A practical method for N-methylation of indoles using dimethyl carbonate

Article abstract of DOI:10.1021/op0102215

A new method for N-methylation of indoles using environmentally safe and less toxic methylating reagent, dimethyl carbonate (DMC), has been developed. The effect of various functional groups on the indole ring has been investigated. This method provides the desired product in high yields with high purity and is suitable for large-scale production. This process was used successfully in a 300-gal reactor train for N-methylation of 6-nitroindole.

Full text of DOI:10.1021/op0102215

Organic Process Research & Development 2001, 5, 604−608
A Practical Method for N-Methylation of Indoles Using Dimethyl Carbonate
Xinglong Jiang,*,† Ashish Tiwari,* Maethonia Thompson, Zhihong Chen, Thomas P. Cleary, and Thomas B. K. Lee
Pharmaceutical Process DeVelopment, Roche Carolina Inc., Florence, South Carolina 29506, U.S.A.
Abstract:
viable substitute for methyl iodide and dimethyl sulfate for
N-methylation of indoles. Herein we report a robust and
highly scalable process for N-methylation of indoles using
dimethyl carbonate (DMC).
A new method for N-methylation of indoles using environmen-
tally safe and less toxic methylating reagent, dimethyl carbonate
(DMC), has been developed. The effect of various functional
groups on the indole ring has been investigated. This method
provides the desired product in high yields with high purity
and is suitable for large-scale production. This process was used
successfully in a 300-gal reactor train for N-methylation of
6-nitroindole.
Results and Discussions
As depicted in Scheme 1, the reaction between an indole
substrate and DMC in the presence of a base was ac-
complished by heating the reagents in dimethylformamide
(DMF) to reflux for 2 to 3 h. The desired N-methylated
product was obtained either by precipitation or extraction
after addition of water to the reaction mixture.
Introduction
N-methylation of indoles with methyl iodide1,2 and
dimethyl sulfate3 in the presence of a variety of bases, such
as NaNH2,4 NaH,5 KOH,6 and NaOH,6 is a classical method
to form N-methylated indole derivatives. However, use of
this method for large-scale manufacturing has several
disadvantages. Methyl iodide has a very low boiling point
(40 °C), causing air emission problems, and it is a suspected
carcinogen.7 Dimethyl sulfate is also highly toxic (LD50 orally
in rats is 440 mg/kg). In addition, the byproducts generated
by these methylating agents can cause waste disposal
problems. In view of these disadvantages, an alternate
methylating reagent and an efficient process for large-scale
manufacturing is highly desirable.
In recent years, dimethyl carbonate (DMC) has emerged
as a methylating agent in organic synthesis. Although it is
less reactive than methyl iodide and dimethyl sulfate, it has
the advantage of being much less toxic. DMC has been
successfully used to introduce a methyl group at the
R-position of arylacetonitriles and methyl aryl acetates.8 It
has also been used to selectively monomethylate primary
aromatic amines9 and N-methylate imidazoles.10 In addition
to DMC, dimethyloxalate has also been used for N-
methylation of indoles, carbazoles, and imidazole.11
During development of a process for a pharmaceutical
drug candidate, we required a less toxic but economically
Initial attempts to N-methylate 6-nitroindole (R ) 6-NO2)
with two types of Zeolite (13X and NaY) provided 1-methyl-
6-nitroindole in high yield (93-95%) with high purity
(>99.6%, area, HPLC). However, the reaction required a
large amount of Zeolite (>1.2 w/w to 6-nitroindole). Other
bases, such as potassium carbonate could also be used.
Potassium carbonate has several advantages over Zeolite. It
is needed only in a small amount and could easily be
removed in the workup by dissolving in water, thus eliminat-
ing a filtration step required for the Zeolite process.
Optimization studies on the stoichiometry of DMC (Table
1) led us to conclude that 2.0-3.0 equiv of DMC with the
substrate would work best for this reaction. Lower quantities
of DMC results in longer reaction times and higher quantities
of DMC drops the boiling point of the reaction mixture, again
prolonging the reaction time.
This process of N-methylation using DMC and potassium
carbonate proved highly scalable. It was used to conduct a
very successful campaign in a 300-gal reactor train for
N-methylation of 6-nitroindole.
Next, we focused our attention on the scope and utility
of the reaction. We examined the substituent effects on indole
system. As can be seen from Table 2, several electron-
withdrawing functional groups were investigated. There is
not much difference in reaction time and yields with
functional groups on the benzene or pyrrole ring of the indole
system. All substrates tested with this method afforded high
yields of N-methylated products.
† Present address: Process Research & Development Novartis Pharmaceuticals
Co., East Hanover, NJ 07936.
(1) Reineeke, M. G.; Sebastian, J. F.; Johnson, H. W., Jr.; Pyun, C. J. Org.
Chem. 1972, 37, 3066.
(2) Nunomoto, S.; Kawakami, Y.; Yamashita, Y.; Takeuchi, H.; Eguchi, S. J.
Chem. Soc., Perkin Trans. 1 1990, 111
(3) Stauton, R. S.; Topham, A. J. Chem. Soc. 1953, 1889.
(4) Potts, K. T.; Saxton, J. E. Organic Syntheses; Wiley: New York, 1973;
Collect. Vol. IV, p 769.
(5) Buchi, G.; Mak, C.-P. J. Org. Chem. 1977, 42, 1784.
(6) Ottoni, O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54, 13915.
(7) Lissel, M.; Rohani-Dezsuli, A. R.; Vogt, G. J. Chem. Res. 1989, 312.
(8) Tundo, P.; Selva, M.; Bomben, A. Org. Synth. 1998, 76, 169.
(9) Selva, M.; Bomben, M.; Tundo, P. J. Chem. Soc., Perkin Trans. 1 1997,
1041.
To investigate the selectivity between N- and O-methy-
lation the reaction between 3-indolylcarboxylic acids and
DMC was studied (Table 3). The selectivity between
esterification and N-methylation was not high. However, as
expected, the esterification was slightly faster than N-
methylation.
The reaction of 3-indolylpropionic acid with dimethyl
carbonate in the presence of potassium carbonate in DMF
afforded 65% N-,O-dimethylated product after 4 h at reflux
temperature, together with 30% of only O-methylated
(10) Lissel, M.; Schmidt, S.; Newmann, B. Synthesis 1986, 382.
(11) Bergman, J.; Norrby, P.; Sand, P. Tetrahedron 1990, 46, 6113.
604
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Vol. 5, No. 6, 2001 / Organic Process Research & Development
10.1021/op0102215 CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Published on Web 11/16/2001

Scheme 1. N-Methylation of indoles using DMC
Table 1. Optimization of DMC stoichiometry
Table 4. Selectivity between N- and C-methylation
reaction time N-methyla N-,C-dimethyla
base
catalyst
(h)
% (2)
% (3)
K2CO3 none
30
2.5
3
2.5
6
89
93
90
92
79
8
2.5
3
3
3.5
none
TBAB
KOH TBAB
NaOH TBAB
NaOH 18-crown-6
ratio (mol) DMC/6-nitroindole
reaction time (h)
yield (%)
0.8
1.1
1.6
2.0
2.2
8
3
2.5
2.0
1.5
50.0
96.5
96.7
95.8
96.4
a Results reported are based on HPLC area %.
decarboxylation of 3-indolylcarboxylic acid at high temper-
ature (128 °C).
Table 2. Electron-withdrawing effects on indole system
With DMC as a methylating agent, the N-methylation of
indole systems containing electron-donating groups was also
studied. For example, N-methylation of 5-methoxyindole
with DMC at reflux temperature for 5 h gave 1-methyl-5-
methoxyindole in 97% isolated yield. However, other
substrates, such as gramine, 3-indolylmethanol, 3-indolyle-
thanol and tryptamine gave complex mixtures.
substituent
(R)
reaction
time (h)
N-methylated
product yield (%)
To further illustrate the utility of this method, 3-indoly-
lacetonitrile was chosen to examine the selectivity between
N-methylation and C-methylation of activated methylene
group. Faul and co-workers have reported quantitative
N-methylation of 3-indolylacetonitrile using methyl iodide.12
We wanted to see if similar selectivity can be obtained with
DMC as methylating agent. The results of our experiments
are listed in Table 4. The reaction of 3-indolylacetonitrile
with DMC in the presence of a base in DMF gave a mixture
of N-methylated and N-,C-dimethylated product. However
the amount of R-methylation can be altered by changing the
reagents and reaction conditions. In the presence of DMC
and potassium carbonate, along with 89% of 1-methyl-3-
indolylacetonitrile (2), dimethylated byproduct (3) was also
produced in 8% yield. However, the reaction was sluggish,
and it took 30 h to convert 3-indolylacetonitrile to the desired
products. This difficulty was overcome by using a phase
transfer catalyst (PTC).
For example, when using 18-crown-6 and a base (NaOH)
the amount of dimethylated byproduct (3) was reduced to
about 3%. Under these reaction conditions, 75-80% of the
desired product, 1-methyl-3-indolylacetonitrile, was obtained
within 5-6 h. With tetrabutylammonium bromide (TBAB)
and a base (NaOH or KOH) the reaction time dropped to
2.5-3 h, and the level of dimethylated byproduct remained
around 3%. However, to our surprise, TBAB alone was just
as effective in achieving selective N-methylation without the
presence of any base.
3-CN
3.5
2.0
3.0
2.0
3.5
3.5
3.5
3.5
97
96
97
97
95
96
85
96
4-NO2
5- NO2
6- NO2
5-Br
6-Cl
3-CHO
3-CO2CH3
Table 3. Selectivity between N- and O-methylation
substituent (R)
3-COOH
reaction time (h)
product yield (%)
5
6
N-,O-dimethylation (50%)
N-methylindole (45%)
N-,O-dimethylation (89%)
O-methylation (8%)
N-,O-dimethylation (95%)
N-,O-dimethylation (65%)
O-methylation (30%)
3-CH2COOH
8
4
3-CH2CH2COOH
8
N-,O-dimethylation (93%)
product. After the reaction mixture was heated at reflux for
another 4 h, only dimethylated product was obtained in 93%
yield. As demonstrated in Table 3, similar results were
observed with 3-indolylacetic acid. With 3-indolylcarboxylic
acid, however, along with 50% of the dimethylated product,
45% of N-methylindole was isolated, probably due to the
For comparison purposes, indoline and aniline were
methylated with DMC. As depicted in reaction Scheme 2,
both indoline and aniline were converted to the desired
(12) Faul, M.; Winnerosky, L.; Krumrich, C. J. Org. Chem. 1998, 63, 6053.
Vol. 5, No. 6, 2001 / Organic Process Research & Development
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605

Scheme 2. N-Methylation of indoline and aniline using
DMC
dimethyl carbonate was added in one portion. The mixture
was again refluxed for another 7 h when TLC indicated
complete disappearance of the starting material. The reaction
mixture was cooled to room temperature, and 150 mL of
water was slowly added. The resulting mixture was extracted
with 150 mL of TBME. The organic layer was washed with
2 × 100 mL of water and evaporated under vacuum to isolate
the product, 1-methylindole, as light-yellow oil in 96.5%
yield.
1H NMR (400 MHz, CDCl3): δ 3.842 (s, 3H), 6.556-
6.536 (d, 1H), 7.088-7.096 (d, 1H), 7.191-7.212 (m, 1H),
7.281-7.319 (m, 1H), 7.374-7.394 (m, 1H), 7.703-7.723
(d, 1H).
13C NMR (400 MHz, CDCl3): δ 32.688, 100.798,
109.121, 119.188, 120.789, 121.403, 128.405, 128.716,
136.614.
products in high yields(>90%). However, a longer reaction
time was required for indoline (9 h). For aniline, 20 h was
required even in the presence of PTC (18-crown-6).
Mechanistic studies for this methylation with dimethyl
carbonate is under way, and the results will be reported in
due course.
N-Methylation of 3-Cyanoindole. One gram (7.03 mmol)
of 3- cyanoindole, 0.5 g of K2CO3, 10 mL of DMF, and 1.8
mL (21.4 mmol) of dimethyl carbonate were mixed together
and heated to reflux (around 130 °C). The reaction was
complete in 3.5 h. The reaction mixture was cooled to 3 °C,
and 25 mL of ice cold water was slowly added. The product
precipitated as oily suspension. The mixture was extracted
with 40 mL of tert-butyl methyl ether (TBME) and washed
with 3 × 25 mL of water. The organic layer was evaporated
under vacuum to obtain the product, 3-cyano-1-methylindole,
as dark oil in 97.4% yield.
Conclusions
Methylation with dimethyl carbonate (DMC) has been
found to be a practical method to prepare N-methylated
indole analogues in high yields and purity. By changing the
reaction conditions, this method provides a high selectivity
of N-methylation over C-methylation in activated methylene
compounds. This method also provides an efficient way to
synthesize N-methylindole carboxylic acid methyl ester (N-
and O-dimethylation) from indole carboxylic acid in one pot.
1H NMR (400 MHz, CDCl3): δ 3.805 (s, 3H), 7.275 (m,
3H), 7.499 (s, 1H), 7.712 (d, 1H).
Experimental Section
Solvents and reagents were obtained from commercial
sources and used without further purification. NMR was
performed on a Varian 400 MHz spectrometer. HPLC was
performed on a Hewlett-Packard 1100 system with UV
detection at 254 nm. Separation was accomplished using a
Zorbax SB-CN column (L ) 250 mm, i.d. ) 4.6 nm) and
mobile phase (with gradient) consisting of 25% acetonitrile:
75% potassium phosphate buffer (pH 2.5).
N-Methylation of 6-Nitroindole. Sixty grams (370
mmol) of 6-nitroindole, 12 g of K2CO3, 240 mL of DMF,
and 66 mL (790 mmol) of DMC were mixed together and
heated to reflux (around 126 °C). The reaction was (moni-
tored by HPLC) complete within 2 h. After the completion
of the reaction, the mixture was cooled to about 5 °C, and
480 mL of ice cold water was added slowly. The product
precipitated as a bright yellow solid during the addition. The
product, N-methyl-6-nitroindole, was washed with 250 mL
of water and dried under vacuum at 60 °C for 24 h to give
a 96% yield.
1H NMR (400 MHz, CDCl3): δ 3.87 (s, 3H), 6.56 (d,
1H), 7.33 (d, 1H), 7.61 (d, 1H), 7.97(d, 1H), 8.27 (d, 1H).
13C NMR (400 MHz, CDCl3): δ 33.14, 102.03, 106.24,
114.68, 120.58, 133.16, 134.54, 135.14, 142.78.
N-Methylation of Indole. Ten grams (85 mmol) of
indole, 5 g of K2CO3, 70 mL of DMF, and 11 mL (130
mmol) of dimethyl carbonate were mixed together and
refluxed (around 130 °C) for 2 h. At this point TLC (silica
gel; hexane:ethyl acetate 7:3, Rf1 0.46, Rf2 0.55) showed
starting material largely unchanged. The reaction mixture
was cooled to about 50 °C, and another 5.5 mL (65 mmol)
13C NMR (400 MHz, CDCl3): δ 33.625, 85.331, 110.413,
116.012, 119.738, 122.127, 123.857, 127.772, 135.625,
136.012.
N-Methylation of 5-Bromoindole. Three grams (15
mmol) of 5-bromoindole, 1.5 g of K2CO3, 20 mL of DMF,
and 3.9 mL (46 mmol) of dimethyl carbonate were mixed
together and heated to reflux (around 130 °C) for 3.5 h. After
the completion of the reaction, the mixture was cooled to
about 3 °C, and 50 mL of ice cold water was slowly added.
The product appeared as light-brown oily suspension. The
product, 5-bromo-1-methylindole, was extracted with 60 mL
of TBME and washed with 3 × 50 mL of water. The solvent
was evaporated under vacuum to isolate the product as light
brown oil in 94.8% yield.
1H NMR (400 MHz, CDCl3): δ 3.678 (s, 3H), 6.372-
6.381 (d, 1H), 6.976-6.984 (d, 1H), 7.098-7.120 (d, 1H),
7.237-7.263 (m, 1H), 7.709-7.714 (d, 1H).
13C NMR (400 MHz, CDCl3): δ 32.862, 100.419,
110.600, 112.542, 123.163, 124.165, 129.907, 130.029,
135.256.
N-Methylation of 6-Chloroindole. One gram (6.59
mmol) of 6-chloroindole, 0.5 g of K2CO3, 10 mL of DMF,
and 1.7 mL (20 mmol) of DMC were mixed together and
heated to reflux (around 130 °C). The reaction was complete
in 3.5 h. The reaction mixture was cooled to 3 °C, and 25
mL of ice cold water was slowly added. The product,
6-chloro-1-methylindole, precipitated as oily suspension. The
mixture was extracted with 30 mL of TBME, which was
washed with 3 × 25 mL of water and evaporated under
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vacuum to isolate the product as light-yellow oil in 96.1%
yield.
Methylation of 3-Indolylacetonitrile. Five grams of
3-indolylacetonitrile, 2.5 g of base (K2CO3/KOH/NaOH), 10
mL of dimethyl carbonate, 40 mL of dimethylformamide
(DMF), and 1 g of catalyst (TBAB/18-crown-6) were mixed
together and heated to reflux. The reaction was monitored,
and the products were identified by HPLC. The products (a
mixture of N-methylated and N-,C-dimethylated 3-indoly-
lacetonitrile) were isolated by cooling the reaction mixture
to room temperature and adding 80 mL of water. Then an
extraction was carried out with 100 mL of TBME which
was washed twice with 100 mL of water. TBME was distilled
under vacuum to about 20 mL. The resulting mixture was
cooled in ice-bath, and 100 mL of heptane was added
dropwise with vigorous agitation. The product precipitated
on cooling to -15 °C. It was filtered, washed with 50 mL
of heptane, and dried under vacuum at 25 °C. No further
purification was performed.
Methylation of Indole-3-carboxylic Acid. Indole-3-
carboxylate (2.5 g), 1.25 g of potassium carbonate, 20 mL
of DMF, and 3.9 mL of dimethyl carbonate (DMC) were
mixed and heated to reflux (about 130 °C) for 5 h. The
reaction was monitored, and the products were identified by
HPLC. After the reaction was complete, the reaction mixture
was cooled to room temperature, and then 50 mL of water
and 100 mL of TBME were added. Two layers were
separated, and the organic layer was washed twice with 50
mL of water. The solvent was evaporated under reduced
pressure. The crude was identified (by HPLC) as 50%
N-methylindole (decarboxylated byproduct) and 50% methyl-
(N-methyl)-indole-3-carboxylate. The crude mixture was
subjected to column chromatography on silica gel (hexane/
ethyl acetate, 70:30) to isolate the pure products.
1H NMR (400 MHz, CDCl3): δ 3.714 (s, 3H), 6.435-
6.445 (m, 1H), 7.002-7.009 (d, 1H), 7.047-7.073 (m, 1H),
7.291-7.296 (m, 1H), 7.493-7.514 (d, 1H).
13C NMR (400 MHz, CDCl3): δ 32.809, 101.110,
109.189, 119.901, 121.623, 126.941, 127.472 129.475,
137.054.
N-Methylation of Indole-3-carboxaldehyde. Three grams
(20 mmol) of indole-3-carboxaldehyde, 1.5 g of K2CO3, 20
mL of DMF, and 5.2 mL (61 mmol) of dimethyl carbonate
were mixed together and heated to reflux (around 130 °C).
The reaction was complete within 3.5 h. The reaction mixture
was cooled to about 3 °C, and 60 mL of ice cold water was
slowly added. The product precipitated as dark oily suspen-
sion. The product was extracted with 60 mL of TBME, which
was washed with 2 × 50 mL of water and evaporated under
vacuum to isolate the product, indole-(1-methyl)-3-carbox-
alehyde, as dark-brown oil in 85% yield.
1H NMR (400 MHz, CDCl3): δ 3.812 (s, 3H), 7.324-
7.327 (m, 3H), 7.605 (s, 1H), 8.3 (d, 1H), 9.938 (s, 1H).
13C NMR (400 MHz, CDCl3): δ 33.678, 109.906,
118.023, 121.999, 122.924,124.024, 125.246, 137.884,
139.356, 184.442.
N-Methylation of Methyl Indolyl-3-carboxylate. Five
grams (29 mmol) of methyl indolyl-3-carboxylate, 2.5 g of
K2CO3, 35 mL of DMF and 7.2 mL (85 mmol) of dimethyl
carbonate were mixed together and heated to reflux (around
130 °C) for 3.5 h. After the completion of the reaction, the
mixture was cooled to about 3 °C, and 100 mL of ice cold
water was slowly added. The product precipitated as pale-
white solid. The product, N-methyl-indolyl-3-carboxylate,
was filtered and washed with 2 × 50 mL of water and dried
in a vacuum at 45 °C for 24 h. No further purification was
performed. The isolated yield was 96.3%.
N-Methylindole: 1H NMR (400 MHz, CDCl3): δ 3.842
(s, 3H), 6.556-6.536 (d, 1H), 7.088-7.096 (d, 1H), 7.191-
7.212 (m, 1H), 7.281-7.319 (m, 1H), 7.374-7.394 (m, 1H),
7.703-7.723 (d, 1H). 13C NMR (400 MHz, CDCl3): δ
32.688, 100.798, 109.121, 119.188, 120.789, 121.403, 128.405,
128.716, 136.614.
1H NMR (400 MHz, CDCl3): δ 3.830 (s, 3H), 3.908 (s,
3H), 7.256-7.361 (m, 3H), 7.777 (s, 1H), 8.160-8.185 (m,
1H).
13C NMR (400 MHz, CDCl3): δ 33.416, 50.948, 106.890,
109.728, 121.631, 121.851, 122.753, 126.569,135.127,
137.152, 165.450.
Methyl-indole-(N-methyl)-3-carboxylate: 1H NMR (400
MHz, CDCl3): δ 3.830 (s, 3H), 3.903 (s, 3H), 7.276-7.342
(m, 3H), 7.777(s, 1H), 8.160-8.185 (m, 1H). 13C NMR (400
MHz, CDCl3): δ 33.416, 50.948, 106.89, 109.728, 121.621,
121.851, 122.753, 126.569, 135.127, 137.152, 165.450.
Methylation of Indole-3-acetic Acid. Three grams of
indole-3-acetic acid, 1.5 g of potassium carbonate (powder),
20 mL of DMF, and 4.3 mL of dimethyl carbonate (DMC)
were mixed together and heated to reflux (about 130 °C)
for 6 h. The reaction was monitored by HPLC. After the
reaction was complete, the reaction mixture was cooled to
room temperature and 50 mL of water and 60 mL of TBME
were added. Two layers were separated, and the organic layer
was washed with 50 mL of water. The solvent was
evaporated under reduced pressure. The crude was identified
(by HPLC) as 89% N-,O-dimethylated product (methyl-
indole-(N-methyl)-3-acetate) and 8% O-methylated product
(methyl-indole-3-acetate). The crude mixture was subjected
N-Methylation of 5-Methoxyindole. One gram (6.79
mmol) of 5-methoxyindole, 0.5 g of K2CO3, 10 mL of DMF,
and 1.7 mL (20 mmol) of dimethyl carbonate were mixed
together and refluxed (around 130 °C) for 5 h. The reaction
was monitored by HPLC. After the completion of the
reaction, the mixture was cooled to about 3 °C, and 30 mL
of ice cold water was slowly added. The product, 1-methyl-
5-methoxyindole, precipitated as white solid. The product
was filtered and washed with 2 × 30 mL of water, followed
by 30 mL of hexane and dried under vacuum at 25 °C for
48 h. The isolated yield was 97.4%.
1H NMR (400 MHz, CDCl3): δ 3.765 (s, 3H), 3.854 (s,
3H), 6.396-6.406 (m, 1H), 6.877-6.905 (m, 1H), 7.015-
7.023 (d, 1H), 7.092-7.098 (d, 1H), 7.202-7.224 (m, 1H).
13C NMR (400 MHz, CDCl3): δ 32.981, 55.916, 100.376,
102.515, 109.905, 111.870, 128.774, 129.305, 132.135,
153.985.
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to column chromatography on silica gel (hexane/ethyl acetate,
70:30) to isolate the pure products.
Methyl-indole-3-propionate: 1H NMR (400 MHz,
CDCl3): δ 2.649-2.687 (m, 2 H), 3.035-3.073 (m, 2 H),
3.585 (s, 3H), 6.783-7.553 (m, 5 h). 13C NMR (400 MHz,
CDCl3): δ 20.603, 34.751, 51.548, 111.260, 114.371,
118.528, 119.127, 121.616, 121.828, 127.040, 136.280,
174.106.
1
Methyl-indole-3-acetate: H NMR (400 MHz, CDCl3):
δ 3.657 (s, 3H), 3.746 (s, 2H), 6.898-7.591 (m, 5 h). 13C
NMR (400 MHz, CDCl3): δ 30.973, 51.813, 107.702,
111.230, 118.528, 119.378, 121.858, 123.239, 126.979,
136.007,172.763
N-Methylation of Indoline. Three grams (25 mmol) of
indoline, 1.5 g of K2CO3, 20 mL of DMF, and 6.4 mL (76
mmol) of DMC were mixed together and heated to reflux
(around 130 °C) for 14 h. The reaction was monitored by
TLC (silica gel, hexane: ethyl acetate; 8:2, Rf indoline )
0.22, Rf1 (component 1) ) 0.48, Rf2 (component 2) ) 0.36)
and HPLC. After 14 h, the percent composition of the
reaction mixture was as follows: indoline, 0.3%; N-meth-
ylindoline, 98.8% (area % HPLC). The reaction mixture was
cooled to room temperature, and 50 mL of water was slowly
added. The product was extracted with 60 mL of TBME,
washed with 3 × 50 mL of H2O. The product, N-methylin-
doline, was isolated as light-yellow oil by evaporating the
solvent under vacuum, in 95% yield.
Methyl-indole-(N-methyl)-3-acetate: 1H NMR (400 MHz,
CDCl3): δ 3.662 (s, 3H), 3.679 (s, 3H), 3.742 (s, 2 H),
6.980-7.569 (m, 5 h). 13C NMR (400 MHz, CDCl3): δ
31.147, 32.717, 52.026, 106.850, 109.339, 119.042, 119.285,
121.864, 127.774, 127.850, 137.000, 172.682.
Methylation of Indole-3-propionic Acid. One gram of
indole-3-propionic acid, 0.5 g of potassium carbonate, 10
mL of DMF, and 1.33 mL of dimethyl carbonate (DMC)
were mixed, and the resulting mixture was heated to reflux
(about 130 °C) for 5 h. The reaction was monitored by
HPLC. After the reaction was complete, the reaction mixture
was cooled to room temperature and 25 mL of water and 40
mL of TBME were added. Two layers were separated, and
the organic layer was washed twice with 5 mL of water.
The solvent was evaporated under reduced pressure. The
crude was identified (by HPLC) as 65% N-,O-dimethylated
product (methyl-indole-(N-methyl)-3-propionate) and 30%
O-methylated product (methyl-indole-3-propionate). The
crude mixture was subjected to column chromatography on
silica gel (hexane/ethyl acetate, 70:30) to isolate the pure
products.
1H NMR (400 MHz, CDCl3): δ 2.726 (s, 3H), 2.892-
2.2.912 (m, 2 H), 3.233-3.274 (m, 2 H), 3.662 (s, 3H),),
6.454-7.606 (m, 4 h).
13C NMR (400 MHz, CDCl3): δ 28.652, 36.147, 56.046,
107.103, 117.655, 124.149, 127.214, 130.165, 153.304.
Acknowledgment
Methyl-indole-(N-methyl)-3-propionate: 1H NMR (400
MHz, CDCl3): δ 2.662-2.701 (m, 2 H), 3.069-3.072 (m,
2 H) 3.643 (s, 3H), 3.662 (s, 3H),), 6.809-7.290 (m, 5 h).
13C NMR (400 MHz, CDCl3): δ 20.389, 32.362, 34.820,
51.373, 109.052, 113.225, 118.604, 118.605, 121.433, 126.122,
127.404, 136.849, 173.658.
We thank M. Kotun for providing the analytical support.
Received for review June 25, 2001.
OP0102215
608
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Vol. 5, No. 6, 2001 / Organic Process Research & Development