Synthesis and Heterocyclization of 3-Arylaminothiocrotonanilides

Article abstract of DOI:10.1023/A:1013902726974

Reactions of acetylthioacetanilide with arylamines in acetic acid in the presence of sodium acetate give 3-arylaminothiocrotonanilides in good yields. When treated with ω-bromoacetophenone in acetone, these products are converted to substituted 4-hydroxy-

Full text of DOI:10.1023/A:1013902726974

Russian Journal of General Chemistry, Vol. 71, No. 11, 2001, pp. 1767 1770. Translated from Zhurnal Obshchei Khimii, Vol. 71, No. 11, 2001,
pp. 1866 1870.
Original Russian Text Copyright
2001 by Borisevich, Samoilenko, Lozinskii, Rusanov, Chernega.
Synthesis and Heterocyclization of 3-Arylaminothiocrotonanilides
A. N. Borisevich, L. S. Samoilenko, M. O. Lozinskii, E. B. Rusanov, and A. N. Chernega
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine
Received June 15, 2000
Abstract Reactions of acetylthioacetanilide with arylamines in acetic acid in the presence of sodium acetate
give 3-arylaminothiocrotonanilides in good yields. When treated with -bromoacetophenone in acetone, these
products are converted to substituted 4-hydroxy- 2-thiazolinium bromides, one of which was dehydrated
to obtain the corresponding thiazolium bromide. The structure of the heterocyclization products was con-
firmed by single crystal X-ray diffraction and NMR study of 2-acetonylidene-3,4-diphenyl-2,3-dihydrothiazole
formed by dehydration of the corresponding 2-thiazolinium salt with simultaneous hydrolysis.
3-Arylaminothiocrotonanilides I containing reactive
enamine and thioamide groups show promise as start-
ing compounds for heterocyclizations. The first re-
presentatives of compounds I were prepared previous-
ly [1]. In this work we developed imroved procedures
for preparing compounds I and studied their cycliza-
tions with -halo carbonyl compounds.
lizable from ethanol and 2-propanol and readily soluble
in acetone and DMSO. The IR spectra of compounds
I show one or two (NH) bands in the range 3250
1
1
3150 cm and (C=C) bands at 1590 1580 cm .
1
The H NMR spectra in DMSO-d6 contain signals
of Me, =CH, NH, and Ar protons (Table 1).
A broadened singlet at 13.0 13.5 ppm is presuma-
bly due to the SH protons in the imidothiol form II
stabilized by intramolecular and intermolecular hydro-
gen bonds (see scheme).
The synthesized anilides I are given in Table 1.
These are yellow crystalline substances well crystal-
I, II, R = p-CH3C6H4 (a), -C10H7 (b), -C10H7 (c), p-CH3OC6H4 (d), p-C2H5OC6H4 (e), p-BrC6H4 (f), p-ClC6H4 (g);
VI, R = R = Ph (a), R = p-CH3C6H4, R = Ph (b); VII, R = Ph; IV, VIII, R = R = Ph.
1070-3632/01/7111-1767$25.00 2001 MAIK Nauka/Interperiodica

1768
BORISEVICH et al.
Table 1. Yields, melting points, elemental anlayses, and 1H NMR spectra of 3-arylaminocrotonanilides Ia Ig
Found, %
H
Calculated, %
H
Comp.
no.
Yield, %
mp,
C
Formula
C
N
C
N
Ia
Ib
Ic
Id
Ie
If
67
94
94
87
93
90
68
159
193 194
140
173 174
143
182 183
170 171
72.47
75.19
75.34
68.26
69.23
54.81
63.05
6.50
5.91
5.84
6.02
6.45
4.17
4.73
9.85
8.70
8.95
9.24
8.55
7.83
9.26
C17H18N2S
72.30
75.43
75.43
68.42
69.22
55.18
63.04
6.42
5.70
5.70
6.07
6.44
4.34
4.96
9.92
8.80
8.80
9.38
8.96
8.04
9.19
C20H18N2S
C20H18N2S
C17H18N2OS
C18H20N2OS
C16H15BrN2S
C16H15ClN2S
Ig
1H NMR spectrum [(CD3)2SO], , ppm
Comp.
no.
Me, s
=CH, s NHAr, s HS C=NAr, s
other signals
Ia
Ib
Ic
Id
Ie
If
2.03, 2.30
1.93
5.53
5.63
5.64
5.46
5.43
5.48
5.56
10.36
10.46
10.44
10.26
10.22
10.50
10.52
13.24
13.54
13.51
13.08
13.06
13.30
13.30
7.11 7.53 m (Ar)
7.10 8.10 m (Ar)
7.12 8.11 m (Ar)
3.70 s (3H, OCH3), 6.80 7.50 m (Ar)
1.21 t (3H, CH3), 4.25 q (2H, CH2), 6.70 7.45 m (Ar)
6.90 7.50 m (Ar)
1.92
1.91
1.92
1.95
Ig
2.08
7.16 7.54 m (Ar)
It is known that structurally related enamino thi-
ones [2] and enamino thioanilides [3] react with
-halo carbonyl compounds to form thiophene deriva-
tives [2, 3] or, under other conditions, substituted
1,4-thazepines [3]. We found that some anilides I in
such reactions can transform, along with heterocyclic
compounds IV and V (pathways a, b), also into
2-thiazolinium and thiazolium derivatives VI and
VIII (pathway c, see scheme).
1
According to the H NMR spectra and elemental
analysis, the heterocyclization of the compounds in
hand is never accompanied by elimination of the
3-R-amino group and formation of thiophenes V
(pathway b, see scheme). As for 1,4-thiazepinium
(IVa) and thiazolium (VIIIa) bromides, they cannot
1
be reliably distinguished by the H NMR spectra and
elemental analysis.
Therefore, we examined the product structure by
single crystal X-ray diffraction. The best crystals
were obtained for compound VII prepared by dehy-
dration of 2-thiazolinium VIa with sulfuric acid
(see scheme).
The general view of the molecule of VII and its
selected geometric parameters are shown in the figure.
The bond lengths and angles in the central thiazoline
ring SC13C14N15C16 have usual values [4 6]. This
ring is almost ideally planar: the deviations of atoms
General view of the 2-acetonylidene-3,4-diphenyl-2,3-di-
hydrothiazole (VII) molecule with numbering of nonhy-
13
drogen atoms. Selected bond lengths, : S C 1.732(3),
from the least-squares plane do not exceed 0.013
.
16
15 14 15 16
C 1.406(3), N C
S C
C
1.733(2), N
1.368(3),
1.400(3),
Because of steric hindrance, the benzene rings C1 6
and C7 12 are turned relative to this plane by 49.0
and 75.4 , respectively. The dihedral angle between
the benzene rings is 68.3 . The C17C18C19O group
is essentially planar (within 0.039 ) and practically
13 14
16 17
17 18
C
1.326(3), C
C
1.376(3), C
C
18
13 16
O C 1.252(3); selected bond angles: C SC 90.3(1) ,
14 15 16
13 14
15 14 13
C
SC
N
C
114.8(2) , SC
109.9(2) .
C
113.9 , N
C
C
111.0(2) ,
16 15
N
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 11 2001

SYNTHESIS AND HETEROCYCLIZATION OF 3-ARYLAMINOTHIOCROTONANILIDES
1769
3
1
coplanar with the thiazoline ring: the dihedral angle
between their planes is as small as 8.1 . The geometry
of the O C18 C17 C16 system suggests strong de-
dcalc 1.276 g cm , 1.853 mm , F(000) 616, space
group P21/c (no. 14). The structure was solved by the
direct method [10] and refined by full-matrix least-
squares [11] in the anisotropic approximation. Refine-
ment was performed using 2124 reflections with
localization of the electron density due to
conjugation.
*
I > 2 (I) {251 refined parameters, 8.46 reflections
per parameter, weight scheme
Thus, we unambiguously found that cyclization of
anilides I with -halo carbonyl compounds follows
pathway c (see scheme), yielding five-membered het-
erocycles: substituted 2-thiazolinium (VI) and thia-
zolium (VIII) derivatives.
4-Hydroxy- 2-thiazolinium derivatives VIa and
VIb were formed in acetone at ambient temperature;
the reaction products precipitated.
= 1/[ (F2o) +
2
(0.0846P)2 + 0.2820P], where P = (Fo2 + 2F2c )/3}.
A correction for abnormal scattering was included;
corrections for absorption were not made. All hydro-
gen atoms were revealed objectively and refined iso-
tropically. The structure was refined to R1(F) 0.042
and RW(F2) 0.111, GOF 1.009. The residual electron
density from the differential Fourier series after the
3
It should be noted that in some cases 4-hydroxy
derivatives of 2-thiazoline could be isolated in the
course of synthesis of thiazoles from thioamides by
the Hansch procedure [7].
last refinement cycle was 0.32 and 0.24 e/
The atomic coordinates are listed in Table 2.
.
Table 2. Atomic coordinates ( 104) and equivalent
isotropic (isotropic for hydrogen atoms) thermal parameters
With the aim of preparing thiazolium derivatives
VIII, we studied dehydration of compounds VI by
heating in some organic solvents and under the action
of sulfuric acid.
2
Ueq
(
103) in the structure of VII
Atom
x
y
z
Ueq
S
6961(1)
8092(2)
3315(3)
3678(4)
2583(5)
1144(4)
771(3)
8052(1)
8372(1)
8366(1)
8523(2)
8488(2)
8304(2)
8143(2)
8176(1)
9140(1)
9885(1)
10273(2)
9921(2)
9180(2)
8788(2)
7982(2)
8347(1)
8717(1)
8632(1)
8976(1)
8850(2)
9284(3)
8612(18)
8642(23)
8261(18)
8005(19)
8059(14)
1105(1)
3651(2)
1511(2)
2801(2)
3886(3)
3713(3)
2445(3)
1350(3)
1191(2)
709(2)
1065(3)
1889(3)
2369(2)
2030(2)
401(2)
398(2)
845(2)
1766(2)
3017(2)
3903(2)
5216(4)
2912(30)
53(1)
60(1)
47(1)
69(1)
85(1)
77(1)
67(1)
53(1)
40(1)
51(1)
62(1)
61(1)
57(1)
48(1)
54(1)
45(1)
42(1)
44(1)
50(1)
53(1)
84(1)
81(9)
Compound VIIIa was prepared in a 55% yield by
briefly heating 2-thiazolinium bromide VIa in alco-
hol in the presence of a catalyst. Refluxing of 2-thia-
zolinium bromide VIb in alcohol or acetone give
intractable mixtures. Dehydration of compounds VI
with sulfuric acid, even according to [8] with cooling,
is accompanied by deamination and formation of
compound VII, which was prepared previously by
an independent procedure [9].
O
C1
C2
C3
C4
C5
C6
1844(3)
3116(2)
2827(3)
1580(3)
648(3)
C7
C98
C10
C11
C12
C13
C14
C15
N16
C17
C
Search for a more convenient dehydrating agent is
a subject of separate study.
948(3)
2193(2)
5830(3)
4528(2)
4411(2)
5634(2)
5814(3)
7102(3)
7279(5)
4704(35)
2991(41)
401(35)
183(41)
1564(28)
EXPERIMENTAL
The IR spectra of I and VI VIII (KBr pellets) were
1
taken on a UR-20 spectrometer. The H NMR spectra
C18
C19
H2
were recorded on an XR-300 spectrometer (300 MHz,
solvent DMSO-d6, internal reference TMS).
H3
4682(42) 115(13)
The product purity was checked by TLC on Silufol
UV-254 plates (eluent hexane chloroform ethyl ace-
tate, 25 : 20 : 5).
H4
4490(33)
2350(34)
531(29)
137(30)
738(30)
83(9)
90(11)
57(7)
72(8)
83(9)
71(8)
75(8)
54(7)
71(8)
54(6)
H5
H6
H98
3401(31) 10088(16)
1396(33) 10784(20)
232(32) 10164(16)
245(31)
2428(26)
6103(28)
5073(27)
8165(52)
7491(58)
6414(55)
X-ray diffraction study of VII was performed with
a 0.21 0.28 0.39-mm single crystal at room tem-
perature on an Enraf Nonius CAD-4 automatic four-
circle diffractometer (CuK radiation, graphite mono-
H10
H11
H12
H13
H17
H19A
H
2085(27)
2919(28)
2330(24)
1147(28)
3242(24)
5270(47) 133(16)
5971(55) 161(20)
5409(44) 138(16)
8914(17)
8286(15)
7695(17)
9328(14)
9522(27)
8995(33)
9559(29)
chromator, scanning rate ratio /2 1.2,
60 ,
sphere segment 0 10, 0
h
k
19, 11 mlax 11).
A total of 2411 reflections were measured, including
2252 unique reflections (averaging R-factor 0.070).
Crystal data: monoclinic, a 8.985(2), b 17.100(3),
H19B
H19C
c 9.992(2)
;
95.83(3) , V 1527.3(5) 3, Z 4,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 11 2001

1770
BORISEVICH et al.
3-Arylaminocrotonanilides Ia Ig. To a stirred
water, and dried in air. Yield 0.35 g (41%); mp 212
213 C (ethanol water, 1 : 1). 1H NMR spectrum
(DMSO-d6), , ppm: 1.83 s (3H, CH3), 5.31 s (1H,
=CH), 6.81 s (1H, =CH), 6.95 7.45 m (10H, Ph).
Found, %: C 73.60; H 5.08; N 4.45; S 10.86.
C18H15NOS. Calculated, %: C 73.68; H 5.15; N 4.77;
S 10.93.
solution of 0.006 mol of arylamine in 4 ml of acetic
acid, we added successively 0.16 g of anhydrous
sodium acetate and 0.005 mol of acetylthioacetanilide.
A precipitate starts to form within 2 3 min. Stirring
was continued for an additional 1 h, and the yellow
precipitate was filtered off, washed on the filter suc-
cessively with 2 ml of acetic acid, 3 ml of water, and
4 ml of isopropyl alcohol, and dried in air. Com-
pounds Ia Ig were recrystallized from 2-propanol.
2-(2-Anilino-1-propen-1-yl)-3,4-diphenylthiazoli-
um bromide VIII. A mixture of 0.002 mol of VII
and catalytic amount of p-toluenesulfonic acid in 4 ml
of absolute methanol was refluxed for 1 h. The solvent
was vacuum-evaporated, and the residue was triturated
with a mixture of 3 ml of 2-propanol and 1 ml of
diethyl ether; the precipitate was filtered off and
washed on the filter with 2 ml of 2-propanol and 3 ml
of diethyl ether. Yield 0.5 g (55%); mp 235 236 C
To prepare anilides If and Ig, the corresponding
halo-substituted anilines were dissolved in acetic acid
on heating to 50 60 C, the above-named agents were
added to the hot solution, the mixture was stirred for
2 h without heating, and the products were isolated
and purified as described above.
(from 2-propanol hexane, 3 : 2). IR spectrum,
,
2-(2-Anilino-1-propen-1-yl)-4-hydroxy-3,4-diphen-
yl- 2-thiazolinium bromide VIa. To a solution of
0.003 mol of 3-anilinocrotonanilide I in 5 ml of
acetone was added 0.003 mol of -bromoacetophen-
one, and the mixture was stirred for 1 h at ambient
temperature. The resulting precipitate was filtered off,
washed with acetone [2 (2.5 3) ml], and dried in air.
Yield 0.96 g (68%); mp 158 159 C. IR spectrum, ,
1
cm : 3120 (=CH), 2920 (Me), 1600 (Ph), 1540 (thia-
1
zole ring). H NMR spectrum (DMSO-d6), , ppm:
2.56 s (3H, CH3), 5.56 s (1H, =CH), 7.06 7.40 m
(15H, 3Ph), 7.72 s (1H, =CH), 10.36 s (1H, NH).
Found, %: C 63.95; H 4.61; Br 17.66; N 6.07.
C24H21BrN2S. Calculated, %: C 64.14; H 4.71; Br
17.75; N 6.23.
1
1
cm : 3200 (NH), 3150 (OH). H NMR spectrum
(DMSO-d6), , ppm: 2.48 s (3H, CH3), 3.98 4.12 q,
AB pattern (2H, CH2, J 12 Hz), 5.19 s (1H, =CH),
7.0 7.69 m (10H, 2Ph), 8.04 s (1H, OH), 11.07 s
(1H, NH). Found, %: C 61.40; H 4.93; N 5.98; S
6.97. C24H23BrN2OS. Calculated, %: C 61.66; H
4.96; N 5.99; S 6.86.
REFERENCES
1. Borisevich, A.N. and Pel’kis, P.S., Zh. Org. Khim.,
1967, vol. 3, no. 7, pp. 1339 1340.
2. Pulst, M. and Greif, D., Z. Chem., 1988, no. 10,
pp. 345 352.
3. Cocco, M.T., Congin, C., and Okmis, V., J. Hetero-
cyclic Chem., 1995, vol. 32, no. 2, pp. 463 466.
4-Hydroxy-3,4-diphenyl-2-(2-p-toluidino-1-pro-
pen-1-yl)- 2-thiazolinium bromide VIb was prepared
similarly. Yield 86.3%; mp 163 165 C. IR spectrum,
4. Shin, W. and Kin, Y.Ch., J. Am. Chem. Soc., 1986,
vol. 108, no. 22, pp. 7078 7082.
1
1
, cm : 3205 (NH), 3180 (OH). H NMR spectrum
(DMSO-d6), , ppm: 2.68 s (3H, CH3), 3.88 4.12 q,
AB pattern (2H, CH2, J 12 Hz), 5.08 s (1H, =CH),
6.78 7.52 m (14H, Ar), 8.00 s (1H, OH), 11.04, 11.36
2 s (1H, NH). Found, %: C 61.10; H 5.25; N 5.51;
S 6.54. C26H27BrN2O2S. Calculated, %: C 61.04;
H 5.32; N 5.47; S 6.26.
5. Dolling, W., Kischkies, K., Stroehl, D., Heine-
mann, F., and Hartung, H., Phosphorus, Sulfur,
Silicon, 1992, vol. 69, no. 2, pp. 267 271.
6. Heinemann, F., Dolling, W., and Hartung, H.,
Acta Crystallogr., Sect. C, 1992, vol. 48, no. 2,
pp. 305 307.
7. Thiazole and Its Derivatives, Metzger, J.V., Ed.,
New York: Wiley, 1976, part 1.
2-Acetonylidene-3,4-diphenyl-2,3-dihydrothi-
azole VII. Concentrated sulfuric acid (0.75 ml) was
added dropwise with stirring and cooling (0 2 C) to
0.64 g of 2-thiazolinium bromide VIa, with simulta-
neous removal of the released gaseous HBr in a vac-
uum. The second portion of sulfuric acid was added
under the same conditions 6 7 min later, and the mix-
ture was stirred for 30 min. The dark red solution was
poured onto ice and filtered after 1 h. The filtrate was
neutralized with 10% aqueous NaOH at cooling with
ice. The precipitate was filtered off, washed with
8. Baganz, H. and Ruger, J., Chem. Ber., 1968, vol. 101,
no. 11, pp. 3872 3882.
9. Borisevich, A.N., Shulezhko, S.A., and Pel’kis, P.S.,
Khim. Geterotsikl. Soedin., 1966, no. 3, pp. 368 371.
10. Sheldrick, G.M., SHELXS 86. Program for the Solu-
tion of Crystal Structures, Gottingen: Univ. of Got-
tingen, 1986.
11. Sheldrick, G.M., SHELXL 93. Program for the Refine-
ment of Crystal Structures, Gottingen: Univ. of Gottin-
gen, 1993.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 71 No. 11 2001