N-methylation of NH-containing heterocycles with dimethyl carbonate catalyzed by TMEDA

Article abstract of DOI:10.1080/00397911.2010.523151

A practical method for N-methylation of NH-containing heterocycles using an environmentally safe and less toxic methylating reagent, dimethyl carbonate, has been developed. N,N,N',N'-tetramethylethylenediamine (TMEDA), an extremely active organocatalyst for the methylation of imides, indoles, benzimidazoles, and piperazines in conjunction with dimethyl carbonate, can lead to N-methylation products with high conversion. The reaction sequence consists of competing alkylation and acylation pathways and involves TMEDA as a nucleophilic catalyst. A possible reaction mechanism is discussed based on the reaction results.

Full text of DOI:10.1080/00397911.2010.523151

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N-Methylation of NH-Containing
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Catalyzed by TMEDA
a
a
a
Sheng-Yin Zhao , Hai-Quan Zhang , Deng-Qing Zhang & Zhi-Yu
a
Shao
a
Department of Chemistry, Donghua University, Shanghai, China
Accepted author version posted online: 30 Jun 2011. Version of
record first published: 14 Sep 2011
To cite this article: Sheng-Yin Zhao, Hai-Quan Zhang, Deng-Qing Zhang & Zhi-Yu Shao (2012): N-
Methylation of NH-Containing Heterocycles with Dimethyl Carbonate Catalyzed by TMEDA, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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1
Synthetic Communications , 42: 128–135, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.523151
N-METHYLATION OF NH-CONTAINING
HETEROCYCLES WITH DIMETHYL CARBONATE
CATALYZED BY TMEDA
Sheng-yin Zhao, Hai-quan Zhang, Deng-qing Zhang, and
Zhi-yu Shao
Department of Chemistry, Donghua University, Shanghai, China
GRAPHICAL ABSTRACT
Abstract A practical method for N-methylation of NH-containing heterocycles using an
environmentally safe and less toxic methylating reagent, dimethyl carbonate, has been
0
0
developed. N,N,N ,N -tetramethylethylenediamine (TMEDA), an extremely active organo-
catalyst for the methylation of imides, indoles, benzimidazoles, and piperazines in conjunc-
tion with dimethyl carbonate, can lead to N-methylation products with high conversion. The
reaction sequence consists of competing alkylation and acylation pathways and involves
TMEDA as a nucleophilic catalyst. A possible reaction mechanism is discussed based on
the reaction results.
Keywords Dimethyl carbonate; methylation; NH-containing heterocycles; TMEDA
INTRODUCTION
Methylation, of nitrogen atoms in particular, is an important reaction in
organic synthesis. It is widely used in the synthesis of natural compounds with
[
1,2]
biological activity.
sulfate, which are highly toxic and their use should be restricted.
carbonate (DMC) as a methylating reagent for NH-containing heterocycles is an
Classic N-methylation reagents are methyl iodide and dimethyl
[
3,4]
Dimethyl
[5]
attractive alternative.
In the N-methylation of NH-containing heterocycles,
[6]
[7]
[8]
reactions of indoles, imidazoles, and pyrazoles with DMC have been reported.
However, the use of this ‘‘green chemical’’ (DMC) as a methylating reagent often
requires high temperatures and long reaction times, because the reactivity of DMC
at moderate temperatures can be significantly less than that of methyl iodide or
dimethyl sulfate. Another problem that is associated with the use of DMC is its dual
behavior as a methylating reagent and as a carbamoylating reagent can lead to poor
Received March 6, 2010.
Address correspondence to Sheng-yin Zhao, Department of Chemistry, Donghua University,
Shanghai, P. O. Box 201620, China. E-mail: syzhao8@dhu.edu.cn
1
28

N-METHYLATION OF NH-CONTAINING HETEROCYCLES
129
selectivity toward the desired N-methyl derivatives. In this respect, catalysis also can
be a way to achieve selectivity when using DMC. Recently, the use of nucleophilic
[
tertiary amines, such as 1,4-diazabicyclo[2.2.2]octane (DABCO) and dimethylami-
9]
[10]
nopyridine (DMAP), as suitable organocatalysts for the N-methylation of indoles
and 2,4-diaminotoluene were also reported. In some cases, a phase-transfer catalyst
[11]
was also employed in these reactions.
However, limited substrates were used
in these studies. Here we present an efficient method for N-methylation of
0
0
NH-containing heterocycles with DMC using a catalytic amount of N,N,N ,N -
tetramethylethylenediamine (TMEDA) under mild conditions.
RESULTS AND DISCUSSION
TMEDA, a cheap and convenient reagent, is a tertiary amine base with weak
The effectiveness of TMEDA as the organocatalyst for
[12]
basicity (pKa ¼ 9.4).
methylation of NH-containing hetercyclic compounds under mild conditions was
demonstrated for the reaction of phthalimide with dimethyl carbonate. In the initial
studies, we chose phthalimide as our model compound to study this reaction,
because the product, N-methylphthalimide, is solid and easy to purify. As depicted
in Scheme 1, the reaction between phthalimide substrate and DMC in the presence of
ꢀ
a base was accomplished by heating the reagents in dimethylformamide at 95 C for
8
h. In the presence of 0.1 equiv of TMEDA, the process afforded the N-methyl
phthalimides in 8 h with 95% yield. In contrast, with 0.1 equiv of triethylamine,
the yield of N-methylphthalimides is 69% and 28% recovered starting material. This
demonstrated that TMEDA is a more effective catalyst than triethylamine. It should
be noted that without any catalyst, the reaction generated no product at all.
Trimethylamine hydrochloride does not play a catalytic role in this reaction
(Table 1. entries 1 and 2).
With a catalytic amount of TMEDA (ꢁ10 mmol% based on phthalimide),
phthalimide reacted with DMC to give N-methylphthalimide (Fig. 1). As shown in
Fig. 1, increasing the amount of TMEDA led to a sharp increase of the yield first
and then to a steady state. The yield approached 95% when using 10mol% of TMEDA.
To futher illustrate the utility of this method for NH-containing heterocyclic
compounds, a series of substrates were applied to this protocol, the results of which
are summarized in Table 2. In some cases, isolated yields were good and ranged from
60% to 90%. Benzotriazole (12) affords a mixture of N-methylation product 13 as
well as N-carbamoylation product 14 in a ratio of 1.5:1 (Scheme 2). A possible expla-
nation is that a more acidic NH will lead to a high carbamoylation product, since the
[14]
[13]
pKa of 12 is ꢂ8.6 and the pKa of 1 is ꢂ14.6.
Scheme 1. Reaction of phthalimide and DMC.

130
S.-Y. ZHAO ET AL.
Table 1. Effect of base on the methylation rate of phthalimide with dimethyl carbonate
c
3 (%)
Entry
Catalyst
1 (%)
4 (%)
a
b
1
None
Me N HCl
Et
Bu
TMEDA
100
0
0
0
0
0
0
0
2
3
4
5
3
100
28
37
0
3
N
69
60
95
3
N
a
All reactions were conducted on a 1.5 g (10 mmol) scale in 5 mL of DMF and 10 mL of
ꢀ
DMC using 0.1 equiv of base at 95 C. The reaction time is 8 h.
b
Yields are based on isolated products.
Products were characterized by their physical constants, comparison with authentic
c
1
samples, and H NMR and MS spectroscopy.
We believe that TMEDA functions as a catalyst in our methylation protocol. A
plausible mechanism for NH-containing compounds is proposed in Scheme 3, in
which TMEDA performs as a nucleophilic catalyst. In the catalytic cycle, TMEDA
reacts with DMC to generate a more activated methylating agent, which presumably
reduces that activation energy required for methylation. A mechanistic study in our
laboratory to clarify the pathways for methylation employing DMC=TMEDA is
under way.
CONCLUSIONS
In summary, we have presented an efficient method for N-methylation of
NH-containing hetercycles with DMC under conventional thermal conditions by
employing TMEDA as an organocatalyst. TMEDA has high catalytic activities
under mild reaction conditions. Although our data are preliminary, this protocol
provides a practical and environmentally friendly process for an important chemical
Figure 1. Effect of catalyst amount. Reaction conditions: Phthalimide, 10 mmol; DMF, 5 mL; DMC,
ꢀ
10 mL; reaction time, 8 h; temperature, 95 C.

N-METHYLATION OF NH-CONTAINING HETEROCYCLES
131
Table 2. N-Methylation of NH-containing heterocyclic compounds with dimethyl carbonate catalyzed
a
by TMEDA
b
Entry
N-Heterocycles
Product
Time (h)
Yield (%)
1
12
86
2
3
8
9
89
87
4
5
6
9
8
90
86
72
12
7
8
60
a
ꢀ
Reaction conditions: N-heterocycles, 10 mmol; DMC, 10 mL; DMF, 5 mL; TMEDA, 1 mmol; 95 C.
Isolated yield.
b
Scheme 2. Reaction of benzotriazole and DMC in the presence of TMEDA.

132
S.-Y. ZHAO ET AL.
Scheme 3. Plausible catalytic cycle for NH methylation catalyzed by TMEDA.
transformation. Futher mechanistic studies are required to elucidate the details and
mechanistic pathways leading to the methylation product.
EXPERIMENTAL
All chemicals were purchased from commercial suppliers and used without
further purification. Yields refer to isolated products. Products were characterized
1
by their physical constants, comparison with authentic samples, and H NMR and
mass (MS) spectroscopy. Melting points were determined with a RY-1 apparatus
1
and were uncorrected. H NMR spectra were recorded using a Bruker AV
4
00-MHz spectrometer in CDCl with tetramethylsilane (TMS) as internal standard.
3
Electron impact (EI) mass spectra were obtained on a HP 5973 MS instrument. The
purity determination of substrates and reaction monitoring were accompanied by
thin-layer chromatography (TLC) on silica-gel polygram SILG=UV 254 plates and
high-performance liquid chromatography (HPLC) analysis. All the products were
1
known compounds, and the data of mp and H NMR accord with those reported
in the literature.
Typical Procedure for the Reaction of NH-Containing Heterocycles
with Dimethyl Carbonate Catalyzed by TMEDA
In a typical procedure, a mixture of the NH-containing heterocycles (10 mmol),
ꢀ
TMEDA (1 mmol), DMC (10 mL), and DMF (5 mL) was stirred and heated to 95 C
for the specified time. The progress of the reaction was monitored by TLC analysis.
After the completion of the reaction, the mixture was cooled to room temperature,
and water (8 mL) was added. After extraction with EtOAc (15 mL ꢃ 2), the organic
phase was washed with water (10 mL ꢃ 2) and dried over NaSO . The solvent was
4
removed, and the residue was recrystallized from ethanol to yield the specified

N-METHYLATION OF NH-CONTAINING HETEROCYCLES
133
1
product. All the products were known compounds, and the data of mp and H NMR
accord with those reported in the literature.
Selected Data
[
N-Methylphthalimide (3) . Mp: 130–132 C; H NMR (CDCl , 400 MHz)
15]
ꢀ
1
3
d 3.22 (s, 3H, CH ), 7.73–7.76 (m, 2H, Ar-H), 7.86–7.89 (m, 2H, Ar-H). MS (EI,
3
þ
m=z): 161 [M] .
[
16]
ꢀ
-Nitro-N-methylphthalimide (5b) . Mp: 178–180 C; H NMR (CDCl ,
3
1
4
4
1
00 MHz) d 3.18 (s, 3H, CH ), 7.96 (d, J ¼ 8.1 Hz, 1H, Ar-H), 8.52 (d, J ¼ 8.1 Hz,
3
þ
H, Ar-H), 8.60 (s, 1H, Ar-H). MS (EI, m=z): 206 [M] .
[
17]
1
1
-Methyl-1H-indole (6b) . Colorless liquid; H NMR (CDCl , 400 MHz) d
3
3
7
.75 (s, 3H, CH ), 6.46 (d, J ¼ 3.8 Hz, 1H, Ar-H), 7.01 (d, J ¼ 3.8 Hz, 1H, Ar-H),
3
.08–7.11 (m, 1H, Ar-H), 7.20–7.22 (m, 1H, Ar-H), 7.28 (d, J ¼ 8.1 Hz, 1H,
þ
Ar-H), 7.61 (d, J ¼ 8.1 Hz, 1H, Ar-H). MS (EI, m=z): 131 [M] .
[
-Methyl-5-bromo-1H-lindole (7b) . Colorless liquid; H NMR (CDCl ,
18]
1
1
3
4
1
00 MHz) d 3.76 (s, 3H, CH ), 6.43 (d, J ¼ 3.4 Hz, 1H, Ar-H), 7.03 (d, J ¼ 3.4 Hz,
3
H, Ar-H), 7.16 (d, J ¼ 8.8 Hz, 1H, Ar-H), 7.28 (dd, J ¼ 8.8 Hz, J ¼ 1.8 Hz, 1H,
þ
Ar-H), 7.76 (d, J ¼ 1.8 Hz, 1H, Ar-H). MS (EI, m=z): 210 [M] .
[
-Methyl-1H-benzimidazole (8b) . Mp: 60–61 C; H NMR (CDCl3,
19]
ꢀ
1
1
4
7
00 MHz) d 3.87 (s, 3H, CH ), 7.29–7.35 (m, 2H, Ar-H), 7.41–7.43 (m, 1H, Ar-H),
3
þ
.83 (d, J ¼ 8.6 Hz, 1H, Ar-H), 7.90 (s, 1H, Ar-H). MS (EI, m=z): 132 [M] .
[
20]
ꢀ
-Methyl-9H-carbazole (9b) . Mp: 80–82 C; H NMR (CDCl , 400 MHz)
3
1
9
d 3.79 (s, 3H, CH ), 7.18 (t, J ¼ 8.6 Hz, 2H, Ar-H), 7.33 (d, J ¼ 7.8 Hz, 2H, Ar-H), 7.40
3
þ
(
t, J ¼ 8.6 Hz, 2H, Ar-H), 8.03 (d, J ¼ 7.8 Hz, 2H, Ar-H). MS (EI, m=z): 181 [M] .
[21]
ꢀ
1
0-Methyl-10H-phenothiazine (10b) . Mp: 97–99 C; H NMR (CDCl ,
1
3
þ
4
00 MHz) d 3.39 (s, 3H, CH ), 6.74–7.21 (m, 8H, Ar-H). MS (EI, m=z): 213 [M] .
3
[
22]
1
1
-Benzoyl-4-methylpiperazine (11b) . Colorless liquid;
H
NMR
(
3
CDCl , 400 MHz) d 2.25 (s, 3H, CH ), 2.38 (brs, 4H, CH ), 3.39 (brs, 2H, CH ),
3
3
2
2
þ
.72 (brs, 2H, CH ), 7.28–7.34 (m, 5H, Ar-H). MS (EI, m=z): 204 [M] .
2
[
-Methyl-1H-benzotrazole (13) . Mp: 60–62 C; H NMR (CDCl3,
23]
ꢀ
1
1
00 MHz): 4.29 (s, 3H, CH ), 7.35–7.40 (m, 1H, Ar-H), 7.48–7.53 (m, 2H, Ar-H),
4
8
3
þ
.02–8.08 (m, 1H, Ar-H). MS (EI, m=z): 133 [M] .
[
24]
ꢀ
1H-Benzotriazole-1-carboxylic acid methyl ester (14) . Mp: 78–80 C;
H NMR (CDCl , 400 MHz): 4.45 (s, 3H, CH ), 7.19–7.33 (m, 2H, Ar-H),
1
3
3
þ
7
.77–7.82 (m, 2H, Ar-H). MS (EI, m=z): 177 [M] .
ACKNOWLEDGMENTS
We are thankful to Donghua University Research Council and Shanghai
Municipal Nature Science Foundation (No. 10ZR1400700) for the partial financial
support of this work.

134
S.-Y. ZHAO ET AL.
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