Cytotoxicity and utility of 1-indanone in the synthesis of some new heterocycles

Article abstract of DOI:10.1248/cpb.58.479

Benzo[d]imidazole 3 and 1,2,4-triazin-5(2H)-one 6 were prepared by the reaction of starting ethyl (3-hydroxy-1H-inden-2-yl)(oxo)-acetate 2 with o-phenylenediamine and thiosemicarbazide respectively. Reaction of 1,4-dihydro-1-phenylindeno[1,2-c]pyrazole-3-

Full text of DOI:10.1248/cpb.58.479

April 2010
Chem. Pharm. Bull. 58(4) 479—483 (2010)
479
Cytotoxicity and Utility of 1-Indanone in the Synthesis of Some New
Heterocycles
Bahira HEGAZI,a Hanan Ahmed MOHAMED,*,a Kamal Mohamed DAWOOD,b and
c
Farid Abdel-Rahem BADRIA
a Applied Organic Chemistry Department, National Research Centre; Dokki, Giza 12622, Egypt: b Chemistry Department,
Faculty of Science, Cairo University; Giza 12613, Egypt: and c Pharmacognosy Department, Faculty of Pharmacy,
Mansoura University; Mansoura 35516, Egypt. Received November 7, 2009; accepted December 14, 2009
Benzo[d]imidazole 3 and 1,2,4-triazin-5(2H)-one 6 were prepared by the reaction of starting ethyl (3-
hydroxy-1H-inden-2-yl)(oxo)-acetate 2 with o-phenylenediamine and thiosemicarbazide respectively. Reaction
of 1,4-dihydro-1-phenylindeno[1,2-c]pyrazole-3-carbohydrazide 8 with phenylisothiocyanate gave thiosemicar-
bazide 9, and its reaction with chloroacetic acid or phenacylbromides led to the formation of thiazolidinone-4-
one 10 or 1,3-thiazoles 12a, b. The reactivity of hydrazide 8 towards fluorinated aldehyde, phthalic anhydride,
and hydrazonoyl chlorides 15a, b was studied to give fluorinated hydrazones, imide bis-hydrazones 13—16. The
newly synthesized compounds were screened for their cytotoxic activities and compounds 6, 8, 9 and 10 were
found the most potentially cytotoxic. The detailed synthesis, spectroscopic and biological data are reported.
Key words 1-indanone; pyrazole; hydrazide; 1,3-thiazole; hydrazonoyl chloride; cytotoxic and antitumor activity
Diketo-esters, the acylation products of active methylene form 2ꢀ, was prepared by reacting the 1-indanone 1 with di-
components with dialkyl oxalate, are valuable multi-purpose ethyl oxalate in the presence of sodium ethoxide according to
intermediates in organic synthesis and their preparation is reported methods.17,18)
well documented. 2,4-Diketo-esters are used in the produc-
It has been reported that the condensation of o-phenylene-
tion of (e.g.) pyrazole-3(5)-ethyl esters and their derivatives diamine with aroylpyruvates led to the synthesis of benzimi-
which are known to be important intermediates in the prepa- dazole nucleus10,19) or quinoxalin-2-one,20) while its conden-
ration of agrochemicals, microbicides, herbicides,1—3) plant sation with ethyl 2-(1,2,3,4-tetrahydro-1-oxonaphthalen-2-
growth regulators and protectants4); they are also used in the yl)-2-oxoacetate gave benzo-1,4-diazepine.21,22) Based on the
production of the 3(2H)-furanone ring system which is the previous literature we report here the reaction of ethyl (3-hy-
key skeletal element of many natural product antitumor droxy-1H-inden-2-yl)(oxo)-acetate 2 with o-phenylenediamine
agents.5) Recently, emphasis has been placed on synthesizing which furnished benzimidazole 3 (Chart 1).
pyrazoles having novel functional groups attached either to
The structure of the benzimidazole derivative 3 was based
C-3 or C-5 of the ring6—10) due to their proven usefulness as on spectral and analytical data. The mass spectrum of 3 dis-
intermediates in the preparation of new biological materials. played the molecular ion peak at m/z 278, which is assigned
For example, compounds including a pyrazole nucleus are to Mꢁꢁ2. H-NMR also confirmed the assigned structure of
1
potential human immunodeficiency virus-1 (HIV-1) in- 3 and excluded the structures 4 and 5. The 1H-NMR of 3 dis-
hibitors,11) insecticides,12) fungicides,12) antiviral agents13) played two singlet protons at 11.87 and 13.45 ppm, assigned
and anticancer activity.14) In relation with the above consider- to NH and OH protons respectively.
ations and in continuation of our previous work in the synthe-
It is reported that aroylpyruvates were condensed with S-
sis of biologically active heterocycles,15,16) we synthesized a methylisothiosemicarbazide hydroiodide in pyridine to give
series of new heterocycles using 1-indanone as synthon for 1,2,4-triazin-5(2H)-ones in moderate to good yields.23) Thus,
evolution of their cytotoxic and antitumor activity.
condensation of ethyl (3-hydroxy-1H-inden-2-yl)(oxo)-ace-
Chemistry Chart 1 outlines the synthetic pathway lead- tate 2 with thiosemicarbazide in refluxing ethanol containing
ing to benzo[d]imidazole 3. Ethyl 2-(2,3-dihydro-1-oxo-1H- a catalytic amount of hydrochloric acid afforded the corre-
inden-2-yl)-2-oxoacetate 2, which is present in tautomeric sponding 1,2,4-triazin-5(2H)-one 6 in 75% yield (Chart 2).
The chemical structure of 6 was well supported by spectral
data such as IR, NMR, mass and elemental analysis. In the
IR spectrum of 6, a broad absorption bands in the 3303—
3146 cmꢂ1 indicates the presence of OH and 2NH groups in
the compound, and its 1H-NMR spectrum showed a singlet at
d 8.69, 9.59 and 12.89 ppm due to the 2NH and OH protons
respectively. In addition, the mass spectrum of 6 showed a
peak corresponding to Mꢁꢁ2 at m/z 261.
Compound 2 was condensed with the phenylhydrazine
hydrochloride to afford the known ethyl 1-phenyl-1,4-dihy-
droindeno[1,2-c]pyrazole-3-carboxylate 7.24) Treatment of
pyrazole-3-carboxylate 7 with excess hydrazine hydrate in
refluxing ethanol gave the new hydrazide 8 in excellent yield
(Chart 2).
Chart 1. Reaction of Diketo-ester with o-Phenylenediamine
© 2010 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: hananm_2004@yahoo.com

480
Vol. 58, No. 4
The chemical structure of hydrazide 8 was confirmed by robenzylidene)-4-oxo-3-phenylthiazolidines 11 in good yield.
spectral data and elemental analysis. In the IR spectrum of 8, The one pot synthesis of 5-(4-fluorobenzylidene)-4-oxo-
a broad absorption bands around 3312—3053 cmꢂ1 indicates 3-phenylthiazolidines 11 was also achieved by refluxing
the presence of NH and NH2 groups in the compound, and its equimolar amounts of thiosemicarbazide 9, chloroacetic acid
1H-NMR spectrum showed a singlet at d 4.50 and 9.50 ppm and 4-flourobenzaldehyde in glacial acetic acid having an ex-
due to the NH2 and NH protons, respectively. In addition, the cess amount of fused sodium acetate. Treatment of thiosemi-
mass spectrum of hydrazide 8 showed a peak corresponding carbazide 9 with phenacylbromides, namely, phenacylbro-
to its molecular ion peak at m/z 290.
mide and 4-chlorophenacylbromide, in ethanol containing
Acid hydrazides can be considered as useful intermediates excess of anhydrous sodium acetate afforded 1,3-thiazole de-
leading to the formation of several heterocycles.25—28) Acid rivatives 12a,b in 62 and 75% yields (Chart 3).
hydrazides have long been known to react with isothio-
The IR spectrum of 10 showed an absorption band at
cyanates and a-haloketones to afford a variety of hetero- 1715 cmꢂ1 due to the carbonyl function of thiazolidinone moi-
cyclic derivatives.29—33) Thus, reaction of hydrazide 8 with ety, the mass spectrum of 11 showed a peak corresponding
phenyl isothiocyanate in absolute ethanol afforded thiosemi- to its molecular ion peak at m/z 571, while the H-NMR
1
carbazides 9 in 89% yield. Condensation of the latter with of compound 12b showed a singlet signal in the region
chloroacetic acid in glacial acetic acid having an excess 7.01 ppm corresponding to C-5 proton of the thiazole ring.
amount of fused sodium acetate afforded thiazolidin-4-one
Treatment of acid hydrazide 8 with 4-fluorobenzaldehyde
10 in moderate yield. Refluxing of 4-thiazolidinone 10 with in refluxing ethanol having a catalytic amount of glacial
4-flourobenzaldehyde in glacial acetic acid in the presence of acetic acid afforded the corresponding hydrazones 13 in 80%
1
an excess amount of fused sodium acetate yielded 5-(4-fluo- yield (Chart 4). The H-NMR of 13 showed a singlet proton
at 8.68 ppm attributed to –CHꢃN–. Treatment of carbohy-
drazide 8 with phthalic anhydride in refluxing glacial acetic
acid furnished the corresponding imide 14 in 48% yield. The
IR spectrum of 14 showed absorption bands at 1785, 1735,
1690 cmꢂ1 characteristic of the three carbonyl groups, and its
mass spectrum showed its molecular ion peak at m/z 420.
Reaction of hydrazide 8 with hydrazonoyl chlorides 15a, b
in refluxing neutral medium give the extra pure bis-hydra-
zono compounds 16a, b in good yields. The formation of bis-
hydrazono compounds 16a, b was indicated by the absence
of one carbonyl band in the IR spectra and appearance of two
1
singlet NH protons around d 10.21, and 10.52 in their H-
NMR spectra.
Cytotoxic Activity34,35) The stock samples were diluted
with Dulbecco’s Modified Eagle’s Medium (DMEM) to de-
sired concentrations ranging from 1 to 100 mg/ml. The final
concentration of dimethyl sulfoxide (DMSO) in each sample
Chart 2
did not exceed 1% v/v. The cytotoxic activity of the com-
Chart 3. Synthesis of 1,3-Thiazoles

April 2010
481
Table 2. Perecentage Viability of Tested Compounds on Different Cell
Lines
% viability
Concentration
Compound
(10—100 mg/ml)
HEPG2 WI 38 VERO MCF 7
3
6
8
9
10
100
100
100
100
100
100
100
100
100
100
100
20
81
19
22
24
22
79
81
78
92
79
12
12
14
16
74
79
92
89
88
79
5
77
65
18
27
30
80
77
95
78
93
83
8
89
21
20
38
28
84
89
92
95
11
12a
12b
13
16a
16b
5-FU
84
78
Zero
90
82
Zero
tor (Sheldon, TC2323, Cornelius, OR, U.S.A.). The medium
was aspirated, fresh medium (without serum) was added and
cells were incubated either alone (negative control) or with
different concentrations of sample to give a final concentra-
tion of (100—50—20—10—5—2 and 1 mg/ml). Cells were
suspended in DMEM medium, 1% antibiotic-antimycotic mix-
ture (10000 U/ml potassium penicillin, 10000 mg/ml strepto-
mycin sulfate and 25 mg/ml Amphotericin B) and 1% L-glut-
amine in 96-well flat bottom microplates at 37 °C under 5%
CO2. After 96 h of incubation, the medium was again aspi-
rated, trays were inverted onto a pad of paper towels, the re-
maining cells rinsed carefully with medium, and fixed with
3.7% (v/v) formaldehyde in saline for at least 20 min. The
fixed cells were rinsed with water, and examined. The cyto-
toxic activity was identified as confluent, relatively unaltered
monolayers of stained cells treated with compounds. Cyto-
toxicity was estimated as the concentration that caused ap-
proximately 50% loss of the monolayer. The assay was used
to examine the newly synthesized compounds. 5-Fluoruracil
was used as a positive control.
Cytotoxicity results are summarized in Table 2. The sam-
ples were classified into 2 categories based on their cytotox-
icity. Compounds 6, 8, 9 and 10 were potentially cytotoxic
(% viability in HEPG2, WI38 and MCF7 cell lines 40 mg/ml)
while other compounds were moderately cytotoxic (40 mg/
mlꢅ% viabilityꢅ100 mg/ml). Viro cell compounds 8, 9 and
10 had potential cytotoxicity. The compound samples in the
first category were used for a further bioassay guided experi-
ment.
Chart 4. Different Reactions with Hydrazide
Table 1. Characteristics of the Synthesized Compounds
Calculated
Compd. Formula
(Found)
mp,
°C
Yield,
%
No.
(MW)
C
H
N
3
6
8
9
C17H12N2O2
(276.09)
C12H9N3O2S
(259.04)
C17H14N4O
(290.12)
C24H19N5OS
(425.13)
C26H19N5O2S
(465.13)
C33H22FN5O2S
(571.15)
73.90
4.38
10.14
ꢆ300
83
62
86
89
45
(74.19) (4.42) (10.29)
55.59 3.50 16.21
(55.69) (3.46) (16.18)
70.33 4.86 19.30
(70.52) (4.64) (19.58)
67.74 4.50 16.46
(67.44) (4.65) (16.17)
67.08 4.11 15.04
(67.18) (4.39) (15.25)
69.34 3.88 12.25
(69.23) (3.67) (12.37)
73.12 4.41 13.32
(73.21) (4.55) (13.47)
68.62 3.96 12.50
(68.69) (3.83) (12.66)
72.72 4.32 14.13
(72.79) (4.38) (14.33)
71.42 3.84 13.33
(71.61) (3.91) (13.38)
66.59 4.51 17.92
(66.63) (4.61) (17.99)
64.13 4.14 17.26
(64.26) (4.29) (17.31)
275—276
165—167
210—212
235—237
10
11
212—214 53 (a)
48 (b)
12a C32H23N5OS
(525.16)
12b C32H22ClN5OS
(559.12)
260—261
271—272
185—186
255—257
271—272
260—262
62
75
80
48
68
79
13
C24H17FN4O
(396.14)
C25H16N4O3
(420.12)
14
16a C26H21ClN6O
(468.15)
16b C26H20ClFN6O
(486.14)
Conclusion
New benzimidazole, 1,2,4-triazin-5(2H)-one, 4-thiazolidi-
none, 1,3-thiazole, hydrazone, imide and bis-hydrazone de-
pounds was tested against malignant human hepatoma rivatives were prepared using 1-indanone as starting material.
(HepG2) cell line, human lung fibroblast cell line (WI38), The cytotoxicity of newly synthesized compounds was iden-
human Caucasian breast adenocarcinoma (MCF-7) and nor- tified; compounds 6, 8, 9 and 10 are the most potentially cy-
mal African green monkey kidney (Vero) cell line. The % vi- totoxic.
ability of cells was examined visually. 5-Fluoruracil was used
as a standard anticancer drug for comparison.
Experimental
Chemistry All melting points were taken on Electrothermal IA 9000
series digital melting point apparatus. Elemental analytical data (in accord
with the calculated values) were obtained from the microanalytical unit,
Cairo University, Giza, Egypt. The IR spectra (KBr) were recorded on a Shi-
Briefly, cells were batch cultured for 10 d, then seeded in
96 well-plates of 10ꢄ103 cells/well in fresh complete growth
medium in 96-well microtiter plastic plates at 37 °C for 24 h
under 5% CO2 using a water jacketed carbon dioxide incuba- madzu CVT-04 spectrophotometer. The H-NMR spectra were recorded at
1

482
Vol. 58, No. 4
270 MHz on a Varian EM-360 spectrometer using tetramethyl silane (TMS) tallized from EtOH/DMF to give the corresponding carbohydrazides 12a, b.
as an internal standard. Chemical shift (d) values are given in parts per mil-
Nꢀ-(3,4-Diphenylthiazol-2(3H)-ylidene)-1-phenyl-1,4-dihydroindeno[1,2-
lion. The mass spectra were determined using a Varian MAT CH-5 spec- c]pyrazole-3-carbohydrazide 12a: IR (KBr) nmax/cmꢂ1 3248 (NH), 1642
trometer (70 eV). Ethyl (3-hydroxy-1H-inden-2-yl)(oxo)-acetate 217,18); ethyl
1-phenyl-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxylate 7,24) hydrazonoyl
chlorides36) were prepared according to the procedures reported in the litera-
ture.
2-[(1H-Benzimidazol-2-yl)(hydroxy)methylene]-2,3-dihydro-1H-
inden-1-one 3 A solution of ethyl 2-(2,3-dihydro-1-oxo-1H-inden-2-yl)-2-
(CꢃO); H-NMR (DMSO-d6) d: 3.90 (s, 2H, indane-3-CH2), 7.03 (s, 1H,
thiazole-H), 7.13—7.95 (m, 19H, ArH), 11.15 (s, 1H, NH, D2O-exchange-
able).
1
Nꢀ-(4-(4-Chlorophenyl)-3-phenylthiazol-2(3H)-ylidene)-1-phenyl-1,4-di-
hydroindeno-[1,2-c]pyrazole-3-carbohydrazide 12b: IR (KBr) nmax/cmꢂ1 1648
(CꢃO), 3245 (NH); 1H-NMR (DMSO-d6) d
: 3.92 (s, 2H, indane-3-CH2), 7.01
oxoacetate 2 (4.64 g, 20 mmol) and o-phenylenediamine (2.48 g, 23 mmol) (s, 1H, thiazole-H), 7.18—7.91 (m, 18H, Ar-H), 11.10 (s, 1H, NH, D2O ex-
in glacial acetic acid (30 ml) was refluxed for 4 h. The formed reddish or- changeable).
ange precipitate was isolated by filtration, washed with ethanol, dried and re-
crystallized from AcOH–H2O (2 : 1, v/v). IR (KBr) nmax/cmꢂ1 3161 (NH),
1687 (CꢃO); 1H-NMR (DMSO-d6) d: 4.09 (s, 2H, indane-3-CH2), 7.05—7.67
(m, 8H, ArH), 11.87 (s, 1H, NH, D2O exchangeable), 13.45 (s, 1H, OH, D2O
exchangeable); MS m/z (%) 278 (Mꢁꢁ2, 22), 277 (Mꢁꢁ1, 16), 64 (100).
6-(3-Hydroxy-1H-inden-2-yl)-3-thioxo-3,4-dihydro-1,2,4-triazin-
5(2H)-one 6 To a solution of ethyl 2-(2,3-dihydro-1-oxo-1H-inden-2-yl)-
2-oxoacetate 2 (2.32 g, 10 mmol) and thiosemicarbazide (0.91 g, 10 mmol) in
absolute ethanol (20 ml), three drops of conc. HCl were added and the reac-
tion mixture was refluxed for 5 h. The formed yellow precipitate was iso-
lated by filtration, washed with ethanol, dried and recrystallized from
Nꢀ-(4-Fluorobenzylidene)-1,4-dihydro-1-phenylindeno[1,2-c]pyrazole-
3-carbohydrazide 13 A mixture of 8 (0.29 g, 1 mmol) and 4-flurobenz-
aldehyde (0.12 g, 1 mmol) in absolute ethanol (30 ml) in the presence of few
drops of glacial acetic acid was refluxed for 4 h. The formed solid was fil-
tered off, washed with ethanol dried and crystallized from EtOH/DMF (3 : 1,
1
v/v). IR (KBr) nmax/cmꢂ1 3191 (NH), 1693 (CꢃO); H-NMR (DMSO-d6) d:
3.92 (s, 2H, indane-3-CH2), 7.31—7.92 (m, 13H, ArH), 8.68 (s, 1H,
–CHꢃN), 11.77 (s, 1H, NH, D2O-exchangeable); MS m/z (%) 397 (Mꢁꢁ1,
23), 244 (100).
1,4-Dihydro-N-(1,3-dioxoisoindolin-2-yl)-1-phenylindeno[1,2-c]pyra-
zole-3-carboxamide 14 A mixture of 8 (0.29 g, 1 mmol) and phthalic an-
DMF–H2O (5 : 1, v/v) to give 6. IR (KBr) nmax/cmꢂ1 3303 (OH), 3224, 3146 hydride (0.15 g, 1 mmol) in glacial acetic acid (20 ml) was refluxed for 8 h.
1
(2NH), 1640 (CꢃO); H-NMR (DMSO-d6) d: 3.92 (s, 2H, indane-3-CH2),
The formed solid was filtered off, dried, and crystallized from AcOH/H2O
7.39—7.74 (m, 4H, ArH), 8.69 (s, 1H, NH, D2O-exchangeable), 9.59 (s, 1H, (3 : 1, v/v). IR (KBr) nmax/cmꢂ1 3067 (NH), 1785, 1735, 1690 (3CꢃO); H-
1
NH), 12.89 (s, 1H, OH); MS m/z (%) 261 (Mꢁꢁ2, 46), 277 (Mꢁꢁ1, 16), 55 NMR (DMSO-d6) d: 3.85 (s, 2H, indane-3-CH2), 7.36—8.13 (m, 13H,
(100).
ArH), 10.97 (s, 1H, NH, D2O-exchangeable); MS m/z (%) 420 (Mꢁ, 33),
1,4-Dihydro-1-phenylindeno[1,2-c]pyrazole-3-carbohydrazide 8 Hy- 259 (100).
drazine hydrate (1.0 g, 20 mmol) was added to ethyl 1,4-dihydro-1-phenylin-
deno[1,2-c]pyrazole-3-carboxylate 7 (3.04 g, 10 mmol) in absolute ethanol
Synthesis of the Bis-hydrazones 16a, b A mixture of 8 (0.29 g, 1
mmol) and appropriate hydrazonoyl chlorides 15a, b (1 mmol) in absolute
(40 ml). The reaction mixture was heated under reflux for 4 h and was then ethanol (30 ml) was refluxed for 4 h. The formed solid was filtered off, dried,
left to cool to room temperature. The precipitate that formed was filtered off, and crystallized from EtOH/DMF (2 : 1).
dried and recrystallized from ethanol. IR (KBr) nmax/cmꢂ1 3312—3153
Nꢀ-Phenyl-2-(2-(1-phenyl-1,4-dihydroindeno[1,2-c]pyrazole-3-car-
1
(NH2, NH), 1669 (CꢃO); H-NMR (DMSO-d6) d: 3.81 (s, 2H, indane-3-
bonyl)hydrazono)propanehydrazonoyl Chloride 16a: IR (KBr)
n
max/cmꢂ1
CH2), 4.50 (s, 2H, NH2, D2O-exchangeable), 7.33—7.81 (m, 9H, ArH), 9.50 3242—3055 (2NH), 1682 (CꢃO); 1H-NMR (DMSO-d6) d: 2.38 (s, 3H,
(s, 1H, NH, D2O-exchangable); MS m/z (%) 290 (Mꢁ, 35), 259 (100).
N-Phenyl-2-(1-phenyl-1,4-dihydroindeno[1,2-c]pyrazole-3-carbon- NH, D2O-exchangeable), 10.49 (s, 1H, NH, D2O-exchangeable).
CH3), 3.95 (s, 2H, indane-3-CH2), 7.28—7.69 (m, 14H, ArH), 10.16 (s, 1H,
yl)hydrazine-carbothioamide 9 A mixture of 8 (1.45 g, 5 mmol) and
Nꢀ-(4-Fluorophenyl)-2-(2-(1-phenyl-1,4-dihydroindeno[1,2-c]pyrazole-3-
phenylisothiocyanate (0.67 g, 5 mmol) in absolute ethanol (30 ml) was
carbonyl)hydrazono)propanehydrazonoyl Chloride 16b: IR (KBr) nmax/cmꢂ1
heated under reflux for 1 h. The formed solid was filtered off, washed with 3246, 3159 (2NH), 1685 (CꢃO); 1H-NMR (DMSO-d6) d: 2.34 (s, 3H, CH3),
ethanol, dried and recrystallized from EtOH/N,N-dimethylformamide (DMF)
3.90 (s, 2H, indane-3-CH2), 7.26—7.71 (m, 13H, ArH), 10.21 (s, 1H, NH,
(3 : 1, v/v). IR (KBr) nmax/cmꢂ1 3209—3107 (3NH), 1642 (CꢃO); 1H-NMR D2O-exchangeable), 10.52 (s, 1H, NH, D2O-exchangeable); MS m/z (%) 486
(DMSO-d6) d: 3.36 (s, 2H, indane-3-CH2), 7.11—7.51 (m, 14H, ArH), 9.45 (Mꢁ, 5), 149 (100).
(s, 1H, NH, D2O-exchangeable), 9.87 (s, 1H, NH, D2O-exchangeable), 10.20
(s, 1H, NH, D2O-exchangeable); MS m/z (%) 427 (Mꢁꢁ2, 8), 426 (Mꢁꢁ1,
Acknowledgements The authors would like to thank Abdelbasset A.
Farahat, Chemistry Department, Georgia State University, Atlanta, Georgia,
12), 426 (Mꢁ, 23), 259 (100).
1,4-Dihydro-Nꢀ-(4-oxo-3-phenylthiazolidin-2-ylidene)-1-phenylin- U.S.A. for recording some of 1H-NMR spectra.
deno[1,2-c]pyrazole-3-carbohydrazide 10
A mixture of 9 (0.425 g,
1 mmol) and chloroacetic acid (0.1 g, 1 mmol) in glacial acetic acid (30 ml)
containing anhydrous sodium acetate (0.33 g, 4 mmol) was heated under re-
flux for 6 h. The reaction mixture was cooled and the resulting precipitate
References
1) Moser H., Boehner B., Foery W., European Patent, EP 268, 554,
Chem. Abstr., 110, 23879 (1988).
was filtered off and recrystallized from ethanol to give 10. IR (KBr) nmax
/
2) Ishii T., Shimortori H., Tanaka Y., Ishikawa K., Japan Patent, JP 01,
168, 675, Chem. Abstr., 112, 35854 (1989).
3) Sekine M., Japan Patent, JP 02, 292, 263, Chem. Abstr., 114, 185497
(1990).
cmꢂ1 3227 (NH), 1651, 1715 (2CꢃO); 1H-NMR (DMSO-d6) d: 3.92 (s, 2H,
indane-3-CH2), 6.92 (s, 2H, thiazolidine-H), 7.29—7.83 (m, 14H, ArH),
9.87 (s, 1H, NH, D2O-exchangeable).
Nꢀ-[5-(4-Fluorobenzylidene)-4-oxo-3-phenylthiazolidin-2-ylidene]-1,4-
dihydro-1-phenylindeno[1,2-c]pyrazole-3-carbohydrazide 11 Method
A: To a solution of 4-thiazolidinone 10 (0.465 g, 1 mmol) and 4-flurobenz-
aldehyde (0.12 g, 1 mmol) in glacial acetic acid (20 ml), anhydrous sodium
acetate (0.33 g, 4 mmol) was added and the reaction mixture was refluxed for
5 h then left to cool at room temperature. The formed solid was filtered off,
dried and recrystallized from EtOH.
Method B: A mixture of 9 (0.425 g, 1 mmol), chloroacetic acid (0.1 g,
1 mmol) and 4-flurobenzaldehyde (0.12 g, 1 mmol) in glacial acetic acid
(20 ml) containing anhydrous sodium acetate (0.33 g, 4 mmol) was heated
under reflux for 5 h. The reaction mixture was left to cool and the formed
solid was filtered off, washed with water, dried and recrystallized from
EtOH. IR (KBr) nmax/cmꢂ1 3230 (NH), 1656, 1692 (2CꢃO); 1H-NMR
(DMSO-d6) d: 3.86 (s, 2H, indane-3-CH2), 7.28—7.86 (m, 18H, ArH), 11.85
(s, 1H, NH, D2O-exchangeable); MS m/z (%) 571 (Mꢁ, 28), 259 (100).
Synthesis of Compounds 12a, b A mixture of 9 (0.425 g, 1 mmol) and
appropriate phenacyl bromide (1 mmol) in absolute ethanol (30 ml) contain-
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