Cyclocondensation of 2,2-dichloroethenylbenzamide and its analogs with amidines and hydrogen sulfide in the presence of bases

Article abstract of DOI:10.1134/S1070363209030268

Available chlorine-containing enamides of the general formula Cl ₂C=CHNHCOR (I) easily react with benzamidine and its derivatives to give 1:1 adducts which under heating with sodium methylate transform to 2-(methoxymethyl)-4,5-diaryl-s-triazines. Reaction of compounds (I) with hydrogen sulfide in the presence of triethylamine yields a mixture of products. Only the corresponding 3,5-bis(acylaminomethyl)-1,2,4-tritiolanes were isolated from the reaction mixture in moderate yield.

Full text of DOI:10.1134/S1070363209030268

ISSN 1070-3632, Russian Journal of General Chemistry, 2009, Vol. 79, No. 3, pp. 500–504. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © B.A. Demidchuk, S.O. Seferov, A.N. Vasilenko, V.S. Brovarets, B.S. Drach, 2009, published in Zhurnal Obshchei Khimii, 2009,
Vol. 79, No. 3, pp. 510–514.
Cyclocondensation of 2,2-Dichloroethenylbenzamide
and Its Analogs with Amidines and Hydrogen Sulfide
in the Presence of Bases
B. A. Demidchuk, S. O. Seferov†, A. N. Vasilenko, V. S. Brovarets, and B. S. Drach
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine,
ul. Murmanskaya 1, Kiev, 02660 Ukraine
e-mail: drach@bpci.kiev.ua
Received July 8, 2008
Abstract―Available chlorine-containing enamides of the general formula Cl2C=CHNHCOR (I) easily react
with benzamidine and its derivatives to give 1:1 adducts which under heating with sodium methylate transform
to 2-(methoxymethyl)-4,5-diaryl-s-triazines. Reaction of compounds (I) with hydrogen sulfide in the presence
of triethylamine yields a mixture of products. Only the corresponding 3,5-bis(acylaminomethyl)-1,2,4-
tritiolanes were isolated from the reaction mixture in moderate yield.
DOI: 10.1134/S1070363209030268
Chlorine-containing enamides I presented in the
scheme are easily formed from the available adducts of
chloral with carboxamides [1, 2]. They were already
used for the preparative synthesis of the derivatives of
1,3-oxazole [3], 1,3-thiazole [4, 5], 1,2,4-thiadiazole
[6] and fused heterocyclic systems [7].
under treating with sodium methylate yield substituted
s-triazines VI but not the oxazole derivatives.
Introduction of two aryl substituents and the
methoxymethyl group in s-triazine ring presents the
undoubtful interest because many known synthetic
procedures for preparing the substituted s-triazines
cannot be used in this case. But chloromethyl analogs
of compounds VI were successfully synthesized by
condensation of enamides ClCH=C(Ts)NHCOR IX
with amidines [12]. It was presumable that reagents
IX might be converted also to compounds VI, but this
approach is much more complicated than the pathway
II→III→VI studied in this work. Absence of these
transformations of the N–H bond in the final products
was confirmed by the IR spectra, and the presence of
the methoxymethyl group in them follows from the 1H
NMR data (Table 1).
In this work two new applications of reagents I for
preparing heterocyclic compounds were found (see
structures II–VIII in the scheme). On the one hand
enamides I were converted to trisubstituted s-triazines
VI, while on the other hand the unknown previously
3,5-bis(acylaminomethyl)-1,2,4-trithiolanes VIII were
obtained. An important role in these transformations is
played evidently by dichloroacetaldehyde N-acyl-
imines II, the prototropic tautomers of reagents I,
which easily react with different nucleophiles [8-10].
Under mild conditions they add various nitrogen-
containing bases including amidines. It was shown
recently that acetamidine when reacted with the
compounds II yields the 1:2 adducts. When heated
with sodium methylate these substances undergo
cyclization to form the new type of 4-functionalyzed
oxazoles [11]. At the same time in this study we have
found that benzamidine and its nearest analogs in the
reaction with compounds II give the 1:1 adducts which
N-Acylimine tautomers II takes up not only various
nitrogen-containing bases, but also S-nucleophiles.
Thiols and thiophenols in the presence of triethylamine
usually give adducts of the general formula Cl2CHCH·
(SR')NHCOR. They were isolated, and their structure
was established reliably in [5, 8].
Analogous adducts are also formed evidently in the
reaction of tautomers II with hydrogen sulfide, but the
intermediates IV could not be isolated because they
quickly transform to other nonidentified compounds.
†
Deceased.
500

CYCLOCONDENSATION OF 2,2-DICHLOROETHENYLBENZAMIDE
H
501
N
N
R
Cl
R
Cl
H
O Cl
O Cl
Ia_Ic
IIa_IIc
NH2
Ar
H2S, Et3N
, Et3N
H2S, Et3N
_
+
NH2
Cl
H
N
H
N
H
N
SH
Cl
R
CHCl2
R
R
Cl
S
O
N
H2N
H
O Cl
O
Ar
IIIa, IIIb , IIId
IVa_IVc
Va_Vc
H2S, Et3N
H2S, Et3N
MeONa, Δ
H
R
N
unidetified products
OMe
N
N
N
V, Et3N
R
SH
O
S
Ar
VIa, VIb, VId
VIIa_VIIc
O
O
S
R
N
H
N
H
R
S
S
VIIIa_VIIIc
I, II, IV, V, VII, VIII: R = Ph (a), 4-MeC6H4 (b), 4-ClC6H4 (c). III, VI: R = Ar = Ph (a), 4-MeC6H4 (b); R = 4-MeC6H4,
Ar = 4-BrC6H4 (d).
Table 1. Spectral data of the compounds synthesized
Comp. no.
IR spectrum, ν, сm–1 (KBr)
1Н NMR spectrum, δ, ppm (DMСО-d6)
5.65 m (1Н, СН), 6.20 d (1Н, СНСl2, 3J 7.2 Hz), 6.71 br.s (2Н, NH2), 7.34–7.92 m (10Н,
2С6Н5), 8.99 d (1Н, NH, 3– 8.7 Hz)
2.34 s (3Н, СН3), 2.35 s (3Н, СН3), 5.62 m (1Н, СН), 6.17 d (1Н, СНСl2, J 7.2 Hz),
6.66 br.s (2Н, NH2), 7.15–7.82 m (8Н, 2С6Н4), 8.91 d (1Н, NH, 3J 8.7 Hz)
1650 (С=О), 3200–3350 (NHac)
IIIа
3
1640 (С=О), 3200–3400 (NHac)
IIIb
IIId
1650 (С=О), 1600 (С=N), 3200– 2.37 с (3Н, СН3), 5.62 m (1Н, СН), 6.18 d (1Н, СНСl2, 3J 7.2 Hz), 6.79 br.s (2Н, NH2),
3400 (NHac)
7.25–7.80 m (8Н, 2С6Н4), 8.93 d (1Н, NH, 3J 9.0 Hz)
3.66 s (3H, OCH3), 4.76 s (2H, CH2), 7.25–8.67 m (10Н, 2С6Н5)
2.45 s (6Н, 2СН3), 3.55 s (3Н, ОСН3), 4.65 s (2Н, СН2), 7.39–8.47 m (8Н, 2C6H4)
VIаа
–
1630–1700, 3050–3500
(bands are absent)
VIb
1630–1700, 3050–3500
(bands are absent)
2.43 s (3Н, СН3), 3.53 s (3Н, ОСН3), 4.69 s (2Н, СН2), 7.43–8.48 m (8Н, 2С6Н4)
VId
3
3
VIIIаb 1640 (C=O), 3250–3380 (NHac)
3.52 m (4H, 2CH2), 5.25 d.d (2H, 2CH, J 5.9, J 8.7 Hz), 7.41–7.87 m (10H, 2С6Н5),
8.80 t (2Н, 2NН, 3J 5.6 Hz)
1640 (С=О), 3250–3420 (NHac)
2.35 s (6H, 2CH3), 3.44 m (4H, 2CH2), 5.28 d.d (2Н, 2СН, 3J 7.1, 3J 8.1 Hz), 7.29–7.77 m
(8H, 2C6H4), 8.84 t (2H, 2NH, 3J 4.6 Hz)
VIIIb
3
3
1640 (С=О), 3300–3390 (NHac)
3.46 m (4Н, 2СН2), 5.28 d.d (2H, 2CH, J 5.9, J 8.1 Hz), 7.57–7.87 m (8H, 2C6H4),
8.98 t (2H, 2NH, 3J 4.7 Hz)
VIIIc
a 1H NMR spectrum of compound VIa was extracted from the spectrum of reaction mixture. b Mass spectrum: m/z 390 [M]+.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 3 2009

502
DEMIDCHUK et al.
Only
the
unknown
previously
3,5-di(acyl-
and VII in the presence of hydrogen sulfide and
triethylamine leads to substituted 1,2,4-trithiolanes
VIII. The possibilty of formation of 1,2,4-trithiolane
ring is doubtless because the reactivity of
dichloromethyl fragment resembles that of the
aldehyde group. It was shown previously [13] that the
latter function can be actually converted to trithiolane
system under the treatment with hydrogen sulfide and
sulfur in the presence of secondary amines.
aminomethyl)-1,2,4-trithiolanes VIII were isolated
from the reaction mixture in 32–41% yield. Their
formation from adducts IV can hardly be imagined. It
is probable that the important role is played by the
intermediates V generated by the substitution of one of
the chlorine atoms in dichloromethyl fragment of
compounds II with the mercapto group. The
subsequent intermolecular condensation of products V
O
S
R
R
Alk2NH
+ H2S + 2S
2 R
_H2O
S
S
H
Intermolecular condensation proceeds also when
compounds II are reacted with hydrogen sulfide as
confirmed by the mass spectral evaluation of
molecular mass of products VIII. At the same time the
presence of two symmetrically located NHCH2CH
correlates with the carbon atom having δC 63.46 ppm
in the HMBC spectrum what unambiguously proves
the structure of the molecule VIIIc. The attributiuon of
the carbon atom signal at δC 63.46 ppm to the
trithiolane fragment agrees with the published data
[14].
1
groups was shown by H NMR spectra (Table 1). The
empirical formula of the substance formed was
confirmed reliably by the elemental analyses data
(Table 2). Besides, COSY, NOESY, HMOC, and
HMBC NMR experiments for compounds VIII
permitted a complete attribution of 1H and 13C spectral
signals. The attribution of signals of protons and
carbon atoms of the 4-ClC6H4C(O) and NHCH2CH
fragments is easy. The triplet at δ 8.97 ppm (CONH)
and the doublet of doublets at δ 5.26 ppm (CH2) in the
COSY spectrum show only one interaction with the
signals at δ 3.50 and δ 3.43 ppm (CH2) what is
confirmed by the sequence of atoms in the NHCH2CH
group. Note that the proton giving signal at δ 5.26 ppm
Consider finally the general stoichiometric equation
presented below. It shows that in the course of com-
plex pathway leading to the compounds VIII not only
nucleophilic substitution of the reactive chlorine atoms
by the sulfur-containing groups, but the redox
reactions also occur because alongside compounds
VIII elemental sulfur is formed.
2II + 4 Et3N + 4 H2S → VIII + 4 Et3NH+ Cl– + S.
Finally note that the application sphere of the
transformations I→VI and I→VIII is probably much
wider than cited in this work.
Table 2. Yields, melting points, and elemental analysis data of the compounds synthesized III–VIII
Yield,
%
mp, °C
Found, %
Cl (Br)
Calculated, %
Cl (Br)
Comp. no.
Formula
(solvent for crystallization)
145–147а (МеОН)
N
N
97
21.17
12.31
11.20
9.43
C16H15Cl2N3O
C18H19Cl2N3O
C17H16BrCl2N3O
C17H15N3O
21.09
12.50
11.54
9.79
IIIа
82
158–159 (МеСN–H2O, 3:1)
155–160 (MeCN)
19.40
19.46
IIIb
IIId
VIа
88
16.04 (18.95)
16.52 (18.62)
b
85
–
–
13.98
13.71
11.10
6.81
–
15.15
13.76
11.35
7.17
80
104–105 (EtOH)
–
(21.49)
–
C19H19N3O
–
(21.58)
–
VIb
82
41c
125–126 (MeOH)
215–216 (MeCOOH)
226–227 (MeCOOH)
C18H16BrN3O
VId
d
C18H18N2O2S3
VIIIа
VIIIb
e
32
–
6.63
C20H22N2O2S3
–
6.69
f
35
235–236 (MeCOOH)
15.98
5.88
C18H16Cl2N2O2S3
15.43
6.10
VIIIc
a
b
c
Corresponds to the reported data [10]. Compound VIa was obtained in a mixture with another compounds as a viscous oil. Yield
according to the procedure a. d Found, %: S 25.12. Calculated, %: S 24.63. e Found, %: S 23.41. Calculated, %: S 22.98. f Found, %: S
20.91. Calculated, %: S 20.94.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 3 2009

CYCLOCONDENSATION OF 2,2-DICHLOROETHENYLBENZAMIDE
503
7.87
7.54
166.04
O
H
H
6
3.43
3.50
5
4
1
H
45.08
Cl
136.94
H
Cl
N
133.39
3
2
63.46
S
129.13
H
N
H
H
129.89
5.26
H
H
S
8.97
S
O
H
Main correlations (shown by arrows) and the attribution of signals (ppm) in the 1H and 13C NMR spectra of compound VIIIc.
Meanwhile, our attempts to involve N-2,2-dichloro-
ethenylacetamide in this reaction failed.
pound IIIa from N-2,2-dichloroethenyl-4-methyl-
benzamide Ib and 4-bromobenzamidine hydrochloride.
EXPERIMENTAL
4,6-Diaryl-2-methoxymethyl-1,3,5-triazines (VIa,
VIb, VId). To a solution of 0.005 mol of one of the
compounds IIIa, IIIb, and IIId in 50 ml of anhydrous
methanol 0.015 mol of sodium methylate in 5 ml of
methanol was added, and the resulting mixture was
refluxed for 4 h. The mixture obtained was cooled,
NaCl precipitate was filtered off, solvent was removed
in a vacuum, and the residue was treated with water.
The crystals formed were filtered off, dried in a
vacuum desiccator over phosphorus pentoxide, and
compounds VIb and VId were purified by
crystallization. For the isolation of compound VIa the
reaction mixture was treated with water and then
extracted with chloroform (3×10 ml), and the extract
was dried over magnesium sulfate. Chloroform was
removed in a vacuum, and compound VIa was isolated
together with the impurities as a viscous oil which was
analyzed without further purification.
IR spectra of compounds were recorded on a
Specord M-80 spectrometer in KBr pellets. 1H and 13C
NMR spectra were taken on a Varian Mercury-400
spectrometer in DMSO-d6 against internal TMS. Mass
spectrum of compound VIIIa was registered on an
Agilent 1100 LC/MSD instrument.
N-(1-Benzoylamino-2,2-dichloroethyl)benzamidine
(IIIa) was obtained as described above [10].
N-(1-p-toluylamino-2,2-dichloroethyl)-4-methyl-
benzamidine (IIIb) was obtained analogously to
compound IIIa from N-2,2-dichloroethenyl-4-methyl-
benzamide Ib and 4-methylbenzamidine hydro-
chloride.
N-(1-p-Toluylamino-2,2-dichloroethyl)-4-bromo-
benzamidine (IIId) was prepared analogously to com-
Table 3. List of correlations in the COSY, NOESY, HMQC, and HMBC spectra of compound VIIIca
1H NMR spectrum, δ, ppm
COSY NOESY
13C NMR spectrum, δ, ppm
1H NMR spectrum,
δ, ppm
HMQC
129.13
129.89
–
HMBC
7.54 (C3H, C5H)
7.87 (C2H, C6H)
8.97 (CONH)
3.50, 3.43 (СH2)
5.26 (CH)
7.87
7.87
129.13 (C3, C5), 133.39 (C1)
128.89 (C2, C6), 136.94 (C4), 166.04 (CO)
166.04 (CO), 45.08 (CH2)
63.46 (CH), 166.04 (CO)
7.54
7.54, 8.97
3.50, 3.43
5.26, 8.97
3.50, 3.43
7.87, 3.50, 3.43, 5.26
5.26, 8.97
45.08
63.46
3.50, 3.43, 8.97
45.08 (CH2), 63.46 (CH)
a Numbering of carbon atoms in the structure VIIIc is shown in the figure.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 79 No. 3 2009

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DEMIDCHUK et al.
the Nitrogen-containing Heterocyclic Compounds on
3,5-Di(acylaminomethyl)-1,2,4-trithiolanes (VIIIa–
the Basis of Amidoalkylating Agents), Kiev: Naukova
Dumka, 1992, p. 66.
3. Vinogradova ,T.K., Turov, V.V., and Drach, B.S., Zh.
Org. Khim., 1990, vol. 26, no. 6, p. 1302.
4. Vinogradova, T.K., Martynyuk, A.P., and Drach, B.S.,
Zh. Org, Khim., 1980, vol. 16, no. 8, p. 1783.
VIIIc). a. A mixture of 0.01 mol of one of the com-
pounds Ia–Ic and 0.02 mol of triethylamine in 20 ml
of diethyl ether was saturated with hydrogen sulfide
for 1 h. The precipitate formed was filtered off,
washed with 10 ml of acetone, then with 10 ml of
water, and dried. Compounds VIIIa–VIIIc were
purified by crystallization.
5. Demidchuk, B.A., Brovarets, V.S., and Drach, B.S., Zh.
Org. Farm. Khim., 2006, vol. 4, no. 1, p. 55.
b. To a solution of 0.01 mol of compound Ia in
20 ml of anhydrous methanol 0.05 mol of sodium
hydrosulfide was added, and the mixture formed was
stirred for 7 days at 20°C. After that 50 ml of water
was added, the precipitate formed was filtered off,
washed with 20 ml of ethanol, and compound VIIIa
was purified by crystallization from acetic acid, yield
33%. The mixed sample of compound VIIIa prepared
according to the procedures a and b gave no
6. Zyabrev, V.S., Popovich, T.K., Kiselev, V.V., Kisi-
lenko, A.A., Kalinin, V.N., Kharchenko, A.V., and
Drach, B.S., Ukr. Khim. Zh., 1995, vol. 61, no. 5, p. 55.
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1
depression of the melting poimt, and their IR and H
NMR spectra were identical.
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