Cascade synthesis of 2-Amino-5-(4-methoxyphenyl)-4-phenyl-1,3-thiazole by Reaction of 4-Chloro-N-[2,2-dichloro-1-(4-methoxyphenyl)-2-phenylethyl] benzenesulfonamide with Thiourea

Article abstract of DOI:10.1134/S1070428011040178

4-Chloro-N-[2,2-dichloro-1-(4-methoxyphenyl)-2-phenylethyl] benzenesulfonamide reacted with thiourea on heating in DMF in the presence of sodium carbonate to give 5-(4-methoxyphenyl)-4-phenyl-1,3- thiazole-2-amine. A probable reaction scheme includes cyclization of the initial N-dichloroethyl amide to N-sulfonyl-2,3-diaryl-2-chloroaziridine which undergoes isomerization with opening of the three-membered ring to 1-arylsulfonylamino-2-chloro-2-(4- methoxyphenyl)-1-phenylethene. The subsequent heterocyclization in the reaction with thiourea is accompanied by aromatization via elimination of the arenesulfonamide fragment. Pleiades Publishing, Ltd., 2011.

Full text of DOI:10.1134/S1070428011040178

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 4, pp. 572–576. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © G.N. Rozentsveig, V.Yu. Serykh, K.A. Chernyshev, I.B. Rozentsveig, G.G. Levkovskaya, L.B. Krivdin, 2011, published in Zhurnal
Organicheskoi Khimii, 2011, Vol. 47, No. 4, pp. 569–573.
Cascade Synthesis of 2-Amino-5-(4-methoxyphenyl)-
4-phenyl-1,3-thiazole by Reaction of 4-Chloro-N-[2,2-dichloro-
1-(4-methoxyphenyl)-2-phenylethyl]benzenesulfonamide
with Thiourea
G. N. Rozentsveig, V. Yu. Serykh, K. A. Chernyshev, I. B. Rozentsveig,
G. G. Levkovskaya, and L. B. Krivdin
Favorskii Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: gelya2010@irioch.irk.ru
Received April 3, 2010
Abstract—4-Chloro-N-[2,2-dichloro-1-(4-methoxyphenyl)-2-phenylethyl]benzenesulfonamide reacted with
thiourea on heating in DMF in the presence of sodium carbonate to give 5-(4-methoxyphenyl)-4-phenyl-1,3-
thiazole-2-amine. A probable reaction scheme includes cyclization of the initial N-dichloroethyl amide to
N-sulfonyl-2,3-diaryl-2-chloroaziridine which undergoes isomerization with opening of the three-membered
ring to 1-arylsulfonylamino-2-chloro-2-(4-methoxyphenyl)-1-phenylethene. The subsequent heterocyclization in
the reaction with thiourea is accompanied by aromatization via elimination of the arenesulfonamide fragment.
DOI: 10.1134/S1070428011040178
We previously developed convenient methods for
C-amidoalkylation of aromatic, functionally substitut-
ed aromatic, and heteroaromatic compounds with the
use of polychloroacetaldehyde imines as amidoalkylat-
ing agents [1–3]. As a result, a wide series of N-poly-
chloroethylsulfonamides RSO2NHCH(Ar)CCl2X be-
came accessible, and we were able to initiate studies
on their biological activity and chemical reactivity.
Synthetic importance of N-polychloroethylsulfon-
amides is determined by the presence in their mole-
cules of NH group and polyhalomethyl fragment; it
was demonstrated by the preparation on their base of
biologically active N-protected amino acids [4], as
well as by cascade reactions leading to amidines [5],
aminocarbonyl compounds [6], imides [7], macro-
heterocyclic systems [8], and aziridines [9]. In addi-
tion, it was found that reactions of N-(1-aryl-2,2,2-tri-
chloroethyl)arenesulfonamides with thioamides in di-
methylformamide in the presence of inorganic bases
lead to the formation of substituted 1,3-thiazoles [10].
Scheme 1.
SO2C6H4Cl-4
(H2N)2C=S
20 min, 60–70°C
1h, 20°C
N
Cl
Tarring
Ar = 4-MeC6H4
Ph
Cl
C6H4Me-4
DMF
NHSO2C6H4Cl-4
Na2CO3
Cl
Ph
II
Ar
Ph
Cl
(H2N)2C=S
1 h, 100°C
Ia, Ib
N
1h, 25–30°C
Ph
C6H4OMe-4
NHSO2C6H4Cl-4
III
Ar = 4-MeOC6H4
–4-ClC6H4SO2NH2
H2N
C6H4OMe-4
S
IV
Ar = 4-MeC6H4 (a), 4-MeOC6H4 (b).
572

CASCADE SYNTHESIS OF 2-AMINO-5-(4-METHOXYPHENYL)-4-PHENYL-1,3-THIAZOLE
573
Scheme 2.
SO2C6H4Cl-4
Ph
N
DMF, Na2CO3
4-ClC6H4SO2
Cl
Cl
Ib
III
N
Ph
C6H4OMe-4
C6H4OMe-4
A
B
In continuation of our systematic studies on the re-
activity of N-polychloroethyl sulfonamides with a view
to develop approaches to functionalized thiazole
systems, in the present work we examined reactions of
thiourea with N-(1-aryl-2,2-dichloro-2-phenylethyl)-
arenesulfonamides Ia and Ib. The direction of trans-
formation of compounds Ia and Ib in DMF in the
presence of sodium carbonate and thiourea strongly
depends on the nature of the aromatic substituent in
position 1 of the ethyl fragment. Compound Ia having
a p-tolyl substituent did not react with thiourea at room
temperature, but it underwent intramolecular cycliza-
tion with formation of 2-chloro-1-(4-chlorophenylsul-
fonyl)-2-(4-methylphenyl)-3-phenylaziridine (II)
(Scheme 1). Substituted aziridine II failed to react with
such ambident N,S-nucleophile as thiourea at room
temperature, whereas the reaction at elevated tempera-
ture was accompanied by tarring, and we did not
succeed in isolating individual products or character-
izing them by spectral methods.
is analogous to the above transformation of chloroaz-
iridine A, was discussed in detail in [11, 12], and
similar transformations of diarylhaloaziridines were
noted in review [13]. In the present work we found that
heating of a mixture containing compound Ib and thio-
urea in DMF in the presence of sodium carbonate at
100°C resulted in the formation of 5-(4-methoxyphen-
yl)-4-phenyl-1,3-thiazol-2-amine (IV) as final product
(Scheme 1).
Presumably, enamide III generated in situ reacts as
tautomer B with thiourea which acts as sulfur-centered
nucleophile and replaces the chlorine atom to give
intermediate substitution product C1. Intramolecular
heterocyclization of the latter yields thiazolidine D
which undergoes aromatization to produce final
aminothiazole IV via elimination of 4-chlorobenzene-
sulfonamide molecule and tautomerization (Scheme 3).
On the other hand, addition of thiourea as nitrogen-
centered nucleophile at the C=N carbon atom of Schiff
base B cannot be ruled out. Intermediate adduct C2
undergoes intramolecular cyclization to thiazolidine D
with subsequent aromatization (Scheme 4). Analogous
formation of thiazoles from adducts structurally related
to C2 [addition products of thioamides to dichloro-
(phenyl)acetaldehyde imines] was reported in [14].
Enamide III did not react with thiourea at room tem-
perature and was recovered from the reaction mixture.
Unlike compound Ia, sulfonamide Ib having
a p-methoxyphenyl substituent reacted with thiourea
under analogous conditions (at room or slightly elevat-
ed temperature) to produce 4-chloro-N-[2-chloro-2-(4-
methoxyphenyl)-1-phenylethenyl]benzenesulfonamide
(III) which was isolated as individual substance.
Compound III is likely to be formed via cyclization
to aziridine A which is unstable due to electron-donat-
ing effect of the 4-methoxyphenyl substituent. Isomer-
ization of aziridine A involves opening of the three-
membered ring and migration of chlorine to give inter-
mediate Schiff base B. Prototropic transformation of
the latter yields more stable enamide III (Scheme 2).
Chloroaziridine II was synthesized by us previous-
ly [9], and its structure was proved by X-ray analysis.
The spectral parameters and melting point of a sample
of II obtained in the present work were identical to
those given in [9].
The 1H and 13C NMR and IR spectra and elemental
composition of compound III were consistent with the
assumed structure. The configuration of the double
Isomerization of halogen-containing aziridines with
ring opening and migration of the halogen atom, which
Scheme 3.
NH
4-ClC6H4SO2 H2N
N
NH
(H2N)2C=S
–HCl
HN
S
S
III
B
IV
Ph
–4-ClC6H4SO2NH2
Ph
NH
C6H4OMe-4
4-ClC6H4SO2
C6H4OMe-4
C1
D
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

ROZENTSVEIG et al.
574
Scheme 4.
NH
(H2N)2C=S
HN
SH
Cl
III
B
D
IV
–HCl
–4-ClC6H4SO2NH2
Ph
NH
4-ClC6H4SO2
C6H4OMe-4
C2
C=C bond in molecule III was unambiguously deter-
5-(4-methoxyphenyl)-4-phenyl-1,3-thiazol-2-amine
(IV) and 4-(4-methoxyphenyl)-5-phenyl-1,3-thiazol-2-
amine (V). The geometric parameters of isomers IV
and V were optimized at the B3LYP/6-311G** level of
theory, and the shielding constants were calculated in
terms of the GIAO/B3LYP approach using three basis
sets: Kutzelnigg IGLO-III and Pople–Dunning
6-311++G** and aug-cc-pVTZ basis sets extended by
diffuse functions. In addition, the shielding constants
were calculated in terms of the polarizable continuum
model (PCM), taking into account that the correspond-
ing experimental chemical shifts were measured from
solutions in DMSO-d6. The solvent effect was taken
into consideration both at the stage of geometry opti-
mization and at the stage of calculation of shielding
constants. The calculated chemical shifts of C4 and C5
in the thiazole ring of isomers IV and V are given in
table together with the experimental values. It is seen
that the C4 signal of both isomers IV and V should
appear in a weaker field relative to the C5 signal. Thus
the results of calculations confirm the HMBC data, i.e.,
formation of isomer IV. In our calculations, considera-
tion of the solvent effect, as well as extension of basis
sets via inclusion of diffuse functions, did not affect
the accuracy of calculation of chemical shifts to
an appreciable extent (see table), which is quite con-
sistent with our previous data [17].
mined by two-dimensional NMR spectroscopy using
1
HMBC H–13C correlation technique (optimized for
JCH = 10 Hz, which corresponds to coupling through
three bonds). The NH proton in the sulfonamide group
gave a cross peak with C2 in the ethylene fragment
(δC 126.67 ppm). The same carbon atom (C2) displayed
coupling with ortho-protons in the p-methoxyphenyl
group. This pattern could be observed only when the
arylsulfonylamino and p-methoxyphenyl groups are
attached to different carbon atoms. Furthermore, ortho-
protons in the phenyl ring showed a cross peak with C1
in the ethylene fragment (δC 139.94 ppm). According
to the NOESY data, the lack of dipole–dipole interac-
tion between protons in the phenyl and p-methoxy-
phenyl rings indicated trans orientation of these sub-
stituents.
1
As follows from the H and 13C NMR spectra,
thiazole IV is formed as a single isomer. Using HMBC
1H–13C correlation technique we succeeded in assign-
ing signals from carbon atoms in the thiazole ring. The
carbon atom linked to the phenyl group resonated in
a weaker field as compared to that connected to the
p-methoxyphenyl group (δC 144.07 and 119.08 ppm,
respectively). As a rule, thiazole systems are character-
ized by downfield signal of C4 due to stronger de-
shielding effect of the ring nitrogen atom [15, 16].
The structure of thiazole IV was additionally con-
firmed by nonempirical quantum-chemical calculations
of shielding constants for both possible isomers,
To conclude, we have demonstrated that trans-
formations of N-(1-aryl-2,2-dichloro-2-phenylethyl)-
arenesulfonamides are strongly determined by the
Chemical shifts of C4 and C5 (δC, ppm) in the thiazole ring of isomers IV and V, calculated by the GIAO/B3LYP method, and
the corresponding experimental values
Gas phase
DMSO
Comp.
no.
Atom
δC (exptl.)a
IGLO-III 6-311++G** aug-cc-pVTZ
IGLO-III
6-311++G** aug-cc-pVTZ
IV
V
C4
C5
C4
C5
145.78
126.48
146.24
124.35
146.45
125.17
146.91
123.54
145.01
125.12
145.82
123.99
144.06
126.67
144.40
124.95
144.57
124.30
145.16
123.86
143.27
125.27
144.13
124.44
144.07
119.02
–
–
a
Relative to tetramethylsilane (DMSO-d6).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 4 2011

CASCADE SYNTHESIS OF 2-AMINO-5-(4-METHOXYPHENYL)-4-PHENYL-1,3-THIAZOLE
575
nature of aromatic substituent in the N-ethyl fragment.
The reaction of 4-chloro-N-[2,2-dichloro-1-(4-me-
thoxyphenyl)-2-phenylethyl)benzenesulfonamide with
thiourea in DMF in the presence of Na2CO3 gave pre-
viously unknown 5-(4-methoxyphenyl)-4-phenyl-1,3-
thiazol-2-amine.
4-ClC6H4), 9.18 s (1H, NH). 13C NMR spectrum
(DMSO-d6), δC, ppm: 55.15 (Me); 113.67, 129.12,
131.03, 159.03 (OC6H4); 126.67 (=CCl); 127.99,
129.04, 130.13, 131.80 (Ph); 127.76, 128.36, 135.41,
137.40 (ClC6H4); 139.94 (=CNH). Found, %:
C 57.95; H 4.00; Cl 16.48; N 3.34; S 7.51.
C21H17Cl2NO3S. Calculated, %: C 58.07; H 3.95;
Cl 16.33; N 3.22; S 7.38.
EXPERIMENTAL
5-(4-Methoxyphenyl)-4-phenyl-1,3-thiazol-2-
amine (IV). A mixture of 0.94 g (0.002 mol) of com-
pound Ib, 0.76 g (0.01 mol) of thiourea, and 0.85 g
(0.008 mol) of Na2CO3 in 15 ml of anhydrous DMF
was stirred for 5 h at 100°C. The mixture was poured
into 30–40 ml of water, and the precipitate was filtered
off, dried, and washed with 50 ml of 10% aqueous
ammonia. Acidification of the filtrate gave 0.36 g
(95%) of 4-chlorobenzenesulfonamide. Yield of amino-
thiazole IV (insoluble in aqueous ammonia) 0.50 g
(89%), mp 161–162°C. IR spectrum, ν, cm–1: 3366–
3273 (NH); 1676 (C=N); 1537, 1503 (C=Carom).
1H NMR spectrum (CDCl3), δ, ppm: 3.74 s (3H, Me),
6.86 and 7.13 (4H, AA′BB′ system, 4-MeOC6H4),
7.06 s (2H, NH2), 7.24 m and 7.49 m (5H, Ph).
13C NMR spectrum (CDCl3), δC, ppm: 55.09 (MeO);
114.19, 119.08, 130.37, 158.38 (C6H4); 119.08 (C5);
127.05, 127.99, 128.31, 135.50 (Ph); 144.07 (C4);
165.62 (C2). Found, %: C 67.99; H 5.01; N 9.95;
S 11.38. C16H14N2OS. Calculated, %: C 68.06; H 5.00;
N 9.92; S 11.35.
1
The H and 13C NMR spectra were recorded on
a Bruker DPX-400 spectrometer at 400.61 and
100.13 MHz, respectively, using tetramethylsilane as
internal reference. The IR spectra were obtained in
KBr on a Bruker IFS-25 instrument. Quantum-chem-
ical calculations were performed with the aid of
GAUSSIAN03 software package [18]. Initial sulfon-
amides Ia and Ib were synthesized according to the
procedures described in [3, 19].
Transformations of 4-chloro-N-[2,2-dichloro-
1-(4-methylphenyl)-2-phenylethyl]benzenesulfon-
amide (Ia). a. A mixture of 2.27 g (0.005 mol) of
compound Ia, 2.12 g (0.02 mol) of Na2CO3, 0.38 g
(0.005 mol) of thiourea, and 10 ml of DMF was stirred
for 24 h at room temperature. The mixture was diluted
with 70 ml of water, and the precipitate was filtered
off, dried, and recrystallized from hexane. Yield of
chloroaziridine II 0.48 g (25%), mp 121–123°C; pub-
lished data [9]: mp 121–123°C. The spectral param-
eters of the product coincided with those given in [9].
b. A mixture of 2.27 g (0.005 mol) of compound Ia,
2.12 g (0.02 mol) of Na2CO3, 0.38 g (0.005 mol) of
thiourea, and 10 ml of DMF was stirred for 20 min at
70°C. After dilution with water, a tarry material sepa-
rated. It was insoluble in water, and we failed to isolate
individual substances therefrom.
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