Synthesis of 2-aryl-4-cyano-1,3-oxazole-5-sulfonyl chlorides and N-substituted sulfonamides

Article abstract of DOI:10.1134/S1070363212110229

Oxidative chlorination of 2-aryl-5-benzylsulfanyl-1,3-oxazole-4- carbonitrile results in the previously unknown 4-cyano-1,3-oxazole-5-sulfonyl chlorides and N-substituted sulfonamides.

Full text of DOI:10.1134/S1070363212110229

ISSN 1070-3632, Russian Journal of General Chemistry, 2012, Vol. 82, No. 11, pp. 1855–1858. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © A.N. Kornienko, S.G. Pil’o, V.M. Prokopenko, V.S. Brovarets, 2012, published in Zhurnal Obshchei Khimii, 2012, Vol. 82, No. 11,
pp. 1865–1869.
Synthesis of 2-Aryl-4-cyano-1,3-oxazole-5-sulfonyl Chlorides
and N-Substituted Sulfonamides
A. N. Kornienko, S. G. Pil’o, V. M. Prokopenko, and V. S. Brovarets
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev-94, 02660 Ukraine
e-mail: brovarets@bpci.kiev.ua
Received September 13, 2011
Abstract–Oxidative chlorination of 2-aryl-5-benzylsulfanyl-1,3-oxazole-4-carbonitrile results in the previously
unknown 4-cyano-1,3-oxazole-5-sulfonyl chlorides and N-substituted sulfonamides.
DOI: 10.1134/S1070363212110229
The 1,3-oxazole fragment is a component of many
natural and synthetic products with various biological
activity [1–7]. Therefore, the functionalization of
oxazole ring is one of the main synthetic approaches to
the new compounds in order to study their biological
effects. In this work we attempt to synthesize the new
1,3-oxazole-5-sulfonyl chloride and N-substituted
sulfonamides functionalized with the nitrile group in
the 4 position. There are no published data on the
synthesis of such compounds.
they underwent cyclization into the substituted 5-
mercaptooxazoles [9]. The latter were immediately
converted into the alkylation products III without
isolation in the individual state (Scheme 1).
Compounds IIIa–IIId are stable colorless crys-
talline substances. Their oxidative chlorination pro-
ceeds in aqueous acetic acid at 0°C to give 2-aryl-4-
cyano-1,3-oxazole-5-sulfonyl chlorides IVa–IVd (55–
75%) along with 2-aryl-4-cyano-5-chloro-1,3-oxa-
zoles (~15–20%). This is confirmed by the elemental
analysis, 1H NMR spectra, and GC-MS data.
The available 2-acylamino-3,3-dichloroacrylo-
nitriles I [8] were chosen as the starting materials. By
the action of an excess of sodium hydrogen sulfide
The crystallization of this mixture (after short-time
heating in hexane or cyclohexane) leads to the partial
Scheme 1.
CN
H
CN
CN
N
N
N
O
(1) NaSH (exess)
(2) HCl
BnCl/Et3N
Ar
Ar
Cl
Ar
SBn
IIIа−IIId
SH
O
O
II
Cl
Iа−Id
Cl2/MeCOOH/H2O
CN
CN
N
N
R1R2NH/Et3N
Ar
Ar
SO2NR1R2
Vа−Vg
SO2Cl
IVа−IVd
Δ
O
O
Ar = Ph (Iа, IIIа–Vа, Vd), 4-MeC6H4 (Ib, IIIb–Vb, Ve), 4-ClC6H4 (Ic, IIIc–Vc, Vf), 4-MeOC6H4 (Id, IIId), 4-MeO-3,5-
Cl2C6H2 (IVd, Vg), R1R2N = (CH2)5N (Vа–Vc), O(CH2)4N (Vd–Vg).
1855

1856
KORNIENKO et al.
Table 1. Yields, melting points and elemental analysis data of compounds III, V, VI
Found, %
N
Calculated, %
N
Comp. Yield,
mp, °С (solvent for
recrystallization)
Formula
no.
%
Cl
S
Cl
S
74а
78а
75а
75а
70
70
70
72
75
75
70
68
65
108–110 (EtOH)
112–114 (EtOH)
118–120 (EtOH)
105–107 (EtOH)
126–128 (EtOH)
188–190 (EtOH)
173–175 (EtOH)
118–120 (EtOH)
200–202 (EtOH)
170–172 (EtOH)
178–180 (EtOH)
103–105 (toluene)
115–117 (toluene)
–
9.45
10.99
10.50
9.80
C17H12N2OS
–
9.58
10.97
10.47
9.81
IIIа
IIIb
IIIc
IIId
Vа
–
10.92
–
9.10
C18H14N2OS
–
10.85
–
9.14
8.51
C17H11ClN2OS
C18H14N2O2S
C15H15N3O3S
C16H17N3O3S
C15H14ClN3O3S
C14H13N3O4S
C15H15N3O4S
C14H12ClN3O4S
C15H13Cl2N3O5S
C25H22N2OS2
C24H19ClN2OS2
8.57
8.72
9.92
8.69
9.95
–
13.19
12.74
11.82
12.25
12.51
11.80
10.01
6.44
10.09
9.69
–
13.24
12.68
11.94
13.16
12.60
11.88
10.05
6.51
10.10
9.68
–
–
Vb
10.15
–
9.13
10.08
–
9.11
Vc
10.10
9.67
10.04
9.62
Vd
–
–
Ve
10.09
16.99
–
9.09
10.02
16.95
–
9.06
Vf
7.69
7.67
Vg
14.82
14.23
14.89
14.22
VIа
VIb
7.92
6.16
7.86
6.21
a Yield by the method а.
elimination of SO2 from products IV and to an
increase (up to 60%) of the 5-chlorooxazole content.
Therefore, sulfonyl chlorides IV were used without
further purification. In the case of compound IIId 4-
methoxyphenyl substituent also undergoes chlorination
to form 4-cyano-2-(3,5-dichloro-4-methoxyphenyl)-
1,3-oxazole-5-sulfonyl chloride IVd.
An alternative approach for obtaining 2-aryl-5-
benzylsulfanyl-1,3-oxazole-4-carbonitriles III includes
the substitution of the chlorine atoms in compounds I
by the benzylthiol fragments followed by the reaction
of compounds VI with silver carbonate, resulting in
the cyclic product III (Scheme 2). Their structure is
unambiguous, since this reaction is well studied [11,
12]. The spectral data of III obtained according to the
Schemes 1 and 2 are identical. However, a dis-
advantage of this approach is a lower yield of the reac-
tion products.
The reactions of sulfonyl chlorides IVa–IVd with
piperidine and morpholine occur in a boiling an-
hydrous dioxane in the presence of triethylamine to
give the sulfonamides IVa–IVd in yields of 65–75%.
Since substituted 1,3-oxazole-5-sulfonyl amides
possess diverse biological activity [13–16], it is
advisable to search for bioactive agents among the
synthesized 2-aryl-4-cyano-1,3-oxazole-5-sulfonamides
Va–Vd that will be reported elswhere.
The elemental analysis data of the synthesized com-
pounds are given in Table 1. Their structure was con-
firmed by the IR, 1H and 13C NMR, and GC-MS spectra.
The IR spectra of oxazoles III, V contain the
absorption bands at 2232–2251 cm–1 belonging to the
cyano moiety. In the spectra of sulfonamides V there
are also additional characteristic absorption bands at
1160–1165 and 1372–1374 cm–1 corresponding to the
symmetric and asymmetric vibrations of the SO2
EXPERIMENTAL
The IR spectra were recorded on a Vertex 70
1
spectrometer from KBr pellets. The H and 13C NMR
spectra were obtained on a Bruker Avance DRX-500
instrument (500 and 125 MHz, respectively) relative to
internal TMS. The GC-MS spectra were taken on an
Agilent 1100 Series high-performance liquid
chromatograph equipped with a diode array with an
Agilent LC\MSD SL mass selective detector. The
parameters of the GC-MS (APCI) analysis are as
1
group. The H and 13C NMR spectra of compounds
III, V contain all the relevant signals (Table 2). In the
GC-MS spectra of sulfonamides Va–Vd there are no
molecular ion peaks, but there are peaks of the
fragments [M – SO2]+, which is characteristic of such
systems [10].
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012

SYNTHESIS OF 2-ARYL-4-CYANO-1,3-OXAZOLE-5-SULFONYL CHLORIDES
Table 2. Spectral data of compounds III, V, VI
1857
Mass spectrum,
Comp. no.
IR spectrum (KBr), ν, cm–1
1Н NMR spectrum (DMSO-d6), δ, ppm
m/z
2239 (C≡N)
4.41 s (2Н, CH2S), 7.33–7.96 m (10Н, 2С6Н5)
293 [M + 1]+
IIIа
IIIbа 2241 (C≡N)
2.44 s (3Н, СН3), 4.24 s (2Н, CH2S), 7.25 m (7Н, С6Н5, С6Н2), 307 [M + 1]+
7.85 d (2Н, С6Н2, 3JHH 7.6 Hz)
2232 (C≡N)
4.25 s (2Н, CH2S), 7.30 m (5Н, С6Н5), 7.49 d, 7.90 d (4Н, С6Н4, 327 [M + 1]+
3JHH 7.5 Hz)
IIIc
2241 (C≡N)
3.86 s (3Н, СН3О), 4.38 s (2Н, CH2S), 7.14 d, 7.90 d (4Н, С6Н4, 323 [M + 1]+
IIId
3JHH 7.6 Hz), 7.31 m (5Н, С6Н5)
1163, 1373 (SO2), 2248 (C≡N)
1.76 m (6Н, 3СН2 piperid), 3.64 m (4Н, 2СН2 piperid), 7.44 m, 7.88 253 [M – SO2]+
m (5Н, С6Н5)
Vа
Vbb
Vc
1165, 1374 (SO2), 2249 (C≡N)
1165, 1374 (SO2), 2251 (C≡N)
1164, 1373 (SO2), 2248 (C≡N)
1161, 1372 (SO2), 2249 (C≡N)
1162, 1372 (SO2), 2246 (C≡N)
1160, 1373 (SO2), 2245 (C≡N)
1.64 m (6Н, 3СН2 piperid), 2.44 s (3Н, СН3), 3.66 m (4Н, 267 [M – SO2]+
2СН2 piperid), 7.45 d, 7.96 d (4Н, С6Н4, 3JHH 7.5 Hz)
1.63 m (6Н, 3СН2 piperid), 3.59 m (4Н, 2СН2 piperid), 7.72 d, 8.07 d 287 [M – SO2]+
(4Н, С6Н4, 3JHH 7.4 Hz)
3.41 m (4Н, 2СН2 mоrpholin), 3.89 m (4Н, 2СН2 mоrpholin), 7.47 m, 255 [M – SO2]+
7.89 m (5Н, С6Н5)
2.43 s (3Н, СН3), 3.60 m (4Н, 2СН2 mоrpholin), 3.72 m (4Н, 269 [M – SO2]+
2СН2 mоrpholin), 7.46 d, 7.97 d (4Н, С6Н4, 3JHH 7.8 Hz)
Vd
Ve
3.62m (4Н, 2СН2 mоrpholin), 3.78 (4Н, 2СН2 mоrpholin), 7.50 d, 7.99 289 [M – SO2]+
Vf
d (4Н, С6Н4, 3JHH 7.7 Hz)
3.63 m (4Н, 2СН2 mоrpholin), 3.76 m (4Н, 2СН2 mоrpholin), 3.89 s 354 [M – SO2]+
(3Н, СН3О), 7.97 s (2Н, С6Н2)
Vg
VIа
1657 (С=О), 2217 (C≡N), 3269 (N–Н) 2.38 s (3Н, СН3), 4.16 s (2Н, CH2S), 4.21 s (2Н, CH2S), 7.30 m 431 [M + 1]+
3
(7Н, С6Н5, С6Н2), 7.80 d (2Н, С6Н2, JHH 8.0 Hz), 10.16 s (1Н,
NH)
VIbc
1658 (С=О), 2212 (C≡N), 3241 (N–Н) 4.17 s (2Н, CH2S), 4.22 s (2Н, CH2S), 7.30 m (5Н, С6Н5), 7.62 452 [M + 1]+
d, 7.90 d (4Н, С6Н4, 3JHH 7.8 Hz), 10.35 s (1Н, NH)
13С NMR spectrum, δС, ppm: 21.64 (СН3), 39.91 (SCH2), 112.61 (C4ox), 118.94 (CN), 122.76 (C5ox), 127.01, 128.23, 129.09, 129.43,
a
130.40, 137.13, 142.99, 154.05, 164.15 (C2ox). b 13С NMR spectrum, δС, ppm: 21.74 (СН3), 22.91 (C4piperid), 25.21 (C
), 46.60 (C
),
piperid
3,5
2,6
piperid
111.35 (C4ox), 117.74 (CN), 122.15 (C5ox), 127.87, 130.57, 144.08, 151.33, 164.14 (C2ox). c 13С NMR spectrum, δС, ppm: 21.55 (СН3), 38.22
(SCH2), 111.87 (NCCNH), 115.56 (CN), 128.32, 129.10, 129.40, 129.47, 129.61, 136.91, 137.22, 143.08, 149.49, 165.31 (CO).
follows: Zorbax SB-C18 column, 1.18 µm 4.6×15 mm
(PN 821975-932); acetonitrile–water (95:5), 0.1%
aqueous trifluoroacetic acid; eluent flow 3 ml min–1,
injection volume 1 μm, UV detectors 215, 254, 285
nm; scanning range m/z 80–1000. The melting points
were measured on a Fisher-Johns instrument.
2-Aryl-5-benzylsulfanyl-4-cyano-1,3-oxazoles
(IIIa–IIId). a. To a solution of 0.01 mol of the
appropriate dichloroacrylonitrile Ia–Id in 50 ml of
methanol was added 0.025 mol of sodium hydrogen
sulfide. The mixture was stirred at 20–25°C for 24 h.
Then methanol was removed in a vacuum. To the
Scheme 2.
CN
H
N
Ag2CO3
2BnSH/2Et3N
Ib, Ic
IIIb, IIIc
Ar
SBn
Δ
O
BnS
VIа, VIb
Ar = 4-MeC6H4 (VIа), 4-ClC6H4 (VIb).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012

1858
KORNIENKO et al.
residue 30 ml of water was added. The solution was
acidified with 5% hydrochloric acid to pH ~ 2. The
precipitate was filtered off, dried, and dissolved in 30
ml of methanol. Then 0.01 mol of triethylamine and
0.011 mol of benzyl chloride were added. The mixture
was boiled for 2–3 h and was left to stand at 20–25°C
for 12 h. The solvent was removed in a vacuum. The
residue was treated with water, and the precipitate was
filtered off and recrystallized.
2-Acylamino-3,3-di(benzylsulfanyl)acrylonitriles
(VIa, VIb). To a solution of 0.01 mol of dichloro-
acrylonitrile Ib or Ic in 30 ml of acetonitrile were
added 0.02 mol of benzyl mercaptan and 0.02 mol of
Et3N. The mixture was kept for 12 h at 20–25°C. Then
the precipitate was filtered off, and the solvent was
removed in a vacuum. The residue was treated with
water, dried, and recrystallized.
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b. To a solution of 0.01 mol of compound VIa or
VIb (obtained as described below) in 50 ml of
anhydrous acetonitrile was added 0.025 mol of silver
carbonate. The suspension was refluxed for 8 h and
was left to stand at 20–25°C for 12 h. Then the
precipitate was filtered off, and acetonitrile was
removed in a vacuum. To the residue was added 50 ml
of water, and the precipitate was filtered off. Com-
pounds IIIb, IIIc were recrystallized from ethanol.
Yield 50%. The mixed melting point for two samples
of compounds IIIb and IIIc obtained by the a and b
methods showed no depression. Their IR and 1H NMR
spectra were identical.
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compound III in 30 ml of 95% acetic acid was bubbled
Cl2 under stirring for 0.5 h at 20°C. The mixture was
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compounds IVa–IVc was added 0.0008 mol of
piperidine and 0.0008 mol of Et3N. The mixture was
heated for 2 h and kept at 20–25°C for 12 h. The
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starting from sulfonyl chlorides IVa–IVd and mor-
pholine.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 82 No. 11 2012