Investigation of the reaction of 3-aroylmethylene-indol-2-ones with 2-hydrazinobenzothiazole

Article abstract of DOI:10.1007/s12039-013-0364-3

The reactions of 3-aroylmethylene-indol-2-ones with 2- hydrazinobenzothiazole in different media and solvent were investigated. The impact of substitution on indolyl nitrogen was also studied. The chemical structure of the products was proven on the basis

Full text of DOI:10.1007/s12039-013-0364-3

c
J. Chem. Sci. Vol. 125, No. 2, March 2013, pp. 299–303. ꢀ Indian Academy of Sciences.
Investigation of the reaction of 3-aroylmethylene-indol-2-ones
with 2-hydrazinobenzothiazole
RENUKA JAIN∗, KANTI SHARMA and DEEPAK KUMAR
Department of Chemistry, University of Rajasthan, Jaipur 302 004, India
e-mail: profrjain@rediffmail.com
MS received 2 February 2012; revised 20 June 2012; accepted 20 July 2012
Abstract. The reactions of 3-aroylmethylene-indol-2-ones with 2-hydrazinobenzothiazole in different media
and solvent were investigated. The impact of substitution on indolyl nitrogen was also studied. The chemi-
1
cal structure of the products was proven on the basis of their spectral (IR, H-NMR, 13C-NMR, Mass) and
analytical studies.
Keywords. 3-Aroylmethylene-indol-2-ones; spiro[indole-pyrazole]; hydrazone; pyridazine; ionic liquid.
1. Introduction
2. Experimental
Keeping in view a variety of pharmacological acti- 2.1 Material, methods and instruments
vities associated with benzothiazole1–3 and pyrazole
nuclei,4–6 it was perceived that the synergistic effect of
heterocyclic moieties in single nucleus might result in
the formation of some worthwhile molecules from the
biological point of view. Therefore, some novel bioac-
tive compounds incorporating these two moieties have
been synthesized. Reaction of indole-2,3-diones7,8 with
acetophenone gave 3-hydroxy-3-phenacyl-indol-2-ones
which on further dehydration with HCl and CH3COOH,
furnishes 3-aroylmethylene-indol-2-ones (1a–b). These
compounds are highly reactive due to the presence of an
alkene system flanked by carbonyl group. The nature of
substituent on the nitrogen atom plays a significant role
in the formation of products.9
Melting points were determined in open end capil-
laries using Gallenkamp melting point apparatus and
are uncorrected. The purity of the compounds was
checked by thin-layer chromatography (TLC) on sili-
ca gel plate using benzene and ethyl acetate (4:1)
as eluent and spots were located by iodine vapours.
The IR spectra were recorded on an 8400S SHI-
MADZU IR spectrometer using KBr pellets and band
positions were recorded in wave numbers (cm−1).
1H- and 13C-NMR spectra were recorded in DMSO-
d6/CDCl3 with TMS as an internal reference on a JEOL
spectrometer at 300 and 75 MHz, respectively. The
ionic liquid, [bmim]PF6 was purchased from ACROS
ORGANICS. 3-Aroylmethylene-indol-2-ones (1a–b)
were prepared according to literature method13 and 2-
hydrazinobenzothiazole (2) by the method of Sharma
et al.14
The reaction of 3-aroylmethylene-indol-2-ones with
various compounds viz., hydrazines,10 thiosemicar-
bazide11 and hydrazinobenzimidazole12 have been pre-
viously investigated by us but the reaction with 2-
hydrazinobenzothiazole has not been studied so far.
In the present report, a detailed investigation of
the reactions of 3-aroylmethylene-indol-2-ones with
2-hydrazinobenzothiazole in different solvent and
medium was undertaken. The effect of substitution on
the indolyl nitrogen has also been studied.
2.2 Synthesis of 3-benzoyl(2-benzothiazolyl
hydrazone)methylene-indol-2(1H) ones 3a–b
Equimolar quantities of 3-aroylmethylene-indol-2-ones
(1a–b) (0.01 mol) and 2-hydrazinobenzothiazole (2)
(0.01 mol) were dissolved in absolute alcohol (10 mL)
and acetic acid (1 mL) added as a catalyst and reac-
tion mixture was refluxed for 4–5 h. After completion
of the reaction as indicated by TLC, the reaction mix-
ture was cooled at room temperature and resultant solid
∗For correspondence
299

300
Renuka Jain et al.
was washed with ethanol, dried and recrystallized from 2.3a 1ꢁ-Benzothiazolo-5ꢁ-phenyl-2ꢁ,4ꢁ-dihydro spiro
ethanol to yield product.
[indole-3,3ꢁ-pyrazol]-2(1H)-one (4a): IR (KBr): 3400
(>NH of indole), 3290 (NH of pyrazole), 1680
1
(>C=O); H-NMR (δ) ppm: 6.25 (1H, s, =CH- of
2.2a 3-Benzoyl(2-benzothiazolyl hydrazone)methylene-
indol-2(1H)-one (3a): IR (KBr): 3200–3380 (NH),
pyrazole), 7.73 (1H, s, -NH of pyrazole), 6.87–8.25
(13H, m, Ar-H), 9.81 (1H, s, >NH of indole); 13C-NMR
(δ) ppm: 110.4 (spiro carbon), 118.2–137.5 (aromatic
carbons), 128.6 (=CH- of pyrazole), 144.7 (C=N),
191.2 (>C=O); MS (m/z): 396 (M+).
1
1670 (>C=O), 1620 (C=N); H-NMR (δ) ppm: 6.18
(1H, s, =CH-), 7.14 (1H, s, -NH), 6.91–7.85 (13H, m,
Ar-H), 10.43 (1H, s, >NH of indole); 13C-NMR (δ)
ppm: 121.3 (=CH-), 117.5–133.8 (aromatic carbons),
147.5 (C=N), 189.2 (>C=O); MS (m/z): 396 (M+).
2.3b 1ꢁ-Benzothiazolo-1-methyl-5ꢁ-phenyl-2ꢁ,4ꢁ-dihydro
spiro[indole-3,3ꢁ-pyrazol]-2(1H)-one (4b): IR (KBr):
2.2b 3-Benzoyl-1-methyl(2-benzothiazolyl hydrazone)
methylene-indol-2(1H)-one (3b): IR (KBr): 3310
(NH), 1690 (>C=O), 1630 (C=N); 1H-NMR (δ) ppm:
3.27 (3H, s, -NCH3), 6.23 (1H, s, =CH-), 7.36 (1H, s,
-NH), 6.82–7.58 (13H, m, Ar-H); 13C-NMR (δ) ppm:
34.8 (NCH3), 122.1 (=CH-), 117.9–137.5 (aromatic
carbons), 149.2 (C=N), 189.3 (>C=O).
1
3310 (NH of pyrazole), 1690 (>C=O); H-NMR (δ)
ppm: 3.48 (3H, s, -NCH3), 6.19 (1H, s, =CH- of pyra-
zole), 7.85 (1H, s, -NH of pyrazole), 6.69–8.21 (13H,
m, Ar-H); 13C-NMR (δ) ppm: 33.2 (-NCH3), 109.9
(spiro carbon), 117.8–137.2 (aromatic carbons), 128.4
(=CH- of pyrazole), 145.2 (C=N), 189.2 (>C=O).
2.3 Preparation of 1ꢁ-benzothiazolo-5ꢁ-phenyl-2ꢁ,4ꢁ-
dihydrospiro[indole-3,3ꢁ-pyrazol]-2(1H)-ones
4a–b
2.4 Preparation of 3-benzothiazolyl-1-phenyl-9H-
pyridazino[3,4-b]indole 5a
Equimolar amount of 1a (0.01 mol) and 2 (0.01 mol)
were dissolved in absolute alcohol (10 mL) and diethyl-
amine (1 mL) added as a catalyst and reaction mix-
ture was refluxed for 4–5 h. After the completion of
the reaction as evidenced by TLC, the reaction mix-
ture was cooled at room temperature and solvent was
evapourated under reduce pressure and the residue
was chromatographed. (Silica gel 200–300 mes; elu-
ent = Pet. ether:EtOAc, 9:1; Pet. ether:EtOAc, 7:3; Pet.
ether:EtOAc, 5:5 to afford 3, 4 and 5, respectively).
A mixture of 1a–b (0.01 mol), 2 (0.01 mol) and
[bmim]PF6, an ionic liquid (5 mL) was taken in a round
bottom flask without catalyst and solution was stirred
magnetically for 4–5 h at 80 2◦C under nitrogen atmo-
sphere. After completion of reaction as evidenced by
TLC, the reaction mixture was cooled at room tem-
perature and contents were neutralized by 10% aque-
ous sodium bicarbonate solution and extracted with
ethyl acetate (3 × 10 mL). The solvent was removed
under reduced pressure. The pasty mass, thus obtained
was extracted with diethyl ether (3 × 10 mL), dried
over anhydrous sodium sulphate, ether distilled off and 2.4a 3-Benzothiazolyl-1-phenyl-9H-pyridazino[3,4-
1
the obtained crude mixture of products was purified b]indole (5a): IR (KBr): 1620 (C=N); H-NMR (δ)
by crystallization with ethanol to yield spiro product ppm: 7.40–8.34 (14H, m, Ar-H); 13C-NMR (δ) ppm:
(4a–b). The ionic liquid layer was washed with water 115.2–138.4 (aromatic carbons); MS (m/z): 378 (M+).
(3 × 10 mL) and kept for 2 h at 80◦C under reduced
Analytical and physical data of the products were
presented in table 1.
pressure. This ionic liquid was used in recycling.
Table 1. Analytical and physical data of the products.
Analysis (%) Calcd./(found)
Product
R
M.P. (◦C) Mol. formula
C
H
N
3a
3b
4a
4b
5a
H
CH3
H
CH3
H
280–82
237–39
268–70
292–94
223–25
C23H16N4OS 69.69/(69.78) 4.04/(4.13) 14.14/(14.07)
C24H18N4OS 70.24/(70.31) 4.39/(4.42) 13.66/(13.57)
C23H16N4OS 69.69/(69.76) 4.04/(4.15) 14.14/(14.03)
C24H18N4OS 70.24/(70.35) 4.39/(4.22) 13.66/(13.61)
C23H14N4S
73.02/(73.15) 3.70/(3.62) 14.81/(14.92)

Reaction of 3-aroylmethylene-indol-2-ones with 2-hydrazinobenzothiazole
301
3. Results and discussion
medium and substitution on indolyl nitrogen. In sim-
ple 3-aroylmethylene-indol-2-one, the reaction gave
Theoretically, this reaction offers three different pos- only spiro[indole-3,3ꢁ-pyrazol]-2-one (4) in [bmim]PF6,
sibilities (scheme 1) viz., formation of hydrazone (3), an ionic liquid (an environmentally benign solvent),
spiro[indole-pyrazole] (4) as well as pyridazino deriva- while it gave a mixture containing hydrazone (3) and
tives (5) depending on the site of condensation. The spiro[indole-pyrazole] (4) in neutral and slightly acidic
products formed depended on the nature of solvent, medium. In basic medium (ethanol with few drops of
N
S
N
HN
O
N
R
C
H
C
O
(4a-b)
O
N
R
[R= H, CH3]
(1a-b)
C
C
N
H
+
O
N
R
N
S
HN
N
(3a-b)
NH
S
NH2
(2)
N
N
N
N
S
(5a)
Scheme 1. Synthesis of compounds (3a–b), (4a–b) and 5a.
Table 2. The reaction of 3-aroylmethylene-indol-2-ones with 2-hydrazinobenzothiazole.
Yielda (%)
R
Solvent and medium
Temp (◦C)
Time (h)
3
4
5
H
H
H
H
EtOH
Reflux
Reflux
Reflux
Reflux
5
5
5
5
5
5
5
5
5
5
30
36
28
55
–
–
34
–
55
52
48
20
85
63
52
72
15
87
–
–
15
16
–
–
–
–
–
–
EtOH (Acidic)
EtOH (Basic)
CH3COOH
[bmim]PF6
EtOH
EtOH (Acidic)
EtOH (Basic)
CH3COOH
[bmim]PF6
H
80
2
CH3
CH3
CH3
CH3
CH3
Reflux
Reflux
Reflux
Reflux
80
–
80
2
aIsolated yield

302
Renuka Jain et al.
Table 3. Studies on the recyclability of [bmim]PF6 for compound 4a.a
IL recovered
(w/w%)
Entry
Run
Time (h)
Temperature (◦C)
Yieldb (%)
1
2
3
Fresh
1
2
5
5
5
80
80
80
2
2
2
85
82
80
97
95
92
aReaction conditions: 0.01 mol of 1a and 2, respectively; 5.0 mL of ionic liquid (IL) was
used for the first run.
bYields of product
diethyl amine) and pure acetic acid this affords a mix- respectively. The structure was further, confirmed by
ture of 3, 4 and 5. In the case of methyl substituted mass spectrum, where molecular ion peak appeared at
indolyl nitrogen, ionic liquid, neutral and basic medium m/z 396 (M+) corresponded to the molecular mass.
afforded only the spiro product (4) while in acidic
The chemical structure of pyridazino derivative (5a)
medium and pure acetic acid mixture of products viz., was proven by their spectral characteristic, marked by
hydrazone (3) and spiro (4) were obtained. Our results disappearance of absorption bands due to >NH and
indicate that when indolyl nitrogen is substituted then carbonyl groups in the IR spectrum and appearance of
pyridazino derivative (5) was not formed at all. The =CH_ peak in the aromatic region at δ 7.40–8.34 ppm
reaction conditions and the yields of the products are in its 1H-NMR spectrum. The structure was further con-
summarized in table 2.
The reactions were carried out in different reac- (M+ at m/z 378) corresponds to the molecular mass.
tion media and found that in acidic, basic and neu- The reactivity of the recycled ionic liquid in the for-
firmed by mass spectrum, where molecular ion peak
tral medium, the reaction resulted in the formation of mation of 4a was studied. The yields of the product in
hydrazone (3), which under certain conditions, when two cycles are presented in table 3, which indicates that
R=H can react with the enolic form eliminating water the yield of 4a decreases in various cycles however the
molecule to give the condensed product i.e., pyridazino ionic liquid can be re-used with significant success.
derivative (5a). Alternatively, nucleophilic Michael
addition of 2 to the 1a–b gives rise to spiro[indole-
pyrazole] (4a–b).
4. Conclusions
Structure assignments to the products are based on
In summary, investigation of the reactions
spectral studies. The formation of hydrazone deriva-
between 3-aroylmethylene-indol-2-ones and 2-
tive 3a was confirmed by their IR spectrum which
hydrazinobenzothiazole was carried out in dif-
shows an absorption band at 3380–3200 cm−1 due to
ferent media and solvents and found that ionic
>NH and 1670 cm−1 due to the >C=O of indole ring
liquid, [bmim]PF6 was a good solvent to achieve
spiro[indole-pyrazole] in excellent yield.
1
along with band at 1620 cm−1 due to >C=N. The H-
NMR spectrum has a peak due to =CH_ at δ 6.18 ppm
along with the multiplet at δ 6.91–7.85 ppm due to the
aromatic protons. In 13C-NMR, signals appeared at δ
189.2, 147.5 and 121.3 ppm due to the >C=O of indole
ring, >C=N and =CH- carbons, respectively. Further,
in the mass spectrum molecular ion peak appeared at
(m/z) 396 (M+).
Acknowledgements
Financial assistance from the University Grants Com-
mission (UGC), New Delhi to KS as Research Awardee,
and for the Council of Scientific and Industrial Research
(CSIR) to DK as SRF, is gratefully acknowledged.
In the IR spectrum of 4a, absorption bands at 3400
and 3290 cm−1 due to >NH of indolinone and pyrazole,
respectively and 1680 cm−1 due to >C=O of indole
are observed. In its 1H-NMR spectrum signals appeared
at δ 6.25 ppm due to pyrazolyl =CH_, δ 9.81 ppm
due to >NH of indole ring and δ 6.87–8.25 ppm
due to aromatic protons. 13C-NMR spectrum exhibited
peaks at δ 191.2, 128.6 and 110.4 ppm due to >C=O
(indole ring), =CH_ (pyrazolyl ring) and spiro carbon,
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