Synthesis of 1-(arenesulfonyl)-2-arylpyrrolidines by reaction of N-(4,4-diethoxybutyl)-4-methylbenzene-sulfonamide with phenols

Article abstract of DOI:10.1134/S1070428016090086

New 1-(arenesulfonyl)-2-arylpyrrolidines were synthesized by reactions of several phenols with N-(4,4-diethoxybutyl)-4-methylbenzenesulfonamide in the presence of trifluoroacetic acid.

Full text of DOI:10.1134/S1070428016090086

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 9, pp. 1304–1307. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © A.V. Smolobochkin, E.A. Anikina, A.S. Gazizov, A.R. Burilov, M.A. Pudovik, 2016, published in Zhurnal Organicheskoi Khimii,
2016, Vol. 52, No. 9, pp. 1316–1319.
Synthesis of 1-(Arenesulfonyl)-2-arylpyrrolidines
by Reaction of N-(4,4-Diethoxybutyl)-4-methylbenzene-
sulfonamide with Phenols
A. V. Smolobochkina, E. A. Anikinab, A. S. Gazizova,* A. R. Burilova, and M. A. Pudovika
a Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center,
Russian Academy of Sciences, ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
*e-mail: agazizov@iopc.ru
b Kazan National Research Technological University,
ul. Karla Marksa 68, Kazan, 420015 Tatarstan, Russia
Received June 2, 2016
Abstract—New 1-(arenesulfonyl)-2-arylpyrrolidines were synthesized by reactions of several phenols with
N-(4,4-diethoxybutyl)-4-methylbenzenesulfonamide in the presence of trifluoroacetic acid.
DOI: 10.1134/S1070428016090086
Over the past decades, 1-(arenesulfonyl)-2-arylpyr-
rolidines have been the subjects of extensive studies.
Such a keen interest in these compounds is determined
by broad spectrum of their biological activity [1–6].
The most common procedure for the synthesis of
1-(arenesulfonyl)-2-arylpyrrolidines is based on intra-
molecular cyclization of aryl-substituted unsaturated
compounds containing a sulfonamide group [7–16].
Disadvantages of this approach include the use of ex-
pensive catalysts and reagents, harsh reaction condi-
tions, and laborious preparation of starting compounds.
Development of a new efficient and accessible method
for the synthesis of 1-(arenesulfonyl)-2-arylpyrroli-
dines is an important problem.
hydroquinone with 2 equiv of 1 in chloroform con-
taining trifluoroacetic acid led to the formation of new
heterocyclic compound 2 (Scheme 1). According to the
1H NMR data, compound 2 was formed as two dia-
stereoisomers, but we succeeded in isolating only one
pure stereoisomer in a poor yield (9%). Presumably,
the low yield of the product is related to both low
reactivity of hydroquinone and its easy oxidation.
Further experiments showed that acetal 1 reacted
with 3-methoxyphenol at a ratio of 2:1 in chloroform
in the presence of trifluoroacetic acid to produce 67%
of pyrrolidine derivative 3 which was a 1:1.3 mixture
of diastereoisomers (according to spectral data).
The reaction of N-(4,4-diethoxybutyl)-4-methyl-
benzenesulfonamide (1) with phenols possessing three
reactive centers was expected to afford a product con-
taining three 1-(arenesulfonyl)pyrrolidine fragments.
However, phloroglucinol reacted with acetal 1 in a way
similar to hydroquinone and 3-methoxyphenol with
formation of bis-pyrrolidine 4 which was isolated as
a mixture of diastereoisomers. Unfortunately, we failed
We have previously shown that polyhydric phenols
react with (4,4-diethoxybutyl)ureas in chloroform in
the presence of trifluoroacetic acid to give 2-arylpyr-
rolidines with a carboxamide moiety on the nitrogen
atom [17–19]. Taking into account similar steric and
electronic characteristic of carboxamide and sulfon-
amide groups, we presumed that analogous reaction of
phenols with N-(4,4-diethoxybutil)sulfonamides
should lead to the formation of 1-(arenesulfonyl)-2-
arylpyrrolidines.
1
to determine their ratio by H NMR due to strong
signal overlap.
Unlike the above reactions, only one position of the
aromatic ring of N-(3-hydroxyphenyl)acetamide was
substituted in the reaction with N-(4,4-diethoxybutyl)-
4-methylbenzenesulfonamide (1). Compound 5 was
isolated in 61% yield. The reasons for the observed
N-(4,4-Diethoxybutyl)-4-methylbenzenesulfon-
amide (1) was synthesized by reaction of 4-methylben-
zenesulfonyl chloride with 4-aminobutanal diethyl
acetal in the presence of triethylamine. The reaction of
1304

SYNTHESIS OF 1-(ARENESULFONYL)-2-ARYLPYRROLIDINES
1305
Scheme 1.
OH
OH
N
4-MeC6H4SO2
HO
SO2C6H4Me-4
N
OH
2
OH
N
OMe
HO
MeO
4-MeC6H4SO2
SO2C6H4Me-4
N
O
O
CF3COOH, CHCl3
20°C, 24 h
S
OEt
OEt
N
2
H
–4EtOH
3
OH
Me
OH
1
HO
OH
N
N
4-MeC6H4SO2
SO2C6H4Me-4
HO
OH
4
H
H
N
OH
HO
N
N
Me
Ac
O
SO2C6H4Me-4
5
difference in the reactivities of N-(3-hydroxyphenyl)-
acetamide and other phenols still remain unclear.
point apparatus. Solvents were purified according to
standard procedures [20].
N-(4,4-Diethoxybutyl)-4-methylbenzenesulfon-
amide (1). 4,4-Diethoxybutan-1-amine, 3.4 g
(20 mmol), was added on cooling (5–8°C) to a mixture
of 3.8 g (20 mmol) of 4-methylbenzenesulfonyl
chloride and 3.5 mL of triethylamine. The mixture was
stirred for 12 h at room temperature and washed with a
saturated aqueous solution of NaHCO3 (100 mL). The
organic phase was separated, and methylene chloride
was removed under reduced pressure. Yield 6.2 g
Thus, N-(4,4-diethoxybutyl)-4-methylbenzenesul-
fonamide reacts with some phenols, namely hydro-
quinone, 3-methoxyphenol, phloroglucinol, and
N-(3-hydroxyphenyl)acetamide, to give 1-arenesul-
fonyl-2-arylpyrrolidine derivatives.
EXPERIMENTAL
The IR spectra were recorded in the range 400–
3600 cm–1 on a UR-20 spectrometer from samples
1
(98%). H NMR spectrum (CDCl3), δ, ppm: 1.19 t
1
(6H, CH3, J = 7.1 Hz), 1.54–1.64 m (4H, CH2), 2.44 s
(3H, CH3), 2.94–3.01 m (2H, CH2), 3.42–3.51 m (2H,
CH2), 3.58–3.66 m (2H, CH2), 4.42 t (1H, CH, J =
5.1 Hz), 4.88 br.s (1H, NH), 7.31 d (2H, Harom, J =
8.0 Hz), 7.76 d (2H, Harom, J = 8.2 Hz).
dispersed in mineral oil. The H NMR spectra were
measured on a Bruker MSL 400 instrument at
400 MHz, and the 13C NMR spectra were taken on
a Bruker Avance 600 spectrometer at 150 MHz; the
chemical shifts were determined relative to the residual
proton and carbon signals of the deuterated solvent.
The elemental analyses were obtained using a Carlo
Erba EA 1108 analyzer. The melting points were meas-
ured in glass capillaries on a Stuart SMP 10 melting
2,5-Bis[1-(4-methylbenzenesulfonyl)pyrrolidin-
2-yl]benzene-1,4-diol (2). Trifluoroacetic acid, 0.27 g
(0.16 mmol), was added to a mixture of 0.51 g
(0.16 mmol) of N-(4,4-diethoxybutyl)-4-methylben-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 9 2016

SMOLOBOCHKIN et al.
1306
zenesulfonamide, 10 mL of anhydrous chloroform, and
0.09 g (0.80 mmol) of hydroquinone. The mixture was
stirred for 24 h at room temperature, and the precip-
itate was filtered off, washed with diethyl ether, and
dried under reduced pressure. Yield 0.08 g (9%),
mp <250°C (from EtOH). IR spectrum, ν, cm–1: 3451
N-{3-Hydroxy-4-[1-(4-methylbenzenesulfonyl)-
pyrrolidin-2-yl]phenyl}acetamide (5). Yield 0.15 g
(61%), mp <250°C (from EtOH). IR spectrum, ν, cm–1:
3413 (O‒H), 3396, 1597 (C=Carom), 1151 (SO2).
1H NMR spectrum (DMSO-d6), δ, ppm: 1.46–1.54 m
(1H, CH2), 1.46–1.54 m (1H, CH2), 1.55–1.73 m (3H,
CH2), 2.02 s (3H, CH3), 2.42 s (3H, CH3), 3.18–3.27 m
(1H, CH2), 3.52–3.59 m (1H, CH2), 4.80–4.87 m (1H,
1
(O‒H), 1598 (C=Carom), 1154 (SO2). H NMR spec-
trum (DMSO-d6), δ, ppm: 1.49–1.57 m (2H, CH2),
1.58–1.72 m (6H, CH2), 2.42 s (6H, CH3), 3.47–3.55 m
(4H, CH2), 4.80–4.85 m (2H, CH), 6.79 s (2H, Harom),
CH), 6.85 d (1H, Harom, J = 8.1 Hz), 7.12 d (1H, Harom
J = 8.4 Hz), 7.31 s (1H, Harom), 7.46 d (2H, Harom
,
,
7.46 d (4H, Harom, J = 8.1 Hz), 7.70 d (4H, Harom
,
J = 8.3 Hz), 7.70 d (1H, Harom, J = 8.2 Hz), 9.53 s
(1H, NH), 9.77 s (1H, OH). 13C NMR spectrum
(DMSO-d6), δ, ppm: 21.49, 23.80, 24.47, 34.00, 49.66,
58.74, 106.53, 109.97, 125.07, 127.31, 127.71, 130.33,
134.87, 139.28, 143.75, 153.99, 168.53. Found, %:
C 61.19; H 5.80; N 7.71; S 8.56. C19H22N2O4S. Cal-
culated, %: C 60.94; H 5.92; N 7.48; S 8.56.
J = 8.2 Hz), 8.83 s (2H, OH). 13C NMR spectrum
(DMSO-d6), δC, ppm: 21.48, 23.10, 33.83, 49.76,
58.80, 113.98, 126.25, 130.37, 130.99, 135.53, 141.27,
144.66. Found, %: C 60.71; H 5.65; N 4.93; S 11.66.
C28H32N2O6S2. Calculated, %: C 60.41; H 5.79;
N 5.03; S 11.52.
5-Methoxy-2,4-bis[1-(4-methylbenzenesulfonyl)-
pyrrolidin-2-yl]phenol (3). Yield 0.3 g (67%),
mp 149–151°C (from EtOH); mixture of diastereoiso-
mers at a ratio of 1:1.3. IR spectrum, ν, cm–1: 3479
This study was performed under financial support
by the Russian Science Foundation (project no. 16-13-
10023).
1
(O‒H), 3445, 1597 (C=Carom), 1153 (SO2). H NMR
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