Synthesis of N-arylsulfonyl-α-thienylglycines from N-(2,2,2-trichloro-1-thienylethyl)arenesulfonamides

Article abstract of DOI:10.1007/s11178-005-0126-x

Reactions of N-(2,2,2-trichloroethylidene)arenesulfonamides with thiophene, 2-chlorothiophene, and 2,5-dichlorothiophene, as well as of N-(2,2,2-trichloro-1-hydroxyethyl)arenesulfonamides with 2-chlorothiophene, lead to formation of the corresponding N-(2

Full text of DOI:10.1007/s11178-005-0126-x

Russian Journal of Organic Chemistry, Vol. 41, No. 1, 2005, pp. 91 -94. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 1, 2005,
pp. 93-96.
Original Russian Text Copyright Ó 2005 by Aizina, Rozentsveig, Ushakova, Levkovskaya, Mirskova.
Synthesis of N-Arylsulfonyl-a-thienylglycines
from N-(2,2,2-Trichloro-1-thienylethyl)arenesulfonamides
Yu. A. Aizina, I. B. Rozentsveig, I. V. Ushakova, G. G. Levkovskaya, and A. N. Mirskova
Favorskii Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: i_roz@irioch.irk.ru
Received March 30, 2004
Abstract—Reactions of N-(2,2,2-trichloroethylidene)arenesulfonamides with thiophene, 2-chlorothiophene, and
2,5-dichlorothiophene, as well as of N-(2,2,2-trichloro-1-hydroxyethyl)arenesulfonamides with 2-chlorothiophene,
lead to formation of the corresponding N-(2,2,2-trichloro-1-thienylethyl)arenesulfonamides.Alkaline hydrolysis
of the latter occurs selectively at the trichloromethyl group to give N-arylsulfonyl-a-thienylglycines.
We previously found that N-(2,2,2-trichloroethyl-
idene)arenesulfonamides and N-(1-X-2,2,2-trichloro-
Scheme 1.
ethyl)arenesulfonamides (where X is a readily departing
&O
&O
group, such as OH, OAlk, OAc, or NHSO2R) are capable
of acting as C-amidoalkylating agents toward aromatic
and heteroaromatic compounds [1–3]. The products of
these reactions, 1-arylsulfonylamino-2,2,2-trichloroethyl-
substituted arenes, undergo alkaline hydrolysis to afford
N-arylsulfonyl(aryl)glycines [4, 5]. N-Arylsulfonyl-
(3-indolyl)-glycines were also synthesized in this way [5].
In continuation of our systematic studies on the amido-
alkyl-ating ability of N-(2,2,2-trichloroethylidene)- and
N-(2,2,2-trichloro-1-hydroxyethyl)arenesulfonamides with
a view to develop synthetic approaches to N-substituted
heterylglycines, in the present work we examined
conditions of synthesis of N-(2,2,2-trichloro-1-thienyl-
ethyl)arenesulfonamides and their alkaline hydrolysis.
6
$U62 1+&+&&O
&O
, ꢀꢁ,E
$U62 1+&+&&O
&+&&O
$U62 1
&O
6
;
6
6
;
,, ꢀꢁ,,Eꢀꢁ,,, ꢀꢁ,,,E
;
6
$U62 1+&+&&O
2+
$U62 1+&+&&O
6
+ 62
Thiophene and chlorothiophenes were brought into
reactions with N-(2,2,2-trichloroethylidene)- and N-(2,2,2-
trichloro-1-hydroxyethyl)arenesulfonamides which were
prepared as described in [6, 7]. N-(2,2,2-Trichloro-
ethylidene)arenesulfonamides reacted with chlorothio-
phenes in the presence of oleum (method a) to give
substituted thiophenes Ia, Ib, IIIa, and IIIb in 82–93%
yield. In the reactions with 2,5-dichlorothiophene, the
substitution occurred at position 3 of the heteroring with
formation of products Ia and Ib, while from 2-chloro-
thiophene 5-(1-arylsulfonylamino-2,2,2-trichloroethyl)-
thiophenes IIa and IIb were obtained (Scheme 1).
;
ꢀ,,,Dꢀꢁ,,,E
I–III,Ar = Ph (a), 4-ClC6H4 (b); II, X = H; III, X = Cl.
Compounds IIa and IIb were also prepared by reaction
of N-(2,2,2-trichloroethylidene)arenesulfonamides with
thiophene in the presence of boron trifluoride–ether
complex, following a procedure analogous to that reported
in [8].
1070-4280/05/4101-0091Ó2005 Pleiades Publishing, Inc.

AIZINA et al.
92
Scheme 2.
IIIa and IIIb in method b were lower, and the reactions
of 2,5-dichlorothiophene with N-(2,2,2-trichloro-1-hydro-
xyethyl)arenesulfonamides under the same conditions
gave no detectable amounts of products Ia and Ib.
ꢀꢁꢂꢃ1D2+ꢃꢀDTꢄꢂ
ꢀꢅꢂꢃ+&O
$U62 1+&+&ꢀ2ꢂ2+
$U62 1+&+&&O
Compounds I–III were brought into hydrolysis in
aqueous alkali. The reaction occurred at the trichloro-
methyl group with high selectivity, and the products were
the corresponding N-arylsulfonyl-a-thienylglycine salts.
The hydrolysis at 70–80°C was complete within 3 h. The
subsequent acidification of the reaction mixture gave
N-arylsulfonyl-a-thienylglycines IV–VI in up to 50% yield
(Scheme 2). Like N-arylsulfonyl-a-arylglycines, amino
acids IV–VI attract interest as potential biologically active
compounds [5].
&O
&O
&O
&O
6
6
,9 ꢀꢁ,9E
, ꢀꢁ,E
ꢀꢁꢂꢃ1D2+ꢃꢀDTꢄꢂ
ꢀꢅꢂꢃ+&O
$U62 1+&+&ꢀ2ꢂ2+
6
$U62 1+&+&&O
6
;
;
9 ꢀꢁ9Eꢀꢁ9, ꢀꢁ9,E
,, ꢀꢁ,,Eꢀꢁ,,, ꢀꢁ,,,E
The hydrolysis of compounds I–III was not
accompanied by dehydrochlorination. On the other hand,
partial hydrolysis of the C–N bond was observed: the
reaction mixtures contained a small amount of the
corresponding arenesulfonamides whose fraction
increased on raising the concentration of alkali, reaction
time, and temperature (above 80°C).
IV–VI, Ar = Ph (a), 4-ClC6H4 (b); V, X = H; VI, X = Cl.
Compounds IIIa and IIIb were also synthesized in
72–75% yield by reaction of 2-chlorothiophene with
N-(2,2,2-trichloro-1-hydroxyethyl)arenesulfonamides in
the presence of concentrated sulfuric acid (method b). It
is seen that the yield of compounds IIIa and IIIb
according to method a is greater than in method b, while
the optimal reaction time is the same in both cases. It
should be noted that variation of the concentration of free
sulfuric anhydride from 3 to 20% in method a has no
appreciable effect on the reaction outcome and that
amidoalkylation of chlorothiophene according to method
b does not occur in sulfuric acid with a concentration
lower than 96%. Moreover, method b turned out to be
unsuitable for the synthesis of N-[2,2,2-trichloro-1-(2,5-
dichloro-3-thienyl)ethyl]arenesulfonamides I and
N-[2,2,2-trichloro-1-(2-thienyl)ethyl]arenesulfonamides II
from 2,5-dichlorothiophene and thiophene, respectively.
Likewise, N-(2,2,2-trichloroethylidene)arenesulfonamides
failed to react with thiophene derivatives in sulfuric acid
instead of oleum. When the amount of oleum or sulfuric
acid was greater than that specified in Experimental, the
yield of compounds I–III decreased; probable reasons
are acidophobic properties of the thiophene system and
side sulfonation of the heteroring.
Compounds I–VI are colorless or slightly colored
crystalline substances which are insoluble in water and
aliphatic hydrocarbons and soluble in polar organic
solvents. The structure of previously unknown compounds
Ia, Ib, IIIa, IVa, IVb, Va, Vb, VIa, and VIb was
determined by spectral methods (see Experimental). The
properties of compounds IIa, IIb, and IIIb were in
agreement with published data [3, 8].
The IR spectra of I–III contained strong absorption
bands due to vibrations of the SO2 and NH groups, while
absorption bands typical of O–H and C=N bonds in the
initial sulfonamides were absent. Glycine derivatives IV–
VI showed in the IR spectra absorption bands cor-
responding to vibrations of the carboxy group. In the
1H NMR spectra of I–III, protons of the NH–CH
fragment give rise to two doublets with a coupling constant
of 9–10 Hz. In addition, multiplet signals from aromatic
1
protons were present. The H NMR spectra of com-
pounds IIIa and IIIb contained an AB system typical of
protons in the heterocyclic fragments. Protons in position
4 of the thiophene ring in Ia and Ib appeared as singlets.
These data are consistent with formation of 2,5-di- and
2,3,5-trisubstituted thiophene derivatives, respectively. In
the 1H NMR spectra of substituted glycines IV–VI we
observed no spin–spin coupling in the NH–CH fragment,
and protons therein appeared as two singlets. Under con-
ditions of fast deuterium exchange, only one singlet
remains in the spectrum. The carboxy proton gives
Presumably, the mechanism of amidoalkylation
involves formation of ArSO2NHC+HCCl3 ion via
protonation of the nitrogen atom in Schiff bases (method
a) or successive protonation of the oxygen atom in the
hydroxy group of hydroxyethyl amides and elimination of
water (method b). The rate of formation of the above
cation and its stability in method b are likely to be lower
than in method a. Therefore, the yields of compounds
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 1 2005

SYNTHESISOFN-ARYLSULFONYL-a-THIENYLGLYCINES
93
a broadened singlet in a weak field. The elemental com-
positions of compounds I–VI do not contradict the
assumed structures.
vigorously stirred for 5 h. The mixture was then treated
as described above in a.
N-[2,2,2-Trichloro-1-(2,5-dichlorothiophen-3-
yl)ethyl]benzenesulfonamide (Ia) was synthesized
according to method a from 2.86 g (0.01mol) of N-(2,2,2-
trichloroethylidene)benzenesulfonamide and 1.53 g (0.01
mol) of 2,5-dichlorothiophene in trichloroethylene in the
presence of 1 ml of oleum. Yield 3.82g (87%), mp 141°C.
Thus, reactions of N-(2,2,2-trichloroethylidene)-
arenesulfonamides with thiophene, 2-chlorothiophene, and
2,5-dichlorothiophene and of N-(2,2,2-trichloro-1-hydroxy-
ethyl)arenesulfonamides with 2-chlorothiophene result in
formation of N-(2,2,2-trichloro-1-thienylethyl)arene-
sulfonamides; alkaline hydrolysis of the latter provides
a convenient method of synthesis of N-arylsulfonyl-a-
thienyl)glycines. Our results confirm the general char-
acter of the synthetic approach to N-substituted a-aryl-
(heteryl)glycines on the basis of hydrolytic transformation
of the corresponding N-trichloroethyl amides.
–1
IR spectrum, n, cm : 3240 (NH); 1160, 1330 (SO2);
1530–1540 (C=Carom); 3040–3060 (C–Harom). 1H NMR
spectrum, d, ppm: 5.29 s (1H, CH), 7.47–7.70 m (5H,
C6H5), 7.20 s (1H, 4-H, thienyl). Found, %: C 32.40;
Cl 42.90; N 3.20; S 15.29. C12H8Cl5NO2S2. Calculated,
%: C 32.79; Cl 40.33; N 3.19; S 14.59.
N-[2,2,2-Trichloro-1-(2,5-dichlorothiophen-3-
yl)ethyl]-4-chlorobenzenesulfonamide (Ib) was
synthesized according to method a from 3.21 g (0.01mol)
of N-(2,2,2-trichloroethylidene)-4-chlorobenzenesulfon-
amide and 1.53 g (0.01 mol) of 2,5-dichlorothiophene.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
DPX-400 spectrometer (400 MHz) from 5–10% solutions
in acetone-d6 containing HMDS as internal reference.
The IR spectra were obtained on a Specord IR75
instrument from samples prepared as KBr pellets.
–1
Yield 4.41 g (93%), mp 154°C. IR spectrum, n, cm :
3230 (NH); 1150, 1310 (SO2); 1520 (C=Carom); 3050–
3060 (C–Harom). 1H NMR spectrum, d, ppm: 5.27 s (1H,
CH), 7.47 d and 7.67 d (4-H, C6H4), 7.16 s (1H, 4-H,
thienyl). Found, %: C 30.29; Cl 43.98; N 2.61; S 12.70.
C12H7Cl6NO2S2. Calculated, %: C 30.41; Cl 44.87;
N 2.95; S 13.53.
N-[2,2,2-Trichloro-1-(2-thienyl)ethyl]benzenesulfon-
amide (IIa) and N-[2,2,2-trichloro-1-(2-thienyl)ethyl]-4-
chlorobenzenesulfonamide (IIb) were synthesized by
reaction of the corresponding N-(2,2,2-trichloroethylid-
ene)arenesulfonamides with thiophene in the presence
of boron trifluoride–ether complex according to the
procedure reported in [8]. N-[2,2,2-Trichloro-1-(5-chloro-
2-thienyl)ethyl]-4-chlorobenzenesulfonamide (IIIb) was
prepared by reaction of N-(2,2,2-trichloroethylidene)-4-
chlorobenzenesulfonamide with 2-chlorothiophene in the
presence of oleum [3].
N-[2,2,2-Trichloro-1-(5-chlorothiophen-2-yl)-
ethyl]benzenesulfonamide (IIIa). a. From 2.86 g
(0.01 mol) of N-(2,2,2-trichloroethylidene)benzenesulfon-
amide and 2.38 g (0.02 mol) of 2-chlorothiophene in tri-
chloroethylene we obtained 3.32 g (82%) of compound
IIIa.
b. From 3.04 g (0.01 mol) of N-(2,2,2-trichloro-1-hy-
droxyethyl)benzenesulfonamide and 2.38 g (0.02 mol) of
2-chlorothiophene we obtained 3.04 g (75%) of compound
Gnereal procedure for amidoalkylation of
thiophene and chlorothiophenes. a. Halothiophene,
0.01–0.02 mol, and oleum containing 3 to 20% of SO3,
0.5–1 ml, were added to a solution of 0.01 mol of
N-(2,2,2-trichloroethylidene)arenesulfonamide [6] in 10–
15 ml of anhydrous trichloroethylene, chloroform, or
carbon tetrachloride. The mixture was vigorously stirred
for 4–5 h, the solvent was distilled off under reduced
pressure, and the residue was washed with 50 ml of 10%
aqueous ammonia and water (until neutral reaction), dried
in air, and recrystallized from acetone–carbon
tetrachloride (1:1).
–1
IIIa. mp 135–136°C. IR spectrum, n, cm : 3220 (NH);
1180, 1340 (SO2); 2940 (C–Haliph); 3060–3090
(C–Harom). 1H NMR spectrum, d, ppm: 5.20 s (1H, CH);
6.85 t, 7.33 d, and 7.65 d (5H, C6H5); 7.02 d and 7.40 d
(2H, 3-H, 4-H, thienyl). Found, %: C 37.40; Cl 34.18;
N 3.32; S 15.30. C12H9Cl4NO2S2. Calculated, %: C 37.52;
Cl 34.08; N 3.37; S 15.41.
2,5-Dichlorothiophen-3-yl(phenylsulfonylamino)-
acetic acid (IVa). A mixture of 2.20 g (0.005 mol) of
N-[2,2,2-trichloro-1-(2,5-dichlorothiophen-3-yl)ethyl]-
benzenesulfonamide and 50 ml of an aqueous solution of
0.60 g (0.015 mol) of sodium hydroxide was stirred for
3 h at 90°C. The mixture was filtered while hot, the filtrate
b. A mixture of 0.01 mol of N-(2,2,2-trichloro-1-
hydroxyethyl)arenesulfonamide [6, 7], 2.38 g (0.02 mol)
of 2-chlorothiophene, 15 ml of chloroform or carbon
tetrachloride, and 1–3 ml of 98–100% sulfuric acid was
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 1 2005

AIZINA et al.
94
was cooled to room temperature, and 10% hydrochloric
acid was added to the filtrate until a solid material no
longer precipitated. The mixture was kept for 2 h, the
precipitate was filtered off, washed with water until
neutral washings, dried, and recrystallized from acetone–
chloroform (1:5). Yield 0.68 g (37%), mp 60°C. IR
each, thienyl). Found, %: C 42.73; Cl 13.45; N 4.13;
S 16.70. C12H10ClNO4S2. Calculated, %: C 43.44;
Cl 10.69; N 4.22; S 19.33.
5-Chlorothiophen-2-yl(phenylsulfonylamino)-
acetic acid (VIa) was synthesized in a similar way from
3.73 g (0.01 mol) of compound IIIa. Yield 1.16 g (35%),
–1
spectrum, n, cm : 3260 (NH); 1140, 1350 (SO2); 1700–
–1
mp 105°C. IR spectrum, n, cm : 3240 (NH); 1180, 1350
1
1710 (C=O); 3420 (OH). H NMR spectrum, d, ppm:
1
(SO2); 1700–1710 (C=O); 3370 (OH). H NMR
5.25 s (1H, CH), 10.62 br.s (1H, OH), 7.63–8.02 m (5H,
C6H5), 6.80 s (1H, 4-H, thienyl). Found, %: C 38.95;
Cl 18.74; N 3.60; S 17.00. C12H9Cl2NO4S2. Calculated,
%: C 39.36; Cl 19.36; N 3.82; S 17.51.
spectrum, d, ppm: 5.35 s (1H, CH), 10.62 br.s (1H, OH),
7.59–8.01 (5H, C6H5), 6.84 (2H, thienyl). Found, %:
C 39.87; Cl 10.69; N 4.34; S 20.47. C12H10ClNO4S2.
Calculated, %: C 43.44; Cl 10.85; N 4.22; S 19.33.
4-Chlorophenylsulfonylamino(2,5-dichlorothio-
phen-3-yl)acetic acid (IVb) was synthesized as
described above for compound IVa from 2.38 g
(0.005 mol) of N-[2,2,2-trichloro-1-(2,5-dichlorothiophen-
3-yl)ethyl]-4-chlorobenzenesulfonamide. Yield 0.95 g
4-Chlorophenylsulfonylamino(5-chlorothiophen-
2-yl)acetic acid (VIb) was synthesized in a similar way
from 2.14 g (0.005 mol) of compound IIIb. Yield 0.74 g
–1
(40%), mp 80°C. IR spectrum, n, cm : 3230 (NH); 1160,
1
1330 (SO2); 1720 (C=O); 3320–3410 (OH). H NMR
–1
(47%), mp 115°C. IR spectrum, n, cm : 3240 (NH); 1160,
spectrum, d, ppm: 5.38 s (1H, CH), 7.57 d and 7.83 d
(4H, C6H4), 7.01 d and 7.40 d (2H, thienyl). Found, %:
C 41.09; Cl 21.25, N 3.13; S 14.76. C12H9Cl2NO4S2.
Calculated, %: C 39.36; Cl 19.36; N 3.82; S 17.51.
1340 (SO2); 1710 (C=O); 3430 (OH). 1H NMR spectrum,
d, ppm: 5.23 s (1H, CH), 13.88 br.s (1H, OH), 7.63 d and
7.98 d (4H, C6H4), 6.78 s (1H, 4-H, thienyl). Found, %:
C 35.30; Cl 25.86; N 3.45; S 15.30. C12H8Cl3NO4S2.
Calculated, %: C 35.97; Cl 26.50; N 3.50; S 16.00.
REFERENCES
Phenylsulfonylamino(2-thienyl)acetic acid (Va)
was synthesized in a similar way from 2.85 g (0.005 mol)
of compound IIa. Yield 0.63 g (53%), mp 98–100°C. IR
1. Levkovskaya, G.G., Drozdova, T.I., Rozentsveig, I.B., and
Mirskova, A.N., Usp. Khim., 1999, vol. 68, p. 638.
2. Rozentsveig, I.B., Levkovskaya, G.G., and Mirskova, A.N.,
Russ. J. Org. Chem., 1999, vol. 35, p. 895.
3. Rozentsveig, I.B., Levkovskaya, G.G., Albanov, A.I., and
Mirskova, A.N., Russ. J. Org. Chem., 2000, vol. 36, p. 671.
4. Rozentsveig, I.B., Levkovskaya, G.G., Mirskova,A.N., and
Kashik, T.V., Russ. J. Org. Chem., 2000, vol. 36, p. 1760.
5. Mirskova,A.N., Rudyakova, E.V., Rozentsveig, I.B., Stupi-
na,A.G., Levkovskaya, G.G., andAlbanov,A.I., Khim.-Farm.
Zh. 2001, no. 6, p. 21.
6. Mirskova, A.N., Levkovskaya, G.G., Gogoberidze, I.T.,
Kalikhman, I.D., and Voronkov, M.G., Zh. Org. Khim., 1985,
vol. 21, p. 269.
7. De Kimpe, N. and Shcamp, N., Org. Prep. Proced. Int., 1979,
vol. 11, nos. 3–4, p. 111.
–1
spectrum, n, cm : 3240 (NH); 1160, 1350 (SO2); 1690–
1
1710 (C=O); 3430–3480 (OH). H NMR spectrum, d,
ppm: 5.41 s (1H, CH); 10.54 br.s (1H, OH); 7.58–8.01
(5H, C6H5); 7.35 d, 7.71 d, and 7.88 d (1H each, thienyl).
Found, %: C 46.45; N 4.82; S 21.61. C12H11NO4S2.
Calculated, %: C 48.47; N 4.71; S 21.36.
4-Chlorophenylsulfonylamino(2-thienyl)acetic
acid (Vb) was synthesized in a similar way from 2.25 g
(0.005 mol) of compound IIb. Yield 0.64 g (43%),
–1
mp 197°C. IR spectrum, n, cm : 3250 (NH); 1170, 1340
1
(SO2); 1690–1710 (C=O); 3440 (1H, OH). H NMR
8. Gogoberidze, I.T., Levkovskaya, G.G., Mirskova,A.N., and
Voronkov, M.G., Zh. Org. Khim., 1984, vol. 20, p. 1100.
spectrum, d, ppm: 5.33 s (1H, CH); 9.00 br.s (1H, OH);
7.68 d, 7.90 d (4H, C6H4); 6.98 t, 7.46 d, and 7.65 d (1H
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 1 2005