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
A new method for N-methylation of indoles using environmen- N-methylation of indoles. Herein we report a robust and
tally safe and less toxic methylating reagent, dimethyl carbonate highly scalable process for N-methylation of indoles using
(DMC), has been developed. The effect of various functional dimethyl carbonate (DMC).
groups on the indole ring has been investigated. This method
provides the desired product in high yields with high purity Results and Discussions
and is suitable for large-scale production. This process was used As depicted in Scheme 1, the reaction between an indole
successfully in a 300-gal reactor train for N-methylation of substrate and DMC in the presence of a base was ac-
6-nitroindole. 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
Introduction after addition of water to the reaction mixture.
N-methylation of indoles with methyl iodide1,2 and Initial attempts to N-methylate 6-nitroindole (R ) 6-NO2)
dimethyl sulfate3 in the presence of a variety of bases, such with two types of Zeolite (13X and NaY) provided 1-methyl-
as NaNH2,4 NaH,5 KOH,6 and NaOH,6 is a classical method 6-nitroindole in high yield (93-95%) with high purity
to form N-methylated indole derivatives. However, use of (>99.6%, area, HPLC). However, the reaction required a
this method for large-scale manufacturing has several large amount of Zeolite (>1.2 w/w to 6-nitroindole). Other
disadvantages. Methyl iodide has a very low boiling point bases, such as potassium carbonate could also be used.
(40 °C), causing air emission problems, and it is a suspected Potassium carbonate has several advantages over Zeolite. It
carcinogen.7 Dimethyl sulfate is also highly toxic (LD50 orally is needed only in a small amount and could easily be
in rats is 440 mg/kg). In addition, the byproducts generated removed in the workup by dissolving in water, thus eliminat-
by these methylating agents can cause waste disposal ing a filtration step required for the Zeolite process.
problems. In view of these disadvantages, an alternate Optimization studies on the stoichiometry of DMC (Table
methylating reagent and an efficient process for large-scale 1) led us to conclude that 2.0-3.0 equiv of DMC with the
manufacturing is highly desirable. substrate would work best for this reaction. Lower quantities
In recent years, dimethyl carbonate (DMC) has emerged of DMC results in longer reaction times and higher quantities
as a methylating agent in organic synthesis. Although it is of DMC drops the boiling point of the reaction mixture, again
less reactive than methyl iodide and dimethyl sulfate, it has prolonging the reaction time.
the advantage of being much less toxic. DMC has been This process of N-methylation using DMC and potassium
successfully used to introduce a methyl group at the carbonate proved highly scalable. It was used to conduct a
R-position of arylacetonitriles and methyl aryl acetates.8 It very successful campaign in a 300-gal reactor train for
has also been used to selectively monomethylate primary N-methylation of 6-nitroindole.
aromatic amines9 and N-methylate imidazoles.10 In addition Next, we focused our attention on the scope and utility
to DMC, dimethyloxalate has also been used for N- of the reaction. We examined the substituent effects on indole
methylation of indoles, carbazoles, and imidazole.11 system. As can be seen from Table 2, several electron-
During development of a process for a pharmaceutical withdrawing functional groups were investigated. There is
drug candidate, we required a less toxic but economically not much difference in reaction time and yields with
functional groups on the benzene or pyrrole ring of the indole
† Present address: Process Research & Development Novartis Pharmaceuticals

Co., East Hanover, NJ 07936.

system. All substrates tested with this method afforded high
(1) Reineeke, M. G.; Sebastian, J. F.; Johnson, H. W., Jr.; Pyun, C. J. Org. yields of N-methylated products.
Chem. 1972, 37, 3066. To investigate the selectivity between N- and O-methy-
(2) Nunomoto, S.; Kawakami, Y.; Yamashita, Y.; Takeuchi, H.; Eguchi, S. J.
Chem. Soc., Perkin Trans. 1 1990, 111 lation the reaction between 3-indolylcarboxylic acids and
(3) Stauton, R. S.; Topham, A. J. Chem. Soc. 1953, 1889. DMC was studied (Table 3). The selectivity between
(4) Potts, K. T.; Saxton, J. E. Organic Syntheses; Wiley: New York, 1973;
Collect. Vol. IV, p 769.
esterification and N-methylation was not high. However, as
(5) Buchi, G.; Mak, C.-P. J. Org. Chem. 1977, 42, 1784. expected, the esterification was slightly faster than N-
(6) Ottoni, O.; Cruz, R.; Alves, R. Tetrahedron 1998, 54, 13915. methylation.
(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. The reaction of 3-indolylpropionic acid with dimethyl
(9) Selva, M.; Bomben, M.; Tundo, P. J. Chem. Soc., Perkin Trans. 1 1997, carbonate in the presence of potassium carbonate in DMF
1041.
(10) Lissel, M.; Schmidt, S.; Newmann, B. Synthesis 1986, 382. afforded 65% N-,O-dimethylated product after 4 h at reflux
(11) Bergman, J.; Norrby, P.; Sand, P. Tetrahedron 1990, 46, 6113. temperature, together with 30% of only O-methylated
604 • 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 4. Selectivity between N- and C-methylation

Table 1. Optimization of DMC stoichiometry

reaction time N-methyla N-,C-dimethyla
base catalyst (h) % (2) % (3)

K2CO3 none 30 89 8
none TBAB 2.5 93 2.5
ratio (mol) DMC/6-nitroindole reaction time (h) yield (%) KOH TBAB 3 90 3
NaOH TBAB 2.5 92 3
0.8 8 50.0 NaOH 18-crown-6 6 79 3.5
1.1 3 96.5 a Results reported are based on HPLC area %.
1.6 2.5 96.7
2.0 2.0 95.8
2.2 1.5 96.4
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
substituent reaction N-methylated substrates, such as gramine, 3-indolylmethanol, 3-indolyle-
(R) time (h) product yield (%) thanol and tryptamine gave complex mixtures.
To further illustrate the utility of this method, 3-indoly-
3-CN 3.5 97 lacetonitrile was chosen to examine the selectivity between
4-NO2 2.0 96
N-methylation and C-methylation of activated methylene
5- NO2 3.0 97
6- NO2 2.0 97 group. Faul and co-workers have reported quantitative
5-Br 3.5 95 N-methylation of 3-indolylacetonitrile using methyl iodide.12
6-Cl 3.5 96 We wanted to see if similar selectivity can be obtained with
3-CHO 3.5 85 DMC as methylating agent. The results of our experiments
3-CO2CH3 3.5 96
are listed in Table 4. The reaction of 3-indolylacetonitrile
with DMC in the presence of a base in DMF gave a mixture
Table 3. Selectivity between N- and O-methylation 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
substituent (R) reaction time (h) product yield (%) products. This difficulty was overcome by using a phase
transfer catalyst (PTC).
3-COOH 5 N-,O-dimethylation (50%)
N-methylindole (45%) For example, when using 18-crown-6 and a base (NaOH)
3-CH2COOH 6 N-,O-dimethylation (89%) the amount of dimethylated byproduct (3) was reduced to
O-methylation (8%) about 3%. Under these reaction conditions, 75-80% of the
8 N-,O-dimethylation (95%) desired product, 1-methyl-3-indolylacetonitrile, was obtained
3-CH2CH2COOH 4 N-,O-dimethylation (65%)
O-methylation (30%) within 5-6 h. With tetrabutylammonium bromide (TBAB)
8 N-,O-dimethylation (93%) 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
product. After the reaction mixture was heated at reflux for as effective in achieving selective N-methylation without the
another 4 h, only dimethylated product was obtained in 93% presence of any base.
For comparison purposes, indoline and aniline were
yield. As demonstrated in Table 3, similar results were
methylated with DMC. As depicted in reaction Scheme 2,
observed with 3-indolylacetic acid. With 3-indolylcarboxylic
both indoline and aniline were converted to the desired
acid, however, along with 50% of the dimethylated product,
45% of N-methylindole was isolated, probably due to the (12) Faul, M.; Winnerosky, L.; Krumrich, C. J. Org. Chem. 1998, 63, 6053.

Vol. 5, No. 6, 2001 / Organic Process Research & Development • 605

Scheme 2. N-Methylation of indoline and aniline using dimethyl carbonate was added in one portion. The mixture
DMC 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, CDCl ): δ 3.842 (s, 3H), 6.556-
3
6.536 (d, 1H), 7.088-7.096 (d, 1H), 7.191-7.212 (m, 1H),
products in high yields(>90%). However, a longer reaction
7.281-7.319 (m, 1H), 7.374-7.394 (m, 1H), 7.703-7.723
time was required for indoline (9 h). For aniline, 20 h was
(d, 1H).
required even in the presence of PTC (18-crown-6). 13C NMR (400 MHz, CDCl ): δ 32.688, 100.798,
3
Mechanistic studies for this methylation with dimethyl
109.121, 119.188, 120.789, 121.403, 128.405, 128.716,
carbonate is under way, and the results will be reported in
136.614.
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
Conclusions
mL (21.4 mmol) of dimethyl carbonate were mixed together
Methylation with dimethyl carbonate (DMC) has been
and heated to reflux (around 130 °C). The reaction was
found to be a practical method to prepare N-methylated
complete in 3.5 h. The reaction mixture was cooled to 3 °C,
indole analogues in high yields and purity. By changing the
and 25 mL of ice cold water was slowly added. The product
reaction conditions, this method provides a high selectivity
precipitated as oily suspension. The mixture was extracted
of N-methylation over C-methylation in activated methylene
compounds. This method also provides an efficient way to with 40 mL of tert-butyl methyl ether (TBME) and washed
synthesize N-methylindole carboxylic acid methyl ester (N- with 3 × 25 mL of water. The organic layer was evaporated
and O-dimethylation) from indole carboxylic acid in one pot. under vacuum to obtain the product, 3-cyano-1-methylindole,
as dark oil in 97.4% yield.
1H NMR (400 MHz, CDCl ): δ 3.805 (s, 3H), 7.275 (m,
Experimental Section 3

Solvents and reagents were obtained from commercial 3H), 7.499 (s, 1H), 7.712 (d, 1H).
13C NMR (400 MHz, CDCl ): δ 33.625, 85.331, 110.413,
sources and used without further purification. NMR was 3

performed on a Varian 400 MHz spectrometer. HPLC was 116.012, 119.738, 122.127, 123.857, 127.772, 135.625,
performed on a Hewlett-Packard 1100 system with UV 136.012.
detection at 254 nm. Separation was accomplished using a N-Methylation of 5-Bromoindole. Three grams (15
Zorbax SB-CN column (L ) 250 mm, i.d. ) 4.6 nm) and mmol) of 5-bromoindole, 1.5 g of K2CO3, 20 mL of DMF,
mobile phase (with gradient) consisting of 25% acetonitrile: and 3.9 mL (46 mmol) of dimethyl carbonate were mixed
75% potassium phosphate buffer (pH 2.5). together and heated to reflux (around 130 °C) for 3.5 h. After
N-Methylation of 6-Nitroindole. Sixty grams (370 the completion of the reaction, the mixture was cooled to
mmol) of 6-nitroindole, 12 g of K2CO3, 240 mL of DMF, about 3 °C, and 50 mL of ice cold water was slowly added.
and 66 mL (790 mmol) of DMC were mixed together and The product appeared as light-brown oily suspension. The
heated to reflux (around 126 °C). The reaction was (moni- product, 5-bromo-1-methylindole, was extracted with 60 mL
tored by HPLC) complete within 2 h. After the completion of TBME and washed with 3 × 50 mL of water. The solvent
of the reaction, the mixture was cooled to about 5 °C, and was evaporated under vacuum to isolate the product as light
480 mL of ice cold water was added slowly. The product brown oil in 94.8% yield.
1H NMR (400 MHz, CDCl ): δ 3.678 (s, 3H), 6.372-
precipitated as a bright yellow solid during the addition. The 3
product, N-methyl-6-nitroindole, was washed with 250 mL 6.381 (d, 1H), 6.976-6.984 (d, 1H), 7.098-7.120 (d, 1H),
of water and dried under vacuum at 60 °C for 24 h to give 7.237-7.263 (m, 1H), 7.709-7.714 (d, 1H).
13C NMR (400 MHz, CDCl ): δ 32.862, 100.419,
a 96% yield. 3
1H NMR (400 MHz, CDCl ): δ 3.87 (s, 3H), 6.56 (d,
3 110.600, 112.542, 123.163, 124.165, 129.907, 130.029,
1H), 7.33 (d, 1H), 7.61 (d, 1H), 7.97(d, 1H), 8.27 (d, 1H). 135.256.
13C NMR (400 MHz, CDCl ): δ 33.14, 102.03, 106.24,
3 N-Methylation of 6-Chloroindole. One gram (6.59
114.68, 120.58, 133.16, 134.54, 135.14, 142.78. mmol) of 6-chloroindole, 0.5 g of K2CO3, 10 mL of DMF,
N-Methylation of Indole. Ten grams (85 mmol) of and 1.7 mL (20 mmol) of DMC were mixed together and
indole, 5 g of K2CO3, 70 mL of DMF, and 11 mL (130 heated to reflux (around 130 °C). The reaction was complete
mmol) of dimethyl carbonate were mixed together and in 3.5 h. The reaction mixture was cooled to 3 °C, and 25
refluxed (around 130 °C) for 2 h. At this point TLC (silica mL of ice cold water was slowly added. The product,
gel; hexane:ethyl acetate 7:3, Rf1 0.46, Rf2 0.55) showed 6-chloro-1-methylindole, precipitated as oily suspension. The
starting material largely unchanged. The reaction mixture mixture was extracted with 30 mL of TBME, which was
was cooled to about 50 °C, and another 5.5 mL (65 mmol) washed with 3 × 25 mL of water and evaporated under
606 • Vol. 5, No. 6, 2001 / Organic Process Research & Development
vacuum to isolate the product as light-yellow oil in 96.1% Methylation of 3-Indolylacetonitrile. Five grams of
yield. 3-indolylacetonitrile, 2.5 g of base (K2CO3/KOH/NaOH), 10
1H NMR (400 MHz, CDCl ): δ 3.714 (s, 3H), 6.435-
3 mL of dimethyl carbonate, 40 mL of dimethylformamide
6.445 (m, 1H), 7.002-7.009 (d, 1H), 7.047-7.073 (m, 1H), (DMF), and 1 g of catalyst (TBAB/18-crown-6) were mixed
7.291-7.296 (m, 1H), 7.493-7.514 (d, 1H). together and heated to reflux. The reaction was monitored,
13
C NMR (400 MHz, CDCl3): δ 32.809, 101.110, and the products were identified by HPLC. The products (a
109.189, 119.901, 121.623, 126.941, 127.472 129.475, mixture of N-methylated and N-,C-dimethylated 3-indoly-
137.054. lacetonitrile) were isolated by cooling the reaction mixture
N-Methylation of Indole-3-carboxaldehyde. Three grams to room temperature and adding 80 mL of water. Then an
(20 mmol) of indole-3-carboxaldehyde, 1.5 g of K2CO3, 20 extraction was carried out with 100 mL of TBME which
mL of DMF, and 5.2 mL (61 mmol) of dimethyl carbonate was washed twice with 100 mL of water. TBME was distilled
were mixed together and heated to reflux (around 130 °C). under vacuum to about 20 mL. The resulting mixture was
The reaction was complete within 3.5 h. The reaction mixture
cooled in ice-bath, and 100 mL of heptane was added
was cooled to about 3 °C, and 60 mL of ice cold water was
dropwise with vigorous agitation. The product precipitated
slowly added. The product precipitated as dark oily suspen-
on cooling to -15 °C. It was filtered, washed with 50 mL
sion. The product was extracted with 60 mL of TBME, which
of heptane, and dried under vacuum at 25 °C. No further
was washed with 2 × 50 mL of water and evaporated under
purification was performed.
vacuum to isolate the product, indole-(1-methyl)-3-carbox-
alehyde, as dark-brown oil in 85% yield. Methylation of Indole-3-carboxylic Acid. Indole-3-
1
H NMR (400 MHz, CDCl3): δ 3.812 (s, 3H), 7.324- carboxylate (2.5 g), 1.25 g of potassium carbonate, 20 mL
7.327 (m, 3H), 7.605 (s, 1H), 8.3 (d, 1H), 9.938 (s, 1H). of DMF, and 3.9 mL of dimethyl carbonate (DMC) were
13C NMR (400 MHz, CDCl ): δ 33.678, 109.906,
3
mixed and heated to reflux (about 130 °C) for 5 h. The
118.023, 121.999, 122.924,124.024, 125.246, 137.884, reaction was monitored, and the products were identified by
139.356, 184.442. HPLC. After the reaction was complete, the reaction mixture
N-Methylation of Methyl Indolyl-3-carboxylate. Five was cooled to room temperature, and then 50 mL of water
grams (29 mmol) of methyl indolyl-3-carboxylate, 2.5 g of and 100 mL of TBME were added. Two layers were
K2CO3, 35 mL of DMF and 7.2 mL (85 mmol) of dimethyl separated, and the organic layer was washed twice with 50
carbonate were mixed together and heated to reflux (around mL of water. The solvent was evaporated under reduced
130 °C) for 3.5 h. After the completion of the reaction, the pressure. The crude was identified (by HPLC) as 50%
mixture was cooled to about 3 °C, and 100 mL of ice cold N-methylindole (decarboxylated byproduct) and 50% methyl-
water was slowly added. The product precipitated as pale- (N-methyl)-indole-3-carboxylate. The crude mixture was
white solid. The product, N-methyl-indolyl-3-carboxylate, subjected to column chromatography on silica gel (hexane/
was filtered and washed with 2 × 50 mL of water and dried ethyl acetate, 70:30) to isolate the pure products.
in a vacuum at 45 °C for 24 h. No further purification was N-Methylindole: 1H NMR (400 MHz, CDCl3): δ 3.842
performed. The isolated yield was 96.3%. (s, 3H), 6.556-6.536 (d, 1H), 7.088-7.096 (d, 1H), 7.191-
1H NMR (400 MHz, CDCl ): δ 3.830 (s, 3H), 3.908 (s,
3 7.212 (m, 1H), 7.281-7.319 (m, 1H), 7.374-7.394 (m, 1H),
3H), 7.256-7.361 (m, 3H), 7.777 (s, 1H), 8.160-8.185 (m, 7.703-7.723 (d, 1H). 13C NMR (400 MHz, CDCl3): δ
1H). 32.688, 100.798, 109.121, 119.188, 120.789, 121.403, 128.405,
13C NMR (400 MHz, CDCl ): δ 33.416, 50.948, 106.890,
3 128.716, 136.614.
109.728, 121.631, 121.851, 122.753, 126.569,135.127, Methyl-indole-(N-methyl)-3-carboxylate: 1H NMR (400
137.152, 165.450.
MHz, CDCl3): δ 3.830 (s, 3H), 3.903 (s, 3H), 7.276-7.342
N-Methylation of 5-Methoxyindole. One gram (6.79
(m, 3H), 7.777(s, 1H), 8.160-8.185 (m, 1H). 13C NMR (400
mmol) of 5-methoxyindole, 0.5 g of K2CO3, 10 mL of DMF,
MHz, CDCl3): δ 33.416, 50.948, 106.89, 109.728, 121.621,
and 1.7 mL (20 mmol) of dimethyl carbonate were mixed
121.851, 122.753, 126.569, 135.127, 137.152, 165.450.
together and refluxed (around 130 °C) for 5 h. The reaction
Methylation of Indole-3-acetic Acid. Three grams of
was monitored by HPLC. After the completion of the
reaction, the mixture was cooled to about 3 °C, and 30 mL indole-3-acetic acid, 1.5 g of potassium carbonate (powder),
of ice cold water was slowly added. The product, 1-methyl- 20 mL of DMF, and 4.3 mL of dimethyl carbonate (DMC)
5-methoxyindole, precipitated as white solid. The product were mixed together and heated to reflux (about 130 °C)
was filtered and washed with 2 × 30 mL of water, followed for 6 h. The reaction was monitored by HPLC. After the
by 30 mL of hexane and dried under vacuum at 25 °C for reaction was complete, the reaction mixture was cooled to
48 h. The isolated yield was 97.4%. room temperature and 50 mL of water and 60 mL of TBME
1H NMR (400 MHz, CDCl ): δ 3.765 (s, 3H), 3.854 (s,
3
were added. Two layers were separated, and the organic layer
3H), 6.396-6.406 (m, 1H), 6.877-6.905 (m, 1H), 7.015- was washed with 50 mL of water. The solvent was
7.023 (d, 1H), 7.092-7.098 (d, 1H), 7.202-7.224 (m, 1H). evaporated under reduced pressure. The crude was identified
13C NMR (400 MHz, CDCl ): δ 32.981, 55.916, 100.376,
3 (by HPLC) as 89% N-,O-dimethylated product (methyl-
102.515, 109.905, 111.870, 128.774, 129.305, 132.135, indole-(N-methyl)-3-acetate) and 8% O-methylated product
153.985. (methyl-indole-3-acetate). The crude mixture was subjected
Vol. 5, No. 6, 2001 / Organic Process Research & Development • 607
to column chromatography on silica gel (hexane/ethyl acetate, Methyl-indole-3-propionate: 1H NMR (400 MHz,
70:30) to isolate the pure products. CDCl3): δ 2.649-2.687 (m, 2 H), 3.035-3.073 (m, 2 H),
Methyl-indole-3-acetate: 1H NMR (400 MHz, CDCl3): 3.585 (s, 3H), 6.783-7.553 (m, 5 h). 13C NMR (400 MHz,
δ 3.657 (s, 3H), 3.746 (s, 2H), 6.898-7.591 (m, 5 h). 13C CDCl3): δ 20.603, 34.751, 51.548, 111.260, 114.371,
NMR (400 MHz, CDCl3): δ 30.973, 51.813, 107.702, 118.528, 119.127, 121.616, 121.828, 127.040, 136.280,
111.230, 118.528, 119.378, 121.858, 123.239, 126.979, 174.106.
136.007,172.763 N-Methylation of Indoline. Three grams (25 mmol) of
Methyl-indole-(N-methyl)-3-acetate: 1H NMR (400 MHz, indoline, 1.5 g of K2CO3, 20 mL of DMF, and 6.4 mL (76
CDCl3): δ 3.662 (s, 3H), 3.679 (s, 3H), 3.742 (s, 2 H), mmol) of DMC were mixed together and heated to reflux
6.980-7.569 (m, 5 h). 13C NMR (400 MHz, CDCl3): δ
(around 130 °C) for 14 h. The reaction was monitored by
31.147, 32.717, 52.026, 106.850, 109.339, 119.042, 119.285,
TLC (silica gel, hexane: ethyl acetate; 8:2, Rf indoline )
121.864, 127.774, 127.850, 137.000, 172.682.
0.22, Rf1 (component 1) ) 0.48, Rf2 (component 2) ) 0.36)
Methylation of Indole-3-propionic Acid. One gram of
and HPLC. After 14 h, the percent composition of the
indole-3-propionic acid, 0.5 g of potassium carbonate, 10
mL of DMF, and 1.33 mL of dimethyl carbonate (DMC) reaction mixture was as follows: indoline, 0.3%; N-meth-
were mixed, and the resulting mixture was heated to reflux ylindoline, 98.8% (area % HPLC). The reaction mixture was
(about 130 °C) for 5 h. The reaction was monitored by cooled to room temperature, and 50 mL of water was slowly
HPLC. After the reaction was complete, the reaction mixture added. The product was extracted with 60 mL of TBME,
was cooled to room temperature and 25 mL of water and 40 washed with 3 × 50 mL of H2O. The product, N-methylin-
mL of TBME were added. Two layers were separated, and doline, was isolated as light-yellow oil by evaporating the
the organic layer was washed twice with 5 mL of water. solvent under vacuum, in 95% yield.
1H NMR (400 MHz, CDCl ): δ 2.726 (s, 3H), 2.892-
The solvent was evaporated under reduced pressure. The 3
crude was identified (by HPLC) as 65% N-,O-dimethylated 2.2.912 (m, 2 H), 3.233-3.274 (m, 2 H), 3.662 (s, 3H),),
product (methyl-indole-(N-methyl)-3-propionate) and 30% 6.454-7.606 (m, 4 h).
O-methylated product (methyl-indole-3-propionate). The 13C NMR (400 MHz, CDCl ): δ 28.652, 36.147, 56.046,
3
crude mixture was subjected to column chromatography on 107.103, 117.655, 124.149, 127.214, 130.165, 153.304.
silica gel (hexane/ethyl acetate, 70:30) to isolate the pure
products. 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, We thank M. Kotun for providing the analytical support.
2 H) 3.643 (s, 3H), 3.662 (s, 3H),), 6.809-7.290 (m, 5 h).
13C NMR (400 MHz, CDCl ): δ 20.389, 32.362, 34.820,
3
Received for review June 25, 2001.
51.373, 109.052, 113.225, 118.604, 118.605, 121.433, 126.122,
127.404, 136.849, 173.658. OP0102215

608 • Vol. 5, No. 6, 2001 / Organic Process Research & Development