Anti-HIV-1 activity of pyrryl aryl sulfone (PAS) derivatives: Synthesis and SAR studies of novel esters and amides at the position 2 of the pyrrole nucleus

Article abstract of DOI:10.1016/j.farmac.2003.11.004

A SAR study has been performed in order to evaluate how much the ester function could be a determinant for the anti-human immunodeficiency virus type-1 activity of pyrryl aryl sulfones (PASs), a potent family of non-nucleoside reverse transcriptase (RT) inhibitors discovered in the last years. Twenty-three new esters were prepared with the aim to enhance the inhibitory potency of 4a and 4c, two PAS agents endowed with good activity (EC₅₀ = 0.14 μM) and deprived of cytotoxicity up to >200 μM. None of test derivatives was as potent as 4a and 4c and lacked of selectivity due to their higher cytotoxicity (compounds 22-25). Antiviral activity correlate with an ester ramified chain.

Full text of DOI:10.1016/j.farmac.2003.11.004

IL FARMACO 59 (2004) 201–210
www.elsevier.com/locate/farmac
Anti-HIV-1 activity of pyrryl aryl sulfone (PAS) derivatives:
synthesis and SAR studies of novel esters and amides
at the position 2 of the pyrrole nucleus
Romano Silvestri a,*, Marino Artico a, Giuseppe La Regina a, Gabriella De Martino a,
Massimiliano La Colla b, Roberta Loddo b, Paolo La Colla b,*
a Dipartimento di Studi Farmaceutici, Università di Roma “La Sapienza”, Piazzale Aldo Moro 5, Rome 00185, Italy
b Dipartimento di Scienze e Tecnologie Biomediche, Università di Cagliari, Cittadella Universitaria, SS 554, Monserrato 09042, Cagliari, Italy
Received 8 August 2003; accepted 15 November 2003
Abstract
A SAR study has been performed in order to evaluate how much the ester function could be a determinant for the anti-human
immunodeficiency virus type-1 activity of pyrryl aryl sulfones (PASs), a potent family of non-nucleoside reverse transcriptase (RT) inhibitors
discovered in the last years. Twenty-three new esters were prepared with the aim to enhance the inhibitory potency of 4a and 4c, two PAS
agents endowed with good activity (EC50 = 0.14 µM) and deprived of cytotoxicity up to >200 µM. None of test derivatives was as potent as 4a
and 4c and lacked of selectivity due to their higher cytotoxicity (compounds 22–25). Antiviral activity correlate with an ester ramified chain.
© 2003 Elsevier SAS. All rights reserved.
Keywords: AIDS; HIV-1; NNRTI; Pyrryl aryl sulfones
1. Introduction
Pyrryl aryl sulfones (PASs, 4) [6–8] are a NNRTI class
discovered in our laboratories during studies on novel anti-
retroviral RT inhibitors related to nitrophenyl phenyl sulfone
(NPPS) (5) [9] and PBTDs (6) [10,11] (Chart 1). SAR studies
on PAS derivatives led to go into the structural requirements
for high antiviral potency, namely the presence of a
p-chloroaniline moiety and an ethoxycarbonyl group at posi-
tion 2 of the pyrrole nucleus [7]. Further SAR studies devoted
to design new substituents on the amino group at position
2 of the aryl moiety led to identify acylamino pyrryl aryl
sulfones (APASs, 8), a NNRTI class which resulted as active
as pyrrolo[1,2-b)[1,2,5]benzothiadiazepines 5,5-dioxide
PBTDs [12].A previous work [7] showed that replacement of
the ethoxycarbonyl function of PAS 980 (4) with some
alkoxy congeners, such as methoxy, n-, iso-propoxy or ally-
loxy groups, furnished compounds as potent as the parent
compound. Furthermore, we observed that in the APAS se-
ries the highest antiviral activity was related to the presence
of a four member acyl chain (methoxyacetyl or methylthio-
acetyl) linked to the amino group of 4 [12]. These findings
suggested us to explore more deeply how substitution of the
ethoxycarbonyl group with different alkoxycarbonyls would
influence the antiviral activity in the PAS series. Some
Anti-acquired immunodeficiency syndrome (AIDS) drugs
fall into three families, the nucleoside reverse transcriptase
inhibitors (NRTIs), the non-nucleoside reverse transcriptase
inhibitors (NNRTIs), and the protease inhibitors (PIs) [1–3].
Highly active antiretroviral therapy (HAART) regimens,
which are based on triple or quadruple combinations of
NRTIs, NNRTIs and PIs, reduce the human immunodefi-
ciency virus (HIV) to very low levels, but are unable to
extirpate the infection. Long period therapies lead to the
emergence of drug resistant mutant strains [4]. Thus, the
need of novel anti-AIDS agents active on mutant strains is
continuous.
NNRTIs received great attention because are HIV-1 selec-
tive, low toxic, and show favorable pharmacokinetic proper-
ties. To date three NNRTIs are on the market, namely nevi-
rapine (1, Viramune®), delavirdine (2, Rescriptor®), and
efavirenz (3, Sustiva®) (Chart 1), but a wide number of
structurally unrelated NNRTIs were identified [5].
* Corresponding authors.
E-mail addresses: romano.silvestri@uniroma1.it (R. Silvestri),
placolla@unica.it (P. La Colla).
© 2003 Elsevier SAS. All rights reserved.
doi:10.1016/j.farmac.2003.11.004

202
R. Silvestri et al. / IL FARMACO 59 (2004) 201–210
O
H C
3
O
S
H C
3
O
N
HN
HN
F C
3
Cl
N
O
CH
N
3
N
HN
N
N
N
H
N
H
O
CH
3
O
nevirapine (1)
®
delavirdine (3)
®þ
efavirenz (3)
®þ
Viramune
Rescriptor
Sustiva
Cl
NH
NO
2
2
O
O
O
O
S
Cl
H N
2
S
N
S
O
O
O
O
S
O
O
HN
O
O
HN
N
CH
3
Cl
L,737-126 (7)
PAS 980 (4)
PBTD 981(6)
Chart 1. Clinically used and sulfone NNRTIs.
NPPS (5)
amides related to the potent indole derivative L-737,126 (7)
were also synthesized [13] (Chart 2).
with formation of amino sulfones 20–27, 29–31, 39–43
(Scheme 1). 1-[(2-Amino-5-chlorophenyl)sulfonyl]-1H-
pyrrole-2-carbohydrazide (44) was obtained starting from
4a, as previously reported [15].
2. Chemistry
2-Hydroxyethyl 1-[(2-amino-5-chlorophenyl)sulfonyl]-
1H-pyrrole-2-carboxylate (28) was obtained by chlorotri-
methylsilane/sodium iodide dealkylation of 2-methoxyethyl
1-[(2-amino-5-chlorophenyl)sulfonyl]-1H-pyrrole-2-
carboxylate (27) in acetonitrile according to Olah [20]
(Scheme 2).
The novel sec-butyl, cyclopropylmethyl, propargyl, cy-
clopentyl, cyclohexyl and 2-methoxyethyl 1H-pyrrole-2-
carboxylic esters were prepared by heating trichloroacetyl-
1H-pyrrole [17] with an equimolar amount of an appropriate
alcohol in the presence of potassium carbonate. A similar
procedure was used in the preparation of N-benzyl, N-methyl
1H-pyrrole-2-carboxyamide in the presence of triethy-
lamine.
1-(Phenylsulfonyl)-1H-pyrroles 9–19, 32, 36 and 37 were
prepared by phase transfer reaction of appropriates phenyl-
sulfonyl chlorides and pyrroles in the presence of 18-
crown-6 and potassium tert-butoxide, according to the pro-
cedure of by Guida and Mathre [14]. For compounds 33–35
and 38 [15] a different procedure was adopted. The phenyl-
sulfonyl chloride or its 5-chloroderivative [16] was reacted
with 2-trichloroacetyl-1H-pyrrole [17] in the presence of
18-crown-6 and potassium tert-butoxide, to give the related
1-(phenylsulfonyl)-2-trichloroacetyl-1H-pyrroles 45 and 46,
which were then treated with amine or hydrazine according
to Bailey [18,19]. Reduction of nitro group was performed by
heating at 60 °C with iron powder in glacial acetic acid
NO
NH
2
2
3. Results and discussion
O
O
Cl
S
N
S
N
O
O
O
O
The anti-HIV-1 activities (EC50s) of PAS derivatives 9–44
together with their cytotoxicities (CC50s) and the corre-
sponding selectivity indexes (SIs) are reported in
Tables 1 and 2. The anti-HIV-1 activities were established by
determining their ability to prevent the virus-induced cyto-
pathogenicity in MT-4 cells, as described elsewhere [21].
Compounds 4a–d [7] and 5 [10] were used as reference
compounds.
Thirty-six compounds were tested, and fifteen of them
showed significant antiviral activity. Four compounds (10,
31, 34 and 40) had EC50 values in the 10–100 µM range.
Eight compounds (21, 23–25, 27–29 and 32) showed EC50
values between 1–10 µM, ranging from 1.6 (21) to 9 µM (28)
with CC50 values from >200 (21, 27, 28 and 32) to 13 µM
O
O
CH
CH
3
3
st
nd
1
generation PASs
2
generation PASs (4)
O
CH
3
O
NH
NH
2
O
O
Cl
S
N
Cl
S
N
O
O
O
O
R
O
CH
3
APAS (8)
20-30, 39-44
Chart 2. SAR studies in the PAS series.

R. Silvestri et al. / IL FARMACO 59 (2004) 201–210
203
R
4
NH2
R1
R
4
R
N
R
4
3
Fe
H
N
Cl
S
N
Cl
S
O
i-BuOK, 18-C-6
O
CH COOH
3
O
O
R
3
R
3
R1
20-27,29-31,39-43
9-19,32,36,37
Cl
S
R
Fe
2
O
O
CH COOH
3
R1
R
S
1
COCCl
N
H
3
NH R
2
5
N
S
N
R2
R2
O
O
O
O
i-BuOK, 18-C-6
COCCl
CONHR
3
5
33-35,38
45,46
a
Scheme 1a. R1: H, Cl, NO2; R2: H, Cl; R3: carboxylic ester (see Table 1),CN; R4: COOEt, 4-methylpiperazin-1-ylmethyl; R5: H, NH2, NHMe, NHEt.
fold) the anti-HIV-1 activity, but this compound resulted
NH2
NH2
R
R
4
4
(CH ) SiCl
3 3
somewhat cytotoxic (compare 22 with 29); (ix) transposition
of the ethoxycarbonyl group of 4a from position 2 of the
pyrrole ring to position 3 dramatically reduced antiviral ac-
tivity and increased cytotoxicity (compare 31 with 4a); (xi)
when the 2-amino group of 4a was replaced with a chlorine
atom, the resulting dichloro derivative 32 was 54-fold less
active than the parent compound, but it resulted no cytotoxic
(compare 32 with 4a).
N
N
Cl
S
Cl
S
O
NaI
O
O
O
O
OH
O
O
CH
O
O
3
28
27
Scheme 2
(29). Derivative 22 displayed the highest antiviral activity
within the series showing EC50 = 0.9 µM, CC50 = 71.3 µM,
and selectivity index = 79.2.
In conclusion, we explored substitutions of the ester func-
tion at the position 2 of the pyrrole ring of PAS derivatives.
Although the new esters were less potent and sometimes
more cytotoxic than the previously reported derivatives
4a–d, this study demonstrated that a ramified ester chain and
the presence of the p-chloroanilino moiety were both crucial
determinants for the anti-HIV-1 activity of PAS derivatives.
SAR analysis led to highlight the following points: (i)
independently from the presence of an alkoxycarbonyl group
or a carboxyamide function at position 2 of the pyrrole ring,
the nitro derivatives 9–19 and 33–38 were quite inactive; (ii)
among the amino derivatives, only ester (20–28, 30 and 31)
or cyano (29) compounds showed high antiviral activity,
whereas the corresponding amides were scarcely active (40)
or inactive (39, 41–44); (iii) the highest antiviral activity
within the series was found in 2-methylpropyl (sec-butyl)
ester of 1-[(2-amino-5-chlorophenyl)sulfonyl]-1H-pyrrole-
2-carboxylic acid (22) which showed EC50 = 0.9 µM,
CC50 = 71.3 µM, and selectivity index = 79.2; (iv) the inhibi-
tory activity of 22 was partially retained when the sec-butyl
chain of the ester function was replaced with the iso-butyl or
the cyclopropylmethyl chain, but it was lost with the n-butyl
chain (compare 22 with 21, 23 and 20, respectively); (v)
substitution the sec-butyl chain of 22 with a methoxyethyl
chain reduced by 3.5-fold the inhibitory activity of the parent
compound; a further about 3-fold reduction of activity was
observed when this chain was replaced with a hydroxyethyl
one (compare 22 with 27 and 28); nevertheless, compounds
27 and 28 were no cytotoxic; (vi) replacement of the sec-
butyl chain of 22 with a propargyl abated twofold the antivi-
ral activity, and increased of the same magnitude the cytotox-
icity (compare 22 with 24); (vii) insertion of cyclic groups
furnished less active (25), inactive (26), or more cytotoxic
(30) compounds; (viii) replacement of the sec-butoxy-
carbonyl function of 22 with a cyano group reduced (3.9-
4. Experimental
4.1. Chemistry
Melting points (m.p.) were determined on a Büchi 510 ap-
paratus and are uncorrected. Boiling points (b.p.) were deter-
mined by distillation under diminished pressure on a pear-
shaped Claisen-Vigreux flask by using Edwards Speedivac
2SC50B high vacuum pump equipped with Edwards Pirani
vacuum gauge. Infrared spectra (IR) were run on Perkin-
Elmer 1310 and SpectrumOne spectrophotometers. Band
position and absorption ranges are given in cm–1. Proton
nuclear magnetic resonance (1H NMR) spectra were re-
corded on Bruker AM-200 (200 MHz) and Bruker Avance
400 MHz FT spectrometers in the indicated solvent. Chemi-
cal shifts are expressed in d units (ppm) from tetramethylsi-
lane. Column chromatographies were packed with alumina
Merck (70–230 mesh) and silica gel Merck (70–230 mesh).
Aluminum oxide thin layer chromatography (TLC) cards

204
R. Silvestri et al. / IL FARMACO 59 (2004) 201–210
Table 1
Table 2
Structures and anti-HIV-1 activities of PAS derivatives 9–32a
Structures and anti-HIV-1 activities of PAS derivatives 33–44a
NO
O
NH
2
Cl
2
NH
O
NO
O
2
2
O
O
Cl
S
N
O
Cl
S
N
O
Cl
S
N
O
R
S O
N
R
S O
N
1
1
R
1
R
COOC H
2
1
5
R
R
2
2
R
2
R
2
9-19
32
4a-d, 20-31
33-38
Compound R1 R2
39-44
b
c
Compound R1
R2
H
CC50 EC50 SId
b
c
CC50
>200
52
EC50
SId
–
9
COO(CH2)3CH3
22
>22
14
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
4ae
4be
4ce
4de
5f
COOCH2CH(CH3)2
COOCH(CH3)C2H5
COOCH2-cyclo-C3H5
COOCH2C≡CH
COO-cyclo-C5H9
COO-cyclo-C6H11
COOCH2CH2OCH3
C≡N
H
H
H
H
H
H
H
H
H
24
1.7
33
34
35
36
37
38
39
40
41
42
43
44
H
CONH2
>200
27
32.5
96
≥32.5 –
Cl CONH2
1.9
–
>96
–
–
–
–
–
–
Cl CONHC2H5
Cl CON(C2H5)2
Cl CON(CH3)C6H5
Cl CONHNH2
16.6
13
>16.6
>13
4.9
11
>4.9
>11
–
17
>17
–
160
12
>160
>12
>200
>200
200
>200
146
87
>200
>200
15
–
H
CONH2
–
1.4
15.5
>1.4
Cl CONH2
13.9
–
COOC6H5
>15.5 –
Cl CONHC2H5
Cl CON(C2H5)2
Cl CON(CH3)C6H5
Cl CONHNH2
>200
>146
>87
H
COOC2H5 0.7
>0.7
–
–
–
COO(CH2)3CH3
COOCH2CH(CH3)2
COOCH(CH3)C2H5
COOCH2-cyclo-C3H5
COOCH2C≡CH
COO-cyclo-C5H9
COO-cyclo-C6H11
COOCH2CH2OCH3
COOCH2CH2OH
C≡N
H
H
H
H
H
H
H
H
H
H
H
>200 >200
>200 1.6
–
>125.0
79.2
>200
>200
–
71.3
39
0.9
2.3
a Data represent mean values for three separate experiments. Variation
among triplicate samples was <15%.
17.0
b Compound concentration (µM) required to reduce the viability of mock-
infected MT-four cells by 50% (MTT-method).
118
53.6
1.86 63.4
2
26.8
–
c Compound concentration (µM) required to achieve 50% protection of
infected MT-4 cells from the HIV-1IIIB-induced cytopathogenicity (MTT-
method).
>200 >200
>200 3.2
62.5
>22.2
3.7
>200
13
9
d Selectivity index: CC50/EC50 ratio.
3.5
>24
15
COOC6H5
24
–
chloride [15]; n-butyl 1H-pyrrole-2-carboxylate was pre-
pared as reported by Harbuck and Rapoport [19], yield 92%,
m.p. 36–39 °C, Ref. [21] m.p. 36–38 °C; iso-butyl 1H-
pyrrole-2-carboxylate was prepared as reported by Harbuck
and Rapoport [19], yield 85%, m.p. 66–67 °C (petroleum
ether), Ref. [22] m.p. 68–69 °C; 2-cyano-1H-pyrrole [23];
phenyl 1H-pyrrole-2-carboxylate [22]; ethyl 1H-pyrrole-3-
carboxylate was prepared according to van Leusen et al. [24],
m.p. 35–38 °C (ligroin), Ref. [25] m.p. 40 °C (ligroin);
2-trichloroacetyl-1H-pyrrole [16]; ethyl 1H-pyrrole-2-
carboxylate [16]; N,N-diethyl 1H-pyrrole-2-carboxyamide
was prepared as reported by Bailey and Johnson [17], yield
48%, m.p. 93–94 °C (cyclohexane), Ref. [26] m.p. 99.5 °C
(ligroin).
H
COOC2H5 44
2.9
–
–
>200 7.6
>26.3
COOCH2CH3
COOCH2CH2CH3
COO CH(CH3)2
COOCH2CH=CH2
–
H
H
H
H
–
>200 0.14 >1428.6
110 0.2 550.0
>200 0.14 >1428.6
100
0.4
250.0
>100 0.5
>200.0
a Data represent mean values for three separate experiments. Variation
among triplicate samples was <15%.
b Compound concentration (µM) required to reduce the viability of mock-
infected MT-four cells by 50% (MTT-method).
c Compound concentration (µM) required to achieve 50% protection of
infected MT-4 cells from the HIV-1IIIB-induced cytopathogenicity (MTT-
method).
d Selectivity index: CC50/EC50 ratio.
e Ref. [7].
f Ref. [10].
4.1.1. General procedure for condensation of benzene-
sulfonyl chlorides with esters of 1H-pyrrole-2-carboxylic
acid, N,N-dialkyl 1H-pyrrole-2-carboxyamides and 2-
trichloroacetyl-1H-pyrrole example
n-Butyl 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyrrole-
2-carboxylate (9). To a stirred mixture of potassium tert-
butoxide (1.34 g, 0.012 mol) and 18-crown-6 (0.28 g, 0.0011
mol) in anhydrous THF (21 ml) was added dropwise a solu-
tion of n-butyl 1H-pyrrole-2-carboxylate (1.67 g, 0.010 mol)
in the same solvent (21 ml). Stirring was maintained for
15 min, then the suspension was cooled to 0 °C, while a
solution of 5-chloro-2-nitrobenzenesulfonyl chloride [15]
Fluka (aluminum oxide precoated aluminum cards with fluo-
rescent indicator at 254 nm) and silica gel TLC cards Fluka
(silica gel precoated aluminum cards with fluorescent indica-
tor at 254 nm) were used for TLC. Developed plates were
visualized by Spectroline ENF 260C/F UV apparatus. Or-
ganic solutions were dried over anhydrous sodium sulfate.
Concentration and evaporation of the solvent after reaction or
extraction was carried out on a rotary evaporator Büchi
Rotavapor operating at reduced pressure. Elemental analyses
were found within 0.4% of the theoretical values (Appen-
dices A and B). Materials: 5-chloro-2-nitrobenzenesulfonyl

R. Silvestri et al. / IL FARMACO 59 (2004) 201–210
205
(2.56 g, 0.010 mol) in anhydrous THF (21 ml) was dropped.
Reaction was stirred at room temperature for 3.5 h, then
concentrated to a small volume and extracted with ethyl
acetate. Organic extracts were washed with brine and dried.
Removal of the solvent furnished the crude product which
was purified on column chromatography (alumina/
chloroform), to yield 9 (88%); m.p. 68–69 °C (cyclohexane).
1H NMR (CDCl3): d 0.92 (t, J = 7.3 Hz, 3H), 1.20–1.50 and
1.50–1.75 (2m, 4H,), 4.11 (t, J = 6.6 Hz, 2H,), 6.34 (m, 1H,),
7.10 (dd, J = 1.8 and 3.6 Hz, 1H), 7.62 (dd, J = 1.8 and
3.2 Hz, 1H), 7.58–7.86 (m, 2H,), 8.32 (d, J = 8.6 Hz, 1H). IR
(nujol): m 1710 cm–1 (CO). Anal. C15H15ClN2O6S (386.80):
C, H, N, Cl, S.
By this general procedure were prepared sulfones 10–19,
32, 36, 37 and 45, 46 iso-Butyl 1-[(5-chloro-2-nitro-
phenyl)sulfonyl]-1H-pyrrole-2-carboxylate (10). Yield 83%
(alumina/chloroform); m.p. 98–99 °C (cyclohexane). 1H
NMR (CDCl3): d 0.92 (d, J = 6.7 Hz, 6H), 1.94 (m,
J = 6.7 Hz, 1H) 3.91 (d, J = 6.7 Hz, 2H), 6.36 (3 line m, 1H),
7.12 (dd, J = 1.8 and 3.6 Hz, 1H), 7.64 (dd, J = 1.8 and
3.3 Hz, 1H), 7.72 (dd, J = 2.1 and 8.5 Hz, 1H), 7.80 (d,
J = 8.5 Hz, 1H), 8.31 ppm (d, J = 2.1 Hz, 1H). IR (nujol): m
1710 cm–1 (CO). Anal. C15H15ClN2O6S (386.80): C, H, N,
Cl, S.
Cyclohexyl 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyr-
role-2-carboxylate (15). Yield 52% (alumina/chloroform);
m.p. 124–125 °C (cyclohexane). 1H NMR (CDCl3): d 1.14–
1.61 (m, 6H), 1.61–1.96 (m, 4H), 4.78 (m, 1H), 6.34 (3 line
m, 1H), 7.10 (dd, J = 1.8 and 3.6 Hz, 1H), 7.60 (dd,
J = 1.8 and 3.3 Hz, 1H), 7.68–7.82 (m, 2H), 8.34 ppm (d,
J = 8.5 Hz, 1H). IR (nujol): m 1710 cm–1 (CO). Anal.
C17H17ClN2O6S (412.84): C, H, N, Cl, S.
2-Methoxyethyl 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-
pyrrole-2-carboxylate (16). Yield 77% (alumina/chloro-
form); m.p. 83–84 °C (toluene/cyclohexane). 1H NMR
(CDCl3): d 3.35 (s, 3H), 3.58 (t, J = 4.6 Hz, 2H), 4.27 (t,
J = 4.6 Hz, 2H), 6.36 (3 line m, 1H), 7.17 (dd, J = 1.8 and
3.6 Hz, 1H), 7.64 (dd, J = 1.8 and 3.2 Hz, 1H), 7.71 (dd,
J = 1.9 and 8.6 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 8.28 ppm (d,
J = 1.9 Hz, 1H). IR (nujol): m 1700 cm–1 (CO). Anal.
C14H13ClN2O7S (388.78): C, H, N, Cl, S.
1-[(5-Chloro-2-nitrophenyl)sulfonyl]-2-cyano-1H-pyrro-
le (17). Yield 68% (silica gel/dichloromethane–petroleum
ether 1:1); m.p. 119–121 °C (toluene/cyclohexane). 1H NMR
(DMSO-d6): d 6.68 (m, 1H), 7.54 (m, 1H), 7.86 (m, 1H), 8.12
(m, 1H), 8.18–8.34 ppm (m, 2H). IR (nujol): m 2220 cm–1
(CN). Anal. C11H6ClN3O4S (311.70): C, H, N, Cl, S.
Phenyl 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyrrole-
2-carboxylate (18). Yield 71% (silica gel/chloroform); m.p.
sec-Butyl 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyrro-
le-2-carboxylate (11).Yield 71% (alumina/chloroform); m.p.
1
1
170–171 °C (toluene/cyclohexane). H NMR (CDCl3): d
119–120 °C (toluene/cyclohexane). H NMR (CDCl3): d
6.46 (m, 1H), 7.11–7.18 (m, 2H), 7.19–7.45 (m, 4H), 7.60–
7.84 (m, 3H), 8.28 ppm (d, J = 2.1 Hz, 1H). IR (nujol): m
1740 cm–1 (CO). Anal. C17H11ClN2O6S (406.80): C, H, N,
Cl, S.
0.86 (t, J = 5.9 Hz, 3H), 1.17 (d, J = 5.7 Hz, 3H), 1.67 (m,
2H), 4.87 (m, 1H), 6.36 (3 line m, 1H), 7.10 (dd, J = 1.8 and
3.6 Hz, 1H), 7.60–7.85 (m, 3H), 8.26 ppm (d, J = 2.0 Hz, 1H).
IR (nujol): m 1700 cm–1 (CO). Anal. C15H15ClN2O6S
(386.81): C, H, N, Cl, S.
Cyclopropylmethyl 1-[(5-chloro-2-nitrophenyl)sulfonyl]-
1H-pyrrole-2-carboxylate (12). Yield 81% (alumina/
chloroform); m.p. 104–105 °C (cyclohexane). 1H NMR
(CDCl3): d 0.27 (m, 2H), 0.53 (m, 2H), 1.10 (m, 1H), 3.95 (d,
J = 7.3 Hz, 2H), 6.37 (3 line m, 1H), 7.16 (dd, J = 1.8 and
3.6 Hz, 1H), 7.64 (dd, J = 1.8 and 3.2 Hz, 1H), 7.71 (dd,
J = 2.0 and 8.6 Hz, 1H), 7.80 (d, J = 8.6 Hz, 1H), 8.25 ppm (d,
J = 2.0 Hz, 1H). IR (nujol): m 1720 cm–1 (CO). Anal.
C15H13ClN2O6S (384.79): C, H, N, Cl, S.
Propargyl 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyr-
role-2-carboxylate (13). Yield 57% (alumina/chloroform);
m.p. 156–157 °C (toluene/cyclohexane). 1H NMR (CDCl3):
d 2.46 (t, J = 2.4 Hz, 1H), 4.75 (d, J = 2.4 Hz, 2H), 6.39 (3 line
m, 1H), 7.22 (dd, J = 1.8 and 3.7 Hz, 1H), 7.62–7.87 (m, 3H),
8.33 ppm (d, J = 2.0 Hz, 1H). IR (nujol): m 1720 (CO),
3270 cm–1 (≡C–H). Anal. C14H9ClN2O6S (368.74): C, H, N,
Cl, S.
Ethyl 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyrrole-3-
carboxylate (19). Yield 57% (silica gel/chloroform–ethanol
9:1); m.p. 108–109 °C (cyclohexane). 1H NMR (CDCl3): d
1.27 (t, J = 7.1 Hz, 3H), 4.32 (q, J = 7.2 Hz, 2H), 6.76 (dd,
J = 1.5 and 3.4 Hz, 1H), 7.23 (m, 1H), 7.72–7.80 (m, 2H),
7.82 (m, 1H), 7.90 ppm (m, 1H). IR (nujol): m 1710 cm–1
(CO). Anal. C13H11ClN2O6S (358.75): C, H, N, Cl, S.
Ethyl1-[(2,5-dichlorophenyl)sulfonyl]-1H-pyrrole-2-car-
boxylate (32). Yield 74 % (silica gel/chloroform); m.p. 88–
89 °C (cyclohexane). 1H NMR (CDCl3): d 1.24 (t, J = 7.1 Hz,
3H), 4.16 (q, J = 7.1 Hz, 2H), 6.33 (m, 1H), 7.10 (m, 1H),
7.38 (d, J = 8.0 Hz, 1H), 7.50 (dd, J = 2.5 and 8.0 Hz, 1H),
7.80 (m, 1H), 8.33 ppm (d, J = 2.5 Hz, 1H). IR (nujol): m
1715 cm–1 (CO). Anal. C13H11Cl2NO4S (348.20): C, H, N,
Cl, S.
N,N-Diethyl 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyr-
role-2-carboxyamide (36). Yield 62% (silica gel/
chloroform–ethanol 9:1); m.p. 113–114 °C (cyclohexane).
1H NMR (CDCl3): d 1.04–1.31 (m, 6H), 3.24–3.55 (m, 4H),
6.28–6.41 (m, 2H), 7.35 (dd, J = 1.6 and 3.2 Hz, 1H), 7.66
(dd, J = 2.0 and 8.5 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H),
7.90 ppm (d, J = 2.0 Hz, 1H). IR (nujol): m 1620 cm–1 (CO).
Anal. C15H16ClN3O5S (385.82): C, H, N, Cl, S.
Cyclopentyl 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyr-
role-2-carboxylate (14). Yield 62% (alumina/chloroform);
1
m.p. 98 °C (cyclohexane). H NMR (CDCl3): d 1.46–2.00
(m, 8H), 5.21 (m, 1H), 6.35 (3 line m, 1H), 7.05 (dd,
J = 1.8 and 3.5 Hz, 1H), 7.61 (dd, J = 1.8 and 3.2 Hz, 1H),
7.71 (dd, J = 2.0 and 8.6 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H),
8.27 ppm (d, J = 2.0 Hz, 1H). IR (nujol): m 1710 cm–1 (CO).
Anal. C16H15ClN2O6S (398.81): C, H, N, Cl, S.
N-Benzyl, N-methyl 1-[(5-chloro-2-nitrophenyl)sulfonyl]-
1H-pyrrole-2-carboxyamide (37). Yield 80%; m.p. 139–
141 °C (toluene/ligroin). 1H NMR (CDCl3): d 2.98 (s, 3H),

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R. Silvestri et al. / IL FARMACO 59 (2004) 201–210
4.66 (s, 2H), 6.32 (m, 1H), 6.44 (m, 1H), 7.10–7.45 (m, 6H),
7.68 (dd, J = 1.9 and 8.5 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H),
8.01 ppm (d, J = 1.9 Hz, 1H). IR (nujol): m 1640 cm-1 (CO).
C19H16ClN3O5S (433.86): C, H, N, Cl, S.
4.1.3. General procedure for reduction of nitro group to
amino, example: n-Butyl 1-[(2-amino-5-chlorophenyl)
sulfonyl]-1H-pyrrole-2-carboxylate (20)
A stirred solution of 9 (1.93 g, 0.005 mol) in glacial acetic
acid (21 ml) was treated portionwise with iron powder (1.5 g)
while heating at 60 °C under stirring. Reaction mixture was
maintained at 60 °C for 2 h, then evaporated to dryness. The
residue was triturated with ice water and extracted with ethyl
acetate. The organic layers were collected, washed with brine
and dried. Removal of the solvent gave a residue which was
purified by column chromatography (alumina/chloroform) to
yield 10 (95%); m.p. 102 °C (cyclohexane). 1H NMR
(CDCl3): d 0.90 (t, J = 7.2 Hz, 3H), 1.20–1.50 and 1.50–1.75
(2m, 4H), 4.13 (t, J = 6.5 Hz, 2H), 5.27 (broad s, 2H, NH2,
disappeared on treatment with D2O), 6.28 (m, 1H), 6.55–
6.76 (m, 2H), 7.06 (dd, J = 1.9 and 3.6 Hz, 1H), 7.56 (d,
J = 9.4 Hz, 1H), 7.66 ppm (dd, J = 1.9 and 3.1 Hz, 1H). IR
(nujol): m 1700 (CO), 3360 and 3450 cm–1 (NH2). Anal.
C15H17ClN2O4S (356.82): C, H, N, Cl, S.
[(2-Nitrophenyl)sulfonyl]-2-trichloroacetyl-1H-pyrrole
(45).Yield 42% (silica gel/chloroform–petroleum ether 1:1);
m.p. 134–136 °C (toluene/cyclohexane). 1H NMR (CDCl3):
d 6.49 (m, 1H), 7.71 (m, 1H), 7.78–7.96 (m, 4H), 8.52 ppm
(m, 1H). IR (nujol):
m
1695 cm–1 (CO). Anal.
C12H7Cl3N2O5S (397.62): C, H, N, Cl, S.
[(5-Chloro-2-nitrophenyl)sulfonyl]-2-trichloroacetyl-1H-
pyrrole (46). Yield 38% (silica gel/chloroform-petroleum
ether 1:1); m.p. 178–180 °C (toluene/cyclohexane). 1H NMR
(CDCl3): d 6.51 (m, 1H), 7.68–7.94 (m, 4H), 8.44 ppm (d,
J = 2.0 Hz, 1H). IR (nujol): m 1695 cm–1 (CO). Anal.
C12H6Cl4N2O5S (432.06): C, H, N, Cl, S.
4.1.2. 1-[(2-Nitrophenyl)sulfonyl]-1H-pyrrole-2-carboxya-
mide (33)
By this general procedure were prepared sulfones 21–27,
29, 31 and 39–43 iso-Butyl 1-[(2-amino-5-chlorophenyl)
sulfonyl]-1H-pyrrole-2-carboxylate (21). Yield 82% (silica
Gaseous ammonia was bubbled through an ice cooled and
stirred solution of 45 (2.38 g, 0.006 mol) in DMF (20 ml) for
1 h, then poured on crushed ice and extracted with ethyl
acetate. Organic extracts were washed with brine and dried.
Evaporation of the solvent gave the crude product which was
purified by column chromatography (silica gel/ethyl acetate)
1
gel/chloroform); m.p. 90–92 °C (cyclohexane). H NMR
(CDCl3): d 0.91 (d, J = 6.7 Hz, 6H), 1.95 (m, J = 6.7 Hz, 1H),
3.92 (d, J = 6.7 Hz, 2H), 5.21 (broad s, 2H, disappeared on
treatment with D2O), 6.31 (m, 1H), 6.63 (d, J = 8.9 Hz, 1H),
7.08 (dd, J = 1.9 and 3.7 Hz, 1H), 7.21 (dd, J = 2.4 and
8.9 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.67 ppm (dd,
J = 1.9 and 3.1 Hz, 1H). IR (nujol): m 1705 (CO), 3370 and
3480 cm–1 (NH2). Anal. C15H17ClN2O4S (356.82): C, H, N,
Cl, S.
1
to yield 33 (33%); m.p. 217–218 °C (ethanol). H NMR
(DMSO-d6): d 6.46 (m, 1H), 7.03 (dd, J = 1.5 and 3.5 Hz,
1H), 7.23 (broad s, 2H, disappeared on treatment with D2O),
7.58 (dd, J = 1.5 and 3.1 Hz, 1H), 7.78–7.99 (m, 3H, ben-
zene), 8.07 ppm (m, 1H, benzene). IR (nujol): m 1660 (CO),
3150, 3270, 3320 and 3450 cm–1 (NH2). Anal. C11H9N3O5S
(295.27): C, H, N, S.
1-[(5-Chloro-2-nitrophenyl)sulfonyl]-1H-pyrrole-2-car-
boxyamide (34). Was prepared as 33 starting from 46; yield
24% (silica gel/ethyl acetate); m.p. 195–196 °C (ethanol). 1H
NMR (CDCl3): d 5.60 (broad s, 2H, disappeared on treat-
ment with D2O), 6.34 (m, 1H), 6.78 (dd, J = 1.6 and 3.5 Hz,
1H), 7.60 (dd, J = 1.6 and 3.3 Hz, 1H), 7.72 (dd, J = 2.1 and
8.5 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 8.26 ppm (d, J = 2.1 Hz,
1H). IR (nujol): m 1665 cm–1 (CO). Anal. C11H8ClN3O5S
(329.71): C, H, N, Cl, S.
N-Ethyl 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyrrole-
2-carboxyamide (35). Was prepared as 33 starting from 46
and gaseous ethylamine, yield 25% (silica gel/chloroform);
m.p. 170–172 °C (toluene/cyclohexane). 1H NMR (CDCl3):
d 1.18 (t, J = 7.3 Hz, 3H), 3.35 (dq, J = 1.5 and 7.3 Hz, 2H,
showed q when NH was irradiated), 5.94 (broad t, 1H, disap-
peared on treatment with D2O), 6.29 (m, 1H, H4-pyrrole),
6.62 (dd, J = 1.7 and 3.6 Hz, 1H), 7.49 (dd, J = 1.7 and
3.4 Hz, 1H), 7.68 (dd, J = 2.1 and 8.6 Hz, 1H), 7.80 (d,
J = 8.6 Hz, 1H), 8.16 ppm (d, J = 2.1 Hz, 1H). IR (nujol): m
1630 (CO), 3320 and 3400 cm–1 (NH). Anal.
C13H12ClN3O5S (357.77): C, H, N, Cl, S.
sec-Butyl 1-[(2-amino-5-chlorophenyl)sulfonyl]-1H-pyr-
role-2-carboxylate (22). Yield 81% (silica gel/chloroform);
1
m.p. 118 °C (cyclohexane). H NMR (CDCl3): d 0.85 (t,
J = 6.0 Hz, 3H), 1.18 (d, J = 5.6 Hz, 3H), 1.59 (m, 2H), 4.89
(m, 1H), 5.24 (broad s, 2H, disappeared on treatment with
D2O), 6.29 (m, 1H), 6.62 (d, J = 8.8 Hz, 1H), 7.04 (dd,
J = 1.9 and 3.6 Hz, 1H), 7.19 (dd, J = 2.4 and 8.8 Hz, 1H),
7.53 (d, J = 2.4 Hz, 1H), 7.65 ppm (dd, J = 1.9 and 3.1 Hz,
1H). IR (nujol): m 1700 (CO), 3370 and 3480 cm–1 (NH2).
Anal. C15H17ClN2O4S (356.82): C, H, N, Cl, S.
Cyclopropylmethyl 1-[(2-amino-5-chlorophenyl)sulfonyl]-
1H-pyrrole-2-carboxylate (23). Yield 74% (silica gel/
chloroform); m.p. 92–93 °C (cyclohexane). 1H NMR
(CDCl3): d 0.27 (m, 2H), 0.53 (m, 2H), 1.12 (m, 1H), 3.98 (d,
J = 7.3 Hz, 2H), 5.22 (broad s, 2H, disappeared on treatment
with D2O), 6.31 (m, 1H), 6.63 (d, J = 8.9 Hz, 1H), 7.12 (dd,
J = 1.9 and 3.7 Hz, 1H), 7.20 (dd, J = 2.4 and 8.9 Hz, 1H),
7.53 (d, J = 2.4 Hz, 1H), 7.67 ppm (dd, J = 1.9 and 3.1 Hz,
1H). IR (nujol): m 1710 (CO), 3370 and 3480 cm–1 (NH2).
Anal. C15H15ClN2O4S (354.80): C, H, N, Cl, S.
Propargyl 1-[(2-amino-5-chlorophenyl)sulfonyl]-1H-pyr-
role-2-carboxylate (24). Yield 57% (alumina/chloroform);
m.p. 103–105 °C (toluene/cyclohexane). 1H NMR (CDCl3):
d 2.47 (t, J = 2.4 Hz, 1H), 4.75 (d, J = 2.4 Hz, 2H), 5.22
(broad s, 2H, disappeared on treatment with D2O), 6.32 (m,

R. Silvestri et al. / IL FARMACO 59 (2004) 201–210
207
1H), 6.63 (d, J = 8.8 Hz, 1H), 7.12–7.27 (m, 2H), 7.55 (d,
J = 2.4 Hz, 1H), 7.70 ppm (dd, J = 1.9 and 3.1 Hz, 1H). IR
(nujol): m 1710 (CO), 3300 (≡C–H), 3380 and 3480 cm–1
(NH2). Anal. C14H11ClN2O4S (338.76): C, H, N, Cl, S.
Cyclopentyl 1-[(2-amino-5-chlorophenyl)sulfonyl]-1H-
pyrrole-2-carboxylate (25). Yield 90% (silica gel/
disappeared on treatment with D2O), 6.60–6.71 (m, 2H),
7.12 (m, 1H), 7.23–7.32 (m, 1H), 7.70 (m, 1H), 7.76 ppm (m,
1H). IR (nujol): m 1710 (CO), 3350 and 3460 cm–1 (NH2).
Anal. C13H13ClN2O4S (328.77): C, H, N, Cl, S.
1-[(2-Aminophenyl)sulfonyl]-1H-pyrrole-2-
carboxyamide (39).Yield 95% (silica gel/ethyl acetate); m.p.
133–134 °C (ethanol). 1H NMR (DMSO-d6): d 6.30 (m, 1H),
6.42 (broad s, 2H, disappeared on treatment with D2O), 6.63
(t, J = 7.6 Hz, 1H), 6.74–6.88 (m, 2H), 7.18–7.40 (overlapped
m and broad s, 2H, 1H disappeared on treatment with D2O),
7.64 (dd, J = 1.6 and 3.1 Hz, 1H), 7.71 (dd, J = 1.3 and
8.2 Hz, 1H), 7.83 ppm (broad s, 1H, disappeared on treat-
ment with D2O). IR (nujol): m 1630 and 1660 (CO), 3120,
3200, 3360 and 3440 cm–1 (CONH2 and PhNH2). Anal.
C11H11N3O3S (265.28): C, H, N, S.
1
chloroform); m.p. 123–124 °C (toluene/cyclohexane). H
NMR (CDCl3): d 1.42–1.96 (m, 8H), 5.09–5.38 (overlapped
broad s and m, 3H, 2H disappeared on treatment with D2O),
6.29 (m, 1H), 6.62 (d, J = 8.8 Hz, 1H), 7.01 (dd, J = 1.8 and
3.6 Hz, 1H), 7.19 (dd, J = 2.3 and 8.8 Hz, 1H), 7.51 (d,
J = 2.3 Hz, 1H), 7.64 ppm (dd, J = 1.8 and 3.0 Hz, 1H). IR
(nujol): m 1700 (CO), 3360 and 3480 cm–1 (NH2). Anal.
C16H17ClN2O4S (368.83): C, H, N, Cl, S.
Cyclohexyl 1-[(2-amino-5-chlorophenyl)sulfonyl]-1H-
pyrrole-2-carboxylate (26). Yield 84% (silica gel/
1-[(2-Amino-5-chlorophenyl)sulfonyl]-1H-pyrrole-2-
carboxyamide (40).Yield 98% (silica gel/ethyl acetate); m.p.
1
chloroform); m.p. 156–157 °C (toluene/cyclohexane). H
1
NMR (CDCl3): d 1.12–1.60 (m, 6H), 1.60–1.92 (m, 4H),
4.81 (m, 1H), 5.27 (broad s, 2H, disappeared on treatment
with D2O), 6.27 (m, 1H), 6.62–6.74 (m, 2H), 7.04 (dd,
J = 1.9 and 3.6 Hz, 1H), 7.58 (d, J = 9.2 Hz, 1H), 7.64 ppm
(dd, J = 1.9 and 3.1 Hz, 1H). IR (nujol): m 1710 (CO),
3360 and 3480 cm–1 (NH2). Anal. C17H19ClN2O4S (382.86):
C, H, N, Cl, S.
173–175 °C (ethanol). H NMR (CDCl3): d 5.31 and 5.76
(2 broad s, 4H, disappeared on treatment with D2O), 6.29 (m,
1H), 6.63 (d, J = 8.8 Hz, 1H), 6.77 (dd, J = 1.7 and 3.6 Hz,
1H), 7.36 (dd, J = 2.4 and 8.8 Hz, 1H), 7.50 (dd, J = 1.7 and
3.2 Hz, 1H), 7.60 ppm (d, J = 2.4 Hz, 1H). IR (nujol): m
1665 cm–1 (CO). Anal. C11H10ClN3O3S (299.73): C, H, N,
Cl, S.
2-Methoxyethyl 1-[(2-amino-5-chlorophenyl)sulfonyl]-
1H-pyrrole-2-carboxylate (27). Yield 89% (alumina/chloro-
form); m.p. 127–128 °C (toluene/cyclohexane). H NMR
N-Ethyl 1-[(2-amino-5-chlorophenyl)sulfonyl]-1H-pyrrole-
2-carboxyamide (41).Yield 71% (silica gel/chloroform–etha-
nol 9:1); m.p. 158–160 °C (ethanol). H NMR (CDCl3): d
1
1
(CDCl3): d 3.35 (s, 3H), 3.60 (t, J = 4.7 Hz, 2H), 4.29 (t,
J = 4.7 Hz, 2H), 5.21 (broad s, 2H, disappeared on treatment
with D2O), 6.30 (m, 1H), 6.62 (d, 1H), 7.13 (dd, J = 1.8 and
3.6 Hz, 1H), 7.20 (dd, J = 2.4 and 8.8 Hz, 1H), 7.54 (d,
J = 2.4 Hz, 1H), 7.67 ppm (dd, J = 1.8 and 3.1 Hz, 1H). IR
(nujol): m 1710 (CO), 3320 and 3430 cm–1 (NH2). Anal.
C14H15ClN2O5S (358.79): C, H, N, Cl, S.
1.21 (t, J = 7.2 Hz, 3H), 3.39 (m, 2H), 5.43 (broad s, 2H,
disappeared on treatment with D2O), 6.24 (broad s, 1H dis-
appeared on treatment with D2O), 6.24 (m, 1H), 6.54–6.70
(m, 2H), 7.21 (dd, J = 2.2 and 8.8 Hz, 1H), 7.33 (dd,
J = 1.7 and 3.1 Hz, 1H), 7.65 ppm (d, J = 2.2 Hz, 1H). IR
(nujol): m 1650 (CO), 3340, 3400 and 3480 cm–1 (NH and
NH2). Anal. C13H14ClN3O3S (327.78): C, H, N, Cl, S.
N,N-Diethyl 1-[(2-amino-5-chlorophenyl)sulfonyl]-1H-
pyrrole-2-carboxyamide (42). Yield 92% (silica gel/
1-[(2-Amino-5-chlorophenyl)sulfonyl]-2-cyano-1H-
pyrrole (29). Yield 92% (silica gel/chloroform); m.p. 149–
150 °C (toluene/cyclohexane). 1H NMR (DMSO-d6): d 6.52
(m, 1H), 6.66 (broad s, 2H, disappeared on treatment with
D2O), 6.89 (d, J = 9.0 Hz, 1H), 7.40 (dd, J = 1.5 and 3.7 Hz,
1H), 7.46 (dd, J = 2.5 and 9.0 Hz, 1H), 7.70 (d, J = 2.5 Hz,
1H), 8.09 ppm (dd, J = 1.5 and 3.0 Hz, 1H). IR (nujol): m
2220 (CN), 3340 and 3480 cm–1 (NH2). Anal.
C11H8ClN3O2S (281.71): C, H, N, Cl, S.
chloroform–ethanol
9:1);
m.p.
142–145
°C
1
(toluene/cyclohexane). H NMR (CDCl3): d 1.14 and 1.24
(2t, J = 7.0 Hz, 6H), 3.29 and 3.51 (2q, J = 7.0 Hz, 4H), 5.58
(broad s, 2H, disappeared on treatment with D2O), 6.24 (m,
2H), 6.54 (d, J = 8.9 Hz, 1H), 7.03 (m, 1H, pyrrole), 7.18 (dd,
J = 2.4 and 8.9 Hz, 1H), 7.74 ppm (d, J = 2.4 Hz, 1H). Anal.
C15H18ClN3O3S (355.84): C, H, N, Cl, S.
N-Benzyl,
N-methyl
1-[(2-amino-5-chlorophenyl)
Phenyl 1-[(2-amino-5-chlorophenyl)sulfonyl]-1H-pyrrole-
sulfonyl]-1H-pyrrole-2-carboxyamide (43). Yield 100%;
m.p. 134–136 °C (toluene/cyclohexane). 1H NMR (CDCl3):
d 2.92 and 3.00 (2s, 3H), 4.54 and 4.74 (2s, 2H), 5.53 (broad
s, 2H, disappeared on treatment with D2O), 6.15–6.38 (m,
2H), 6.58 (d, J = 8.8 Hz, 1H), 7.02–7.42 (m, 7H), 7.81 ppm
(m, 1H). IR (nujol): m 1610 (CO), 3320 and 3450 cm–1
(NH2). Anal. C19H18ClN3O3S (403.88): C, H, N, Cl, S.
2-carboxylate (30). Yield 61% (silica gel/chloroform); m.p.
125–126 °C (toluene/cyclohexane). H NMR (CDCl3): d
1
5.15 (broad s, 2H, disappeared on treatment with D2O), 6.40
(m, 1H), 6.50 (d, J = 8.9 Hz, 1H), 7.02–7.29 (m, 4H),
7.29–7.44 (m, 3H), 7.51 (d, J = 2.4 Hz, 1H), 7.78 ppm (dd,
J = 1.9 and 3.1 Hz, 1H). IR (nujol): m 1740 (CO), 3360 and
3460 cm–1 (NH2). Anal. C17H13ClN2O4S (376.81): C, H, N,
Cl, S.
4.1.4. 2-Hydroxyethyl 1-[(2-amino-5-chlorophenyl)
sulfonyl]-1H-pyrrole-2-carboxylate (28)
Chlorotrimethylsilane (0.54 g, 0.005 mol) was added at
room temperature to a stirred mixture of 27 (0.90 g, 0.0025
Ethyl 1-[(2-amino-5-chlorophenyl)sulfonyl]-1H-pyrrole-
3-carboxylate (31). Yield 31% (silica gel/chloroform); m.p.
120 °C (toluene/cyclohexane). 1H NMR (CDCl3): d 1.33 (t,
J = 7.2 Hz, 3H), 4.27 (q, J = 7.2 Hz, 2H), 5.21 (broad s, 2H,

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R. Silvestri et al. / IL FARMACO 59 (2004) 201–210
mol), sodium iodide (0.75 g, 0.005 mol) and acetonitrile
(30 ml) while flushing continuously with anhydrous nitro-
gen, then reaction was refluxed for 24 h under nitrogen
atmosphere.After cooling the mixture was diluted with water
and extracted with ethyl acetate. Organic layer was shaken
with brine, 5% sodium thiosulfate, then with brine and dried.
After concentration to a small volume, the mixture was
passed trough an alumina column eluting with the same
solvent. First fractions afforded traces of starting material,
further elution furnished 28 (35%); m.p. 110–111 °C
(toluene/cyclohexane). 1H NMR (CDCl3): d 2.07 (t,
J = 6.6 Hz, 1H, disappeared on treatment with D2O), 3.84 (m,
2H), 4.32 (m, 2H), 5.17 (broad s, 2H, disappeared on treat-
ment with D2O), 6.34 (m, 1H), 6.66 (d, J = 8.8 Hz, 1H), 7.15
(dd, J = 1.9 and 3.7 Hz, 1H), 7.25 (dd, J = 2.4 and 8.8 Hz,
1H), 7.56 (d, J = 2.4 Hz, 1H), 7.68 ppm (dd, J = 1.9 and
3.2 Hz, 1H). IR (nujol): m 1720 cm–1 (CO). Anal.
C13H13ClN2O5S (344.77): C, H, N, Cl, S.
9.27 ppm (broad s, 1H, disappeared on treatment with D2O).
IR (nujol): m 1680 (CO), 3270 and 3340 cm–1 (NH and ≡CH).
Anal. C8H7NO2 (149.15): C, H, N.
Cyclopentyl 1H-pyrrole-2-carboxylate. Was prepared as
sec-butyl ester using cyclopentanol; purification on silica gel
column (chloroform), yield 96%; b.p. 119–120/0.035–
0.040 mmHg, m.p. 61 °C (petroleum ether). 1H NMR
(CDCl3): d 1.52–2.06 (m, 8H), 5.34 (m, 1H), 6.23 (m, 1H),
6.84–6.96 (m, 2H), 9.55 ppm (broad s, 1H, disappeared on
treatment with D2O). IR (nujol): m 1670 (CO), 3240 cm–1
(NH). Anal. C10H13NO2 (179.22): C, H, N.
Cyclohexyl 1H-pyrrole-2-carboxylate. Was prepared as
sec-butyl ester using cyclohexanol; purification on silica gel
column (chloroform), yield 90%; m.p. 46–50 °C (petroleum
1
ether, –25 °C). H NMR (CDCl3): d 1.08–1.68 (m, 6H),
1.68–1.86 (m, 2H), 1.86–2.04 (m, 2H), 4.96 (m, 1H), 6.24
(m, 1H), 6.93 (m, 2H), 9.48 ppm (broad s, 1H, disappeared
on treatment with D2O). IR (nujol): m 1670 (CO), 3280 cm–1
(NH). Anal. C11H15NO2 (193.24): C, H, N.
2-Methoxyethyl 1H-pyrrole-2-carboxylate. Was prepared
as the sec-butyl ester using 2-methoxyethanol; purification
on silica gel column (dichloromethane), yield 95%; b.p.
4.1.5. Synthesis of pyrrole-2-carboxylates and
carboxyamides
sec-Butyl 1H-pyrrole-2-carboxylate.
A mixture of
1
108–110/0.15 mmHg. H NMR (CDCl3): d 3.42 (s, 3H),
2-trichloroacetyl-1H-pyrrole [17] (6.00 g, 0.028 mol), potas-
sium carbonate (4.00 g, 0.029) and sec-butanol (2.30 g,
0.031 mol) was stirred at 60 °C for 17 h. After cooling the
mixture was dissolved in chloroform, filtered and evaporated
to a residue which was passed through a silica gel column
(dichloromethane), yield 87%; b.p. 100–102 °C/0.16 mmHg.
1H NMR (CDCl3): d 0.65 (t, J = 7.4 Hz, 3H), 1.30 (d,
J = 6.2 Hz, 3H), 1.70 (m, 2H), 5.03 (m, 1H), 6.26 (m, 1H),
6.92 (m, 2H), 9.50 ppm (broad s, 1H, disappeared on treat-
ment with D2O). IR (neat): m 1690–1710 (CO), 3160 cm–1
(NH). Anal. C9H13NO2 (167.21): C, H, N.
Cyclopropylmethyl 1H-pyrrole-2-carboxylate. Was pre-
pared sec-butyl ester using cyclopropanemethanol; purifica-
tion on silica gel column (chloroform), yield 96%; b.p. 107–
108/0.025–0.030 mmHg, m.p. 49–50 °C (petroleum ether,
+4 °C). 1H NMR (CDCl3): d 0.34 (m, 2H), 0.58 (m, 2H), 1.20
(m, 1H), 6.27 (m, 1H), 6.96 (m, 2H), 9.36 ppm (broad s, 1H,
disappeared on treatment with D2O). Anal. C9H11NO2
(165.19): C, H, N.
3.69 and 4.43 (2t, J = 4.7 Hz, 4H), 6.25 (m, 1H), 6.95 (m,
2H), 9.60 ppm (broad s, 1H, disappeared on treatment with
D2O). IR (neat): m 1710–1720 (CO), 3280–3300 cm–1 (NH).
Anal. C8H11NO3 (169.18): C, H, N.
N-Benzyl, N-methyl 1H-pyrrole-2-carboxyamide. A mix-
ture of 2-trichloroacetyl-1H-pyrrole [17] (5.31 g, 0.025 mol),
triethylamine (3.03 g, 0.03 mol) and N-benzylmethylamine
(15.73 g, 0.13 mol) was heated at 60 °C for 20 h. Removal of
the excess of N-benzylmethylamine gave the crude amide
which was purified on silica gel column (ethyl acetate), yield
97%; m.p. 98–100 °C (ligroin). 1H NMR (CDCl3): d 3.19 (s,
3H), 4.83 (s, 2H), 6.20 (m, 1H), 6.53 (broad, 1H), 6.92 (m,
1H), 7.25–7.38 (m, 5H), 10.19 ppm (broad s, 1H, disap-
peared on treatment with D2O). IR (nujol): m 1605 (CO),
3260 cm–1 (NH). Anal. C13H14N2O (214.26): C, H, N.
Acknowledgements
Propargyl 1H-pyrrole-2-carboxylate. Was prepared as the
sec-butyl ester using propargyl alcohol; purification on alu-
mina column (chloroform), yield 85%; m.p. 60–61 °C
(ligroin/n-hexane). 1H NMR (CDCl3): d 2.50 (t, J = 2.4 Hz,
1H), 4.86 (d, J = 2.4 Hz, 2H), 6.28 (m, 1H), 6.99 (m, 2H),
Authors thank the Italian Ministero della Salute, Istituto
Superiore di Sanità, Fourth National Research Program on
AIDS (grants no. 40C.8 and 40D.46) for financial support.
Authors also acknowledge the financial support of the Italian
MIUR (cofin 2000).

R. Silvestri et al. / IL FARMACO 59 (2004) 201–210
209
Appendix A
Appendix B
Elemental analyses of derivatives 9–32
Elemental analyses of derivatives 33–37 and 39–43
Compound Elemental analyses calculated/found
Compound
Elemental analyses calculated/found
C
H
N
Cl
S
C
H
N
Cl
S
33
34
35
36
37
39
40
41
42
43
44.75
44.48
40.07
39.74
43.64
43.45
46.70
46.81
52.60
52.38
49.80
49.57
44.08
44.26
47.64
47.77
50.63
50.82
56.50
56.41
3.07
2.90
2.45
2.37
3.38
3.31
4.18
4.20
3.72
3.66
4.18
4.09
3.36
3.27
4.30
4.17
5.10
5.13
4.49
4.48
14.23
14.06
12.74
12.83
11.75
11.66
10.89
10.82
9.69
–
10.86
10.77
9.72
9.50
8.96
9.02
8.31
8.30
7.39
7.40
12.09
11.83
10.70
10.56
9.78
9.76
9.01
9.04
7.94
7.87
9
46.58
46.42
46.58
46.72
46.58
46.42
46.82
46.73
45.60
45.38
48.19
48.01
49.46
49.52
43.25
43.09
42.39
42.51
50.19
50.36
43.52
43.48
50.49
50.18
50.49
50.60
50.49
50.56
50.78
50.84
49.64
49.82
52.10
52.11
53.33
53.57
46.87
46.86
45.29
45.43
46.90
47.08
54.19
54.21
47.49
47.56
47.86
47.77
3.91
3.88
3.91
3.98
3.91
3.88
3.41
3.38
2.46
2.39
3.79
3.80
4.15
4.12
3.37
3.42
1.94
2.16
2.73
2.80
3.09
2.97
4.80
4.81
4.80
4.71
4.80
4.81
4.26
4.09
3.27
3.10
4.65
4.48
5.00
5.07
4.21
4.10
3.80
3.77
2.86
2.78
3.48
3.44
3.99
4.17
3.40
3.88
7.24
7.18
7.24
7.20
7.24
7.30
7.28
7.35
7.60
7.72
7.02
6.89
6.79
6.85
7.21
7.20
13.48
13.55
6.89
6.90
7.81
7.68
7.85
7.79
7.85
7.83
7.85
7.73
7.90
7.79
8.27
8.21
7.60
7.45
7.32
7.39
7.81
7.76
8.13
8.05
14.92
15.13
7.43
7.43
8.52
8.38
17.17
17.04
9.17
9.20
9.17
9.21
9.17
9.20
9.21
9.29
9.61
9.80
8.89
8.97
8.59
8.60
9.12
9.06
11.37
11.21
8.72
8.68
9.88
9.91
9.94
9.97
9.94
10.09
9.94
10.12
9.99
10.02
10.47
10.65
9.61
9.73
9.26
9.21
9.88
9.81
10.28
10.41
12.58
12.89
9.41
9.40
10.78
10.65
21.74
21.56
8.29
8.35
8.29
8.30
8.29
8.16
8.33
8.28
8.69
8.55
8.04
7.95
7.77
7.71
8.25
8.30
10.29
10.16
7.88
7.80
8.94
8.80
8.98
8.90
8.98
8.97
8.98
8.87
9.04
9.01
9.46
9.41
8.69
8.60
8.37
8.42
8.94
8.85
9.30
9.47
11.38
11.19
8.51
8.35
9.75
9.84
9.83
9.81
–
10.75
10.66
9.91
9.73
9.19
9.15
8.17
8.11
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
9.70
15.84
15.48
14.02
13.92
12.82
12.77
11.81
11.86
10.40
10.37
–
11.83
11.99
10.82
10.84
9.96
9.82
8.78
8.80
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