Synthesis of pyrrolyl and pyrazolyl sulfonamides

Article abstract of DOI:10.1007/s10593-013-1186-4

A new class of pyrrolyl and pyrazolyl sulfonamides was prepared from styrene-ω-sulfonanilides by treatment with tosylmethyl isocyanide and diazomethane, respectively.

Full text of DOI:10.1007/s10593-013-1186-4

Chemistry of Heterocyclic Compounds, Vol. 48, No. 11, February, 2013 (Russian Original Vol. 48, No. 11, November, 2012)
SYNTHESIS OF PYRROLYL AND PYRAZOLYL SULFONAMIDES
V. Padmavathi1*, M. Swapna1, S. Nagi Reddy1, and A. Padmaja1
A new class of pyrrolyl and pyrazolyl sulfonamides was prepared from styrene-ω-sulfonanilides by
treatment with tosylmethyl isocyanide and diazomethane, respectively.
Keywords: diazomethane, pyrazolylsulfonamide, pyrrolylsulfonamide, styrene-ω-sulfonanilides,
tosylmethyl isocyanide.
Scientific efforts have continuously been directed towards the design and synthesis of five-membered
heterocycles because of their utility as pharmacological agents. Netropsin and distamycin are pyrrole
polyamides and are naturally occurring anticancer antibiotics [1]. Multistep synthetic routes for 3,4-di-
substituted pyrroles have been reported either by coupling of imines and nitroalkanes or using Friedel–Craft's
acylation with an electron-withdrawing group on pyrrole nitrogen or 3,4-silylated precursors [2]. Pyrroles have
also been prepared from Michael acceptors and tosylmethyl isocyanide (TosMIC) [3, 4]. Several pyrazole
derivatives received increased attention due to their biological activities as potential HIV-1 inhibitors [5],
insecticides [6], fungicides [6], antiviral [7], anti-inflammatory [8], antiobesity [9], and anticancer agents [10].
Among the different known methods for the synthesis of pyrazoles, Huisgen's 1,3-dipolar cycloaddition is a
versatile one [11]. Recent syntheses of pyrazoles via 1,3-dipolar cycloaddition includes reaction of nitrile imines
and alkynes [12] or enamines [13], hydrazones and nitroolefins [14], diazo compounds and alkynes [15], and
azomethine imines and alkynes [16]. We have exploited various activated olefins for the synthesis of a variety
of mono- and bis-heterocycles [17, 18]. However, there are no reports to our knowledge about the use of styrene
sulfonamides for the development of five-membered heterocycles.
The present communication deals with the synthesis of pyrrolyl and pyrazolyl sulfonamides from
styrene-ω-sulfonanilides 1a-c. The compounds 1a-c were prepared by the Knoevenagel condensation of aryl-
aminosulfonylacetic acids with arylaldehydes. The arylaminosulfonylacetic acids were obtained by the well-
known chain of reactions from substituted anilines [19].
The olefin group present in compounds 1a-c was exploited to develop pyrrole and pyrazoline rings.
1
Treatment of compounds 1a-c with TosMIC gave 4-aryl-3-arylaminosulfonylpyrroles 2a-c. The H NMR
spectrum of compound 2a showed two singlets at 6.56 and 7.17 ppm due to H-2 and H-5 protons of the pyrrole
ring in addition to two broad singlets at 8.41 and 10.45 ppm due to SO2NH and NH fragments. The latter signals
disappeared by deuteration. Similarly, 1,3-dipolar cycloaddition of diazomethane to compounds 1a-c at a
temperature of about -20°C produced 4-aryl-3-arylaminosulfonyl-1-methylpyrazolines 3a-c. It appears that
N-methylation also took place during the course of cyclization.
_______
*To whom correspondence should be addressed, e-mail: vkpuram2001@yahoo.com.
1Sri Venkateswara University, Tirupati-517 502, Andhra Pradesh, India.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1755-1759, November, 2012.
Original article submitted June 9, 2011.
0009-3122/13/4811-1641©2013 Springer Science+Business Media New York
1641

O
O
R
NC
S
R
R
HA
Me
O
H
O
(TosMIC)
N
S
N
S
NaH, DMSO
Et2O
H
O
O
HB
R
1a–c
N
H
2a–c
CH2N2
Et2O, Et3N
R
R
R
R
O
O
O
O
Chloranil
Xylene
S
S
N
N
3
4
5
H
H
HA
HM
HX
2 N
N
1N
Me
N
Me
4a–c
3a–c
a R = H, b R = Me, c R = Cl
1
The H NMR spectrum of compound 3a showed the AMX splitting pattern for methine and methylene
protons of pyrazoline ring. The three double doublets observed at 4.22, 3.94, and 3.55 ppm were assigned to
pyrazoline ring protons HA, HM, and HX, respectively. The coupling constants indicated that HA and HM are in
cis, HA and HX in trans, and HM and HX in geminal position to each other. A sharp singlet was observed at 3.14
ppm due to NCH3 group. Apart from these, a broad singlet was observed at 8.37 ppm due to NH, which
disappeared on deuteration. Aromatization of compounds 3a-c with chloranil in xylene resulted in 4-aryl-
3-arylaminosulfonyl-1-methylpyrazoles 4a-c. The absence of the AMX splitting pattern confirmed the formation
1
of compounds 4a-c. The H NMR spectrum of compound 4a displayed two sharp singlets due to the NCH3
group and the H-5 proton (overlapping with multiplet signal of phenyl protons), and a broad singlet due to NH
proton. The signal due to NH disappeared by deuteration. The structures of the compounds were further
established by IR and 13C NMR spectra.
Thus, a simple substrate, styrene-ω-sulfonanilide, was exploited to obtain new sulfonamide-linked
pyrroles and pyrazoles adopting the 1,3-dipolar cycloaddition methodology.
EXPERIMENTAL
1
The IR spectra were recorded on a Thermo Nicolet IR 200 FT-IR spectrometer in KBr pellets. The H
and 13C NMR spectra were recorded on a Bruker Spectrospin instrument (400 and 100 MHz, respectively) in
DMSO-d6 using TMS as internal standard. The elemental microanalyses were performed on a Perkin Elmer
240C Elemental Analyzer. Melting points were determined in open capillaries on a Mel-Temp apparatus and are
uncorrected. The purity of the compounds was checked by TLC (silica gel H, BDH, eluent EtOAc–hexane, 1:3).
The starting arylaminosulfonylacetic acids were prepared by the literature procedure [19].
Styrene-ω-sulfonanilides 1a-c (General Method). A mixture of arylaldehyde (1 mmol), pyridine
(4 ml), AcONH4 (1.00 g, 13 mmol), arylaminosulfonylacetic acid (0.21 g, 1 mmol), and toluene (25 ml) were
refluxed for 20–24 h with azeotropic removal of water. The solution was cooled and washed successively with
dilute HCl, dilute Na2SO3, and brine. Then it was extracted with 10% KOH. The potassium salt of styrene
sulfonamide was separated as oil with the aqueous phase. The two-phase aqueous extract was washed with ether
1642

and acidified with HCl. Then, it was extracted with ether. Removal of the solvent under vacuum furnished a
solid which on recrystallization from cyclohexane gave compounds 1a-c.
(E)-N,2-Diphenylethenesulfonamide (1a). Yield 0.20 g (77%). White solid; mp 108-112°C (mp 113°C
1
[19]). IR spectrum, ν, cm-1: 3332 (NH), 1632 (C=C), 1317, 1138 (SO2). H NMR spectrum, δ, ppm (J, Hz): 8.45
(1H, br. s, NH); 8.04 (1H, d, J = 14.7, HA); 7.84 (1H, d, J = 14.7, HB); 7.22-7.38 (10H, m, H Ph). 13C NMR
spectrum, δ, ppm: 145.4 (CHA); 131.3 (CHB); 139.3, 136.1, 134.2, 133.8, 131.2, 126.7, 125.6, 124.3 (C Ph).
Found, %: C 64.75; H 5.01; N 5.48. C14H13NO2S. Calculated, %: C 64.84; H 5.05; N 5.40.
(E)-N,2-Bis(4-methylphenyl)ethenesulfonamide (1b). Yield 0.23 g (83%). White solid; mp
1
124-126°C. IR spectrum, ν, cm-1: 3348 (NH), 1625 (C=C), 1320, 1143 (SO2). H NMR spectrum, δ, ppm (J,
Hz): 8.48 (1H, br. s, NH); 8.02 (1H, d, J = 14.6, HA); 7.87 (1H, d, J = 14.6, HB); 7.15–7.38 (8H, m, H Ar); 2.39
(3H, s, CH3), 2.37 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 144.6 (CHA); 131.5 (CHB); 137.2, 136.8, 133.7,
132.5, 130.9, 127.4, 124.8, 124.2 (C Ar); 23.7 (CH3); 23.5 (CH3). Found, %: C 66.93; H 5.87; N 4.82.
C16H17NO2S. Calculated, %: C 66.87; H 5.96; N 4.87.
(E)-N,2-Bis(4-chlorophenyl)ethenesulfonamide (1c). Yield 0.25 g (77%). White solid; mp 116-118°C.
IR spectrum, ν, cm-1: 3341 (NH), 1628 (C=C), 1323, 1146 (SO2). 1H NMR spectrum, δ, ppm (J, Hz): 8.42 (1H,
br. s, NH); 8.08 (1H, d, J = 14.8, HA); 7.89 (1H, d, J = 14.8, HB); 7.25-7.39 (8H, m, H Ar). 13C NMR spectrum,
δ, ppm: 146.7 (CHA); 131.8 (CHB); 138.4, 136.2, 131.8, 131.4, 129.7, 129.5, 126.5, 126.1, 124.5 (C Ar). Found,
%: C 51.28; H 3.35; N 4.32. C14H1lCl2NO2S. Calculated, %: C 51.23; H 3.38; N 4.27.
4-Aryl-3-arylaminosulfonylpyrroles 2a-c (General Method). In a 100 ml two-necked round-
bottomed flask fitted with a calcium chloride guard-tube and a septum and equipped with a magnetic stirrer,
NaH (0.06 g, 2.5 mmol) in abs. Et2O (8 ml) was stirred at rt for 20 min. To this, a mixture of TosMIC (0.97 g,
5.0 mmol) and compound 1a-c (1.29 g, 5.0 mmol) in DMSO (8 ml) and abs. Et2O (4 ml) was added dropwise
via a syringe. The stirring was continued for another 18-20 h, and the whole was diluted with H2O. It was
extracted with Et2O and dried over anhydrous Na2SO4. Removal of the solvent in vacuo gave a crude product,
which was purified by column chromatography (eluent EtOAc–hexane, 1:3).
4-Phenyl-3-phenylaminosulfonylpyrrole (2a). Yield 1.02 g (69%). White solid; mp 125-127°C. IR
1
spectrum, ν, cm-1: 3235 (NH), 1621 (C=C), 1335, 1147 (SO2). H NMR spectrum, δ, ppm: 10.45 (1H, br. s,
NH); 8.41 (1H, br. s, SO2NH); 7.22-7.82 (10H, m, H Ph); 7.17 (1H, s, H-5); 6.56 (1H, s, H-2). 13C NMR
spectrum, δ, ppm: 137.8, 135.9, 131.2, 130.8, 128.3, 126.8, 126.2, 122.8 (C Ph); 120.5 (C-5); 115.7 (C-2);
105.8 (C-4); 104.5 (C-3). Found, %: C 64.53; H 4.67; N 9.32. C16H14N2O2S. Calculated, %: C 64.41; H 4.73;
N 9.39.
4-(4-Methylphenyl)-3-(4-methylphenyl)aminosulfonylpyrrole (2b). Yield 1.06 g (65%). White solid;
1
mp 146-148°C. IR spectrum, ν, cm-1: 3238 (NH), 1625 (C=C), 1339, 1132 (SO2). H NMR spectrum, δ, ppm:
10.44 (1H, br. s, NH); 8.43 (1H, br. s, SO2NH); 7.18-7.86 (8H, m, H Ar); 7.13 (1H, s, H-2); 6.68 (1H, s, H-5);
2.34 (3H, s, CH3); 2.32 (3H, s, CH3). 13C NMR spectrum, δ, ppm: 138.1, 136.5, 131.8, 130.5, 128.8, 127.4,
125.9, 123.6 (C Ar); 119.8 (C-5); 114.2 (C-2); 105.9 (C-4); 104.7 (C-3); 23.4 (CH3); 23.1 (CH3). Found, %: C 66.14;
H 5.61; N 8.66. C18H18N2O2S. Calculated, %: C 66.23; H 5.56; N 8.58.
4-(4-Chlorophenyl)-3-(4-chlorophenyl)aminosulfonylpyrrole (2c). Yield 1.24 g (68%). White solid;
1
mp 163-165°C. IR spectrum, ν, cm-1: 3343 (NH), 1618 (C=C), 1337, 1143 (SO2). H NMR spectrum, δ, ppm:
10.47 (1H, br. s, NH); 8.45 (1H, br. s, SO2NH); 7.25–7.91 (8H, m, H Ar); 7.23 (1H, s, H-5); 6.54 (1H, s, H-2).
13C NMR spectrum, δ, ppm: 137.5, 136.8, 130.1, 129.7, 128.9, 128.8, 122.2, 121.9 (C Ar); 117.5 (C-5); 113.2
(C-2); 106.4 (C-4); 102.1 (C-3). Found, %: C 52.45; H 3.32; N 7.71. C16H12Cl2N2O2S. Calculated, %: C 52.33;
H 3.29; N 7.63.
4-Aryl-3-arylaminosulfonyl-1-methylpyrazolines 3a-c (General Method). To a cooled solution of
compound 1a-c (0.64 g, 2.5 mmol) in CH2Cl2 (10 ml), 0.4 M Et2O solution of CH2N2 (20 ml) and Et3N (0.06 g,
0.6 mmol) were added. The reaction mixture was kept at -20 to -15C temperature for 40-48 h. The solvent was
removed under reduced pressure. The resultant solid was purified by column chromatography (eluent EtOAc–
hexane, 1:3).
1643

1-Methyl-4-phenyl-3-phenylaminosulfonylpyrazoline (3a). Yield 0.55 g (71%). White solid; mp 136-
138°C. IR spectrum, ν, cm-1: 3327 (NH), 1589 (C=N), 1335, 1141 (SO2). 1H NMR spectrum, δ, ppm (J, Hz): 8.37
(1H, br. s, NH); 7.02-7.33 (10H, m, H Ph); 4.22 (1H, dd, JAM = 12.0, JAX = 6.9, HA); 3.94 (1H, dd, JAM = 12.0,
JMX = 10.9, HM); 3.55 (1H, dd, JAX = 6.9, JMX = 10.9, HX); 3.14 (3H, s, NCH3). 13C NMR spectrum, δ, ppm:
137.5, 136.8, 130.1, 129.7, 128.9, 128.8, 122.2, 121.9 (C Ph); 117.5 (C-5); 113.2 (C-2); 106.4 (C-4); 102.1 (C-3).
Found, %: C 61.04; H 5.43; N 13.20. C16H17N3O2S. Calculated, %: C 60.93; H 5.43; N 13.32.
1-Methyl-4-(4-methylphenyl)-3-(4-methylphenyl)aminosulfonylpyrazoline (3b). Yield 0.61 g (72%).
1
White solid; mp 152-154°C. IR spectrum, ν, cm-1: 3342 (NH), 1594 (C=N), 1340, 1138 (SO2). H NMR
spectrum, δ, ppm (J, Hz): 8.45 (1H, br. s, NH); 7.13-7.52 (8H, m, H Ar); 4.30 (1H, dd, JAM = 12.3, JAX = 6.7,
HA); 3.95 (1H, dd, JAM = 12.3, JMX = 10.7, HM); 3.52 (1H, dd, JAX = 6.7, JMX = 10.7, HX); 3.11 (3H, s, NCH3);
2.37 (3H, s, ArCH3); 2.35 (3H, s, ArCH3). 13C NMR spectrum, δ, ppm: 148.7 (C-3); 139.5, 136.7, 132.8, 131.6,
130.2, 128.8, 126.4, 123.7 (C Ar); 56.5 (C-5); 51.2 (C-4); 42.3 (NCH3); 23.7 (ArCH3); 23.5 (ArCH3). Found, %:
C 63.06; H 6.11; N 12.33. C18H21N3O2S. Calculated, %: C 62.95; H 6.16; N 12.23.
4-(4-Chlorophenyl)-3-(4-chlorophenyl)aminosulfonyl-1-methylpyrazoline (3c). Yield 0.72 g (75%).
White solid; mp 187-189°C. IR spectrum, ν, cm-1: 3344 (NH), 1606 (C=N), 1336, 1144 (SO2). 1H NMR spectrum,
δ, ppm (J, Hz): 8.41 (1H, br. s, NH); 7.10-7.45 (8H, m, H Ar); 4.28 (1H, dd, JAM = 12.4, JAX = 6.8, HA); 3.97
13
(1H, dd, JAM = 12.4, JMX = 11.0, HM); 3.52 (1H, dd, JAX = 6.8, JMX = 11.0, HX); 3.10 (3H, s, NCH3). C NMR
spectrum, δ, ppm: 146.5 (C-3); 140.5, 137.6, 132.4, 130.2, 129.2, 128.8, 127.9, 122.2 (C Ar); 59.3 (C-5); 51.9
(C-4); 42.9 (NCH3). Found, %: C 49.92; H 3.97; N 11.05. C16H15Cl2N3O2S. Calculated, %: C 50.01; H 3.93;
N 10.93.
4-Aryl-3-arylaminosulfonyl-1-methylpyrazoles 4a-c (General Method). A solution of compounds
3a-c (0.32 g, 1 mmol) and chloranil (0.25 g, 1 mmol) in xylene (10 ml) was refluxed for 24-32 h. Then the
reaction mixture was treated with a 5% NaOH solution. The organic layer was separated and repeatedly washed
with water. It was dried over anhydrous Na2SO4, and the solvent was removed on a rotary evaporator. The
resultant solid was purified by recrystallization from 2-PrOH.
1-Methyl-4-phenyl-3-phenylaminosulfonylpyrazole (4a). Yield 0.20 g (65%). White solid; mp 155-
1
157°C. IR spectrum, ν, cm-1: 3340 (NH), 1623 (C=C), 1583 (C=N), 1333, 1140 (SO2). H NMR spectrum, δ,
ppm: 8.35 (1H, br. s, NH); 6.98-7.35 (11H, m, H-5, H Ph); 3.27 (3H, s, NCH3). 13C NMR spectrum, δ, ppm:
149.5 (C-3); 138.6 (C-5); 137.4 (C-4); 138.2, 136.8, 132.5, 131.8, 129.3, 128.2, 126.4, 125.8 (C Ph); 42.8
(NCH3). Found, %: C 61.45; H 4.87; N 13.52. C16H15N3O2S. Calculated, %: C 61.32; H 4.82; N 13.41.
1-Methyl-4-(4-methylphenyl)-3-(4-methylphenyl)aminosulfonylpyrazole (4b). Yield 0.22 g (67%).
White solid;.mp 174-176°C. IR spectrum, ν, cm-1: 3340 (NH), 1623 (C=C), 1583 (C=N), 1333, 1140 (SO2).
1H NMR spectrum, δ, ppm: 8.32 (1H, br. s, NH); 6.92-7.32 (9H, m, H-5, H Ar); 3.24 (3H, s, NCH3); 2.35 (3H,
s, ArCH3); 2.32 (3H, s, ArCH3). 13C NMR spectrum, δ, ppm: 149.8 (C-3); 138.1 (C-5); 136.8 (C-4); 137.3,
135.6, 132.2, 131.5, 129.8, 129.1, 128.3, 125.4 (C Ar); 42.5 (NCH3); 23.9 (ArCH3), 23.7 (ArCH3). Found, %:
C 63.25; H 5.66; N 12.40. C18H19N3O2S. Calculated, %: C 63.32; H 5.61; N 12.31.
4-(4-Chlorophenyl)-3-(4-chlorophenyl)aminosulfonyl-1-methylpyrazole (4c). Yield 0.25 g (68 %).
White solid; mp 201-203°C. IR spectrum, ν, cm-1: 3347 (NH), 1625 (C=C), 1603 (C=N), 1337, 1145 (SO2).
1H NMR spectrum, δ, ppm: 8.38 (1H, br. s, NH); 7.04-7.39 (9H, m, H-5, H Ar); 3.24 (3H, s, NCH3). 13C NMR
spectrum, δ, ppm: 148.7 (C-3); 139.6 (C-5); 138.8 (C-4); 138.7, 136.2, 132.8, 131.3, 129.5, 128.4, 127.5, 125.6
(C Ar); 43.0 (NCH3). Found, %: C 50.34; H 3.38; N 11.06. C16H13Cl2N3O2S. Calculated, %: C 50.27; H 3.43;
N 10.99.
The authors are grateful to DST, New Delhi, for financial assistance under a major research project.
1644

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