Synthesis of triazolyl-oxadiazolyl-thiazolyl- and thiadiazolylbenzofuran of potential biological activity

Article abstract of DOI:10.1080/10426500210654

4,7-Dimethoxy (Ia) and 4-methoxy (Ib) 6-hydroxybenzofuran-5-carbohydrazide were reacted with aryl or alkyl isothiocyanates to give the corresponding thiosemicarbazides (IIa-h). Cyclization of the substituted thiosemicarbazides with sodium hydroxide led to the formation of 1,3,4-triazol-2-yl-benzofuran derivatives (IIIa-d). Desulfurization of thiosemicarbazide by mercuric oxide gave 1,3,4-oxadiazolyl-benzofuran (IVa-c). Treatment of thiosemicarbazide with ethyl bromo-acetate or α-bromopropionic acid yielded 4-thiazolidin-2-yl-carbonyl-benzofuran (Va-h). The reaction of compounds IIb,e,f with sulphuric acid or phosphorus oxychloride gave 1,3,4-thiadiazol-2-yl-benzofuran (VIa-d, VII).

Full text of DOI:10.1080/10426500210654

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Synthesis of Triazolyl-Oxadiazolyl-Thiazolyl- and
Thiadiazolylbenzofuran of Potential Biological Activity
S. M. S. Atta a , N. M. Fawzy a , F. A. Ahmed a & A. H. Abdel-Rahman b
a Chemistry of Natural Products Department , National Research Centre , Dokki, Cairo, Egypt
b Department of Chemistry, Faculty of Science , Mansoura University , Egypt
Published online: 27 Oct 2010.
To cite this article: S. M. S. Atta , N. M. Fawzy , F. A. Ahmed & A. H. Abdel-Rahman (2002) Synthesis of Triazolyl-Oxadiazolyl-
Thiazolyl- and Thiadiazolylbenzofuran of Potential Biological Activity, Phosphorus, Sulfur, and Silicon and the Related
Elements, 177:4, 863-875, DOI: 10.1080/10426500210654
To link to this article: http://dx.doi.org/10.1080/10426500210654
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Phosphorus, Sulfur and Silicon, 2002, Vol. 177:863–875
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
SYNTHESIS OF TRIAZOLYL-OXADIAZOLYL-
THIAZOLYL- AND THIADIAZOLYLBENZOFURAN
OF POTENTIAL BIOLOGICAL ACTIVITY
S. M. S. Atta,a N. M. Fawzy,a F. A. Ahmed,a
and A. H. Abdel-Rahmanb
Chemistry of Natural Products Department, National Research
Centre, Dokki, Cairo, Egypta and Department of Chemistry,
Faculty of Science, Mansoura University, Egyptb
(Received July 1, 2001; accepted October 11, 2001)
4,7-Dimethoxy (Ia) and 4-methoxy (Ib) 6-hydroxybenzofuran-5-
carbohydrazide were reacted with aryl or alkyl isothiocyanates to
give the corresponding thiosemicarbazides (IIa–h). Cyclization of the
substituted thiosemicarbazides with sodium hydroxide led to the for-
mation of 1,3,4-triazol-2-yl-benzofuran derivatives (IIIa–d). Desulfur-
ization of thiosemicarbazide by mercuric oxide gave 1,3,4-oxadiazolyl-
benzofuran (IVa–c). Treatment of thiosemicarbazide with ethyl
bromo-acetate or -bromopropionic acid yielded 4-thiazolidin-2-yl-
carbonyl-benzofuran (Va–h). The reaction of compounds IIb,e,f with
sulphuric acid or phosphorus oxychloride gave 1,3,4-thiadiazol-2-yl-
benzofuran (VIa–d, VII).
Keywords: Benzofurans; thiosemicarbazides
INTRODUCTION
A wide variety of pharmacological properties has been shown to be as-
3
sociated with benzofuran derivatives.1 Various thiosemi-carbazides4
and their cyclized products such as triazoles,5 oxadiazoles6,7
thiazolidinones,8,9 and thiadiazoles are also associated with a broad
spectrum of biological properties including analgesic,6,10 anti-
proteolytic,11 anti inflammatory,12 muscle relaxant,7 antifungal, and
antibacterial activities.13
Address correspondence to Abdel-Rahman, Department of Chemistry, Faculty of
Science, Mansoura University, Egypt. E-mail: arahmanh@hotmail.com
863

864
S. M. S. Atta et al.
Continuous of our work on the synthesis of heterocyclic compounds
derived from the naturally occurring furochromones (khellin and vis-
nagin) of pharmacological interest, This work deals with synthesis
and characterization of new compounds containing benzofuran nucleus
combined with thiosemicarbazide, 1,3,4-triazolyl, 1,3,4-oxadiazolyl, thi-
azolidinonyl and 1,3,4-thiadiazolyl moieties which are expected to pos-
sess high biological activity.
RESULTS AND DISCUSSION
In the present investigation, 4,7-dimethoxy-(Ia) and 4-methoxy-6-
hydroxybenzofuran-5-carbo-hydrazide (Ib) were prepared14,15 from the
naturally occurring khellin and visnagin respectively.
Compounds Ia and/or Ib were reacted with isothiocyanates namely,
(benzoyl-, ethyl-, phenyl-, p-chlorophenyl-, and cyclohexylisothio-
cyanate) by heating in dioxane at 80 C for
2 h to afford
1-(4,7-di-methoxy-6-hydroxy-5-benzofuranylcarbonyl)-(IIa–d) and 1-
(4-methoxy-6-hydroxy-5-benzofuranylcarbonyl)-4-substituted thiosem-
icarbazides (IIe–h) in excellent yields.
The structures of the products II were assigned on the basis of their
elemental analysis and spectral data. For example, the infrared spectra

Benzofuran Derivatives
865
1
of compounds II showed absorption bands at 3400–3300 cm (OH),
1
1
3290–3118 cm (NH), 1650–1640 cm (C O) and the vibration cou-
1
pling due to N C S functions at 1240–1280 cm
.
Cyclization of 1-[4,7-dimethoxy-6-hydroxy-5-benzofuranylcarbonyl)-
4-substituted thiosemicarbazide (IIb) by heating with sodium hydrox-
ide at 90–95 C for 10 h leads to the formation of 4,7-dimethoxy-6-
hydroxy-5-[1-substituted-5-mercapto-1H-1,3,4-triazol-2-yl]benzofuran
IIIa. Similar treatment of IIe,g,h leads to the formation 4-methoxy-6-
hydroxy-5-[1-substituted-5-mercapto-1H-1,3,4-triazol-2-yl]benzofuran
IIIb–d. (cf. Scheme 1).
SCHEME 1
The elemental analysis and spectral data of compounds IIIa–d were
compatible with the suggested structures. The infrared spectra of com-
1
pounds IIIa–d showed absorption bands at 3360–3320 cm charac-
1
teristic for OH group, 3274–3223 cm (NH) and a stretching band
1
in the region of 1614–1625 cm characteristic for the C N of triazole
ringe. Meanwhile, the stretching frequency of band C O was disap-
peared. In solid state, compounds IIIa–d exist predominantly in the
1
thioxo-form as it is shown by the C S band at 1230–1284 cm in the
IR spectra of these compounds.5
1
The H-NMR spectra of the compounds III revealed clearly the ab-
sence of two singlet signals corresponding to the two protons of (2NH)

866
S. M. S. Atta et al.
and exhibited two singlets due to OH and SH (exchangeable with D2O)
of triazole.
The observation that several 1,3,4-oxadiazole derivatives exhibit
analgesic,6,7 antiproteolytic,11 anti-inflammatory,12 tranquilizing and
muscle relaxant7 properties created an interest in the preparation of the
novel series of 4,7-dimethoxy-, (IVa,b) and 4-methoxy-6-hydroxy-5-(5-
substituted amino-1,3,4-oxadiazol-2-yl)benzofuran (IVc) for evaluation
as antibacterial agents.
Desulfurization of thiosemicarbazides IIa,d,h by yellow mercuric
oxide in boiling ethanol yielded 4,7-dimethoxy-, and 4-methoxy-
6-hydroxy-5-(5-substituted
amino-1,3,4-oxadiazol-2-yl)benzofurans
(IVa–c) in a good yield.
The structure of the products IVa–c were identified by elemental
1
analysis, IR, H-NMR, and mass spectra. The IR spectra of the 1,3,4-
oxadiazoles IVa–c, lacked the C O absorption band and showed the
OH, NH and C N vibrational bands.
Various 4-thiazolidinones are associated with a broad spec-
trum biological properties including anticonvulsant and antibacterial
activities.9,10 Treatment of IIb,d,e,f,g,h with ethyl bromoacetate in the
presence of anhydrous sodium acetate, furnished the 4,7-dimethoxy-,
(Va,b) and 4-methoxy-6-hydroxy-5-{[(3-substituted-4-thiazolidinon-2-
yl) hydrazino]carbonyl}benzofurans (Vc–f). Meanwhile, treatment of
compounds IId,h with -bromopropionic acid yielded 4,7-dimethoxy-,
(Vg)
and
4-methoxy-6-hydroxy-5-{[(3-p-chlorophenyl-5-methyl-4-
thiazolidinon-2-yl)hydrazino]carbonyl}benzo-furan (Vh), respectively.
The structure of compounds Va–f was confirmed by elemental anal-
ysis and spectroscopic methods. For example, the IR spectra of com-
1
pounds V showed C O bands at 1650-1644 cm (CONH N). The
strong band at 1722–1713 cm 1 characteristic for C O of thiazolidinone
ring which appeared in the spectra of V provided firm support for ring
1
closure.10,16 The H-NMR spectra of compounds Va–f revealed clearly

Benzofuran Derivatives
867
the absence of the two singlet signals corresponding the two protons
of the 2-NH groups. The spectra of compounds Va–e displayed an addi-
tional singlet at 3.90, 4.20, 4.10, 3.85, and 4.05 ppm respectively due
to (S CH2) which proved thiazolidinone ring closure.17
The structures of Vg and Vh were based on elemental analysis and
spectral data.
Furthermore, several 1,3,4-thiadiazole derivatives were reported to
possess biological activity. Several procedures were reported for the de-
hydrative cyclization of substituted thiosemicarbazides to their 1,3,4-
thiadiazole analogous utilizing a variety of dehydrating agents, that
is, sulphuric acid, phosphorus oxychloride, or polyphosphoric acid.
Accordingly, treatment of compounds IIb,e,h with sulphuric acid at
ambient temperature for 24 h yielded the corresponding 4,7-di-
methoxy- and 4-methoxy-6-hydroxy-5-(5-substituted amino-1,3,4-thia-
diazol-2-yl)benzofurans (VIb–d) in moderate yields (50–55%). Rela-
tively higher yields (62–66%) of compounds (VIa–d) were obtained on
carrying out the cyclization by heating of IIa,b,e,h with phosphorus
oxychloride.
Attempt to cyclize 1-(4,7-dimethoxy)-6-hydroxy-5-carbonylbenzo-
furanyl)-4-benzoylthiosemicarbazide (IIa) by the action of sulfuric
acid failed to yield the target compound VIa; the debenzoylated

868
S. M. S. Atta et al.
product 4,7-dimethoxy-6-hydroxy-5-(5-amino-1,3,4-thiadiazole-2-yl)-
benzofuran (VII) was obtained instead. On the other hand, cyclization
of IIa using phosphorus oxychloride yielded the target product VIa.
The assignment of structures VIa–d were based on elemental anal-
ysis and spectral data. The IR spectra of VIa–d revealed clearly the
absence of the stretching band characteristic for O C N group and
1
1
showed the strong bands at 1618–1620 cm and 3180–3223 cm
corresponding to C N and NH groups respectively.
EXPERIMENTAL
All melting points were determined on a GallenKamp electrothermal
melting point apparatus and are uncorrected. Elemental analysis was
carried out in Microanalytical unit, National Research Centre. Infrared
spectra were recorded on Jasco FTIR-300E fourier transform infrared
spectrometer and Perkin-elmer FTIR 1000 E spectrum using KBr wafer
technique. 1H-NMR spectra were determined on Jeol-EX-270 MHz
1H-NMR spectrometer using TMS as an internal standered. The mass
spectra were determined on GC/MS finnigan mat SSQ 7000 Digital
DEC 3000. The purity of the synthesized compounds was tested by thin
layer chromatography (TLC): Merck Plates.
Preparation of 1-(4,7-dimethoxy-6-hydroxy-
5-benzofuranyl-carbonyl)-(IIa–d) and 1-[(4-methoxy-
6-hydroxy-5-benzofuranylcarbonyl)-4-substituted
Thiosemicarbazides IIa–h
General Procedure
To
a
suspension of 4,7-dimethoxy-6-hydroxybenzofuran-5-
carbohydrazide (Ia) and/or 4-methoxy-6-hydroxybenzofuran-5-
carbohydrazide (Ib) (0.01 mol) in dioxane (50 ml), the appropriate
isothiocyanate (0.01 mol) was added. The reaction mixture was
heated at 80 C with stirring for 2 h and then left overnight at room
temperature. The solid so obtained was filtered and crystallized from
the appropriate solvent to give (IIa–h) in good yields (see Table I).

Benzofuran Derivatives
869
S
TABLE I The Physical and Analytical Data of the New Compounds IIa–h
Analysis calcd. found %
Comp. m.p.
C
Appearance
no. (yield %) solvent of cryst.
Formula
(m. wt)
C
H
N
IIa
255
(98)
210
(90)
210
(85)
245
(96)
205
(88)
220
(95)
210
(87)
205
(92)
215
(73)
250
(75)
235
(68)
yellow
dioxane
orange
ethanol
colourless
ethanol
buff
dioxane
yellow
ethanol
pale yellow
dioxane
colorless
ethanol
colorless
ethanol
brown
ethanol/H2O
buff
ethanol
white
ethylacetate/
pet. ether
(60–80 C)
white
ethanol
pale gray
ethanol
buff
ethanol
buff
ethanol
colorless
CHCl3
colorless
ethanol
white
chloroform
white
ethanol
white
ethanol
white cotton
ethanol
C19H17N3O6S
(415.44)
C14H17N3O5S
(339.38)
54.93
54.65
49.55
49.45
55.80
56.06
51.25
51.05
50.47
50.46
56.10
56.02
56.18
56.01
52.11
51.99
52.33
51.84
53.60
53.21
59.11
58.98
4.12
4.06
5.05
5.11
4.42
4.51
3.82
3.64
4.89
4.87
3.92
3.72
5.82
6.01
3.61
3.51
4.70
4.73
4.50
4.56
5.54
5.65
10.12
9.98
7.72
7.38
9.45
8.95
8.28
7.88
6.60
7.55
10.37
10.96
8.32
8.22
8.82
8.46
8.19
8.09
9.98
9.94
11.01
10.87
9.28
8.97
IIb
IIc
12.38
12.35
10.85
10.59
9.96
C18H17N3O5S
(387.42)
C18H16ClN3O5S
(421.86)
C13H15N3O4S
(309.35)
IId
IIe
9.66
13.58
13.38
10.90
10.20
11.62
11.17
10.73
10.63
13.08
12.78
14.42
13.81
12.17
11.89
IIf
C18H15N3O5S
(385.40)
IIg
IIh
IIIa
IIIb
IIIc
C17H21N3O4S
(363.44)
C17H14ClN3O4S
(391.84)
C
14H15N3O4S
(321.36)
C
13H13N3O3S
(291.33)
C17H19N3O3S
(345.42)
IIId
IVa
IVb
IVc
Va
160
(70)
230
(65)
195
(66)
265
(68)
235
(90)
260
(86)
225
(90)
195
(85)
275
(83)
222
(78)
C17H12ClN3O3S
(373.82)
54.62
54.01
59.84
58.61
55.75
54.97
57.14
56.81
50.65
50.18
52.01
51.98
51.57
51.49
56.56
55.90
52.84
52.28
56.47
56.19
3.24
3.62
3.96
3.74
3.64
3.50
3.38
3.35
4.52
4.25
3.49
3.21
4.33
4.14
5.25
5.42
3.27
3.24
3.55
3.85
11.24
10.85
11.01
10.43
10.84
10.76
11.76
11.12
11.08
10.41
9.09
8.58
7.98
C
19H15N3O6
(381.35)
C18H14ClN3O5
(387.78)
C
17H12ClN3O4
(357.75)
C16H17N3O6S
8.45
8.15
6.94
6.76
9.18
9.08
7.95
7.79
7.49
7.32
7.45
6.25
(379.40)
Vb
Vc
C
20H16ClN3O6S
(461.89)
9.10
C
15H15N3O5S
(349.37)
12.03
11.94
10.42
9.92
9.73
9.43
Vd
Ve
C19H21N3O5S
(403.46)
C
19H14ClN3O5S
(431.86)
Vf
C20H15N3O6S
(425.43)
9.88
9.46
(Continued on next page)

870
S. M. S. Atta et al.
TABLE I The Physical and Analytical Data of the New Compounds IIa–h
(Continued)
Analysis calcd. found %
Comp.
no.
m.p.
C
Appearance
Formula
(m. wt)
(yield %) solvent of cryst.
C
H
N
S
Vg
230
(88)
224
(88)
>260
(66)
white
ethanol
white
ethanol
brown
dioxane/
C21H18ClN3O6S 52.99 3.81
(477.50) 52.01 3.98
C20H16ClN3O5S 53.87 3.26
8.83
7.71
9.42
9.80
6.74
6.90
7.19
7.50
8.07
8.15
Vh
VIa
(247.50)
19H15N3O5S
(397.41)
54.05 3.59
57.42 3.80 10.57
57.18 3.68 10.93
C
methanol
VIb
VIc
VId
VII
248
(62)
260
(62)
270
(65)
>260
(46)
brown
ethanol
brown
ethanol
yellow
dioxane
gray
C14H15N3O4S
(321.36)
52.33 4.70 13.08
51.98 4.62 12.85
53.59 4.49 14.42 11.10
53.28 4.35 14.25 10.98
9.98
9.76
C
13H13N3O3S
(291.33)
C17H12ClN3O3S 54.63 3.24 11.24
8.56
8.39
(373.75) 54.28 3.15 11.40
C12H11N3O4S
292.98
49.15 3.78 14.33 10.91
48.89 3.54 14.01 11.01
ethanol
Preparation of 4,7-dimethoxy-, and 4-methoxy-
6-hydroxy-5-[1-substituted-5-mercapto-
1H-1,3,4-triazol-2-yl)benzofuran derivatives IIIa–d
General Procedure
A suspension of thiosemicarbazide derivatives IIb,e,g,h (0.01 mol)
in sodium hydroxide (5 ml, 2 N), was refluxed under stirring for 10 h.
The reaction mixture was then cooled and neutralized with dilute hy-
drochloric acid. The precipitate thus obtained was filtered, washed with
water several times, dried, and crystallized from the proper solvent to
give IIIa–d. (see Table I).
Preparation of 4,7-dimethoxy-and 4-methoxy-
6-hydroxy-5-(5-substituted Amino-1,3,4-oxadiazol-
2-yl)benzofuran Derivatives IVa–c
General Procedure
A mixture of the thiosemicarbazides IIa,d,h (0.002 mol) and excess
yellow mercuric oxide (2 g) in 30 ml ethanol was refluxed for 4–6 h. The
reaction mixture was allowed to cool to room temperature (to allow the
sedimentation of the black mercuric sulphide), filtered, and mercuric
sulphide was washed with ethanol. The filtrate and alcoholic washing
were combined, treated with water until a permenant turbidity existed
and allowed to stand overnight. The product was separated and crys-
tallized from the proper solvent to give IVa–c. in good yields.

Benzofuran Derivatives
871
TABLE II The Spectral Data of the Compounds Va–h
Comp
no.
Mass M+
(m/z, %)
IR ( , cm 1) KBr
1H-NMR (DMSO-d6, , ppm)
IIa
3420 (OH); 3211,
3175 (NH); 1670
(CO Ph); 1647
3.9, 4.2 (6H, 2s, 2OCH3); 7.3, 8.05
(2H, dd, Furan H-3, H-2, J =
2.5 Hz); 7.55, 7.95 (5H, m, Ar H);
12.0, 12.1, 12.4 and 13.65 (4H, 4s,
3NH and one OH, D2O exchange)
1.1 (3H, t, CH2CH3); 3.45 (2H, q,
CH2CH3); 3.9 and 4.05 (6H, ss,
2OCH3); 7.3, 8.05 (2H, dd, Furan
H-3, H-2, J = 2.5 Hz); 7.55–7.95
(m, 5H Ar H); 7.7, 9.6, 10.25 and
10.9 (4H, 4s, 3NH and one OH,
D2O exchange)
415
(19%)
(C
O NH) and
1245 (C S)
3367 (OH); 3274,
3166 (NH); 1643
(CO NH) and
1284 (C S)
IIb
IIc
339
(33%)
3322 (OH); 3270-
3118 (NH); 1640
(CO NH) and
1261 (C S)
3.9, 4.0 (6H, ss, 2OCH3); 7.15, 7.95
(2H, dd, furan H-3, H-2, J = 2.5 Hz);
7.2–7.65 (5H, m,
387
(6.95%)
Ar H); 9.3, 10.1, 10.55 and 11.0
(4H, 4s, 3NH and one OH, D2O
exchange)
IId
IIe
—
—
421
309
(58.8)
3364 (OH); 3291-
3160 (NH); 1643
(CO NH) and
1279 (C S)
1.15 (3H, t, CH2CH3); 3.5 (2H, q,
CH2CH3); 4.1 (3H, s, OCH3); 6.75
(1H, s, H-7); 7.2, 7.85 (2H, dd, furan
H-3, H-2, J = 2.5 Hz); 7.15, 9.6,
10.25 and 11.25 (4H, 4s,
3NH and one OH, D2O exchange)
4.35 (3H, s, OCH3); 6.75 (1H, H-7);
7.25, 8.0 (2H, dd, furan H-3, H-2,
J = 2.5 Hz); 7.5–7.9 (5H, m,
Ar H); 11.95, 12.02, 12.45 and
13.55 (4H, 4s, 3NH and OH, D2O
exchange)
IIf
3315 (OH); 3215-
3164 (NH); 1670
(CO Ph); 1640
(CO NH) and
1253 (C S)
385
(34%)
IIg
3363 (OH); 3273,
3157 (NH); 1650
(CO NH) and
1252 (C S)
1.15–2.5 (10H, m, cyclohexyl);
4.1 (1H, m, cyclohexyl); 4.33 (3H,
s, OCH3); 6.55 (1H, s, H-7);
6.85, 7.45 (2H, dd, furan H-3, H-2,
J = 2.5 Hz); 6.75, 9.0, 11.0, 12.75
(4H, 4s, 3NH and OH, D2O
exchange)
363
(29.4%)
IIh
3360 (OH); 3247–
3160 (NH); 1642
(CO NH) and
1281 (C S)
4.1 (3H, s, OCH3); 6.8 (1H, s, H-7);
7.20, 7.85 (2H, dd, furan H-3,
H-2, J = 2.5 Hz); 7.45 and
391
(29.4%)
7.65 (4H, dd, AB system Ar H,
JH.H = 8 Hz); 9.45, 10.15, 10.50
and 11.4 (4H, 4s, 3NH and OH,
D2O exchange)
(Continued on next page)

872
S. M. S. Atta et al.
TABLE II The Spectral Data of the Compounds Va–h (Continued)
Comp
no.
Mass M+
(m/z, %)
IR ( , cm 1) KBr
1H-NMR (DMSO-d6, , ppm)
IIIa
3360 (OH); 3274 (NH);
1625 (C N) and
1284 (C S)
1.0 (3H, t, CH2CH3); 3.6 (2H, q,
CH2CH3); 3.85 (3H, s, OCH3);
3.9 (3H, s, OCH3); 7.2, 7.9 (2H,
dd, furan H-3, H-2, J = 2.5 Hz);
9.75 and 13.75 (2H, 2s, OH and
SH, D2O exchange)
321
(100%)
IIIb
IIIc
IIId
IVa
3360 (OH); 3213 (NH);
1614 (C N) and
1281 (C S)
1.05 (3H, t, CH2CH3); 3.7 (2H, q,
CH2CH3); 4.05 (3H, s, OCH3);
6.83 (1H, s, H-7); 7.22, 7.85 (2H, dd,
furan H-3, H-2, J = 2.5 Hz);
10.33 and 13.75 (2H, 2s, OH and
SH, D2O exchange)
0.8–2.35 (10, m, cyclohexyl); 4.12
(1H, m, cyclohexyl); 4.3 (3H, s,
OCH3); 6.9 (1H, s, H-7); 7.0, 7.45
(2H, dd, furan H-3, H-2, J =
2.5 Hz); 9.45 and 13.40 (2H, 2s,
OH and SH, D2O exchange)
3.09 (3H, s, OCH3); 6.62 (1H, s, H-7);
7.20 and 7.45 (4H, dd, AB system
Ar H, J = 8 Hz); 7.1, 7.75 (2H, dd,
furan H-3, H-2, JH.H = 2.5 Hz);
10.22 and 13.70 (2H, ss, OH and
SH, D2O exchange)
291
(100%)
3320 (OH); 3231 (NH);
1624 (C N) and
1249 (C S)
345
(100%)
3323 (OH); 3220 (NH);
1619 (C N) and
1236 (C S)
373
(100%)
3440 (OH); 3230 (NH);
1670 (CO Ph) and
(CO Ph) and
3.97 (3H, s, OCH3); 4.05 (3H, s, OCH3);
7.27, 8.02 (2H, dd, furan H-3, H-2,
J = 2.5 Hz); 7.55–8.19 (5H, m,
Ar H); 10.0, 12.00 (2H, ss, NH and
OH, D2O exchange)
381
(69%)
1620 (C N)
IVb
IVc
387
(91%)
357
3330 (OH); 3164 (NH)
and 1627 (C N)
4.05 (3H, s, OCH3); 6.8 (1H, s, H-7);
7.15, 7.80 (2H, dd, furan H-3, H-2,
J = 2.5 Hz); 7.36, 7.65 (4H, dd,
Ar H); 10.35 and 10.7 (2H, ss, NH
and OH, D2O exchange)
(100%)
Va
Vb
3257 (OH); 3143 (NH);
1713 (CO-ring) and
1.25 (3H, t, CH2CH3); 3.7 (2H, q,
CH2CH3); 3.9 (2H, s, CH2-ring);
4.06 and 4.2 (6H, ss, 2OCH3);
6.81, 7.55 (2H, dd, furan H-3, H-2,
J = 2.5 Hz); 10.7 and 13.4 (2H, ss,
OH and NH, D2O exchange)
379
(66%)
1650 (C
O N)
3276 (OH); 3167 (NH);
1722 (CO-ring) and
4.05 and 4.10 (6H, ss, 2OCH3);
4.2 (2H, s, CH2 of ring);
461
(45%)
1644 (C
O
N)
6.85–7.55 (6H, m, H-3, H-2, of
furan + 4Ar H); 10.6 and 13.15
(2H, ss, NH and OH, D2O exchange)

Benzofuran Derivatives
873
TABLE II The Spectral Data of the Compounds Va–h (Continued)
Comp
no.
Mass M+
(m/z, %)
IR ( , cm 1) KBr
1H-NMR (DMSO-d6, , ppm)
Vc
3265 (OH); 1718
(CO-ring) and
1.17 (3H, t, CH2CH3); 3.7 (2H, q,
CH2CH3); 4.1 (2H, s, CH2-ring);
4.20 (3H, s, OCH3); 6.70 (1H, s,
H-7); 7.15, 7.80 (2H, dd, furan H-3,
H-2, J = 2.5 Hz); 10.55 and 11.75
(2H, ss, NH and OH, D2O
379
(66%)
1644 (C
O N)
exchange)
Vd
3260 (OH); 3164 (NH);
1715 (CO-ring) and
1.15–2.5 (10H, m, cyclohexyl); 4.45
(1H, m, cyclohexyl); 3.85
402.94
(100%)
1650 (C
O
N)
(2H, s, CH2-ring); 4.26 (3H, s,
OCH3); 6.85 (2H, overlaped of d
and s, H-3 of furan, JH.H = 2.5 Hz
and H-7); 7.45 (1H, d, furan H-2,
JH.H = 2.5 Hz); 10.55 and 13.37
(2H, ss, NH and OH, D2O exchange)
4.05 (2H,s -CH2-ring); 4.20 (3H, s,
OCH3); 6.73 (1H, s, H-7); 7.16,
7.82 (2H, dd, furan H-3, H-2,
J = 2.5 Hz); 7.45 and 7.64 (4H, dd,
Ar H); and 10.57, 11.57 (2H, ss,
NH and OH, D2O exchange)
1.65 (3H, d, CH3-ring); 4.15 (3H, s,
OCH3); 4.55 (1H, q, methine
proton of ring); 6.70 (1H, s, H-7);
7.14, 7.85 (2H, dd, furan H-3, H-2,
J = 2.5 Hz); 7.45–7.60 (4H, dd,
Ar H); and 10.55, 11.65 (2H, ss,
NH and OH, D2O exchange)
1.65 (3H, d, CH3-ring); 4.15 (3H, s,
OCH3); 4.55 (1H, q, methine
proton of ring); 6.70 (1H, s, H-7);
7.14, 7.85 (2H, dd, furan H-3, H-2,
J = 2.5 Hz ); 7.45–7.60 (4H, dd,
Ar H); and 10.55, 11.65 (2H, ss,
NH and OH, D2O exchange)
3.99, 4.23 (6H, ss, 2OCH3); 7.30, 7.95
(2H, dd, furan H-3, H-2, J = 2.5 Hz);
12.96 (1H, s, NH, exchanged with
D2O); and at 13.2 (1H, br.s, OH,
exchanged with D2O)
Ve
3247 (OH); 3158 (NH);
1715 (CO-ring) and
433
1648 (C
O N)
Vh
Vg
VIa
VIb
3400 broad (OH);
3180 (NH); 1679
(CO Ph) and
1625 (C N)
397
(49%)
3300 broad (OH);
3190 (NH) and
1620 (C N)
1.5 (3H, t, CH2CH3); 3.4 (2H, q,
CH2CH3); 3.85, 4.05 (6H, ss,
2OCH3); 7.25, 7.90 (2H, dd, furan
H-3, H-2, J = 2.5 Hz); 12.9 (1H, s,
NH exchangeable with D2O)
and 13.2 (1H, br.s, OH exchanged
by D2O)
321.1
(100%)
(Continued on next page)

874
S. M. S. Atta et al.
TABLE II The Spectral Data of the Compounds Va–h (Continued)
Comp
no.
Mass M+
(m/z, %)
IR ( , cm 1) KBr
1H-NMR (DMSO-d6, , ppm)
VIc
1.2 (3H, t, CH2CH3); 3.5 (2H, q,
CH2CH3); 4.2 (3H, s, OCH3);
6.85 (1H, s, H-7); 7.25, 7.95 (2H,
dd, furan H-3, H-2, J = 2.5 Hz);
8.30 (1H, s, NH, exchanged by D2O)
and 9.73 (1H, br.s, OH exchanged
by D2O)
291
(100%)
VId
VII
3400 broad (OH);
3223 broad (NH)
4.22 (3H, s, OCH3); 6.9 (1H, s, H-7);
7.20, 7.92 (2H, dd, furan H-3, H-2,
J = 2.5 Hz); 7.40 (2H, d, AB system
of p Cl Ph, JH.H = 8 Hz); 7.66
373
(100%)
and 1618 (C
O N)
(2H, d, 2H of p Cl phenyl, JH.H
=
8 Hz); 10.75 and 10.85 (2H, ss, NH
and OH, D2O exchange)
3300 (OH); 3140 (NH2)
and 1620 (C N)
3.95 and 4.07 (6H, ss, 2OCH3); 7.05
and 7.30 (2H, dd, furan H-3 and
H-2, J = 2.5 Hz); 10.85 (1H, S, OH)
and 10.95 and 11 (2H, S, NH2)
exchangable with D2O
293
(85%)
Preparation of 4,7-dimethoxy- and 4-methoxy-
6-hydroxy-5-[(3-substituted-4-thiazolidinone-2-yl)-
hydrazono]-carbonyl]-benzofuran Derivatives Va–h
General Procedure
A
mixture of the appropriate thiosemicarbazide derivative
IIb,d,e,f,g,h (0.005 mol) and ethyl bromoacetate (1.66 g, 0.01 mol) or
-bromopropionic acid (1.52 g, 0.01 mol) in absolute ethanol 40 ml in
the presence of anhydrous sodium acetate (3.28 g, 0.04 mol) was re-
fluxed for 3 h. The reaction mixture was cooled, diluted with water, and
allowed to stand overnight. The solid thus obtained was washed with
water, dried and crystallized from the proper solvent to give Va–f.
Preparation of 4,7-dimethoxy- (VIa,b) and 4-methoxy-
6-hydroxy-5-[(5-substituted-amino-1,3,4-thiadiazo-2-yl)-
benzofuran Derivatives VIa–d, VII
General Procedure
Method A. Phosphorus oxychloride (15 ml) was added to the appro-
priate thiosemicarbazide IIa,b,e,g,h (0.005 mol) and the mixture was
heated under reflux for 2–4 h. The mixture was then evaporated in
vacuo and the residue was washed with dilute ammonium hydroxide

Benzofuran Derivatives
875
solution and water, dried and crystallized from the appropriate solvent
to give (VIa–d) VII. in 62–66% yields.
Method B. Concentrated sulphuric acid (15 ml) was added dropwise
to the appropriate thiosemicarbazide IIa,b,e,g,h (0.005 mol) and the
mixture was stirred at ambient temperature for 24 h. The mixture
was then poured onto crushed ice (100 g) and the separated solid was
filtered, washed with dilute ammonium hydroxide solution and water,
dried, and crystallized from the appropriate solvent to give (VIa–d) VII
in 50–55% yield. (The yield of method A and purity were relatively
higher than those in method B.)
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