Reaction of 2-(4-arylthiazol-2-yl)-4-chloro-3-oxobutyronitriles with secondary aliphatic amines

Article abstract of DOI:10.1023/A:1012747903598

We have obtained 2-(4-arylthiazol-2-yl)-4-chloro-3-oxobutyronitriles by acylation of 4-aryl-2-cyanomethylthiazoles with α-chloroacetyl chloride. We have studied their reaction with secondary aliphatic amines, leading to formation of 4-dialkylamino-2-(4-arylthiazol-2-yl)-3-oxobutyronitriles, and also intramolecular alkylation with formation of 3-aryl-7-cyano-6(5H)-oxopyrrolo[2,1-b]thiazoles. We have determined some aspects of the tautomerism of the synthesized compounds.

Full text of DOI:10.1023/A:1012747903598

Chemistry of Heterocyclic Compounds, Vol. 37, No. 8, 2001
REACTION OF 2-(4-ARYLTHIAZOL-2-YL)-
4-CHLORO-3-OXOBUTYRONITRILES
WITH SECONDARY ALIPHATIC AMINES
Yu. M. Volovenko, T. A. Volovnenko, and A. V. Tverdokhlebov
We have obtained 2-(4-arylthiazol-2-yl)-4-chloro-3-oxobutyronitriles by acylation of 4-aryl-2-
cyanomethylthiazoles with α-chloroacetyl chloride. We have studied their reaction with secondary
aliphatic amines, leading to formation of 4-dialkylamino-2-(4-arylthiazol-2-yl)-3-oxobutyronitriles, and
also intramolecular alkylation with formation of 3-aryl-7-cyano-6(5H)-oxopyrrolo[2,1-b]thiazoles. We
have determined some aspects of the tautomerism of the synthesized compounds.
Keywords: 4-aryl-2-cyanomethylthiazoles, α-chloroacetyl chloride, 2-(4-arylthiazol-2-yl)-4-chloro-3-
oxobutyronitriles, 3-aryl-7-cyano-6(5H)-oxopyrrolo[2,1-b]thiazoles, 4-dialkylamino-2-(4-arylthiazol-2-
yl)-3-oxobutyronitriles.
Earlier we developed a convenient method for synthesis of 2-(2-azahetaryl)-4-chloro-3-oxobutyronitriles
1a-e from the corresponding 2-cyanomethylazaheterocycles [1-3] and showed that the chlorine atom in
compounds 1a-e is easily substituted by various nitrogen-containing nucleophiles, with the possibility of
subsequent heterocyclization [2-6]. However, there have been practically no studies of substitution of the
chlorine in the chloro derivatives 1 by secondary aliphatic amines [3]. When compounds 1 are reacted with
highly basic dialkylamines, the reaction proceeds ambiguously: along with formation of the substitution
products, there is intramolecular alkylation at the nitrogen atom of the heterocyclic substituent with cleavage of
HCl and synthesis of 2(1H)-oxo-3-cyanopyrrolo[1,2-a]azaheterocycles 2. The latter are the only products
obtained when halonitriles 1 are heated in high-boiling solvents [7] or when they are treated with bases (Et3N,
K2CO3) [2].
O
Cl
Het
CN
N
CN
1a–e
2
O
Me
N
N
;
c–e
a Het =
; b
X
N
S
c X = S, d X = NH, e X =NMe
__________________________________________________________________________________________
Taras Shevchenko Kiev National University, Kiev 252601, Ukraine; e-mail: atver@mail.univ.kiev.ua.
Translated from Khimiya Geterotsiklichesikh Soedinenii, No. 8, pp. 1101-1111, August, 2001. Original article
submitted January 6, 2000.
0009-3122/01/3708-1011$25.00©2001 Plenum Publishing Corporation
1011

Thus nucleophilic substitution of the chlorine atom in compounds 1a-e by a dialkylamino group is
associated with certain difficulties due to the action of the amine as a base in intramolecular alkylation.
4-Amino-3-oxobutyronitriles are of interest from a pharmacological point of view [8, 9].
2-Ethoxycarbonyl- [10-13], 2-iminoyl- [14], and 2-aryl-substituted [15, 16] 4-amino-3-oxobutyronitriles have
been known for a long time, and so has their biological activity. It is specifically the presence of such biological
activity that has stimulated synthesis of novel derivatives of such compounds [17-19], mainly as a result of
variation in the amine moiety of the molecule. At the same time, 2-hetaryl-substituted 4-dialkylamino-3-
oxobutyronitriles have been unknown so far. In this connection, it seems important to develop a method for
obtaining 2-(2-azahetaryl)-4-dialkylamino-3-oxobutyronitriles by nucleophilic substitution of the halogen in
compounds 1. The need to exclude undesirable intramolecular alkylation imposes the following requirements on
the properties of the heterocyclic substituent: the basicity of its nitrogen atom should be as low as possible
and/or the nitrogen atom should be sterically hindered. Considering this, as the starting halonitriles we chose
2-(4-arylthiazol-2-yl)-3-oxo-4-chlorobutyronitriles 3-5, since they satisfy the indicated requirements, and the
4-aryl-2-cyanomethylthiazoles 6-8 required to synthesize them are readily available [20-22].
Halonitriles 3-5 were synthesized by C-acylation of cyanomethylthiazoles 6-8 by α-chloroacetyl
chloride. The reaction was carried out in dioxane using pyridine as the base; the yields of compounds 3-5 were
60% to 90%. Their structure was confirmed by analytical and spectral data (Tables 1 and 2). According to the
latter, halonitriles 3-5 exist in the NH tautomeric form with an intramolecular hydrogen bond. Thus in their IR
spectra, we see an intense band for stretching vibrations of the conjugated nitrile group in the 2180-2195 cm-1
region. A medium intensity band for the stretching vibrations of the NH bond is observed in the 3130-3150 cm-1
1
region. In the H NMR spectra of compounds 3-5, recorded in DMSO-d6, we observe a two-proton singlet for
the methylene group in the 4.50-4.45 ppm region and a one-proton singlet at 7.61-7.58 ppm, corresponding to
the proton in the 5 position of the thiazole ring. Since the chelate proton on the nitrogen atom is deshielded by
the carbonyl group and the heterocyclic ring, its signal is observed downfield at 13.50-12.90 ppm, as a
broadened one-proton singlet that disappears when D2O is added. The protons of the substituent R resonate in
the characteristic regions.
When we treated halonitriles 3-5 with a two-fold excess of secondary aliphatic amine in dioxane, we
obtained 2-(4-arylthiazol-2-yl)-4-dialkylamino-3-oxobutyronitriles 9e-g,i,j,l-o,u, 10a-c,f,h-p,t-w, 11a-e,g,j-
m,o-u,w in 60% to 80% yields. In this case, we did not observe formation of the products of intramolecular
alkylation of 12, 13 (Scheme 1).
In contrast to the starting halonitriles 3-5, for the aminonitriles 9-11, along with the CH tautomer A, the
existence of two more tautomeric forms with an intramolecular hydrogen bond is possible: B and C. As in the
1
preceding case, in neither the IR spectra nor the H NMR spectra do we observe signals from tautomeric form
A, which allows us to eliminate its existence both in the liquid and solid phases. In the IR spectra of
aminonitriles 9-11, there is an intense band for the stretching vibrations of the conjugated nitrile group in the
2180-2200 cm-1 region and a medium intensity band for the stretching vibrations of the NH group in the
3140-3160 cm-1 region. Such data correspond to both form B and form C, so it is not possible to draw a
conclusion based on these data concerning the ratio of tautomers B and C in the solid phase.
The 1H NMR spectra allow us to assume that in DMSO-d6, aminonitriles 9-11 exist in tautomeric form
1
C. Thus the signal of the exchanging proton is observed in the H NMR spectra of compounds 9-11 as a
broadened one-proton singlet in the 9.80-9.08 ppm region, which is 3.5-4.0 ppm lower than in the starting
chloronitriles 3-5. On going from compounds 3-5 to tautomeric form B of aminonitriles 9-11, the structural
fragment of the six-membered chelate ring is retained, and substitution of the chlorine by an amino group cannot
be the reason for such a significant diamagnetic shift. If we consider the tautomeric form C, then the nature of
the diamagnetic shift becomes quite easily explainable. Thus formation of an intramolecular hydrogen bond
with participation of the nitrogen atom of the dialkylamino group fixes the exocyclic orientation of the carbonyl
group, as a result of which the chelate proton no longer is found within the zone of its deshielding effect.
1012

Scheme 1
O
R
Cl
CH2Cl
N
CH2CN
CH2Cl
PyH
S
6–8
R
H
R
O
O
N
N
CH2Cl
S
S
3–5
CN
CN
Et3N
HNR'R''
H
R
R
O
R
O
N
NR'R''
NR'R''
O
N
N
S
S
S
CN
CN
CN
A
12, 13
B
R''
R'
3, 6, 9 R = Ph
H
4, 7, 10, 12 R = 4-ClC6H4
5, 8, 11, 13 R = 4-BrC6H4
N
R
N
O
S
CN
C
9 e–g, i,j, l–o, u;
10 a–c, f, h–p, t–w
11 a–e, g, j–m, o–u, w
;
; e
; c
N
O
N
N
; d
PhCH2
N
R"R'N a n-Pr2N; b
g n-BuNMe; h (Me CH–CH –CH ) N; i (n-C H ) N; j (n-C H ) N;
;
f
PhCH2
N
N
2
2
2 2
6
13 2
4
9 2
O
;
N
;
N
; m
N
2-MeOC6H4
2-EtOC6H4
2-FC6H4
N
N
l
k
H2N
p
N ;
;
N
o
;
N
Ph2CH
N
N
n
q
EtO2C
;
s
;
Ph
N
;
r
t
N ;
Et
N
N
Me
N
N
N
Me
;
w
N
u cyclo-C6H11NMe ;
v
N
Me
Et
1013

TABLE 1. Characteristics of Synthesized Compounds
Found, %
——————
Com-
pound
Empirical
formula
mp, °С
Yield, %
Calculated, %
N
3
S
4
Cl
5
1
3
2
6
7
C13H9ClN2OS
C13H8Cl2N2OS
C13H8BrClN2OS
C25H25N3OS
10.05
10.12
11.64
11.59
12.93
12.81
173
211
196
286
276
218
155
221
230
270
238
195
236
216
291
284
231
233
209
223
204
241
269
250
210
219
241
>300
173
240
66
73
92
74
70
62
64
75
64
71
79
68
71
60
74
69
59
77
70
68
62
74
71
78
70
64
75
71
73
69
8.93
10.28
22.84
4
9.00
10.30
22.79
7.89
7.88
9.00
9.02
5
10.05
7.78
9e
10.11
7.72
C24H24N4OS
13.51
13.45
7.69
7.70
9f
C18H21N3OS
12.84
9.82
9g
12.83
9.79
C25H35N3OS
9.88
9.87
7.59
7.53
9i
C21H27N3OS
11.30
8.63
9j
11.37
8.68
C24H24N4O2S
C19H20N4O2S
C23H21FN4OS
C21H23N3O3S
C20H23N3OS
12.91
12.95
7.46
7.41
9l
15.18
8.74
9m
9n
15.21
8.70
13.33
13.32
7.66
7.62
10.60
8.11
9o
10.57
8.07
11.82
11.89
9.10
9.07
9u
C19H22ClN3OS
C18H18ClN3OS
C17H16ClN3OS
C24H23ClN4OS
C23H30ClN3OS
C25H34ClN3OS
C21H26ClN3OS
C25H25ClN4O2S
C24H23ClN4O2S
C19H19ClN4O2S
C23H20ClFN4OS
C21H22ClN3O3S
C30H27ClN4OS
C23H21ClN4OS
C20H22ClN3OS
C20H22ClN3OS
C20H22ClN3OS
11.12
8.61
9.40
9.43
10a
10b
10c
10f
10h
10i
10j
10k
10l
10m
10n
10o
10p
10t
10u
10v
10w
11.18
8.53
11.74
11.68
8.87
8.91
9.87
9.85
12.11
9.33
10.21
10.25
12.15
9.27
12.48
12.42
7.08
7.11
7,91
7.86
9.80
7.49
8.22
8.21
9.73
7.42
9.12
9.13
6.92
6.97
7.74
7.71
10.42
7.99
7.80
7.78
10.40
7.94
11.69
11.65
6.62
6.67
7.33
7.37
11.94
6.84
7.62
7.59
12.00
6.87
14.01
13.91
8.01
7.96
8.82
8.80
12.29
7.11
7.74
7.79
12.31
7.05
9.79
9.73
7.42
7.39
8.18
8.21
10.61
6.01
6.76
6.73
10.63
6.08
12.86
12.82
7.29
7.34
8.09
8.11
10.86
8.24
9.19
9.14
10.83
8.27
10.75
10.83
8.26
8.27
9.09
9.14
10.88
8.21
9.13
9.14
10.83
8.27
1014

TABLE 1 (continued)
1
11a
11b
11c
11d
11e
11g
11j
2
3
4
5
6
7
C19H22BrN3OS
C18H18BrN3OS
C17H16BrN3OS
C17H16BrN3O2S
C25H24BrN3OS
C18H20BrN3OS
C21H26BrN3OS
C25H25BrN4O2S
C24H23BrN4O2S
C19H19BrN4O2S
C21H22BrN3O3S
C30H27BrN4OS
C22H18BrN3OS
C19H21BrN4OS
C18H19BrN4OS
C23H21BrN4OS
C20H22BrN3OS
C20H22BrN3OS
9.98
7.62
7.63
18.97
19.01
213
302
271
245
281
234
213
221
252
269
212
244
275
263
278
276
>300
238
75
74
78
79
71
77
77
75
74
74
76
70
71
75
64
70
70
76
10.00
10.41
7.96
19.81
10.39
7.93
19.76
10.74
10.77
8.21
8.22
20.45
20.47
10.39
7.93
19.68
10.34
7.89
19.67
8.48
8.50
6.51
6.48
16.14
16.16
10.32
7.84
19.65
10.34
7.89
19.66
9.35
9.37
7.12
7.15
17.85
17.82
10.65
6.13
15.18
11k
11l
10.66
6.10
15.21
11.01
10.95
6.21
6.27
15.59
15.62
12.58
7.18
17.89
11m
11o
11p
11q
11r
11s
11t
12.52
7.17
17.86
8.79
8.82
6.74
6.73
16.74
16.77
9.76
5.59
14.02
9.80
5.61
13.98
9.32
9.29
7.11
7.09
17.59
17.66
13.00
7.45
18.40
12.93
7.40
18.44
13.29
13.36
7.68
7.65
19.09
19.05
11.61
6.69
16.62
11.64
6.66
16.60
9.70
9.72
7.41
7.42
18.40
18.48
11u
11w
9.79
7.40
18.49
9.72
7.42
18.48
Formation of a hydrogen bond as a result of the lone electron pair of the nitrogen atom of the
dialkylamino group slightly reduces the electron density there, which should lead to some increase in its
negative inductive effect and consequently to an additional paramagnetic shift of the signals of the α-protons of
the substituents R' and R''. In fact, the hydrogen atoms of the substituents R' and R'' in compounds 9-11
α
resonate 0.20-0.55 ppm downfield from the same atoms in the starting amines HNR'R'', which supports the
1
hypothesis that tautomeric form C predominates in solution. In this respect, the H NMR spectra of
2-(4-arylthiazol-2-yl)-4-(4-benzylpiperazino)-3-oxobutyronitriles 9f, 10f are most informative. In tautomeric
form B of compounds 9f, 10f, the piperazine ring is symmetric, the alkyl substituents are attached to both its
nitrogen atoms and they have similar electronic properties; consequently, the magnetic environments for the
protons in the 2 (6) and 3 (5) positions of the piperazine ring differ insignificantly, which allows us to expect
similar chemical shifts for them. In contrast, in tautomer C of aminonitriles 9f, 10f, the properties of the
nitrogen atoms of the piperazine moiety are different, since one of them is involved in formation of a hydrogen
bond. Consequently, the magnetic environments of those protons are different, and they should resonate at
1
different values. In practice, in the H NMR spectra of compounds 9f, 10f the signals from protons of the
δ
piperazine ring are observed as two four-proton spin-coupled triplets at 3.33 ppm and 2.78 ppm. The 0.55 ppm
difference is clear evidence in favor of tautomeric form C. An analogous nonequivalence of the protons of the
1
piperazine ring also is apparent in the H NMR spectra of 2-(4-arylthiazol-2-yl)-4-(4-alkylpiperazino)-3-
oxobutyronitriles 11p,r,s.
1015

TABLE 2. 1H NMR Spectra of Synthesized Compounds
Com-
δ, ppm, spin-spin coupling constants, J (Hz)
pound
1
2
13.05 (1Н, s, NH); 7.78 (2Н, dd, J = 7.0, J = 2.0, 2'- and 6'-HR);
7.58-7.47 (4H, m, 3'-, 4'-, 5'-HR + S–CH=); 4.50 (2H, s, СН2)
3
4
12.95 (1H, s, NH); 7.83 (2Н, d, J = 8.5, 2'- and 6'-HR);
7.60+7.55 (3H, s+d, J = 8.5, S–CH= + 3'- and 5'-HR); 4.47 (2H, s, СН2)
13.42 (1H, s, NH); 7.71 (4Н, distorted s, HR); 7.61 (1H, s, S–CH=); 4.49 (2H, s, СН2)
5
9.48 (1Н, br. s, NH); 7.92 (2Н, dd, J = 8.0, J = 2.0, 2'- and 6'-HR); 7.49-7.18 (9H, m,
S–CH= + 3'-, 4'-, 5'-HR + HPh); 4.14 (2H, s, C(O)СН2N); 3.40 (2H, m, N(CH2);
3.10 (2H, m, NCH2); 2.31 (2H, d, J = 6.0, CH2Ph); 1.74 (5H, m, –CH(CH2)2)
9e
9.18 (1Н, br. s, NH); 7.93 (2Н, dd, J = 7.5, J = 1.5, 2'- and 6'-HR);
9f
7.34 (9H, m, S–CH= +3'-, 4'-, 5'-HR + HPh); 4.19 (2H, s, C(O)СН2N);
3.67 (2H, s, NCH2Ph); 3.33 (4H, t, J = 5.0, N(CH2)2); 2.78 (4H, t, J = 5.0, N(CH2)2)
9.30 (1H, br. s, NH); 7.92 (2Н, dd, J = 8.0, J = 2.0, 2'- and 6'-HR);
7.37 (4H, m, S–CH= + 3'-, 4'-, 5'-HR); 4.16 (2H, s, C(O)СН2N);
3.09 (2H, t, J = 7.0, NCH2); 2.80 (3H, s, NCH3); 1.65 (2H, m, NCH2CH2);
1.31 (2H, m, CH2CH3); 0.90 (3H, t, J = 9.0, CH2CH3)
9.10 (1H, br. s, NH); 7.92 (2Н, dd, J = 8.0, J = 1.5, 2'- and 6'-HR);
7.47+7.37 (4H, s+m, S–CH= + 3'-, 4'-, 5'-HR); 4.14 (2H, s, C(O)СН2N);
3.09 (4H, distorted t, J = 5.0, N(CH2)2); 1.62 (4H, m, N(CH2CH2)2);
1.25 (12H, br. distorted s, 2(CH2)3–CH3); 0.86 (6H, t, J = 6.0, 2CH3)
9g
9i
9.13 (1H, br. s, NH); 7.91 (2Н, dd, J = 8.0, J = 1.5, 2'- and 6'-HR); 7.47+7.37 (4H,
s+m, S–CH= + 3'-, 4'-, 5'-HR); 4.16 (2H, s, C(O)СН2N); 3.12 (4H, t, J = 7.5, NCH2);
1.64 (4H, m, N(CH2CH2)2); 1.29 (4H, m, 2CH2CH3); 0.90 (6H, t, J = 7.0, 2CH3)
9.33 (1Н, br. s, NH); 7.93 (2Н, dd, J = 8.0, J = 1.5, 2'- and 6'-HR); 7.44 (4H, m,
S–CH= + 3'-, 4'-, 5'-HR); 6.99 (4H, m, Hо-phenylene); 4.32 (2H, s, C(O)СН2N);
3.80 (3H, s, OCH3); 3.45 (4H, distorted t, N(CH2)2); 3.32 (4H, distorted t, N(CH2)2)
9j
9l
9.35 (1H, br. s, NH···O); 7.92 (2Н, dd, J = 8.0, J = 1.5, 2'- and 6'-HR);
7.50-7.26 (5H, m, S–CH= + 3'-, 4'-, 5'-HR + NHamide); 6.91 (1H, br. s, NHamide);
4.17 (2H, s, C(O)СН2N); 3.48 (2H, m, NCH2); 3.14 (2H, m, NCH2);
2.32 (1H, m, >CH–CO); 1.92 (4H, m, СН2)2СН–)
9.15 (1Н, br. s, NH); 7.93 (2Н, dd, J = 7.5, J = 1.5, 2'- and 6'-HR); 7.50–7.05 (8H, m,
S–CH= + 3'-, 4'-, 5'-HR + Hо-phenylene); 4.32 (2H, s, C(O)СН2N);
3.42 (8Н, two distorted t, 2N(CH2)2)
9m
9n
9o
9.41 (1Н, br. s, NH); 7.93 (2Н, dd, J = 8.0, J = 1.5, 2'- and 6'-HR); 7.39 (4H, m,
S–CH= + 3'-, 4'-, 5'-HR); 4.25 + 4.14 (4H, s+q, J = 8.5, C(O)СН2N + OCH2);
3.64-3.02 (5H, m, –CH2–N–CH2–CH–CO); 1.92 (4H, m, >CHCH2CH2);
1.22 (3H, t, J = 8.5, CH3)
9.20 (1Н, br. s, NH); 7.92 (2Н, dd, J1 = 7.5, J2 = 1.5, 2'-, 6'-HR); 7.45+7.33 (4Н, s+m,
S–CH= + 3'-,5'-,4'-HR); 4.10 (2H, s, C(O)СН2N); 3.15 (1H, m, N–CH<);
2.75 (3H, s, NCH3); 2.00-1.28 (10H, m, (СН2)5)
9u
9.13 (1H, br. s, NH); 7.94 (2H, d, J = 8.5, 2'- and 6'-HR); 7.52+7.45 (3H, s+d, J = 8.5,
S–CH= + 3'- and 5'-HR); 4.15 (2H, s, C(O)СН2N); 3.09 (4H, t, J = 9.5, N(CH2)2);
1.66 (4H, m, 2CH2CH3); 0.90 (6H, t, J = 8.5, 2CH3)
9.27 (1H, br. s, NH); 7.94 (2H, d, J = 8.5, 2'- and 6'-HR); 7.45 (3H, s+d, J = 8.5,
S–CH= + 3'- and 5'-HR); 4.14 (2H, s, C(O)СН2N); 3.10 (~4H, distorted t, N(CH2)2);
1.76 (6H, m, (CH2)3)
10a
10b
10c
10f
10h
10i
9.73 (1H, br. s, NH); 7.94 (2H, d, J = 8.5, 2'- and 6'-HR); 7.50+7.44 (3H, s+d, J = 8.5,
S–CH= + 3'- and 5'-HR); 4.29 (2H, s, C(O)СН2N); 3.33 (4H, t, J = 5.0, N(CH2)2);
1.95 (4H, t, J = 5.0, (CH2)2)
9.20 (1Н, br. s, NH); 7.94 (2H, d, J = 8.5, 2'- and 6'-HR); 7.50+7.45+7.35 (8H, s+d
(J = 8.5)+s, S–CH= + 3'- and 5'-HR + HPh); 4.20 (2H, s, C(O)СН2N);
3.65 (2H, s, NCH2Ph); 3.32 (4H, t, J = 5.0, N(CH2)2); 2.78 (4H, t, J = 5.0, N(CH2)2)
9.10 (1H, br. s, NH); 7.95 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.53+7.45 (3H, s+d, J = 8.5,
S–CH= + 3'- and 5'-HR); 4.14 (2H, s, C(O)СН2N); 3.13 (4H, distorted t, J = 5.0,
N(CH2)2); 1.56 (6H, m, 2CH2–CH<); 0.89 (12H, d, J = 6.0, 4CH3)
9.08 (1H, br. s, NH); 7.93 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.50+7.44 (3H, s+d, J = 8.5,
S–CH= + 3'- and 5'-HR); 4.15 (2H, s, C(O)СН2N); 3.10 (4H, distorted t, J = 7.0,
N(CH2)2); 1.61 (4H, m, N(CH2CH2)2); 1.27 (12H, br. distorted s, 2(CH2)3–CH3);
0.86 (6H, t, J = 6.0, 2CH3)
1016

TABLE 2 (continued)
1
2
9.08 (1H, br. s, NH); 7.94 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.52+7.45 (3H, s+d, J = 8.5,
S–CH= + 3'- and 5'-HR); 4.15 (2H, s, C(O)СН2N); 3.11 (4H, t, J = 7.5, N(CH2)2);
1.62 (4H, m, N(CH2CH2)2); 1.31 (4H, m, (CH2CH3)2); 0.90 (6H, t, J = 7.5, 2CH3)
9.10 (1Н, br. s, NH); 7.95 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.52+7.46 (3H, s+d, J = 8.5,
S–CH= + 3'- and 5'-HR); 6.94 (4H, m, Hо-phenylene); 4.32 (2H, s, C(O)СН2N);
4.03 (2H, q, J = 9.0, OCH2); 3.44–3.10 (8H, m, N(CH2CH2)2N);
1.36 (3H, t, J = 9.0, CH3)
10j
10k
9.60 (1H, br. s, NH); 7.95 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.52+7.44 (3H, s+d, J = 8.5,
S–CH= + 3'- and 5'-HR); 6.97 (4H, distorted q, Hо-phenylene); 4.32 (2H, s, C(O)СН2N);
3.80 (3H, s, OCH3); 3.40 (8H, m, N(CH2CH2)2N)
9.40 (1H, br. s, NH···O); 7.94 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.52+7.46+7.39 (4H,
s+d (J = 8.5)+br. s, S–CH= + 3'- and 5'-HR + NHamide); 6.91 (1H, br. s, NHamide);
4.18 (2H, s, C(O)СН2N); 3.43 (2H, m, NCH2); 3.10 (2H, m, NCH2);
2.33 (1H, m, >CH–CO); 1.92 (4H, m, (СН2)2СН–)
10l
10m
9.70 (1Н, br. s, NH); 7.93 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.52+7.46 (3H, s+d, J = 8.5,
S–CH= + 3'- and 5'-HR); 7.12 (4H, m, Hо-phenylene); 4.33 (2H, s, C(O)СН2N);
3.41 (8Н, distorted s, N(CH2CH2)2N)
9.45 (1H, br. s, NH); 7.93 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.51+7.45 (3H, s+d, J = 8.5,
S–CH= + 3'- and 5'-HR); 4.23+4.12 (4H, s+q, J = 8.0, C(O)СН2N + OCH2);
3.67-3.11 (5H, m, –CH2–N–CH2–CH–CO); 1.90 (4H, m, >CHCH2CH2);
1.22 (3H, t, J = 8.0, CH3)
10n
10o
9.33 (1Н, br. s, NH); 7.92 (2Н, d, J = 8.0, 2'- and 6'-HR); 7.35 (13H, m, 3'-,
5'-HR + S–CH= + Ph2); 4.51 (1H, s, Ph2CH); 4.21 (2H, s, C(O)СН2N);
3.33 (4H, t, J = 5.0, N(CH2)2); 2.65 (4H, t, J = 5.0, N(CH2)2)
9.36 (1Н, br. s, NH); 7.93 (2Н, d, J = 8.0, 2'- and 6'-HR); 7.50-7.20 (5H, m,
S–CH= + 3'- and 5'-HR + 3'- and 5'-HPh); 6.93 (3H, m, 2'-, 4'-, 6'-HPh); 4.29 (2H, s,
C(O)СН2N); 3.36 (8H, distorted s, N(CH2CH2)2N)
10p
10t
9.30 (1Н, br. s, NH); 7.93 (2Н, d, J = 8.0, 2'- and 6'-HR); 7.47+7.43 (3H, s+d, J = 8.0,
S–CH= + 3'- and 5'-HR); 4.09 (3H, s, distorted C(O)СН2N + N–CH<); 2.76 (3H, s,
NCH3); 1.91-1.00 (10H, m, (CH2)5)
9.28 (1Н, br. s, NH); 7.93 (2Н, d, J = 9.0, 2'- and 6'-HR); 7.51+7.45 (3H, s+d, J = 9.0,
S–CH= + 3'- and 5'-HR); 4.06 (3H, s, distorted C(O)СН2N + N–CH<); 3.36 (2H, t,
J = 5.0, NCH2); 1.73 (8H, m, (CH2)3 + CH2CH3); 0.89 (3H, t, CH3)
9.15 (1Н, br. s, NH); 7.92 (2Н, d, J = 9.0, 2'- and 6'-HR); 7.49+7.44 (3H, s+d, J = 9.0,
S–CH= + 3'- and 5'-HR); 4.14 (2H, s, C(O)СН2N); 3.33 (4H, m, N(CH2)2);
2.01 (4H, m, CH2(CH<)2); 0.87 (6H, d, J = 7.5, 2CH3)
9.31 (1Н, br. s, NH); 7.97 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.55 (2Н, d, J = 8.5, 3'- and
5'-HR); 7.43 (1H, s, S–CH=); 4.22 (2H, s, C(O)СН2N); 3.43 (4H, t, J = 8.0, N(CH2)2);
1.86 (4H, m, CH2CH3); 1.02 (6H, t, J = 10.0, 2CH3)
9.40 (1Н, br. s, NH); 7.89 (2Н, d, J = 10.0, 2'- and 6'-HR); 7.57+7.53 (3H,
d (J = 10.0)+s, 3'- and 5'-HR + S–CH=); 4.14 (2H, s, C(O)СН2N); 3.06 (4H, distorted t,
N(CH2)2); 1.75 (6H, m, (CH2)3)
9.80 (1H, br. s, NH); 7.88 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.57+7.53 (3H, d (J = 8.5)+s,
3'- and 5'-HR + S–CH=); 4.30 (2H, s, C(O)СН2N); 3.33 (4H, distorted t, J = 6.0, N(CH2)2);
1.93 (4H, t, J = 6.0, (CH2)2)
9.52 (1Н, br. s, NH); 7.89 (2Н, d, J = 9.0, 2'- and 6'-HR); 7.56+7.50 (3H, d (J = 9.0)+s,
3'- and 5'-HR + S–CH=); 4.24 (2H, s, C(O)СН2N); 3.87 (4H, t, J = 5.0, О(CH2)2);
3.33 (4H, t, J = 5.0, N(CH2)2)
9.10 (1Н, br. s, NH); 7.88 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.58+7.49 (3H, d (J = 8.5)+s,
3'- and 5'-HR + S–CH=); 7.24 (5H, m, HPh); 3.95 (2H, s, C(O)СН2N); 3.33 (4H, m,
N(CH2)2); 2.85 (2H, d, J = 10.0, CH2Ph); 1.63 (5H, m, –CH(CH2)2)
10u
10v
10w
11a
11b
11c
11d
11e
11g
9,39 (1Н, br. s, NH); 7.88 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.60+7.54 (3H, d (J = 8.5)+s,
3'- and 5'-HR + S–CH=); 4.17 (2H, s, C(O)СН2N); 3.09 (2H, t, J = 11.0, NCH2);
2.80 (3H, s, NCH3); 1.64 (2H, m, NCH2CH2); 1.31 (2H, m, CH2CH3);
0.90 (3H, t, J = 7.5, CH2CH3)
9.18 (1Н, br. s, NH); 7.95 (2Н, d, J = 10.0, 2'- and 6'-HR); 7.56 (2Н, d, J = 10.0, 3'- and
5'-HR); 7.42 (1H, s, S–CH=); 4.22 (2H, s, C(O)СН2N); 3.47 (4H, t, J = 9.5, N(CH2)2);
1.86 (4H, m, N(CH2CH2)2); 1.44 (4H, m, 2CH2CH3); 0.95 (6H, t, J = 8.0, 2CH3)
9.15 (1Н, br. s, NH); 7.97 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.56 (2Н, d, J = 8.5, 3'- and
5'-HR); 7.43 (1H, s, S–CH=); 7.00 (4H, m, Hо-phenylene); 4.36 (2H, s, C(O)СН2N); 4.11 (2H,
q, J = 7.0, OCH2); 3.78+3.63 (8H, two t, J1 = J2 = 5.0, N(CH2CH2)2N);
1.43 (3H, t, J = 7.0, CH3)
11j
11k
1017

TABLE 2 (continued)
1
2
9.50 (1Н, br. s, NH); 7.95 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.56 (2Н, d, J = 8.5, 3'- and
5'-HR); 7.41 (1H, s, S–CH=); 7.02 (4H, m, Hо-phenylene); 4.34 (2H, s, C(O)СН2N);
3.89 (3H, s, OCH3); 3.75 (4H, t, J = 6.0, N(CH2)2); 3.57 (4H, t, J = 6.0, N(CH2)2)
9.60 (1Н, br. s, NH); 7.88 (2Н, d, J = 8.0, 2'- and 6'-HR); 7.53 (4H, m,
S–CH= + 3'-,5'-HR + NHamide); 6.91 (1H, br. s, NHamide); 4.18 (2H, s, C(O)СН2N);
3.44 (4H, m, N(CH2)2); 2.34 (1H, m, >CH–CO); 1.92 (4H, m, (СН2)2СН–)
9.25 (1Н, br. s, NH); 7.96 (2Н, d, J = 90, 2'- and 6'-HR); 7.54 (2Н, d, J = 9.0, 3'- and
5'-HR); 7.43 (1H, s, S–CH=); 4.26 + 4.20 (4H, s+q, J = 9.0, C(O)СН2N + OCH2);
3.80-3.50 (5H, m, –CH2–N–CH2–CH–CO); 1.90 (4H, m, >CHCH2CH2);
1.27 (3H, t, J = 9.0, CH3)
11l
11m
11o
9.33 (1Н, br. s, NH); 7.87 (2Н, d, J = 9.0, 2'- and 6'-HR); 7.62-7.20 (13H, m, 3'-,
5'-HR + S–CH= + HPh2); 4.52 (1H, s, Ph2CH); 4.20 (2H, s, C(O)СН2N);
3.33 (4H, t, J = 5.0, N(CH2)2); 2.65 (4H, t, J = 5.0, N(CH2)2)
9.27 (1Н, br. s, NH); 7.96 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.54 (2Н, d, J = 8.5, 3'- and
5'-HR); 7.42+7.33 (5H, s+m, S–CH= + Hо-phenylene); 4.75 (2H, s, ArCH2N);
4.38 (2H, s, C(O)СН2N); 3.92 (2H, t, J = 6.0, NCH2CH2);
3.41 (2H, t, J = 6.0, NCH2CH2)
11p
11q
9.45 (1Н, br. s, NH); 7.88 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.56+7.48 (3H, d (J = 8.5)+s,
3'- and 5'-HR + S–CH=); 3.95 (2H, s, C(O)СН2N); 3.17 (4H, t, J = 5.0, N(CH2)2);
2.91 (4H, t, J = 5.0, N(CH2)2); 2.85 (2H, q, J = 6.0, NCH2CH3);
1.07 (3H, t, J = 6.0, CH3)
9.29 (1Н, br. s, NH); 7.88 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.58 (2Н, d, J = 8.5, 3'-
and 5'-HR); 7.42 (1H, s, S–CH=); 3.98 (2H, s, C(O)СН2N); 3.64 (3Н, s, NCH3);
3.33 (4H, t, J = 5.0, N(CH2)2); 2.91 (4H, t, J = 5.0, N(CH2)2)
9.15 (1Н, br. s, NH); 7.87 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.56+7.48 (3H,
d (J = 8.5)+s, 3'- and 5'-HR + S–CH=); 7.27 (2H, dd, J = 7.5, J = 8.5, 3'-, 5'-HPh);
6.94 (3H, m, J = 7.5, J = 8.5, 2'-, 4'-, 6'-HPh); 4.28 (2H, s, C(O)СН2N);
3.47 (8H, distorted s, N(CH2CH2)2N)
11r
11s
11t
9.20 (1Н, br. s, NH); 7.86 (2Н, d, J = 8.5, 2'- and 6'-HR); 7.58 (2Н, d, J = 8.5, 3'-
and 5'-HR); 7.48 (1H, s, S–CH=); 4.10 (3H, s, distorted C(O)СН2N + N–CH<);
2.76 (3H, s, NCH3); 2.00-1.32 (10H, m, (CH2)5)
11u
11w
9.40 (1Н, br. s, NH); 7.87 (2Н, d, J = 9.0, 2'- and 6'-HR); 7.57+7.50 (3H,
d (J = 9.0)+s, 3'- and 5'-HR + S–CH=); 4.14 (2H, s, C(O)СН2N);
3.23 (4H, m, N(CH2)2); 1.94 (4H, m, CH2(CH<)2); 0.87 (6H, d, J = 7.5, 2CH3)
7.81 (2Н, d, J = 8.0, 2', 6'-HR); 7.60+7.54 (3Н, s+d, J = 8.0, 2-H + 3',5'-HR);
12
13
4.48 (2Н, s, СН2)
7.79 (2Н, d, J = 8.0, 2', 6'-HR); 7.58+7.55 (3Н, s+d, J = 8.0, 2-H + 3',5'-HR);
4.41 (2Н, s, СН2)
1
The position of the signals from the residual protons in the H NMR spectra of aminonitriles 9-11 is
analogous to their position in the starting compounds 3-5. The only exception is the two-proton singlet of the
oxomethylene moiety, which for compounds 9-11 is observed upfield (4.38-3.95 ppm) due to the smaller
negative inductive effect of the nitrogen atom compared with the chlorine atom. Elemental analysis data for
aminonitriles 9-11 agree well with the calculated values (Table 2).
The existence of aminonitriles 9-11 in DMSO-d6 solution in tautomeric form C is explained by
realization in aprotic medium of the strongest possible hydrogen bond. The latter is more stable in tautomer C
than in tautomer B for two reasons. First of all, the system of linked five-membered and seven-membered rings
is less strained than the analogous system of five-membered and six-membered rings. Secondly, the lone
electron pair of the nitrogen atom of the dialkylamino group, localized on an sp3-hybridized orbital, is more
suitable for creating a hydrogen bond than the lone electron pair of the oxygen atom, occupying an
sp2-hybridized orbital. The possibility is not excluded that in protic medium, the tautomeric equilibrium for
compounds 9-11 will be different.
1018

3-Aryl-6(5H)-oxo-7-cyanopyrrolo[2,1-b]thiazoles 12, 13, which formation could be avoided when
chloronitriles 3-5 reacted with secondary amines, were obtained from compounds 4, 5 by treatment with
triethylamine. The structure of pyrrolothiazoles 12, 13 was confirmed by analytical and spectral data. Their IR
spectra reveal an intense band for stretching vibrations of the conjugated nitrile group in the 2180-2190 cm-1
1
region but no absorption above 3050 cm-1. In the H NMR spectra of compounds 12, 13, we observe a
two-proton singlet for the methylene group in the 4.50-4.45 ppm region and a one-proton singlet at 7.60 ppm
assigned to the proton in the 2 position. The protons of the substituent R resonate in the regions characteristic
for them. According to the spectral data, the pyrrolothiazoles 12, 13 exist completely in the ketone form.
Thus applying the procedure in [1] to 4-aryl-2-cyanomethylthiazoles 6-8 allowed us to obtain
2-(4-arylthiazol-2-yl)-3-oxo-4-chlorobutyronitriles 3-5. By nucleophilic substitution of the chlorine atom in
compounds 3-5 by secondary aliphatic amines, we synthesized the series of 2-(4-arylthiazol-2-yl)-4-
dialkylamino-3-oxobutyronitriles 9e-g,i,j,l-o,u, 10a-c,f,h-p,t-w, 11a-e,g,j-m,o-u,w, which are potentially
biologically active substances.
EXPERIMENTAL
The course of the reactions was monitored using TLC (Silufol UV-254, chloroform–methanol, 9:1). The
1
IR spectra were recorded on a Pye Unicam SP 3-300 in KBr pellets. The H NMR spectra were recorded in
DMSO-d6 on a Bruker WP-100 SY with operating frequency 100 MHz.
The analytical characteristics of the compounds obtained are indicated in Table 1. Their spectral
characteristics are presented in Table 2.
4-Aryl-2-cyanomethylthiazoles 6-8 were obtained according to the procedure in [20-22].
2-(4-Arylthiazol-2-yl)-4-chloro-3-oxobutyronitriles 3-5. -Chloroacetyl chloride (12 ml, 0.15 mol)
α
was added, with stirring by hand, over a 3-5 min period to a solution of 4-aryl-2-cyanomethylthiazole 6-8
(0.15 mol) and pyridine (15 ml, 0.19 mol) in warm (40-50°C) absolute dioxane (100-130 ml). The mixture was
heated on a water bath for 40-60 min. After cooling, the precipitate was filtered off and carefully washed with
water. The halonitriles 3-5 obtained were suitable for further use. Analytical samples of compounds 3-5 were
purified by recrystallization from dioxane (compounds 4, 5) or n-butanol (compound 3).
4-Dialkylamino-2(4-arylthiazol-2-yl)-3-oxobutyronitriles 9e-g,i,j,l-o, 10a-c,f,h-p,t-w, 11a-e,g,j-m,o-
u,w. The corresponding secondary amine (6 mmol) was added to a suspension of the halonitrile 3-5 (3 mmol) in
dioxane (5-10 ml) and then refluxed until the halonitrile dissolved. The solution obtained was refluxed for about
40 min longer, until compounds 3-5 disappeared from the reaction mixture (according to TLC). After this, the
mixture was cooled, the precipitate was filtered off, carefully washed with water, dried, and recrystallized from
dioxane (compounds 9e,i,j,m-o, 10b,c,h,i,l-p,u-w, 11a-e,g,j,l,m,q-u,w) or n-butanol (compounds 9f,g,e,u,
10a,f,j,k,t, 11k,p).
b
Triethylamine (0.55 ml, 4 mmol) was added
3-Aryl-7-cyano-6(5H)-oxopyrrolo[2,1- ]thiazoles 12, 13.
to a suspension of halonitrile 4, 5 (3 mmol) in dioxane (5 ml), and the mixture obtained was refluxed for 7-9 h
until compounds 4-5 disappeared completely from the reaction mixture (according to TLC). After cooling, the
precipitate was filtered off, washed with water, dried, and recrystallized from dimethylformamide.
b
Yield 57%; mp 226°C. Found, %:
3-(4-Chlorophenyl)-7-cyano-6(5H)-oxopyrrolo[2,1- ]thiazole 12.
Cl 12.93; N 10.17; S 11.64. C13H7ClN2OS. Calculated, %: Cl 12.90; N 10.20; S 11.67.
b
Yield 46%; mp 211°C. Found, %:
3-(4-Bromophenyl)-7-cyano-6(5H)-oxopyrrolo[2,1- ]thiazole 13.
Br 25.08; N 8.81; S 9.99. C13H7BrN2OS. Calculated, %: Br 25.03; N 8.78; S 10.05.
This research was done with the financial support of the company Du Pont de Nemours International S. A.
1019

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1020