Synthesis of sufamides of indole series

Article abstract of DOI:10.1134/S1070428009110153

The reaction of indoles with chlorosulfonyl isocyanate yields indolylcarbonylsulfamoyl chlorides. Their reaction with amines afforded a series of indole-containing sulfamides.

Full text of DOI:10.1134/S1070428009110153

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 11, pp. 1675−1677. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © K.F. Suzdalev, S.V. Den’kina, 2009, published in Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 11, pp. 1682−1684.
Synthesis of Sufamides of Indole Series
K. F. Suzdalev and S. V. Den’kina
Research Institute of Physical and Organic Chemistry at Southern Federal University,
Rostov-on-Don, 344090 Russia
e-mail: sofia1984@inbox.ru
Received October 28, 2008
Abstract—The reaction of indoles with chlorosulfonyl isocyanate yields indolylcarbonylsulfamoyl chlorides.
Their reaction with amines afforded a series of indole-containing sulfamides.
DOI: 10.1134/S1070428009110153
Compound IIa was described as an unstable inter-
mediate in the preparation of a nitrile and an amide of
indole-3-carboxylic acid [7, 8]. Substance IIb was obtain-
ed by us for the first time. It turned out that both com-
pounds were relatively stable and could be stored in
a refrigerator for about a month. However we failed to
obtain their NMR spectra due to a low solubility in CDCl3
and a high chemical activity toward the other solvents.
The reaction of sulfamoyl chlorides IIa and IIb with
amines occurs through a nucleophilic substitution of
chlorine and results in the formation of sulfamides of the
indole series IIIa–IIIj (Scheme 1) proving the structure
of the initial compounds.
Compounds containing a fragment N–SO2–N exhibit
antiviral action [1], inhibit phosphodiesterase [2], are
antagonists of dopamine D2 [3] and leucotriene [4].
The high biological activity of indole derivatives is due
to the fact that the indole bicycle belongs to important
privileged structures [5]. This is evidently related to the
molecular recognition of the exogenous compounds of
the indole series since many endogenous substances, for
instance, serotonin (a most important neuromediator)
contain an indole fragment [6].
We investigated the possibility to prepare the indole
derivatives containing an N–SO2–N moiety. To this end
a reaction was applied between indoles and a chloro-
sulfonyl isocyanate (CSI). The acylation of indoles Ia
and Ib with the chlorosulfonyl isocyanate occurs at the
position 3 leading to the formation of sulfonyl chlorides
IIa and IIb (Scheme 1).
1
In the H NMR spectra of compounds IIIa–IIIj
proton signals appear of both indole and amine fragments.
In the IR spectra peaks characteristic of NH group were
present in the region 3407– 3060 cm–1, and the peaks of
carbonyl group, in the range 1687–1627 7 cm–1.
Scheme 1.
2
R
O
S
O
O
H
R2
NHSO2Cl
2HN
N
N
3
R
3
R
.
O=C=NSO2Cl
O
_
2 3
R R NH HCl
N
R1
N
R1
N
R1
IIIà_IIIj
Ià, Ib
IIa, IIb
I, II, R1 = H (a), Me (b); III, R1 = Me, R2 = H, R3 = 1,3-thiazol-2-yl (a); R1 = R2 = H: R3 = 4-FC6H4 (b), cyclohexyl (c),
4-ClC6H4 (d); R1 = H.
1675

SUZDALEV, DEN’KINA
1676
Scheme 2.
O
S
O
H
H
N
N
CN
H2N
NHAc
NHAc
O
+
IIa
MeCN
N
N
H
H
V
IV
With some strongly basic amines the reaction occurs
not along Scheme 1. Carbonylsulfamoyl chloride IIa with
an N-(4-aminophenyl)acetamide furnished a mixture of
compounds IV and V (Scheme 2).
anhydrous ether was added dropwise within 1 h at
constant stirring and temperature of 3–4°C 0.1 mol of
CSI in 100 ml of anhydrous ether. Then the stirring of
the reaction mixture cooled by an ice bath continued for
1 h more. The slightly colored precipitate was filtered
off and dried in a vacuum-desiccator. Yield 85%, mp 160–
162°C. Found, %: C 44.1; H 3.2; Cl 12.9; N 10.2; S 11.4.
C10H9ClN2O3S. Calculated, %: C 44.0; H 3.3; Cl 12.9;
N 10.3; S 11.3.
The IR spectrum of the mixture of compounds IV and
V contained peaks of groups NH (3367 and 3233 cm–1),
1
C≡N (2227 cm–1), C=O (1660 cm–1). In the H NMR
spectrum the protons signal of NH groups of compound
V was observed in the region 12.0 ppm, that of compound
IV, in the region 11.6 ppm. The ratio of compounds IV
and V was 1:2. The signals of nitrile IV were identified
by superimposing with the spectrum of the mixture the
spectrum of the pure compound IV prepared by an
independent procedure [7].
Indol-3-ylcarbonylsulfamides IIIa–IIIj. To a dis-
persion of 3 mmol of sulfamoyl chloride IIa or IIb in
acetonitrile was added 6 mmol of amine, the mixture was
heated to boiling, 2–3 ml of water was added causing the
dissolution of precipitated amine hydrochloride, then more
10–15 ml of water was added till turbidity. Afterwards
the precipitate separated that was filtered off and dried.
According to 1H NMR data the products obtained were
pure and did not require recrystallization.
Chloride IIa in reaction with imidazole did not undergo
the nucleophilic substitution but formed only the known
nitrile of indole-3-carboxylic acid (IV) identified by the
NMR spectrum and melting point [7].
N-[(1-Methyl-1H-indol-3-yl)carbonyl]-N'-(1,3-
thiazol-2-yl)sulfamide (IIIa). Yield 31%, mp 150–
153°C. IR spectrum, ν, cm–1: 3227, 3060 (NH); 1633
Thus based on the reaction of 1H-indol-3-ylcarbonyl-
sulfamoyl chlorides with amines a wide range of indole-
containing sulfamides can be obtained promising for the
screening of their biological action.
1
(C=O). H NMR spectrum, δ, ppm: 3.8 s (3H, CH3),
6.7–7.4 m (5Harom), 7.4 d (1Harom), 8.1 m (1Harom), 8.3 m
(1Harom), 11 s (1H, NHCO), 12 br.s (1H, NHamine). Found,
%: C 46.4; H 3.6; N 16.7; S 19.0. C13H12N4O3S2.
Calculated, %: C 46.4; H 3.7; N 16.6; S 19.0.
EXPERIMENTAL
1H NMR spectra were registered on a spectrometer
Varian Unity 300 from solutions in DMSO-d6. IR spectra
were recorded on a spectrophotometer Specord 75-IR
from mulls in mineral oil. The data of elemental analyses
of the synthesized compounds are in agreement with the
theoretically calculated values within the common
experimental errors.
N-(1H-Indol-3-ylcarbonyl)-N'-(4-fluorophenyl)-
sulfamide (IIIb). Yield 81%, mp 201–204°C. IR spec-
trum, ν, cm–1: 3327, 3326 (NH); 1633 (C=O). 1H NMR
spectrum, δ, ppm: 6.9–7.4 m (7Harom), 8.1 m (1Harom),
8.2 m (1Harom), 10.2 s (1H, NHamine), 11.25 s (1H,
NHCO), 11.6 s (1H, NHindole). Found, %: C 54.1; H 3.6;
N 12.6; S 9.6. C15H12FN3O3S. Calculated, %: C 54.0;
H 3.6; N 12.6; S 9.7.
1H-Indol-3-yl-carbonylsulfamoyl chloride (IIa)
was obtained by procedures [7, 8], mp 175–180OC (mp
was not reported in [7, 8]).
N-(1H-Indol-3-ylcarbonyl)-N'-cyclohexyl-
sulfamide (IIIc). Yield 47%, mp 220–223°C. IR
spectrum, ν, cm–1: 3307, 3260(NH); 1627(C=O).
1H NMR spectrum, δ, ppm: 1.0–2.0 m (10H, 5CH2),
(1-Methyl-1H-indol-3-yl)carbonylsulfamoyl
chloride (IIb). To 0.1 mol of indole Ib in 200 ml of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 11 2009

SYNTHESIS OF SUFAMIDES OF INDOLE SERIES
1677
spectrum, δ, ppm: 1.2 m [6H, N(CH2–CH3)2], 3.2 m [4H,
N(CH2–CH3)2], 7.0–8.3 m (5Harom), 11.1 s (1H, NHCO),
11.6 s (1H, NHindole). Found, %: C 52.9; H 5.8; N 14.2;
S 10.7. C13H17N3O3S. Calculated, %: C 52.9; H 5.9;
N 14.3; S 10.5.
3.1 m (1H, CH), 7.0–7.4 m (4H, Harom, NHamine), 8.1 m
(1Harom), 8.3 m (1Harom), 11.0 s (1H, NHCO), 11.6 s (1H,
NHindole). Found, %: C 56.1; H 6.0; N 13.1; S 10.0.
C15H19 N3O3S. Calculated, %: C 56.0; H 5.9; N 13.0;
S 9.9.
Ethyl 4-({[(1H-indol-3-ylcarbonyl)amino]-
sulfonyl}amino)benzoate (IIIi). Yield 60%, mp 165–
168°C. IR spectrum, ν, cm–1: 3187 (NH), 1713(CO2Et),
N-(1H-Indol-3-ylcarbonyl)-N'-(4-chlorophenyl)-
sulfamide (IIId). Yield 67%, mp 205–208°C. IR spec-
trum, ν, cm–1: 3320, 3227 (NH); 1627 (C=O). 1H NMR
spectrum, δ, ppm: 7.0–7.4 m (7Harom), 8.1 m (1Harom),
8.3 m (1Harom), 10.4 s (1H, NHamine), 11.35 s (1H,
NHCO), 11.6 s (1H, NHindole). Found, %: C 51.5; H 3.5;
Cl 10,1; N 12.0; S 9.2. C15H12ClN3O3S. Calculated, %:
C 51.6; H 3.4; Cl 10.0; N 12.0; S 9.1.
1
1687 (C=O). H NMR spectrum, δ, ppm: 1.3 t (3H,
CH2CH3), 4.2 q (2H, CH2CH3), 7.0–8.3 m (9Harom),
10.9 s (1H, NHamine), 11.5 s (1H, NHCO), 11.6 s (1H,
NHindole). Found, %: C 53.4; H 3.7; N 11.7; S 8.9.
C16H13N3O5S. Calculated, %: C 53.3; H 3.8; N 11.6;
S 9.0.
2,3-Dihydroindol-1-yl-N-(1H-indole-3-carbonyl)-
sulfonamide (IIIe). Yield 76%, mp 132–135°C. IR spec-
trum, ν, cm–1: 3287, 3260 (NH); 1660 (C=O). 1H NMR
spectrum, δ, ppm: 3.2 t (2H, CH2), 4.4 t (2H, CH2N),
6.8–7.4 m (7Harom), 8.0 d (1Harom), 8.3 s (1Harom), 11.5 s
(1H, NHCO), 11.6 s (1H, NHindole). Found, %: C 59.8;
H 4.4; N 12.3; S 9.4. C17H15N3O3S. Calculated, %:
C 59.8; H4.4; N 12.4; S 9.3.
Methyl 4-({[(1H-indol-3-ylcarbonyl)amino]-
sulfonyl}amino)benzoate (IIIj). Yield 55%, mp 196°C.
IR spectrum, ν, cm–1: 3407, 3327, 3180(NH); 1707
(CO2Me); 1687 (C=O). 1H NMR spectrum, δ, ppm: 3.8 s
(3H, CH3), 7.0–8.3 m (9Harom), 10.9 s (1H, NHamine),
11.5 s (1H, NHCO), 11.6 s (1H, NHindole). Found, %:
C 54.7; H 4.1; N 11.3; S 8.6. C17H15N3O5S. Calculated,
%: C 54.6; H 4.0; N 11.4; S 8.7.
N-(1H-Indol-3-ylcarbonyl)-4-morpholino-
sulfonamide (IIIf). Yield 55%, mp 184–186°C. IR spec-
trum, í, cm–1: 3310, 3227 (NH); 1640 (C=O). 1H NMR
spectrum, δ, ppm: 3.3 m (4H, CH2NCH2morph), 3.6 m (4H,
CH2OCH2morph), 7.0 m (2Harom), 7.4 d (1Harom), 8.1 m
(1Harom), 8.3 m (1Harom), 11.1 s (1H, NHCO), 11.7 s (1H,
NHindole). Found, %: C 50.5; H 4.9; N 13.6; S 10.4.
C13H15N3O4S. Calculated, %: C 51.0; H 4.8; N 13.6; S
10.3.
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1
ν, cm–1: 3287, 3053 (NH); 1647 (C=O). H NMR
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 11 2009