Studies on the synthesis of furobenzisoxazole derivatives

Article abstract of DOI:10.1007/s10593-009-0383-7

The present investigation reports the synthesis of new furobenzisoxazole derivatives. Posner reaction of hydroxyfurocoumarin has been studied, wherein the two reaction products are identified as 5-methylfuro[2′,3′:4,5] benzo[1,2-d]isoxazol-3-yl)acetic aci

Full text of DOI:10.1007/s10593-009-0383-7

Chemistry of Heterocyclic Compounds, Vol. 45, No. 9, 2009
STUDIES ON THE SYNTHESIS OF
FUROBENZISOXAZOLE DERIVATIVES
J. M. Patel1, S. S. Soman1*
The present investigation reports the synthesis of new furobenzisoxazole derivatives. Posner reaction of
hydroxyfurocoumarin has been studied, wherein the two reaction products are identified as
5-methylfuro[2',3':4,5]benzo[1,2-d]isoxazol-3-yl)acetic acid and 1-(6-hydroxy-3-methylbenzofuran-
5-yl)ethanone oxime, depending on the conditions used. 1,3,4-Oxadiazole, 2-mercapto-1,3,4-oxadiazole
and thiazolidinone derivatives of furobenzisoxazole were synthesized from hydrazide.
Keywords: furobenzisoxazole, 2-mercapto-1,3,4-oxadiazole, 1,3,4-oxadiazole, thiazolidinone, Posner
reaction.
Zonisamide, a 1,2-benzisoxazole derivative, is an important antiepileptic agent available on the market
[1, 2]. It has a close resemblance to indole and the 1,2-benzisoxazole nucleus can be substituted for the indole
nucleus as far as auxin (plant cell growth substance) like activity is concerned [3]. Several 3-substituted
1,2-benzisoxazole derivatives have been reported to show anticonvulsive activity [4]. 1,2-Benzisoxazole
phosphoradiamidates as a novel antitumor prodrug via bioreductive activation have been also studied [5].
Flucloxacillin, Oxacillin, Cloxacillin, and Dicloxacillin belong to the class of new isoxazole penicillins in
current clinical use [6].
Some furobenzisoxazole derivatives are reported to possess hypotensive, uricosuric, and diuretic activities
and, hence, are useful as therapeutics for the treatment of hyperuricemia, edema, and hypertension [7, 8], which
prompted us to synthesize new furobenzisoxazole derivatives. Several reports are available in the literature for the
synthesis of 1,2-benzisoxazole [9–11], but not much work has been done for the synthesis of furobenzisoxazole. We
report herein the synthesis of some new furobenzisoxazole derivatives from hydroxyfurocoumarin.
We have synthesized new hydroxyfurocoumarin, which on Posner reaction [12] with hydroxylamine
gave furobenzisoxazole. New derivatives of furobenzisoxazole have been synthesized, and interesting
observations have been recorded during the course of studies.
As shown in Scheme 1, 1-(6-hydroxy-3-methylbenzofuran-5-yl)ethanone 1 [13] and 1-(4-hydroxy-
3-methyl-benzofuran-5-yl)ethanone 2 [13] on reaction with pulverized sodium and diethyl carbonate [14] gave
new linear 5-hydroxy-3-methylfuro[3,2-g]chromen-7-one 3 and angular 7-hydroxy-3-methylfuro[3,2-g]chromen-
1
7-one 4 isomers, respectively. The structures of both compounds were confirmed by their H NMR spectra.
_______
* To whom correspondence should be addressed, e-mail: shubhangiss@rediffmail.com, jakpatel21@yahoo.com.
1Department of Chemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara 390002,
India.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1352-1360, September, 2009.
Original article received April 27, 2009.
0009-3122/09/4509-1081©2009 Springer Science+Business Media, Inc.
1081

Compound 3 showed a singlet at δ 5.74 ppm for one proton at H-6 and another singlet at δ 11.72 ppm
corresponding to 5-OH (enolic hydroxyl). The 1H NMR spectrum of compound 4 showed singlets at δ 5.65 and δ
12.00 ppm, both corresponding to one proton each for H-6 and 5-OH, respectively. However, the angular isomer 4
could not be studied further because of the poor yields of 1-(4-hydroxy-3-methylbenzofuran-5-yl)ethanone 2 [13].
Scheme 1
O
O
OH
O
O
OC(OEt)2
∆
Pulv. Na,
O
Me
Me
OH
Me
1
3
Me
Me
O
O
HO
O
O
OC(OEt)2
∆
Pulv. Na,
O
Me
OH
4
2
NH2OH·HCl, NaHCO3,
OH
O
∆
pyridine,
N
OH
Me
Me
O
5
3
NH2OH·HCl, NaHCO3,
MeOH,
O
∆
N
OH
Me
6
O
Posner reaction of 5-hydroxy-3-methylfuro[3,2-g]chromen-7-one 3 with hydroxylamine hydrochloride
using pyridine gave 1-(6-hydroxy-3-methylbenzofuran-5-yl)ethanone oxime 5 as the major product; but when
the reaction was carried out in methanol the major product obtained was 5-methylfuro[2',3':4,5]benzo-
[1,2-d]isoxazole-3-yl)acetic acid 6, as shown in Scheme 1. This indicates that the use of pyridine favors the
formation of hydroxyacetophenone oxime 5 via decarboxylation. The 1H NMR spectrum of compound 5 showed
singlets at δ 11.48 and 15.1 ppm for one proton each, indicating 6-OH and NOH protons, respectively. The other
NMR signals confirmed the structure. The IR spectrum of compound 5 showed absorption bands at 3374 (s) for
the hydroxy group of ketoxime and 1596 cm–1 (s) for >C=N imine, which further confirmed the structure. The
1H NMR spectrum of compound 6 showed a singlet at δ 4.05 ppm corresponding to two protons of the
3-CH2COO group and a broad singlet at 9.50 ppm for one proton of carboxylic acid. The IR spectrum of
compound 6 showed a broad shallow band at 2547-3128 for OH and a band at 1726 cm–1 (s) for C=O of
carboxylic acid.
Carboxylic acid 6 was then converted into its ethyl ester 7, which on reaction with hydrazine hydrate
1
gave (5-methylfuro[2',3':4,5]benzo[1,2-d]isoxazol-3-yl)acetic acid hydrazide 8 as shown in Scheme 2. The H
NMR spectrum of compound 8 showed a singlet for one proton at δ 9.15 ppm for CONH, and all other
1082

signals are in good agreement with the proposed structure. It was further supported by IR spectrum, which
showed absorption bands at 3320 cm–1 (s) for NH stretching of CONH and NH stretching of NH2 and a band at
1646 cm–1 (s) for C=O stretching of CONH.
Scheme 2
+
O
O
O
O
EtOH, H
N2H4· H2O, EtOH
N
6
N
∆
∆
H
OEt
N
NH2
Me
Me
8
7
O
O
As shown in Scheme 3, the reaction of hydrazide 8 with furfuraldehyde gave the Schiff base (5-methyl-
1
furo[2',3':4,5]benzo[1,2-d]isoxazol-3-yl)acetic acid furan-2-ylmethylenehydrazide 9. The H NMR spectrum of
compound 9 in DMSO indicated the existence of the Schiff base in two interconverting tautomeric structures:
(5-methylfuro[2',3':4,5]benzo[1,2-d]isoxazol-3-yl)acetic acid furan-2-ylmethylenehydrazide (9a) and 3-(5-furan-
2-yl-4,5-dihydro[1,3,4]oxadiazol-2-ylmethyl)-5-methylfuro[2'3':4,5]benzo[1,2-d]isoxazole (9b). The ratio of
compounds 9a:9b was found to be approximately 2:1 by integration. Also the signals for the minor tautomer 9b
Scheme 3
O
O
N
N
Me
NH
9b
O
O
O
O
O
O
8
N
O
H
∆
EtOH,
N
N
Me
9a
O
,
Ac2O
∆
O
O
O
O
N
N
O
N
Me
Me
Me
N
Me
11
10
O
O
pyridine,
∆
OH
O
Ac2O,
∆
Me
5
N
O
O
Me
Me
12
1083

were found to be slightly deshielded as compared with the major tautomer 9a. A singlet at δ 4.07 for one proton
at H-5' and a singlet at δ 11.64 ppm again for one proton at 4'-HN confirmed the existence of the 9b tautomer.
The NH-proton of CONH was observed at 11.45 ppm for 9a tautomer. Two doublets at 2.22 and δ 2.28 ppm both
with J = 1 Hz indicated 5-CH3 of 9a and 9b tautomer, respectively. The LCMS showed the [M+1] peak at 324.3.
To prepare 1-[2-furan-2-yl-5-(5-methylfuro[2',3':4,5]benzo[1,2-d]isoxazol-3-ylmethyl)[1,3,4]oxadiazol-3-yl]-
ethanone (10), compound 9 was subjected to cyclization by refluxing in acetic anhydride; but instead of
compound 10, to our surprise, the product obtained was identified as 3,5-dimethylfuro[2',3':4,5]benzo-
[1,2-d]isoxazole (11) from its 1H NMR spectrum.
The formation of compound 11 was further confirmed by synthesizing it alternatively from ketoxime 5.
Acetylation of compound 5 by refluxing it with acetic anhydride gave 5-(1-acetoxyiminoethyl)-6-hydroxy-
3-methylbenzofuran 12, which on cyclization in pyridine gave 3,5-dimethylfuro[2',3':4,5]benzo[1,2-d]isoxazole (11).
The desired 1,3,4-oxadiazole nucleus was synthesized from hydrazide 8 by the reaction with carbon
disulfide in the presence of methanolic potassium hydroxide, which gave 5-(5-methylfuro[2',3':4,5]benzo-
[1,2-d]isoxazol-3-yl-methyl)[1,3,4]oxadiazole-2-thiol 13 (Scheme 4). The 1H NMR spectrum of compound 13 in
DMSO showed once again the existence of tautomerism between 5-(5-methylfuro[2',3':4,5]benzo-
[1,2-d]isoxazol-3-ylmethyl)[1,3,4]oxadiazole-2-thiol 13a and 5-(5-methylfuro[2',3':4,5]benzo[1,2-d]isoxazol-
3-yl-methyl)-3H-[1,3,4]oxadiazole-2-thione 13b. The ratio of compounds 13a:13b from integration was found
to be 2:1. The 1H NMR spectrum of compound 13 showed a doublet at δ 2.30 (J = 1.3 Hz) for 5'-CH3, a singlet
at δ 4.53 for 5-CH2, a quartet at δ 7.56 (J = 1.3 Hz) for H-6', two doublets at δ 7.61-7.62 (J = 0.6 Hz) and δ 7.78
(J = 0.4 Hz) for H-8' and H-4', respectively, a singlet at δ 7.62 for 3-NH of 13b tautomer, and a singlet at δ 14.33
ppm for 2-SH of 13a tautomer. Further the IR spectrum showed an absorption band at 3434 cm–1 (w) for the NH
stretching vibration of 13b tautomer, a band at 2753 cm–1 (m) for the SH stretching vibration of 13a tautomer
and a band at 1277 cm–1 (m) for the >C=S stretching vibration of 13b tautomer. The LCMS of compound 13
showed [M+1] peak at 288.3, which is in agreement with its molecular weight 287.3.
Scheme 4
O
O
O
O
CS2, KOH
MeOH,
N
8
N
∆
N
N
Me
N
Me
NH
S
O
O
13a
13b
SH
Schiff base 9 reacted with thioglycolic acid in the presence of zinc chloride to give thiazolidinone
derivative N-(2-furan-2-yl-4-oxothiazolidin-3-yl)-2-(5-methylfuro[2',3':4,5]benzo[1,2-d]isoxazol-3-yl)acetamide 14
as shown in Scheme 5.
Scheme 5
OH
O
O
HS
O
N
O
H
N
9a
N
Me
ZnCl2, PhMe
S
O
14
O
1
The H NMR of compound 14 showed signals at δ 3.71-3.75 (1H, d, J = 16 Hz, Ha-5' of thiazolidinone
ring), 3.85-3.89 (1H, d, J = 16 Hz, Hb-5' of thiazolidinone ring), and 5.90 (1H, s, H-2' of thiazolidinone ring),
and the singlet for one proton at δ 10.94 ppm indicated the CONH-proton, which confirmed the structure.
1084

Thus, the present investigation provides new heterocyclic derivatives from 4-hydroxycoumarin. The Posner
reaction of 4-hydroxycoumarin is known to give a mixture of 1,2-benzisoxazole-3-acetic acid and
2-hydroxyacetophenone oximes. When pyridine is used as a solvent, 2-hydroxyacetophenone oximes is the major
product, which can be minimized by the use of methanol as a solvent. The compounds prepared can be investigated
for possible pharmacological activity.
EXPERIMENTAL
Melting points (uncorrected) were determined using a scientific capillary melting point apparatus. Purity of
the compounds was checked by TLC on Acme's silica gel G plates using UV/iodine vapor as a visualizing agent and
Acme's silica gel (60-120 mesh) was used for column chromatographic purification. Elemental analyses were carried
out on a Perkin-Elmer C, H, N, S analyzer (Model-2400). IR spectra were recorded on a Perkin-Elmer FT-IR
spectrometer (spectrum RX1) using potassium bromide optics. The mass spectrum was obtained on a Perkin-Elmer
Sciex Triple Quadrupole LC/MS/MS mass spectrometer (EI, 70 eV) (Model-016932) using ion spray source. NMR
spectra were recorded on a Bruker 400 MHz spectrophotometer in (CD3)2SO (compounds 3,4,6,8,9a,b,13a,b,14) or
CDCl3 (compounds 5,11). Chemical shifts are relative to tetramethylsilane; relative peak areas were in agreement
with all assignments.
General Procedure for the Preparation of Compounds 3 and 4.
5-Hydroxy-3-methylfuro[3,2-g]chromen-7-one (3). A solution of 1-(6-hydroxy-3-methylbenzofuran-
5-yl)ethanone (1) (2 g, 10.51 mmol) in diethyl carbonate (25 ml) was slowly added to pulverized sodium (0.48
g, 21.03 mmol) under anhydrous conditions. After stirring the reaction mixture for 10 min at room temperature
it was gradually heated to reflux temperature and maintained for 30 min*. It was then allowed to cool to room
temperature, and methanol (15 ml) was added to decompose the unreacted sodium. The reaction mass was then
poured into water (50 ml) and the aqueous layer washed twice with toluene (25 ml). Concentrated hydrochloric
acid was slowly added to the aqueous layer until pH 2, and the solid obtained was collected by filtration. The
crude product was crystallized from acetonitrile–ethanol, 9:1, as light-cream colored crystals (1 g, 44%);
1
mp 262-263°C. IR spectrum, ν, cm–1: 3426, 1707, 1597, 1575, 1513, 1338, 1296, 1137. H NMR spectrum, δ,
ppm (J, Hz): 2.28 (3H, d, J = 1.2, 3-CH3); 5.74 (1H, s, H-6); 7.36 (1H, s, H-9); 7.47 (1H, q, J = 1.2, H-2); 8.01
(1H, s, H-4); 11.72 (1H, s, 5-OH). Found, %: C 66.47; H 3.58. C12H8O4. Calculated, %: C 66.67; H 3.73.
7-Hydroxy-3-methylfuro[3,2-g]chromen-7-one (4). Light-brown crystals (acetonitrile−ethanol, 9:1),
yield 41%; mp 284°C. IR spectrum, ν, cm–1: 3422, 1710, 1593, 1571, 1518, 1330, 1288, 1135. 1H NMR spectrum,
δ, ppm (J, Hz): 2.48 (3H, d, J = 1.4, 3-CH3); 5.65 (1H, s, H-6); 7.34-7.36 (1H, d, J = 8.7, H-9); 7.53 (1H, q,
J = 1.4, H-2); 7.71-7.73 (1H, d, J = 8.7, H-8); 12.00 (1H, s, 7-OH). Found, %: C 66.47; H 3.58. C12H8O4.
Calculated, %: C 66.67; H 3.73.
1-(6-Hydroxy-3-methylbenzofuran-5-yl)ethanone Oxime (5). To a solution of compound 3 (1.5 g,
6.93 mmol) in pyridine (15 ml), a solution of hydroxylamine hydrochloride (1.68 g, 24.28 mmol) in water (5 ml)
was added and the reaction mixture was refluxed for 12 h. It was cooled to room temperature, poured into ice-
hydrochloric acid and the solid obtained was collected by filtration. The crude product was crystallized from
toluene/petroleum ether (60-80°C), 3:7, the mixture as light-brown crystals (0.65 g, 45.65%); mp 184–186°C. IR
1
spectrum, ν, cm–1: 3374, 1634, 1597, 1464, 1374, 1263, 1139, 1024. H NMR spectrum, δ, ppm (J, Hz): 2.21
(3H, d, J = 1.3, 3-CH3); 2.45 (3H, s, N=CCH3); 7.03 (1H, s, H-7); 7.29 (1H, q, J = 1.3, H-2); 7.52 (1H, s, H-4);
11.48 (1H, s, 6-OH); 15.10 (1H, s, NOH). Found, %: C 64.11; H 5.22; N 6.69. C11H11NO3. Calculated, %:
C 64.38; H 5.40; N 6.83.
_______
* Highly exothermic reaction.
1085

5-Methylfuro[2',3':4,5]benzo[1,2-d]isoxazole-3-yl)acetic acid (6). To a solution of compound 3 (2.5 g,
11.56 mmol) in methanol (25 ml) hydroxylamine hydrochloride (2.81 g, 40.47 mmol) and sodium bicarbonate
(3.40 g, 40.47 mmol) were added, and the reaction mixture was refluxed for 15 h. Excess methanol was distilled
off and the reaction mass was dissolved in 10% sodium bicarbonate solution (100 ml) and filtered off.
Concentrated hydrochloric acid was slowly added to the filtrate until pH 2 and the solid obtained was collected
by filtration. The crude compound was purified by column chromatography using a chloroform−methanol, 9:1,
mixture to get white crystals 6 (1.45 g, 54.2%); mp 170-172°C (dec.). IR spectrum, ν, cm–1: 3471, 3095, 2924,
2638, 1726, 1630, 1532, 1352, 1307, 1126. 1H NMR spectrum, δ, ppm (J, Hz): 2.28 (3H, d, J = 1.3, 5-CH3); 4.05
(2H, s, 3-CH2COO); 7.47–7.48 (1H, q, J = 1.3, H-6); 7.54 (1H, d, J = 0.8, H-8); 7.76 (1H, d, J = 0.5, H-4); 9.50
(1H, br. s, COOH). Found, %: C 62.31; H 3.88; N 5.93. C12H9NO4. Calculated, %: C 62.34; H 3.92; N 6.06.
(5-Methylfuro[2',3':4,5]benzo[1,2-d]isoxazol-3-yl)acetic Acid Ethyl Ester (7). To a solution of
compound 6 (1.5 g, 6.48 mmol) in absolute ethanol (25 ml), one drop of concentrated sulfuric acid was added,
and the solution was refluxed for 5 h. Excess ethanol was distilled off under reduced pressure, and the reaction
mixture was poured into ice-water. The product was extracted with diethyl ether (25 ml) and washed with 10%
sodium bicarbonate solution (25 ml) followed by washing with water (25 ml). Diethyl ether was distilled off to
get ester 7 (1.2 g, 71.3%). The product was used without further purification for the next reaction.
(5-Methylfuro[2',3':4,5]benzo[1,2-d]isoxazol-3-yl)acetic Acid Hydrazide (8). To a solution of
hydrazine hydrate 99% (0.35 g, 6.94 mmol) in absolute ethanol (15 ml), a solution of ester 7 (1.2 g, 4.62 mmol)
in absolute ethanol (5 ml) was added dropwise at reflux temperature. After completion of addition it was further
refluxed for 6 h. Excess ethanol was distilled off and the reaction mass was cooled to room temperature. The
crystals obtained were filtered off and washed with ethanol. The product was recrystallized from ethanol to get
white crystals of hydrazide 8 (0.8 g, 70.5%); mp 193–194°C. IR spectrum, ν, cm–1: 3320, 1646, 1529, 1368,
1121. 1H NMR spectrum, δ, ppm (J, Hz): 2.30 (3H, d, J = 1.2, 5-CH3); 3.97 (2H, s, 3-CH2CO); 7.49 (1H, q, J =
1.2, H-6); 7.54 (1H, s, H-8); 7.92 (1H, s, H-4); 9.15 (1H, s, CONH). Found, %: C 58.49; H 4.38; N 17.01.
C12H11N3O3. Calculated, %: C 58.77; H 4.52; N 17.13.
(5-Methylfuro[2',3':4,5]benzo[1,2-d]isoxazol-3-yl)acetic Acid Furan-2-ylmethylenehydrazide (9a)
or
3-(5-Furan-2-yl-4,5-dihydro[1,3,4]oxadiazol-2-ylmethyl)-5-methylfuro[2'3':4,5]benzo[1,2-d]isoxazole
(9b). A solution of hydrazide 8 (0.5 g, 2.03 mmol) and freshly distilled furfuraldehyde (0.19 g, 2.03 mmol) in
absolute ethanol (15 ml) was refluxed for 6 h. Excess ethanol was distilled off and the reaction mass was cooled
to room temperature. The crystals obtained were filtered off and washed with ethanol. The product was
recrystallized from ethanol to get light-yellow crystals of hydrazide 9 (0.45 g, 68.3 %); mp 195°C (dec.). IR
1
spectrum, ν, cm–1: 3435, 3031, 1670, 1630, 1571, 1547, 1368, 1123. H NMR spectrum, δ, ppm (J, Hz):
hydrazide 9a – 2.22 (3H, d, J = 1, 5-CH3); 4.48 (2H, s, 3-CH2CO); 6.51–6.52 (1H, m, H-4'); 6.73 (1H, d, J = 3,
H-3'); 7.49-7.56 (3H, m, H-5', H-6, and CH=N); 7.84 (1H, s, H-8); 7.95 (1H, s, H-4); 11.45 (1H, s, CONH);
isoxazole 9b – 2.28 (1.5H, d, J = 1, 5-CH3); 4.07 (1H, s, H-5'); 4.48 (2H, s, 3-CH2); 6.47-6.48 (0.5H, m, H-4'');
6.78 (0.5H, d, J = 3, H-3''); 7.49–7.56 (1H, m, H-5'', H-6); 8.00 (0.5H, s, H-8); 8.13 (0.5H, s, H-4); 11.64 (0.5H,
s, 4'-NH). LCMS (EI): m/z (I, %) 362.1 [M+K] (5.76), 346.1 [M+Na] (23.07), 325.3 [M+2] (36.53), 324.3
[M+1] (100). Found, %: C 62.91; H 3.88; N 12.73. C17H13N3O4. Calculated, %: C 63.16; H 4.05; N 13.00.
3,5-Dimethylfuro[2',3':4,5]benzo[1,2-d]isoxazole (11). A solution of hydrazide 9a (0.5 g, 1.54 mmol)
in acetic anhydride (15 ml) was refluxed for 8 h. Excess acetic anhydride was distilled off under reduced
pressure and the reaction mass was poured into ice water. The solid formed was collected by filtration and
purified by column chromatography using petroleum ether (60-80°C)−ethyl acetate, 7:3, mixture to give white
crystals of isoxazole 11 (0.15 g, 51.8%); mp 135°C. IR spectrum, ν, cm–1: 3102, 2963, 1726, 1631, 1598, 1388,
1340, 1261, 1106, 1066. 1H NMR spectrum, δ, ppm (J, Hz): 2.29 (3H, d, J = 1.2, 5-CH3); 2.63 (3H, s, 3-CH3);
7.46 (q, J = 1.2, H-6); 7.53 (1H, s, H-8); 7.63 (1H, s, H-4). LCMS (EI): m/z (I, %) 210.1 [M+Na] (9.61); 189.3
[M+2] (40.38); 187.9 [M+1] (100); 147.2 (3.84); 124.2 (9.61). Found, %: C 70.33; H 4.68; N 7.23. C11H9NO2.
Calculated, %: C 70.58; H 4.85; N 7.48.
1086

5-(1-Acetoxyiminoethyl)-6-hydroxy-3-methylbenzofuran (12). A solution of oxime 5 (0.5 g,
2.43 mmol) was refluxed in acetic anhydride (25 ml) for 4 h. Excess acetic anhydride was distilled off under
reduced pressure and the reaction mass was poured into ice water. The solid formed was collected by filtration.
The crude product (0.42 g, 69.71%) was used without further purification for the next step.
3,5-Dimethylfuro[2',3':4,5]benzo[1,2-d]isoxazole (11) from Ester (12). A solution of crude ester 12 in
dry pyridine (15 ml) was refluxed for 4 h. The reaction mass was cooled to room temperature and then poured
into an ice–hydrochloric acid mixture. The solid formed was collected by filtration and purified by column
chromatography using petroleum ether (60-80°C)–ethyl acetate, 7:3, mixture to give white crystals of isoxazole 11
(0.15 g, 47.2%); mp 135°C.
5-(5-Methylfuro[2',3':4,5]benzo[1,2-d]isoxazol-3-ylmethyl)[1,3,4]oxadiazole-2-thiol (13a) or 5-(5-
Methylfuro[2',3':4,5]benzo[1,2-d]isoxazol-3-ylmethyl)-3H-[1,3,4]-oxadiazole-2-thione (13b). A solution of
hydrazide 8 (1 g, 4.07 mmol) and carbon disulfide (0.31 g, 4.07 mmol) in 1% methanolic potassium hydroxide
(20 ml) was refluxed for 8 h until the evolution of hydrogen sulfide gas ceased. Excess methanol was distilled
off and the reaction mass was poured into ice water. The aqueous solution was made alkaline by addition of
potassium hydroxide (1 g, 17.8 mmol), stirred for 15 min, and filtered off. To the filtrate, concentrated
hydrochloric acid was added until pH 2, and the solid formed was collected by filtration. The crude product was
purified by column chromatography using a chloroform−methanol, 9:1, mixture to give yellowish-brown
crystals 13 (0.7 g, 59.75%); mp 222°C. IR spectrum, ν, cm–1: 3434, 3076, 2926, 2753, 1628, 1596, 1529, 1494,
1377, 1333, 1295, 1277, 1149, 1121, 1058. 1H NMR spectrum, δ, ppm (J, Hz): 2.30 (3H, d, J = 1.3, 5'-CH3);
4.53 (2H, s, 5-CH2); 7.56 (1H, q, J = 1.3, H-6'); 7.61-7.62 (1H, d, J = 0.6, H-8'); 7.62 (0.5H, s, 3-HN – 13b
tautomer); 7.78 (1H, d, J = 0.4, H-4'); 14.33 (1H, s, 2-SH – 13a tautomer). LCMS (EI), m/z (I, %) 326.1 [M+K]
(3.70); 310.1 [M+Na] (16.66); 305.2 [M+NH4] (35.18); 289.1 [M+2] (18.51); 288.3 [M+1] (100). Found, %:
C 54.11; H 3.01; N 14.41; S 10.94. C13H9N3O3S. Calculated, %: C 54.35; H 3.16; N 14.63; S 11.16.
N-(2-Furan-2-yl-4-oxothiazolidin-3-yl)-2-(5-methylfuro[2',3':4,5]benzo[1,2-d]-isoxazol-3-yl)acet-
amide (14). A solution of hydrazide 9a (0.5 g, 1.54 mmol), thioglycolic acid (0.21 g, 2.31 mmol), and a
catalytic amount of fused zinc chloride in dry toluene (20 ml) was subjected to azeotropic distillation for 12 h.
The reaction mixture was washed with water and toluene was recovered under reduced pressure. The crude
product was purified by column chromatography using a petroleum ether (60–80°C)–ethyl acetate, 8:2, mixture
to give light-yellow crystals 14 (0.21 g, 34.2%); mp 201°C (dec.). 1H NMR spectrum, δ, ppm (J, Hz): 2.27 (3H,
d, J = 1, 5-CH3); 3.71-3.75 (1H, d, J = 16, Ha-5' thiazolidinone); 3.85-3.89 (1H, d, J = 16, Hb-5'
thiazolidinone); 4.02 (2H, s, 3-CH2CO); 5.90 (1H, s, H-2' thiazolidinone); 6.43-6.44 (1H, m, H-4'' furan); 6.53
(1H, m, H-3'' furan); 7.74-8.07 (4H, m, H-4,6,7, H-5''); 10.94 (1H, s, CONH). Found, %: C 57.11; H 3.64; N 9.98.
C19H15N3O5S. Calculated, %: C 57.42; H 3.80; N 10.57.
The authors thank the Head of the Department of Chemistry, The Maharaja Sayajirao University of Baroda
for providing the necessary facilities. One of the authors (JMP) is thankful for financial assistance from AICTE
(National Doctoral Fellowship) and UGC, New Delhi.
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