A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid derivatives and indoles based on the Reissert reaction

Article abstract of DOI:10.1016/j.tetlet.2018.09.039

The formation of 3-(2-nitrophenyl)pyruvic acid and its amide and ester derivatives – key compounds for the Reissert indole synthesis – was achieved under various reaction conditions via the acid catalyzed hydrolysis of 5-(2-nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one, which is readily available from 3-(2-nitrophenyl)oxirane-2-carboxamide. A new and highly efficient method for the synthesis of indole-2-carboxylic acid derivatives via the intramolecular reductive cyclization of o-nitrophenylpyruvic acid and its amide and ester derivatives was developed using Na₂S₂O₄ in dioxane/water at reflux.

Full text of DOI:10.1016/j.tetlet.2018.09.039

Accepted Manuscript
A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid
derivatives and indoles based on the Reissert reaction
Vakhid A. Mamedov, Vera L. Mamedova, Victor V. Syakaev, Gul'naz Z.
Khikmatova, Dmitry E. Korshin, Temur A. Kushatov, Shamil K. Latypov
PII:
S0040-4039(18)31129-8
https://doi.org/10.1016/j.tetlet.2018.09.039
TETL 50278
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
1 August 2018
11 September 2018
14 September 2018
Please cite this article as: Mamedov, V.A., Mamedova, V.L., Syakaev, V.V., Khikmatova, G.Z., Korshin, D.E.,
Kushatov, T.A., Latypov, S.K., A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid
derivatives and indoles based on the Reissert reaction, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.09.039
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A new and efficient method for the synthesis of 3-(2-
nitrophenyl)pyruvic acid derivatives and indoles based on
the Reissert reaction
Vakhid A. Mamedov,* Vera L. Mamedova, Victor V. Syakaev, Gul’naz Z. Khikmatova,
Dmitry E. Korshin, Temur A. Kushatov, Shamil K. Latypov
A.E. Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center of the Russian
Academy of Sciences, Arbuzov Str. 8, 420088 Kazan, Russian Federation, e-mail: mamedov@iopc.ru
Tel.: +7 843 2727304; Fax: +7 843 2732253
A b s t r a c t
The formation of 3-(2-nitrophenyl)pyruvic acid and its amide and ester derivatives – key
compounds for the Reissert indole synthesis – was achieved under various reaction conditions
via the acid catalyzed hydrolysis of 5-(2-nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one,
which is readily available from 3-(2-nitrophenyl)oxirane-2-carboxamide. A new and highly
efficient method for the synthesis of indole-2-carboxylic acid derivatives via the intramolecular
reductive cyclization of o-nitrophenylpyruvic acid and its amide and ester derivatives was
developed using Na2S2O4 in dioxane/water at reflux.
Keywords: 3-(2-Nitrophenyl)oxirane-2-carboxamide; 5-(2-Nitrobenzyliden)-2,2-dimethyl-1,3-
oxazolidin-4-one; 3-(2-Nitrophenyl)pyruvic acid derivatives; Intramolecular reductive
cyclization; Indole-2-carboxylic acid derivatives.
1. Introduction
The indole moiety is one of the most widely distributed heterocyclic systems in Nature, and
its derivatives continue to attract significant attention, especially in the pharmaceutical sector.1
Owing to their structural diversity and remarkable biological functions, numerous efforts have
been devoted to the development of methods for synthesizing indoles. Despite the considerable
progress achieved for the synthesis of indole derivatives, the preparation of some specific
substituted patterns remains difficult. Indole-2-carboxylic acid derivatives have been reported to
display a wide range of biological functions such as inhibition of cPLA2,2 cytosolic
1

phosphorylase A2α,3 HIV-1 integrase4 and antagonism of the histamine H4 receptor.5 The
synthesis of these compounds is constantly improving and new methods are proposed, often
using well-known named reactions such as the Reissert method,6 Hemetsberg-Knittel
indolization,7 Cadogan-Sundberg synthesis,8 Hech-Jeffery reaction,9 Fisher cyclization10 and
Heck reaction.11 Modern methods for the preparation of indole-2-carboxylic acid derivatives
often do not differ in their starting material availability12-14 or are associated with the use of
metal catalysts.15,16 No methods leading directly to amides of indole-2-carboxylic acid have been
reported in the literature. For the preparation of indole-2-carboxylic acid esters, esterification
with alcohols in the presence of sulfuric acid is often used.17 The esterification of indole-2-
carboxylic acid with diazomethane under mild conditions leads to methyl indole-2-carboxylate in
good yields.18 The known methods for the conversion of indole-2-carboxylic acid esters into
amides are not easy to perform or require the use expensive catalysts.19
The Reissert method involves the condensation of о-nitrotoluenes with oxalates in the
presence of a base, followed by reduction of the resulting o-nitrophenylpyruvates.6 Despite the
moderate yields of o-nitrophenylpyruvates in the first stage of the process, this method remains
mostly in demand for the synthesis of indole-2-carboxylates. In this paper, we present a
modification of the Reissert method and successfully use it to obtain indole-2-carboxylic acid,
and its amide and ester derivatives, by-passing the hydrolysis, esterification and amidation steps.
2. Results and Discussion
As part of an ongoing research program regarding pyruvic acid derivatives, we were
interested in developing a novel methodology based on the degradation of 5-benzyliden-2,2-
dimethyl-1,3-oxazolidin-4-one). We recently published preliminary results, related to this work,
where the reaction of trans-3-(2-nitrophenyl)oxirane-2,3-carboxamide (1)20 with acetone in the
presence of conc HBr was found to give syn-5-(α-bromo-2-nitrobenzyl)-2,2-dimethyl-1,3-
oxazolidin-4-one (2) via acid catalyzed ring opening and ring closure processes.21 It was also
found that syn-5-(α-bromo-2-nitrobenzyl)-1,3-oxazolidin-4-one (2) was easily converted to
trans-5-(2-nitrobenzylidene)-2,2-dimethyl-1,3-oxazolidin-4-one (3) when exposed to K2CO3 in
MeOH at room temperature.21 The substitution of conc HBr for HCl in this work led to the same
result (Scheme 1).
2

Scheme 1. Synthesis of 5-benzyliden-2,2-dimethyl-1,3-oxazolidin-4-one 3.
Herein, we have extended our studies to the syntheses of 3-(2-nitrophenyl)pyruvic acid
derivatives 4 and indoles 5. trans-5-(2-Nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one 3
was the starting compound in the syntheses of 3-(2-nitrophenyl)pyruvic acid (4a), its amide (4b)
and ester derivatives (4c-e) (Scheme 2), which are key compounds in the Reissert indole
synthesis. Compound 4b was obtained by a short-term (3 min) heating of 3 in conc HCl. In this
case the process was terminated with the addition of water. A longer (2 h) heating of 3 in
hydrochloric acid resulted in 4a. Esters 4c-e were obtained by bubbling gaseous HCl through the
corresponding alcohol solution of 3 until it was completely saturated. Then the solutions were
kept for 16 h at room temperature, or in the case of 4e heated at reflux in i-PrOH for 2 h.
Scheme 2. Transformation of 5-benzyliden-2,2-dimethyl-1,3-oxazolidin-4-one 3 to 3-(2-
nitrophenyl)pyruvic acid and its derivatives (all compounds gave elemental analysis for C, H, N,
1
13
within 0.2% of the calculated value and the structures were confirmed by IR, and H NMR, C
NMR spectroscopy, isolated yield is shown).
A notable feature of phenylpyruvic acid derivatives 4 is their tautomerism, allowing the
compounds to exist in solution as a mixture of two isomers: the keto form and the enol form.
3

Compounds 4 may exist in solution as 3-(2-nitrophenyl)pyruvic acid (A) and 2-hydroxy-3-(2-
1
nitrophenyl)acrylic acid (B) derivatives (Scheme 3). In the H NMR spectrum of amide 4b in
DMSO-d6, only tautomer A is detected. The 1H NMR spectra of compounds 4a, 4c-e in DMSO-
d6 exhibited the signals from both tautomeric forms: for 4a the molar ratio is close to 1:1, for 4c
and 4d the enol form predominates (A:B = 1:1.5 and 1:1.2, respectively) and for 4e the ketone
form predominates (A:B = 1.2:1). At the same time in the 1H NMR spectra of esters 4c and 4d in
CDCl3 the ketone form was mainly detected (А:В = 16:1 and 19:1, respectively).
Scheme 3. Keto-enol tautomerism of 4.
The geometry of B (Scheme 3) was determined by NMR long-range coupling constants
13
3
(3JC(О)–H) in the С(1Н) NMR spectra in DMSO-d6 (see ESI). It is well known that the JC-H
coupling constant across the double bond is 9.5-15.2 Hz for isomers with trans arrangement of
the interacting nucleuses C and H and 2.9-6.2 Hz for isomers with cis arrangement of these
atoms.22 The values of 3JC(О)–H for tautomers B of 4c-d were 3.6, 2.8, and 3.0 Hz, respectively,
and indicate cis configuration, which corresponds to the literature data23 regarding the geometry
of similar compounds.
It was also found that 2-nitrophenylpyruvic acid and its amide and ester derivatives can be
reduced using a threefold excess of Na2S2O4 at reflux in dioxane/water (1:1) for 3 h with
formation of the corresponding indole derivatives 5a-e, which were easily isolated in almost
quantitative yields after aqueous workup (Table 1).
Table 1. Reissert indole synthesis by the reduction of 2-nitrophenylpyruvic acid derivatives with
Na2S2O4
Entry Substrate
R
Producta Yieldb (%)
1
2
3
OH
96
97
96
4a
4b
4c
5a
5b
5c
NH2
OMe
4

4
5
OEt
98
97
4d
4e
5d
5e
i-OPr
a All compounds gave elemental analysis for C, H, N, within 0.2% of the calculated value and
the structures were confirmed by IR, and 1H NMR, 13C NMR spectroscopy.
b Isolated yield.
It should be noted that methyl indol-2-carboxylate 5c can be obtained via intramolecular
reductive cyclization with Na2S2O4 directly from methyl 3-(2-nitrophenyl) oxirane-2-carboxylate
6, which in turn is synthesized by the Darzens condensation of 2-nitrobenzaldehyde and methyl
monochloroacetate with t-BuOK in dry THF (Scheme 4). When a threefold excess of Na2S2O4
was used and the reaction mixture was heated at reflux in water-dioxane for 3 h, the formation of
1
methyl indol-2-carboxylate 5c was observed only in 20% yield (in the H NMR spectra of the
crude product were also found starting compound 6). However, the yield of 5c was increased to
80% when a fivefold excess of Na2S2O4 was used and the reaction time was increased to 12 h.
Scheme 4. Synthesis of methyl indol-2-carboxylate 5с directly from methyl 3-(2-
nitrophenyl)oxirane-2-carboxylate 6.
3. Conclusion
In summary, we have reported an efficient approach to the synthesis of 3-(2-
nitrophenyl)pyruvic acid, and its amide and ester derivatives, as well as a modified Reissert
indole synthesis via reduction of the 2-nitrophenylpyruvic acid derivatives with Na2S2O4. It has
been shown that methyl indol-2-carboxylate 5c can be obtained in high yield via intramolecular
reductive cyclization with Na2S2O4 directly from methyl 3-(2-nitrophenyl)oxirane-2-carboxylate.
Given the value of pyruvic acid and indole derivatives in medicine, biology and materials
science, this work may become valuable for further transformations involving these building
blocks.
Acknowledgements
5

This work was partially supported by the Russian Science Foundation (grant No 18-13-
00315).
Supplementary data
Supplementary data (1H NMR and 13C NMR spectra, detailed Experimental procedures)
associated with this article can be found, in the online version, at …
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Highlights:
From: A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid
derivatives and indoles based on the Reissert reaction
•
•
•
•
3-(2-Nitrophenyl)oxirane-2-carboxylate is used as a new reagent
3-(2-Nitrophenyl)pyruvic acid derivatives are used in the synthesis of indoles
3-(2-Nitrophenyl)oxirane-2-carboxamide is used as a new reagent
Methyl indol-2-carboxylate is obtained from 3-(2-nitrophenyl)oxirane-2-carboxylate
9

Graphical abstract
A new and efficient method for the synthesis of 3-(2-
nitrophenyl)pyruvic acid derivatives and indoles based on
the Reissert reaction
Vakhid A. Mamedov, Vera L. Mamedova, Victor V. Syakaev, Gul’naz Z. Khikmatova,
Dmitry E. Korshin, Temur A. Kushatov, Shamil K. Latypov
10