting in a N-methoxycarbonylated product (Scheme 2). Also, reaction
Scheme 1. Plausible mechanism of methylation of imidazole with DMC (BAl-2
mechanism).

3024
S. Ouk et al.
Scheme 2. Formation of by-product, N,N-carbonyldimorpholine, via B -2 mechanism.
Ac
temperature plays an important role in the orientation toward one of these
mechanisms. Methylation is favored while temperature rises.
CONCLUSION
DMC is a convenient reagent for N-methylation of basic NH-containing het-
erocycles. The absence of catalyst and high selectivity toward methylation at
high temperatures enables DMC to replace toxic dimethyl sulfate or methyl
halides. For high-boiling-point starting material, the reaction can even be
carried out at atmospheric pressure by progressively loading and withdrawing
DMC and methanol respectively. However, reaction in a sealed tube or in a
high-boiling-point solvent would be the solution to raise temperature for the
methylation of a low-boiling-point compound. Therefore, DMC provides an
alternative clean and easy route to N-methylated nitrogen-containing
heterocyclic.
EXPERIMENTAL
Methods
N-methylation of imidazole: A 100-ml reactor equipped with a mechanical
stirrer and a distillation column (l ¼ 200 mm, f ¼ 15 mm) was loaded with
3
4.02 g (0.5 mol) of imidazole. The reactor was heated to 1708C. Once it
attained 1708C, DMC was progressively fed into the reactor with a velocity
2
1
21
.
of 9 g h
.
(0.1 mol h ) during 9 h. Methanol and the excess of DMC
were withdrawn at the end of the distillation column to maintain the
reaction temperature constant at 1708C. After reaction, 1-methylimidazole
was purified by distillation.
The other syntheses were carried out according to this experimental
procedure.

N-Methylation of Heterocycles
3025
Data
1
-Methylimidazole: H NMR (200 MHz, CDCl ) d (ppm) : 3.24 (s, 3H),
1
3
1
3
6
.48 (s, 1H), 6.61 (s, 1H), 7.00 (s, 1H); C NMR (50 MHz, CDCl ) d
3
(
ppm): 32.8, 119.9, 128.6, 137.4.
1
1
-Methylpyrazole: H NMR (200 MHz, DMSO, d ) d (ppm): 3.73
6
(
s, 3H), 6.16 (t, J ¼ 2.0 Hz, 1H), 7.36 (d, J ¼ 1.6, 1H), 7.57 (d, J ¼ 2.2,
1
3
1
H); C NMR (50 MHz, DMSO, d ) d (ppm): 47.9, 104.8, 130.0, 138.3.
6
1
1
,3-Dimethylpyrazole: H NMR (200 MHz, CDCl ) d (ppm): 1.86
3
1
3
(
NMR (50 MHz, CDCl ) d (ppm): 13.2, 38.0, 104.8, 130.4, 147.9.
s, 3H), 3.34 (s, 3H), 5.57 (d, J ¼ 1.9 Hz, 1H), 6.78 (d, J ¼ 2.0 Hz, 1H);
C
3
1
1
,5-Dimethylpyrazole: H NMR (200 MHz, CDCl ) d (ppm): 1.80
3
(
s, 3H), 3.24 (s, 3H), 5.57 (d, J ¼ 1.9 Hz, 1H), 6.92 (d, J ¼ 1.6 Hz, 1H);
3
1
3
C NMR (50 MHz, CDCl ) d (ppm): 10.6, 35.5, 104.7, 137.5, 137.8.
1
1
,3,5-Trimethylpyrazole: H NMR (200 MHz, CDCl ) d (ppm): 2.79
3
1
3
(
s, 6H), 3.80 (s, 3H), 5.84 (s, 1H); C NMR (50 MHz, CDCl ) d (ppm):
3
7
.5, 14.1, 34.4, 106.3, 143.9, 150.0.
1
1
-Methylpyrrole: H NMR (200 MHz, CDCl ) d (ppm): 4.03 (s, 3H),
3
1
3
6.73 (t, J ¼ 2.0 Hz, 2H), 7.09 (t, J ¼ 2.0 Hz, 2H); C NMR (50 MHz,
CDCl ) d (ppm): 36.1, 108.7, 122.0.
3
1
4
-Methylmorpholine: H NMR (200 MHz, CDCl ) d (ppm): 2.28
3
1
3
(
(
s, 3H), 2.40 (t, J ¼ 4.6 Hz, 4H), 3.71 (t, J ¼ 4.8 Hz, 4H); C NMR
50 MHz, CDCl ) d (ppm): 45.8, 54.9, 66.2.
3
1
-Methylpiperazine: H NMR (200 MHz, CDCl ) d (ppm): 1.46
1
3
1
3
(
(
s, 1H), 2.26 (s, 3H), 2.37 (s, 4H), 2.88 (t, J ¼ 2.4 Hz, 4H); C NMR
50 MHz, CDCl ) d (ppm): 46.1, 46.7, 56.5.
3
1
,4-Dimethylpiperazine: H NMR (200 MHz, CDCl ) d (ppm): 2.29
1
s, 6H), 2.44 (s, 8H); C NMR (50 MHz, CDCl ) d (ppm): 46.1, 55.0.
3
1
3
(
3
1
Methyl 1-pyrrole carboxylate: H NMR (200 MHz, CDCl ) d (ppm):
.95 (s, 3H), 6.36 (t, J ¼ 2.4 Hz, 2H), 7.40 (t, J ¼ 2.4 Hz, 2H); C NMR
3
1
3
3
(
50 MHz, CDCl ) d ppm : 53.8, 112.5, 120.0, 150.9.
3
1
N,N-Carbonyldimorpholine: H NMR (200 MHz, D O) d (ppm): 3.02
2
1
s, 8H), 3.30 (s, 8H); C NMR (50 MHz, D O) d (ppm): 64.5, 68.8, 165.1.
3
(
2
ACKNOWLEDGMENT
We thank Soci e´ t e´ Nationale des Poudres et Explosifs for financial and
technical support of this work.
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