Convenient synthesis of pyrrole- and indolecarboxylic acid tert-butylesters

Article abstract of DOI:10.1081/SCC-200032421

The tert-butylesters of pyrrole- and indolecarboxylic acids are readily accessed by reacting the appropriate carboxylic acids with N,N-dimethylformamide di-tert-butyl acetal.

Full text of DOI:10.1081/SCC-200032421

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Convenient Synthesis of
Pyrrole‐ and Indolecarboxylic
Acid tert‐Butylesters
Joachim Ludwig a & Matthias Lehr a
a Institute of Pharmaceutical and Medicinal
Chemistry, Universityof Münster, Hittorfstrasse
58‐62, D‐48149, Münster, Germany
Published online: 19 Apr 2010.
To cite this article: Joachim Ludwig & Matthias Lehr (2004): Convenient Synthesis
of Pyrrole‐ and Indolecarboxylic Acid tert‐Butylesters, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry,
34:20, 3691-3695
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 20, pp. 3691–3695, 2004
Convenient Synthesis of Pyrrole- and
Indolecarboxylic Acid tert-Butylesters
*
Joachim Ludwig and Matthias Lehr
Institute of Pharmaceutical and Medicinal Chemistry,
University of Mu¨nster, Hittorfstrasse 58-62,
D-48149 Mu¨nster, Germany
ABSTRACT
The tert-butylesters of pyrrole- and indolecarboxylic acids are readily
accessed by reacting the appropriate carboxylic acids with N,N-dimethyl-
formamide di-tert-butyl acetal.
Key Words: di-tert-butyl acetal; tert-Butylester; N,N-Dimethylforma-
mide; Indolecarboxylic acid; Pyrrolecarboxylic acid.
For the synthesis of particular enzyme inhibitors, we needed tert-butyl-
esters of pyrrole- and indolecarboxylic acids as starting materials. To our
*
Correspondence: Matthias Lehr, Institute of Pharmaceutical and Medicinal
Chemistry, University of Mu¨nster, Hittorfstrasse 58-62, D-48149 Mu¨nster, Germany;
Fax: þ49 251 83 32144; E-mail: lehrm@uni-muenster.de.
3691
DOI: 10.1081/SCC-200032421
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

3692
Ludwig and Lehr
surprise, the simple tert-butylesters of pyrrole-3-, indole-4-, indole-5-, and
indole-7-carboxylic acid have not been described until now. For the synthesis
of the isomeric tert-butyl pyrrole-2-, indole-2-, indole-3-, and indole-6-
carboxylates, nonuniform methods have been published. Tert-butyl pyrrole-
2-carboxylate (3a) and tert-butyl indole-2-carboxylate (3c) have been
obtained by treatment of the corresponding acid with 2-methylprop-1-en
in the presence of sulfuric acid.[1–3] Beside this standard procedure for
the synthesis of tert-butylesters, tert-butyl 2,2,2-trichloroacetimidate/
boron trifluoride diethyl etherate was applied for the conversion of
pyrrole-2-carboxylate to its tert-butyl ester 3a.[4] Furthermore, indole-2-
carboxylic acid tert-butyl ester (3c) was prepared by thermal cyclization
of tert-butyl 2-azidocinnamate.[5] Irradiation of 3-diazo-4-oxo-3,4-dihydro-
quinoline in the presence of tert-butanol led to tert-butyl indole-3-
carboxylate (3d).[6] Indole-6-carboxylic acid ester 3g was afforded in a
Leimgruber–Batcho indole synthesis by treatment of 3-nitro-4-methyl-
benzoic acid tert-butylester with dimethylformamide dimethyl acetal/
pyrrolidine and subsequent hydrogenation in the presence of palladium on
charcoal.[7]
In our efforts to find a general direct route to all isomeric tert-butyl
pyrrole- and indolecarboxylates starting from the commercially available
carboxylic acids 1a–h, we first reacted indole-2- and -3-carboxylic acid, res-
pectively, with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, tert-butanol,
4-dimethylaminopyridine in CH2Cl2. With this method, the esterification
of N-protected amino acids had been achieved.[8] Unfortunately, product
formation did not occur in our case. The indole-3-carboxylic ester 3d could
be obtained in 78% yield by conversion of indole-3-carboxylic acid into its
acid chloride by reaction with thionyl chloride and catalytic amounts of
dimethylformamide (DMF) in tetrahydrofuran (THF) at room temperature
for 1 h followed by treatment with an excess of tert-butanol and triethylamine
under reflux for 2 h. However, in the case of the indole-2-carboxylic acid, this
reaction did not lead to the desired product.
Applying a method reported by Widmer for the synthesis of several
benzoic acid tert-butyl ester,[9] all isomeric tert-butyl pyrrole- and indole-
carboxylates (3a–h) could be readily afforded by reacting the carboxylic
acids 1a–h with an excess of N,N-dimethylformamide di-tert-butyl acetal
in refluxing benzene (Sch. 1). The yield of the products ranged from 32–
89% (Table 1).
In conclusion, N,N-dimethylformamide di-tert-butyl acetal was succes-
sfully employed to convert pyrrole- and indolecarboxylic acids into
their tert-butyl esters. The tert-butyl pyrrole-3-, indole-4-, indole-5-, and
indole-7-carboxylates synthesized with this method have not been described
before.

Synthesis of Pyrrole- and Indolecarboxylic Acid tert-Butylesters
3693
Scheme 1.
EXPERIMENTAL
Melting points were determined on a Bu¨chi B-540 apparatus and are
uncorrected. Hydrogen nuclear magnetic resonance (1H-NMR) spectra were
recorded on a Varian Mercury Plus 400 spectrometer (400 MHz). Mass
spectra were obtained on a Finnigan EI GCQ system.
Table 1. Preparation of tert-butyl pyrrole- and indolecarboxylates employing
N,N-dimethylformamide di-tert-butyl acetal.
Melting point
Position of the
ester moiety
Product
Yield (%)
Observed 8C
Lit. 8C
3a
3b
3c
2
3
2
75
58
89
87–89
82–84
104–105
49–50[1]
—
103–105[3]
109–110[5]
Oil[6]
3d
3e
3f
3
4
5
6
7
67
56
32
57
49
Oil
96
—
—
91–93
100–101
65–67
3g
3h
Not reported[7]
—

3694
Ludwig and Lehr
Representative Procedure
Pyrrole-3-carboxylic acid (1b) (0.50 g, 4.50 mmol) was suspended in
dry benzene (15 ml). N,N-Dimethylformamide di-tert-butyl acetal (2) (90%
purity, 4.07 g, 18 mmol) was added dropwise to the refluxing mixture within
30 min. The solution was refluxed for a further 30 min, cooled, diluted with
diethyl ether, and washed with sodium carbonate solution (5%), water, and
brine. The organic layer was dried with sodium sulfate, and the solvent was
evaporated. The residue was purified by silica gel chromatography (petroleum
ether/ethyl acetate, 9 : 1) and recrystallized from petroleum ether to give 3b as
a white solid.
For the synthesis of the indole derivatives, the amount of solvent was
doubled.
Spectral Data of New Pyrrole- and Indolecarboxylic
Acid tert-Butylesters
Tert-butyl pyrrole-3-carboxylate (3b). 1H-NMR (CDCl3): d (ppm) ¼
1.55 (s, 9H), 6.59 (m, 1H), 6.72 (m, 1H), 7.34 (m, 1H), 8.75
(s, broad, 1H). Mass spectrometry (MS) (EI) m/z (%): 167 Mþ (2),
111 (37), 94 (100).
Tert-butyl indole-4-carboxylate (3e). 1H-NMR (CDCl3): d (ppm) ¼ 1.68
(s, 9H), 7.18 (m, 1H), 7.23 (m, 1H), 7.34 (m, 1H), 7.57 (d, 1H), 7.88
(dd, 1H), 8.39 (s, broad, 1H). MS (EI) m/z (%): 217 Mþ (19), 161
(100), 144 (71).
Tert-butyl indole-5-carboxylate (3f). 1H-NMR (CDCl3): d (ppm) ¼ 1.63
(s, 9H), 6.64 (m, 1H), 7.26 (m, 1H), 7.38 (d, 1H), 7.87 (dd, 1H), 8.36
(m, 1H), 8.40 (s, broad, 1H). MS (EI) m/z (%): 217 Mþ (37), 161
(100), 144 (72).
Tert-butyl indole-7-carboxylate (3h). 1H-NMR (CDCl3): d (ppm) ¼ 1.66
(s, 9H), 6.59 (m, 1H), 7.14 (t, 1H), 7.30 (m, 1H), 7.84 (m, 2H), 9.88
(s, broad, 1H). MS (EI) m/z (%): 217 Mþ (15), 161 (100).
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Synthesis of Pyrrole- and Indolecarboxylic Acid tert-Butylesters
3695
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Received in the UK March 30, 2004