First example of favorskii ethynylation of pyrrolecarbaldehydes: Synthesis of 1-(1-methyl-1H-pyrrol-2-yl)prop-2-yn-1-ol

Article abstract of DOI:10.1134/S107042801501008X

1-(1-Methyl-1H-pyrrol-2-yl)prop-2-yn-1-ol has been synthesized for the first time by ethynylation of 1-methyl-1H-pyrrole-2-carbaldehyde with acetylene in the superbasic system KOH-DMSO-H₂O under atmospheric pressure.

Full text of DOI:10.1134/S107042801501008X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2015, Vol. 51, No. 1, pp. 51–53. © Pleiades Publishing, Ltd., 2015.
Original Russian Text © L.N. Sobenina, O.V. Petrova, D.N. Tomilin, A.V. Ivanov, V.S. Shcherbakova, A.I. Mikhaleva, B.A. Trofimov, 2015, published in
Zhurnal Organicheskoi Khimii, 2015, Vol. 51, No. 1, pp. 57–58.
First Example of Favorskii
Ethynylation of Pyrrolecarbaldehydes: Synthesis
of 1-(1-Methyl-1H-pyrrol-2-yl)prop-2-yn-1-ol
L. N. Sobenina, O. V. Petrova, D. N. Tomilin, A. V. Ivanov, V. S. Shcherbakova,
A. I. Mikhaleva, and B. A. Trofimov
Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: boris_trofimov@irioch.irk.ru
Received September 4, 2014
Abstract—1-(1-Methyl-1H-pyrrol-2-yl)prop-2-yn-1-ol has been synthesized for the first time by ethynylation
of 1-methyl-1H-pyrrole-2-carbaldehyde with acetylene in the superbasic system KOH–DMSO–H2O under
atmospheric pressure.
DOI: 10.1134/S107042801501008X
Propargyl alcohols derived from pyrrolecarbalde-
hydes and acetylenes are important synthetic interme-
diates that are increasingly used in drug design [1–6].
For example, they are used in the synthesis of protein
kinase inhibitors and modulators [1] and as building
blocks in the preparation of anti-inflammatory drugs,
in particular for the treatment of rheumatoid arthrosis
[2]. Some compounds of this series have recently been
patented [3] as starting compounds for the synthesis of
EDG-1 receptor antagonists that are efficient in the
prophylactics and treatment of inflammatory processes
and diseases related to anomalous angiogenesis, hyper-
tensive cerebral crisis, brain ischemia, malignant tu-
mors, cerebral and myocardial infarctions, nephritises,
pneumonia, immune disorders, Crohn’s diseases,
colitises, and chronic diarrhea.
carbonyl compounds with acetylenes in the presence of
potassium hydroxide) with aromatic and heteroaro-
matic aldehydes was considered to be inefficient [7–9].
Only recently we succeeded in developing a specific
version of the Favorskii reaction, which made it
possible to obtain secondary acetylenic alcohols in
46–67% yield from aromatic and heteroaromatic alde-
hydes as well [10, 11]. The developed procedure is
based on the use of the heterogeneous catalytic system
KOH–H2O–DMSO. Here, reduction of the basicity of
the system via controllable addition of water prevented
acetylene–allene isomerization and subsequent trans-
formations of the resulting secondary acetylenic
alcohol.
However, this new modification of the Favorskii
reaction turned out to be inapplicable to ethynylation
of pyrrolecarbaldehyde. In fact, no expected propargyl
alcohol was obtained from 1H-pyrrole-2-carbaldehyde
(the initial compound was completely recovered from
the reaction mixture) under the conditions ensuring
1-(Pyrrol-2-yl)prop-2-yn-1-ols are commonly syn-
thesized [4–6] by reaction of pyrrolecarbaldehydes
with alkynylmagnesium halides (Iotsitch reagents)
since the classical Favorskii reaction (ethynylation of
Scheme 1.
OH–
–H2O
CHO
CHO
O
CHO
CHO
N
N
N
N
H
CH
HC
C–
≡
N
N
OH
H
H
51

SOBENINA et al.
52
Scheme 2.
HC CH
CH
KOH–H2O–DMSO
CHO
N
N
OH
Me
Me
1
2
potassium hydroxide, and 3 mL (10% relative to
DMSO) of water was cooled to –5 to –7°C, and
acetylene was passed through that mixture over
a period of 30 min under stirring. A solution of 2.0 g
(18 mmol) of 1-methyl-1H-pyrrole-2-carbaldehyde (1)
in 10 mL of DMSO was added dropwise over a period
of 1.5 h while continuing passing acetylene and
stirring. When the addition of 1 was complete, acet-
ylene was passed through the mixture for 1.5 h more.
successful synthesis of secondary acetylenic alcohols
from furfural and thiophene-2-carbaldehyde [10]. Pre-
sumably, this is the result of intramolecular negative
charge transfer from the ionized pyrrole fragment to
the carbonyl group, which considerably reduces elec-
trophilicity of the latter (Scheme 1).
Taking the above stated into account, we believed
that 1-substituted pyrroles in which proton abstraction
from the nitrogen atom is impossible should react with
acetylene according to the conventional scheme to
produce secondary acetylenic alcohols [10]. This
assumption was confirmed completely. The reaction of
1-methyl-1H-pyrrole-2-carbaldehyde (1) with acet-
ylene in a suspension of KOH in DMSO/H2O afforded
the expected propargyl alcohol 2 in 62% yield (calcu-
lated on the reacted aldehyde 1 whose conversion was
50%, Scheme 2). The reaction was carried at a KOH–
H2O–DMSO molar ratio of 1:4.5:11 in a stream of
acetylene under atmospheric pressure at –5 to –7°C
(3 h). Unreacted pyrrolecarbaldehyde 1 was removed
from the reaction mixture by extraction with hexane.
1
According to the H NMR data, the mixture contained
compound 1 (50% of the initial amount) which was
removed by extraction with hexane (5×30 mL) at
12–14°C, whereas the main part of product 2 remained
in aqueous DMSO. The hexane extracts were combined
and washed with water, and the aqueous washings
were combined with the aqueous DMSO fraction
diluted with water (1:2) and extracted with diethyl
ether (5×30 mL). The extract was washed with water,
dried over Na2SO4, and evaporated, and the oily resi-
due was passed through a layer of alumina using
hexane as eluent. Yield 0.74 g (62% on the reacted
aldehyde 1). IR spectrum, ν, cm–1: 3368, 3280, 1628,
1601, 1490, 1473, 1329, 1249, 1019, 891, 812, 748,
Thus, we were the first to demonstrate that ap-
propriate version of the Favorskii reaction can be suc-
cessfully used to synthesize secondary acetylenic al-
cohols from 1-substituted 1H-pyrrole-2-carbaldehydes.
The discovered reaction opens new prospects in the
development and practical application of pharmaco-
logically important 1-(1H-pyrrol-2-yl)prop-2-yn-1-ols.
1
730, 628. H NMR spectrum, δ, ppm: 2.12 br.s (1H,
OH), 2.60 d (1H, ≡CH, J = 2.3 Hz), 3.79 s (3H, NMe),
5.45 d (1H, CHOH, J = 3.2 Hz), 6.03 m (1H, 3-H),
13
6.30 m (1H, 4-H), 6.61 m (1H, 5-H). C NMR spec-
trum, δC, ppm: 132.0, 124.4, 108.8, 106.6, 82.1, 73.7,
57.5, 34.1. Found, %: C 81.42; H 5.54; N 5.99.
C16H13NO. Calculated, %: C 81.68; H 5.57; N 5.95.
EXPERIMENTAL
REFERENCES
The spectral and analytical data were obtained
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hexamethyldisiloxane as internal reference. The
elemental analysis was obtained on a Thermo Finnigan
1112 elemental analyzer. All initial reagents and
solvents were commercial products.
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