Heterocyclic synthesis containing bridgehead nitrogen atom: Synthesis of 3-[(2H)- 2-oxobenzo[b]pyran-3-yl]-s-triazolo[3,4-b]-1,3,4-thiadiazine and thiazole derivatives

Article abstract of DOI:10.1002/hc.10109

The reaction of 2H-2-oxobenzo[b]-pyran-3-hydrazide (2) with carbon disulfide in basic DMF afforded potassium thiocarbamate 3, which readily underwent heterocyclization upon its reaction with hydrazine and/or phenacyl bromide to yield 1,2,4-tiazole (4) and thiazole 7 derivatives, respectively. Condensation of 4 with substituted phenacyl bromide and/or chloranil gave 1,2,4-triazole[3,4-b]thiadiazine (5a,b) and 3,10-bis-[2H-2-oxobenzo[b]pyran-3-yl]-6,13-dichloro-bis-[2H-2-oxobenzo[b]pyran-3 -yl]- 6,13-dichloro-bis-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazino [5′,6′-b:5′,6′-e]cyclohexa-1,4-diene (6), respectively. Cyclization of thiosemicarbazide 10 by refluxing it in sodium hydroxide and/or phosphoryl chloride afforded triazole 13 and thiadiazole 15 derivatives, respectively. Also, 10 reacted with phenacyl bromide in the presence of anhydrous sodium acetate to give the oxothiazolidine derivative 17. The structure of the synthesized compounds were confirmed by elemental analyses, IR, ¹H NMR, and mass spectra.

Full text of DOI:10.1002/hc.10109

Heteroatom Chemistry
Volume 14, Number 2, 2003
Heterocyclic Synthesis Containing Bridgehead
Nitrogen Atom: Synthesis of 3-[(2H )-
2-Oxobenzo[b]pyran-3-yl]-s-triazolo[3,4-b]-
1,3,4-thiadiazine and Thiazole Derivatives
M. A. Raslan and M. A. Khalil
Chemistry Department, Faculty of Science, South Valley University, Aswan, Egypt
Received 23 May 2002; revised 30 June 2002
antiseptic, analgesic, antiasthmatic, diuretic, antihy-
ABSTRACT: The reaction of 2H-2-oxobenzo[b]-
pertensive, anticholinergic, anti-inflammatory, an-
pyran-3-hydrazide (2) with carbon disulfide in basic
titumor, and hypotensive effects [1–11]. There are
DMF afforded potassium thiocarbamate 3, which re-
known drugs containing the 1,2,4-triazole group,
adily underwent heterocyclization upon its reaction
e.g. Triazolom and Alprazolam [12,13]. Addition-
with hydrazine and/or phenacyl bromide to yield 1,2,4-
ally, several of the 3-substituted thio-1,2,4-triazoles
tiazole (4) and thiazole 7 derivatives, respectively.
have shown biological activity against tuberculosis
Condensation of 4 with substituted phenacyl bromide
[14,15], as anticoccidal agents in chicken [16], and
and/or chloranil gave 1,2,4-triazole[3,4-b]thiadiazine
in cephalosporins as antibacterial agents [17].
(5a,b) and 3,10-bis-[2H-2-oxobenzo[ b]pyran-3-yl]-
s-Triazolo[3,4-b]-1,2,4-thiadiazine
derivatives
6,13-dichloro-bis-1,2,4-triazolo[3,4-b]-1,3,4-thiadia-
zino[5ꢀ,6ꢀ-b:5ꢀ,6ꢀ-e]cyclohexa-1,4-diene (6), respec-
tively. Cyclization of thiosemicarbazide 10 by refluxing
it in sodium hydroxide and/or phosphoryl chloride
afforded triazole 13 and thiadiazole 15 derivatives,
respectively. Also, 10 reacted with phenacyl bromide
in the presence of anhydrous sodium acetate to
give the oxothiazolidine derivative 17. The structure
of the synthesized compounds were confirmed by
elemental analyses, IR, 1H NMR, and mass spec-
constitute an important class of organic compounds
with diverse biological activities such as antipara-
sitic, analgesic, antibacterial, and CNS depressant
[18–22]. Thiazole derivatives are also associated
with a broad spectrum of biological properties,
including anticonvulsant [23,24], antimicrobial
[25–27], antituberculous, and bacteriostatic activ-
ities [28,29]. On the other hand coumarines, an
important group of organic compounds, are used
as additives to food and cosmetics [30], optical
brightening agent [31], and dispersed fluorescent
and laser dyes [32].
ꢁ
C
tra.
2003 Wiley Periodicals, Inc. Heteroatom Chem
14:114–120, 2003; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.10109
Therefore, compounds containing 1,2,4-triazole,
s-triazolo[3,4-b]-1,3,4-thiadiazine, thiazole, and cou-
marine moieties are expected to possess potential
biological activities. Our previous work aimed at
developing new approaches to the synthesis of poly-
functionally substituted heterocyclic compounds of
expected biological activity [33–38]. Herein we re-
port the synthesis of heterocyclic compounds con-
taining the aforementioned rings via readily avail-
able ethyl 2H-2-oxobenzo[b]pyran-3-carboxylate.
INTRODUCTION
1,2,4-Triazole derivatives have been found to be ac-
tive compounds having therapeutic nature, such as
Correspondence to: M. A. Raslan; e-mail: raslanma@yahoo.com.
2003 Wiley Periodicals, Inc.
c
ꢁ
114

Heterocyclic Synthesis Containing Bridgehead Nitrogen Atom 115
C S group at 1215–1190 cm−1. The 1H NMR spectra
of 7 exhibited a singlet signal for thiazole H-5, pyrane
H-4, and NH protons at δ 6.42, 6.72, and 9.24 ppm,
respectively, in addition to aromatic protons at δ
7.23–8.31 ppm. Product 7 was found to be identical
in all respects with an authentic sample prepared by
an independent method [40].
Ethyl 2H-2-oxobenzo[b]pyran-3-carboxylate (1)
reacts with hydrazine hydrate to give 2H-2-oxoben-
zo[b]pyran-3-hydrazide (2). Hydrazide 2 reacts with
carbon disulfide in N,N-dimethylformamide con-
taining potassium hydroxide at room temperature
to give the nonisolable potassium thiocarbamate
salt (3), which was subjected to heterocyclization
through its reaction with hydrazine hydrate to afford
4-amino-5-[2H-2-oxobenzo[b]pyran-3-yl]-1,2,4-tria-
zole-3-thione (4). The structure of 4 was established
on the basis of analytical and spectral data. Thus,
the IR spectrum of reaction product 4 showed the
presence of an NH2 and an NH group at 3310 and
3180 cm−1, C H aromatic at 3050 cm−1, and CO
group at 1712 cm−1. The 1H NMR spectrum showed
the presence of singlet signals (D2O-exchangeable)
at δ 5.21 and 13.46 ppm corresponding to NH2 and
SH protons, respectively, in addition to pyrane H-4
and phenyl protons at δ 6.69 and 7.35–8.4 ppm,
respectively.
Cyclization of 4-amino-5-[2H-2-oxobenzo[b]-
pyran-3-yl]-1,2,4-triazole-3-thione (4) with substi-
tuted phenacyl bromide has been the most useful
method for the formation of s-triazolo[3,4-b]-1,3,4-
thiadiazine ring system. However, this cyclization
has afforded different products under various
reaction conditions [39]. Thus, the treatment of 4
with 4-substituted phenacyl bromide in absolute
ethanol containing potassium carbonate resulted
in cyclocondensation to give the corresponding 6-
substituted phenyl 3-[2H-2-oxobenzo[b]pyran-3-yl]-
7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (5a,b).
The structures of 5a,b were established on the
basis of elemental analyses and spectral data. IR
spectra showed no absorption bands assignable
to NH2 and NH groups. The 1H NMR spectra
of 5a exhibited a singlet signal for SCH2 and
pyran H-4 protons at δ 4.55 and 6.65 ppm, respec-
tively, in addition to aromatic protons at δ 7.35–
8.46 ppm.
Reaction of hydrazide 2 with the appropriate
aromatic aldehydes afforded 3-(arylidenehydr-
azinocarbonyl)-2H-2-oxobenzo[b]pyrane (8), which
on condensation with mercaptoacetic acid in dry
benzene gave the corresponding3-[(2-phenyl-4-oxo-
thiazolidinyl)aminocarbonyl]-2H-2-oxobenzo-[b]-
pyrane (9) (Scheme 1). The IR spectrum of the com-
pound 8a showed NH stretching at 3340 cm−1 and
two C O group stretchings at 1712 and 1670 cm−1,
while in 9a NH group stretching at 3211 cm−1 and
three C O group stretchings at 1730, 1715, and
1
1670 cm−1. The H NMR spectra of 8a showed a
singlet at δ 7.13 ppm for one proton of N CH,
while it is shifted upfield to δ 5.84 ppm in 9a, because
the sp2 carbon of 8a was transformed into the sp3
1
carbon of 9a. Also, H NMR of 9a showed double
doublets at δ 3.72 and 3.88 ppm for two protons
of COCH2S .
Treatment of an ethanolic solution of 4 with chlo-
ranil in the presence of anhydrous sodium acetate
afforded the corresponding 3,10-bis-[2H-2-oxobenzo-
[b]pyran-3-yl]-6,13-dichloro-bis-1,2,4-triazolo[3,4-b]-
1,3,4-thiadiazino[5ꢀ,6ꢀ-b:5ꢀ,6ꢀ-e]cyclohexa-1,4-diene
(6). The structure of 6 was established on the basis
of elemental analyses and spectral data. The 1H
NMR spectra of 6 showed only signals for pyrane
H-4 and aromatic protons.
Reaction of N-potassium thiocarbamate salt 3
with phenacyl bromide gave thiazole derivative 7.
The structure of 7 was established on the basis of ele-
mental analyses and spectral data. IR spectra showed
an absorption band assignable to NH group at 3450–
3320 cm−1, 2C O groups at 1710, 1670 cm−1, and
SCHEME 1

116 Raslan and Khalil
Reaction of phenyl isothiocyante with 2H-2-
oxobenzo[b]pyran-3-hydrazide (2) in dioxane gave 1-
(3-carbonyl-2H-2-oxobenzo[b]pyrane)-4-phenyl thio-
semicarbazide (10) (Scheme 2). Structure of 10
was assigned to this product on the basis of ele-
mental analysis and spectral data (see Experimental
section).
presence of anhydrous potassium carbonate gave N-
methyl-N-[5-(2H-2-oxobenzo-[b]pyran-3-yl)-1,3,4-
thiadiazol-2-yl]aniline (12). Also, reaction of 13 with
ethyl bromoacetate afforded the triazole derivative
11b. All structures of the compounds 12, 13, and 15
were established on the basis of elemental analysis
and spectral data (see Experimental section).
Reaction of 10 with methyl iodide in N,N-
dimethylformamide at room temperature in the
presence of anhydrous potassium carbonate gave
a solid product of molecular formula C18H13N3O2S
(M+ = 453), which may be formulated as 11a or its
Reaction of 10 with ethyl bromoacetate in abso-
lute ethanol containing anhydrous sodium acetate
did not afford the expected triazole 11b but gave
[(3-phenyl-4-oxothiazolidin-2-ylidene)hydrazonyl]
[2H-2-oxobenzo[b]pyran-3-yl] ketone (17). Forma-
tion of 17 is assumed to proceed via the intermediate
16, which undergoes cyclization via elimination
of ethanol molecule. The structure of 17 was es-
tablished on the basis of elemental analyses and
spectral data. Their IR spectra showed a new C O
1
isomer 12. Structure 11a was indicated by the H
NMR spectra, which gave conclusive evidence for
the triazole structure (see Experimental section).
The structure of triazole 11a was proven by the inde-
pendent synthesis, which involved cyclization of 10
with sodium hydroxide to afford 4-phenyl-5-(2H-2-
oxobenzo[b]pyran-3-yl)-1,2,4-triazole-3-thione (13).
Methylation of 13 with methyl iodide yielded 3-
methylthio-5-(2H-2-oxobenzo[b]pyran-3-yl)-4-phe-
nyl-1,2,4-triazole (11a). In addition, the structure of
11a was further confirmed by alternative synthesis
of its isomer 12. Heating of 10 with phosphoryl chlo-
ride gave 2-anilino-5-(2H-2-oxobenzo[b]pyran-3-yl)-
1,3,4-thiadiazole (15). Reaction of 15 with methyl
iodide in DMF and/or trimethyl phosphate in the
1
group at 1735 cm−1 and the H NMR displayed an
additional singlet at δ 4.31 ppm (S CH2), which
provided firm support for the ring closure [41].
EXPERIMENTAL
All melting points are uncorrected. IR spectra were
measured as KBr pellets on a Pye Unicam SP 1000
1
spectrophotometer. H NMR spectra were recorded
in DMSO-d6 at 200 MHz on a Varian Gemini NMR
spectrometer, using TMS as internal reference; the
chemical shifts are expressed as δ values (ppm).
13C NMR spectra were measured on a Varian XL-
300 (300 MHz) spectrometer. Mass spectra were
obtained on a Shimadzu GCMS-QP 1000 EX
mass spectrometer at 70 eV. Elemental analyses
were carried out at the Microanalytical Center of
Cairo University. Ethyl (2H)-2-oxobenzo-[b]pyran-3-
carboxylate (1) was prepared according to literature
procedures [42].
(2H)-2-Oxobenzo[b]pyran-3-hydrazide (2)
Hydrazine hydrate (0.25 g, 5 mmol) was added
to a solution of ethyl 2H-2-oxobenzo[b]pyran-3-yl
carboxylate (1) (0.22 g, 1 mmol) in ethanol (30 ml).
The reaction mixture was heated under reflux for 2 h,
concentrated in vacuum, cooled, and diluted with ice
water. The precipitate obtained was filtered, washed
with ice water, dried, and recrystallized from diox-
ane to afford 2 in 80% yield; m.p. 208◦C; IR (KBr) ꢀ
3340, 3160 (NH and NH2), 3050 (CH aromatic), 1709,
1675 (2CO) cm−1; 1H NMR [DMSO-d6]: δ = 4.72 (sbr,
2H, NH2 D2O-exchangeable), 6.73 (s, 1H, pyran H-
4), 7.32–8.42 (m, 4H, Ar-H), 9.8 (sbr, 1H, NH D2O-
exchangeable). Calcd for C10H8N2O3: C, 58.82; H,
3.96; N, 13.72%. Found: C, 58.79; H, 3.89; N, 13.7%.
SCHEME 2

Heterocyclic Synthesis Containing Bridgehead Nitrogen Atom 117
5b: Yield, 65%; m.p. 198◦C; IR (KBr) ꢀ 3062 (CH
4-Amino-5-[2H-2-oxobenzo[b]pyran-3-yl]-
1,2,4-triazole-3-thione (4) and N-(4-Phenyl-
2-thioxothiazol-3-yl)-2H-2-oxobenzo[b]pyran-
3-carboxamide (7)
1
aromatic), 1710 (C O), 1580 (C N) cm−1; H NMR
[DMSO-d6]: δ = 2.43 (s, 3H, CH3), 4.53 (s, 2H, CH2),
6.7 (s, 1H, pyran H-4), 7.22–8.36 (m, 8H, Ar-H); m/z
374 (M+). Calcd for C20H14N4O2S: C, 64.15; H, 3.78;
N, 14.97; S, 8.56%. Found: C, 64.2; H, 3.75; N, 14.88;
S, 8.6%.
General Procedures: To a stirred solution of a hy-
drazide 2 (0.2 g, 1 mmol) in DMF (20 ml), carbon
disulfide (0.076 g, 1 mmol) and potassium hydroxide
(0.056 g, 1 mmol) in water (5 ml) were added. The re-
action mixture was heated on a boiling water bath for
2 h, then left to cool till 25◦C. To this cold reaction
mixture, hydrazine hydrate (0.1 g, 2 mmol) and/or
phenacyl bromide (0.199 g, 1 mmol) was added. The
reaction mixture was cooled, diluted with ice wa-
ter (30 ml), and neutralized with hydrochloric acid.
The solid product formed on standing overnight was
filtered, washed thoroughly with cold water, and
dried. Recrystallization from ethanol yielded the cor-
responding 4 and/or 7 in 70–80% yield, respectively.
4: Yield, 80%; m.p. 233◦C; IR (KBr) ꢀ 3310, 3180
(NH and NH2), 3050 (CH aromatic), 1712 (C O),
3,10-Bis-[2H-2-oxobenzo[b]pyran-3-yl]-6,13-
dichloro-bis-1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazino[5ꢀ,6ꢀ-b:5ꢀ,6ꢀ-e]cyclohexa-1,4-diene (6)
A mixture of 4 (0.52 g, 2 mmol), tetrachloro-1,4-
benzoquinone (0.25 g, 1 mmol), and anhydrous
sodium acetate (0.072 g, 1 mmol) in absolute ethanol
(25 ml) was refluxed for 6–8 h (TLC control). The
reaction mixture acquired a reddish color and a vi-
olet solid separated. The solid product was filtered,
washed with water several times, and recrystallized
from DMF to afford 6 in 55% yield; m.p. 185◦C;
IR (KBr) ꢀ 3060 (CH aromatic), 1713 (C O) cm−1;
1H NMR [DMSO-d6]: δ = 6.68 (s, 1H, pyran H-4),
7.48–8.53 (m, 8H, Ar-H); m/z 659 (M+ + 1). Calcd for
C23H10N8O4S2Cl2: C, 51.15; H, 1.54; N, 17.05; S, 9.75;
Cl, 10.78%. Found: C, 51.23; H, 1.52; N, 16.99; S,
9.74; Cl, 10.77%.
1
1560 (NC S) cm−1; H NMR [DMSO-d6]: δ = 5.21
(sbr, 2H, NH2 D2O-exchangeable), 6.69 (s, 1H, pyran
H-4), 7.35–8.40 (m, 4H, Ar-H), 13.46 (s, 1H, SH D2O-
exchangeable); m/z 260 (M+). Calcd for C11H8N4O2S:
C, 50.76; H, 3.01; N, 21.53; S, 12.32%. Found: C,
50.72; H, 3.1; N, 21.51; S, 12.3%.
3-(Arylidenehydrazinocarbonyl)-2H-
2-oxobenzo[b]pyrane (8a,b)
7: Yield, 72%; m.p. 115◦C; IR (KBr) ꢀ 3450–3320
(NH), 3060 (CH aromatic), 1710, 1670 (2C O), 1215–
1
1190 (C S) cm−1; H NMR [DMSO-d6]: δ = 6.42 (s,
A solution of 2 (0.21 g, 1 mmol) in ethanol (25 ml) and
an appropriate aldehyde (1 mmol) was heated under
reflux for 3–6 h (TLC control). The reaction mixture
was cooled, the separated solid was filtered, washed
with small amount of cold ethanol, and recrystallized
from ethanol to yield the corresponding 8a,b in 70–
80% yield.
1H, thiazole H-5), 6.72 (s, 1H, pyran H-4), 7.23–8.31
(m, 9H, Ar-H), 9.24 (s, 1H, NH D2O-exchangable);
13C NMR (DMSO) 126.1–154.2 (C aromatic), 146.12
(C-4 thiazole), 181.4 (C-5 thiazole), 165.2 (C S),
182.3 (C O pyrane), 184.5 (CONH); m/z 380 (M+).
Calcd for C19H12N2O3S2: C, 59.98; H, 3.19; N, 7.37; S,
16.85%. Found: C, 59.94; H, 3.11; N, 7.4; S, 16.81%.
8a: Yield, 74%; m.p. 258◦C; IR (KBr) ꢀ 3340, 3180
(NH), 3055 (CH aromatic), 1712, 1670 (2C O) cm−1;
1H NMR [DMSO-d6]: δ = 6.71 (s, 1H, pyran H-4),
7.13 (s, 1H, N CH), 7.31–8.45 (m, 9H, Ar-H), 9.96
(s, 1H, NH D2O-exchangeable); m/z 272 (M+). Calcd
for C17H12N2O3: C, 69.85; H, 4.15; N, 9.59%. Found:
C, 69.86; H, 4.09; N, 9.56%.
6-Substituted Phenyl 3-[2H-2-Oxobenzo[b]-
pyran-3-yl]-7H-1,2,4-triazolo[3,4-b]-1,3,4-
thiadiazines (5a,b)
A mixture of 4 (0.26 g, 1 mmol), an appropriate
phenacyl bromide derivative (1 mmol), and fused
potassium carbonate (2 mmol) in absolute ethanol
(20 ml) was refluxed for 4–6 h. After removal of
the ethanol under reduced pressure, the resulting
solid product was filtered and washed with water.
The crude product was recrystallized from dioxane
to yield the corresponding 5a,b in 60–65% yield.
5a: Yield, 62%; m.p. 218◦C; IR (KBr) ꢀ 3059 (CH
8b: Yield, 75%; m.p. 275◦C; IR (KBr) ꢀ 3441 (OH),
3208–3180 (NH), 3060 (CH aromatic), 1708, 1675
1
(2C O) cm−1; H NMR [DMSO-d6]: δ = 6.67 (s, 1H,
pyran H-4), 7.12–8.23 (m, 10H, Ar-H and N CH),
9.94 (s, 1H, NH D2O-exchangeable), 11.74 (s, 1H,
OH). Calcd for C17H12N2O4: C, 66.23; H, 3.93; N,
9.09%. Found: C, 66.21; H, 3.98; N, 9.1%.
1
aromatic), 1706 (C O), 1582 (C N) cm−1; H NMR
3-[(2-Phenyl-4-oxothiazolidinyl)-
[DMSO-d6]: δ = 4.55 (s, 2H, CH2), 6.65 (s, 1H, pyran
H-4), 7.35–8.46 (m, 9H, Ar-H); m/z 360 (M+). Calcd
for C19H12N4O2S: C, 63.32; H, 3.36; N, 15.55; S, 8.9%.
Found: C, 63.34; H, 3.22; N, 15.5; S, 8.8 %.
aminocarbonyl]-2H-2-oxobenzo[b]pyrane (9a,b)
A mixture of 8a,b (1 mmol) and mercaptoacetic
acid (0.092 g, 1 mmol) was refluxed in dry benzene

118 Raslan and Khalil
(25 ml), using a Dean–Stark water separator. The
excess benzene was evaporated in vaccuo. The re-
sulting residue was triturated with saturated sodium
bicarbonate solution until carbon dioxide evolution
ceased and was allowed to stand overnight. The solid
thus obtained was washed with water, dried, and re-
crystallized from ethanol to yield the corresponding
9a,b in 70–75% yield.
mixture was stirred for 3–5 h at room temperature
(TLC control) and then poured into iced water. After
another stirring for 1 h, the precipitated product
was collected by filtration, washed with water, dried,
and recrystallized from ethanol to afford 11a with
yield, 54%; m.p. 190–192◦C; IR (KBr) ꢀ 3058 (CH aro-
1
matic), 1712 (C O) cm−1; H NMR [DMSO-d6]: δ =
2.79 (s, 3H, CH3), 6.81 (s, 1H, pyran H-4), 7.33–8.41
(m, 9H, Ar-H); m/z 335 (M+). Calcd for C18H13N3O2S:
C, 64.45; H, 3.91; N, 12.53; S, 9.56%. Found: C, 64.43;
H, 3.93; N, 12.52; S, 9.62%.
9a: Yield, 74%; m.p. 235◦C; IR (KBr) ꢀ 3211
(NH), 3060 (CH aromatic), 1730, 1715, 1670 (3C O)
cm−1; 1H NMR [DMSO-d6]: δ = 3.72–3.88 (dd, J-
15.9 Hz, 2H, CH2), 5.84 (s, 1H, NCHS), 6.82 (s,
1H, pyran H-4), 7.12–8.22 (m, 9H, Ar-H), 10.84
(s, 1H, NH D2O-exchangeable); m/z 368 (M+ + 1).
Calcd for C19H14N2O4S: C, 62.28; H, 3.86; N, 7.65;
S, 8.75%. Found: C, 62.25; H, 3.88; N, 7.62;
S, 8.74%.
4-Phenyl-5-(2H-2-oxobenzo[b]pyran-3-yl)-
1,2,4-triazole-3-thione (13)
A suspension of the thiosemicarbazide 10 (0.34 g,
1 mmol) in sodium hydroxide solution (5%, 15 ml)
was heated under reflux for 1 h. The reaction mix-
ture was cooled, and then adjusted to pH 6 with 10%
hydrochloric acid. The precipitate formed was fil-
tered, washed with water several times, dried, and
recrystallized from aqueous dioxane to yield 13 with
76% yield; m.p. 241–242◦C; IR (KBr) ꢀ 3190 (NH),
3050 (CH aromatic), 1708 (C O), 1575 (C N), 1270
9b: Yield, 75%; m.p. 218◦C; IR (KBr) ꢀ 3398 (OH),
3225–3180 (NH), 3060 (CH aromatic), 1732, 1705,
1
1668 (3C O) cm−1; H NMR [DMSO-d6]: δ = 3.84–
4 (dd, J-16 Hz, 2H, CH2), 5.91 (s, 1H, NCHS), 6.89
(s, 1H, pyran H-4), 7.12–8.22 (m, 9H, Ar-H), 9.71 (s,
1H, OH), 10.71 (s, 1H, NH D2O-exchangeable); 13C
NMR (DMSO) 126.2–156 (C aromatic), 30.12 (CH2S),
61.4 (SCHN), 171.2 (C O), 180.2 (C O pyran), 181.3
(CONH). Calcd for C19H14N2O5S: C, 59.67; H, 3.7; N,
7.33; S, 8.38%. Found: C, 59.72; H, 3.65; N, 7.32; S,
8.31%.
1
(NC S) cm−1; H NMR [DMSO-d6]: δ = 6.69 (s, 1H,
pyran H-4), 7.31–8.23 (m, 9H, Ar-H), 14.11 (s, 1H, SH
D2O-exchangeable). Calcd for C17H13N3O2S: C, 64.46;
H, 3.91; N, 12.53; S, 9.56%. Found: C, 64.42; H, 3.9;
N, 12.54; S, 9.52%.
1-(3-Carbonyl-2H-2-oxobenzo[b]pyran-3-yl)-
4-phenyl thiosemicarbazide (10)
3-Methylthio-5-(2H-2-oxobenzo[b]pyran-3-yl)-
4-phenyl-1,2,4-triazole (11a) and Ethyl [5-(2H-
2-oxobenzo[b]pyran-3-yl)-4-phenyl-
To a boiling solution of 2 (0.21 g, 1 mmol) in dioxane
(30 ml), phenyl isothiocyanate (0.15 g, 1 mmol) was
added. The reaction mixture was heated under re-
flux for 1 h. The reaction mixture was left to stand at
room temperature overnight. The solid product
which separated was filtered, washed with ether,
dried, and recrystallized from dioxane to yield
product 10 with 72% yield; m.p. 142◦C; IR (KBr)
ꢀ 3410, 3329, 3313, 3230–3217 (NH), 3060 (CH
aromatic), 1708, 1665 (2C O), 1340 (C S) cm−1;
1H NMR [DMSO-d6]: δ = 6.89 (s, 1H, pyran H-
4), 7.14–8.25 (m, 9H, Ar-H), 9.1, 10.35, 10.82 (3s,
1,2,4-triazole-3-yl]acetate (11b)
General Procedures: The Meracptotriazole 13 (0.32
g, 1 mmol) was dissolved in an ethanolic solution of
sodium ethoxide prepared from sodium metal (0.023
g, 0.001 g-atom) in ethanol (50 ml) and then added
methyl iodide (0.28 g, 2 mmol) and/or ethyl bromoac-
etate (0.17 g, 1 mmol) was added gradually to the
resulting solution. The reaction mixture was heated
under reflux for 2 h, concentrated, cooled, filtered,
washed several times with water, and recrystallized
from ethanol to afford the corresponding product
11a,b with 63–68% yield.
each 1H, 3NH D2O-exchangeable); m/z 340 (M+
1). Calcd for C17H13N3O3S: C, 60.16; H, 3.89; N,
12.39; S, 9.45%. Found: C, 60.21; H, 3.86; N, 12.4;
S, 9.43%.
+
11b: Yield, 64%; m.p. 235–236◦C; IR (KBr) ꢀ
3050 (CH aromatic), 2980 (CH aliphatic), 1710, 1729
(2C O), 1600 (C N) cm−1; 1H NMR [DMSO-d6]: δ =
1.18 (t, 3H, J-7 Hz, CH3), 4.11 (q, 2H, J-7 Hz, CH2),
4.21 (s, 2H, SCH2), 6.82 (s, 1H, pyran H-4), 7.16–
8.23 (m, 9H, Ar-H). Calcd for C21H17N3O4S: C, 61.9;
H, 4.21; N, 10.32; S, 7.87%. Found: C, 61.89; H, 4.11;
N, 10.31; S, 7.85%.
3-Methylthio-5-(2H-2-oxobenzo[b]pyran-3-yl)-
4-phenyl-1,2,4-triazole (11a)
Methyl iodide (0.21 g, 1.5 mmol) was added to a mix-
ture of 10 (0.34 g, 1 mmol) and anhydrous sodium
carbonate (1.5 mmol) in DMF (10 ml). The reaction

Heterocyclic Synthesis Containing Bridgehead Nitrogen Atom 119
reaction mixture was refluxed for 2–3 h, then cooled,
diluted with water, and allowed to stand overnight.
The solid product thus obtained was washed with
water, dried, and recrystallized from ethanol/water
to yield 17 with yield, 53%; m.p. 265–266◦C; IR (KBr)
ꢀ 3450, 3201 (OH and NH), 3060 (CH aromatic),
2-Anilino-5-(2H-2-oxobenzo[b]pyran-3-yl)-
1,3,4-thiadiazole (15)
A solution of 10 (0.34 g, 1 mmol) in phosphoryl
chloride (5 ml) was refluxed for 30 min. The excess
of phosphoryl chloride was removed under reduced
pressure and the residue was poured into cold wa-
ter. The organic layer was extracted with dichloro-
methane (4 × 20 ml) and the extracts were dried
over sodium sulfate. The solvent was removed un-
der reduced pressure and the resulting solid product
was collected by filtration, dried, and recrystallized
from methanol to yield 15 with yield, 60%; m.p. 115–
117◦C; IR (KBr) ꢀ 3190 (NH), 3050 (CH aromatic),
1
1735, 1718, 1670 (3C O) cm−1; H NMR [DMSO-
d6]: δ = 4.31 (s, 2H, SCH2), 6.82 (s, 1H, pyran H-
4), 7.12–8.22 (m, 9H, Ar-H), 10.23 (s, 1H, NH D2O-
exchangeable); m/z 379 (M+). Calcd for C19H13N3O4S:
C, 60.15; H, 3.46; N, 11.08; S, 8.45%. Found: C, 60.16;
H, 3.45; N, 11.05; S, 8.43%.
1
1712 (C O) cm−1; H NMR [DMSO-d6]: δ = 6.78 (s,
REFERENCES
1H, pyran H-4), 7.21–8.27 (m, 9H, Ar-H), 10.46 (s,
1H, NH D2O-exchangeable); m/z 321 (M+). Calcd for
C17H13N3O2S: C, 64.46; H, 3.91; N, 12.53; S, 9.56%.
Found: C, 64.45; H, 3.89; N, 12.51; S, 9.57%.
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