A facile synthesis of novel spiro indoline-based heterocycles through 1,3-dipolar cycloaddition reactions

Article abstract of DOI:10.3184/174751912X13279492179667

A simple and efficient one-pot route for the synthesis of novel spiro [indolin-3,3'-1,2,4-triazol] derivatives by 1,3-dipolar cycloaddition reaction of nitrilimines and isatin imines under classical or microwave irradiation conditions is described. Spiro

Full text of DOI:10.3184/174751912X13279492179667

94 RESEARCH PAPER
FEBRUARY, 94–95
JOURNAL OF CHEMICAL RESEARCH 2012
A facile synthesis of novel spiro indoline-based heterocycles through
1,3-dipolar cycloaddition reactions
Saeid Souzangarzadeha, Atiye Baziana and Hossein Anaraki-Ardakanib*
aDepartment of Chemistry, Shahre-Rey Branch, Islamic Azad University, Tehran, Iran
bDepartment of Chemistry, Mahshahr Branch, Islamic Azad University, Mahshahr, Iran
A simple and efficient one-pot route for the synthesis of novel spiro [indolin–3,3′-1,2,4-triazol] derivatives by 1,3-
dipolar cycloaddition reaction of nitrilimines and isatin imines under classical or microwave irradiation conditions
is described. Spiro heterocyclic compounds possess pharmacological properties such as antimicrobial, analgesic,
anti-inflammatory, antimycobacterial, antifungal, antitumor and antiviral activities.
Keywords: spiro indole, 1,3-dipolar cycloaddition, nitrilimines, microwave irradiation, antimicrobial activity
Spiro heterocyclic compounds possess variious pharmacologi-
cal properties and hence their synthesis is of interest to organic
chemists. Such compounds display pronounced antimicrobial,1
analgesic,2 anti-inflammatory,2 antimycobacterial,3 antifun-
gal,4 antitumor5,6 and antiviral5,6 activities.
Among these heterocycles, spiro indoles have been identi-
fied as privileged structures in medicinal chemistry and have
attracted increasing interest in the recent years.7–10 Also 1,2,4-
triazoles and their derivatives constitute an important class of
organic compounds with diverse agricultural, industrial and
biological activities11–13 including antimicrobial14,15 sedative,
anticonvulsant 16 and anti-inflammatory properties.17
Considering the above reports, the development of new and
simple synthetic methods for the efficient preparation of spiro
indole heterocycles containing 1,2,4-triazole ring fragments is
therefore an interesting challenge. In continuation of our previ-
ous work on the synthesis of spiroindoles,18,19 we now describe
a one-pot synthesis of new spiro [indolin–triazol] derivatives 3
from 1,3-dipolar cycloaddition reactions of isatin imines 1 and
nitrilimines 2 (generated in situ from the corresponding hydra-
zonyl chlorides20,21) in fairly good yields under classical or
microwave irradiation conditions (Scheme 1).
Initially, we studied the reaction of isatin imine 1 and
1-(chloro(phenyl)methylen)-2-phenylhydrazine 2a in the
presence of triethylamine in MeCN at room temperature.
The reaction was complete after 18 h (reaction progress was
monitored by TLC) and 2′,5′-diphenyl-4′-(3-methyl-5-thioxo-1H-
1,2,4-triazol-4(5H)-yl)-2′,4′-dihydrospiro[indolin-3,3′[1,2,4]
triazol]-2-one (3a) was obtained in 82% yield.
In order to improve the yields, we examined the reaction
under different conditions including refluxing in various
solvents (EtOH, THF, MeCN and toluene) and also under
microwave irradiation. In refluxing solvents, after 48 h, the
yields of products were low (<40%). We found that the best
results were obtained under microwave irradiation. By using
microwave irradiation, the reaction time was reduced greatly
Scheme 1
* Correspondent. E-mail: hosseinanaraki@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2012 95
Table 1 Comparison of preparation methods
for C24H19N7OS: C, 63.56; H, 4.22; N, 21.62; S,7.07. Found: C, 63.72;
H, 4.42; N, 21.51; S, 7.31%.
3
X
Time/ha
Yield/%b Time/minc Yield/%d
5′-(4-Bromophenyl)-4′-(3-methyl-5-thioxo-1H-1,2,4-triazol-4(5H)-
yl)- 2′-phenyl- 2′,4′-dihydro spiro[indolin-3,3′[1,2,4]triazol]-2-one
(3b): Yellow crystals, yield 86% (conventional 80%), m.p. 292–
294 °C; IR (KBr) (νmax, cm−1): 3242 (NH), 1736, 1568 (C=O, C=N,
ester); S, 6.351H NMR (500 MHZ, CDCl3): δ 2.3 (3 H, s, CH3), 6.6–7.6
(aromatic), 9.8 (H, NH), 10.7 (H, NH); 13C NMR (125.8 MHz, CDCl3):
δ 16.1 (CH3), 89.7 (spiro carbon), 116.2–144.1 (aromatic), 150.2,
151.8 (2C=N), 169.6 (C=O), 187.1 (C=S); mass, m/z (%) = 531
[M+,11]. Anal. Calcd for C24H18BrN7OS: C, 54.14; H, 3.41; N, 18.42;
S, 6.02. Found: C, 54.34; H, 3.31; N, 18.16%.
a
b
c
H
4-Br
18
18
18
19
82
80
77
70
3
3
3
4
87
86
84
78
4-Cl
d
2,3-di NO2
a Time for reactions based on Method A.
b Pure isolated yields of products 3 from Method A.
a Time for reactions based on Method B.
b Pure isolated yields of products 3 from Method B.
5′-(4-Chlorophenyl)-diphenyl- 4′-(3-methyl-5-thioxo-1H-1,2,4-triazol-
4(5H)-yl)- 2′-phenyl- 2′,4′-dihydro spiro[indolin-3,3′[1,2,4]triazol]-
2-one (3c): Yellow crystals,yield 84% (conventional 77%), m.p.
298–300 °C; IR (KBr) (νmax, cm−1): 3242 (NH), 1715, 1560 (C=O,
C=N, ester); 1H NMR (500 MHZ, CDCl3): δ 2.2 (3 H, s, CH3), 6.6–7.8
(aromatic), 9.80 (H, NH), 10.85 (H, NH); 13C NMR (125.8 MHz,
CDCl3): δ 15.7 (CH3), 89.4 (spiro carbon), 115.8–144.3 (aromatic),
150. 9, 152.3 (2C=N), 167.3 (C=O), 185.8 (C=S); mass, m/z (%) =
487 [M+,11]. Anal. Calcd for C24H18ClN7OS: C, 59.07; H, 3.72; N,
20.09; S,6.57. Found: C, 59.27; H, 3.62; N, 20.22; S,6.32%.
from 18 hours to 3 min and the yield of the reaction was
enhanced by 5% compared to the classical method (Table 1).
The structures of compounds 3a–d were deduced from their
1
mass spectra, elemental analyses, and high-field H and 13C
NMR spectra, as well as the IR spectra, which displayed
3240–3278 (NH), at 1715–1752(C=O) and at 1568–1658 cm−1
(C=N).
In the 13C NMR spectra, the carbonyl absorption at 167–
169 ppm, imine carbon (C=N) at 149–153 ppm, and a signal
at 89–90 ppm attributable to the spiro carbon atom, are in
agreement with proposed structure 3, but not with structure 4.
In conclusion, 1,3-dipolar cycloaddition of isatin imine 1
and nitrilimines 2 by microwave irradiation provides a facile,
high yielding, rapid method, for the synthesis of a number of
interesting spiro [indolin-3,3′-1,2,4-triazol] derivatives 3.
5′-(3,5-Dinitrophenyl)-diphenyl- 4′-(3-methyl-5-thioxo-1H-1,2,4-triazol-
4(5H)-yl)- 2′-phenyl- 2′,4′-dihydro spiro[indolin-3,3′[1,2,4]triazol]-
2-one (3d): Yellow crystals, yield 78% (conventional 70%), 295–
296 °C; IR (KBr) (νmax, cm−1): 3278 (NH), 1752, 1658 (C=O, C=N,
1
ester); H NMR (500 MHZ, CDCl3): δ 2.2 (3 H, s, CH3), 6.5–8.8
(aromatic), 10.7 (H, NH), 10.9 (H, NH); 13C NMR (125.8 MHz,
CDCl3): δ 15.8 (CH3), 90.1 (spiro carbon), 115.1–149.2 (aromatic),
152.2, 153.1 (2C=N), 169.3 (C=O), 186.2 (C=S), Mass, m/z (%) = 543
[M+,10]. Anal. Calcd for C24H17N9O5S: C, 53.04; H, 3.15; N, 23.19; S,
5.90 Found: C, 53.34; H, 3.25; N, 23.27; S, 5.62%.
Experimental
Received 1 January 2012; accepted 16 January 2012
Paper 1201076 doi: 10.3184/174751912X13279492179667
Published online: 23 February 2012
CAUTION: Results may not be reproducible and there can be
hazards in using a domestic microwave oven for chemical
purposes.
Melting points were measured on the Electrothermal 9100 apparatus
and are uncorrected. Elemental analyses for C, H, and N were per-
formed using a Heracus CHN-O-Rapid analyzer. IR spectra were
measured on a Bomem FT-IR-MB100 spectrometer. 1H and 13C NMR
spectra were measured with a Bruker DRX-300 Avance spectrometer.
Mass spectra were recorded on a Hewlett-Packard 5973 mass
spectrometer operating at an ionization potential of 70 eV. Microwave
irradiations were carried out in a National Oven, Model 5250 (Japan)
at 2450 MHz. The chemicals used in this work were purchased
from Fluka (Buchs, Switzerland) and were used without further
purification.
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General procedure
Method A: To a magnetically stirred solution of hydrazonyl chloride
(5 mmol) and isatin imine (5 mmol) in MeCN (15 mL), a mixture of
triethylamine (5 mmol) in MeCN (5 mL) at room temperature was
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and ice water (5mL) were added to the reaction mixture and kept at
room temperature. The resulting crystalline product was filtered and
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recrystallisation twice from ethanol/water.
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2′,5′-Diphenyl- 4′-(3-methyl-5-thioxo-1H-1,2,4-triazol-4(5H)-yl)-
2′,4′-dihydro spiro[indolin-3,3′[1,2,4]triazol]-2-one (3a): Yellow
crystals, yield 87% (conventional 82%), m.p. 302–303 °C; IR (KBr)
(νmax, cm−1): 3275 (NH), 1747, 1608 (C=O, C=N, ester); H NMR
1
(500 MHZ, CDCl3): δ 2.18 (3 H, s, CH3), 6.68–7.71 (aromatic), 9.92
(H, NH); 10.92 (H, NH), 13C NMR (125.8 MHz, CDCl3): δ 15.8 (CH3),
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