Mendeleev
Communications
Mendeleev Commun., 2014, 24, 100–101
Synthesis of 3,3-dimethyl-2-phenyl-3H-pyrrole from isopropyl phenyl
ketoxime and acetylene: a side formation of 4,4-dimethyl-5-phenyl-
1-vinyl-2-pyrrolidinone as clue to the reaction mechanism
Dmitrii A. Shabalin, Tatyana E. Glotova, Elena Yu. Schmidt,
Igor A. Ushakov, Al’bina 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.2014.03.012
Isopropyl phenyl ketoxime reacts with acetylene in the KOH/DMSO suspension (atmospheric pressure, 90°C, 4 h) to afford
3,3-dimethyl-2-phenyl-3H-pyrrole (30%) and 4,4-dimethyl-5-phenyl-1-vinyl-2-pyrrolidinone (5%) that is likely originated from
4,4-dimethyl-5-phenyl-3,4-dihydro-2H-pyrrol-2-ol as the key reaction intermediate.
3H-Pyrroles represent difficult-to-access and hence poorly studied
class of non-aromatic pyrroles. They possess potentially rich
chemistry as fundamentally prone to diverse rearrangements,
addition and cycloaddition reactions.1,2 Some 3H-pyrroles exhibit
antimicrobial and antitumor activities.3 Despite their obvious
theoretical and practical appeal, until now no general synthesis of
these compounds was elaborated. Just several sporadic reactions
leading to functionalized 3H-pyrroles were reported.4 This is
likely due to thermodynamic instability of 3H-pyrroles,1 and
therefore their high tendency to rearrangements and addition
reactions. The reaction of phenyl(2-thienyl) isopropyl ketoximes
1a,b with acetylene in superbasic systems of the KOH/DMSO
type, leading to 3,3-dimethyl-2-(het)aryl-3H-pyrroles 2a,b in
53 and 11% yields, respectively (Scheme 1), previously briefly
described only on two examples5,6 has a certain potential to be
developed into a general methodology.
Me
Me
Me
Me
Ph
Ph
KOH/DMSO
90 °C, 4 h
+
HC CH
N
N
OH
1a
2a (30%)
Me
Me
Me
Me
Ph
Me
Ph
Me
+
+
+
O
OH
Ph
N
N
N
3 (5%)
4 (4%)
Scheme 2
5 (2%)
In this case, the yield of the major product, 3H-pyrrole 2a,
was 30%, and those of side products 3, 4 and 5 being 5, 4 and
Me
Me
Me
Me
R
R
The reaction of isopropyl phenyl ketoxime 1a with acetylene in the
KOH/DMSO system. Acetylene was bubbled (40–45 ml min–1) through
a solution of oxime 1a (4.075 g, 25 mmol) and KOH∙0.5H2O (1.625 g,
25 mmol) in DMSO (50 ml) at 90°C for 4 h. The mixture was cooled,
poured into ice water (300 ml), and extracted with diethyl ether (5×100 ml).
The extract was washed with water (2×50 ml) and dried over MgSO4.
After distilling off the solvent, the residue (3.53 g) was chromatographed
on the column (1.9×50 cm, basic Al2O3, hexane–diethyl ether with gradient
from 1:0 to 0:1) to afford recovered oxime 1a (0.33 g, 9%), 3H-pyrrole 2a,
pyrrolidinone 3, pyrroline 4 and hydroxypyrroline 5.
3,3-Dimethyl-2-phenyl-3H-pyrrole 2a: yield 1.06 g, 30%; yellow oil,
Rf = 0.49 (hexane–diethyl ether, 1:1). Physical-chemical characteristics
were identical to the literature data.5 13C NMR (CDCl3) d: 22.4 (2Me),
55.6 (C3), 127.7, 128.5, 129.9, 133.1 (Ph), 138.7 (C4), 140.0 (C5), 183.4
(C2). 15N NMR (CDCl3) d: –66.4. MS (EI), m/z: 171 [M]+.
4,4-Dimethyl-5-phenyl-1-vinyl-2-pyrrolidinone 3: yield 0.16 g, 5%;
viscous yellow oil [Rf = 0.42 (hexane–diethyl ether, 1:1)] or light yellow
crystals, mp 74–76°C (hexane). IR (KBr, n/cm–1): 2870–2965 (CH), 1697
(C=O), 1633 (C=C, NCH=CH2). 1H NMR (CDCl3) d: 0.69 (s, 3H,
Me), 1.30 (s, 3H, Me), 2.24 (d, 1H, CH2, 2J 17.0 Hz), 2.53 (d, 1H, CH2,
2J 17.0 Hz), 4.10 (d, 1H, Hb, 3J 16.2 Hz), 4.32 (d, 1H, Ha, 3J 9.2 Hz), 4.44
(s, 1H, H5), 7.08 (m, 2H, Ho), 7.13 (dd, 1H, Hx, 3J 9.2 Hz, 3J 16.2 Hz),
7.30–7.38 (m, 3H, Hm, Hp). 13C NMR (CDCl3) d: 24.7 (Me), 30.5 (Me),
37.5 (C4), 44.7 (C3), 71.1 (C5), 96.4 (Cb), 126.4, 127.9, 128.4 (Ph), 128.7
(Ca), 137.4 (Ci), 173.2 (C=O). 15N NMR (CDCl3) d: –230.2. Found (%):
C, 78.36; H, 7.82; N, 6.43. Calc. for C14H17NO (%): C, 78.10; H, 7.96;
N, 6.51. MS (EI), m/z: 215 [M]+.
KOH/DMSO
+
HC CH
N
N
OH
1a,b
a R = Ph
b R = 2-thienyl
2a,b
Scheme 1
A better understanding of the reaction mechanism is the
shortest way to its optimization. In this connection, side products
often serve as reliable indicators of the reaction stages and help
to deduce its key intermediates.
Here we report on isolation of a new side product of the super-
base-catalyzed reaction between isopropyl phenyl ketoxime 1a and
acetylene, namely 4,4-dimethyl-5-phenyl-1-vinyl-2-pyrrolidinone
3 along with pyrroline 4 and hydroxypyrroline 5 (Scheme 2).†
†
The IR spectra were recorded on a Bruker IFS25 spectrophotometer as
KBr pellets or thin films. Mass spectra were recorded on an Agilent 5975C
spectrometer. Sample introduction was carried out through an Agilent
6890N gas chromatograph: the column was an HP-5MS (0.25 mm×30 m×
× 0.25 mm); helium as a carrier gas, constant flow. NMR spectra were
recorded on Bruker DPX-400 and AV-400 spectrometers (400.1, 100.6 and
40.5 MHz for 1H, 13C and 15N, respectively) in CDCl3 or DMSO-d6.
Aluminum oxide was used for column chromatography, and Silufol plates
for TLC. Visualization was performed with iodine vapour.
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