Synthesis of 2-aryl-2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-ones and 7-aryl-2,3,6,7-tetrahydro-5H-imidazo[2,1-b]-1,3-thiazin-5-ones

Article abstract of DOI:10.1023/A:1026162824927

The reaction of 2-mercaptobenzimidazole, 5-ethoxy-2-mercaptobenzimidazole, and 2-mercaptoimidazoline with cinnamoyl chloride, its derivatives, and heteroanalogs was studied. Convenient methods were found for the synthesis of 2-aryl-2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-ones and 7-aryl-2,3,6,7-tetrahydro-5H-imidazo[2,1-b]-1,3-thiazin-5-ones.

Full text of DOI:10.1023/A:1026162824927

Chemistry of Heterocyclic Compounds, Vol. 39, No. 7, 2003
SYNTHESIS OF 2-ARYL-2,3-DIHYDRO-
a
4H-[1,3]THIAZINO[3,2- ]BENZIMIDAZOL-4-ONES
AND 7-ARYL-2,3,6,7-TETRAHYDRO-5H-
b
IMIDAZO[2,1- ]-1,3-THIAZIN-5-ONES
V. N. Britsun and M. O. Lozinskii
The reaction of 2-mercaptobenzimidazole, 5-ethoxy-2-mercaptobenzimidazole, and 2-mercapto-
imidazoline with cinnamoyl chloride, its derivatives, and heteroanalogs was studied. Convenient
methods were found for the synthesis of 2-aryl-2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-
ones and 7-aryl-2,3,6,7-tetrahydro-5H-imidazo[2,1-b]-1,3-thiazin-5-ones.
Keywords: 2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-ones, 7-aryl-2,3,6,7-tetrahydro-5H-
imidazo[2,1-b]thiazin-5-ones.
4H-1,3-Thiazin-4-one derivatives have various types of biological activity and may be used as pesticides
and herbicides [1], fungicides [2], and antituberculosis agents [3]. Condensed heterocyclic systems containing
the 4H-1,3-thiazin-4-one structure such as derivatives of 2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-
one and 2,3,6,7-tetrahydro-5H-imidazo[2,1-b]-1,3-thiazin-5-one hold promise in this regard. These compounds
are obtained as a rule through multistep syntheses [4-8]. Information on the single-step synthesis of these
compounds by the reaction of 2-mercaptobenzimidazole (1a) and 2-mercaptoimidazoline (5) with the acid
chloride of acrylic acid is very limited [9, 10].
2-Aryl-2,3-dihydro-4H-[1,3]thiazino[3,2-a]benzimidazol-4-ones 4a-k were obtained in our single-step
method by the reaction of 2-mercaptobenzimidazole (1a) and 5-ethoxy-2-mercaptobenzimidazole (1b) and
substituted 2b-g and heteroanalogs 2h-j without isolation of intermediate N-cinnamoylimidazoles 3.
O
O
C
H
N
Cl
O
Py
Ar
N
N
S
+
R
Ar
SH
– Py •HCl
S
Ar
N
H
N
3
R
N
R
4a–k
1a,b
2a–j
1 a R = H, b R = EtO; 2, 4 a-j R = H, a Ar = Ph, b Ar = 4-MeOC6H4, c Ar = 4-FC6H4,
d Ar = 3-O2NC6H4, e Ar = 3,4-(MeO)2C6H3, f Ar = 3,4,5-(MeO)3C6H2, g Ar = 2-MeOC6H4,
h Ar = 2-thienyl, i Ar = 2-furyl, j Ar = 1-(3,4-methylenedioxy)phenyl; 4k R = EtO, Ar = Ph;
3 R = H, Ar = 2-MeOC6H4
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev 02094, Ukraine; e-mail:
iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1103-1108, July,
2003. Original article submitted April 6, 2000; revision submitted March 16, 2001.
960
0009-3122/03/3907-0960$25.00©2003 Plenum Publishing Corporation

1
The elemental analysis data, melting points, and product yields are given in Table 1. The H NMR
1
spectra of these compounds are given in Table 2. This reaction may be followed conveniently using H NMR
spectroscopy since signals at 3.3-5.5 ppm (an ABX proton system for the thiazine ring) appear during the
reaction instead of the two doublets at 7.6-7.9 ppm (signals for the protons of the double bond in starting acid
chlorides 2a-j).
Availability of the starting compounds, experimental simplicity, and high product yields are advantages
of our single-step method. The reaction proceeds under mild conditions by heating the reagents in pyridine–
benzene at reflux for 2 h. The highest yields (69-82%) were obtained with cinnamoyl chloride 2a and its para-
and meta-phenyl derivatives 2b-d. The yields of the desired products were somewhat lower using
3-heterylacryloyl chlorides 2h-j (61-72%).
TABLE 1. Characteristics of Compounds Synthesized
Found, %
——————
Com-
pound
Empirical
formula
Calculated, %
mp, °С*
Yield, %
C
H
N
C17H14N2O2S
C16H12N2OS
65.90
65.80
4.61
4.52
9.08
9.03
206-208
121-123
140-143
135-138
192-195
170-173
215-218
100-103
120-123
130-133
157-160
152-155
197-200
184-185
207-210
142-145
175-179
205-208
153-156
52
73
69
71
82
67
68
53
72
63
61
68
49
50
52
50
49
54
47
3
68.65
4.34
10.20
4а
4b
4c
4d
4e
4f
68.57
4.29
10.00
C17H14N2O2S
C16H11FN2ОS
C16H11N3O3S
C18H16N2O3S
C19H18N2O4S
C17H14N2O2S
C14H10N2OS2
C14H10N2O2S
C17H12N2O3S
C18H16N2O2S
C21H18N2O2S
C23H22N2O4S
C21H16N4O6S
C12H13 Cl N2OS
C13H15ClN2O2S
C12H12ClN3O3S
C10H11ClN2OS2
65.91
65.80
4.33
4.52
9.09
9.03
64.31
3.61
9.53
64.44
3.69
9.40
59.24
59.08
3.17
3.38
13.12
12.92
63.54
4.58
8.40
63.53
4.70
8.23
61.54
61.62
4.98
4.86
7.50
7.57
65.62
4.35
9.18
4g
4h
4i
65.80
4.52
9.03
58.99
58.74
3.66
3.50
9.71
9.79
62.03
3.51
10.17
62.22
3.70
10.37
62.71
62.96
3.93
3.70
8.52
8.64
4j
65.87
4.78
8.83
4k
6a
6b
6c
8а
8b
8c
8d
66.66
4.94
8.64
69.87
69.61
4.48
4.97
7.51
7.73
65.28
5.06
6.48
65.40
5.21
6.63
55.60
55.75
3.68
3.54
12.57
12.39
53.88
4.71
10.30
53.63
4.84
10.43
52.47
52.26
5.21
5.03
9.47
9.38
45.47
3.71
13.17
45.93
3.83
13.40
43.57
43.72
4.22
4.01
10.43
10.20
_______
* Products 4a,c,g-i, and 8a were recrystallized from ethanol, 4b,e,j,k, 8b,d
were recrystallized from ethanol–pyridine, and 3, 4d,f, 6a-c, and 8c were
recrystallized from pyridine.
961

The formation of isomers A and B is possible in the reaction of 1b and 2a.
O
O
6
4
6
R
3
3
7
5
5
4
7
8
2
N
2
N
8
Ar
Ar
R
S
S
9
N
9
N
1
10
10
A
B
1H NMR spectroscopy showed that 4k is one of these isomers. Since the ethoxy group is a type-1
substituent, we should propose that the acylation should proceed predominantly at the nitrogen atom at position
5 to give isomer A. In order to clarify the isomer type of 4k, we assigned the signals of 6-H and 9-H in the
spectra of 4a and 4k. The signal for 6-H in 4a affected by the amide group lies downfield at 8.16 ppm, while the
signal for 9-H is at 7.42 ppm. The doublet for of 6-H in 4k is at 7.99 ppm (J = 8.7 Hz), while the singlet for 9-H
is at 7.13 ppm, which corresponds to structure A.
Experimentally, this is a single-step process though, in fact, it is a sequence of at least two reactions,
namely, N-acylation and addition of the mercapto group at the double bond. It is unclear which of these
reactions is primary and which secondary. Thus, we attempted to determine the probable scheme for this
reaction. The reaction of 1a with o-methoxycinnamoyl chloride 2g, whose methoxy group sterically hinders
heterocyclization, was selected for study. Product 3 (R = H) was isolated from the reaction mixture. Since
signals of the double bond protons of this compound are at 7.72 and 7.94 ppm as in starting 2, this compound is
the product of N-acylation. The IR spectrum of this product has bands for both NH (3100-2900 cm-1) and SH
groups (2600-2450 cm-1). Product 3 (R = H) probably exists as a mixture of thione and thiol forms, while the
heterocyclization, in all likelihood, proceeds through the thiol form. Thus, we may assume that N-acylation is
the primary reaction followed by conversion of the thione form into the thiol and reaction of the thiol group with
the activated double bond to give the thiazine ring.
The direction of the reaction of cinnamoyl chloride and its derivatives with 2-mercaptoimidazoline 5
depends significantly on the nature of solvent used. Thus, only N-acylation products are formed in pyridine
(analogously to the acylation of 2-mercaptoimidazoline by acetic anhydride [11]), while heterocyclization
proceeds smoothly in acetone (probably through intermediate 7) to give the acid chlorides of 7-aryl-2,3,6,7-
tetrahydro-5H-imidazo[2,1-b]-1,3-thiazin-5-ones (8a-d):
O
C
H
Ar
Ar
N
N
N
Py
2a–d
S
+
S
N
H
5
C
O
Me2CO
6a–c
O
Ar
SH
N
.
.
N
C
O
N
N
HCl
S
Ar
.
HCl
7
8a–d
2, 6, 8 a Ar = Ph, b Ar = 4-MeOC6H4, c Ar = 3-O2NC6H4; 2, 8 d Ar = 2-thienyl
962

TABLE 2. 1H NMR Spectral Data for 3, 4a-4k, 6a-6c, and 8a-8d
Com-
Chemical shifts, δ, ppm
pound
3.94 (3Н, s, СН3О); 7.17-7.58 (7Н, m, Ar); 7.72 (1Н, d, Ar); 7.94 (1Н, d, Ar);
8.22 (1Н, d, Ar)
3
3.14 (1H, m, Н-3); 3.85 (1H, m, Н-3); 5.40 (1Н, m, СН-2); 7.35-7.60 (8Н, m, Ar);
4а
4b
4c
8.16 (1Н, d, Ar)
3.75 (3Н, s, СН3О); 3.85 (1Н, m, Н-3); 5.37 (1Н, m, Н-2); 7.00-7.52 (6Н, m, Ar);
7.62 (1Н, d, Ar); 8.17 (1Н, d, Ar)
3.43 (1Н, m, Н-3); 3.80 (1Н, m, Н-3); 5.41 (1Н, m, Н-2); 7.26-7.59 (7Н, m, Ar);
8.16 (1Н, d, Ar)
3.55 (1Н, m, Н-3); 3.93 (1Н, m, Н-3); 5.59 (1Н, m, Н-2); 7.39-8.40 (8Н, m, Ar)
4d
4e
3.24 (1Н, m, Н-3); 3.73 (6Н, d, 2СН3О); 3.85 (1Н, m, Н-3); 5.31 (1Н, m, Н-2)
6.99-7.36 (5Н, m, Ar); 8.17 (1Н, d, Ar); 8.18 (1Н, d, Ar )
3.67 (3Н, s, СН3О); 3.79 (6Н, s, 2СН3О); 3.93 (1Н, m, Н-3); 5.31 (1Н, m, Н-2);
6.80 (2Н, s, Ar), 7.38 (2Н, m, Ar); 7.63 (1Н, d, Ar); 8.18 (1Н, d, Ar)
4f
3.42 (1Н, m, Н-3); 3.71 (1Н, m, Н-3); 3.91 (3Н, s, СН3О); 5.55 (1Н, m, Н-2);
4g
7.02-7.57 (7Н, m, Ar); 8.18 (1Н, d, Ar)
3.65 (2Н, m, СН2); 5.67 (1Н, m, Н-2); 7.03-7.65 (6Н, m, Ar); 8.16 (1Н, d, Ar)
4h
4i
3.61 (2Н, m, СН2); 5.44 (1Н, m, Н-2); 6.46 (2Н, s, Ar); 7.36-7.66 (4Н, m, Ar);
8.19 (1Н, d, Ar)
3.17 (1Н, m, Н-3); 3.79 (1Н, m, Н-3); 5.33 (1Н, m, Н-2); 6.05 (2Н, s, ОСН2О);
6.96-7.37 (5Н, m, Ar); 7.60 (1Н, d, Ar); 8.17 (1Н, d, Ar)
1.35 (3Н, t, СН3СН2О); 3.40 (1Н, m, Н-3); 3.78 (1Н, m, Н-3); 4.06 (2Н, q, СН3СН2О);
5.37 (1Н, m, Н-2); 6.90 (1Н, d, Ar); 7.13 (1Н, s, Ar); 7.31-7.60 (5Н, m, Ar);
7.99 (1Н, d, Ar)
4j
4k
4.30 (4Н, s, 2СН2); 7.47 (6Н, m, Ph); 7.60 (2H, d, 2 =СН–СО–); 7.68 (4Н, m, Ph);
6а
6b
6c
8а
8b
8c
8.08 (2Н, d, 2Ar–CH=)
3.80 (6Н, s, 2СН3О); 4.38 (4Н, s, 2СН2); 7.04 (4Н, d, p-C6H4); 7.61 (6Н, m, Ar);
7.98 (2Н, d, 2Ar–CH=)
4.11 (4Н, s, 2СН2 ); 7.72-8.08 (8Н, m, Ar); 8.27 (2Н, d, m-NO2C6H4);
8.49 (2Н, s, m-NO2C6H4)
3.22 (1Н, m, Н-6); 3.41 (1Н, m, Н-6); 3.92-4.20 (4Н, m, 2СН2); 5.29 (1Н, m, Н-7);
7.47 (5Н, m, Ph); 8.05 (1Н, br. s, NН)
3.13 (1Н, m, Н-6); 3.53 (1Н, m, Н-6); 3.76 (3Н, s, СН3О); 3.81-4.20 (4Н, m, 2СН2);
5.25 (1Н, m, Н-7); 7.17 (2Н, d, p-C6H4); 7.44 (2Н, d, p-C6H4); 8.10 (1Н, br. s, NН)
3.36 (1Н, m, Н-6); 3.58 (1Н, m, Н-6); 3.85-4.18 (4Н, m, 2СН2); 5.47 (1Н, m, Н-7);
7.76 (1Н, t, m-NO2C6H4); 7.94 (1Н, d, m-NO2C6H4); 8.23 (1Н, d, m-NO2C6H4);
8.35 (1Н, s, m-NO2C6H4 ); 8.18 (1Н, br. s, NН)
3.32 (1Н, m, Н-6); 3.63 (1Н, m, Н-6); 3.67-4.13 (4Н, m, 2СН2); 5.46 (1Н, m, Н-7);
8d
7.04 (1Н, t, Het); 7.16 (1Н, d, Het); 7.59 (1Н, d, Het); 8.15 (1Н, br. s, NН)
Compounds 1a and 5 can exist in both the thione and thiol forms. The difference in their reactivity may
be attributed to the likelihood that 1a exists significantly as the thiol, while the thione form is more
characteristic for 5. Furthermore, the content of the thiol form of 5 increases with increasing solvent polarity
[12]. Thus, the heterocyclization of 5 to give 8 occurs only under conditions enhancing the content of the thiol
form, which corresponds to the structure of salt 7.
Therefore, the reactions of cinnamoyl chloride, its derivatives and heteroanalogs with 1a and 5 are
simimilar in nature and serve as a convenient method for the synthesis of 2-aryl-2,3-dihydro-4H-
[1,3]thiazino[3,2-a]benzimidazol-4-ones (4a-k) and hydrochloride salts of 7-aryl-2,3,6,7-tetrahydro-5H-
imidazo[2,1-b]-1,3-thiazin-5-ones (8a-d). A scheme for heterocyclization has been proposed. The structures of
1
these products were demonstrated using H NMR and IR spectroscopy, and their composition was shown by
elemental analysis.
963

EXPERIMENTAL
1
The H NMR spectra were taken on a Varian-300 spectrometer at 300 MHz in DMSO-d6 with TMS as
the internal standard. The IR spectra were obtained on Specord IR-75 spectrometer for KBr pellets.
1-[3-(2-Methoxyphenyl)acryloyl]benzimidazole-2-thiol (3). A solution of 3-(2-methoxyphenyl)-
acryloyl chloride (2g) (1.96 g) in benzene (4 ml) was added to a solution of 1a (1.6 g, 10 mmol) in pyridine
(5 ml) at 20°C and stirred for 20 min. Then, water (30 ml) was added. The precipitate formed was filtered off,
washed with ethanol, and dried. IR spectrum, ν, cm-1: 3000 (NH), 2500 (SH), 1690 (C=O), 1600 (C=N), 1510
(NH–C=S).
a
2-Aryl-2,3-dihydro-4H-[1,3]thiazino[3,2- ]benzimidazole-4-thiones (4a-k) and 1,3-Di(3-
arylacryloyl)imidazoline-2-thiones (6a-c). A solution of 3-arylacryloyl chloride 2 (10 mmol) in benzene (4 ml)
was added to a solution of 2-mercapto derivative 1a, 1b, or 5 (10 mmol) in pyridine (5 ml) and heated at reflux
for 2 h (12 h for 4g). The solution was cooled and water (30 ml) was added. The precipitate formed was filtered
off, washed with ether, dried, and recrystallized from the solvent indicated in Table 1.
b
7-Aryl-2,3,6,7-tetrahydro-5H-imidazo[2,1- ]-1,3-thiazine-5-ones
Hydrochlorides
(8a-d).
3-arylacryloyl chloride 2 (10 mmol) was added to a mixture of 2-mercaptoimidazoline 5 (10 mmol) and acetone
(20 ml), heated at reflux for 4 h, and cooled. The precipitate formed was filtered off, washed with acetone, and
dried.
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964