Reactivity of cyanothioformamides and 3-(4-bromophenyl)-5-imino-4-oxazolidinethione toward ortho-substituted nucleophiles

Article abstract of DOI:10.1002/hc.10042

The substituted benzoazoles 4 and 5a,b were obtained by the reaction of cyanothioformamides 1d and 1b or 1c with o-substituted aromatic amines 2b and 2c, respectively. Fused pyrimidinones 10, 12, and 14 were synthesized by the reaction of oxazolidinethion

Full text of DOI:10.1002/hc.10042

Heteroatom Chemistry
Volume 13, Number 7, 2002
Reactivity of Cyanothioformamides and 3-
(4-Bromophenyl)-5-imino-4-oxazolidinethione
Toward Ortho-Substituted Nucleophiles
Mohamed S. A. El-Gaby,1 Yousry A. Ammar,2 Ahmed M. Sh.
El-Sharief, Medhat A. Zahran,2 and Ahmed A. Khames1
1Department of Chemistry, Faculty of Science, Al-Azhar University at Assiut, Assiut 71524, Egypt
2Department of Chemistry, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
Received 10 September 2001; revised 3 November 2001
ABSTRACT: The substituted benzoazoles 4 and
5a,b were obtained by the reaction of cyanothiofor-
mamides 1d and 1b or 1c with o-substituted aromatic
amines 2b and 2c, respectively. Fused pyrimidi-
nones 10, 12, and 14 were synthesized by the reac-
tion of oxazolidinethione (9) with 2-amino aromatic
and heteroaromatic carboxylic acids. The structures
of the synthesized compounds were established based
on elemental analysis and spectral data studies.
ꢀ
C
2002 Wiley Periodicals, Inc. Heteroatom Chem 13:611–
616, 2002; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.10042
INTRODUCTION
A
literature survey reveals that cyanothiofor-
mamides, which contain a potentially nucleophilic
nitrogen atom ꢀ to a cyano function ꢀ group, are ver-
satile reagents which have been extensively utilized
in heterocyclic synthesis [1–3]. The present contribu-
tion represents an extension of our recent work [4–7]
on cyanothioformamides 1 and deals with their re-
activity toward ortho-substituted anilines to furnish
fused heterocycles. In addition, the reactivity of
oxazolidinethione (9) toward similar reagents was
investigated.
RESULTS AND DISCUSSION
Compound 1a reacted with an equimolar amount of
o-phenylenediamine (2a) in absolute ethanol in the
presence of a catalytic amount of triethylamine un-
der reflux to yield 2-mercaptobenzimidazole (3). The
assigned structure for compound 3 was based on
microanalytical and spectral data. The IR spectrum
displays a lack of absorption of the C N group
and the presence of an NH band at 3150 cm−1.
Also, compound 3 was synthesized by treatment
of 2a with carbon disulfide in ethanol in the
Correspondence to: Mohamed S. A. El-Gaby; e-mail: m elgaby@
hotmail.com.
c
ꢀ
2002 Wiley Periodicals, Inc.
611

612 El-Gaby et al.
presence of potassium hydroxide [8]. Formation of
3
from 1a is assumed to take place via elimina-
tion of hydrogen cyanide and 4-methylaniline. Treat-
ment of compound 1d with o-aminophenol (2b)
in N,N-dimethylformamide catalyzed by piperidine
produced the benzoxazole derivative 4. Analytical
and spectral data are consistent with the proposed
structure. The mass spectrum of 4 shows a molec-
ular ion peak at m/z = 301 (100%) corresponding
to the molecular formula C19H15N3O (Fig. 1). The
formation of 4 is assumed to proceed via elimina-
tion of hydrogen cyanide and hydrogen sulfide. Cy-
clocondensation of 1b and 1c with o-chloroaniline
(2c) in dioxane/TEA furnished the benzimidazole
derivatives 5a,b. Microanalytical and spectroscopic
data for 5a and 5b are consistent with the assigned
structure. Thus, the IR spectra exhibit absorption
bands corresponding to the NH group, but not to
the C N group. The formation of 5 is assumed
to proceed through initial elimination of hydrogen
cyanide followed by loss of hydrogen chloride [9]. On
the other hand, reaction of 1c with o-chlorophenol
(2d) yielded the thiocarbamate 6, via elimination of
hydrogen cyanide (Scheme 1).
SCHEME 1
proceed via thiourea formation followed by loss of
water. Compounds 7a and 7b were also obtained
by an independent synthetic route by treatment of
2e with the appropriate aryl isothiocyanate in re-
fluxing ethanol/TEA [10]. On refluxing compounds
Quinazolinones 7a,b were obtained by reflux-
ing anthranilic acid (2e) with compounds 1c
and 1d in ethanol containing triethylamine. The
formation of quinazolinones 7a,b is believed to
FIGURE 1 Fragmentation pattern of compound 4.

Reactivity of Cyanothioformamides and 3-(4-Bromophenyl)-5-imino-4-oxazolidinethione 613
1a and 1c with an equimolar amount of cate-
chol (2f) in dimethylformamide in the presence
of triethylamine,1,3-benzodioxole derivatives 8a,b
were obtained. Formation of 8 is assumed to pro-
ceed by elimination of hydrogen cyanide and hydro-
gen sulfide (Scheme 2).
Oxazolidine (9) was synthesized by the reac-
tion of cyanothioformamide (1c) with acetaldehyde
in the ether in the presence of triethylamine at
room temperature. The reactivity of 9 toward com-
pounds containing an amino group with a vicinal
carboxyl group was investigated. Thus, refluxing of
9 with anthranilic acid (2e) in absolute ethanol con-
taining triethylamine furnished a yellow product
which is formulated as the quinazolinone deriva-
tive 10. The structure of 10 was established by mi-
croanalytical and spectral data. The IR spectrum of
10 exhibit characteristic bands for NH and C O
functional groups. The 1H NMR spectrum of 10
(DMSO-d6) show signals at 11.40 and 12.10 ppm
assigned to 2 NH protons and a multiplet at 6.77–
7.74 ppm assigned to aromatic protons. Also, the
mass spectrum of 10 contains a molecular ion peak
at m/z = 360 (79%), which is in agreement with
the proposed formula C15H10BrN3OS. Presumably,
the formation of 10 takes place by nucleophilic
attack of the amino group of anthranilic acid on
the imino group of compound 9 with loss of ac-
etaldehyde [5], followed by cyclization with elimi-
nation of water (Scheme 3). In a similar man-
ner, compound 9 was treated with the heterocyclic
ortho-amino carboxylic acids 5-amino-1-phenyl-
pyrazole-4-carboxylic acid (11) and 2-amino-4,5,6,7-
tetrahydrobenzo[b]thiophene-3-carboxylic acid (13)
SCHEME 3
to yield the novel condensed pyrimidines 12 and 14,
respectively (Scheme 3).
This investigation was extended to include a
study of the reactivity of compound 9 toward bi-
nucleophiles. Thus, compound 9 was treated with an
equimolar amount of o-phenylenediamine (2a) in ab-
solute ethanol, in the presence of a catalytic amount
of triethylamine, to yield the quinoxaline derivative
15. Compound 15 is probably formed through nucle-
ophilic attack by a molecule of 2a on the imino group
of 9 with loss of acetaldehyde [5], followed by cycl-
ization with elimination of hydrogen sulfide. On the
other hand, when compound 9 was allowed to react
with o-aminophenol (2b) as the binucleophile, the
thioamide derivative 16 was obtained. The other pos-
sible structure (17) for this product was excluded on
the basis of microanalytical and spectral data. Simi-
larly, 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-
3-carbonitrile (18) reacted with compound 9 to give
the novel thioamide 19 (Scheme 4).
EXPERIMENTAL
All melting points are uncorrected and were de-
termined on a digital Gallen-Kamp MFB-595 in-
strument. IR spectra (KBr) were measured on a
1
Shimadzu 440 spectrometer H NMR spectra were
obtained in dimethylsulfoxide on a Varian Gemini
200 MHz spectrometer using TMS as an internal
standard; chemical shifts are reported as δ units.
Mass spectra were obtained on a GC MS-QP 1000 Ex
mass spectrometer at 70 eV. Elemental analyses
SCHEME 2

614 El-Gaby et al.
The starting compounds 1a–d [11], 11 [12], 13
[13], and 18 [14] were prepared according to previ-
ously reported procedures.
2-Mercaptobenzimidazole (3)
A mixture of cyanothioformamide (1a) (0.01 mol),
o-phenylenediamine (2a) (0.01 mol), and triethy-
lamine (0.5 ml) in absolute ethanol (30 ml) was re-
fluxed for 3 h. The resulting solid obtained was re-
crystallized from ethanol. MS (%): 150 (M+; 100), 151
(M + 1; 10), 149 (M − 1; 8.8), 65 (18.1), and 52 (10.8).
2-[N-(4-phenylaminophenyl)]benzoxazolamine (4)
A mixture of cyanothioformamide (1d) (0.01 mol),
o-aminophenol (2b) (0.01 mol), and triethylamine
(0.5 ml) in N,N-dimethylformamide (10 ml) was re-
fluxed for 3 h, then allowed to cool, and poured
into cold water (50 ml). Its acidification with HCl
yielded a solid product which was recrystallized from
ethanol. MS (%): 301 (M+; 100), 302 (M + 2; 21.8),
300 (7.1), 22b (1.6), 208 (3.7), 193 (3.0), 169 (13.5),
150 (6.0), 128 (2.7), 77 (8.6), and 76 (1.5).
SCHEME 4
were carried out at the Microanalytical Center of
Cairo University. Physical and analytical data for the
synthesized compounds are given in Table 1. The
spectral data are collected in Table 2.
TABLE 1 Melting Points, Yields, and Analytical Data of the Synthesized Compounds
Elemental Analyses (Calcd./Found)
Compd. No.
M.p. ( ◦C)
112–114
90–91
Yield (%)
60
Formula (Mol. Wt)
C
H
N
4
5a
5b
6
C19H15N3O (301)
75.75
75.60
59.88
59.80
51.14
51.20
45.54
45.60
50.45
50.20
69.56
69.50
74.67
74.50
53.80
53.70
42.10
42.20
50.00
50.10
50.72
50.72
48.57
48.70
53.33
53.20
48.00
48.10
48.69
48.70
5.02
5.00
3.45
3.50
2.95
2.90
2.62
2.60
2.70
2.80
4.34
4.30
4.89
4.90
2.76
2.80
3.15
3.10
2.77
2.60
2.81
2.80
3.33
3.40
3.50
3.49
3.42
3.40
3.58
3.50
13.95
14.10
10.74
10.60
9.18
9.00
4.08
4.10
8.40
8.50
12.17
12.20
6.22
6.10
4.82
4.90
9.82
9.70
11.66
11.70
16.43
16.50
10.00
10.00
17.78
17.60
12.00
12.00
13.37
13.40
72
C
C
C
C
C
C
C
C
C
C
C
C
C
C
13H9ClN2S (260.5)
13H9BrN2S (305)
13H9BrClNOS (342.5)
14H9BrN2OS (333)
20H15N3OS (345)
14H11NO2 (225)
140–142
>300
70
68
7a
7b
8a
8b
9
300–301
300–302
182–182
180–181
118–119
190–191
120–122
125–126
150–151
100–101
110–111
84
90
74
80
13H8BrNO2 (290)
10H9BrN2OS (285)
15H10BrN3OS(360)
18H12BrN5OS (426)
17H14BrN3OS2 (420)
14H11BrN4 (315)
84
10
12
14
15
16
19
87
81
83
67
65
14H12BrN3OS (350)
17H15BrN4S2 (419)
64

Reactivity of Cyanothioformamides and 3-(4-Bromophenyl)-5-imino-4-oxazolidinethione 615
TABLE 2 Spectroscopic Data of the Synthesized Compounds
Compd. No.
IR (KBr, cm−1
3400, 3380 (NH)
)
1H NMR (ppm) (DMSO-d6)
4
6.87–7.91 (m,13H, Ar-H), 8.90, 10.52 (2s, 2H, 2NH; exchangeable
upon treatment with D2O)
5a
5b
6
3250 (NH)
3400 (NH)
3394 (NH)
6.80–8.10 (m, 8H, Ar-H), 12.21 (s, 1H, NH; exchangeable upon
treatment with D2O)
6.65–7.79 (m, 8H, Ar-H), 11.91 (s, 1H, NH; exchangeable upon
treatment with D2O)
7.10–7.86 (m, 8H, Ar-H), 8.51 (s, 1H, NH; exchangeable upon
treatment with D2O)
7a
7b
3250 (NH), 1680 (C O)
3400, 3220 (NH), 1670 (C O)
6.89–7.99 (m, 13H, Ar-H), 8.39, 13.00 (2s, 2H, 2NH; exchangeable
upon treatment with D2O)
8a
8b
9
1640 (C N)
1630 (C N)
3240 (NH) 2950 (CH-aliph)
1580 (C N)
3280, 3200 (NH), 1680 (C O)
2.20 (s, 3H, CH3), 6.90–7.82 (m, 8H, Ar-H)
6.81–7.90 (m, 8H, Ar-H)
1.18 (d, 3H, CH3), 5.22 (q, 1H, CH), 7.58–7.81 (m, 4H, Ar-H), 8.71
(s, 1H, NH; exchangeable upon treatment with D2O)
6.77–7.74 (m, 8H, Ar-H), 11.40, 12.10 (2s, 2H, 2NH; exchangeable
upon treatment with D2O)
6.91–7.69 (m, 9H, Ar-H), 7.87 (s, 1H, pyrazole-H), 11.15, 12.14
(2s, 2H, 2NH; exchangeable upon treatment with D2O)
1.73 (m, 8H, 4CH2), 7.65–7.90 (m, 4H, Ar-H) 11.18, 12.00 (2s, 2H,
2NH; exchangeable upon treatment with D2O)
7.37–8.12 (m, 8H, Ar-H), 9.60 (Hump, 2H, NH2; exchangeable upon
treatment with D2O), 10.40 (s, 1H, NH; exchangeable upon
treatment with D2O)
10
12
14
15
3290, 3420 (NH), 1690 (C O)
3230, 3190 (NH) 2900 (CH-aliph)
1680 (C O)
3450, 3224 (NH, NH2)
16
19
3420, 3300 (NH), 1640 (C N)
3460, 3320 (NH), 2900 (CH-aliph),
2200 (C N)
1.67 (m, 8H, 4CH2), 6.90–7.74 (m, 4H, Ar-H), 9.05, 9.74, 11.31
(3s, 3H, 3NH; exchangeable upon treatment with D2O)
product was recrystallized from dioxane. MS (7a; %):
332 (M+; 48), 334 (M + 1; 32), 194 (6.88), 162 (13),
129 (16), 119 (32), 91 (17,13), 77 (19.57), 76 (17.60),
and 55 (100).
1-(4-Substituted phenyl)-2-mercaptobenzimida-
zoles (5a,b)
A mixture of 1b or 1c (0.01 mol), o-chloroaniline (2c)
(0.01 mol), and triethylamine (0.5 ml) in dioxane
(20 ml) was heated under reflux for 24 h. Then it
was allowed to cool and was poured into cold wa-
ter (5 ml). The solid product was recrystallized from
ethanol. MS (5b; %): 304 (M+; 14), 306 (M + 1; 11.25),
307 (M + 2; 13.75), 264 (11.25), 261 (38), 225 (16),
169 (20), 127 (33), 119 (21.88), 91 (44), 77 (37), 76
(48), and 75 (100).
2-(4-Substituted phenyl)imino-1,3-
benzodioxoles (8a,b)
A mixture of 1a or 1c (0.01 mol), catechol (2f)
(0.01 mol), and a few drops of triethylamine in N,N-
dimethylformamide (10 ml) was refluxed for 1 h,
then allowed to cool. The solid product was collected
and recrystallized from dioxane. MS (8b; %): 291
(M + 1; 10.88), 292 (M + 2; 7.65), 171 (12), 157 (20),
135 (27), 119 (41), 105 (16), 91 (40.29), 90 (27), 77
(78), 76 (32), and 55 (100).
2-Chlorophenyl-N-(4-bromophenyl)-
thiocarbamate (6)
A mixture of 1c (0.01 mol), o-chlorophenol (2d)
(0.01 mol), and triethylamine (0.5 ml) was fused at
120◦C for 1 h, then cooled and the product was tri-
turated with ethanol (30 ml). The solid product was
recrystallized from ethanol.
3-(4-Bromophenyl)-5-imino-2-methyl-4-
oxazolidinethione (9)
A solution of 1c (0.01 mol) in dry ether (20 ml) was
treated with acetaldehyde (0.01 mol) and triethyl-
amine (0.5 ml). The reaction mixture was stirred
at room temperature for 0.5 h, then mixed with
n-hexane to give a solid which was recrystallized
from ethanol.
Quinazolinones (7a,b)
A mixture of 1c or 1d (0.01 mol), anthranilic acid
(2e) (0.01 mol), and triethylamine (0.5 ml) in abso-
lute ethanol (30 ml) was refluxed for 3 h. The solid

616 El-Gaby et al.
water (50 ml). The solid product was collected and
recrystallized from ethanol.
Formation of 2-[N-(4-Bromophenyl)thiocarba-
moyl]-4-(1H)quinazolinone (10), 6-[N-(4-
Bromophenyl)thiocarbamoyl]-1-phenyl-
pyrazolo[3,4-d]-4-(1H)pyrimidinone (12), and
2-[N-(4-Bromophenyl)thiocarbamoyl]-5,6,7,8-
tetrahydro[b]thieno-4-(1H)pyrimidinone (14)
N-(4-Bromophenyl)-2-[2-(3-cyano-4,5,6,7-
tetrahydro)benzo[b]thienyl]amino-2-iminothio-
acetamide (19)
A mixture of 9 (0.01 mol), an o-amino carboxylic acid
derivative (0.01 mol), and triethylamine (0.5 ml) in
absolute ethanol (20 ml) was refluxed for 15 min.
The solid product formed was collected and recrys-
tallized from dioxane. MS (10; %): 360 (M+; 79), 361
(M + 1; 56), 362 (M + 2; 11.90), 326 (14), 280 (44),
177 (28.25), 119 (100), 91 (33.90), and 71 (9.76).
MS (12; %): 426 (M+; 7.14), 371 (7), 296 (10.7), 274
(15), 219 (10.71), 194 (9.52), 186 (26), 153 (47.62),
119 (10.71), 95 (11.90), 78 (3.57), and 64 (100). MS
(14; %): 420 (M+; 7.46), 386 (4.48), 305 (11.94), 289
(13), 260 (66.42), 258 (93.66), 236 (10.45), 183 (100),
172 (37.31), 148 (25.75), 118 (53), 90 (17), and 77
(1.12).
A mixture of 9 (0.01 mol), 2-amino-4,5,6,7-tetrahy-
drobenz[b]-3-thiophenecarbonitrile (18) (0.01 mol),
triethylamine (0.5 ml), and ethanol/DMF (1:1
volume, 20 ml) was heated under reflux for 36 h,
then it was allowed to cool and was poured into cold
water (100 ml). The solid product was recrystallized
from ethanol. MS (%): 418 (M+; 2.2), 420 (M + 2;
1.3), 397 (1.7), 358 (5.9), 285 (1.3), 273 (16.3), 202
(4.0), 193 (5.1), 192 (41.3), 183 (0.7), and 178 (100).
REFERENCES
[1] Papadopoulos, E. P. J Org Chem 1979, 44(22), 3858.
[2] Ketcham, R.; Schaumann, E. J Org Chem 1980,
45(19), 3748.
[3] Khattak, I.; Ketcham, R.; Schaumann, E.; Adiwidjaja,
G. J Org Chem 1985, 50(19), 3431.
[4] El-Sharief, A. M. Sh.; Ammar, Y. A.; Mohamed, Y. A.;
El-Gaby, M. S. A. Phosphorus, Sulfur Silicon 1999,
148, 117.
[5] El-Sharief, A. M. Sh.; Ammar, Y. A.; Mohamed, Y. A.;
El-Gaby, M. S. A. Phosphorus, Sulfur Silicon 1999,
148, 215.
[6] El-Sharief, A. M. Sh.; Atalla, A. A.; Hussein, A. M.;
El-Gaby, M. S. A.; Hassan, A. A. Phosphorus, Sulfur
Silicon, 2000, 160, 141.
[7] El-Sharief, A. M. Sh.; Hussein, A. M.; El-Gaby,
M. S. A.; Atalla, A. A.; Ahmed, A. A. Phosphorus,
Sulfur Silicon, 2001, 170, 47.
[8] Van Allan, J. A.; Deacon, B. D. Org Synth Coll IV 1963,
569.
[9] Mukerjee, A. K.; Ashare, R. Chem Rev 1991, 91(1), 1.
[10] El-Gaby, M. S. A. Phosphorus, Sulfur Silicon 2000,
156, 157.
[11] Reissert, A.; Bruggemann, K. Ber Dtsch Chem Ges
1924, 57, 981.
2-[N-(4-Bromophenyl)2,3-quinoxaline-
diamine (15)
A mixture of 9 (0.01 mol), o-phenylenediamine (2a)
(0.01 mol), triethylamine (0.5 ml), and absolute
ethanol (30 ml) was heated under reflux for 3 h, then
allowed to cool and poured into cold water (50 ml).
The precipitated product was collected and recrys-
tallized from ethanol. MS (15; %): 315 (M+; 20), 316
(M + 1; 4.9), 314 (M −1; 27), 300 (M − NH; 7.7), 299
(M − NH2; 45), 284 (1.8), 275 (18.13), 257 (18.1), 234
(15.8), 212 (68.9), 198 (35.7), 183 (25.3), 170 (100),
134 (20), 133 (47), and 129 (10.5).
N-(4-Bromophenyl)-2-(2-hydroxyphenylamino)-
2-iminothioacetamide (16)
[12] Pathak, U. S.; Gadha, S.; Rathod, I. S. Indian J Chem,
Sect B 1994, 33, 734.
[13] Gewald, K. Z Chem 1967, 7(5), 186.
[14] Gewald, K.; Schinke, E.; Boettcher, H. Chem Ber
1966, 99, 44.
A mixture of 9 (0.01 mol), o-aminophenol (2b)
(0.01 mol), triethylamine (0.5 ml), and absolute
ethanol (30 ml) was heated under reflux for 24 h,
then it was allowed to cool and was poured into cold