Synthesis of novel isoxazolyl 1,6-Dithia-4,9-diazaspiro[4,4]nonane-3,8- diones and 1-Oxa-6-thia-2,4,9-triazaspiro[4,4]non-2-ene-8-ones

Article abstract of DOI:10.1080/10426500802705164

The key intermediates, 3-(5-methyl-3-isoxazolyl)-2-arylimino-1,3-thiazolan- 4-ones (3), were obtained from 3-amino-5-methylisoxazole (1) by reaction with chloroacetyl chloride followed by treatment with aryl isothiocyanates. Cyclocondensation of 3 with me

Full text of DOI:10.1080/10426500802705164

Phosphorus, Sulfur, and Silicon, 184:3139–3148, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802705164
Synthesis of Novel Isoxazolyl
1,6-Dithia-4,9-diazaspiro[4,4]nonane-3,8-diones and
1-Oxa-6-thia-2,4,9-triazaspiro[4,4]non-2-ene-8-ones
E. Rajanarendar, S. Raju, and A. Siva Rami Reddy
Department of Chemistry, Kakatiya University, Warangal, India
The key intermediates, 3-(5-methyl-3-isoxazolyl)-2-arylimino-1,3-thiazolan-4-ones
(3), were obtained from 3-amino-5-methylisoxazole (1) by reaction with chloroacetyl
chloride followed by treatment with aryl isothiocyanates. Cyclocondensation
of
3 with mercapto acetic acid furnished novel isoxazolyl 1,6-dithia-4,9-
diazaspiro[4,4]nonane-3,8-diones (4). Cycloaddition of 3 with benzonitrile oxides
afforded novel isoxazolyl 1-oxa-6-thia-2,4,9-triazaspiro[4,4]non-2-ene-8-ones (5).
Keywords Cycloaddition; cyclocondensation; isoxazolyl spiro thiazolidinones
INTRODUCTION
The discovery of new agents displaying high antimicrobial activity is
an important topic of research in medicinal chemistry.1 Spirothiazo-
lidinones are heterocyclic nuclei that have stimulated much interest
in medicinal and biological chemistry.2,3 They are known to possess
anti-inflammatory,4 fungistatic,5 bacteriostatic,6 anticonvulsant,7 and
antitubercular8 activities. Similarly, the isoxazole unit constitutes an
easily accessible nucleus that is present in a number of natural and
pharmacological compounds,9 displays a wide range of organic reactivi-
ties, and could be used as an effective means of preparing new molecular
scaffolds.10 Several of these derivatives are potent antitumor,11 CNS-
active,12 analgesic,13 antimicrobial,14 and chemotherapeutic agents.15
Therefore, we thought it useful to construct a system that combines
these biolabile rings together in a single molecular framework to see
the additive effect towards their biological activities. A literature sur-
vey reveals that there is no report on the synthesis of the title molecules
so far. In view of these observations and also as a sequel to our search
for biologically active nitrogen and sulfur heterocycles16 linked to an
Received 8 July 2008; accepted 15 December 2008.
Address correspondence to E. Rajanarendar, Department of Chemistry, Kakatiya Uni-
versity, Warangal 506 009, India. E-mail: eligeti rajan@yahoo.co.in
3139

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E. Rajanarendar et al.
isoxazole ring, we wish to report the synthesis of novel spiro thiazolidi-
nones containing the isoxazole moiety.
RESULTS AND DISCUSSION
The synthetic scheme of compounds 2, 3, 4, and 5 is shown
in Scheme 1. The reaction of 3-amino-5-methylisoxazole (1) with
chloroacetyl chloride in the presence of triethyl amine in dry ben-
zene furnished N-1-(5-methyl-3-isoxazolyl)-2-chloroacetamide (2). The
chloroacetamide (2) reacted with aryl isothiocyanates in the pres-
ence of K2CO3 in CH3CN to afford the key intermediate viz., 3-(5-
methyl-3-isoxazolyl)-2-arylamino-1,3-thiazolan-4-ones (3). The mecha-
nism involves the addition of an amide derivative to isothiocyanate
in the presence of a base; subsequent cyclization takes place by
nucleophilic substation of chlorine by the sulfur atom of isothio-
cyanate. This mechanism was in agreement with an earlier obser-
vation.17 Cyclocondensation of (3) with mercapto acetic acid in 1,4-
dioxane led to the formation of novel 4-(5-methyl-3-isoxazolyl)-9-aryl-
1,6-dithia-4,9-diazaspiro[4,4]nonane-3,8-diones (4). Cycloaddition of
(3) with benzonitrile oxides, generated in situ, from benzhydroxam-
oyl chloride in the presence of triethyl amine at ice cold temperature
furnished the novel 9-(5-methyl-3-isoxazolyl)-3,4-diaryl-1-oxa-6-thia-
2,4,9-triazaspiro[4,4]non-2-ene-8-ones (5) (Scheme 1). The structure of
the products 2, 3, 4, and 5 have been elucidated on the basis of spectral
(IR, 1H NMR, and MS) and microanalytical data (Tables I–V).
Chloroacetamide (2) exhibited two strong absorption bands in the IR
spectra at 1680 and 3320 cm−1 due to C O and NH functional groups
respectively. The 1H NMR spectrum of (2) showed two singlets at δ 4.2
and 7.6 due to CH2 and NH protons, respectively, and the signal at δ
7.6 disappeared upon shaking with D2O. The mass spectrum of (2) dis-
played the molecular ion [M+H]+ peak at m/z 175. Compounds (3) dis-
played characteristic absorption bands in the IR spectra around 1630
and 1690 cm−1 due to C N and C O functional groups, respectively,
1
confirming cyclocondensation. The H NMR spectra of 3 exhibited a
sharp singlet around δ 4.2 due to CH2 protons. Isoxazole methyl pro-
tons exhibited as a sharp singlet at δ2.2, whereas the isoxazole ring
proton appeared as a singlet at δ 6.2. Aromatic protons resonated as
complex mulitiplet between δ 7.2–7.6. The mass spectrum of the product
(3) agrees well with the cyclized structure, which showed the molecu-
lar ion peak [M+H]+ at m/z 274. The 1H NMR spectra of (4) displayed
two distinct singlets around δ 4.2 and 4.4 due to methylene protons of
thiazolidinone rings, confirming the formation of spirothiazolidinone
rings. The mass spectrum of (4) confirmed the structure by exhibiting

Synthesis of Isoxazolyl Spiro Thiazolidinones
3141
SCHEME 1
1
the molecular ion peak [M+H]+ at m/z 349. H NMR spectra of (5)
showed a prominent singlet around δ 4.0–4.3 due to the thiazolidinone
ring CH2 protons. The mass spectrum of (5) also agrees well with the
structure, which showed the molecular ion peak [M+H]+ at m/z 393,
confirming the cycloaddition reaction.

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Synthesis of Isoxazolyl Spiro Thiazolidinones
3145
TABLE IV Spectral Data of Compounds 3 and 4
Mass
spectra m/z
Compd. IR (ν
cm−1
)
1H NMR (δ ppm)
[M+H]+
max
3a
3b
1630 C
N
2.21 (s, 3H, CH3), 4.21 (s, 2H, CH2), 6.20 (s,
1H, isoxazole-H), 7.20–7.63 (m, 5H, Ar-H).
2.31 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.16
(s, 2H, CH2), 6.24 (s, 1H, isoxazole-H),
7.00–7.65 (m, 4H, Ar-H).
262
292
1690 C
1635 C
1685 C
O
N
O
3c
3d
1630 C
1695 C
1640 C
1685 C
N
O
N
O
2.13 (s, 3H, CH3), 4.00 (s, 2H, CH2), 6.00 (s,
1H, isoxazole-H), 7.15–8.00 (m, 4H, Ar-H).
2.20 (s, 3H, CH3), 2.40 (s, 3H, CH3), 4.20 (s,
2H, CH2), 6.30 (s, 1H, isoxazole-H),
7.00–8.20 (m, 4H, Ar-H).
296
276
3e
4a
1630 C
1680 C
1710 C
1275 C
N
O
O
S
2.20 (s, 3H, CH3), 4.05 (s, 2H, CH2), 6.40 (s,
1H, isoxazole-H), 7.00–7.55 (m, 4H, Ar-H).
2.22 (s, 3H, CH3), 4.21 (s, 2H, CH2), 4.40 (s,
2H, CH2), 6.10 (s, 1H, isoxazole-H),
7.21–8.20 (m, 5H, Ar-H).
310
315
4b
4c
4d
4e
1720 C
1280 C
O
S
2.10 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.25
(s, 2H, CH2), 4.45 (s, 2H, CH2), 6.08 (s, 1H,
isoxazole-H), 7.50–8.40 (m, 4H, Ar-H).
2.20 (s, 3H, CH3), 4.20 (s, 2H, CH2), 4.42 (s,
2H, CH2), 6.12 (s, 1H, isoxazole-H),
7.22–8.00 (m, 4H, Ar-H).
2.15 (s, 3H, CH3), 2.32 (s, 3H, CH3), 4.20 (s,
2H, CH2), 4.42 (s, 2H, CH2), 6.15 (s, 1H,
isoxazole-H), 7.20–8.00 (m, 4H, Ar-H).
2.20 (s, 3H, CH3), 4.25 (s, 2H, CH2), 4.40 (s,
2H, CH2), 6.10 (s, 1H, isoxazole-H),
7.50–8.50 (m, 4H, Ar-H).
345
349
329
392
1715 C
1270 C
O
S
1710 C
1285 C
O
S
1720 C
1275 C
O
S
In summary, we have synthesized novel spiro thiazolodines carrying
isoxazole moiety by cyclocondensation and cycloaddition reactions. In
view of the potential activity of spiro thiazolidinones, we predict that
the newly synthesized novel isoxazolyl spiro thiazolidinones may act
as drug candidates, and the activity data will be published elsewhere.
EXPERIMENTAL
All the melting points were determined on a Cintex melting point ap-
paratus and are uncorrected. Analytical TLC was performed on Merck
precoated 60 F254 silica gel plates. Visualization was done by expos-
ing them to iodine vapor. IR spectra (KBr pellet) were recorded on
1
a Perkin-Elmer BX series FT-IR spectrophotometer. H NMR spectra

3146
E. Rajanarendar et al.
TABLE V Spectral Data of Compounds 5
Mass
spectra m/z
Compd. IR (ν
cm−1
)
1H NMR (δ ppm)
[M+H]+
max
5a
1635 C
1680 C
N
O
2.20 (s, 3H, CH3), 4.02 (s, 2H, CH2), 6.10 (s,
1H, isoxazole-H), 7.20–8.20 (m, 10H,
Ar-H).
393
5b
5c
1640 C
1670 C
1640 C
1680 C
N
O
N
O
2.10 (s, 3H, CH3), 4.18 (s, 2H, CH2), 6.00 (s,
1H, isoxazole-H), 7.00–8.02 (m, 9H, Ar-H).
2.32 (s, 3H, CH3), 3.81 (s, 2H, OCH3), 4.21
(s, 2H, CH2), 6.51 (s, 1H, isoxazole-H),
7.50–8.50 (m, 9H, Ar-H).
427
423
5d
5e
5f
1635 C
1685 C
N
O
2.22 (s, 3H, CH3), 3.12 (s, 3H, OCH3), 4.32
(s, 2H, CH2), 6.20 (s, 1H, isoxazole-H),
7.20–8.50 (m, 8H, Ar-H).
2.10 (s, 3H, CH3), 2.50 (s, 3H, CH3), 4.02 (s,
2H, CH2), 6.41 (s, 1H, isoxazole-H),
7.10–7.62 (m, 9H, Ar-H).
457
407
438
1635 C
1670 C
N
O
1635 C
1695 C
N
O
2.20 (s, 3H, CH3), 4.12 (s, 2H, CH2), 6.00 (s,
1H, isoxazole-H), 7.80–8.62 (m, 9H, Ar-H).
were recorded on a Varian Gemini 300 MHz spectrometer. Chemical
shift values are given in ppm (δ) with tetramethylsilane as internal
standard. Mass spectral measurements were carried out by EI method
on a Jeol JMC-300 spectrometer at 70 eV. Elemental analyses were
performed on Carlo Erba 106 and Perkin-Elmer model 240 analyzers.
N1-[5-Methyl-3-isoxazolyl]-2-chloroacetamide (2)
3-Amino-5-methylisoxazole (1) (0.01 mol), chloroacetyl chloride (0.01
mol), and triethyl amine (0.5 mL) were taken in dry benzene (15 mL),
and the contents were refluxed with stirring for 4–6 h. The precipitated
triethyl amine hydrochloride was removed by filtration. The gummy
product obtained after the removal of solvent at ambient temperature
was triturated with methanol. Recrystallization of the product was
effected from aqueous methanol.
Compound 2: mp 62◦C; Yield: 85%, IR (KBr): 3320 (NH), 1680 (C O);
1H NMR (200 MHz, CDCl3): δ 2.21 (s, 3H, CH3), 4.20 (s, 2H, CH2), 6.40
(s, 1H, isoxazole-H), 7.60 (s, 1H, NH); MS [M+H]+ m/z: 175; Anal.
C6H7N2O2Cl: Found C, 41.40; H, 4.06; N, 16.03. Calcd. C, 41.37; H,
4.02; N, 16.09%.

Synthesis of Isoxazolyl Spiro Thiazolidinones
3147
3- (5-Methyl-3-isoxazolyl)-2-arylimino-1,3-thiazolan-4-ones (3)
To a solution of N1-(5-methyl-3-isoxazolyl)-2-chloroacetamide (2) (0.01
mol) in aceto nitrile (15 mL), aryl isothiocyanate (0.01 mol) was added in
the presence of K2CO3 (0.5 g). The reaction mixture was refluxed while
stirring for about 8 h. The solvent was removed under reduced pressure,
and the residue was purified by recrystallization from methanol to give
(3a–e) (Table I).
4-(5-Methyl-3-isoxazolyl)-9-aryl-1,6-dithia-4,9-
diazaspiro[4,4]nonane-3,8-dione (4)
A mixture of compound (3) (0.01 mol) and mercapto acetic acid (0.01
mol) was dissolved in 1,4-dioxane (15 mL), and the contents were re-
fluxed for 5–8 h. After completion of the reaction (monitored by TLC),
the reaction mixture was allowed to cool and was poured over crushed
ice. The organic layer was extracted with ethyl acetate (20 mL), washed
with 10% sodium bicarbonate solution (1 × 20 mL), and dried over an-
hydrous sodium sulfate. The solvent was removed under vacuum, and
the residue was recrystallized from methanol to give (4a–e) (Table II).
9-(5-Methyl-3-isoxazolyl)-3,4-diaryl-(1-oxa-6-thia)2,4,9-
triazaspiro[4,4]non-2-ene-8-ones (5)
A mixture of compound 3 (0.01 mol) in dry chloroform (50 mL) was
cooled in an ice/salt bath, and a solution of benzhydroxamoyl chloride
(0.01 mol) in chloroform (10 mL) was added. Triethyl amine (0.01 mol)
in chloroform (10 mL) was added to the reaction mixture at 0◦C over
a period of 15 min with constant stirring. After the addition was com-
pleted, the stirring was continued for another 4 h at 0◦C. The chloroform
layer was washed with water (2 × 25 mL) to remove triethyl amine hy-
drochloride, and the organic layer was dried (Na2SO4). The solvent was
removed at ambient temperature, and the crude product was triturated
with light petrol repeatedly to obtain a residue. Recrystallization from
benzene gave (5a–f) (Table III).
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