Synthesis of some heterocycles of expected biological activity through the action of isatin-3-thiosemicarbazone on acetylenic ketones and esters

Article abstract of DOI:10.1080/10426500210227

Isatin-3-thiosemicarbazone (1) reacted with 1-aryl-3-phenylprop-2-yn-1-ones (2a-c) in n-butanol to give 4-aryl-6-phenyl-2-[2-oxo-2H,3H-benzo(b) pyrrolidine-3-iminyl]-imino-2H-1,3-thiazines (3a-c). Similar treatment of 1 with acetylenic esters (4a-c) gave the 6-substituted derivatives of 2-imino-3-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl]-2,3-dihydro-4-oxo-1,3- thiazine (5a-c). Treatment of 1 with 4a-c in the presence of sodium ethoxide in ethanol gave the 6-substituted derivatives of 3-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl]-4-oxo-2-thioxo-1,2,4- trihydropyrimidine (6a-c). However, when 1 was refluxed with 1-p-chlorophenyl-3-phenylprop-2-yn-1-one (2b) in ethanol it gave a mixture of 2,4,6-tris[2-oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl] amino-1,3,5-triazine (7) and Z,Z-3,3′-thiodi(1-p-chlorophenyl-3-phenylprop-2-en-1-one) (8). The aziridine imine derivative (9) and the pyrazole derivatives (10a and b) were the only isolated products upon treatment of 3c, 6a, and 6c and 3a and 3b with hydrazine hydrate, respectively. Structures of all new compounds are evidenced by microanalytical and spectral data.

Full text of DOI:10.1080/10426500210227

Phosphorus, Sulfur and Silicon, 2002, 177:173–188
C
Copyright 2002 Taylor & Francis
1042-6507/02 $12.00 + .00
SYNTHESIS OF SOME HETEROCYCLES
OF EXPECTED BIOLOGICAL ACTIVITY THROUGH
THE ACTION OF ISATIN-3-THIOSEMICARBAZONE
ON ACETYLENIC KETONES AND ESTERS
Ahmed S. A. Youssef
Chemistry Department, Faculty of Science, Ain Shams
University, Abbassia, Cairo, Egypt
(Received November 28 2000.)
Isatin-3-thiosemicarbazone (1) reacted with 1-aryl-3-phenylprop-2-
yn-1-ones (2a–c) in n-butanol to give 4-aryl-6-phenyl-2-[2-oxo-2H,3H-
benzo(b) pyrrolidine-3-iminyl]-imino-2H-1,3-thiazines (3a–c). Similar
treatment of 1 with acetylenic esters (4a–c) gave the 6-substituted
derivatives of 2-imino-3-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl]-
2,3-dihydro-4-oxo-1,3-thiazine (5a–c). Treatment of 1 with 4a–c in
the presence of sodium ethoxide in ethanol gave the 6-substituted
derivatives of 3-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl]-4-oxo-2-
thioxo-1,2,4-trihydropyrimidine (6a–c). However, when 1 was refluxed
with 1-p-chlorophenyl-3-phenylprop-2-yn-1-one (2b) in ethanol it
gave a mixture of 2,4,6-tris[2-oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl]
amino-1,3,5-triazine (7) and Z,Z-3,30-thiodi(1-p-chlorophenyl-3-
phenylprop-2-en-1-one) (8). The aziridine imine derivative (9) and
the pyrazole derivatives (10a and b) were the only isolated products
upon treatment of 3c, 6a, and 6c and 3a and 3b with hydrazine
hydrate, respectively. Structures of all new compounds are evidenced
by microanalytical and spectral data.
Keywords: Acetylenic ketones and esters; diaziridineimine;
iminothiazine; isatin-3-thiosemicarbazone; triaminotriazine
INTRODUCTION
12
Several reports1
have described the addition of nitrogen and sul-
fur containing compounds to acetylenic ketones and esters. Nontermi-
nal acetylenic esters such as dimethyl acetylenedicarboxylate, methyl
methylpropiolate and methyl phenylpropiolate reacted with thioamides
Address correspondence to Ahmed S. A. Youssef, Chemistry Department, Faculty of
Science, Ain Shams University, Abbassia, Cairo, Egypt. E-mail: ahmedy67@hotmail.com
173

174
A. S. A. Youssef
3
to give heterocycles or 1:1 addition products.1
Propiolic esters,
however, reacted with 1-substituted thiosemicarbazides to give isomeric
4
mixtures of 3,30-thiodiacrylates2 although in two reports1,4 a mix-
ture of the thiodiacrylates, 1,3-thiazine-4-ones and thiosemicarbazone
derivatives was obtained. The aim of the present work is to prepare new
heterocyclic compounds of expected antiinflammatory and poxvirus ac-
22
tivities through reaction13,14 of isatin-3-thiosemicarbazone13
with
acetylenic ketones and esters as well as to study the behavior of the
reaction course in different media.
RESULTS AND DISCUSSION
Isatin-3-thiosemicarbazone (1) reacted with 1-aryl-3-phenylprop-2-yn-
1-ones (2a–c) in refluxing n-butanol to give 4-aryl-6-phenyl-2-[2-oxo-
2H,3H-benzo(b)pyrrolidine-3-iminyl] imino-2H-1,3-thiazines (3a–c).
The structure of 3a–c was elucidated from analytical and spec-
tral data (cf. Experimental section). Thus, the infrared spectra show
1
sharp bands in the region 1710–1700 cm characteristic of C O of
1
cyclic imide. The lack of a band in the region of 1670–1650 cm
characteristic of carbonyl group of , -unsaturated ketones infers the
existence of these compounds in the thiazine structure. The IR spectra
1
also show a band in the region 3420–3400 cm characteristic of NH.
1
Adequate evidence for the structure was obtained from the H-NMR
spectra which show only one broad singlet at about 10.8 attributable
to NH (imide) which collapses rapidly on deuteration. Further support
for the assigned structure was gained from mass spectra which show
the correct molecular ion beside some of the abundant peaks.
Similar treatment of 1 with acetylenic esters (4a–c) yields the
6-substituted derivatives of 2-iminothiazine (5a–c) as orange to brown
crystalline solids. The structure of 5a–c was established from their an-
alytical and spectral data. IR spectra show bands of NH and C O of
cyclic imides. The 1H-NMR spectra show signals attributable to olefinic
and NH protons, in case of 5c, signals characteristic of ethyl group are
also observed. These data are consistent with two possible six mem-
bered ring structures 5a and 5b (cf. Scheme 1). The mass spectral data
were particularly valuable in assigning one of them.4 The existence of
peaks corresponding to loss of HN C (arrow a) and H N C S (arrow b)
(cf. Scheme 1), can be explained satisfactorily in terms of their existence
as structure 5a rather than 5b.
1H-NMR spectra shed further light on the structure 5a as they
showed broad signal at 10.8 consistent with (NH) of pyrrolidinone
ring and another broad signal corresponding to imino proton in the
down field region at
12.7. The down field value for this signal

Isatin-3-Thiosemicarbazones and Acetylenic Ketones
175
SCHEME 1
suggests the existence of compound 5 as chelated imino 5a rather than
chelated amino 5b as shown above.
The reaction of 1 with 2a–c and with 4a–c in absence of basic cat-
alyst proceeds initially via nucleophilic attack by the sulfur atom at
the -acetylenic carbon followed by intramolecular cyclocondensation
with the carbonyl group as mentioned in previous several reports with
thioamides2,4,5,11,12,19,20 where the susceptibility of the acetylenic bond
is further enhanced through conjugation with electron withdrawing car-
bonyl group. This fact ruled out the formation of the alternative struc-
tures 30 and 50 (Figure 1).
FIGURE 1

176
A. S. A. Youssef
FIGURE 2
The reaction of 1 with acetylenic esters 4a–c in the pres-
ence of sodium ethoxide in ethanol gave the 6-substituted deriva-
tives of 3-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl]-4-oxo-2-thioxo-
1,2,4-trihydropyrimidine (6a–c).
The structure of the thione derivatives (6a–c) was rigidly estab-
lished by studying its spectroscopic properties. Thus, their IR spec-
tra are devoid of
and shows a strong absorption in the region of
S
H
1
1119–1095 cm (C S). This excludes the formation of similar thi-
azine structure like 5a but instead a pyrimidinone-2-thione (6a–c) is
formed. Its existence in the thione form,21 rather than the thiol form22 is
documented. Further evidence for the pyrimidinone-2-thione structure
1
(6a–c) was gained from the H-NMR spectra which show a signal at
about 6.6 (CH ), a broad signal in the region 10.79–10.51 corre-
sponding to (NH) of pyrrolidinone ring and another broad signal for
(NH) thioimido hidden in the signals of the aromatic ring. It was ob-
served that the signal of NH (thioimido) of diethyl acetylenedicarboxy-
late adduct (6c) was shifted in the down field region at about 10.59.
This could be explained by its existence in the chelated form which is
in consistence with the lower absorption frequency of the carbonyl es-
ter group in its IR spectrum as shown in Figure 2. Mass spectra of 6
support the assigned structure (cf. experimental).
The formation of pyrimidine-2-thione derivatives 6a–c in the pres-
ence of ethanolic sodium ethoxide23 can be explained on the basis of
attack by the anion 11 on the acetylenic ester, which is a strong nu-
cleophile, rather than by the sulfur atom. However, in the absence of
a basic catalyst the thiourea attacks the acetylenic bond preferentially
by the sulfur atom.4,5 This is probably due to the fact that the polar-
ized C S group is more nucleophilic than the amino group, since the
latter carries a partial positive charge due to p- conjugation.23 The
initial attack of the anion 11 to the acetylenic bond followed by cy-
clization gave the pyrimidine-2-thione derivative 6a–c. However, when

Isatin-3-Thiosemicarbazones and Acetylenic Ketones
177
FIGURE 3
1-aryl-3-phenylprop-2-yn-1-ones (2a–c) were treated with 1 under sim-
ilar conditions they gave 1-aroyl-3-benzoyl methanes rather than the
pyrimidine-2-thiones as reported with thiourea.23 The formation of
aroylbenzoylmethanes rather than pyrimidine-2-thiones could be in-
terpreted on the basis of the preferential base catalysed addition of
water to the acetylenic bond, rather than the addition of anion 11a
because of its weak nucleophilicity as a result of the electron with-
drawing effect from the thiocarbonyl carbon by the central nitrogen
conjugated with indolinyl moiety as shown in Figure 3.
On the other hand 1-p-chlorophenyl-3-phenylprop-2-yn-1-one (2b)
reacted with 1 in refluxing ethanol to afford the triamino-1,3,5-
triazine derivative 7 along with the Z,Z-3,30-thiodi-(1-p-chlorophenyl-
2-phenylprop-2-en-1-one) (8).
The structure of triamino-1,3,5-triazine derivative 7 was confirmed
on the basis of its spectral data (cf. experimental). Thus IR spectrum de-
void of absorptions characteristic of phenyl and p-chlorophenyl groups
which infers the absence of these moieties. It shows also one strong
band at 1710 (C O imido) and two bands at 3420, 3250 cm 1 (NH). The
1H-NMR spectrum shows signal at 11.04 (NH imido), a signal for (NH
amino) hidden in the aromatic region and multiplet signals for the four
adjacent hydrogens of benzene ring of indolinyl moiety. As the total in-
tegration corresponds to the third number of protons in the compound
7, this means that it has an element of symmetry. Further proof for the
proposed structure 7, was gained from mass spectrum which shows the
correct molecular ion beside some of abundant peaks (cf. fragmentation
pattern Scheme 2).
The formation4,5,12 of sulfide 8 could be explained on the basis
of initial attack by the sulfur atom of the thiosemicarbazone 1 at the
-carbon of the acetylenic ketone to give a 1:1 addition product (not
isolated); a 1:1 addition product was isolated from similar reactions
under special conditions.2 The reaction between the addition product
and a second molecule of the acetylenic ketone may give the final
product (8) and the intermediate (X) (not isolated) which undergoes

SCHEME 2
178

Isatin-3-Thiosemicarbazones and Acetylenic Ketones
179
SCHEME 3
intermolecular trimerisation to give the triamino1,3,5-triazine deriva-
tive 7 (cf. Scheme 3). This compound was not isolated in any of the
previous reports.4,5,12
Treating an ethanolic solution of 1,3-thiazine derivatives 3a–c or
pyrimidine-2-thione derivatives 6a,c with hydrazine hydrate gave only
the diaziridine imine derivative 9 together with the pyrazole deriva-
tives 10a–c. In case of 3c,9 was isolated and 10c was detected by TLC
in the reaction mixture, whereas in case of 3a,b; 10a,b were isolated
and 9 was detected by TLC in the reaction mixture.
The structure of the diaziridine imine 9 was deduced from spectro-
scopic data (cf. experimental). Thus, its IR spectrum devoid of bands
characteristic of phenyl and substituted phenyl groups which proves
the absence of these moieties. It shows absorptions characteristic of
C O and NH groups. A good evidence for the assigned structure was
1
given from its H-NMR spectrum as it shows signals at 10.71 (NH
imido) and two doublet signals centered at 10.55, 9.57 for two NH
protons (J = 15.4 Hz). The appearance of one of the two doublets in the
down field region suggests the existence of the compound in its chelated
form mentioned in Scheme 6.
Mass spectrum shows a weak molecular ion. Scheme 4 shows the
fragmentation pattern of compound 9 and structures of some fragments.
The formation of 9 and 10 from 3a–c could be explained on the basis
of nucleophilic ring fission by hydrazine hydrate through attack at ei-
ther C2 or C6 as shown in Scheme 5. On the other hand, the reaction of

180
A. S. A. Youssef
SCHEME 4
hydrazine hydrate with the pyrimidine-2-thione derivatives 6a,c seems
to proceed through attack at the thiono carbon followed by ring fission
to give 9 as illustrated in Scheme 5.
EXPERIMENTAL
All melting points are not corrected. IR spectra were measured on a
Unicam SP1200 or FTIR Mattson (Infinity series) spectrometers as KBr
1
discs. Unless otherwise stated the H-NMR spectra were measured in
DMSO solutions on Varian Gemini 200 MHz or Brucker ES 200 MHz
instruments with chemical shift ( ) expressed in ppm downfield from
Me4Si. Mass spectra were recorded on Shimadzu GC-MS-Qp 1000 Ex or
Finnigan GCQ instruments operating at 70 ev. Column chromatogra-
phy and TLC were runned on silica Gel Voeim, activity 111/30 mm
according to Brockmann and Schodder and TLC aluminum sheets
Silica Gel 60 F254 (Merck, Federal Republic Germany).
Starting Material
Isatin-3-thiosemicarbazone (1)
To a solution of isatin (34 mmol) in ethanol (50 ml) was added
thiosemicarbazide (34 mmol) followed by three drops of piperidine. The

Isatin-3-Thiosemicarbazones and Acetylenic Ketones
181
SCHEME 5
reaction mixture was refluxed over water bath for 10 min whereby a
yellow cannary solid separates. Crystallization from ethanol gave a yel-
low crystals (90% yield), m.p. 248–250 C. lit.,29 m.p. 255 C. IR
3440, 3160 (NH), 1695 (C O imido). H-NMR (DMSO) 6.94 (d, Hd,
max
1
Jdc = 7.6 Hz), 7.00 (t, Hb, Jab, Jbc = 7.2, 7.6 Hz), 7.37 (t, Hc, Jcb
=
Jcd = 7.6 Hz), 7.67 (d, Ha, Jab = 7.0 Hz), 8.72 (s, 1H, 5H exchangeable),
9.07 (s, 1H, NHx exchangeable), 11.23 (s, 1H, NHy exchangeable), 12.49
1
(s, 1H, NHz exchangeable). H-NMR data shows the existence of this
compound in solution in the thiol form.
General procedure for the reaction of Isatin-3-thiosemicarbazone
(1) with acetylenic ketones (2a–c) or acetylenic esters (4a–c) in
n-butanol. A mixture of 1 (4.9 mmol) and 2a–c or 4a–c (4.9 mmol) was
refluxed in n-butanol (20 ml) for 12 h and the concentrated solution
(10 ml), was left to stand at room temperature overnight to precipitate
a solid which was recrystallized from a suitable solvent to give 3a–c or
5a–c respectively.
4,6-Diphenyl-2-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl]imino-2H-
1,3-thiazine (3a). (70% yield) dark red crystals, m.p. 241–243 C (from
1
1,4-dioxane). IR
3400 (NH), 1705 (C O), 1595, 1560 cm (C N
max
and/or C C). 1H-NMR (DMSO) 6.89–8.42 (m, 15H, ArH+ CH ),
10.82 (s, 1H, NH exchangeable). EIMS m/z (%), 410 (M++2,0.23), 408

182
A. S. A. Youssef
SCHEME 6
(M+, 1.2), 333 (M++2-Ph, 0.17), 331 (M+-Ph, 1), 305 (M++2-Ph CO,
0.48) 303 (M+-Ph CO, 3.2), 290 (M++2-Ph HNCO,0.28), 288 (M+-
Ph HNCO, 1.5), 263 (9), 248 (10), 191 (13), 144 (14), 78 (Base), 77
(21), 52 (10), 51 (14). Anal. Calcd for C24H16N4OS: C, 70.57; H, 3.95; N,
13.71; S, 7.85. Found: C, 70.42; H, 3.87; N, 13.59; S, 7.76%.
4-p-Chlorophenyl-6-phenyl-2-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-
iminyl] imino-2H-1,3-thiazine (3b). (82% yield), dark red crystals,
m.p. 280–282 C (from 1,4-dioxane). IR
3410 (NH), 1700 (C O),
max
1590, 1570 cm (C N and/or C C). 1H-NMR (CDCl3) 6.84–8.50
(m, 14H, ArH + CH ), 10.91 (s, 1H, NH exchangeable). EIMS m/z (%)
442 (M+ + 2,1.4), 440 (M+, 2.43), 297 (10), 273 (21), 272 (17), 271 (50),
249 (10), 248 (48), 227 (11), 225 (28), 221 (18), 190 (11), 189 (17), 146
(11), 145 (13), 144 (27), 134 (12), 118 (18), 116 (12), 91 (10), 90 (14), 89
(36), 88 (Base), 87 (18), 58 (13), 57 (23). Anal. Calcd for C24H15N4OSCl :
1

Isatin-3-Thiosemicarbazones and Acetylenic Ketones
183
C, 65.08; H, 3.41; N, 12.65; S, 7.24. Found: C, 64.95; H, 3.50; N, 12.71;
S, 7.11%.
4-Methoxyphenyl-6-phenyl-2-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-
iminyl] imino-2H-1,3-thiazine (3c). (71% yield), dark red crystals,
m.p. 293–295 C (from 1,4-dioxane). IR
3420 (NH), 1710 (C O),
max
1
1
1590, 1565 cm (C N and/or C C). H-NMR (DMSO) 3.89 (s, 3H,
OMe), 6.91–8.43 (m, 14H, ArH + CH ), 10.75 (s, 1H, NH exchange-
able). EIMS m/z (%) 440 (M++2, 3.03), 438 (M+, 22), 363 (M++2,0.89),
361 (M+-Ph, 7), 335 (M++2-Ph CO, 2.32), 333 (M+-Ph CO, 4), 331
(M+-C6H4OMe-p, 4), 320 (M++2-Ph HNCO, 2.5) 318 (M+-Ph HNCO,
20), 319 (M++2-Ph NCO, 11.7), 317 (M+-Ph NCO, 40), 303, (29), 294
(28), 293 (67), 279 (42), 278 (48), 268 (53), 267 (73), 264 (42), 252 (32),
250 (23), 248 (35), 225 (20), 222 (23), 221 (89), 206 (34), 178 (47), 165
(23), 159 (25), 149 (34), 146 (24), 145 (23), 144 (74), 121 (32), 118 (38),
116 (32), 105 (24), 104 (21), 95 (28), 91 (33), 85 (29), 83 (33), 81 (22), 77
(26), 76 (34), 69 (28), 67 (23), 63 (23), 57 (41), 55 (36), 51 (Base). Anal.
Calcld for C25H18N4O2S: C, 68.48; H, 4.14; N, 12.78; S, 7.31. Found: C,
68.39; H, 4.26; N, 12.85; S, 7.42%.
6-p-Chlorophenyl-2-imino-3-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-
iminyl]-2,3-dihydro-4-oxo-1,3-thiazine (5a). (75% yield), orange crys-
tals, m.p. 277–279 C (from 1,4-dioxane). IR
1705, 1660 (C O), 1610, 1590 cm
3450, 3200 (NH),
max
1
(C N and/or C C). 1H-NMR
(DMSO) 6.83 ( CH), 6.88 (d, Hd, Jdc = 7.8 Hz), 7.02 (t, Hb, Jbc,
Jba = 7.2, 7.6 Hz), 7.37 (t, Hc, Jcd, Jcb = 7.8, 7.6 Hz), 7.63 (d, two ortho
H’s, Jortho = 8.6 Hz), 7.82 (d, two meta H’s, Jortho = 8.6 Hz), 8.44 (d, Ha,
Jab = 7.8 Hz), 10.75 (s, 1H, NH imido, exchangeable), 12.75 (br.s, 1H,
NH imino, exchangeable). EIMS m/z (%) 384 (M++2,12), 382 (M+, 26),
357 (M++2-HNC, 8), 355 (M+-HNC, 26), 356 (M++2-CO, 27.3), 354
(M+-CO, 77), 328 (39), 327 (25), 326 (82), 323 (M+-HNCS, 12), 197 (30),
196 (25), 171 (29), 170 (47), 168 (Base), 165 (25), 163 (57), 162 (27),
161 (39), 155 (29), 149 (35), 148 (35), 147 (58), 146 (21), 145 (24), 144
(25), 139 (22), 137 (61), 136 (40), 133 (43), 132 (46), 131 (27), 119 (82),
118 (56), 105 (22), 104 (48), 103 (62), 92 (60), 91 (28), 89 (33), 87 (28),
77 (27), 76 (32), 64 (22), 62 (34), 58 (22), 57 (20), 55 (20), 51 (32). Anal.
Calcd for C18H11NO2SCl: C, 56.47; H, 2.89; N, 14.63; S, 8.37. Found: C,
56.39; H, 2.91; N, 14.54; S, 8.29%.
6-p-Methoxyphenyl-2-imino-3-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-
iminyl]-2,3-dihydro-4-oxo-1,3-thiazine (5b). (70% yield), brown crys-
tals, m.p. 284–286 C (from 1,4-dioxane). IR
3453, 3130 (NH),
max
1
2923, 2853 (alkyl-H), 1710, 1676 (C O), 1616, 1570 cm (C N and/or
1
C C). H-NMR (DMSO) 3.83 (s, 3H, OMe), 6.71 (s, 1H, CH ), 6.86
(d, Hd, Jcd = 7.8 Hz), 7.00 (t, Hb, Jbc, Jab = 7.2, 7.5 Hz), 7.1 (d, two

184
A. S. A. Youssef
meta H’s, Jortho = 7.8 Hz), 7.36 (t, Hc, Jbc, Jcd = 7.71, 7.8 Hz), 7.74 (d,
two ortho H’s, Jortho = 7.8 Hz), 8.41 (d, Ha, Jab = 7.2 Hz), 10.72 (s, 1H,
NH imido, exchangeable), 12.62 (br.s, 1H, NH imino exchangeable).
EIMS m/z (%) 380 (M++2,0.22), 378 (M+, 1.3), 353 (M++2-HNC, 0.21),
351 (M+-HNC, 1.3), 319 (M+-HNCS, 1), 164 (20), 149 (35), 89 (35), 88
(Base), 57 (31). Anal. Calcd for C19H14N4O3S: C, 60.31; H, 3.73; N,
14.80; S, 8.47. Found: C, 60.22; H, 3.82; N, 14.91; S, 8.58%.
6-Ethoxycarbonyl-2-imino-3-[2-oxo-2H , 3H-benzo(b)pyrrolidine-3-
iminyl]-2,3-dihydro-4-oxo-1,3-thiazine (5c). (85% yield), orange
crystals, m.p. 282–284 C (decomp.), (from 1,4-dioxane). IR
max
3440, 3310 (NH), 1730 (C O) ester, 1710, 1690 (C O) amide, 1610,
1
1570 cm
(C N and/or C C). 1H-NMR (DMSO)
1.27 (t, 3H,
COOCH2CH3, J = 7.7 Hz), 4.27 (q, 2H, COOCH CH3, J = 7.7 Hz), 6.71
(s, H, CH ), 6.89 (d, Hd, Jcd = 7.0 Hz), 7.03 (t, Hb2, Jab, Jbc = 7.4, 7.6 Hz),
7.4 (t, Hc, Jbc, Jcd = 7.6, 7.8 Hz), 8.20 (d, Ha, Jab = 7.4 Hz), 10.83 (s, 1H,
NH imido, exchangeable), 13.27 (br.s, 1H, NH imino exchangeable).
EIMS m/z (%) 346 (M++2,0.81), 344 (M+, 7), 331 (M++2-Me, 1.2) 329
(M+-Me, 2), 315 (M+-Et, 3), 317 (M+-HNC, 4), 301 (M+ +2-OEt, 2.8),
299 (M+-OEt, 5), 273 (M++2-CO2Et, 1.5), 271 (M+-CO2Et, 7), 174 (35),
149 (37), 147 (20), 146 (71), 145 (29), 144 (74), 131 (54), 121 (24), 119
(37), 118 (Base), 116 (27), 105 (41), 104 (22), 97 (23), 95 (38), 91 (56), 87
(20), 85 (33), 81 (34), 79 (21), 77 (28), 71 (28), 69 (39), 67 (28), 57 (41),
55 (38), 51 (46). Anal. Calcd for C15H12N4O4S : C, 52.32 ; H, 3.51 ; N,
16.27 ; S, 9.31. Found: C, 52.41; H, 3.59; N, 16.34; S, 9.46%.
General procedure for the reaction of isatin-3-thiosemicarbazone (1)
with acetylenic esters 4a–c and acetylenic ketones 2a–c in ethanolic
sodium ethoxide. An alcoholic solution of isatin-3-thiosemicarbazone
(1) (5 mmol) in 20 ml of ethanol was added to a solution of the
acetylenic esters 4a–c or acetylenic ketones 2a–c (5 mmol) and sodium
ethoxide (0.12 g Na) in ethanol (20 ml) and the mixture was refluxed
for 1 h.
In case of 1 with 4a–c, the reaction mixture was poured into ice
cold water to give a precipitate which was recrystallized from a proper
solvent to give 6a–c. The aqueous solution was acidified with conc. HCl
to give unreacted 1.
6-p-Chlorophenyl-3-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl]-4-oxo-
2-thioxo-1,2,4-trihydropyrimidine (6a). (71% yield), orange crystals,
m.p. >320 C (from 1,4-dioxane). IR
3401, 3363 (NH), 1710, 1689
max
(C O), 1604, 1535 (C N and/or C C), 1119 cm (C S). 1H-NMR
(DMSO) 6.62 (s, 1H, CH ), 6.79–7.74 (m, 9H, ArH + NH), 10.51 (s,
1H, NH imido, exchangeable). EIMS m/z (%) 384 (M++2, 0.15), 382
1

Isatin-3-Thiosemicarbazones and Acetylenic Ketones
185
(M+, 1), 325 (M++2-HNCS, 0.12), 323 (M+-HNCS, 0.89), 273 (M++2-
C6H4Cl-p, 0.25), 271 (M+-C6H4Cl-p, 0.78), 257 (M++2-C6H4Cl-p NH,
12.24), 255 (M+-C6H4Cl-p NH, 39), 248 (M++2-CH C C6H4Cl, 0.32),
246 (M+-CH C C6H4Cl-p, 0.38), 227 (M+-CH C C6H4Cl-p C S,
19), 213 (M+-CH C C6H4Cl-p SH, 16), 141 (28.98), 139 (94.96), 138
(CH C C6H4Cl-p, 38.1), 136 (CH C C6H4Cl-p, Base), 104 (13), 103
(20), 77 (10), 76 (16), 75 (21), 74 (11). Anal. Calcd for C18H11N4O2SCl:
C, 56.47; H, 2.89; N, 14.63; S, 8.37. Found: C, 56.52; H, 2.92; N, 14.71;
S, 8.45%.
6-p-Methoxyphenyl-3-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl]-4-
oxo-2-thioxo-1,2,4-trihydropyrimidine (6b). (65% yield), brown crys-
tals, m.p. >300 C (from dil. dioxane). IR
3444, 3252 (NH), 1715,
max
1650 (C O), 1618, 1586 (C N and/or C C), 1135 cm 1 (C S). 1H-NMR
(CDCl3) 3.8 (s, 3H, OMe), 6.69 (s, 1H, CH ), 6.82–8.23 (m, 9H, ArH
+ NH), 10.79 (br.s, 1H, NH imido, exchangeable). EIMS m/z (%) 380
(M++2,0.4), 378 (M+,1), 235 (31), 188 (25), 160 (Base), 159 (37), 145
(19), 133 (14), 132 (66), 117 (13), 104 (65), 77 (41), 76 (13), 75 (15), 51
(22). Anal. Calcd for C19H14N4O3S: C, 60.31; H, 3.73; N, 14.80; S, 8.47.
Found: C, 60.42; H, 3.69; N, 14.86; S, 8.51%.
6-Ethoxycarbonyl-3-[2-oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl]-4-oxo-
2-thioxo-1,2,4-trihydropyrimidine (6c). (80% yield), orange red cry-
stals, m.p. >320 C (from n-butanol). IR
3487, 3228 (NH), 2932,
max
1
2854 (alkyl-H), 1722 (C O), 1627, 1589 (C N and/or C C), 1059 cm
(C S). 1H-NMR (DMSO) 1.35 (t, 3H, COOCH2CH3, J = 7.72 Hz), 4.31
(q, 2H, COOCH2CH3, J = 7.72 Hz), 6.47–8.36 (m, 5H, ArH + CH ),
10.59 (br.s, 1H, NH thioimido, exchangeable), 10.79 (s, 1H, NH imido,
exchangeable). EIMS m/z (%) 346 (M++2, 0.02), 344 (M+, 0.5), 331
(M++2-CH3, 0.18), 329 (M+-CH 3,1), 285 (M++HNCS, 0.13), 273
(M++2-CO2C2H5, 0.18), 271 (M+-CO2C2H5, 0.5), 262 (M++2-
CH C CO2C2H5, 0.36), 260 (M+-CH C CO2C2H5, 7), 258 (M++2-
CO2C2H5 NH, 0.62), 256 (M++2-CO2C2H5 NH, 1.54), 227 (M+-
CO2C2H5 C S, 1.1), 145 (1.7), 144 (67), 118 (Base), 117 (11), 116
(22), 104 (10), 91 (34), 64 (13), 63 (18), 55 (12). Anal. Calcd for
C15H12N4O4S:C, 52.32; H, 3.51; N, 16.27; S, 9.31. Found: C, 52.18; H,
3.62; N, 16.34; S, 9.25%.
In case of 1 with 2a–c, the reaction mixture was poured into ice
cold HCl, extracted with CHCl3 and the combined extract was con-
centrated and chromatographed over silica gel. Elution with diethyl
ether petroleum b.p. 40–60 (1:5 v/v) gave 1-phenyl-3-arylpropan-1,3-
diones which were identified by TLC and mixed m.p.’s with authentic
specimens29 prepared by refluxing an alcoholic solution of acetylenic
ketones 2a–c with dil. HCl.

186
A. S. A. Youssef
Conversion of the iminothiazine (5c) to the pyrimidine-2-thione (6c).
An ethanolic solution of 2-iminothiazine (5c) (0.2 g, 0.6 mmol) in 10 ml
ethanol was added to solution of sodium ethoxide (0.04 g Na in 5 ml
ethanol) and the mixture was refluxed for 1 h. The reaction mixture
was poured into ice cold HCl to give a solid. Recrystallization from
n-butanol gave an orange crystals which proved to be 6c by TL, m.p
and mixed m.p.
Reaction of Isatin-3-thiosemicarbazone (1) with 1-p-chlorophenyl-3-
phenylprop-2-yn-1-one (2b) in ethanol. To a solution of the thiosemi-
carbazone (1) (2.3 mmol) in ethanol (15 ml) was added a solution of
the acetylenic ketone (2b) (2.3 mmol) in ethanol (10 ml) and the whole
mixture was heated over water bath for 15 h. On leaving the reaction
mixture to stand at room temperature overnight, it gave a solid which
was fractionally crystallized to give 7 and (8).
2,4,6-Tris [2-oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl]amino-1,3,5-
triazine (7). (13% yield), red crystals, m.p. 295–297 C (from 1,4-
1
dioxane). IR
3440, 3250 (NH), 1710 (C O), 1600, 1560 cm (C N
max
and/or C C). 1H-NMR (DMSO) 6.91–7.54 (m, 5H, ArH + NH amino),
11.05 (br.s, 1H, NH imido exchangeable). EIMS m/z (%) 558 (M+,
0.22), 467 (M+ 91, 1.1), 372 (M+ 186, 1), 371 (M+-H, 6), 290 (37),
240 (27), 234 (35), 214 (25), 212 (67), 176 (23), 146 (44), 145 (21), 144
(46), 133 (45), 129 (47), 119 (22), 118 (Base), 117 (21), 104 (52), 103
(51), 91 (41), 90 (21), 76 (46), 75 (34), 63 (33), 51 (22). Anal. Calcd for
C18H12N8O2:C, 58.06; H, 3.25; N, 30.09. Found: C, 57.92; H, 3.18; N,
30.19%.
(Z,Z)-3,30-Thiodi-(1-p-chlorophenylprop-2-en-1-one) (8). (10% yield),
orange crystals, m.p. 199–200 C (lit.5 m.p. 199) (from EtOH), it was
identified through TLC and mixed m.p. with authentic specimen pre-
pared from the reaction of 1-p-chlorophenyl-3-phenylprop-2-yn-1-one
with thiourea in ethanol at room temperature.
Reactions of 1,3-thiazine derivatives 3a–c or pyrimidine-2-thione
derivatives 6a,c with hydrazine hydrate. Hydrazine hydrate (1 ml) was
refluxed for 3 h with an ethanolic solution of 3a–c, 6a, or 6c (0.5 g),
odor of H2S gas was smelled during the reaction. The reaction mixture
was concentrated (3.0 ml) and chromatographed over silica gel. In case
of 3c, 6a, and 6c), elution with petroleum ether (b.p. 40–60/ether) (2/1
v/v) gave the diaziridine imine 9.
However, in the case of 3a and 3b, the concentrated reaction mixture
gave a solid which was then recrystallized from a suitable solvent to give
the pyrazole derivatives 10a and 10b.

Isatin-3-Thiosemicarbazones and Acetylenic Ketones
187
(2-Oxo-2H,3H-benzo(b)pyrrolidine-3-iminyl) diaziridineimine (9).
(30% yield), yellow crystals, m.p. 210–212 C (from ethanol/benzene). IR
max 3357, 3156 (NH), 1686 (C O), 1657, 1586 cm 1 (C N and/or C C).
1H-NMR (DMSO) 6.87 (d, Hd, Jcd = 7.8 Hz), 6.98 (t, Hb, Jbc, Jba
=
7.4, 7.8 Hz), 7.17 (t, Hc, Jcd, Jcb = 7.6, 7.8 Hz), 7.37 (d, Ha, J = 7.4 Hz),
9.57 (d, 1H, NHa, J = 15.2 Hz, exchangeable), 10.56 (d, 1H, NHb,
J = 15.0 Hz exchangeable), 10.70 (br.s, 1H, NH imido, exchangeable).
EIMS m/z (%) 201 (M+, 0.5), 161 (M+ 40, 98), 133 (30), 118 (14), 105
(32), 104 (Base), 91 (13), 90 (28), 79 (13), 78 (31), 77 (29), 76 (18), 75 (12),
64 (19), 63 (25), 62 (13), 53 (10), 52 (28), 51 (36), 50 (32). Anal. Calcd
for C9H7N5O:C, 53.73; H, 3.51; N, 34.81. Found: C, 53.81; H, 3.59; N,
34.79%.
3,5-Diphenylpyrazole (10a). m.p. 199–200 C, (lit.30 m.p. 199), unde-
pressed on admixture with an authentic specimen prepared by treating
2a with hydrazine hydrate.31,32
3(5)-p-Chlorophenyl-5(3)-phenylpyrazole (10b). m.p. 214–215 C
(lit,31 m.p. 214–215 C), undepressed on admixture with an authentic
specimen31 obtained by the reaction of 2a with hydrazine hydrate.
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