Synthesis and antimicrobial activity of novel spirocompounds with pyrazolone and pyrazolthione moiety

Article abstract of DOI:10.1002/jhet.5570440108

(Chemical Equation Presented) The paper focuses on the utility of 2-pyrazoline-5-ones and 2-pyrazoline-5-thiones as active Michael donors for the synthesis of novel spirocyclohexanone derivatives. The sulphur containing compounds when screened for antimicrobial activity showed promising inhibition of S.Typhi, S Aures and E Coli bacteria.

Full text of DOI:10.1002/jhet.5570440108

Jan-Feb 2007
49
Synthesis and Antimicrobial Activity of Novel
Spirocompounds with Pyrazolone and Pyrazolthione Moiety
Madhukar S Chande*, Pravin A Barve & Vijay Suryanarayan
Department of Chemistry, The Institute Of Science, 15, M Cama Road, Mumbai 400 032, India.
chandems@vsnl.com
Received January 16, 2006
R
X
R
X
N
N
N
N
O
7
1
a: R = CH3 , X = O, b : R = Ph , X = O c: R = CH3 , X =S d : R = Ph , X =S
The paper focuses on the utility of 2-pyrazoline-5-ones and 2-pyrazoline-5-thiones as active Michael
donors for the synthesis of novel spirocyclohexanone derivatives. The sulphur containing compounds when
screened for antimicrobial activity showed promising inhibition of S.Typhi, S Aures and E Coli bacteria.
J. Heterocyclic Chem., 44, 49 (2007).
INTRODUCTION
pyrazoline-5-thiones 1c,d from 2-pyrazoline-5-ones 1a,b
according to literature methods using P2S5 or Lawessons
reagent resulted in poor yields [7]. The application of
microwave irradiation was used as an alternative for this
reaction. As anticipated, the microwave-assisted reaction
of 2-pyrazoline-5-one 1a with Lawessons reagent gave 2-
pyrazoline-5-thione 1c in 70% yield (Scheme 1). The
reaction was clean without any major side products.
Similarly 1,3-diphenyl-2- pyrazoline-5-thione 1d [8] was
obtained from 1,3-diphenyl – 2 - pyrazoline-5-one 1b in
75% yield.
Michael addition is one of the oldest well-known
reactions, which involves the formation of a carbon-
carbon bond and has found extensive applications in
organic synthesis. The reaction, usually carried out in
basic conditions, deals with the addition of compounds
containing active methylene group (donors) to activated ꢀ
systems (acceptors). More recently, the use of
organometallics [1] and ionic liquids [2] has gained
considerable importance to carry out this reaction, since it
leads to products with high enantioselectivity.
Spiro compounds are well known to possess varied
pharmacological activities and hence their synthesis has
always been a challenge and of attraction to organic
chemists. Over the past decade we have reported some
exciting synthetic strategies for the synthesis of this
exclusive class of compounds [3].
Scheme 1
R
R
Lawessons Reagent
N
N
N
N
MW (180W/80°C, 5 min)
S
O
Recently, we have been actively exploring the Michael
addition reaction on heterocyclic and carbocyclic systems
bearing active methine [4] and methylene [5] groups. We
have successfully employed the Michael adducts as key
intermediates for synthesis of some interesting
spirocompounds. Thus, continuing our work along this
line, we herein wish to report the efficacy of pyrazoline-5-
thiones and pyrazoline-5-ones as Michael donors for
synthesis of biologically active novel spirocyclohexanone
derivatives.
1a: R = CH3
1b: R = Ph
1c: R = CH3
1d: R = Ph
The Michael addition of 1a,b with acceptors like
methyl acrylate 2 and acrylonitrile 3 proceeded smoothly
leading to diadducts. Thus diadducts 4a,b were obtained
by interaction of 2-pyrazoline-5-ones 1a,b respectively
with two equivalents of methyl acrylate 2 and two
equivalents of sodium amide in DMF at ambient
temperature. If equimolar ratios of 2-pyrazoline-5-ones
1a,b and Michael acceptor 2 were used the diadducts 4a,b
were isolated together with unreacted starting material.
The existence of the carbonyl peak due to 2-pyrazoline-5-
one in 13C-NMR spectra of both the diadducts 4a,b rules
out the possibility of the O-alkylated diadducts and
RESULTS AND DISCUSSION
2-Pyrazoline-5-ones 1a,b and 2-pyrazoline-5-thiones
1c,d are active Michael donors because of the methylene
group at position 4. Although, 2-pyrazoline-5-one 1a,b
can be easily synthesized [6], the synthesis of 2-

50
M. S. Chande, P. A. Barve and V. Suryanarayan
Vol 44
suggests
a
regioselective Michael addition [8,9].
Studies of the Michael addition on 1 was further
extended to acrylonitrile 3. In case of 1-phenyl-3-
methyl-2-pyrazoline-5-one 1a with two moles of
Compound 4a on hydrolysis afforded the dicarboxylic
acid 5a [10].
Scheme 2
O
R
O
O
R
O
R
NaOMe / MeOH
(when R=-Ph)
2
N
N
O
O
N
N
N
N
O
NaNH2 / DMF
O
O
O
7a: R = CH3
7b: R = Ph
4a: R = CH3
4b: R = Ph
1a: R = CH3
1b: R = Ph
HBr-CH3COOH(33%)
CH3COOH
O
O
H
O
R
O
R
O
O
O
N
N
NaOMe / MeOH
(when, R= CH3)
N
N
conc. HCl
O
H
O
5a ( R = CH3)
6a
acrylonitrile under identical reaction conditions used
for 1a-d gave a mixture of mono adduct 8a [11a] and
spiroderivative 10a.
Dieckmann condensation of 4a in presence of alkoxide
afforded the spirocyclohexyl-ꢀ-ketoester 6a, which on
hydrolysis and decarboxylation furnished the spirocyclo-
hexanone derivative 7a. Compound 4b on Dieckmann
condensation directly furnished 7b (Scheme 2).
However, under identical conditions used for 1a,b, the
Michael addition of 2-pyrazoline-5-thiones 1c,d and
methyl acrylate 2 led directly to the formation of the spiro-
cyclohexanone derivatives. Thus, 6d obtained from 1d was
hydrolysed and decarboxylated to give 7d. Interestingly,
1c directly afforded 7c after workup (Scheme 3).
Diadducts were not isolated in these reactions.
These two compounds were separated on the basis of
their solubility difference in benzene. The formation of
10a could be envisaged as an in situ Thorpe-Ziegler
cyclization of the diadduct 9a [10]. However, 1b-d under
similar reaction conditions furnished only the Thorpe-
Ziegler cyclized product, 10b-d [12,Note]. The cyclo-
hexanone derivatives 7a-d was obtained by the hydrolysis
and decarboxylation of the respective spiro compounds
10a-d. Therefore, an alternative, unambiguous and
independent method for the synthesis of compounds 7a-d
has been established (Scheme 4).
Scheme 3
The spirocyclohexanone derivatives containing the
sulfur atoms were screened for their antimicrobial
activity. The results showed inhibition of S. Typhi, S.
Aureus and E. Coli bacteria.
The details are outlined in Table 1. In case of E. coli,
the data has been compared with standard drugs like silver
sulphadiazine and gentamicin while the activity of 2-
pyrazoline-5-thione derivatives seems to be very
promising.
In conclusion, we have described a mild, efficient and
convenient method for the synthesis of 1-phenyl-3-
substituted-2-pyrazoline-5-thiones from the corresponding
2-pyrazoline-5-ones. We have been successful in utilizing
the pyrazoline-5-ones and pyrazoline-5-thiones as
Michael donors for the synthesis of novel and rather
inaccessible spirocompounds with potential biological
activity. Compounds 4, 6, 7, 10, 11 reported are new and
have been characterized by spectral and analytical data.
O
O
R
S
Ph
S
O
O
O
2
N
N
N
N
NaNH2 / DMF
(when R= -Ph)
1c (R = CH3)
1d (R = Ph)
6d
33% HBr-CH3COOH
CH3COOH
NaNH2 / DMF
(when R = CH3)
O
O
2
Ph
CH3
N
N
O
O
N
N
S
S
7c
7d

Jan-Feb 2007
Synthesis and Antimicrobial Activity of Novel Spirocompounds
with Pyrazolone and Pyrazolthione Moiety
51
Scheme 4
R
N
R
X
N
N
N
R
X
N
N
N
N
3
N
N
+
NaNH2 / DMF
XH
9a-d
8a
observed only when
R= CH3 and X=O
1a: R = CH3, X = O
1b: R = Ph, X = O
1c: R = CH3, X =S
1d: R = Ph, X =S
insitu
N
N
R
X
R
R
33% HBr-CH3COOH
CH3COOH
N
N
N
N
N
N
NH
NH2
O
X
X
10a: R = CH3, X = O
10b: R = Ph, X = O
10c: R = CH3, X =S
10d: R = Ph, X =S
7a-7d
Table 1: Antibacterial activity studies by drug diffusion method [5d]
Compound
Concentration
diameter of zone of inhibitory (mm)
μg/ml
E. coli
S. typhosa
S. aureus
7c
7c
7c
7d
7d
7d
40
60
100
40
60
100
8
9
12
9
11
13
7
9
11
7
7
10
9
10
14
10
12
13
14
12
Silver sulphadiazine
Gentamicin
added the appropriate 2-pyrazoline-5-one or 2-pyrazoline-5-
thione, 1a-d (10 mmoles) at 10–15°C. After the addition was
complete methyl acrylate (1.72 g, 20 mmoles) was added
dropwise over a period of 5 minutes. Stirring was continued for
7 hours and then the reaction mixture was poured into crushed
ice (30 g) and acidified with 20% aqueous hydrochloric acid to
pH 3. The resulting mixture was triturated with ice-water and
extracted with ethyl acetate (2 x 25 ml). The combined organic
layers were washed with water (3 x 40 ml), brine and dried
(Na2SO4). Removal of solvent under vacuum afforded the crude
product, which was crystallised using appropriate solvent to give
4a,b, 6d and 7c in 92%, 82%, 53% and 42% respectively.
EXPERIMENTAL
General Procedure for the Thiation of 2-pyrazoline-5-
ones (1a,b) with Lawessons reagent.
The appropriate 2-pyrazoline-5-one 1a,b (10 mmoles) and
Lawesson’s reagent (15 mmoles) were mixed together and
subjected to microwave irradiation for 5 min. The sticky mass
thus obtained was treated with hot 25% aqueous alkali (50 ml)
and filtered. The filtrate was treated with cold 20% dilute HCl
(35 ml) to regenerate the product. The sticky mass was triturated
and crystallized from methanol to afford pure 2-pyrazoline-5-
thiones 1c,d in 70% and 75% yield respectively.
1–Phenyl–3–methyl-4,4–di[carbmethoxyethyl]-2-pyrazoline-
5-one (4a). This compound was obtained as brown oil (purified
by column chromatography, 5% ethyl acetate: 95% hexane) ir
(CCl4): 2976, 2864, 1739, 1712, 1597 cm-1. 1HNMR (CDCl3,
500 MHz): ꢀ 2.06 - 2.28 (m, 11H, 4x-CH2 and -CH3), 3.63 (s,
6H, 2x-OCH3), 7.19-7.89 (m, 5H, phenyl protons). 13CNMR
(CDCl3, 500 MHz): ꢀ 13.6, 28.6 & 29.3 (4x-CH2), 51.7 (2x-
OCH3), 57.3, 118.8, 125.3, 128.8, 137.4, 161.7, 172.3, 174.0 &
175.3. Anal. Calcd. for C18H22N2O5 (346): C, 62.42; H 6.40; N,
8.09, Found: C, 62.39; H, 6.42; N, 8.04.
1-Phenyl-3-methyl-2-pyrazoline-5-thione (1c). This
compound was obtained as colorless needles, m.p : 107° (lit [7],
109°C).
1,3-Diphenyl-4H-pyrazol-5-thione (1d). This compound
was obtained as light yellow crystals, m.p: 82°C yield: 1.89 gm
1
(75%). HNMR (CDCl3, 300MHz): ꢀ 2.56 (s, 2H, CH2), 7.35-
8.07 (m, 10H, phenyl protons). 13CNMR (CDCl3, 300MHz): ꢀ
29.85, 125.37, 125.63, 125.72, 128.28, 128.66, 128.72, 132.18,
134.50, 138.85, 151.81 ppm.; EI ms: m/z 252(100),
224(20),148(25), 102(20), 77(40). Anal. Calcd. for C15H12N2S:
C, 71.40; H, 4.79; N, 11.10. Found: C, 71.36; H, 4.76; N, 11.11.
General Procedure for the Reaction of 2-Pyrazoline-5-
ones (1a,b) and 2-Pyrazoline-5-Thiones (1c,d) with Methyl
Acrylate (2). To a stirred solution of sodium amide (20
mmoles) in dry DMF (25 mL) in nitrogen atmosphere, was
1,3-Diphenyl-4,4-di[carbmethoxyethyl]-2-pyrazoline-5-one
(4b). This compound was obtained as light orange crystals
(methanol), m.p 180°, ir (CHCl3): 2975, 2858, 1740, 1711, 1597
1
cm-1. HNMR (CDCl3, 500 MHz): ꢀ 2.05-2.49 (m, 8H, 4x-CH2),
3.54 (s, 6H, 2x-OCH3), 7.18-8.04 (m, 10H, phenyl protons).

52
M. S. Chande, P. A. Barve and V. Suryanarayan
Vol 44
13CNMR (CDCl3, 500 MHz): ꢀ 23.2 (2x-CH2), 29.0 (2x-CH2-
CO), 51.9 (2x-OCH3), 59.6, 118.7, 125.0, 127.9, 128.3 128.6,
129.1, 131.1, 136.1, 156.7, 170.9, 171.3, 171.8.
Anal. Calcd. for C23H24N4O5 (408): C, 67.63; H, 5.92; N, 6.86.
Found; C, 67.62; H, 5.89; N, 6.84.
9-Carbmethoxy-2,3-diaza–2,4-diphenyl-8-oxo-1-thio-spiro-
[5.4]-dec-3-ene (6d). This compound was obtained was brown
oil (purified by column chromatography, 5% ethyl acetate: 95%
hexane), ir (CHCl3) 3065, 2929, 1741, 1712 1597 cm-1. 1H NMR
(CDCl3, 300 MHz) : ꢀ 2.55 (m, 2H, -CH2), 2.94 (m, 4H, 2x-
CH2), 3.61(s, 3H, O-CH3), 3.75 (t, 1H, -CH) and 7.31- 7.87 (m,
10H, phenyl protons). 13C NMR (CDCl3, 300 MHz): 30.44,
33.96, 42.76, 51.86, 109.17, 110.67, 120.37, 125.64, 125.76,
128.22, 128.66, 128.77, 132.21, 134.54, 138.88, 151.84, 171.66,
210.98. EI ms: m/z: 392(90), 353(60), 315(25), 284(32),
193(55), 154(100), 137(41), 110(40), 77(15).
acid solution (10 ml) was added. The contents were refluxed for
5 hr and poured onto 25 g crushed ice. The solid which
separated was collected by filtratioin, dried and crystallised 50%
methanol as light brown solid, yield 2.33 g (70%), mp >250°.
Under similar reaction conditions 7a was synthesized from 6a. ir
(CHCl3): 2966, 1709, 1593 cm-1. 1H NMR spectrum (CDCl3, 300
MHz): ꢀ 2.29-2.86 (m, 8H, -CH2), 7.31-8.09 (m, 10H, phenyl
protons). 13CNMR spectrum (CDCl3, 300 MHz): 29.62, 34.75,
109.92, 123.73, 125.33, 125.62, 126.23, 127.29, 128.24, 132.18,
138.89, 140.10, 152.02, 207.70 ppm. Mass spectrum (m/z):
334(9%), 266(100%), 199(8%), 148(15%), 135(12%), 91(30%)
and 77(80%). Anal. Calcd. for C20H18N2OS (334): C, 71.86; H,
5.39; N, 8.38. Found: C, 71.90; H 5.35; N, 8.32.
1-Phenyl-3-methyl-4,4-di(carboxyethyl)-2-pyrazoline-5-one
(5a). Compound 4a (1.73 g, 5 mmoles) was refluxed in conc.
HCl (30 ml) for 5 hrs. The reaction mixture was cooled and solid
that separated was collected by filtration, washed with water and
dried, then dissolved in aq. saturated sodium bicarbonate (25 ml)
and filtered. The filtrate on acidification with 10% dil HCl
(10ml) furnished dicarboxylic acid 5a as colorless solid in pure
Anal. Calcd. for C16H16N2O3S (392): C, 60.74%; H, 5.10%; N,
8.85%, Found: C, 60.76%; H, 5.18%; N, 8.82%.
2,3-Diaza-4-methyl-8-oxo-2-phenyl-1-thio-spiro[5.4]dec-3-
ene (7c). This compound was obtained as offwhite crystals
(petroleum ether:chloroform (90:10) mixture), m.p 152°C, ir
(CHCl3): 2927, 1714, 1598 cm-1. 1H NMR (CDCl3, 500 MHz): ꢀ
2.10 (m, 4H, 2 x -CH2), 2.27 (m, 4H, 2 x CH2-C=O), 2.31 (s, 3H,
CH3) and 7.24-7.47 (m, 5H, phenyl protons). 13C NMR (CDCl3,
500 MHz): ꢀ 13.19, 29.92, 32.57, 109.75, 125.60, 127.35,
128.48, 138.92, 149.01, 151.93, 210.04 ppm. EI ms: m/z:
272(8), 256(10), 240(12), 207(40), 180(100), 164(25), 135(13),
117(20), 108(9), 77(28). Anal. Calcd. for C15H16N2OS (272): C,
66.18; H, 5.88; N,10.32. Found: C, 66.15; H, 5.87; N,10.26.
9-Carbmethoxy-2,3-diaza-4-methyl-2-phenyl-1,8-dioxo-
spiro[5.4]dec-3-ene (6a). To freshly prepared sodium
methoxide solution [(125 mg, 5 mmoles) of sodium in dry
methanol (30 ml)] was added 4a (1.73 g, 5 mmoles) at room
temperature and refluxed for 5 hrs. The reaction mixture was
then cooled and poured onto crushed ice containing a few drops
of conc. HCl. A brown solid separated which became a sticky
mass at room temperature. This oily residue was purified by
column–chromatography (10% ethyl acetate: 90% hexane) to
1
form, yield 1.10 g (70%), mp 130°C (lit [10], 142°C), HNMR
(CDCl3, 500 MHz): ꢀ 1.90-2.09 (m, 8H, 4x-CH2), 2.11 (s, 3H,
CH3), 7.21-7.08 (m, 5H, phenyl protons), 12.25 (br, 2H, 2x-
COOH; D2O exchangeable). 13CNMR (CDCl3, 500 MHz): ꢀ
13.48, 28.56 & 29.27 (4x-CH2), 57.26, 118.64, 124.93, 128.55,
137.43, 161.82, 173.58, 174.05 ppm.
Anal. Calcd. for
C16H18N2O5 (318): C, 60.37; H,5.70; N,8.80. Found : C, 60.36;
H, 5.68; N,8.74.
General Procedure for the Reaction of 2-Pyrazoline-5-ones
1a,b and 2-Pyrazoline-5-Thiones 1c,d with Acrylonitrile (3).
To a stirred solution of sodium amide (20 mmoles) in dry DMF
(25 mL) in nitrogen atmosphere, was added the appropriate 2-
pyrazoline-5-one (or 2-pyrazoline-5-thione) 1a-d (10mmoles) at
10–15°C. After the addition was complete acrylonitrile (1.06 g,
20 mmoles) was added dropwise over a period of 10 minutes.
Stirring was continued for 7 hours and then the reaction mixture
was poured into crushed ice (35 g) and acidified with 20%
aqueous hydrochloric acid to pH 3. The resulting mixture was
triturated with ice-water and extracted with ethyl acetate
(2x25ml). The combined organic layers were washed with water
(3x40ml), brine and dried (Na2SO4). Removal of solvent under
vacuum afforded the crude product, which was crystallized
using appropriate solvent to give 8a, 10a-d in 30%, 45%, 94%,
60%, 71% respectively.
4-Cyano-3-methyl-1-phenyl-2-pyrazoline-5-one (8a) (benzene
insoluble). 1 g of the crude product from the reaction of 1a and
3 was dissolved in benzene resulting in a partially soluble mixture.
The insoluble residue was collected by filtration and crystallized
from benzene to give 8a (colorless shining needles). mp 162°C (lit
[11a], 160°C) yield ; 0.4 g. 1H NMR spectrum (CD3COCD3, 300
MHz): ꢀ 2.28 (broad singlet, 2H, -CH2CN), 2.68 (broad singlet,
2H, -CH2), 2.87 (s, 3H, -CH3), 7.17 (t, 1H, phenyl proton), 7.42 (t,
2H, phenyl protons), 7.82 (d, 2H, phenyl proton), 9.70 (broad,
1H,-OH) ppm. M+ (CI) m/z: 227 (100%), 174 (20%), 117(18%).
Anal. Calcd. for C13H13N3O (227): C, 68.71%; H, 5.77%; N,
18.49%. Found: C, 68.69%; H, 5.77%; N,18.42%.
1
yield 1.27 g (81%) of 6a as a semi-solid. HNMR (CDCl3, 500
MHz): ꢀ 2.04-2.33 (m, 9H, 3x-CH2 & 1x-CH3), 3.62 (s, 3H,-
OCH3), 4.60 (br,1H,-CH-CO tautomeric), 7.19-7.87 ( m, 5H,
phenyl protons). Anal. Calcd. for C10H14N2O4(314): C, 64.96; H,
5.77; N, 8.91. Found: C, 64.94; H, 5.74; N, 8.88.
2,3-Diaza-2,4-diphenyl-1,8-dioxospiro[5.4]dec-3-ene (7b)
from 4b. Compound 4b (2.04 g, 5 mmoles), was added to a
solution of freshly prepared sodium methoxide solution, [(125
mg, 5 mmoles) of sodium in dry methanol (30 ml)] at room
temperature and refluxed for 5 hrs. The reaction mixture was
then cooled, poured onto crushed ice (30 g) and acidified with
cold 10% dil HCl (pH 2). The product which separated was
collected by filtration and crystallized from 50% ethanol as pale
yellow crystals, yield, 1.20 g (76%), m.p 105°C, ir (CHCl3):
1
3011, 1709, 1597 cm-1. H NMR (CDCl3, 300 MHz): ꢀ 2.09-
2.85 & 3.85 (m, 8H, 4x-CH2), 7.05 – 7.98 (m, 10H, phenyl
protons). 13C-NMR (CDCl3, 300 MHz): ꢀ 28.78, 31.17, 57.57,
118.75, 126.52, 128.14, 128.55, 129.33, 129.82, 130.76, 137.23,
158.28, 173.28, 212.58 ppm. Anal. Calcd. for C20H18N2O2 (318):
C, 75.45; H, 5.70; N. 8.80. Found: C, 75.44; H 5.69; N, 8.78.
Synthesis of 2,3-Diaza-2,4-diphenyl-8-oxo-1-thio-spiro[5.4]-
dec-3-ene (7d). 9-Carbmethoxy-2,3-diaza-2,4-diphenyl-8-oxo-
1-thio-spiro[5.4]dec-3-ene 6d (3.92 g, 0.01 mol) was taken in
glacial acetic acid (25 ml) and 33% hydrobromic acid in acetic
2,3-Diaza-4-methyl-2-phenyl-9-cyano-8-imino-1-oxospiro-
[5.4]-dec-3-ene 10a (benzene soluble). The benzene soluble
product from the reaction of 1a and 3 was crystallized from a
mixture of benzene: pet ether (50:50) (light brown solid). mp
164°C ir (CHCl3): 3325, 3026, 2245, 1708, 1597 cm–1. 1H NMR
(CDCl3 500MHz): ꢀ 1.37 (br, 1H,-NH, D2O exchangeable), 2.05

Jan-Feb 2007
Synthesis and Antimicrobial Activity of Novel Spirocompounds
with Pyrazolone and Pyrazolthione Moiety
53
(s, 3H, CH3), 2.22-3.27 (m, 10H, 3x-CH2 & 1x-CHCN), 7.23-
7.91 (m, 5H, phenyl protons). 13CNMR spectrum (CDCl3, 300
MHz): 12.29, 22.92, 23.54, 29.48, 32.06, 58.28, 117.23, 118.98,
126.44, 129.27, 136.52, 156.21, 158.26, 170.21. M+ (m/z):
280(12%), 187(54%), 159(18%), 122(20%), 105(26%),
77(100%). Anal. Calcd. for C16H16N4O (280): C, 68.55%; H,
5.75%; N, 19.99%. Found: C, 68.52%; H, 5.73%; N, 19.94%.
2,3-Diaza-2,4-diphenyl-9-cyano-8-amino-1-oxo-spiro[5.4]-
dec-3,8-diene (10b). This compound was obtained as light
brown solid (50% benzene:pet ether) mp 90°, ir (CHCl3): 3325,
3021, 2251,1708, 1669 (weak, -NH2 bending vibrations), 1597
Shinde, Microbiology Department, The Institute of Science,
for microbial testing, is highly acknowledged.
REFERENCES AND NOTES
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1
cm–1. H NMR (CDCl3, 500 MHz): ꢀ 2.13-2.85 (m, 6H, 3x-
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(1999); [d] M. S. Chande, A. Md. Pankhi, V. V. Sugdare and S. B.
Ambhaikar, Indian J. Chem., 38(B), 925, (1999); [e] M. S. Chande, R.
M. Joshi, Indian J. Chem., 38(B), 218 (1999); [f]; M. S. Chande, S. K.
Balel, Indian J. Chem., 35(B), 377 (1996); [g] M. S. Chande, J. D.
Bhandari and A. S. Karyekar, Indian J. Chem., 34(B), 990, (1995); [h]
M. S. Chande, N. M. Paingankar, Indian J. Chem., 34(B), 603, (1995).
[4] M. S. Chande, V. Suryanarayan, Tetrahedron. Lett., 43, 5173
(2002).
[5a] M. S Chande, V Suryanarayan, Chem. Heterocycl. Compd., 39,
1094 (2003); [b] M. S. Chande, R. R. Khanwelkar, Tetrahedron Lett., 46,
7787 (2005); [c] M. S. Chande, V. Suryanarayan, J. Chem. Res., 6, 345
(2005); [d] M. S. Chande, R. S. Verma, P. A. Barve, R. R. Khanwelkar, R.
B. Vaidya and K. B. Ajaikumar, Eur. J. Med. Chem., 40, 1143 (2005).
[6] A. I. Vogel, Vogels Text Book of Practical Organic
Chemistry, 5th Edition, p, 807.
CH2), 5.30 (br, 2H, -NH2, tautomeric), 7.07-7.71 (m, 10H,
phenyl protons). 13C NMR spectrum (CDCl3, 300 MHz): 23.94,
26.38, 31.90, 59.05, 118.63, 119.57, 126.91, 127.12, 127.54,
127.93, 128.22, 128.61, 129.18, 132.37, 136.72, 156.52, 170.12.
Anal. Calcd. for C21H18N4O (342): C, 73.67%; H, 5.30%; N,
16.36%. Found: C, 73.64%; H, 5.26%; N, 16.31%.
2,3-Diaza-4-methyl-2-phenyl-9-cyano-8-amino-1-thio-spiro-
[5.4]-dec-3,8-diene (10c). This compound was obtained was
grey solid (50% methanol). mp 195°C, ir (KBr): 3421, 2930,
1
2248 1596 cm–1. H NMR (CDCl3, 500MHz): ꢀ 1.65 (br, 1H
NH, D2O exchangeable), 2.16-2.43 (m, 10H, 3 x -CH2, 1x-CH3, -
CHCN), 6.29 (broad, D2O exchangeable, -NH2 tautomeric) 7.20-
7.50 (m, 5H, phenyl protons). 13CNMR (CDCl3, 500MHz):
12.37, 13.66, 28.67, 29.71, 107.51, 110.04, 114.80, 125.12,
127.97, 128.94, 133.81, 139.43, 149.41, 152.38 ppm. Anal.
Calcd. for C16H16N4S (296): C, 64.84%; H, 5.44%; N, 18.90%.
Found: C, 64.88%; H, 5.46%; N, 18.84%.
[7] S. Devi, A. Nayak and A. S. Mittra, J. Indian Chem. Soc., 61,
335 (1984).
[8] A. Maquestiau, Y. Van Haverbeke and J. C. Vanovervelt,
Bulletin des Societes Chimiques Belges, 86, 949 (1977).
[9a] J. J. Bergman, B. M. Lynch, J. Heterocyclic Chem., 11, 135,
(1974); [b] G. A. Chmutova, O. N. Kataeva, H. Ahlbrecnt, A. R.
Kurbangalieva, A. I. Mouchan, A. T. H. Lenstra, H. J. Geise, I. A.
Litvinov, J. Mol. Structure, 570, 215 (2001).
2,3-Diaza-2,4-diphenyl-9-cyano-8-amino-1-thio-spiro[5.4]-
dec-3,8-diene (10d). This compound was obtained as grey solid
(50% methanol). mp >250°, ir (KBr): 3439 (-NH), 3062, 2204,
1
1597 cm-1. HNMR (CDCl3, 300MHz) ꢀ 1.75 (s, broad, C=NH,
D2O exchangeable), 2.05-2.81(m, 7H, 3x-CH2, -CHCN), 7.01 -
7.82 (m, 10H, phenyl protons). DEPT NMR experiment of the
compound showed methylene carbons at 22.60, 29.58, and 31.23
(3x-CH2), methine carbons at 111.41 (CH-CꢀN), 124.94,
125.70, 125.86, 127.84, 128.33, 128.75, 128.80, 128.95.
13CNMR (CDCl3 300 MHz): 22.60, 29.58, 31.23, 104.90,
111.41, 118.83, 124.94, 125.70, 125.86, 127.84, 128.33, 128.75,
128.80, 128.95, 138.78 and 151.73 ppm. M+ (m/z): 358(35%),
235(20%), 135(8%), 132(12%), 103(100%), 91(60%), 77(45%).
Anal. Calcd. for C21H18N4S (358): C, 70.36; H, 5.06; N, 15.63.
Found: C, 70.34; H, 5.07; N, 16.58.
General Procedure for the Hydrolysis and Decarboxyl-
ation of 10. Compounds 10a-d (10 mmoles), glacial acetic acid
(25 ml) and 33% hydrobromic acid in acetic acid (10 ml) were
heated under reflux for 6 hr. The reaction mixture was cooled
and poured onto crushed ice to obtain crude 7a-d. Crystallization
using appropriate solvent, as discussed earlier in this section,
gave the pure compound in 71%, 83%, 42% & 65%. The
structure was confirmed by mixed melting point, co-tlc and co-ir
with the authentic sample obtained by the alternate route via
methyl acrylate.
[10] M. H. Elnagdi and M. Ohta, Bulletin of the Chemical Society
of Japan, 46, 3818 (1973).
[11a] A. N. Kost, S. I. Suminov, R. S. Sagitullin and V. V. Ershov,
Zhurnal Obshchei Khimii, 30, 2286 (1960); Chem. Abstr., 55, 54244
(1961); [b] V. G. Vinokurov, V. S. Troitskaya, I. I. Grandberg and Y. A.
Pentin, Zhurnal Obshchei Khimii, 33, 2597 (1963); Chem. Abstr., 60,
3143 (1964).
[12] Note: When the reaction conditions were altered by replacing
sodamide/DMF with TEA/C2H5OH the diadduct was isolated in one of the
reactions. Thus for example, 1c (0.01 mol), 3 (0.02 mol) and triethylamine
(0.02 mol) in ethanol (20 ml) were refluxed for 12 hrs. The reaction
mixture was poured onto 20 g crushed ice and acidified with 5 ml of 15%
dil HCl. The oil, which separated, was extracted in ethyl acetate. The
organic phase was washed well with water, brine and dried over sodium
sulphate. Removal of organic solvent afforded a brown oil, which on
column chromatography gave the diadduct 9c in 45% yield. The IR
1
spectrum displayed the characteristic peak at 2245 cm-1. H-NMR (500
MHz, CDCl3): ꢁ 2.33 (s, 3H, -CH3), 2.48 (t, 4H, 2 x –CH2-CN, J = 7.5 Hz),
2.79 (t, 4H, 2 x –CH2-CH2, J = 7.5 Hz) and 7.40 - 7.57 (m,5H, phenyl
protons). 13C NMR (500 MHz, CDCl3) ꢁ 13.21, 17.58, 17.87, 29.20, 30.32,
108.96, 117.09, 124.71, 127.57, 128.53, 131.55, 149.25, 152.47 ppm.
Acknowledgement. The authors are thankful to RSIC, IIT
Mumbai, TIFR, Dept. of Chem., University of Pune and The
Institute of Science, Mumbai for ir, nmr, ms measurements and
for elemental analysis of all new compounds. The help rendered
by Dr. Kiron Singh Jathar, National College, Bandra, Mumbai in
carrying out experiment under microwave and Ms Dipali
N
CH3
N
CH3
3
N
N
N
N
C2H5OH/TEA
N
S
S
1c
9c