One-pot synthesis of 3-(E)-styrylpyrroles from (E)-styrylmethyl ketoximes and acetylene

Article abstract of DOI:10.1016/j.mencom.2013.11.012

(E)-Styrylmethyl ketoximes react with acetylene in KOH/DMSO superbase system (90 C, 1 h) to afford stereoselectively 3-(E)-styrylpyrroles.

Full text of DOI:10.1016/j.mencom.2013.11.012

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 340–341
One-pot synthesis of 3-(E)-styrylpyrroles from
(E)-styrylmethyl ketoximes and acetylene
Elena Yu. Schmidt, Nadezhda V. Zorina, Elena V. Ivanova, Inna V. Tatarinova,
Igor A. Ushakov, Albina I. Mikhaleva and Boris A. Trofimov*
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
664033 Irkutsk, Russian Federation. Fax: +7 3952 419 346; e-mail: boris_trofimov@irioch.irk.ru
DOI: 10.1016/j.mencom.2013.11.012
(E)-Styrylmethyl ketoximes react with acetylene in KOH/DMSO superbase system (90°C, 1 h) to afford stereoselectively 3-(E)-styrylpyrroles.
Ph
Ph
b,g-Unsaturated ketones are the valuable intermediates in fine
organic synthesis1 and key structures in drug design.2 They are
less accessible than their thermodynamically stable a,b-isomers
readily accessible by crotonic condensation. Generally, the syn-
thesis of b,g-enones is multi-stage,3 often requires exotic starting
materials4 or metal complex catalysts.5
NH2OH
HC CH/ KOH/DMSO
90 °C, 1 h
25 °C, 24 h
R
R
from 2a,b from 2c
O
N
Ph
Ph
OH
Recently, we have found that ketones regio- and stereoselec-
tively add to (het)arylacetylenes at 80–100°C in the presence of
superbase systems MOH/DMSO (M = Na, K, Cs),6 KOH/ButOH/
DMSO7 or ButOK/DMSO8 to afford E-configured b,g-enones in
high yields (Scheme 1).
1a–c
2a 96%
2b 92%
2c 97%
R
R
N
N
H
a R = Ph
b R = 2-naphthyl
c R = 4-PhC6H4
3a 35%
3b 33%
3c 38%
R2
R2
R1
R1
MOR/DMSO
R3
HC CR3
+
Scheme 2
80–100 °C,
30–60 min
O
O
up to 92%
b,g-Enone oximes 2a–c. A mixture of enone 1a–c (3.00 mmol),
NH2OH·HCl (0.40 g, 5.75 mmol) and pyridine (15 ml) was stirred at
room temperature for 24 h and then poured into water (50 ml). The
crystalline precipitate was collected by filtration, washed with water, and
dried in vacuo. After recrystallization from ethanol pure oximes 2a–c
were obtained, identical in characteristics with the literature.9 E-con-
figuration in the hydroxylamino moiety was confirmed by the published
data.17 E-configuration of the olefinic moiety was determined by 3J values
(16.1–16.2 Hz) between protons at the double bond.
R1, R2 = Alk, Ar, cycloalkyl, hetaryl; R3 = Ar, hetaryl
M = Na, K, Cs; R = H, But
Scheme 1
The application of this reaction as the first stage in the
syntheses of more complex molecules seems to be promising.
In this line, over the last few years we have published one-pot
syntheses of 2,5-diarylfurans6 from ketones and 4-nitrophenyl-
acetylene as well as D2-isoxazolines9 from ketones, arylacetylenes
and hydroxyl amine.
In continuation of these studies, here we preliminarily report
on the KOH/DMSO superbase system-catalyzed stereoselective
synthesis of 3-(E)-styrylpyrroles from b,g-enone oximes and
acetylenes through the Trofimov reaction.10
We have found that oximes 2a,b (prepared from ketones 1a,b
and hydroxylamine hydrochloride in pyridine) on treatment with
acetylene in the superbase system KOH/DMSO (molar ratio of
oxime 2:KOH = 1:1, initial acetylene pressure at room tem-
perature, 11–13 atm, 90°C, 1 h) stereoselectively gave 1-vinyl-
3-(E)-styrylpyrroles 3a,b (Scheme 2).† Isolated yields of pyrroles
3a,b after column chromatography were 35 and 33%, respec-
tively. The E-configuration of the styryl moiety was determined
by 3J values (16.1–16.2 Hz) between olefinic protons.
Pyrroles 3a–c. A mixture of oxime 2 (3.50 mmol), KOH·0.5H2O (0.23 g,
3.50 mmol) and DMSO (50 ml) was placed into a 0.25-l steel rotating
autoclave. The autoclave was fed with acetylene to the pressure of 11–13 atm
and then decompressed to atmospheric pressure to remove air. The autoclave
was fed with acetylene again (initial pressure at ambient temperature was
11–13 atm, which reached a maximum of 23–25 atm on heating to 90°C
and then dropped upon acetylene consumption during the reaction), and
heating was maintained for 1 h. The reaction mixture, after cooling to room
temperature, was diluted with cold (5–10°C) water (50 ml), neutralized with
NH4Cl and extracted with diethyl ether (5×20 ml). The organic extracts
were washed with water (3×15 ml) and dried (K2CO3). After removal of
the solvent, the crude residue was subjected to column chromatography
(SiO2, eluent benzene) to give pure pyrroles 3a–c and isoxazolines 4a–c.
2-Phenyl-3-(E)-styryl-1-vinylpyrrole 3a: yield 0.33 g, 35%; yellow oil.
IR (film, n/cm–1): 3182, 1631, 1597, 1518, 1415, 1247, 1063, 1035, 960, 912,
893, 748, 733, 695. 1H NMR, d: 7.52–7.50 (m, 2H, Hm), 7.38–7.39 (m, 1H,
Hp), 7.36–7.34 (m, 2H, Ho'), 7.33–7.31 (m, 2H, Ho), 7.26–7.24 (m, 2H, Hm'),
7.13–7.11 (m, 1H, Hp'), 7.11 (d, 1H, H5, 3J 3.2 Hz), 6.88 (d, 1H, Ha, 3J 16.1 Hz),
3
3
3
6.82 (d, 1H, Hb, J 16.1 Hz), 6.72 (dd, 1H, HX, J 15.8 Hz, J 8.9 Hz),
6.63 (d, 1H, H4, 3J 3.2 Hz), 5.10 (dd, 1H, HA, 3J 15.8 Hz, 2J 1.2 Hz), 4.60 (dd,
1H, HB, 3J 8.9 Hz, 2J 1.2 Hz). 13C NMR, d: 138.4 (Ci'), 132.5 (C2), 131.5
(N–CH=CH2), 131.3 (Co), 130.8 (Ci), 128.6 (Cm'), 128.5 (Cm), 128.0 (Cp),
126.6 (Cp'), 125.9 (Co'), 125.8 (Cb), 122.1 (C3), 121.6 (Ca), 118.1 (C5), 107.2
(C4), 98.2 (N–CH=CH2). 15N NMR, d: –208.0. Found (%): C, 88.39;
H, 6.37; N, 5.07. Calc for C20H17N (%): C, 88.52; H, 6.31; N, 5.16.
1H, 13C and 15N NMR spectra were recorded on a Bruker AVANCE 400
†
instrument (400.13, 100.61 and 40.56 MHz respectively) equipped with
inverse gradient 5 mm probe in CDCl3 with HMDS as internal standard.
All 2D NMR spectra were recorded using a standard gradient Bruker pulse
programs. IR spectra were obtained on a Bruker Vertex 70 spectrometer.
© 2013 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2013, 23, 340–341
Noteworthy, oxime 2c reacted with acetylene under the same
The work was supported by the Russian Foundation for Basic
Research (grant no.11-03-00270-a).
conditions to furnish 3-(E)-styryl-1H-pyrrole 3c (Scheme 2), the
corresponding 1-vinylpyrrole was detected in the reaction mix-
ture in trace amounts only (1H NMR).
References
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nucleophilic addition of the oxime moiety to the double bond of
a,b-unsaturated oximes 5a–c (Scheme 3).
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Ph
KOH /
DMSO
KOH /
DMSO
R
Ph
2a–c
O
N
R
N
OH
5a–c
4a R = Ph, 18%
4b R = 2-naphthyl, 15%
4c R = 4-PhC6H4, 22%
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3-(E)-Styrylpyrroles synthesized represent heterocyclic ana-
logues of stilbenes, widely abundant in nature (plant antioxidants
resveratrol11 and pterostilbene12), which are used in medicine
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nonlinear-optical materials14). The known methods for the syn-
thesis of 3-styrylpyrroles (not always stereoselective) are laborious
and multi-stage. They are limited by the Wittig reaction of
N-methyl-3-formylpyrrole with the corresponding phosphorus
ylides15 and reduction of N-tosyl protected 3-benzoylpyrrole with
subsequent dehydration of the forming secondary alcohol.16
Despite the moderate yields of 3-(E)-styrylpyrroles, their syn-
thesis from b,g-enone oximes and acetylene may have preparative
significance as one-pot stereoselective approach from readily
available starting materials (in fact from ketones and acetylenes)
under transition-metal-free conditions.
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2-(2-Naphthyl)-3-(E)-styryl-1-vinylpyrrole 3b: yield 0.37 g, 33%; yellow
oil. IR (KBr, n/cm–1): 3181, 3056, 2604, 1631, 1596, 1521, 1504, 1414,
1336, 1237, 1131, 960, 914, 894, 861, 822, 748, 732, 695. 1H NMR, d:
7.92–7.57 (m, 7H, Hnaphthyl), 7.36–7.35 (m, 2H, Ho), 7.28–7.26 (m, 2H,
Hm), 7.20 (d, 1H, H5, 3J 3.3 Hz), 7.17–7.15 (m, 1H, Hp), 6.97 (d, 1H, Ha,
3J 16.2 Hz), 6.90 (d, 1H, Hb, 3J 16.2 Hz), 6.81 (dd, 1H, HX, 3J 15.6 Hz, 3J
8.8 Hz), 6.72 (d, 1H, H4, 3J 3.3 Hz), 5.18 (dd, 1H, HA, 3J 15.6 Hz, 3J 1.1 Hz),
4.66 (dd, 1H, HB, 3J 8.8 Hz, 3J 1.1 Hz). 13C NMR, d: 138.3 (Ci), 133.2,
132.8, 131.5, 130.6, 128.8, 128.3, 128.1, 127.8 (10Cnaphthyl), 132.4 (C2), 131.5
(N–CH=CH2), 128.6 (Cm), 126.6 (Cp), 125.9 (Co, Cb), 122.4 (C3), 121.5
(Ca), 118.3 (C5), 107.2 (C4), 98.3 (N–CH=CH2). Found (%): C, 89.31;
H, 5.71; N, 4.24. Calc. for C24H19N (%): C, 89.68; H, 5.96; N, 4.36.
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2-(Biphenyl-4-yl)-3-(E)-styrylpyrrole 3c: yield 0.43 g, 38%; white powder
,
mp 132–134°C. IR (KBr, n/cm–1): 3423, 3027, 1632, 1599, 1488, 1444,
1267, 1248, 1098, 1074, 1006, 959, 908, 843, 766, 728, 659. 1H NMR, d:
8.23 (br.s, 1H, NH), 7.74–7.72 (m, 2H, Hm), 7.70–7.68 (m, 2H, Ho'),
7.58–7.56 (m, 2H, Ho), 7.52–7.49 (m, 4H, Hm', Ho''), 7.43–7.41 (m, 1H,
Hp'), 7.38–7.35 (m, 2H, Hm''), 7.32 (d, 1H, Ha, 3J 16.1 Hz), 7.25–7.23 (m,
1H, Hp''), 6.98 (d, 1H, Hb, 3J 16.1 Hz), 6.90–6.88 (m, 1H, H5), 6.68–6.67
(m, 1H, H4). 13C NMR, d: 140.6 (Ci'), 139.8 (Cp), 138.6 (Ci''), 131.9 (Ci),
130.9 (C2), 129.0 (Cm'), 128.9 (Cp'), 128.6 (Cm''), 128.1 (Co), 127.6 (Cm),
127.1 (Co'), 126.9 (Cp''), 126.0 (Co''), 126.2 (Cb), 122.0 (Ca), 120.0 (C3), 119.2
(C5), 107.2 (C4). 15N NMR, d: –234.5 (1H, NH, 1J 96.0 Hz). Found (%):
C, 89.45; H, 6.14; N, 4.19. Calc. for C24H19N (%): C, 89.68; H, 5.96; N, 4.36.
17 A. V. Afonin, D. V. Pavlov, I. A. Ushakov, E. Yu. Schmidt and A. I.
Mikhaleva, Magn. Reson. Chem., 2009, 47, 879.
Received: 12th July 2013; Com. 13/4160
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