Reaction of 2-acylamino-3,3-dichloroacrylonitriles with 2-aminothiophenol

Article abstract of DOI:10.1134/S1070363210090136

Reactions of 2-acylamino-3,3-dichloroacrylonitriles with 2-aminothiophenol in the presence of triethylamine was shown to lead to 2-aryl-3,3-bis(2- aminophenylsulfanyl)acrylonitrile, which suffered a transformation into 5-amino-4-(benzothiazol-2-yl)oxazole

Full text of DOI:10.1134/S1070363210090136

ISSN 1070-3632, Russian Journal of General Chemistry, 2010, Vol. 80, No. 9, pp. 1795–1799. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © O.V. Shablykin, S.A. Chumachenko, V.S. Brovarets, 2010, published in Zhurnal Obshchei Khimii, 2010, Vol. 80, No. 9, pp. 1476–
1480.
Dedicated to the memory of the teacher,
Professor Boris S. Drach
Reaction of 2-Acylamino-3,3-dichloroacrylonitriles
with 2-Aminothiophenol
O. V. Shablykin, S. A. Chumachenko, 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 October 13, 2009
Abstract―Reactions of 2-acylamino-3,3-dichloroacrylonitriles with 2-aminothiophenol in the presence of
triethylamine was shown to lead to 2-aryl-3,3-bis(2-aminophenylsulfanyl)acrylonitrile, which suffered a
transformation into 5-amino-4-(benzothiazol-2-yl)oxazole derivatives at heating without solvent. The formation
of the same compounds from these reagents proceeded in one step in the presence of N,N-dimethylaniline. The
presence of primary amino groups in the derivatives of 5-aminooxazole was confirmed by acylation and further
transformation, which was used also for indroduction of various biophoric sites in 5 position of the oxazole
ring.
DOI: 10.1134/S1070363210090136
Substitution of chlorine atoms in 2-acylamino-3,3-
dichloroacrylonitriles (I) by nitrogen- and sulfur-
containing nucleophiles is of stable interest, because
such reactions can be used for producing a variety of
functionalized heterocycles [1–5].
faster than the soft S-nucleophile, even in the presence
of a weak base. It is logical to assume that the first
stage of the process leads to the same adduct B
regardless of the nature of base. The intermediate B is
then transformed differently then the used base is weak
or strong (Scheme 3).
We have investigated the reaction of 2-acylamino-
3,3-dichloroacrylonitriles I with 2-aminothiophenol
(II) (Scheme 1). It should be noted that depending on
the used base the difference exists in the nature of
interaction of reagents. Thus, in the case of
triethylamine, the reaction proceeds rapidly and leads
to acyclic products III formed by the replacement of
two labile chlorine atoms in the reagents I with two 2-
aminothiophenol residues. But under the influence of a
weak base, N,N-dimethylaniline, the condensation is
slow and leads to substituted oxazoles V.
There is no doubts in the high lability of the
chlorine atoms in the structure B: firstly, the α-effect
operates, as in many other α-halosulfides, and
secondly, the chlorine atoms are additionally activated
by the acceptor nitrile group. Therefore, in the
presence of a weak base obviously an intramolecular
cyclization occurs with further elimination of hydrogen
chloride, which is advantageous because it facilitates
the formation of aromatic thiazole ring: B → D. On the
other hand, at the action on B of a strong base a rapid
splitting a hydrogen chloride may proceed even in the
early stages of the process. This results in an inert
enamide structure D with the hardly labile chlorine
atom that has been proved experimentally for many
types of the enamidonitriles ArSCCl=C(CN)NHCOR,
which do not interact even with highly basic amines.
Although it seems that all these facts confirm the
possible mechanism of formation of the final products
in the complex process I + II → V, yet it must be
The question arose about the influence of the base
on the mechanism of interaction of the reagents I and
II. At first glance it seems that at the early stages of
the process different intermediates, A and B, can be
generated leading to different final compounds, III and
V, respectively (Scheme 2).
However, it is unlikely that the hard N-nucleophile
interacts with the soft center, the dichlorovinyl group,
1795

1796
SHABLYKIN et al.
Scheme 1.
H
N
Cl
H2N
NS
R
2PhNMe2
2Et3N
H2N
+
Cl
O
CN
Ia−Ic
II
NS
H
N
S
N
H
N
N
R
Δ
R
NH2
S
S
S
N
R
O
CN
NH2
O
C
N
NH2
..
O
IIIa, IIIb (55−57%)
IV
Va−Vc (45−73%)
R1COCl, Et3N
R = Ph
N
N
N
S
S
S
N
PCl5/POCl3
N
O
N
NaSH
Ph
NH
O
Ph
N
Ph
NH
R = 4-MeC6H4
O
O
Cl
S
R1
4-MeC6H4
4-MeC6H4
VIa, VIb (58−64%)
VII
VIII
R2NH2
NaN3
N
N
S
N
S
N
N
Ph
N
N
Ph
N
O
N
O
NHR2
4-MeC6H4
4-MeC6H4
IXa, IXb (59−65%)
X
I, V: R = Me (a), Ph (b), 4-MeC6H4 (c); III: R = Ph (a), 4-MeC6H4 (b); IV: R1 = Me (a), 4-MeC6H4 (b); IX: R2 = H (a), Me (b).
Scheme 2.
I + II
NH2
S
PhNMe2
Et3N
H
N
H
N
NH
R
HS
R
Cl
Cl
CN
O
CN
O
B
V
A
III
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 9 2010

REACTION OF 2-ACYLAMINO-3,3-DICHLOROACRYLONITRILES
1797
Scheme 3.
H
NH2
Cl
S
R
N
Cl
O
CN
C
Et3N
PhNMe2
H
N
Cl
H
N
N
NH2
R
S
R
S
×
O
CN
O
..
C
N
E
D
HS
.
PhNMe2 HCl
Et3N
H2N
V
III
recognized that for the unequivocal evidence further
special studies are needed. Nevertheless, the structure
of new 5-amino-1,3-oxazole derivatives V was reliably
proven using a complex of spectral and chemical
studies. For example, it was found using infrared
spectra that in this cyclocondensation nitrile and
acylamine residues participated (Table 2). A complex
study by the methods of the 1H and 13C NMR
correlation spectroscopy (COSY, NOESY, HMQC and
HMBC) was carried out with one of these compounds
(Va), and characteristic signals in the 13C NMR spectra
and the main correlations confirming the proposed
structure were found (see the figure).
and sodium azide. These reactions are important not
only to prove the structure of the key compounds V,
but are also of considerable preparative interest for the
introduction of various biophoric sites to the 5 position
of the oxazole ring (compounds VIII–X, Scheme 1).
EXPERIMENTAL
IR spectra of the compounds were recorded on a
Vertex 70 spectrometer from the tablets with KBr. The
1H NMR spectra were recorded on a Varian-300
instrument (300 MHz), the NMR spectra of
1
heteronuclear H–13C correlation were obtained on a
Mercury-400 spectrometer (400 and 100 MHz
respectively) from solutions in DMSO-d6 with TMS as
an internal reference. The melting points were
measured on a Fisher–Johns unit.
Products Vb and Vc were synthesized also by
authentic procedure, at heating the compounds IIIa
and IIIb, respectively, at 150°C in a vacuum (20 mm
Hg). In this case, in the first stage the cyclization is
likely to occur to the substituted benzothiazole IV with
liberation of the 2-aminothiophenol molecule, by
analogy with the published data [6]. Then proceeds a
known intramolecular cyclization [7–9] involing the
amide fragment and the nitrile group which leads to
the 5-aminooxazole derivatives V.
7.78
121.29
H
7.39
126.70
H
154.81
162.65
7.23
123.83
H
N
106.70
150.74
7.94
The presence of primary amino groups in
compounds V was evidenced not only by the 1H NMR
spectra, but also by acylation and further reaction of
compound VIb with phosphorus pentachloride, which
led to the expected imidoyl chloride VII. Based on the
last reaction we succeeded to carry out condensations
with sodium hydrogen sulfide, ammonia, methylamine,
H122.41
S
133.19
N
132..8341 CH3
NH2
7.18
O
155.15
Principal correlations (shown by arrows) and assignment of
signals (ppm) in the 1H and 13C NMR spectra of compound Va.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 9 2010

1798
SHABLYKIN et al.
Table 1. Spectral data of synthesized compounds
1HNMR spectrum (DMSO-d6), δ, ppm
IR spectrum (KBr), ν, cm–1
Comp. no.
2210 (C≡N), 3100–3600 (NH as.)
4.89 s (2Н, NH2), 5.39 s (2Н, NH2), 6.32–7.89 m (13Н, С6Н5, 2 С6Н4),
10.18 s (1Н, NН)
IIIа
IIIb
Va
2210 (C≡N), 3100–3600 (NH as.)
2.38 s (3Н, CН3), 5.00 s (2Н, NH2), 5.44 s (2Н, NH2), 6.42–7.80 m (12Н,
3С6Н4), 10.14 s (1Н, NН)
1645 [δ(NH2)], 2100–2300 (no bands), 3150, 2.35 s (3Н, СН3), 7.06 br.s (2H, NH2), 7.19–7.90 m (4H, С6Н4 )
3240 (NH2)
1650 [δ(NH2)], 2100–2300 (no bands), 3160, 7.31–8.02 m (9Н, С6Н5, С6Н4), 7.64 br.s (2H, NH2)
Vb
3250 (NH2)
1650 [δ(NH2)], 2100–2300 (no bands), 3170, 2.37 s (3Н, СН3), 7.27–7.77 m (8Н, 2С6Н4), 7.59 br.s (2H, NH2)
Vc
3255 (NH2)
3100–3600 (NH as.)
3180–3550 (NH as.)
3200–3500 (NH as.)
3100–3500 (NH as.)
2.43 s (3Н, СН3), 7.42–8.20 m (9H, С6Н5, С6Н4 ), 11.82 s (1H, NH)
2.45 s (3Н, СН3), 7.39–8.10 m (13H, С6Н5, 2С6Н4), 11.06 s (1H, NH)
2.41 s (3Н, СН3), 7.39–8.20 m (13H, С6Н5, 2С6Н4), 12.36 s (1H, NH)
VIа
VIb
VIII
IXa
2.42 s (3Н, СН3), 7.39–8.42 m (13H, С6Н5, 2С6Н4), 7.82 br.s (1H, NH),
8.45 br.s (1H, NH)
3200–3400 (NH as.)
2.30 s (3Н, СН3), 3.56 s (3Н, СН3), 7.08–8.11 m (13H, С6Н5, 2С6Н4), 7.82
IXb
X
br.s (1H, NH), 8.83 br.s (1H, NH)
2100–2300, 3000–3500 (no bands)
2.42 s (3Н, СН3), 7.18–8.33 m (13H, С6Н5, 2С6Н4)
Table 2. Yields, melting points, and data of elemental analysis of compounds III, V–X
Found, %
Yield,
Calculated, %
Comp. no.
mp, °С
Formula
%
N
S
N
S
57
55
45
68а
73а
58
64
95
45
65
59
86
167–168
13.12
15.05
C22H18N4OS2
C23H20N4OS2
C11H9N3OS
13.39
12.95
18.17
14.32
13.67
12.53
10.21
9.77
15.32
IIIа
IIIb
Vа
111–112
12.81
18.03
14.09
13.65
12.39
10.09
9.61
14.59
13.71
10.57
10.25
9.63
14.82
13.86
10.93
10.43
9.56
173–174
243–244
C16H11N3OS
C17H13N3OS
C18H13N3O2S
C24H17N3O2S
C24H16ClN3OSb
C24H17N3OS2
C24H18N4OS
C25H20N4OS
C24H16N6OS
Vb
251–252
Vc
175–177
VIa
VIb
VII
VIII
IXа
IXb
X
237–238
7.62
7.79
227–228
7.13
7.46
215 (decomp.)
144–145
9.75
14.92
7.61
9.83
15.00
7.81
13.44
13.03
18.99
13.65
13.20
19.25
230–231
7.58
7.55
170 (decomp.)
7.07
7.35
a By method a. b Found,%: Cl 8.39. Calculated,%: Cl 8.25.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 80 No. 9 2010

REACTION OF 2-ACYLAMINO-3,3-DICHLOROACRYLONITRILES
1799
2-Acylamino-3,3-bis(2-aminophenylsulfanyl)acrylo-
nitrile (IIIa, IIIb). To a mixture of 0.02 mol of 2-
aminothiophenol and 0.025 mol of N,N-dimethyl-
aniline in 20 ml of dimethylformamide was added at
0–10°C a solution of 0.01 mol of compound Ib or Ic in
20 ml of tetrahydrofuran. The mixture was stirred for
12 h at 20–30°C, the solvent was removed in a
vacuum, the residue was treated with 10 ml of aqueous
ethanol (1:1), the precipitate was filtered off, washed
with water, and compounds IIIa, IIIb were purified by
crystallization from ethanol.
obtained was used for further syntheses without
additional purification.
N-[4-(Benzothiazol-2-yl)-2-phenyloxazol-5-yl]-4-
methylthiobenzamide (VIII). To a suspension of
0.01 mol of compound VII in 20 ml of acetonitrile was
added 0.025 mol of sodium hydrogen sulfide, the
mixture was stirred for 3 h, then 20 ml of water was
added, and the precipitate formed was filtered off.
Compound VIII obtained was purified by
crystallization from ethanol.
N-[4-(Benzothiazol-2-yl)-2-phenyloxazol-5-yl]-4-
methylbenzamidine (IXa, IXb). Through a sus-
pension of 0.01 mol of compound VII in 20 ml of
anhydrous ethanol at 20–25°C ammonia or methyl-
amine was passed for 30 min. The solvent was then
removed in a vacuum, the residue was treated with
water, the precipitate formed was filtered off, and
compound IXa or IXb was purified by crystallization
from aqueous ethanol (1:1).
2-Alkyl(aryl)-5-amino-4-(benzothiazol-2-yl)-1,3-
oxazole (Va–Vc). a. To a solution of 0.01 mol of a
compound Ia–Ic in 20 ml of ethanol was added
0.02 mol of 2-aminothiophenol and 0.025 mol of N,N-
dimethylaniline, the mixture was stirred for 2 weeks at
20–30°C, the precipitate was filtered off, washed with
water and cold ethanol, and then compound Va–Vc
formed was purified by crystallization from aceto-
nitrile.
4-(Benzothiazol-2-yl)-5-[5-(4-methylphenyl)tetra-
zol-1-yl]-2-phenyl-1,3-oxazole (X). To a suspension
of 0.01 mole of compound VII in 20 ml of acetonitrile
was added 0.03 mol of sodium azide, the mixture was
stirred at 20–25°C for 48 h, the precipitate formed was
filtered off and washed with water. Compound X was
purified by crystallization from ethanol.
b. 0.01 mol of compound IIIa or IIIb was heated in
a vacuum (20 mm Hg) at 150°C till the evolution of 2-
aminothiophenol ceased. Then the melt was cooled,
ground in ethanol, and filtered. Compounds Vb, Vc
were purified by crystallization from acetonitrile, yield
46–55%. The mixed samples of compounds Vb or Vc
obtained by different methods did not give depression
1
of the melting point; IR and H NMR spectra of the
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methylbenzimidoyl chloride (VII). To a solution of
0.01 mol of phosphorus pentachloride in 10 ml of
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VIb, the mixture was refluxed for 4 h, cooled to 20°C,
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