Synthesis and properties of N-(2,2,2-trichloroethyl)-2- thiophenesulfonamides

Article abstract of DOI:10.1023/B:RUJO.0000010224.50448.f5

Chlorination of 2-thiophenesulfonamide gave unstable N,N-dichloro-2- thiophenesulfonamide which was brought into reactions with 1,2-polyhaloethenes. The condensation of 2-thiophenesulfonamide with trichloroacetaldehyde afforded N-(2,2,2-trichloro-1-hydroxyethyl)-2-thiophenesulfonamide which reacted with benzene, toluene, 2-chlorothiophene, and phenol to form the corresponding N-(1-aryl-2,2,2-trichloroethyl)-2-thiophenesulfonamides. Under more severe conditions, the latter were converted into 1,1-diaryl-2,2,2-trichloroethanes. The reaction of N-(2,2,2-trichloro-1-hydroxyethyl)-2-thiophenesulfonamide with substituted arenes, including phenol, was regioselective: only the corresponding para-substituted products were obtained. Hydrolysis of N-[2,2,2-trichloro-1-(4- tolyl)ethyl]-2-thiophenesulfonamide yielded N-(2-thienylsulfonyl)-2-(4-tolyl) glycine.

Full text of DOI:10.1023/B:RUJO.0000010224.50448.f5

Russian Journal of Organic Chemistry, Vol. 39, No. 9, 2003, pp. 1334 1337. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 9, 2003,
pp. 1406 1409.
Original Russian Text Copyright
2003 by Aizina, Rozentsveig, Levkovskaya, Mirskova.
Synthesis and Properties
of N-(2,2,2-Trichloroethyl)-2-thiophenesulfonamides
Yu. A. Aizina, I. B. Rozentsveig, G. G. Levkovskaya, and A. N. Mirskova
Favorskii Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
fax: (3952)396046
Received August 23, 2002
Abstract Chlorination of 2-thiophenesulfonamide gave unstable N,N-dichloro-2-thiophenesulfonamide
which was brought into reactions with 1,2-polyhaloethenes. The condensation of 2-thiophenesulfonamide with
trichloroacetaldehyde afforded N-(2,2,2-trichloro-1-hydroxyethyl)-2-thiophenesulfonamide which reacted with
benzene, toluene, 2-chlorothiophene, and phenol to form the corresponding N-(1-aryl-2,2,2-trichloroethyl)-2-
thiophenesulfonamides. Under more severe conditions, the latter were converted into 1,1-diaryl-2,2,2-tri-
chloroethanes. The reaction of N-(2,2,2-trichloro-1-hydroxyethyl)-2-thiophenesulfonamide with substituted
arenes, including phenol, was regioselective: only the corresponding para-substituted products were obtained.
Hydrolysis of N-[2,2,2-trichloro-1-(4-tolyl)ethyl]-2-thiophenesulfonamide yielded N-(2-thienylsulfonyl)-2-
(4-tolyl)glycine.
Design of compounds possessing sulfonamide,
polyhaloalkyl, and thienyl fragments in a single
molecule is an important problem, for such derivatives
are promising from the viewpoint of their biological
activity due to the presence of pharmacophoric
groups. Moreover, they can also be used as inter-
mediate products in fine organic synthesis.
While continuing our systematic studies in the field
of synthetic approaches to N-polyhaloethyl amides
on the basis of the reaction of N,N-dihalo amides
with polyhaloethenes [1], we have synthesized N,N-di-
chloro-2-thiophenesulfonamide (II) by chlorination of
2-thiophenesulfonamide (I) (Scheme 1) and examined
its behavior in reactions with tri- and 1,2-dichloro-
ethenes. 2-Thiophenesulfonamide was obtained as
shown in Scheme 1 without isolation of 2-thiophene-
sulfonyl chloride, which considerably simplified the
experimental procedure and increased the yield of
I. The chlorination of 2-thiophenesulfonamide in
aqueous alkali gave up to 70% of dichloro amide II.
The formation of N,N-dichloro amide II was con-
firmed by the data of IR spectroscopy and elemental
analysis (see Experimental). In the IR spectrum we
observed two absorption bands belonging to the sul-
fonyl group, while NH2 absorption typical of 2-thio-
phenesulfonamide was absent.
N,N-Dichloro-2-thiophenesulfonamide (II) turned
out to be unstable. It readily undergoes decomposition
in 20 h at room temperature or instantaneously on
heating with formation of tar-like compounds of
unknown composition. For that reason we failed to
synthesize N-(2-polychloroethylidene)-2-thiophenesul-
fonamides and their derivatives via reaction of II with
trichloroethylene and 1,2-dichloroethenes. No reaction
occurred in the cold, whereas heating of the reaction
mixture resulted in tarring.
Scheme 1.
With the goal of developing synthetic approaches
to N-(trichloroethyl)thiophenesulfonamides we were
the first to effect condensation of 2-thiophenesulfon-
amide with trichloroacetaldehyde. As a result, we
obtained N-(2,2,2-trichloro-1-hydroxyethyl)-2-thio-
1070-4280/03/3909-1334$25.00 2003 MAIK Nauka/Interperiodica

SYNTHESIS AND PROPERTIES OF N-(2,2,2-TRICHLOROETHYL)-.. .
1335
Scheme 2.
Scheme 3.
X = H (a), CH3 (b), OH (c).
phenesulfonamide (III) which was then brought into
reactions with aromatic and heteroaromatic substrates.
We have found that 2-thiophenesulfonamide reacts
with trichloroacetaldehyde in the presence of a cata-
lytic amount of sulfuric acid. The use of a large
amount of sulfuric acid, as well as prolonging the
reaction over 3 h and overheating of the reaction
mixture, favors formation of 1,1,1-trichloro-2,2-bis-
(2-thienylsulfonylamino)ethane (IV) as by-product
(Scheme 2).
By analogy with N-(1-hydroxy-2-polychloroethyl)-
arenesulfonamides [2], amide III readily reacts under
similar conditions with benzene, toluene, phenol, and
2-chlorothiophene, yielding the corresponding sub-
stituted arenes Va Vc. In the reaction with toluene,
the substitution occurs in a regioselective fashion, at
the para position of the benzene ring. Likewise,
the C-amidoalkylation of 2-chlorothiophene afforded
the corresponding 5-substituted derivative (Scheme 3).
Increase of the reaction time, e.g., in the C-amido-
alkylation of 2-chlorothiophene, leads to formation
of 1,1,1-trichloro-2,2-bis(2-chlorothienyl)ethane (VI).
This result indicates that amides V are capable of
alkylating arenes and that the thiophenesulfonamide
fragment is a departing group in this process. We can
also state that the 2-thienylsulfonylamino group is
a better nucleofuge than arylsulfonylamino, for
analogous derivatives of benzenesulfonic acids do not
give rise to 1,1-diaryl-2,2,2-trichloroethanes under
similar conditions [2, 3].
III V contain absorption bands due to vibrations of
the SO2 and NH groups, which are absent in the
spectrum of VI. Amide III also showed in the IR
spectrum absorption of the hydroxy group.
The NH CH fragment in compounds III V
gives two characteristic doublets in the 1H NMR
spectra. In addition, the spectra of III VI contain
signals from the thiophene ring protons, amides Va
and Vb display signals from the benzene ring protons,
and a singlet from the CH proton is observed in the
spectrum of VI. The relative intensities of the above
signals are consistent with the assigned structures.
We previously showed [4] that N-(2,2,2-trichloro-
ethyl)arenesulfonamides can be used in the synthesis
of N-sulfonyl- -arylglycines. We have found that
compounds like V can also be involved in analogous
syntheses. Alkaline hydrolysis of amide Vb afforded
N-(2-thienylsulfonyl)-2-(4-tolyl)glycine sodium salt
which was treated with hydrochloric acid to isolate
amino acid VII in 35% yield (Scheme 4).
Scheme 4.
In the IR spectrum of VII absorption bands belong-
ing to the COOH, OH, NH, and SO2 groups were
1
present. Its H NMR spectrum contained signals from
The structure of compounds III VI was determined
by IR and 1H NMR spectroscopy and elemental
analysis. The IR spectra of thiophenesulfonamides
protons of the para-substituted benzene ring, thio-
phene ring, and NCH group; signals from the NH
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003

1336
AIZINA et al.
and OH protons were not observed due to fast H D
exchange.
Compounds III VII are crystalline substances,
which are soluble in acetone, dimethyl sulfoxide, and
aqueous alkali and insoluble in water.
N-(2,2,2-Trichloroethyl-1-hydroxy)-2-thiophene-
sulfonamide (III). A mixture of 1.47 g (0.01 mol) of
trichloroacetaldehyde, 1.63 g (0.01 mol) of 2-thio-
phenesulfonamide, and one drop of concentrated sul-
furic acid was heated under thorough stirring until
it melted. It was then heated for 20 min at 60 70 C
and repeatedly washed with water, and the residue
was dried in air. Yield 3.04 g (98%), mp 124 126 C.
EXPERIMENTAL
1
IR spectrum, , cm : 1160, 1340 (SO2); 2850 2950
1
The H NMR spectra were recorded on a Bruker
(C Haliph); 3080 3105 (C Harom); 3200 (NH),
DPX-400 spectrometer (400 MHz) from 5 10% solu-
tions in deuterated solvents; hexamethyldisiloxane
was added as internal reference. The IR spectra were
obtained on a Specord 75IR spectrometer from
samples pelleted with KBr.
1
3470 br (OH). H NMR spectrum (DMSO-d6),
,
ppm: 5.22 d (1H, CH, J = 8.8 Hz); 7.17 t, 7.68 d,
and 7.92 d (3H, 2-thienyl); 7.95 br.s (1H, OH); 9.16 d
(1H, NH, J = 8.8 Hz). Found, %: C 23.36; H 1.72;
Cl 35.18; N 4.43; S 20.48. C6H6Cl3NO3S2. Calcu-
lated, %: C 23.20; H 1.95; Cl 34.24; N 4.51; S 20.64.
2-Thiophenesulfonamide (I). Thiophene, 8 ml
(0.1 mol), was added dropwise over a period of 1 h
under vigorous stirring and cooling to a mixture of
39.88 ml (0.6 mol) of chlorosulfonic acid and 40 ml
of carbon tetrachloride. The rate of addition was
controlled in such a way that the temperature did not
exceed 5 C. The mixture was diluted with 20 ml of
carbon tetrachloride, stirred for 10 15 min, and
poured onto ice. The organic phase was separated,
the aqueous phase was extracted with carbon tetra-
chloride (3 10 ml), the extracts were combined with
the organic phase and evaporated under reduced
pressure, the tarry residue was mixed with 50 ml of
20% aqueous ammonia, and the mixture was left to
stand for 20 h on exposure to air. The mixture was
then neutralized to pH 6.5 with 10% hydrochloric
acid and kept for 2 3 h, and the precipitate of amide
I was filtered off and purified by reprecipitation from
10% aqueous ammonia, followed by recrystallization
from ethanol chloroform (1:3). Yield 13.53 g (83%),
1,1,1-Trichloro-2,2-bis(2-thienylsulfonylamino)-
ethane (IV). A mixture of 1.47 g (0.01 mol) of tri-
chloroacetaldehyde, 1.63 g (0.01 mol) of 2-thiophene-
sulfonamide, 5 ml of dry benzene, and 2 ml of con-
centrated sulfuric acid was heated for 30 min at 80 C.
The mixture was evaporated under reduced pressure,
and the solid residue was repeatedly washed with
1
water and dried. According to the H NMR data, the
product was a mixture of amides III and IV at a ratio
of 2.5:1; the calculated yield of IV was 1.17 g (50%).
1H NMR spectrum of IV (DMSO-d6), , ppm: 5.65 t
(1H, CH); 7.08 t, 7.58 d, and 7.83 d (6H, 2-thienyl);
9.53 d (2H, NH, J = 9.2 Hz).
N-(2,2,2-Trichloro-1-phenylethyl)-2-thiophene-
sulfonamide (Va). A mixture of 3.11 g (0.01 mol) of
amide III, 8 ml of benzene, and 1 ml of concentrated
sulfuric acid was vigorously stirred for 4 h at room
temperature. Excess benzene was removed under
reduced pressure, and the residue was washed first
with 10 ml of 5% aqueous ammonia and then with
water until neutral washings. Yield 3.30 g (90%),
1
mp 141 142 C [5]. IR spectrum, , cm : 1160, 1320
(SO2); 1560 (C Carom); 3090 3105 (C Harom); 3240,
3310 (NH2).
1
mp 142 143 C. IR spectrum, , cm : 1160, 1330
(SO2); 2940 2960 (C Haliph); 3080 3095 (C Harom);
3260 (NH). H NMR spectrum (DMSO-d6), , ppm:
N,N-Dichloro-2-thiophenesulfonamide (II).
Amide I, 1.63 g (0.01 mol), was added in small
portions under stirring to a solution of 0.80 g
(0.02 mol) of sodium hydroxide in 15 ml of water.
The solution was filtered, and gaseous chlorine was
passed through the filtrate, maintaining the tempera-
ture below 10 C, until a solid no longer precipitated.
The product was filtered off, washed with cold water
until a negative test for chloride ion in the washings,
and dried over P2O5 under reduced pressure. Yield
1.62 g (70%), decomposes above 30 C. IR spectrum,
1
5.30 d (1H, CH, J = 10.2 Hz); 6.84 t, 7.32 d, and
7.56 d (3H, 2-thienyl); 7.25 m and 7.60 m (5H, Ph);
9.11 d (1H, NH, J = 10.2 Hz). Found, %: C 38.56;
H 2.74; Cl 28.37; N 3.58; S 17.43. C12H10Cl3NO2S2.
Calculated, %: C 38.88; H 2.72; Cl 28.69; N 3.78;
S 17.30.
N-[2,2,2-Trichloro-1-(4-tolyl)ethyl]-2-thiophene-
sulfonamide (Vb) was synthesized as described above
for compound Va from 3.11 g (0.01 mol) of amide III
and 8 ml of toluene. Yield 3.71 g (96%), mp 149
1
, cm : 1160, 1370 (SO2); 3100, 3110 (C Harom).
1
Found, %: C 24.33; H 1.52; Cl 18.51; N 7.23;
S 32.48. C4H3Cl2NO2S2. Calculated, %: C 24.43;
H 1.54; Cl 18.03; N 7.12; S 32.61.
150 C. IR spectrum, , cm : 1160, 1340 (SO2);
2900 2980 (C Haliph); 3060 3100 (C Harom);
1
3250 br (NH). H NMR spectrum (DMSO-d6),
,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003

SYNTHESIS AND PROPERTIES OF N-(2,2,2-TRICHLOROETHYL)-.. .
1337
1
ppm: 2.22 s (3H, Me); 5.18 d (1H, CH, J = 10.4 Hz);
6.85 t, 7.32 d, and 7.67 d (3H, 2-thienyl); 7.01 and
7.40 (4H, C6H4 AA BB system); 9.37 d (1H, NH).
Found, %: C 40.51; H 3.22; Cl 27.37; N 3.68;
S 16.54. C13H12Cl3NO2S2. Calculated, %: C 40.59;
H 3.14; Cl 27.65; N 3.64; S 16.67.
1.30 g (35%). H NMR spectrum of VI (DMSO-d6),
, ppm: 6.30 s (1H, CH); 7.07 d and 7.23 d (4H,
5-chloro-2-thienyl).
N-(2-Thienylsulfonyl)-2-(4-tolyl)glycine (VII).
A mixture of 1.92 g (0.005 mol) of amide Vb, 0.80 g
(0.02 mol) of NaOH, and 50 ml of water was stirred
for 3 h at the boiling point. The mixture was filtered
while hot, the filtrate was cooled to room temperature,
and 10% hydrochloric acid was added dropwise until
a solid no longer precipitated. The mixture was kept
for 2 h, and the precipitate was filtered off, washed
with water until neutral washings, and dried. Yield
0.54 g (35%), mp 48 55 C (from acetone chloroform,
N-[2,2,2-Trichloro-1-(4-hydroxyphenyl)ethyl]-2-
thiophenesulfonamide (Vc). A mixture of 3.11 g
(0.01 mol) of amide III, 1.88 g (0.02 mol) of phenol,
10 ml of carbon tetrachloride, and 0.5 ml of concen-
trated sulfuric acid was stirred for 3 h. The precipitate
was filtered off and washed first with 20 ml of carbon
tetrachloride and then repeatedly with water until
neutral washings. Yield 3.02 g (78%), mp 194 196 C.
1
1:3). IR spectrum, , cm : 1170, 1350 (SO2); 1700
1
IR spectrum, , cm : 1170, 1345 (SO2); 2930 2960
(C O); 3080 3100 (C Harom); 3220 br (NH);
1
(C Ha1liph); 3080 3100 (C Harom); 3280 (NH); 3430
3450 br (OH). H NMR spectrum (CDCl3), , ppm:
(OH). H NMR spectrum (DMSO-d6), , ppm: 5.04 d
(1H, CH, J = 10.5 Hz); 6.83 t, 7.29 d, and 7.61 d (3H,
2-thienyl); 6.53 and 7.25 (4H, C6H4, AA BB system);
9.23 d (1H, NH). Found, %: C 37.33; H 2.65;
Cl 27.41; N 3.72; S 16.43. C12H10Cl3NO3S2. Calcu-
lated, %: C 37.27; H 2.61; Cl 27.50; N 3.62; S 16.58.
2.30 s (3H, Me); 4.08 s (1H, CH); 7.04 t, 7.63 d, and
7.82 d (3H, 2-thienyl); 7.05 and 7.20 (4H, C6H4,
AA BB system). Found, %: C 37.33; H 2.65; Cl 27.41;
N 3.72; S 16.43. C12H10Cl3NO3S2. Calculated, %:
C 37.27; H 2.61; Cl 27.50; N 3.62; S 16.58.
N-[2,2,2-Trichloro-1-(5-chloro-2-thienyl)ethyl]-2-
thiophenesulfonamide (Vd) was synthesized as
described above for compound Va from 3.11 g
(0.01 mol) of amide III and 4.60 ml (0.05 mol) of
2-chlorothiophene (reaction time 3 h). Yield 2.96 g
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1
(72%), mp 112 116 C. IR spectrum, , cm : 1170,
1
1350 (SO2); 2950 (C Haliph); 3240 (NH). H NMR
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10.0 Hz); 7.11 t, 7.50 d, and 7.81 d (3H, 2-thienyl);
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