Studies on heterocyclization of acetoacetanilide

Article abstract of DOI:10.1007/s13738-012-0128-x

Base-induced cyclocondensation of acetoacetanilide (1) and benzoyl isothiocyanate (2) afforded mercaptopyridine (4). Compound 4 reacted with NaOCl in presence of NH₄OH/NaOH to produce isothiazolopyridine (6). Heterocyclization of 4 by ethyl bro

Full text of DOI:10.1007/s13738-012-0128-x

J IRAN CHEM SOC (2013) 10:85–91
DOI 10.1007/s13738-012-0128-x
ORIGINAL PAPER
Studies on heterocyclization of acetoacetanilide
•
Mohamed Sherif Mohamed Assy
•
•
Nabil Yousif Mohamed Galahom
Received: 23 March 2012 / Accepted: 13 June 2012 / Published online: 7 August 2012
Ó Iranian Chemical Society 2012
Abstract Base-induced cyclocondensation of acetoace-
tanilide (1) and benzoyl isothiocyanate (2) afforded mer-
captopyridine (4). Compound 4 reacted with NaOCl in
presence of NH4OH/NaOH to produce isothiazolopyridine
(6). Heterocyclization of 4 by ethyl bromoacetate and/or
phenacyl bromide afforded pyridothiazapene and pyridine
derivatives 7, 8, respectively. The synthesis of pyrazolo-
pyridine (9) was achieved by reaction of 4 with hydrazine
hydrate. Oxidative cyclization of 4 by Br2 produced iso-
thiazolopyridine (10). Chlorination of compound 4 yielded
isothiazolopyridine dioxide (11). Compound 1 transformed
into pyrane derivatives 12 and 13 by reaction with ben-
zylidenemalononitrile and benzylideneacetophenone,
respectively. Heterocyclization of compound 1 by ethyl-
cyanoacetate and diethyloxalate afforded pyridine and
cyclopentane derivatives 14 and 15, respectively. Com-
pound 1 heterocyclized to indenopyrane (16) or indeno-
pyrrole (17) upon reacted with ninhydrin on cold and hot
condition, respectively. Heterocyclization of compound 1
and benzilmonohydrazone afforded pyridazine derivative
18. Coupling of 1 with diazonium salt afforded hydrazone
19 which cyclized using CS2/KOH gave pyridazine
derivative 20.
Introduction
The pyridine substructure was one of the most important het-
erocycle found in natural products, pharmaceuticals and
functional materials [1, 2]. Substituted pyridines were reported
as leukotriene B-4 antagonists [3–8]. Pyridine-based deriva-
tives were an important class of compounds with a wide range
of activities [9–13]. Moreover, pyridine derivatives containing
multi-functional groups such as streptonigrin, streptonigrone
and lavendamycin were reported as anticancer drugs, and
cerivastatin was reported as the HMGCoA enzyme inhibitors
[14]. The project was directed towards the synthesis of new
pyridines using new synthetic route. It has found that hetero-
cyclization of acetoacetanilide and benzilmonohydrazone
afforded hydrazine derivatives, on the other hand heterocyc-
lization of acetoacetanilide by ethylcyanoacetate and diethy-
loxalate afforded pyridine and cyclopentane derivatives,
respectively. Cyclocondensation of acetoacetanilide and ben-
zoylisothiocyanate afforded mercaptopyridine.
Experimental
All melting points are uncorrected. IR spectra (KBr discs)
were recorded on FT/IR-400 spectrophotometer (Perkin-
Keywords Heterocyclization Á Acetoacetanilide Á
Pyridine Á Pyridazine
1
Elmer). H NMR spectra were recorded on Varian 300
MHZ (DMS-d6) solutions. Chemical shifts are reported as
d values relative to tetramethylsilane (TMS) as internal
reference. The elemental analyses were carried out at
Micro Analytical Center, Cairo University.
M. Sherif (&) Á M. Assy Á M. Galahom
Department of Chemistry, Faculty of Science,
Zagazig University, Zagazig, Egypt
e-mail: meahsherif@hotmail.com
4-Hydroxy-2-mercapto-N,6-diphenylnicotinamide (4)
N. Yousif
Department of Photochemistry, National Research Center,
Cairo, Egypt
A mixture of acetoacetanilide (1) (0.01 mol), benzoyl
isothiocyanate (2) (0.01 mol) and TEA (3 drops) in acetone
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J IRAN CHEM SOC (2013) 10:85–91
(10 ml) was heated under reflux for 6 h. The solid product
obtained upon cooling, poured on ice, was filtered off, dried,
andcrystallizedfromethanol gave (4)asyellowcrystals;m.p.
160–162 °C, yielded 60 %. IR (KBr, cm-1) mmax: 3,303
(OH), 3,151 (NH), 1,680 (CO), 2,610 (SH). 1H-NMR
(500 MHz, CDCl3) d: 11.2 (s, 1H, SH); 9.8 (s, 1H, NH); 9.5
(s, 1H, OH); 7.4–7.9 (m, 11H, aromatic protons and pyridine
protone) ppm. Anal. Calcd. for C18H14N2O2S(322), calcu-
lated: C, 67.06; H, 4.38; N, 8.69; found: C, 67.10; H, 4.5; N,
8.66.
yielded 65 %. IR (KBr, cm-1) mmax: 3,430 (OH), 3,050
(NH), 1,826 (CO), 1,680 (CO). 1H-NMR (500 MHz,
CDCl3) d: 13.6 (s, 1H, NH); 12.7 (s, 1H, OH); 3.3 (s, 2H,
CH2); 7.4–7.9 (m, 16H, aromatic proton and pyridine
proton) ppm. Anal. Calcd. for C26H20N2O3S (440), calcu-
lated: C, 70.89; H, 4.58; N, 6.36; found: C, 70.87; H, 4.57;
N, 6.37.
6-Phenyl-1H-pyrazolo[3,4-b]pyridine-3,4-diol (9)
A mixture of compound (4) (0.01 mol) and hydrazine
hydrate (0.01 mol) in ethanol (10 ml) was heated under
reflux for 3 h. The solid product obtained upon cooling,
was filtered off, dried, and crystallized from ethanol gave
(9) as yellow crystals; m.p. 180–184 °C, yielded 70 %. IR
(KBr, cm-1) mmax: 3,776 (OH), 3,696 (OH), 3,305 (NH).
1H-NMR (500 MHz, CDCl3) d: 9.8 (s, 1H, OH); 8.3 (s, 1H,
OH); 4.4 (s, 1H, NH), 6.6–7.4 (m, 6H, aromatic proton and
pyridine proton) ppm. Anal. Calcd. for C12H9N3O2 (227),
calculated: C, 63.43; H, 3.99; N, 18.49; found: C, 63.44; H,
3.97; N, 18.48.
4-Hydroxy-6-phenylisothiazolo[5,4-b]pyridin-3(2H)-
one (6)
A solution of sodium hypochloride (20 ml) was added drop
wise over a period of 20 min to a stirred solution of com-
pound (4) (0.01 mol) in aqueous sodium hydroxide solution
(3.3 %, 40 ml), and ammonium hydroxide (3.3 %, 40 ml)
at room temperature. The reaction mixture was neutralized
by HCl, and the precipitated solid was filtered off, washed
with water, dried and crystallized from ethanol gave (6) as
yellow crystals; m.p. 216–218 °C, yielded 56 %. IR (KBr,
cm-1) mmax: 3,383 (OH), 3,239 (NH), 1,698 (CO). 1H-NMR
(500 MHz, CDCl3) d: 11 (s, 1H, NH); 10.8 (s, 1H, OH); 7–8
(m, 6H, aromatic protons and pyridine proton) ppm. Anal.
Calcd. for C12H8N2O2S (244), calculated: C, 59.00; H, 3.30;
N, 11.47; found: C, 59.10; H, 3.35; N, 11.43.
4-Hydroxy-2,6-diphenylisothiazolo[5,4-b]pyridin-
3(2H)-one (10)
A mixture of compound (4) (0.01 mol) and bromine
(0.01 mol) in pyridine (10 ml) was heated under reflux for
5 h. The reaction mixture was neutralized by HCl, and the
precipitated solid was filtered off, washed with water, dried
and crystallized from ethanol gave (10) as white crystals;
(E)-3,6-Dihydroxy-4,8-diphenylpyrido[3,2-f] [1,
4]thiazepin-5(4H)-one (7)
m.p. 105–107 °C, yielded 78 %. IR (KBr, cm-1) mmax
:
A mixture of compound (4) (0.01 mol), ethyl bromoacetate
(0.01 mol) and TEA (3 drops) in ethanol (10 ml) was
heated under reflux for 3 h. The solid product obtained
upon cooling, was filtered off, dried, and crystallized from
ethanol gave (7) as yellow crystals; m.p. 132–134 °C,
yielded, 75 %. IR (KBr, cm-1) mmax: 3,429 (OH), 3,250
3,426 (OH), 1,758 (CO). 1H-NMR (500 MHz, CDCl3) d: 9
(s, 1H, OH); 8–8.9 (m, 11H, aromatic proton and pyridine
proton) ppm. Anal. Calcd. for C18H12N2O2S (320), calcu-
lated: C, 67.48; H, 3.78; N, 8.74; found: C, 67.46; H, 3.77;
N, 8.72.
1
(OH), 1,675 (CO). H-NMR (500 MHz, CDCl3) d: 11.5
(s, 1H, OH); 10.8 (s, 1H, OH); 4.1 (s, 1H, = CH); 7.4–7.9
(m, 11H, aromatic proton and pyridine proton) ppm. Anal.
Calcd. for C20H14N2O3S (362), calculated: C, 66.28; H,
3.89; N, 7.73; found: C, 66.25; H, 3.90; N, 7.72.
4-Hydroxy-2,6-diphenylisothiazolo[5,4-b]pyridine-1,1-
dioxide-3(2H)-one (11)
Chlorine gas was bubbled through a suspension of (4) (2 g)
in acetic acid (10 ml, 25 %) for about 2 h at 10 °C. The
resulting precipitate was collected by filtration washed with
water, dried and crystallized from the ethanol gave (11) as
white crystals; m.p. 256–258 °C, yielded 62 %. IR (KBr,
4-Hydroxy-2-(2-oxo-2-phenylethylthio)-N,6-
diphenylnicotinamide (8)
cm-1) mmax: 3,297 (OH), 1,649 (CO), 1,143 (SO2). H-
1
A mixture of compound (4) (0.01 mol), phenacyl bromide
(0.01 mol) and TEA (3 drops) in ethanol (10 ml) was
heated under reflux for 3 h. The solid product obtained
upon cooling, was filtered off, dried, and crystallized from
the ethanol gave (8) as yellow crystals; m.p. 210–212 °C,
NMR (500 MHz, CDCl3) d: 9.1 (s, 1H, OH); 7.3–8
(m, 11H, aromatic proton and pyridine proton) ppm. Anal.
Calcd. for C18H12N2O4S (352), calculated: C, 61.35; H,
3.43; N, 7.95; found: C, 61.36; H, 3.41; N, 7.93.
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J IRAN CHEM SOC (2013) 10:85–91
87
228–230 °C, yielded 69 %. IR (KBr, cm-1) mmax: 3,778
(OH), 3,699 (OH), 3,292 (NH), 1,676 (CO), 1,650 (CO). 1H-
NMR (500 MHz, CDCl3) d: 11.9 (s, 1H, OH); 10.8 (s, 1H,
OH); 8.8 (s, 1H, NH); 3.4 (s, 1H, CH cyclopentane); 6.8 (s,
1H, CH); 7.2–7.9 (m, 5H, aromatic proton and pyrrol proton)
ppm. Anal. Calcd. for C12H9NO4 (231), calculated: C, 62.34;
H, 3.92; N, 6.06; found: C, 62.33; H, 3.90; N, 6.07.
6-Amino-5-cyano-2-methyl-N,4-diphenyl-4H-pyran-3-
carboxamide (12)
A mixture of acetoacetanilide (1) (0.01 mol), benzylidene-
malononitrile (0.01 mol) and TEA (3 drops) in ethanol
(10 ml) was heated under reflux for 3 h. The solid product
obtained upon cooling, was filtered off, dried and crystallized
from acetic acid gave (12) as white crystals. m.p. 210–212 °C
yielded 78 %. IR (KBr, cm-1) mmax: 3,438 (NH), 3,341 (NH),
2,177(CN), 1,713(CO). 1H-NMR (500 MHz, CDCl3) d: 14.3
(s, 1H, NH); 7.1–7.5 (m, 10H, aromatic proton); 5.9 (s, 1H,
CH pyran); 4.3 (s, 2H, NH2); 2.3 (s, 3H, CH3) ppm. Anal.
Calcd. for C20H17N3O2 (331), calculated: C, 72.49; H, 5.17;
N, 12.68; found: C, 72.48; H, 5.15; N, 12.66.
3a, 8b-Dihydroxy-2-methyl-4-oxo-N-phenyl-4,8b-
dihydro-3a H-indeno[1,2-b]furan-3-carboxamide (16)
A mixture of acetoacetanilide (1) (0.01 mol) and ninhydrin
(0.01 mol) in ethanol and left at room temperature with
stirring for 4 h. The solid product obtained, was filtered off,
dried and crystallized from ethanol gave (16) as white
crystals. m.p. 206–208 °C, yielded 65 %. IR (KBr, cm-1
max: 3,420 (OH), 3,302 (OH), 3,230 (OH), 3,020 (NH),
)
2-Methyl-N,4,6-triphenyl-4H-pyran-3-carboxamide
(13)
m
1
1,734 (CO), 1,655 (CO). H-NMR (500 MHz, CDCl3) d:
12.7 (s, 1H, NH); 6.5 (s, 1H, OH); 6.6 (s, 1H, OH); 7.1–7.7
(m, 9H, aromatic proton); 2.2 (s, 3H, CH3) ppm. Anal.
Calcd. for C19H15NO5 (337), calculated: C, 67.65; H, 4.48;
N, 4.15; found: C, 67.64; H, 4.46; N, 4.16.
A mixture of acetoacetanilide (1) (0.01 mol), benzylid-
eneacetophenone (0.01 mol) and TEA (3 drops) in ethanol
(10 ml) was heated under reflux for 3 h. The solid product
obtained upon cooling, was filtered off, dried and crystal-
lized from acetic acid gave (13) as white crystals. m.p.
254–258 °C, yielded 76 %. IR (KBr, cm-1) mmax: 3,298
(NH), 1,649 (CO). 1H-NMR (500 MHz, CDCl3) d: 10
(s, 1H, NH); 6.5 (s, 1H, CH pyran); 7–7.7 (m, 15H, aro-
matic proton); 2.4 (s, 3H, CH3) ppm. Anal. Calcd. for
C25H21NO2 (367), calculated: C, 81.72; H, 5.76; N, 3.81;
found: C, 81.73; H, 5.74; N, 3.80.
3-Acetyl-3a,8b-dihydroxy-1-phenyl-1,3,3a,8b-
tetrahydroindeno[1,2-b]pyrrole-2,4-dione (17)
A mixture of acetoacetanilide (1) (0.01 mol) and ninhydrin
(0.01 mol) in ethanol (10 ml) was heated under reflux for
2 h. The solid product obtained upon cooling, was filtered
off, dried and crystallized from the ethanol gave (17) as
white crystals. m.p. 170–180 °C, yielded 55 %. IR (KBr,
cm-1) mmax: 3,693 (OH), 3,303 (OH), 1,836 (CO), 1731
6-Hydroxy-4-methyl-2-oxo-1-phenyl-1,2-
dihydropyridine-3-carbonitrile (14)
1
(CO), 1,655 (CO). H-NMR (500 MHz, CDCl3) d: 6.5 (s,
A mixture of acetoacetanilide (1) (0.01 mol), ethyl cya-
noacetate (0.01 mol) and TEA (3 drops) in dimethylform-
amide (10 ml) was heated under reflux for 6 h. The solid
product obtained upon cooling and pouring on ice, was fil-
tered off, dried and crystallized from ethanol gave (14) as
brown crystals. m.p. 202–204 °C, yielded 72 %. IR (KBr,
cm-1) mmax: 3,273 (OH), 2,261 (CN), 1,677 (CO). 1H-NMR
(500 MHz, CDCl3) d: 10.2 (s, 1H, OH); 7–7.5 (m, 5H, aro-
matic proton and pyridine proton); 2.4 (s, 3H, CH3) ppm.
Anal. Calcd. for C13H10N2O2 (226), calculated: C, 69.02; H,
4.46; N, 12.38; found: C, 69.03; H, 4.45; N, 12.36.
1H, OH); 6.6 (s, 1H, OH); 6.6–7.4 (m, 9H, aromatic pro-
ton); 5.7 (s, 1H, CH pyrrol); 2.4 (s, 3H, CH3) ppm. Anal.
Calcd. for C19H15NO5 (337), calculated: C, 67.65; H, 4.48;
N, 4.15; found: C, 67.64; H, 4.49; N, 4.14.
3-Methyl-N,5,6-triphenyl-4,5-dihydropyridazine-4-
carboxamide (18)
A mixture of acetoacetanilide (1) (0.01 mol) and ben-
zilmonohydrazone (0.01 mol) in pyridine (10 ml) was
heated under reflux for 4 h. The reaction mixture was
cooled, poured on ice and neutralized by HCl; the solid
product obtained was filtered off, dried and crystallized
from acetic acid gave (18) as a yellow crystals. m.p.
204–206 °C yielded 76 %. IR (KBr, cm-1) mmax: 3346
2,5-Dihydroxy-3-oxo-N-phenylcyclopenta-1,4-
dienecarboxamide (15)
1
A mixture of acetoacetanilide (1) (0.01 mol), diethyloxalate
(0.01 mol) and TEA (3 drops) in dimethylformamide (10 ml)
was heated under reflux for 6 h. The solid product obtained
upon cooling and pouring on ice, was filtered off, dried and
crystallized from ethanol gave (15) as brown crystals. m.p.
(NH), 1681 (CO). H-NMR (500 MHz, CDCl3) d: 11.9 (s,
1H, NH); 7.3–7.8 (m, 15H, aromatic proton); 1.8 (s, 3H,
CH3) ppm. Anal. Calcd. for C24H19N3O (365), calculated:
C, 78.88; H, 5.24; N, 11.55; found: C, 78.84; H, 5.25; N,
11.51.
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OH
O
NHPh
Ph
N
SH
O
O
O
C
TEA
Ph
4
H3C
N
Ph
N
C
S
H
1
O
S
O
2
Ph
Ph
H3C
N
N
5
Scheme 1 Synthetic method of nicotinamide 4
6-Mercapto-4-oxo-N,1-diphenyl-1,4-
dihydropyridazine-3-carboxamide (20)
Results and discussion
As a part of a program directed towards the synthesis of
some new azole and azine of expected biological activity
[15, 16]. The present study describes the synthesis of some
azole and azine from simple available laboratory reagents.
A new synthetic route for pyridine from benzoyl isothio-
cyanate and acetoacetanilide is devised. Thus, when
acetoacetanilide 1 is allowed to react with benzoyl isothi-
ocyanate 2 in the presence of (TEA) produced pyridine
derivative 4 as yellow crystals; m.p. 160–162 °C, yielded
60 %. IR: 3,303 (OH), 3,151 (NH), 1,680 (CO), 2,610
A mixture of (19) (0.01 mol) [prepared by a solution of (1)
(0.01 mol) in ethanol (10 ml) containing sodium acetate
(0.01 mol), was cooled to 0–5 °C, treated with a solution of
benzene diazonium chloride (0.01 mol), stirred for 5 min and
left at room temperature for 2 h. The solid product obtained
was filtered off, dried and crystallized from ethanol gave (19)
as a yellow crystals. m.p. 106–108 °C], carbon disulfide and
potassium hydroxide (0.01 mol) in dimethylformamide
(10 ml), was heated under reflux for 6 h. The reaction mix-
ture was cooled, poured on ice and neutralized by HCl; the
solid product obtained was filtered off, dried and crystallized
from ethanol gave (20) as yellow crystals. m.p. 170–172 °C,
yielded 58 %. IR (KBr, cm-1) mmax: 3,428 (NH), 2,447 (SH),
1724 (CO), 1,670 (CO). 1H-NMR (500 MHz, CDCl3) d: 13.6
(s, 1H, SH); 12.6 (s, 1H, NH); 6.9 (s, 1H, pyridazine proton);
7.1–7.6 (m, 10H, aromatic proton) ppm. Anal. Calcd. for
C17H13N3O2S (323), calculated: C, 63.14; H, 4.05; N, 12.99;
found: C, 63.12; H, 4.04; N, 12.97.
1
(SH). H-NMR: 11.2 (s, 1H, SH); 9.8 (s, 1H, NH); 9.5 (s,
1H, OH); 7.4–7.9 (m, 11H, aromatic protons and pyridine
protone) ppm., and not the expected pyrimidine 5
(Scheme 1).
The formation of 4 from the base induced of 1 to 2 may
be proceed via the formation of nonisolable thioamide 3
that undergo interamolecular cyclocondensation via the
addition of methyl function to the carbonyl function
affording the final product 4 (Scheme 2).
O
O
O
O
O
C
Ph
H3C
N
H
Ph
N
C
Ph
S
H3C
N
H
O
HN
S
Ph
1
3
2
OH
O
NHPh
Ph
N
SH
4
Scheme 2 Proposed mechanism for synthesis of nicotinamide 4
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J IRAN CHEM SOC (2013) 10:85–91
89
OH
OH
OH
O
OH
N
O
NH2NH2
NaOH / NH4OH
NaOCl
NHPh
SNH2
N
N
NH
H
Ph
Ph
N
9
Ph
N
S
Ph
5
6
OH
OH
O
O
OH
N
O
Br2
NPh
BrCH2CO2Et
TEA
NHPh
N
OH
N
S
Ph
Ph
N
SH
Ph
S
10
7
4
OH
N
O
OH
O
Cl2
O
N
Ph
PhCCH2Br
NHPh
Ph
S
O
O
Ph
Ph
N
S
11
O
8
Scheme 3 Heterocyclization of nicotinamide 4
Mercaptopyridine (4) seemed to be of suitable located
functionality for further heterocyclization. Thus, treatment
of compound (4) with NaOH/NH4OH and NaOCl affor-
ded isothiazolopyridine (6) as yellow crystals; m.p.
216–218 °C, yielded 56 %. IR: 3383 (OH), 3239 (NH),
mercaptopyridine (4) was allowed to react with Cl2 in
acetic acid yielded isothiazolopyridine dioxide (11) as
white crystals; m.p. 256–258 °C, yielded 62 %. IR: 3,297
(OH), 1,649 (CO), 1,143 (SO2). 1H-NMR: 9.1 (s, 1H, OH);
7.3–8 (m, 11H, aromatic proton and pyridine proton) ppm
(Scheme 3).
1
1698 (CO). H-NMR: 11 (s, 1H, NH); 10.8 (s, 1H, OH);
7-8 (m, 6H, aromatic protons and pyridine proton) ppm.
The formation of (6) from the reaction of (4) and NaOCl
may be proceed via the formation of sulphenyl chloride
followed by amination affording sulphenamide (5) and
finally intramolecular cyclodehydration affording the final
product (6). Base-induced reaction of mercaptopyridine (4)
with ethylbromoacetate afforded pyridothiazapine (7) as
yellow crystals; m.p. 132–134 °C, yielded, 75 %. IR: 3,429
(OH), 3,250 (OH), 1,675 (CO). 1H NMR: 11.5 (s, 1H, OH);
10.8 (s, 1H, OH); 4.1 (s, 1H, =CH); 7.4-7.9 (m, 11H,
aromatic proton and pyridine proton) ppm. Reaction of
The reaction of acetoacetanilide (1) and benzylidene-
malononitrile resulted in cycloaddition afforded pyrane
derivative (12) as white crystals. m.p. 210–212 °C yielded
78 %. IR: 3,438 (NH), 3,341 (NH), 2,177 (CN), 1,713
1
(CO). H-NMR: 14.3 (s, 1H, NH); 7.1–7.5 (m, 10H, aro-
matic proton); 5.9 (s, 1H, CH pyran); 4.3 (s, 2H, NH2); 2.3
(s, 3H, CH3) ppm. The reaction of acetoacetanilide (1) with
benzylideneacetophenone produced 4H-pyrane (13) as
white crystals. m.p. 254–258 °C, yielded 76 %. IR: 3298
(NH), 1649 (CO). 1H-NMR: 10 (s, 1H, NH); 6.5 (s, 1H, CH
pyran); 7-7.7 (m, 15H, aromatic proton); 2.4 (s, 3H, CH3)
ppm. Pyrane derivative (13) was potentiated by the pres-
ence of 4H-proton at d 5.6 in addition to NH signal at
10 ppm. Base-induced condensation of compound (1) and
ethylcyanoacetate yielded pyridine derivative (14) as
brown crystals. m.p. 202–204 °C, yielded 72 %. IR: 3,273
(OH), 2,261 (CN), 1,677 (CO). 1H-NMR: 10.2 (s, 1H, OH);
7–7.5 (m, 5H, aromatic proton and pyridine proton); 2.4 (s,
3H, CH3) ppm. The reaction of acetoacetanilide with nin-
hydrin was studied. Thus, when ninhydrin was allowed to
react with acetoacetanilide (1) on cold yielded indenofu-
rane (16) as white crystals. m.p. 206–208 °C, yielded
65 %. IR: 3,420 (OH), 3,302 (OH), 3,230 (OH), 3,020
(NH), 1,734 (CO), 1,655 (CO). 1H-NMR: 12.7 (s, 1H, NH);
6.5 (s, 1H, OH); 6.6 (s, 1H, OH); 7.1–7.7 (m, 9H, aromatic
proton); 2.2 (s, 3H, CH3) ppm. When the reaction of nin-
hydrin and acetoacetanilide was conducted under reflux
produced indenopyrrolo (17) as white crystals. m.p.
9
mercaptopyridine (4) with x-bromoacetophenone resulted
in alkylation affording benzoylmethylmercaptopyridine (8)
as yellow crystals; m.p. 210–212 °C, yielded 65 %. IR:
3,430 (OH), 3,050 (NH), 1,826 (CO), 1,680 (CO). 1H-
NMR: 13.6 (s, 1H, NH); 12.7 (s, 1H, OH); 3.3 (s, 2H,
CH2); 7.4–7.9 (m, 16H, aromatic proton and pyridine
proton) ppm. The synthesis of pyrazolopyridine (9) was
achieved by reaction of mercaptopyridine (4) with hydra-
zine hydrates, as yellow crystals; m.p. 180–184 °C, yielded
1
70 %. IR: 3776 (OH), 3696 (OH), 3305 (NH). H-NMR:
9.8 (s, 1H, OH); 8.3 (s, 1H, OH); 4.4 (s, 1H, NH), 6.6–7.4
(m, 6H, aromatic proton and pyridine proton) ppm. When
mercaptopyridine (4) refluxed with Br2 in pyridine resulted
in oxidative cyclization afforded isothiazolopyridine (10)
as white crystals; m.p. 105–107 °C, yielded 78 %. IR:
1
3,426 (OH), 1,758 (CO). H-NMR: 9 (s, 1H, OH); 8–8.9
(m, 11H, aromatic proton and pyridine proton) ppm. When
123

90
J IRAN CHEM SOC (2013) 10:85–91
O
O
O
Ph
OH
OH
OH
NHPh
Ph
O
O
NC
NC
CN
NHPh
O
CH3
OH
O
H2N
CH3
Ph
on cold
16
12
O
O
O
O
O
OH
OH
CH3
O
O
PhHN
H3C
Ph
Ph
OH
Ph
H3C
N
O
Ph
O
H
N
O
1
OH Ph
13
reflux
17
H2N
O
O
N
CONHPh
Ph
NC
Ph
NCCH2COEt
O
N
H3C
Ph
Ph
H3C
OH
N
N
Ph
14
18
CO2Et
CO2Et
O
CH3
O
Ph
N
HO
NHPh
Ph
N
Cl
O
H
N
H
N
O
N
O
H
Ph
15
19
O
O
CS2 / KOH
NHPh
N
HS
N
Ph
20
Scheme 4 Heterocyclization of acetoacetanilide (1)
170–180 °C, yielded 55 %. IR: 3,693 (OH), 3,303 (OH),
1,836 (CO), 1,731 (CO), 1,655 (CO). 1H-NMR: 6.5 (s, 1H,
OH); 6.6 (s, 1H, OH); 6.6–7.4 (m, 9H, aromatic proton);
5.7 (s, 1H, CH pyrrol); 2.4 (s, 3H, CH3) ppm. Refluxing of
acetoacetanilide (1) and benzilmonohydrazone afforded
pyridazine derivative (18) as a yellow crystals. m.p.
204–206 °C yielded 76 %. IR: 3,346 (NH), 1,681 (CO).
1H-NMR: 11.9 (s, 1H, NH); 7.3–7.8 (m, 15H, aromatic
proton); 1.8 (s, 3H, CH3) ppm. Base-induced reaction of
acetoacetanilide (1) with diethyloxalate afforded cyclo-
pentane derivative (15) as brown crystals. m.p.
228–230 °C, yielded 69 %. IR: 3,778 (OH), 3,699 (OH),
pyridazine derivative (20) as yellow crystals. m.p.
170–172 °C, yielded 58 %. IR: 3,428 (NH), 2,447 (SH),
1,724 (CO), 1,670 (CO). H-NMR: 13.6 (s, 1H, SH); 12.6
1
(s, 1H, NH); 6.9 (s, 1H, pyridazine proton); 7.1–7.6 (m,
10H, aromatic proton) ppm (Scheme 4).
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