Cyanamides in the synthesis of 1,3-thiazole and 1,3-thiazine derivatives

Article abstract of DOI:10.1134/S1070428007120159

Hetaryl, aroyl, and aryl cyanamides react with 2-sulfanylbenzoic acid, 2-aminobenzenethiol, and 2-aminoethanethiol to give derivatives of 2-amino-4H-1,3-benzothiazin-4-one, 1,3-benzothiazol-2-amine, and 4,5-dihydro-1,3-thiazol-2-amine.

Full text of DOI:10.1134/S1070428007120159

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 12, pp. 1825–1829. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © A.S. Shestakov, N.V. Gusakova, Kh.S. Shikhaliev, A.G. Timoshkina, 2007, published in Zhurnal Organicheskoi Khimii, 2007,
Vol. 43, No. 12, pp. 1822–1826.
Cyanamides in the Synthesis of 1,3-Thiazole
and 1,3-Thiazine Derivatives
A. S. Shestakov, N. V. Gusakova, Kh. S. Shikhaliev, and A. G. Timoshkina
Voronezh State University, Universitetskaya pl. 1, Voronezh, 394006 Russia
e-mail: chocd261@chem.vsu.ru
Received January 26, 2007; revised July 31, 2007
Abstract—Hetaryl, aroyl, and aryl cyanamides react with 2-sulfanylbenzoic acid, 2-aminobenzenethiol, and
2-aminoethanethiol to give derivatives of 2-amino-4H-1,3-benzothiazin-4-one, 1,3-benzothiazol-2-amine, and
4,5-dihydro-1,3-thiazol-2-amine.
DOI: 10.1134/S1070428007120159
Cyanamides are convenient building blocks in the
synthesis of various aliphatic, aromatic, and hetero-
cyclic compounds [1]. Conjugation between lone elec-
tron pair on the amino nitrogen atom and the triple
C≡N bond increases the electron density on the cyano
nitrogen atom. Just enhanced nucleophilicity of the
latter in combination with fairly high electrophilicity
of the triple-bonded carbon atom is responsible for the
high reactivity of cyanamides in various heterocycliza-
tions. Advances in the preparative chemistry of cyan-
amides and accessibility of such sulfur-containing
compounds as 2-sulfanylbenzoic acid (I), 2-aminoben-
zenethiol (II), and 2-aminoethanethiol (III; it is also
known as radioprotective agent Mercamine) make it
possible to widely use these compounds in the syn-
thesis of S,N-containing heterocycles.
bamoyl cyanide [2], cyanamide H2NCN, cyanogua-
nidine, and cyanourea [3, 4]. We used as cyano com-
ponents cyanamides V–XI. Methods of preparation of
these compounds were reviewed in [5].
The reaction of acid I with cyanamides may in-
volve initial nucleophilic attack by the cyano nitrogen
atom on the electrophilic carbonyl carbon atom. How-
ever, it seems more likely that the reaction begins with
addition of soft nucleophilic SH group at the triple-
bonded carbon atom with formation of intermediate
thiourea derivative A. The subsequent intramolecular
cyclization yields benzothiazinones IV as shown in
Scheme 1. This reaction sequence is supported by the
following. First, heterocyclic analog of 2-sulfanylben-
zoic acid (I), 2-sulfanylpyridine-3-carboxylic acid, in
which the nucleophilicity of the SH group is reduced,
reacted only with compound VIa containing a fairly
electrophilic carbon atom in the cyanamide moiety; as
a result, the corresponding 2-amino-4H-pyrido[3,2-e]-
2-Amino-4H-1,3-benzothiazin-4-one derivatives
(IV) can be obtained from acid I via reactions with
compounds having a cyano group, e.g., phenylcar-
Me
O
O
CN
CN
N
N
N
H
H
CN
Me
N
N
R1
SR2
H
V
VIa, VIb
VIIa, VIIb
H
H
H
CN
CN
NH
N
N
N
NH
CN
CN
N
N
N
H
N
H
N
R3
VIIIa, VIIIb
IX
X
XI
R1 = H (a), 4-Cl (b); R2 = Me (a), Et (b); R3 = 2-MeO (a), 4-MeO (b).
1825

SHESTAKOV et al.
1826
Scheme 1.
O
O
S
COOH
NH
OH
N
+
RNHCN
–H2O
O
SH
S
NHR
NHR
I
A
IVa–IVf
O
O
OH
SH
NHCN
N
O
+
–H2O
N
N
S
N
Ph
H
IVg
IV, R = 4,6-dimethylpyrimidin-2-yl (a), 2-MeOC6H4 (b), 4-ClC6H4CO (c), 2-MeSC6H4CO (d), 2-EtSC6H4CO (e),
4,5-dihydro-1H-imidazol-2-yl (f).
[1,3]thiazin-4-one derivative IVg was obtained. 2-Sul-
fanylpyridine-3-carboxylic acid failed to react with
cyanamides V and VIII–XI, and the initial compounds
were recovered from the reaction mixtures. Second, no
reaction occurred between cyanamides and salicylic
acid [3] which is an oxygen-containing analog of I.
Finally, in keeping with published data [6], hetero-
cyclizations of 2-sulfanylbenzoic acid (I) with dielec-
trophiles most frequently involve intermediate sulfides.
was formed as a result of oxidation. We found that
the use of hydrochloric acid as general acid catalyst
ensures shorter reaction time and prevents formation of
by-products (Scheme 2).
Presumably, the heterocyclization involves interme-
diate formation of thioureas B and C. A similar inter-
mediate was presumed in the reactions of 2-amino-
benzenethiol (II) with N,N′-diarylcarbodiimides [14]
(which may be regarded as structural analogs of cyan-
amides) and aromatic nitriles [11]. Protonation of the
imino nitrogen atom in intermediate thiourea B facili-
tates subsequent elimination of that nitrogen atom.
An analogous mechanism with participation of type C
intermediate was proposed previously for the forma-
tion of 2-aminodihydrothiazole from S-aminoethyliso-
thiuronium bromide on heating [15]. In the reaction
with cyanamide X incorporating a basic guanidine
fragment, 2 equiv of HCl was necessary.
The thiazole ring can also be built up on the basis
of the N–C–C–S dinucleophilic system [7] in com-
pounds II and III. Ring closures with such 2-amino-
thiols require an electrophilic one-carbon fragment.
Benzothiazole derivatives may be obtained from
2-aminobenzenethiol (II) and carboxylic acids [8] or
their derivatives [9, 10], including nitriles [11, 12].
Reactions with some hetaryl-substituted cyanamides
were also reported [13]. However, when such com-
pounds were heated with thiol II in boiling ethanol
over a period of 5 h, only the corresponding disulfide
The structure of benzothiazinone IVc and benzo-
thiazole XIIc was confirmed by independent syn-
Scheme 2.
NH2
SH
NH2
N
S
H+
NH2
+
RNHCN
NHR
–H+
S
NHR
II
B
XIIa–XIIe
Me
NH2
S
H+
N
N
NH2
NHR
+
HSCH2CH2NH2
V
–H+
S
N
N
Me
H
III
C
XIII
XII, R = 4,6-dimethylpyrimidin-2-yl (a), 4-MeOC6H4 (b), PhCO (c), 2-EtSC6H4CO (d), 3a,4,5,6,7,7a-hexahydro-
1H-benzimidazol-2-yl (e).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007

CYANAMIDES IN THE SYNTHESIS OF 1,3-THIAZOLE
1827
Scheme 3.
O
O
O
S
N
Cl
N
O
+
S
NH2
Cl
N
H
Cl
XIV
IVc
N
N
BzCl
NH2
NHBz
S
S
XV
XIIc
theses, acylation of 2-amino-4H-1,3-benzothiazin-4-
one (XIV) and 1,3-benzothiazol-2-amine (XV) with
4-chlorobenzoyl chloride and benzoyl chloride, respec-
tively (Scheme 3).
4-Chloro-N-(4-oxo-4H-1,3-benzothiazin-2-yl)-
benzamide (IVc). Yield 1.05 g (33%), mp 238–
240°C (a).
b. 4-Chlorobenzoyl chloride, 1.87 g (10.5 mmol),
was added to a solution of 1.78 g (10 mmol) of thia-
zinone XVI in 10 ml of anhydrous pyridine, and the
mixture was stirred for 2 h and diluted with cold water.
The precipitate was filtered off and recrystallized from
EXPERIMENTAL
The progress of reactions and the purity of products
were monitored by TLC using Merck UV-254 plates;
eluent chloroform–methanol (20:1). The 1H NMR spec-
tra were measured on a Bruker AC-300 spectrometer
(300 MHz) relative to TMS as internal reference.
1
DMF. Yield 1.39 g (44%), mp 237–239°C. H NMR
spectrum (DMSO-d6–CCl4), δ, ppm: 7.22 t (1H, Harom
J = 7 Hz), 7.35 d (1H, Harom, J = 9 Hz), 7.55 d (2H,
arom, J = 8 Hz), 7.65 d (1H, Harom, J = 8 Hz), 7.76 t
,
H
(1H, Harom, J = 8 Hz), 7.93 d (2H, Harom, J = 9 Hz),
12.52 s (1H, NH). Found, %: C 56.60; H 2.84; N 8.96.
C15H9ClN2O2S. Calculated, %: C 56.88; H 2.86; N 8.84.
2-(4,6-Dimethylpyrimidin-2-ylamino)-4H-
1,3-benzothiazin-4-one (IVa). a. A mixture of 1.54 g
(10 mmol) of acid I and 1.48 g (10 mmol) of cyan-
amide V in dioxane was heated for 5 h under reflux. It
was then evaporated on a rotary evaporator, and the
residue was recrystallized from dioxane–DMF (1:1).
2-Methylsulfanyl-N-(4-oxo-4H-1,3-benzothiazin-
2-yl)benzamide (IVd). Yield 1.87 g (57%), mp 194–
1
195°C. H NMR spectrum (DMSO-d6–CCl4), δ, ppm:
1
Yield 1.00 g (35%), mp 240–241°C. H NMR spec-
2.42 s (3H, SCH3), 7.20 t (1H, Harom, J = 8 Hz), 7.33 d
(1H, Harom, J = 9 Hz), 7.45–7.56 m (2H, Harom), 7.61–
7.75 m (2H, Harom), 8.21 br.s (1H, Harom), 8.29 d
(1H, Harom, J = 8 Hz), 12.41 s (1H, NH). Found, %:
C 58.50; H 3.74; N 8.64. C16H12N2O2S2. Calculated,
%: C 58.52; H 3.68; N 8.53.
trum (DMSO-d6–CCl4), δ, ppm: 2.48 s (6H, CH3),
6.90 s (1H, 5′-H), 7.42–7.53 m (2H, Harom), 7.63 t
(1H, Harom, J = 7 Hz), 8.22 d (1H, Harom, J = 8 Hz),
11.85 br.s (1H, NH). Found, %: C 59.36; H 4.17;
N 19.86. C14H12N4OS. Calculated, %: C 59.14; H 4.25;
N 19.70.
2-Ethylsulfanyl)-N-(4-oxo-4H-1,3-benzothiazin-
2-yl)benzamide (IVe). Yield 1.57 g (46%), mp 185–
Benzothiazinones IVb–IVf were synthesized in
a similar way.
1
187°C. H NMR spectrum (DMSO-d6–CCl4), δ, ppm:
1.47 t (3H, CH2CH3, J = 7 Hz), 2.92 q (2H, CH2CH3,
J = 8 Hz), 7.21 t (1H, Harom, J = 7 Hz), 7.33–7.76 m
2-(2-Methoxyphenylamino)-4H-1,3-benzothia-
zin-4-one (IVb). After evaporation of the reaction
mixture, the residue was recrystallized from propan-2-
ol. Yield 0.80 g (28%), mp 131–132°C. 1H NMR spec-
trum (DMSO-d6), δ, ppm: 3.78 s (3H, OCH3), 6.93–
7.25 m (4H, Harom), 7.44 t (2H, Harom, J = 9 Hz), 7.51 t
(1H, Harom, J = 8 Hz), 8.19 d (1H, Harom, J = 9 Hz),
11.79 br.s (1H, NH). Found, %: C 63.34; H 4.16;
N 9.74. C15H12N2O2S. Calculated, %: C 63.36; H 4.25;
N 9.85.
(5H, Harom), 8.32 br.s (1H, Harom), 8.28 d (1H, Harom
,
J = 8 Hz), 12.60 s (1H, NH). Found, %: C 59.82;
H 4.28; N 8.22. C17H14N2O2S2. Calculated, %: C 59.63;
H 4.12; N 8.18.
2-(Imidazolidin-2-ylideneamino)-4H-1,3-benzo-
thiazin-4-one (IVf). Yield 1.60 g (65%), mp 278–
1
280°C. H NMR spectrum (DMSO-d6), δ, ppm: 3.62 s
(4H, CH2), 7.39–7.50 m (2H, Harom), 7.60 t (1H, Harom
,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007

SHESTAKOV et al.
1828
J = 10 Hz), 8.21 d (1H, Harom, J = 14 Hz), 8.48 s
(2H, NH). Found, %: C 53.46; H 4.01; N 22.72.
C11H10N4OS. Calculated, %: C 53.65; H 4.09; N 22.75.
b. Benzoyl chloride, 2.95 g (21 mmol), was added
dropwise to a solution of 3.00 g (20 mmol) of
1,3-benzothiazol-2-amine (XV) in 10 ml of anhydrous
pyridine. The mixture was stirred for 0.5 h at room
temperature and diluted with cold water, and the
precipitate was filtered off and recrystallized from
dioxane. Yield 3.15 g (62%), mp 177–179°C. 1H NMR
N-(4-Oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)-
benzamide (IVg). A solution of 2.33 g (15 mmol)
of 2-sulfanylpyridine-3-carboxylic acid and 2.19 g
(15 mmol) of cyanamide VIa in 20 ml of N,N-di-
methylacetamide was heated for 5 h at 100°C. The
mixture was cooled and poured into 150 ml of cold
water, and the precipitate was filtered off and recrys-
tallized from propan-2-ol–dioxane (1:2). Yield 0.46 g
spectrum (DMSO-d6–CCl4), δ, ppm: 7.33 d (1H, Harom
J = 8 Hz), 7.45 t (1H, Harom, J = 7 Hz), 7.55 m (2H,
Harom), 7.63 t (1H, Harom, J = 7 Hz), 7.79 d (1H, Harom
,
,
J = 8 Hz), 8.03 d (1H, Harom, J = 8 Hz), 8.17 d (2H,
Harom, J = 8 Hz), 12.88 s (1H, NH). Found, %: C 66.15;
H 3.98; N 11.04. C14H10N2OS. Calculated, %: C 66.12;
H 3.96; N 11.02.
1
(10%), mp 232°C. H NMR spectrum (DMSO-d6–
CCl4), δ, ppm: 7.50 m (2H, Harom), 7.59 m (2H, Harom),
8.19 m (2H, Harom), 8.54 m (1H, Harom), 8.81 s
(1H, Harom), 12.77 br.s (1H, NH). Found, %: C 59.46;
H 3.09; N 14.93. C14H9N3O2S. Calculated, %: C 59.30;
H 3.18; N 14.82.
2-Ethylsulfanyl-N-(1,3-benzothiazol-2-yl)benz-
amide (XIId). Yield 2.01 g (32%), mp 118–120°C.
1H NMR spectrum (DMSO-d6–CCl4), δ, ppm: 1.33 t
(3H, CH2CH3, J = 7 Hz), 2.98 q (2H, CH2CH3, J =
7 Hz), 7.38–7.56 m (5H, Harom), 7.65 d (1H, Harom, J =
8 Hz), 7.76 d (1H, Harom, J = 8 Hz), 12.78 s (1H, NH).
Found, %: C 61.04; H 4.57; N 8.94. C16H14N2OS2.
Calculated, %: C 61.12; H 4.49; N 8.91.
N-(4,6-Dimethylpyrimidin-2-yl)-1,3-benzothia-
zol-2-amine (XIIa). a. Concentrated hydrochloric
acid, 1.8 ml (20 mmol), was slowly added dropwise
under stirring to a mixture of 2.50 g (20 mmol) of
2-aminobenzenethiol (II) and 2.96 g (20 mmol) of
cyanamide V in 20 ml of isopropyl alcohol, and the
mixture was carefully heated to the boiling point and
maintained boiling over a period of 1 h. It was then
cooled and poured into 150 ml of cold water, a solution
of 0.8 g (20 mmol) of sodium hydroxide in 50 ml of
water was added, and the precipitate was filtered off
and recrystallized from dioxane. Yield 4.56 g (89%),
N-(3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-
yl)-1,3-benzothiazol-2-amine (XIIe). Concentrated
hydrochloric acid, 1.8 ml (20 mmol), was added drop-
wise under stirring to a mixture of 1.68 g (10 mmol) of
2-aminobenzenethiol (II) and 1.25 g (10 mmol) of
cyanamide X in 20 ml of isopropyl alcohol, and the
mixture was heated for 1 h at the boiling point. It was
then cooled and poured into 150 ml of cold water,
a solution of 0.8 g (20 mmol) of sodium hydroxide in
50 ml of water was added, and the precipitate was
filtered off and recrystallized from dioxane. Yield
1
mp 245–246°C. H NMR spectrum (DMSO-d6), δ,
ppm: 2.42 s (6H, CH3), 6.87 s (1H, 5′-H), 7.22 t (1H,
Harom, J = 7 Hz), 7.39 t (1H, Harom, J = 8 Hz), 7.68 d
(1H, Harom, J = 9 Hz), 7.92 d (1Harom, J = 9 Hz),
11.62 br.s (1H, NH). Found, %: C 60.86; H 4.67;
N 21.96. C13H12N4S. Calculated, %: C 60.92; H 4.72;
N 21.86.
1
0.76 g (28%), mp 260–262°C. H NMR spectrum
(DMSO-d6–CCl4), δ, ppm: 1.3–1.5 m (4H, CH2),
1.75 d (2H, CH2, J = 6 Hz), 2.1 d (2H, CH2, J =
12 Hz), 3.1 d (2H, CH, J = 5 Hz), 7.1 t (1H, Harom, J =
1,3-Benzothiazoles XIIb–XIId were synthesized in
a similar way.
7 Hz), 7.25 t (1H, Harom, J = 8 Hz), 7.51 d (1H, Harom
,
J = 8 Hz), 7.7 d (1H, Harom, J = 8 Hz), 8.1 s (1H, NH).
Found, %: C 61.76; H 5.96; N 20.54. C14H16N4S. Cal-
culated, %: C 61.74; H 5.92; N 20.57.
N-(4-Methoxyphenyl)-1,3-benzothiazol-2-amine
(XIIb). The product was recrystallized from toluene–
petroleum ether (2:1). Yield 1.79 g (35%), mp 154–
N-(4,6-Dimethylpyrimidin-2-yl)-4,5-dihydrothia-
zol-2-amine hydrochloride (XIII). A mixture of
2.27 g (20 mmol) of 2-aminoethanethiol hydrochloride
and 2.96 g (20 mmol) of cyanamide V in 15 ml of
dioxane was heated while adding distilled water until
complete decoloration of the mixture. The mixture was
then heated for 2 h under reflux and filtered, the filtrate
was evaporated on a rotary evaporator, and the residue
was recrystallized from propan-2-ol–water (2:1). Yield
1
155°C. H NMR spectrum (DMSO-d6–CCl4), δ, ppm:
3.77 s (3H, OCH3), 7.12 d (2H, Harom, J = 9 Hz), 7.53–
7.68 m (4H, Harom), 8.10 d (1H, Harom, J = 9 Hz), 8.25 d
(1H, Harom, J = 9 Hz), 10.36 s (1H, NH). Found, %:
C 65.76; H 4.56; N 11.02. C14H12N2OS. Calculated, %:
C 65.60; H 4.72; N 10.93.
N-(1,3-Benzothiazol-2-yl)benzamide (XIIc). Yield
3.05 g (60%), mp 178–180°C (a).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 12 2007

CYANAMIDES IN THE SYNTHESIS OF 1,3-THIAZOLE
1829
1
6. Koval’, I.V., Russ. J. Org. Chem., 2006, vol. 42, p. 625.
2.01 g (41%), mp 168°C. H NMR spectrum
(DMSO-d6–CCl4), δ, ppm: 2.34 s (6H, CH3), 3.12 d.t
(2H, SCH2, J4,5 = 7, J5,5 = 21 Hz), 3.75–3.88 m (2H,
CH2), 7.58 s (1H, 5′-H), 6.92 s (1H, NH), 10.09 br.s
(HCl). Found, %: C 44.33; H 4.95; N 22.78. C9H12N4S·
HCl. Calculated, %: C 44.15; H 4.81; N 22.89.
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Katritzky, A.R. and Rees, C.W., Eds., Oxford:
Pergamon, 1997, vol. 3, p. 995.
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Saito, T., and Yoshino, K., Chem. Pharm. Bull., 1992,
vol. 40, p. 2387.
9. Quast, H. and Schmidt, E., Chem. Ber., 1969, vol. 102,
p. 568.
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