Utility of phthalimidoacyl isothiocyanate in synthesis of quinazolines, benzoxazoles, benzimidazoles, 1,2,4-triazoles, and oxatriazepines

Article abstract of DOI:10.1080/10426507.2011.597804

Phthalimidoacyl isothiocyanates 1a,b participated in a wide range of addition-cyclization reactions. Simultaneous or subsequent cyclization of the obtained adducts gave derivatives of quinazoline, benzoxazole, benzimidazole, 1,2,4-triazole, and oxatriazepine. The structures of all the products were confirmed by microanalytical and spectroscopic data.

Full text of DOI:10.1080/10426507.2011.597804

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Utility of Phthalimidoacyl Isothiocyanate
in Synthesis of Quinazolines,
Benzoxazoles, Benzimidazoles, 1,2,4-
Triazoles, and Oxatriazepines
M. M. Hemdan a , A. F. M. Fahmy a , N. F. Aly a , I. A. Hegazi a & A. A.
El-Sayed a
a Department of Chemistry, Faculty of Science, Ain Shams University,
Abbasia, Cairo, Egypt
Published online: 05 Jan 2012.
To cite this article: M. M. Hemdan , A. F. M. Fahmy , N. F. Aly , I. A. Hegazi & A. A. El-Sayed (2012):
Utility of Phthalimidoacyl Isothiocyanate in Synthesis of Quinazolines, Benzoxazoles, Benzimidazoles,
1,2,4-Triazoles, and Oxatriazepines, Phosphorus, Sulfur, and Silicon and the Related Elements, 187:2,
181-189
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Phosphorus, Sulfur, and Silicon, 187:181–189, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.597804
UTILITY OF PHTHALIMIDOACYL ISOTHIOCYANATE
IN SYNTHESIS OF QUINAZOLINES, BENZOXAZOLES,
BENZIMIDAZOLES, 1,2,4-TRIAZOLES, AND
OXATRIAZEPINES
M. M. Hemdan, A. F. M. Fahmy, N. F. Aly, I. A. Hegazi,
and A. A. El-Sayed
Department of Chemistry, Faculty of Science, Ain Shams University, Abbasia,
Cairo, Egypt
GRAPHICAL ABSTRACT
Abstract Phthalimidoacyl isothiocyanates 1a,b participated in
a wide range of
addition–cyclization reactions. Simultaneous or subsequent cyclization of the obtained
adducts gave derivatives of quinazoline, benzoxazole, benzimidazole, 1,2,4-triazole, and
oxatriazepine. The structures of all the products were confirmed by microanalytical and
spectroscopic data.
Keywords Benzimidazoles; benzoxazoles; oxatriazepines; phthalimidoacyl isothiocyanate;
quinazolines; 1,2,4-triazoles
INTRODUCTION
Aroyl isothiocyanates are bifunctional reagents capable of participating in a wide
range of addition–cyclization reactions.1 The strong electron-attracting power of their aroyl
Received 19 April 2011; accepted 14 June 2011.
Address correspondence to M. M. Hemdan, Department of Chemistry, Faculty of Science, Ain Shams
University, 11566 Abbasia, Cairo, Egypt. E-mail: mhemdan39@hotmail.com
181

182
M. M. HEMDAN ET AL.
groups enhances the reactivity of the adjacent isothiocyanato function and promotes nucle-
ophilic addition at this center.2 Simultaneous or subsequent cyclization of the adducts gave
access to a variety of heterocyclic rings of different sizes, including bicyclic condensed
ring systems.1–13 Isothiocyanates may serve as a versatile building block to prepare a
wide class of nitrogen, sulfur, and oxygen heterocycles besides thiourea derivatives, which
are reported to exhibit biological activities as antibacterial, antifungal, herbicides, and
pesticides.14–16
In the present investigation, phthalimidoacyl isothiocyanates underwent reactions
with different nucleophilic reagents to provide a versatile synthetic route to derivatives of
quinazoline, benzoxazole, benzimidazole, 1,2,4-triazole, and oxatriazepine.
RESULTS AND DISCUSSION
The new derivatives were prepared according to the reaction sequences depicted
in Schemes 1 and 2. As shown in Scheme 1, the reaction of isothiocyanates 1a,b with
anthranilic acid produced thiourea derivatives 2a,b. Heating of compounds 2a,b with
polyphosphoric acid gave quinazoline derivatives 3a,b. The infrared (IR) spectra of com-
pounds 2 and 3 showed absorption bands correlated with υ (NH), υ (C O), and υ (C S).
Their 1H NMR spectra displayed signals corresponding to alkyl and aromatic protons, as
well as signals of NH protons. 13C chemical shifts of 2a and 3a showed 14 types of carbon
atoms in agreement with their structures. Further highlights on the assigned structures of
compounds 2a,b and 3a,b were gained from their mass spectrum (MS) data that revealed
MS peaks consistent with the assigned structures (see Experimental section).
O
R
CH
R'
C
N=C=S
1a,b
XH
NH2
PhCONHNH2
DCC
NH2
COOH
R'RCHCONHCSNHNHCOPh
S
NH-C
6a,b
HX
NHCOCHRR'
S
PPA
COOH
R'RHCCOHN
4a-d
N
H
2a,b
N
NH
Ph
S
N
H
N
-H2S
COCHRR'
S
7a) R' = H
b)
R' = CH3
X
N
N-COCHRR'
R'RCHCOHN
O
5a) R'=H; X=O
b) R'=CH3;X=O
c) R'=H; X=NH
3a,b
O
d)
R'=CH3;X=NH
R =
N
O
Scheme 1

UTILITY OF PHTHALIMIDOACYL ISOTHIOCYANATE
183
Ph
HN
N
Acetonitrile
RR'CH
S
N
8a) R'= H
b)
O
C
R'= CH3
PhNHNH2
H+
R
CH
R'
N=C=S
1a,b
CH3
NH
N-Ph
H3C
O
Acetone
RH2C
N
S
9
Scheme 2
o-Aminophenol and o-phenylenediamine reacted with isothiocyanate 1a in the ab-
sence of dicyclohexylcarbodiimide (DCC) to produce the thiourea derivatives 4a and 4c,
respectively. However, the treatment of o-aminophenol and o-phenylenediamine with 1a,b
in the presence of an equivalent amount of DCC afforded benzoxazoles 5a,b or benzimida-
zoles 5c,d. The formation of compounds 5a–d can be rationalized on the basis of formation
of the thiourea derivatives 4 as intermediates (isolated in the absence of DCC) followed by
cyclization. The structures of compounds 5a–d were proved by their microanalytical and
spectral data. Their IR spectra showed absorption bands correlated with υ (NH), υ (C O),
and υ (C N). The 1H NMR spectra of compounds 5a–d showed signals corresponding to
alkyl and aromatic protons in addition to NH protons in the downfield region. 13C chemical
shifts of 4a,c and 5a showed 13 types of carbon atoms, while 5c showed only 10 signals
that correspond to 10 different types of carbon atoms. The MS revealed the molecular ion
peaks for compounds 5a–d (see Experimental section). Unfortunately compounds 4a,c did
not show the molecular ion peaks; however, their MS peaks correspond very well to the
proposed structures.
The treatment of 1a,b with benzoyl hydrazine in acetonitrile gave thiosemicarbazide
derivatives 6a,b (Scheme 1). Cyclization of compounds 6a,b was achieved on heating with
polyphosphoric acid to give 1,2,4-triazoline derivatives 7a,b. The formation of compounds
7 was explained on the basis of the removal of a molecule of water from N-4 and benzoyl
carbonyl group. Another mode of cyclization of 6 through elimination of a molecule of
water from N-1 and aroyl carbonyl group was excluded due to the absence of aroyl ion
fragment at m/z 105 in their mass spectra.
The structures of compounds 6a,b and 7a,b were elucidated from their microanalyt-
ical and spectral data that revealed a pattern completely in agreement with their proposed
structures. Thus, their IR spectra showed υ (NH), doublet in the region (1779–1700 cm−1
)
1
for coupling carbonyl bands of cyclic imides, and υ (C S). H NMR of 6a and 7a,b
displayed signals for CH2, CH3, and CH, protons at δ: 4.73–4.57, 1.59, and 5.19 ppm,
integrating two, three, and one proton, respectively. Aromatic protons exhibited a multiplet
in the region 7.43–8.16 ppm, integrating nine protons, as well as a broad singlet due to NH
protons in the downfield region, which are exchangeable with D2O. 13C chemical shifts of
6a and 7a showed the different types of carbon atoms for each compound, including C O
signal in the region 162.2–167.8 ppm and C S signal in the region 167.4–180.1 ppm.

184
M. M. HEMDAN ET AL.
Moreover, MS of 6b and 7a,b revealed the molecular ion peaks. The MS of compound 6a
did not show its molecular ion peak, but it showed [M+ − (CO2+H2S)] peak in addition to
some of the abundant peaks consistent with the assigned structure.
Similar treatment of phthalimidoacyl isothiocyanates 1a,b with phenyl hydrazine in
acetonitrile yielded 1,2,4-triazoline-3-thione derivatives 8a,b in one-pot reaction (Scheme
2). The formation of compounds 8a,b was visualized to proceed via condensation of
phenylhydrazine with the carbonyl group of 1a,b followed by cyclization with the isothio-
cyanato group. However, phthalimidoacetyl isothiocyanate (1a) was reacted with phenyl-
hydrazine in dry acetone to afford oxatriazepine-5-thione derivative 9 in one-pot reaction.
The formation of compound 9 can be explained on the basis of nucleophilic addition of
isopropylidene phenylhydrazone (obtained as a side product of the reaction of phenylhy-
drazine with acetone) on the carbon atom of isothiocyanato group followed by cyclization
(Scheme 3). Another method of preparing compound 9 was achieved by the treatment of
isothiocyanate 1a with acetone phenylhydrazone in boiling acetonitrile. Moreover, heating
of an ethanolic solution of 9 with a catalytic amount of concentrated HCl yielded 1,2,4-
triazoline 8a and acetone as shown in Scheme 3. The acetone was isolated as acetone
2,4-dinitrophenylhydrazone.17
H3C CH3
CH3
CH3
CH3
CH3
1a
PhNHNH2
+
N
O
Ph NH
N
Ph
S
O
C
N
C
RCH2
N
H
H3C CH3
CH3
H3C
O
N
Ph
S
H
NH
Ph
H+
CH3
HN
N
O
C
N
C
O
+
N
Ph
CH3
RCH2
RCH2
N
S
N
RH2C
N
S
8a
9
Scheme 3
The IR spectral data of compounds 8a,b and 9 showed υ (NH), two bands corre-
sponding to coupling carbonyl groups of cyclic imide, υ (C N), and υ (C S). Their 1H
NMR displayed a pattern completely in accord with their structures. 13C chemical shifts of
8a and 9 showed 11 and 13 peaks related to their carbon atoms, respectively. Further proof
for the assigned structure of compounds 8a,b was gained from their MS, which revealed
their molecular ion peaks as base peaks corresponding to their molecular formulas. The
MS peaks of compound 9 showed a fragment at m/z 148 as a base peak corresponding to
acetone phenylhydrazone ion.
CONCLUSION
The electron-withdrawing power of the phthalimido moiety enhances the reactivity
of both isothiocyanate function and carbonyl group of 1. It is observed from all reactions

UTILITY OF PHTHALIMIDOACYL ISOTHIOCYANATE
185
mentioned that the nucleophilic addition proceeds either at the isothiocyanate group
(Scheme 1) or at the carbonyl group (Scheme 2) of the title compounds 1a,b, followed
by simultaneous or subsequent cyclization.
EXPERIMENTAL
General
Melting points of the reaction products were determined in open capillary tubes
on a Gallenkamp melting point apparatus and were uncorrected. The elemental analysis
was performed on a Perkin-Elemer 2400 CHN elemental analyzer. The IR spectra were
recorded on a Perkin-Elemer Model 297 Infrared spectrometer and Pye Unicam SP1200
1
spectrophotometer using the KBr wafer technique. The H NMR and 13C NMR spectra
were measured on a Oxford NMR 300-Varian Gemini 2000 NMR spectrometer, JEOL
JNM-EX 270 FT NMR spectrometer, Varian Gemini 200 MHz, and Brucker AC-200
MHz with chemical shift (δ) expressed in ppm downfield, with tetramethylsilane (TMS)
as internal standard, in DMSO-d6. Mass spectra were determined using a Kratos Model
MS 25 mass spectrometer (Magnetic Sector) and HP Model MS-5988 at 70 eV. Thin layer
chromatography (TLC) was run using TLC aluminum sheets silica gel F254 (Merck). It was
carried out by monitoring the progress of all reactions and homogeneity of the synthesized
compounds.
Synthesis of Phthalimidoacyl Isothiocyanates (1a,b)
To a solution of phthalimido acetyl chloride or 2-phthalimido propionyl chloride
(3 mmol) in dry acetonitrile (30 mL) or dry acetone (30 mL), solid ammonium thiocyanate
(3 mmol) was added. The reaction mixture was stirred for 30 min at room temperature.18,19
The precipitated ammonium chloride was filtered off to give a clear solution of isothio-
cyanates 1a,b.
Reaction of Isothiocyanate (1a,b) with Different Nucleophiles
General Procedure. To a solution of isothiocyanate la or 1b (3 mmol) in dry
acetonitrile or acetone (50 mL), anthranilic acid, o-aminophenol, o-phenylenediamine,
benzoylhydrazine, phenylhydrazine, or acetone phenylhydrazone was added. An equivalent
amount of DCC was added in the case of the reaction of 1a,b with o-aminophenol or o-
phenylenediamine. The mixture was refluxed for 2–3 h (TLC) and then cooled to room
temperature. The precipitated solid was sucked, washed with ethanol, and crystallized from
the suitable solvent to give the corresponding compounds.
2-(3-(2-(1,3-Dioxoisoindolin-2-yl)Acetyl)Thioureido)Benzoic Acid (2a). 75% yield;
pale yellow crystals; mp 214 ◦C–217 ◦C (ethanol); IR (KBr) υ (cm−1): 3240, 3200 (NH),
1780, 1710 (C O), 1225 (C S); 1H NMR (DMSO-d6) δ: 4.57 (s, 2, CH2), 7.29–8.23 (m,
8, ArH), 11.91 (br. s, 2, NH, exchangeable), 13.11 (br. s, 1, OH, exchangeable); 13C NMR
(DMSO-d6): 40.3 (CH2), Ar C [123.6 (C COOH), 124.4 (2CH), 126.3 (CH), 127.2 (CH),
130.5 (CH), 131.6 (2C), 132.1 (2CH), 135.0 (CH), 138.0 (C NH)], 167.3 (2CO), 167.5
(CO), 167.6 (CO), 178.9 (CS); MS (70 eV) m/z (%): 306 [M+ − (CO2 + SH), 22], 262
(5), 188 (2), 160 (100), 137 (3), 105 (9); anal. calcd. for C18H13N3O5S (383.40): C 56.39,
H 3.42, N 10.96; found: C 56.33, H 3.20, N 10.83.

186
M. M. HEMDAN ET AL.
2-(3-(2-(1,3-Dioxoisoindolin-2-yl)Propanoyl)Thioureido)Benzoic Acid (2b). 70%
yield; pale yellow crystals; mp 190 ◦C–192 ◦C (ethanol); IR (KBr) υ (cm−1): 3288, 3032
1
(NH), 1780, 1694 (C O), 1235 (C S); H NMR (DMSO-d6) δ: 1.60 (d, J = 7.2 Hz, 3,
CH3), 5.04 (q, J = 7.2 Hz, 1, CH), 7.29–8.13 (m, 8, ArH), 11.68, 12.83 (br. s, 2, NH,
exchangeable), 13.45 (br. s, 1, OH, exchangeable); MS (70 eV) m/z (%): 397 (M+, 2), 205
(9), 174 (100), 146 (43), 104 (15); anal. calcd. for C19H15N3O5S (397.40): C 57.42, H
3.80, N 10.57; found: C 57.13, H 3.62, N 10.43.
N-(2-Hydroxyphenylcarbamothioyl)-2-(1,3-Dioxoisoindolin-2-yl)-Acetamide (4a).
75% yield; pale yellow crystals; mp 216 ◦C–218 ◦C (ethanol); IR (KBr) υ (cm−1): 3311,
1
3128 (NH), 1774, 1707 (C O), 1380 (C S); H NMR (DMSO-d6) δ: 4.61 (s, 2, CH2),
7.20–7.90 (m, 8, ArH), 10.18, 11.86 (br. s, 2, NH, exchangeable), 12.32 (br. s, 1, OH,
exchangeable); 13C NMR (DMSO-d6): 40.5 (CH2), Ar C [115.1 (CH), 118.3 (CH), 123.0
(CH), 123.4 (2CH), 125.7 (C), 126.5 (CH), 131.5 (2C), 134.8 (2CH), 148.7 (C OH)],
167.3 (C O), 168.2 (2C O), 176.5 (C S); MS (70 eV) m/z (%): 278 [M+ − (CO2 +
SH), 2], 188 (22), 160 (100), 146 (9), 104 (17), 76 (16); anal. calcd. for C17H13N3O4S
(355.4): C 57.46, H 3.69, N 11.82; found: C 57.27, H 3.54, N 11.75.
N-(2-Aminophenylcarbamothioyl)-2-(1,3-Dioxoisoindolin-2-yl)Acetamide (4c). 87%
yield; pale yellow crystals; mp 220 ◦C–222 ◦C (acetic acid); IR (KBr) υ (cm−1): 3360–3260
(NH2), 3190 (NH), 1780, 1730, 1715 (C O), 1322 (C S); 1H NMR (DMSO-d6) δ: 4.27
(s, 2, CH2), 6.75–7.93 (m, 8, ArH), 5.3 (br. s, 2, NH2, exchangeable), 11.33, 11.97 (br. s, 2,
NH, exchangeable); 13C NMR (DMSO-d6): 40.5 (CH2), Ar C [115.8 (CH), 116.0 (CH),
123.0 (C NH), 123.4 (2CH), 127.3 (CH), 127.8 (CH), 131.4 (2C), 134.8 (2CH), 143.3
(C NH2)], 167.3 (C O), 167.2 (2C O), 179.4 (C S); MS (70 eV) m/z (%): 320 (M+ −
H2S, 12), 190 (31), 160 (100), 146 (19), 104 (27), 76 (34); anal. calcd. for C17H14N4O3S
(354.4): C 57.62, H 3.98, N 15.81; found: C 56.90, H 3.80, N 15.38.
N-(Benzo[d]oxazol-2-yl)◦-2-(1,3-Dioxoisoindolin-2-yl)Acetamide (5a). 72% yield;
◦
pale yellow crystals; mp 266 C–268 C (acetic acid); IR (KBr) υ (cm−1): 3130 (NH),
1
1774, 1724, 1629 (C O), 1578 (C N); H NMR (DMSO-d6) δ: 4.71 (s, 2, CH2),
7.11–8.00 (m, 8, ArH), 12.30 (br. s, 1, NH, exchangeable); 13C NMR (DMSO-d6): 40.7
(CH2), Ar C [109.5 (CH), 117.9 (CH), 122.9 (CH), 123.3 (2CH), 124.2 (CH), 131.1
(2C), 134.3 (2CH), 140.1 (C N, oxazole), 147.2 (C O, oxazole)], 154.3 (C N), 164.9
(CO), 166.9 (2CO); MS (70 eV) m/z (%): 321 (M+, 5), 162 (9), 161 (93), 160 (100), 134
(23), 104 (26); anal. calcd. for C17H11N3O4 (321.29): C 63.55, H 3.45, N 13.08; found: C
63.51, H 3.20, N 13.00.
N-(Benzo[d]oxazol-2-yl)-2-(1,3-Dioxoisoindolin-2-yl)Propanamide (5b). 62% yield;
pale yellow crystals; mp 215 ◦C–216 ◦C (toluene); IR (KBr) υ (cm−1): 3236 (NH), 1778,
1719, 1635 (C O), 1584 (C N); 1H NMR (DMSO-d6) δ: 1.60 (d, J = 7.0 Hz, 3, CH3),
5.08 (q, J = 7.2 Hz, 1, CH), 7.28–7.96 (m, 8, ArH), 11.93 (br. s, 1, NH, exchangeable);
MS (70 eV) m/z (%): 336 (M+ + 1, 3), 335 (M+, 7), 202 (2), 174 (77), 161 (100), 104 (11);
anal. calcd. for C18H13N3O4 (335.31): C 64.47, H 3.91, N 12.53; found: C 64.41, H 3.78,
N 12.47.
N-(1H-Benzo[d]imidazol-2-yl)-2-(1,3-Dioxoisoindolin-2-yl)Acetamide (5c). 67%
◦
◦
yield; pale yellow crystals; mp 282 C–284 C (acetic acid); IR (KBr) υ (cm−1): 3350,
1
3264 (NH), 1776, 1717, 1638 (C O), 1585 (C N); H NMR (DMSO-d6) δ: 4.58 (s, 2,
CH2), 7.11–7.98 (m, 8, ArH), 12.20 (br. s, 2, 2NH, exchangeable); 13C NMR (DMSO-d6):
41.0 (CH2), Ar C [113.8 (2CH), 121.4 (2CH), 123.3 (2CH), 131.7 (2C), 134.7 (2CH),
135.3 (2C)], 147.0 (imidazole-C), 167.6 (CO), 167.8 (2CO); MS (70 eV) m/z (%): 320

UTILITY OF PHTHALIMIDOACYL ISOTHIOCYANATE
187
(M+, 7), 189 (2), 162 (5), 161 (32), 160 (100), 104 (24); anal. calcd. for C17H12N4O3
(320.30): C 63.75, H 3.78, N 17.49; found: C 63.52, H 3.68, N 17.36.
N-(1H-Benzo[d]imidazol-2-yl)-2-(1,3-Dioxoisoindolin-2-yl)Propanamide (5d). 67%
yield; pale yellow crystals; mp 255 ◦C–257 ◦C (ethanol); IR (KBr) υ (cm−1): 3378, 3226
1
(NH), 1778, 1717, 1637 (C O), 1586 (C N); H NMR (DMSO-d6) δ: 1.65 (d, J = 7.2
Hz, 3, CH3), 5.06 (q, J = 7.2 Hz, 1, CH), 7.09–7.95 (m, 8, ArH), 12.87 (br. s, 2, 2NH,
exchangeable); MS (70 eV) m/z (%): 335 (M+ + 1, 2), 334 (M+, 7), 202 (1), 174 (40), 160
(100), 104 (9); anal. calcd. for C18H14N4O3 (334.33): C 64.66, H 4.22, N 16.76; found: C
64.18, H 3.98, N 16.65.
N-(2-Benzoylhydrazinecarbonothioyl)-2-(1,3-Dioxoisoindolin-2-yl)Acetamide (6a).
80% yield; pale yellow crystals; mp 211 ◦C–213 ◦C (ethanol); IR (KBr) υ (cm−1): 3344,
1
3210 (NH), 1779, 1700 (C O), 1280 (C S); H NMR (DMSO-d6) δ: 4.57 (s, 2, CH2),
7.43–7.94 (m, 9, ArH) 11.05, 11.74, 12.02 (br. s, 3, NH, exchangeable); 13C NMR (DMSO-
d6): 40.4 (CH2), Ar C [123.6 (2CH), 127.8 (2CH), 128.6 (2CH), 131.6 (3C), 132.2 (CH),
135.0 (2CH)], 164.8 (C O), 167.5 (C O), 167.8 (2C O), 180.1 (C S); MS (70 eV) m/z
(%): 304 (M+ − (CO2+H2S), 1 (1), 240 (9), 160 (9), 105 (100), 77 (45); anal. calcd. for
C18H14N4O4S (382.39): C 56.54, H 3.69, N 14.65; found: C 56.28, H 3.63, N 14.62.
N-(2-Benzoylhydrazinecarbonothioyl)-2-(◦1,3-Dioxoisoindolin-2-yl)Propanamide
◦
(6b). 85% yield; pale yellow crystals; mp 193 C–195 C (ethanol); IR (KBr) υ (cm−1):
3372, 3288 (NH), 1777, 1706 (C O), 1283 (C S); 1H NMR (DMSO-d6) δ: 1.52 (d, J =
7.0 Hz, 3, CH3), 5.22 (q, J = 7.2 Hz, 1, CH), 7.52–7.97 (m, 9, ArH) 9.8, 10.76, 12.96 (br.
s, 3, NH, exchangeable); MS (70 eV) m/z (%): 397 (M+ + 1, 0.5), 396 (M+, 1), 174 (100),
130 (23), 105 (89), 77 (60); anal. calcd. for C19H16N4O4S (396.42): C 57.57, H 4.07, N
14.13; found: C 57.28, H 3.63, N 14.32.
2-((2-Phenyl-3-Thioxo-2,3-Dihydro-1H-1,2,4-Triazol-5-yl)Methyl)Isoindoline-1,3-
◦
◦
Dione (8a). 79% yield; pale yellow crystals; mp 228 C–230 C (ethanol); IR (KBr) υ
(cm−1): 3344 (NH), 1771, 1716 (C O), 1599 (C N), 1288 (C S); 1H NMR (DMSO-d6)
δ: 4.93 (s, 2, CH2), 7.40–8.18 (m, 9, ArH), 13.43 (br. s, 1, NH, exchangeable); 13C NMR
(DMSO-d6): 32.9 (CH2), Ar C [123.5 (2CH), 123.7 (2CH), 127.9 (CH), 128.9 (2CH),
131.9 (2C), 134.8 (2CH), 137.7 (C N)], 148.0 (C N), 166.0 (2CO), 167.4 (CS); MS (70
eV) m/z (%): 338 (M+ + 2, 7), 337 (M+ + 1, 24), 336 (M+, 100), 304 (20), 104 (50), 91
(72); anal. calcd. for C17H12N4O2S (336.37): C 60.70, H 3.60, N 16.66; found: C 60.60, H
3.52, N 16.70.
2-(1-(2-Phenyl-3-Thioxo-2,3-Dihydro-1H-1,2,4-T◦riazol-5-yl)Ethyl)Isoindoline-1,3-
◦
Dione (8b). 72% yield; pale yellow crystals; mp 226 C–228 C (toluene); IR (KBr) υ
(cm−1): 3363 (NH), 1777, 1716 (C O), 1592 (C N), 1280 (C S); 1H NMR (DMSO-d6)
δ: 1.75 (d, J = 7.0 Hz, 3, CH3), 5.56 (q, J = 7.0 Hz, 1, CH), 7.44–8.01 (m, 9, ArH), 13.92
(br. s, 1, NH, exchangeable); MS (70 eV) m/z (%): 352 (M+ + 2, 6), 351 (M+ + 1, 17), 350
(M+, 100), 202 (39), 105(52), 91 (18); anal. calcd. for C18H14N4O2S (350.39): C 61.70, H
4.03, N 15.99; found: C 61.67, H 4.35, N 15.78.
2-((2,2-Dimethyl-4-Phenyl-5-Thioxo-2,3,4,5-Tetrahydro-1,3,4,6-Oxatriazepin-7-
◦
◦
yl)Methyl)Isoindoline-1,3-Dione (9). 85% yield; colorless crystals; mp 197 C–199 C
(ethanol); IR (KBr) υ (cm−1): 3218 (NH), 1768, 1714 (C O), 1612 (C N), 1283 (C S);
1H NMR (DMSO-d6) δ: 1.6 (s, 6, 2CH3), 5.12 (s, 2, CH2), 7.06–7.98 (m, 9, ArH), 11.70 (s,
1, NH, exchangeable); 13C NMR (DMSO-d6): 22.7 (2CH3), 43.9 (CH2), 80.7 (C(CH3)2),
Ar C [123.6 (2CH), 125.2 (2CH), 127.6 (CH), 128.7 (2CH), 131.7 (2C), 135.0 (2CH),
138.6 (C N)], 167.5 (oxatriazepine C N), 168.0 (2CO), 172.8 (CS); MS (70 eV) m/z

188
M. M. HEMDAN ET AL.
(%): 188 (20), 160 (65), 148 (100), 146 (6), 104 (9), 92 (64); anal. calcd. for C20H18N4O3S
(394.45): C 60.90, H 4.60, N 14.20; found: C 60.91, H 4.32, N 14.01.
General Procedure. A solution of compounds 2a,b or 6a,b (0.01 mol) in glacial
aceti◦c acid (30 mL) was added to polyphosphoric acid (20 mL). The mixture was heated at
150 C–180 ◦C) for 1 h and then left to cool at room temperature. The precipitated solid
obtained after the addition of ice-cold water was filtered off and recrystillized from the
suitable solvent to give 3a,b or 7a,b, respectively.
2-(2-Oxo-2-(4-Oxo-2-Thioxo-1,2-Dihydroquinazolin-◦3(4H)-yl)Ethyl)Isoindoline-
◦
1,3-Dione (3a). 69% yield; pale green crystals; mp 270 C–272 C (DMF); IR (KBr)
1
υ (cm−1): 3290 (NH), 1774, 1721, 1640 (C O), 1290 (C S); H NMR (DMSO-d6) δ:
4.56 (s, 2, CH2), 7.45–8.12 (m, 8, ArH), 11.68 (br. s, 1, NH, exchangeable); 13C NMR
(DMSO-d6): 40.5 (CH2), Ar C [119.4 (C), 123.5 (2CH), 124.6 (CH), 127.5 (CH), 129.2
(CH), 131.7 (2C), 135.0 (2CH), 136.6 (CH), 147.4 (C)], 152.5 (CO), 167.5 (CO), 167.7
(2CO), 184.2 (CS); MS (70 eV) m/z (%): 365 (M+, 5), 306 (23), 332 (11), 178 (100), 146
(32), 104 (52); anal. calcd. for C18H11N3O4S (365.40): C 59.17, H 3.03, N 11.50; found:
C 58.93, H 3.22, N 11.46.
2-(1-Oxo-1-(4-Oxo-2-Thioxo-1,2-Dihydroquinazolin-3(4H)-yl)Propan-2-
yl)Isoindoline-1,3-Dione (3b). 77% yield; pale green crystals; mp 260 ◦C–262 ◦C
(acetic acid); IR (KBr) υ (cm−1): 3212 (NH), 1778, 1716, 1637 (C O), 1283 (C S); 1H
NMR (DMSO-d6) δ: 1.55 (d, J = 7.2 Hz, 3, CH3), 5.07 (q, J = 7.2 Hz, 1, CH), 7.49–8.05
(m, 8, ArH), 12.24 (br. s, 1, NH, exchangeable); MS (70 eV) m/z (%): 379 (M+, 12), 205
(51), 174 (100), 146 (4), 104 (13); anal. calcd. for C19H13N3O4S (379.40): C 60.15, H
3.45, N 11.08; found: C 60.10, H 3.22, N 10.96.
2-(2-Oxo-2-(3-Phenyl-5-Thioxo-1H-1,2,4-Triazol-4(5H)-yl)Ethyl)Isoindoline-1,3-
Dione (7a). 80% yield; pale yellow crystals; mp 305 ◦C–307 ◦C (acetic acid); IR (KBr) υ
(cm−1): 3280 (NH), 1774, 1721 (C O), 1566 (C N), 1270 (C S); 1H NMR (DMSO-d6)
δ: 4.73 (s, 2, CH2), 7.70–8.16 (m, 9, ArH), 12.60 (br. s, 1, NH, exchangeable); 13C NMR
(DMSO-d6): 40.3 (CH2), Ar C [123.4 (2CH), 127.0 (2CH), 129.4 (2CH), 130.0 (C),
130.7 (CH), 131.6 (2C), 134.8 (2CH)], 158.3 (triazole C-3), 162.2 (C O), 166.2 (2C O),
167.4 (C S); MS (70 eV) m/z (%): 364 (M+, 5), 204 (90), 160 (100), 104 (49), 91 (37);
anal. calcd. for C18H12N4O3S (364.38): C 59.33, H 3.32, N 15.38; found: C 59.24, H 3.19,
N 14.79.
2-(1-Oxo-1-(3-Phenyl-5-Thioxo-1H-1,2,4-Triazol-4(5H)-yl)Propan-2-yl)Isoindoline-
◦
◦
1,3-Dione (7b). 82% yield; pale yellow crystals; mp 284 C–286 C (acetic acid); IR
(KBr) υ (cm−1): 3277 (NH), 1777, 1722 (C O), 1558 (C N), 1283 (C S); H NMR
1
(DMSO-d6) δ: 1.59 (d, J = 7.2 Hz, 3, CH3), 5.19 (q, J = 7.2 Hz, 1, CH), 7.52–7.97 (m, 9,
ArH), 12.96 (br. s, 1, NH, exchangeable); MS (70 eV) m/z (%): 378 (M+, 3), 204 (100),
174 (90), 161 (90), 130 (28), 104 (12); anal. calcd. for C19H14N4O3S (378.40): C 60.31, H
3.73, N 14.81; found: C 59.80, H 3.90, N 14.70.
Acid Hydrolysis of Oxatriazepine (9). A mixture of compound 9 (0.01 mol)
and 2,4-dinitrophenylhydrazine (0.01 mol) in ethanol (20 mL) containing concentrated
hydrochloric acid (32%; 3 mL) was boiled under reflux for 15 min. The reaction mixture
was concentrated and then chromatographed over silica gel. Elution with 1:4 (v/v) ethyl
◦
◦
◦
◦
acetate and petroleum ether 60 C–80 C gave orange crystals, mp 127 C–128 C, and
yield 92%. It was proven to be acetone 2,4 dinitrophenylhydrazone by mp and mixed mp.
However, elution with 1:1 (v/v) ethyl acetate and petroleum ether 60 ◦C–80 ◦C gave white
crystals, mp 228 ◦C–230 ◦C, and 80% yield. It was proven to be a triazole derivative 8a by
mp and mixed mp.

UTILITY OF PHTHALIMIDOACYL ISOTHIOCYANATE
189
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