Heterocyclizations via POCl3-based multicomponent reactions: A new approach to one-pot synthesis of a new spirosystem, 7-methyl-5-[4-(aryl/ heteryl)thiazol-2-yl]-5,6-diazaspiro[2,4]hept-6-en-4-ones

Article abstract of DOI:10.1080/00397910903372341

A novel multicomponent reaction involving phenacylbromide, thiosemicarbazide, and α-acetyl-γ-butyrolactone in the presence of POCl₃, forming 7-methyl-5-[4-(aryl/heteryl)thiazole-2-yl]-5,8-diaza spiro[2,4]hept-6-en-4-ones in good yields, is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903372341

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Heterocyclizations via POCl3-Based
Multicomponent Reactions: A New
Approach to One-Pot Synthesis of
a New Spirosystem, 7-Methyl-5-
[4-(aryl/heteryl)thiazol-2-yl]-5,6-
diazaspiro[2,4]hept-6-en-4-ones
V. Rajeswar Rao a & V. Ravinder Reddy a
a Department of Chemistry, National Institute of Technology,
Warangal, India
Version of record first published: 04 Oct 2010
To cite this article: V. Rajeswar Rao & V. Ravinder Reddy (2010): Heterocyclizations via POCl3-Based
Multicomponent Reactions: A New Approach to One-Pot Synthesis of a New Spirosystem, 7-Methyl-5-
[4-(aryl/heteryl)thiazol-2-yl]-5,6-diazaspiro[2,4]hept-6-en-4-ones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:21, 3186-3195
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Synthetic Communications1, 40: 3186–3195, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903372341
HETEROCYCLIZATIONS VIA POCl3-BASED
MULTICOMPONENT REACTIONS: A NEW APPROACH
TO ONE-POT SYNTHESIS OF A NEW SPIROSYSTEM,
7-METHYL-5-[4-(ARYL/HETERYL)THIAZOL-2-
YL]-5,6-DIAZASPIRO[2,4]HEPT-6-EN-4-ONES
V. Rajeswar Rao and V. Ravinder Reddy
Department of Chemistry, National Institute of Technology, Warangal, India
A novel multicomponent reaction involving phenacylbromide, thiosemicarbazide, and a-acetyl-
c-butyrolactone in the presence of POCl3, forming 7-methyl-5-[4-(aryl/heteryl)thiazole-2-
yl]-5,8-diaza spiro[2,4]hept-6-en-4-ones in good yields, is described.
Keywords: a-Acetyl-c-butyrolactone; 3-(2-bromoacetyl)coumarin; phenacylbromides; spiro compound; thiazole
INTRODUCTION
In view of the wide range of biological activates exhibited by 2H-1-
benzopyran-2-ones, pyrazoles, and thiazoles, we became interested in synthesizing
these moieties in one molecule, which is expected to enhance their biological activity
as compared to simple pyrazolothiazoles. Based on these observations, we report
the synthesis of a new spirosystem, 7-methyl-5-[4-(aryl=heteryl)thiazol-2-yl]-5,6-
diazaspiro[2,4]hept-6-en-4-ones.
Thiazoles are generally synthesized by Hantzsch’s thiazole synthesis from
a-halogenoketones and thioureas or thioamides. Dodson and King[1] and others[2]
synthesized aminothiazoles by a modification of the method. The method still
remains a cumbersome and time-consuming process.
A literature survey[3] clearly revealed that normally 2-pyrazol-4-yl-substituted
thiazoles are prepared in two distinct methods, one involving preparation of thiazole
first and then building a pyrazole in the next step or vice versa. Unlike the literature
methods, we have synthesized a 2-pyrazol-4-yl-substituted thiazole system in one step.
Though the previous methodologies are quite useful, they have some limitations,
such as the requirement to isolate intermediates and longer reaction times, and the
overall yields are poor. None of these methods are simple, nor can they be usefully
applied for the generation of functionally substituted pyrazolothiazoles. It is thus evi-
dent that there remains scope for the development of clean and efficient methodologies
involving single-step reactions for the preparation of the title compounds. In the
Received July 21, 2009.
Address correspondence to V. Rajeswar Rao, Department of Chemistry, National Institute of
Technology, Warangal 506 004, AP, India. E-mail: vrajesw@yahoo.com
3186

HETEROCYCLIZATIONS VIA POCl3-BASED MULTICOMPONENT REACTIONS 3187
present investigation, there is a simultaneous selective ring-closure reaction involving
the formation of three rings at time, such as thiazole, pyrazole, and carbocyclic rings,
with spiro linkages at the third position of coumarin in an acidic medium.
RESULTS AND DISCUSSION
In continuation of our earlier work on the synthesis of heterocyclic systems from
a-halo carbonyl compounds,[4] we report herein a facile, novel route for the synthesis
of 7-methyl-5-[4-(aryl=heteryl)-2-yl]-5,6-diazaspiro[2.4]hept-6-en-4-ones in a single
step from easily available starting materials. The reaction involves simultaneous
cyclization, leading to the formation of thiazole, pyrazolone, and cyclopropane rings.
As shown in Scheme 1 and Table 1, the reaction of aryl bromomethylketones=
heterylbromomethylketones with thiosemicarbazide and a-bromoacetyl-c-butyrolac-
tone in POCl3 under heating yielded the title compounds in one step.
Our experiment was first conducted by adding equimolar quantities of
phenacyl bromide, thiosemicarbazide, and a-acetyl-c-butyrolactone in POCl3 under
heating, which yielded 7-methyl-5-[4-phenyl-thiazol-2-yl]-5,6-diazaspiro[2.4]hept-6-
one rather than an expected compound such as {2-[5-hydroxy-4-(2-hydroxy-ethyl)-
3-methyl-pyrazol-4-yl]-thiazol-4-yl}benzene, as confirmed by spectral analysis. The
infrared (IR) spectra of 4a displayed bands in the region 1621 cmꢀ1 (amide, ꢀC O),
=
1602 cmꢀ1 (ꢀC N). The H NMR spectrum of 4a displayed characteristic signals at
1
=
1.83 (ABq, 2H, spiro ꢀCH2ꢀCH2), 1.94 (ABq, 2H, CH2ꢀCH2), and 2.10 (s, 3H, CH3).
In the mass spectrum of 4a, molecular ion was recorded at m=z 306 (M þ Na), 284 (M þ 1).
Further examination of the scope of the reaction revealed that substituted
3-(2-bromoacetyl)chromenes, thiosemicarbazide, and a-acetyl-c-butyrolactone can
also participate in the reaction and produce substituted 7-methyl-5-[4-(2-oxo-2H-
chromen-3-yl)thiazol-2-yl]-5,6-diazaspiro[2.4]hept-6-en-4-one. The formation of the
product (4b) was confirmed by spectral and analytical data. For the conformation
of this product, we recorded 2D 1H and 13C correlation NMR spectra. In 2D
NMR, each spot on the HETCOR plot has been labeled. The carbon peak at
13.1 ppm and the proton singlet at 2.1 ppm correspond to the methyl group, the car-
bon peaks at 20.2 and 20.2 ppm and the protons of AB quartets at 1.83 and 1.95 ppm
correspond to the methylene group, and the carbon peak at 116.7 ppm and the pro-
ton singlet at 8.29 ppm correspond to the H-5 of thiazole. The carbon peak at
116.7 ppm and the proton doublet at 7.37 ppm correspond to H-8 of coumarin.
The carbon peak at 125.0 ppm and the proton doublet of doublets at 7.28 ppm
correspond to the H-6 of coumarin. The carbon peak at 128.8 ppm and the proton
doublet at 7.65 ppm correspond to H-5 of coumarin.
The carbon peak at 131.8 ppm and the proton doublet of doublets correspond
to the H-7 of coumarin at 7.53 ppm. The carbon peak at 140.1 ppm and the proton
Scheme 1. One-step preparation of 7-methyl-5-[4-aryl/heteryl-thiazol-2-yl]-5,6-diazaspiro[2,4]hept-6-one.

3188
V. RAJESWAR RAO AND V. RAVINDER REDDY
Table 1. Synthesis of 7-methyl-5-[4-phenyl-thiazol-2-yl]-5,6-diazaspiro-
[2.4]hept-6-one
Yielda (%)
No.
Ar
Method 1
Method 2
4a
60
45
4b
4c
55
60
54
55
4d
4e
40
40
48
46
4f
55
65
43
45
4g
aYields refer to isolated yield. Compounds are characterized by 1H,
13C NMR, and IR spectra.
singlet at 8.8 ppm correspond to the HꢀC4 of coumarin. The proton of C4 of cou-
marin is deshielded. Therefore, a spot on the HETCOR plot for this group appears
at 140.1 ppm on the carbon axis and at 8.8 ppm on the proton axis. It is interesting
that the methyl group of the diazaspiro[2.4]hept-6-en-4-one appears downfield of the
methylene group (2) in the proton spectrum (2.1d ppm). In the carbon spectrum,
however, the carbon peak for methyl appears upfield of methylene carbons. Thus,
these HETCOR values confirm the assigned structure. Based on these observations,
we concluded that the product was 7-methyl-5-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-
yl]-5,6-diazaspiro[2.4]hept-6-en-4-one rather than {2-[5-hydroxy-4-(2-hydroxy-
ethyl)-3-methyl-pyrazol-4-yl]-thiazol-4-yl}-chromen-2-one.
Mechanistically, a second possible reaction pathway could be envisaged
(Scheme 2) in this process: condensation of aryl=heteryl bromomethylketones
with thiosemicarbazide in anhydrous ethanol at room temperature, resulting in
the formation of uncyclized 2-oxo-2-(2-aryl=2-oxo-2H-chromen-3-yl)ethylhydrazi-
necarbimidathioatehydrobromide (5) (Table 2). Condensation of these uncyclized

HETEROCYCLIZATIONS VIA POCl3-BASED MULTICOMPONENT REACTIONS 3189
Scheme 2. Method 2: stepwise synthesis of 7-methyl-5-[4-phenyl-thiazol-2-yl]-5,6-diazaspiro[2.4]hept-6-
one and mechanism of the reaction.
compounds (5) with a-acetyl-c-butyrolactone (3) in POCl3 under reflux resulted in the
formation of title compounds (4) instead of the expected 6 or 7 or both (Scheme 2). It
is believed that during the reaction of 5 with a-acetyl-c-butyro lactone in POCl3, the
compound 6 formed changes into the corresponding chloroethyl derivatives 8, which
undergo in situ intramolecular cyclization with the loss of HCl to give spiro com-
pound 4. Cyclization of intermediate 7 or 8 leads to either product 4 or 9 or both,
depending upon the mode of cyclization. In our case, only one product, 4, was
obtained as evidenced by thin-layer chromatography (TLC). The formation 9 can
be ruled out on the basis of spectral evidence. It is interesting to note that during
the course of the reaction, selective intramolecular ring closure occurs to give 4.
EXPERIMENTAL
All the reagents and solvents were purchased from commercial sources and
were used without further purification unless otherwise stated. 3-(2-Bromoacetyl)

3190
V. RAJESWAR RAO AND V. RAVINDER REDDY
Table 2. Synthesis of 2-oxo-2-(phenyl)ethylhydrazine carbimidazo thioatehy-
drobromide
No.
Ar
Yielda (%)
92
5a
5b
5c
92
88
5d
90
5e
5f
88
90
91
5g
aYields refer to isolated yield. Compounds are characterized by 1H, 13C
NMR, and IR spectra.
coumarins[5] were prepared by the literature procedure. Melting points were determ-
ined in open capillaries with a Cintex melting-point apparatus (Mumbai, India) and
were uncorrected. CHNS analysis was done on a Carlo Erba EA 1108 automatic
elemental analyzer. The purity of the compounds was checked by TLC plates
(E. Merek, Mumbai, India). IR spectra (KBr) were recorded on a BrukerWM-4(X)
1
spectrometer (577 model). H NMR spectra were recorded on a Bruker WM-300
spectometer in d ppm using tetramethylsilane (TMS) as internal standard. Mass
spectra (EI-MS) were determined on
API-2000, ESI) at 12.5 eV.
a Perkin-Elmer instrument (SCIEX
General Procedure for 4
A mixture of aryl=3-coumarinyl bromomethyl ketone (10 mmol), thiosemicar-
bazide (10 mmol), and a-acetyl-c-butyrolactone (10 mmol) in POCl3 (12 ml) was
refluxed for 1 h. The reaction mixture was poured in ice-cold water (60 ml). The
product formed was purified by column chromatography on silica (eluent, ethyl
acetate=hexanes 1.5:8.5) to give the title compound in 40–65% yield. All the other
compounds were prepared by a similar procedure.

HETEROCYCLIZATIONS VIA POCl3-BASED MULTICOMPONENT REACTIONS 3191
7-Methyl-5-[4-phenyl-thiazol-2-yl]-5,6-diazaspiro[2.4]hept-6-one (4a)
ꢀ1
Mp 120–122 ꢁC. IR (KBr) n (cm ), 1720 (lactone, ꢀC O), 1621 (amide,
=
1
=
=
ꢀC O), 1602 (ꢀC N). H NMR spectrum (300 MHz, CDCl3) d ppm: 1.83 (ABq,
2H, spiro ꢀCH2ꢀCH2), 1.94 (ABq, 2H, CH2ꢀCH2), 2.10 (s, 3H, CH3), 7.2–7.45
(m, 4H, Ar-H), 7.97 (d, J ¼ 7.8 Hz, 2H, Ar-H); 13C NMR spectrum (300 MHz,
CDCl3), 13.06, 20.0 (for two carbons), 33.7, 108.1, 126.9 (for two carbons), 128.5,
128.9 (for two carbons), 134.5, 151.4, 155.9, 162.8, 172.1. ESI-MS: m=z 306
(Mþ þNa), 284 (Mþ þ1). Anal. calcd. for C15H13N3OS: C, 63.58; H, 4.62; N,
14.83; S,11.32. Found: C, 63.52; H, 4.53; N, 14.79; S, 11.36.
7-Methyl-5-[4-(2-oxo-2H-chromen-3-yl)thiazol-2-yl]-5,6-
diazaspiro[2.4]hept-6-en-4-one (4b)
Crystalline solid. 55% yield, mp 270–271 ꢁC. IR (KBr) n (cmꢀ1), 1720 (lactone,
ꢀC O), 1635 (amide, ꢀC O), 1610 (ꢀC Nꢀ). 1H NMR spectrum (300 MHz,
CDCl3) d ppm: 1.83 (ABq, 2H, spiro CH2ꢀCH2), 1.95 (ABq, 2H, spiro CH2ꢀCH2),
2.11 (s, 3H, CH3), 7.37 (d, J ¼ 8.1 Hz, 1H, C8 of coumarin), 7.28 (dd, J ¼ 8.1 Hz, 1H,
C6 of coumarin), 7.65 (d, J ¼ 7.8 Hz, 1H, C5 of coumarin), 7.53 (dd, J ¼ 7.8 Hz, 1H,
C7 of coumarin), 8.29 (s, 1H, thiazole), 8.8 (s, 1H, C4 of coumarin); 13C NMR spec-
trum (300 MHz, CDCl3): 13.1, 20.2 (for two carbon atoms), 33.8, 115.5, 116.7, 119.9,
120.9, 125, 128.8, 131.8, 140.1, 144.1, 153.4, 155.5, 160.2, 163.2, 172.2. ESI-MS: m=z
352 (Mþ þ 1). Anal. calcd. for C18H13N3O3S: C, 61.53; H, 3.73; N, 11.96; S, 9.12.
Found: C, 61.59; H, 3.67; N, 11.91; S, 9.08.
=
=
=
5-[4-(6-Chloro-2-oxo-2H-chromen-3-yl)thiazol-2-yl]-7-methyl-5,6-
diazaspiro[2.4]hept-6-en-4-one (4c)
Crystalline solid, yield 60%, mp 253–255 ꢁC. IR (KBr), n (cmꢀ1), 1721 (lactone,
ꢀC O), 1635 (amide, ꢀC O), 1604 (ꢀC N). 1H NMR spectrum (300 MHz,
CDCl3), d ppm: 1.83 (ABq, 2H, spiro CH2ꢀCH2), 1.93 (ABq, 2H, spiro CH2ꢀCH2),
2.11 (s, 3H, C7 methyl of spiro system), 7.30–7.61 (m, 3H, Ar-H), 8.31 (s, 1H, C5 of
thiazole), 8.73 (s, 1H, C4 of coumarin).13C NMR spectrum (300 MHz, CDCl3): 13.1,
20.3 (for two carbon atoms), 33.8, 116.3, 118.2, 121.0, 121.9, 127.8, 130.3, 131.7,
138.7, 143.7, 151.8, 155.6, 159.6, 163.3, 172.1. Anal. calcd. for C18H12ClN3O3S: C,
56.03; H, 3.13; N, 10.89; S, 8.31. Found: C, 56.11; H, 3.17; N, 10.82; S, 8.34.
=
=
=
5-[4-(6-Bromo-2-oxo-2H-chromen-3-yl)thiazol-2-yl]-7-methyl-5,6-
diazaspiro[2.4]hept-6-en-4-one (4d)
Crystalline solid, yield 40%, mp 237–240 ꢁC. IR (KBr), n (cmꢀ1), 1720 (lactone,
ꢀC O), 1635 (amide, ꢀC O), 1601 (ꢀC N). 1H NMR spectrum (300 MHz,
CDCl3), d ppm: 1.77 (ABq, 2H, spiro CH2ꢀCH2), 2.09 (ABq, 2H, spiro CH2ꢀCH2),
2.37 (s, 3H). 7.42 (d, J ¼ 8.4 Hz, 1H, Ar-H), 7.76–7.89 (m, 2H, Ar-H), 8.28 (s, 1H,
thiazole), 8.72 (s, 1H, C4 of coumarin). ESI-MS: m=z 430 (Mþ þ 1). Anal. calcd.
for C18H12BrN3O3S: C, 50.25; H, 2.81; N, 9.77; S, 7.45. Found: C, 50.17; H, 2.77;
N, 9.83; S, 7.41.
=
=
=

3192
V. RAJESWAR RAO AND V. RAVINDER REDDY
5-[4-(6,8-Dibromo-2-oxo-2H-chromen-3-yl)thiazol-2-yl]-7-methyl-5,6-
diazaspiro[2.4]hept-6-en-4-one (4e)
Crystalline solid, yield 40%, mp 240–243 ꢁC. IR (KBr), n (cmꢀ1), 1732 (lactone,
ꢀC O), 1635 (amide, ꢀC O), 1615 (ꢀC N). 1H NMR spectrum (300 MHz,
CDCl3), d ppm: 1.85 (ABq, 2H, spiro CH2ꢀCH2), 1.95 (ABq, 2H, spiro CH2ꢀCH2),
2.11 (s, 3H, C7 methyl of spiro system), 7.68 (m, 1H, Ar-H), 7.92 (s, 1H, aromatic).
8.32 (s, 1H, C5 thiazole), 8.68 (s, 1H, C4 of coumarin). Anal. calcd. for
C18H11Br2N3O3S: C, 42.46; H, 2.81; N, 8.25; S, 6.30. Found: C, 42.39; H, 2.16; N,
8.21; S, 6.26.
=
=
=
5-[4-(8-Methoxy-2-oxo-2H-chromen-3-yl)thiazol-2-yl]-7-methyl-5,6-
diazaspiro[2.4]hept-6-en-4-one (4f)
Crystalline solid, yield 55%, mp 228–230 ꢁC. IR (KBr), n (cmꢀ1), 1723 (lactone,
ꢀC O), 1625 (amide, ꢀC O), 1607 (ꢀC N). 1H NMR spectrum (300 MHz,
CDCl3), d ppm: 1.77 (ABq, 2H, spiro CH2ꢀCH2), 2.06 (ABq, 2H, spiro CH2ꢀCH2),
2.27 (s, 3H, C7 methyl of spiro system), 3.94 (s, 3H, CH3 of methoxy group),
7.27–7.53 (m, 3H, Ar-H), 8.19 (s, 1H, C5 thiazole), 8.69 (s, 1H, C4 of coumarin).
Anal. calcd. for C19H15N3O4S: C, 59.83; H, 3.96; N, 11.02; S, 8.41. Found: C,
59.87; H, 3.93; N, 11.10; S, 8.44.
=
=
=
5-[4-(5,6-Benzo-2-oxo-2H-chromen-3-yl)thiazol-2-yl]-7-methyl-5,6-
diazaspiro[2.4]hept-6-en-4-one (4g)
Crystalline solid, yield 65%, mp 245–248 ꢁC. IR (KBr), n (cmꢀ1), 1716 (lactone,
ꢀC O), 1627 (amide, ꢀC O), 1610 (ꢀC N). 1H NMR spectrum (300 MHz,
CDCl3), d ppm: 1.85 (ABq, 2H, spiro CH2ꢀCH2), 1.97 (ABq, 2H, spiro CH2ꢀCH2),
2.13 (s, 3H, C7 methyl of spiro system), 7.50–7.73 (m, 3H, Ar-H), 7.92 (d, J ¼ 8.1 Hz,
1H, aromatic), 7.99 (d, J ¼ 9 Hz, 1H, aromatic), 8.36 (s, 1H, C5 thiazole), 8.56 (d,
J ¼ 6 Hz, 1H, aromatic), 9.55 (s, 1H, C4 of coumarin). ESI-MS: m=z 402 [Mþ þ 1],
421 [Mþ þ Na]. Anal. calcd. for C22H15N3O3S: C, 65.82; H, 3.77; N, 10.47, S,
7.99. Found: C, 65.87; H, 3.75; N, 10.44; S, 7.96.
=
=
=
General Procedure for Compound 5
A
mixture of arylbromomethyl ketone=3-(2-bromoacetyl)chromen-2-one
(10 mmol) and thiosemicarbazide (10 mmol) was taken in anhydrous ethanol
(25 ml) and stirred for 2 h at 20–25 ꢁC. The crystalline solid thus obtained was filtered
and washed with ethanol (5 ml). Compound 5 was isolated in 88–92% yield.
2-Oxo-2-(phenyl)ethylhydrazine Carbimidozothioatehydrobromide (5a)
ꢀ1
Yield 92%, mp 205–207 ꢁC. IR (KBr), n (cm ), 1607 (br, ꢀC N), 1660
=
1
=
(ꢀC O). H NMR (DMSO-d6) d ppm: 3.61–3.71 (ABq, 2H, SCH2ꢀ), 7.33–7.54
(m, 6H, Ar-H and 1H of ꢀNH, D2O exchangeable), 7.71 (m, 2H, ꢀNH2, D2O
=
exchangeable), 9.39 (s, 1H, ꢀNH, D2O exchangeable), 10.07 (s, 1H, ꢀC NH,
D2O exchangeable). 13C NMR spectrum (300 MHz, DMSO-d6) d ppm: 41.4, 97.1,

HETEROCYCLIZATIONS VIA POCl3-BASED MULTICOMPONENT REACTIONS 3193
127.2 (for two carbons), 129.6 (for two carbons), 130, 139.5, 171.2. ESI-MS: m=z 210
(Mþ þ 1). Anal. calcd. for C9H11N3OS ꢂ HBr: C, 37.25; H, 4.17; N, 14.48; S, 11.05.
Found: C, 37.16; H, 4.09; N, 14.39; S, 11.08.
2-Oxo-2-(2-oxo-2H-chromen-3-yl)ethylhydrazinecarbimidothioate
Hydrobromide (5b)
ꢀ1
Yield 92%, mp 218–220 ꢁC. IR (KBr), n (cm ) 1607 (C C), 1625 (ꢀC N),
=
=
1654 (ꢀC O), 1711 (lactone, ꢀC O). 1H NMR spectrum (DMSO-d6) d ppm:
3.40 (d, J ¼ 12 Hz, 1H, SCH2-), 3.97 (d, J ¼ 12 Hz, 1H, SCH2ꢀ), 5.14 (s, 2H,
ꢀNH2, D2O exchangeable), 7.37–7.49 (m, 2H, Ar-H), 7.62 (m, 1H, Ar-H), 7.83 (d,
=
=
J ¼ 7.2 Hz, 1H, Ar-H), 8.09 (s, 1H, ꢀNH, D2O exchangeable), 8.41 (s, 1H, C4 of cou-
þ
=
marin), 9.17 (s, 1H, ꢀC NH, D2O exchangeable), 9.75 (s, 1H, C¼NH2 , D2O
exchangeable). ESI-MS: m=z 278 (Mþ þ 1). Anal. calcd. for C12H11N3O3S ꢂ HBr:
C, 40.24; H, 3.38; N, 11.73; S, 8.95. Found: C, 40.47; H, 3.04; N, 11.67; S, 8.89.
2-Oxo-2-(6-chloro-2-oxo-2H-chromen-3-
yl)ethylhydrazinecarbimidothioate Hydrobromide (5c)
ꢀ1
Yield 88%, mp 205–207 ꢁC. IR (KBr), n (cm ) 1593 (C C), 1625 (ꢀC N),
=
=
1651 (ketone ꢀC O), 1712 (lactoneꢀC O). 1H NMR spectrum (DMSO-d6) d
ppm: 3.39 (d, J ¼ 12 Hz, 1H, SCH2-), 3.97 (d, J ¼ 12 Hz, 1H, SCH2ꢀ), 5.14 (s, 2H,
ꢀNH2, D2O exchangeable), 7.52 (d, J ¼ 9 Hz, 1H, Ar-H), 7.73 (dd, 1H, Ar-H),
=
=
8.09–8.16 (m, 2H, aromatic and ꢀNH, D2O exchangeable), 8.39 (s, 1H, C4 of
þ
=
coumarin), 9.17 (s, 1H, ꢀC NH, D2O exchangeable), 9.77 (s, 1H, C¼NH2 ,
exchangeable). ESI-MS: m=z 312 (Mþ þ 1). Anal. calcd. for C12H10ClN3O3S ꢂ HBr:
C, 36.72; H, 2.82; N, 9.03; S, 8.16. Found: C, 36.75; H, 2.84; N, 9.01; S, 8.11.
2-Oxo-2-(6-bromo-2-oxo-2H-chromen-3-
yl)ethylhydrazinecarbimidothioate Hydrobromide (5d)
ꢀ1
Yield 90%, mp 210–212 ꢁC. IR (KBr), n (cm ) 1594 (C C), 1622 (ꢀC N),
=
=
1
=
=
1654 (ꢀC O), 1713 (lactoneꢀC O). H NMR spectrum (DMSO-d6) d ppm: 3.42
(d, J ¼ 15 Hz, 1H, SCH2-), 3.97 (d, J ¼ 12 Hz, 1H, SCH2ꢀ), 5.14 (s, 2H, ꢀNH2,
D2O exchangeable), 7.47 (d, J ¼ 9 Hz, 1H, Ar-H), 7.85 (d, J ¼ 9 Hz, 1H, Ar-H),
8.14 (s, 1H, ꢀNH, D2O exchangeable), 8.23 (s, 1H, Ar-H), 8.38 (s, 1H, C4 of cou-
þ
=
marin), 9.18 (s, 1H, ꢀC NH, D2O exchangeable), 9.75 (s, 1H, C¼NH2 , exchange-
able). 13C NMR spectrum (DMSO-d6) d ppm: 37.4, 93.7, 117.0, 119.1, 121.4, 127.0,
132.2, 135.9, 143.1, 153.6, 159.0, 170.4. Anal. calcd. for C12H10BrN3O3S ꢂ HBr: C,
32.97; H, 2.54; N, 9.61; S, 7.33. Found: C, 32.91; H, 2.49; N, 9.67; S, 7.39.
2-Oxo-2-(6,8-dibromo-2-oxo-2H-
chromen-3-yl)ethylhydrazinecarbimidothioate Hydrobromide (5e)
ꢀ1
Yield 88%, mp 210–212 ꢁC. IR (KBr), n (cm ) 1603 (C C), 1627 (ꢀC N),
=
=
1
=
=
1660 (ꢀC O), 1727 (lactoneꢀC O). H NMR spectrum (DMSO-d6) d ppm: 3.38
(d, J ¼ 12 Hz, 1H, SCH2ꢀ), 3.99 (d, J ¼ 12 Hz, 1H, SCH2ꢀ), 5.15 (s, 2H, ꢀNH2,
D2O exchangeable), 8.19 (s, 1H, ꢀNH, D2O exchangeable), 8.23 (d, J ¼ 3 Hz, 1H,

3194
V. RAJESWAR RAO AND V. RAVINDER REDDY
Ar-H), 8.26 (d, J ¼ 3 Hz, 1H, Ar-H), 8.37 (s, 1H, C4 of coumarin), 9.21 (s, 1H,
þ
=
ꢀC NH, D2O exchangeable), 9.79 (s, 1H, C¼NH2 , exchangeable). Anal. calcd.
for C12H9Br2N3O3S ꢂ HBr: C, 27.93; H, 1.95; N, 8.14; S, 6.21. Found: C, 27.88; H,
1.93; N, 8.14; S, 6.21.
2-Oxo-2-(8-methoxy-2-oxo-2H-
chromen-3-yl)ethylhydrazinecarbimidothioate Hydrobromide (5f)
ꢀ1
Yield 90%, mp 228–230 ꢁC. IR (KBr), n (cm ) 1611 (C C), 1623 (ꢀC N),
=
=
1656 (ketoneꢀC O), 1714 (lactoneꢀC O). 1H NMR spectrum (DMSO-d6) d
ppm: 3.37 (d, J ¼ 12 Hz, 1H, SCH2ꢀ), 3.93 (s, 3H, methoxy group), 3.97 (d,
J ¼ 12 Hz, 1H, SCH2-), 5.13 (s, 2H, ꢀNH2, D2O exchangeable), 7.29–7.46 (m, 3H,
=
=
Ar-H), 8.08 (s, 1H, ꢀNH, D2O exchangeable), 8.37 (s, 1H, C4 of coumarin), 9.17
þ
=
(s, 1H, ꢀC NH, D2O exchangeable), 9.74 (s, 1H, C¼NH2 , exchangeable). Anal.
calcd. for C13H13N3O3S ꢂ HBr: C, 40.22; H, 3.53; N, 10.82; S, 8.26. Found: C,
40.12; H, 3.57; N, 10.77; S, 8.21.
2-Oxo-2-(5,6-benzo-2-oxo-2H-chromen-3-
yl)ethylhydrazinecarbimidothioate Hydrobromide (5g)
ꢀ1
Yield 91%, mp 240–242 ꢁC. IR (KBr), n (cm ) 1606 (ꢀC N), 1659 (ketone
=
ꢀC O), 1704 (lactoneꢀC O), 3345 (ꢀNH). 1H NMR spectrum (DMSO-d6) d
ppm: 3.46 (d, J ¼ 12 Hz, 1H, SCH2ꢀ), 4.06 (d, J ¼ 12 Hz, 1H, SCH2-), 5.20 (s, 2H,
ꢀNH2, D2O exchangeable), 7.65–7.84 (m, 3H, Ar-H), 8.12 (d, J ¼ 9 Hz, 1H,
Ar-H), 8.23 (s, 1H, ꢀNH, D2O exchangeable), 8.31 (d, J ¼ 9 Hz, 1H, Ar-H), 8.51
=
=
=
(d, J ¼ 9 Hz, 1H, Ar-H), 9.10 (s, 1H, C4 of coumarin), 9.22 (s, 1H, ꢀC NH, D2O
exchangeable), 9.80 (s, 1H, C¼NHþ2 , exchangeable). Anal. calcd. for C16H13N3O3S ꢂ
HBr: C, 47.07; H, 3.46; N, 10.29; S, 7.85. Found: C, 47.01; H, 3.49; N, 10.25; S, 7.81.
General Procedure for Cyclization of 5 with POCl3, Leading to 4
2-Acetylbutyrolactone (5 mmol) was added to a suspension of 2-oxo-2-(aryl-2-
oxo-2H-chromen-3-yl)ethylhydrazinecarbimidathioate hydrobromide 5 (5 mmol) in
POCl3 (7.2 ml) at 20–25 ꢁC. The suspension was heated to 95 ꢁC, and the stirring con-
tinued for 2 h. The reaction mixture was cooled to 20 ꢁC, and anhydrous ethanol was
added (20 ml). The product was filtered and purified by chromatography on silica gel
(eluent, ethyl acetate=hexane 1.5:8.5) to give 4 in 40–50% yield. The compounds
obtained by method 2 were found to be identical to those obtained by method 1. This
was confirmed by their mixed mp measurements, co-TLC, and spectral data.
CONCLUSION
In summary, we have described an elegant and simple methodology for the
synthesis of 7-methyl-5-[4-(aryl=2-oxo-2H-chromen-3-yl)thiazol-2-yl]-5,6-diaza-
spiro[2.4]hept-6-en-4-one. The synthesis involves a one-step selective ring closure
leading to simultaneous formation of three rings at a time. Advantages of the present
protocol are (i) ready availability of the starting materials and mild reaction

HETEROCYCLIZATIONS VIA POCl3-BASED MULTICOMPONENT REACTIONS 3195
conditions, (ii) environmentally safe, (iii) simple operational procedure, and (iv)
good yields. The protocol is certainly superior to classical methods available for
the preparation individual cyclic systems and other multistep syntheses. This reac-
tion can be extended to other heterocyclic a-halo ketones.
ACKNOWLEDGMENT
The authors thank Dr. G. K. A. S. S. Narayan, APL Research Centre,
Hyderabad, India, for his help in molecular design.
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