Convenient method of synthesizing 3-ethoxycarbonyl indoles

Article abstract of DOI:10.1021/jo0601821

We have developed a convenient two-step procedure for the synthesis of 3-ethoxycarbonyl indoles from commercially available materials. The two-step procedure involves the synthesis of 2-aryl-3-hydroxypropenoic acid ester, followed by a catalytic reduction

Full text of DOI:10.1021/jo0601821

SCHEME 1
Convenient Method of Synthesizing
3-Ethoxycarbonyl Indoles
M. Shahidul Islam, Courtney Brennan, Qinwei Wang, and
M. Mahmun Hossain*
Department of Chemistry and Biochemistry, UniVersity of
Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201
SCHEME 2
mahmun@uwm.edu
ReceiVed January 26, 2006
simple, convenient two-step synthesis of 3-ethoxycarbonyl
indoles (1) from commercially available starting materials.9
Our method is based on the catalytic hydrogenation of 2-(2-
nitroaryl)-3-hydroxypropenoic acid esters (2) to 3-ethoxycar-
bonyl indoles (1; Scheme 1).
We have developed a convenient two-step procedure for the
synthesis of 3-ethoxycarbonyl indoles from commercially
available materials. The two-step procedure involves the
synthesis of 2-aryl-3-hydroxypropenoic acid ester, followed
by a catalytic reduction. This method is efficient, simple,
and selective.
The 2-(2-nitroaryl)-3-hydroxypropenoic acid esters (2) were
prepared from 2-nitrobenzaldehydes (3) and ethyl diazoacetate
in the presence of 10% of iron Lewis acid, Fp+BF4 (Fp )
-
Cp(CO)2Fe).10 Several nitroaryl acid esters were synthesized
in good yields using this iron Lewis acid. Moreover, we recently
found that a simple Brønsted acid such as tetrafluoroboric acid
(HBF4) also catalyzes the reaction of 2-nitrobenzaldehydes with
ethyl diazoacetate to yield the 2-nitroarylacrylic acid ester in
very good yields (Scheme 2).11 The results from both Lewis
acids are summarized in Table 1. The yields of some propenoic
acid esters were also improved by carrying out these reactions
at a lower temperature (entries 3, 6, and 11).
The indole moiety is found in numerous natural and unnatural
products and is an important building block of several families
of alkaloids.1 Many of them have biological activities such as
Indocin2 (anti-inflammatory), Oncovin1b,3 (anti-cancer), Lescol4
(cholesterol-lowering), and Vinblastine5 (anti-cancer). Probably
the best-known compound containing the indole structure is
tryptophan, which is an essential amino acid.6 Many methods
exist for the synthesis of indoles, and they vary in complexity
and starting materials. The most famous synthesis is the Fischer
indole synthesis.7 One major drawback of this method is that a
mixture of indoles can result from unsymmetrical ketones. Many
other methods are known,8 but very few methods for synthesiz-
ing 3-substituted indole rings are available. Here, we report a
The reduction of the nitro group to the amine was carried
out using Pd/C in methanol under 3 atm of hydrogen for 24 h.
The Pd/C was removed by filtering the crude mixture through
Celite, and the indole was isolated by column chromatography
1
and identified by H and 13C NMR, CHN analysis, or HRMS.
The results of the reduction are listed in Table 2. The
unsubstituted indole gave the best result and was isolated in
90% yield.
In our attempt to improve the yield of the indole, we tried a
few different reducing agents, SnCl2‚2H2O,12 TiCl3 with am-
monium acetate,13 and ammonium formate with Pd/C.14 When
(1) (a) Rahman, A.; Basha, A. Indole Alkaloids; Harwood Academic
Publishers: Amsterdam, The Netherlands, 1998; p 141. (b) Gupta, R. R.
Heterocyclic Chemistry; Springer Publishing: New York, 1999; Vol. 2, p
193.
(2) Physicians Desk Reference, 51st ed.; Medical Economics, Co.:
Oradell, New Jersey, 1997; p 2395.
(3) Physicians Desk Reference, 51st ed.; Medical Economics, Co.:
Oradell, New Jersey, 1997; p 1723.
(4) (a) Physicians Desk Reference, 51st ed.; Medical Economics, Co.:
Oradell, New Jersey. 1997; p 1521. (b) Gupta, R. R. Heterocyclic Chemistry;
Springer Publishing: New York, 1999; Vol. 2, p 192.
(5) For a review on medicinal chemistry of Vinblastine, see: In The
Alkaloids: Antitumor Bisindole Alkaloids from Catharanthus roseus (L.);
Brossi, A., Suffness, M., Eds.; Academic Press, Inc.: San Diego, CA, 1990;
Vol. 37, pp 133-204.
(6) Meister, A. The Biochemistry of The Amino Acids, 2nd ed.; Academic
Press: New York, 1965; p 202.
(7) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New
York, 1970; p 142. (b) Jones, A. R. In ComprehensiVe Heterocyclic
Chemistry; Katrizky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford,
1984; Vol. 4, p 334. (c) Gupta, R. R. Heterocyclic Chemistry; Springer
Publishing: New York, 1999; Vol. 2, p 199. (d) Nakazaki, M.; Yamamoto,
K. J. Org. Chem. 1976, 41, 1877.
(8) For reviews, see: (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1
2000, 1045. (b) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 1999, 2848.
(c) Sundberg, R. J. Indoles; Academic Press: San Diego, CA, 1996. (d)
Moody, C. J. Synlett 1994, 681. (e) Gribble, G. W. Contemp. Org. Synth.
1994, 145. (f) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1.
(9) Aromatic aldehydes and ethyl diazoacetate are commercially avail-
able. Ethyl diazoacetate is also prepared in our laboratory following the
known procedure: Searle, N. E. In Organic synthesis; Rabjohn, N., Ed.;
Wiley: New York, 1963; Collect. Vol. No. IV, p 424. There is no difference
in the yield of the products by using commercial ethyl diazoacetate or by
using a freshly prepared one.
(10) Mahmood, S. J.; Hossain, M. M. J. Org. Chem. 1998, 63, 3333.
(11) Dudley, M.; Morshed, M. M.; Brennan, C.; Islam, M. S.; Ahmad,
M. S.; Atuu, M. R.; Branstetter, B.; Hossain, M. M. J. Org. Chem. 2004,
69, 7599.
(12) Faul, M. M. Tin (II) Chloride. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 7,
p 4893.
10.1021/jo0601821 CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/11/2006
J. Org. Chem. 2006, 71, 4675-4677
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TABLE 1. Isolated Yields of 2-Aryl-3-hydroxypropenoic Acid Ester from 2-Nitrobenzaldehydes and EDA
SCHEME 3
the propenoic acid esters were treated with these reducing
agents, no indoles were observed. As a result of a long reaction
time (24 h), we suspect some kind of polymerization during
reduction lowers the yield of the indole products. We also tried
adding a small amount of acetic acid during the reduction with
H2 on Pd/C to hopefully speed up the cyclization process and
to minimize the polymerization. However, no change in the yield
or in the reaction time was observed.
4676 J. Org. Chem., Vol. 71, No. 12, 2006

TABLE 2. Isolated Yields of 3-Ethoxycarbonyl Indoles by
Reduction
SCHEME 4
carboxylic acid (Scheme 4). The o-nitrophenylpyruvic ester was
synthesized from o-nitrotoluene and diethyl oxalate in the
presence of sodium ethoxide. The cyclization provides 2-sub-
stituted indoles, whereas our method produces the indoles with
an ester group at the 3 position. Our method certainly compli-
ments the Reissert approach and could be useful in the area of
heterocyclic chemistry. Work is underway using our methods
to synthesize some important biologically active products
containing 3-substituted indoles.
Experimental Section
HBF4‚OEt2-Catalyzed Reaction between 2-Nitrobenzaldehyde
and Ethyl Diazoacetate. To a solution of 2-nitrobenzaldehyde
(0.170 g, 1.15 mmol) in freshly distilled dichloromethane (15 mL)
was added HBF4‚OEt2 (0.02 mL, 0.115 mmol) at 0 °C. Ethyl
diazoacetate9 (0.153 mL, 1.38 mmol) was diluted in 4 mL of freshly
distilled dichloromethane and drawn into a gastight syringe. The
diluted ethyl diazoacetate was then added to the aldehyde over a
period of 6-7 h with the help of a syringe pump. The reaction
mixture was allowed to stir for an additional 16 h at 0 °C and then
filtered through a silica plug. The solvent was removed by rotary
evaporation and products were isolated by column chromatography
(silica gel, 2-10% ethyl acetate in pentane/hexane), providing ethyl
3-hydroxy-2-(2-nitrophenyl)propenate (2a)17 in 73% yield. 1H NMR
(CDCl3, 300 MHz): δ 11.93 (d, 1H, J ) 13 Hz), 7.94 (d, 1H, J )
8 Hz), 7.55 (t, 1H, J ) 8 Hz), 7.44 (t, 1H, J ) 8 Hz), 7.23 (m,
2H), 4.12 (br q, 2H), 1.12 (t, 3H, J ) 7 Hz). 13C NMR (CDCl3, 75
MHz): δ 169.85, 162.05, 149.05, 133.16, 132.10, 129.09, 128.44,
124.69, 106.50, 61.19, 13.62. Anal. Calcd. for C11H11NO5: C,
55.69; H, 4.68; N, 5.91. Found: C, 55.86; H, 4.60; N, 5.82.
Pd-Catalyzed Hydrogenation of Ethyl 3-Hydroxy-2-(2-nitro-
phenyl)propenate. A sample of ethyl 3-hydroxy-2-(2-nitrophenyl)-
propenate (0.167 g, 0.702 mmol) was dissolved in 10 mL methanol,
and 35 mg of Pd/C was added to the solution. The mixture was
stirred under hydrogen gas at 3 atm of pressure for 24 h. The Pd/C
was removed by passing the crude through a pad of Celite. The
solvent was removed by rotary evaporation, and indole-3-carboxylic
acid ethyl ester (1a)18 was isolated in 90% yield by column
The synthesis only requires two steps: first, the synthesis of
the 2-(2-nitroaryl)-3-hydroxypropenoic acid esters and then the
reduction to the corresponding indoles. Our proposed mechanism
(Scheme 3) entails reduction of the nitro group and subsequent
cyclization to the indole. Once the amine is formed, cyclization
is spontaneous. The cyclization is similar to the methods of
Reissert15 and others16 in that a nitro group is reduced to an
amine, which then undergoes a nucleophilic attack to form a
five-membered ring, followed by loss of water to form the indole
ring.
1
chromatography (silica gel, 0-10% EtOAc in pentane). H NMR
(CDCl3, 300 MHz): δ 8.66 (br s, 1H, NH), 8.21 (m, 1H), 7.94 (d,
1H, J ) 3 Hz), 7.43 (m, 1H), 7.32 (m, 2H), 4.44 (q, 2H, J ) 7
Hz), 1.45 (t, 3H, J ) 7 Hz). 13C NMR (CDCl3, 75 MHz): δ 165.25,
135.99, 130.85, 125.71, 123.09, 121.92, 121.49, 111.37, 109.08,
59.74, 14.46.
The classical Reissert indole synthesis15 involved the reduc-
tive cyclization of o-nitrophenylpyruvic ester to indole-2-
(13) Ho, T.; Wong, C. M. Synthesis 1974, 45.
Supporting Information Available: Detailed experimental
procedures and compound characterizations for 1b, 1c, 1d, 1e, 2b,
and 2d and other related information. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) (a) Ram, S.; Ehrenkaufer, R. E. Tetrahedron Lett. 1984, 25, 3415.
(b) Kabalka, G. W.; Pace, R. D.; Wadgaokar, P. P Synth. Commun. 1990,
20, 2453.
(15) (a) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New
York, 1970; p 176. (b) Jones, A. R. In ComprehensiVe Heterocyclic
Chemistry; Katrizky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford,
1984; Vol. 4, p 317. (c) Gupta, R. R. Heterocyclic Chemistry; Springer
Publishing: New York, 1999; Vol. 2, p 194.
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Heterocycl. Chem. 2004, 41, 3. (b) Belley, M.; Scheigetz, J.; Dube, P.;
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K.; Repic, O. Synth. Commun. 1995, 25, 95. (d) van den Berg, E. M. M.;
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Chem. 1966, 31, 345.
JO0601821
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