Synthesis and antioxidant activities of some novel fluorinated spiro[oxindole-thiazolidine] fused with sulfur and phosphorus heterocycles

Article abstract of DOI:10.1080/17415993.2014.896363

Facile routes were achieved for the synthesis of novel fluorinated spiro[oxindole-thiazolidinone] fused with some sulfur and phosphorus heterocycles starting from 5-fluoro-3^′-(4-fluorophenyl)-4 ^′H-spiro[indole-3,2^′-thiazol

Full text of DOI:10.1080/17415993.2014.896363

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Synthesis and antioxidant activities of
some novel fluorinated spiro[oxindole-
thiazolidine] fused with sulfur and
phosphorus heterocycles
Tarik E. Alia & Reda M. Abdel-Rahmanb
a Department of Chemistry, Faculty of Education, Ain Shams
University, Roxy 11711, Cairo, Egypt
b Department of Chemistry, Faculty of Science, King Abdulaziz
University, Jeddah, Saudi Arabia
Published online: 24 Mar 2014.
To cite this article: Tarik E. Ali & Reda M. Abdel-Rahman (2014) Synthesis and antioxidant
activities of some novel fluorinated spiro[oxindole-thiazolidine] fused with sulfur and phosphorus
heterocycles, Journal of Sulfur Chemistry, 35:4, 399-411, DOI: 10.1080/17415993.2014.896363
To link to this article: http://dx.doi.org/10.1080/17415993.2014.896363
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Journal of Sulfur Chemistry, 2014
Vol. 35, No. 4, 399–411, http://dx.doi.org/10.1080/17415993.2014.896363
Synthesis and antioxidant activities of some novel fluorinated
spiro[oxindole-thiazolidine] fused with sulfur and phosphorus
heterocycles
Tarik E. Alia∗ and Reda M. Abdel-Rahmanb
aDepartment of Chemistry, Faculty of Education, Ain Shams University, Roxy 11711, Cairo, Egypt;
bDepartment of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
(Received 9 January 2014; accepted 17 February 2014)
Facile routes were achieved for the synthesis of novel fluorinated spiro[oxindole-thiazolidinone] fused with
some sulfur and phosphorus heterocycles starting from 5-fluoro-3ꢀ-(4-fluorophenyl)-4ꢀH-spiro[indole-3,2ꢀ-
thiazolidine]-2,4ꢀ(1H)-dione (1) via its reaction with trifluoroacetamide, 2-chloro-6-fluorobenzaldehyde
and hydrazine hydrate followed by treatment with some suitable sulfur and phosphorus reagents. The
antioxidant activities of the synthesized compounds were also evaluated.
S and P
heterocycle
O
S
F
S
F
N
N
N
H
O
N
H
O
F
F
Keywords: spiro[oxindole-thiazolidine]; fluorine; sulfur and phosphorus heterocycles; antioxidant
activities
1. Introduction
The spiro[oxindole-thiazolidinone] system is a structural unit presented in many pharmaco-
logically important synthetic and natural compounds.[1] These compounds have biological
antiproliferative,[2] antitumor,[3] antimicrobial,[4] anti-inflammatory,[5] antihistamic [6] and
anticonvulsant activities.[7] Incorporation of fluorine atoms in different heterocycles is known to
affect the course of the reaction besides influencing the biological activities.[8–10] In addition,
sulfur- and phosphorus-containing heterocyclic compounds play an important role in organic
chemistry due to diversity of their chemical transformations and broad spectrum of biological
activities.[11–17] We hope that coupling of some sulfur and phosphorus heterocycles with the flu-
orinated spiro[oxindole-thiazolidine] system in one molecular frame may lead to better biological
properties. Consequently, in continuation of our research devoted to preparation of new bioactive
∗Corresponding author. Email: tarik_elsayed1975@yahoo.com
© 2014 Taylor & Francis

400 T.E. Ali and R.M. Abdel-Rahman
sulfur and phosphorus compounds,[18–20] we report here the synthesis of some novel fluorinated
spiro[oxindole-thiazolidine] fused with a selection of sulfur and phosphorus heterocycles. The
antioxidant properties of the synthesized compounds were also evaluated.
2. Results and discussion
2.1. Chemistry
The most convenient method for the synthesis of 2,3-disubstituted-4-thiazolidinones is the one-
pot three-component reaction of a primary amine, an oxo-compound and a thiolic agent.[21–23]
Thus, 5-fluoro-3ꢀ-(4-fluorophenyl)-4ꢀH-spiro[indole-3,2ꢀ-thiazolidine]-2,4ꢀ(1H)-dione (1) was
obtained via reaction of 4-fluoroaniline, 5-fluoroisatin and thioglycolic acid in dry dioxane in the
presence of anhydrous zinc chloride (Scheme 1).[23] The IR spectrum of compound 1 showed the
characteristic absorption bands 3277 (NH), 1728 (C Ooxindole) and 1682 (C Othiazolidinone) cm−1
Also, its H-NMR spectrum revealed the characteristic methylene protons as two doublets at δ
.
=
=
1
3.85 and 4.29 ppm with a coupling constant of 15 Hz. Furthermore, the specific carbon atoms CH2,
=
=
C-spiro, C Othiazolidinone and C Ooxindole were observed at δ 32.7, 70.3, 172.4 and 176.5 ppm,
respectively, in its 13C-NMR spectrum. The molecular ion of compound 1 was also observed at
m/z 332 (42%) in its mass spectrum.
O
O
F
F
+
OH
+
H2N
SH
N
H
O
Dioxane
anhydrous ZnCl2
O
S
F
N
N
H
O
F
1
Scheme 1. The reaction of 5-fluoroisatin, 4-fluoroaniline and thioglycolic acid in the presence
of anhydrous zinc chloride.
Compound 1 turned out to be a fairly reactive compound to generate 2, 5 and 8 via its condensa-
tion with trifluoroacetamide, 2-chloro-6-fluorobenzaldehyde and hydrazine hydrate, respectively.
Thus, treatment of compound 1 with trifluoroacetamide in the presence of glacial acetic
acid afforded beige crystals of 5-fluoro-3ꢀ-(4-fluorophenyl)-5ꢀ-(trifluoroacetyl)-spiro[indole-3,2ꢀ-
thiazolidine]-2,4ꢀ(1H)-dione (2) (Scheme 2). The structure of compound 2 was confirmed by both
spectral and elemental analysis. Its IR spectrum indicated the presence of three carbonyl groups at
1748 (C Otrifluoroacetyl), 1717 (C Ooxindole) and 1650 (C Othiazolidinone) cm−1. Also, the 1H-NMR
spectrum of compound 2 showed a characteristic singlet at δ 4.68 ppm, which was assigned to
=
=
=

Journal of Sulfur Chemistry 401
the proton at C–5 of the thiazolidinone moiety. The carbon atoms of trifluoroacetyl group were
observed at δ 113.6 (CF3) and 172.6 (C O) ppm in the 13C-NMR spectrum of compound 2.
=
Moreover, its mass spectrum showed the molecular ion peak at m/z 428 (62%) that agrees with
the proposed formula.
F3C
O
N
H
S
O
O
S
F
F
F3CCONH2
N
gl. CH3COOH
N
O
N
O
H
H
2
F
F
1
Scheme 2. Trifluoroacetylation of compound 1 with trifluoroacetamide in glacial acetic acid.
When the trifluoroacetyl derivative 2 was treated with thiourea and methyl phosphoric diamide,
in refluxing absolute ethanol containing few drops of piperidine as a catalyst, 5-fluoro-3ꢀ-
(4-fluorophenyl)-5ꢀ-thioxo-7ꢀ-(trifluoromethyl)-spiro{indole-3,2ꢀ-thiazolo[4ꢀ,5ꢀ-d] pyrimidin}-2-
one (3) and 5-fluoro-7ꢀ-(4-fluorophenyl)-4ꢀ-(trifluoromethyl)-2ꢀ-methyl-2ꢀ-oxido-1ꢀ,2ꢀ-dihydro-
spiro{indole-3,6ꢀ-thiazolo[4ꢀ,5ꢀ-d][1,3,2]diazaphosphinin}-2-one (4) were obtained, respectively,
in moderate yields (Scheme 3). The IR and 13C-NMR spectra of compounds 3 and 4 indicated
the disappearance of the carbonyl groups of the thiazolidinone and trifluoroacetyl moieties of
compound 2. Furthermore, their 1H-NMR spectra exhibited two singlets for the NH protons of
the pyrimidinethione and diazaphosphorine rings which suggest existence of the two products in
tautomeric forms A and B due to amino-imino tautomerism (Scheme 3).
Recently, α,β-unsaturated ketones have been reported as reactive chemical precursors for
the synthesis of bioactive heterocycles.[24,25] Thus, compound 1 was allowed to condense
with 2-chloro-6-fluorobenzaledyde in absolute ethanol with few drops of piperidine as catalyst
to afford a product identified as 5ꢀ-(2-chloro-6-fluorobenzylidene)-5-fluoro-3ꢀ-(4-fluorophenyl)-
4ꢀH- spiro[indole-3,2ꢀ-thiazolidine]-2,4ꢀ-(1H)-dione (5) (Scheme 4). The structure of compound
5 was established on the basis of 1H- and 13C-NMR spectral data that confirmed disappearance
of the methylene group of compound 1 (see Section 4).
Compound 5 appears to be a logical starting material for synthesis of the target hete-
rocycles via its reaction with some sulfur and phosphorus nucleophiles. Thus, reaction of
compound 5 with thioglycolic acid in dry dioxane containing anhydrous potassium carbonate
furnished 6ꢀ-(2-chloro-6-fluorophenyl)-5-fluoro-3ꢀ-(4-fluorophenyl)-2ꢀ,3ꢀ-dihydro-spiro{indole-
3,2ꢀ-thieno[3,4-d]thiazol}-2-one (6) in good yield (Scheme 5). A plausible mechanism involved
an initial Michael-type addition of the thiol group of thioglycolic acid to the activated double
bond in compound 5, followed by cyclocondensation between the active methylene and the car-
bonyl group to give the nonisolable intermediate B. Decarboxylation and aromatization of the
intermediate B produced the final product 6 (Scheme 5). The chemical structure of compound 6
was deduced from the absence of thiazolidinone carbonyl or hydroxyl groups in its IR and 13C-
NMR spectra that confirms the decarboxylation process. Also, its 1H-NMR spectrum displayed
a characteristic singlet at δ 6.20 ppm due to the C2–H proton of the thiophene moiety. Moreover,
the molecular ion peak of compound 6 was recorded at m/z 500 (M+, 7%) in its mass spectrum,
which agreed with the suggested structure.

402 T.E. Ali and R.M. Abdel-Rahman
2
O
P
S
H2N
NH2
CH3
H2N
NH2
EtOH
EtOH
piperidine
piperidine
H
CH3
H
N
F3C
S
N
S
F3C
P
O
N
N
S
F
F
N
N
N
O
N
O
H
H
F
4A
F
3A
CH3
F3C
S
N
N
F3C
S
N
N
S
P
O
NH
NH
F
F
N
O
N
H
O
H
3B
4B
F
F
Scheme 3. The reaction of compound 2 with thiourea and methyl phosphoric diamide.
F
F
O
S
CHO
Cl
O
F
S
N
Cl
F
N
EtOH
N
O
Piperidine
H
N
H
O
F
1
F
5
Scheme 4. Condensation reaction of compound 1 with 2-chloro-6-fluorobenzaldehyde.
Consequently, it has been found that the one-pot reaction of the compound 5 with diethyl phos-
phite in the presence of BF3·Et2O at 80–90◦C for 16 h afforded 3ꢀ-(2-chloro-6-fluorophenyl)-2ꢀ-
ethoxy-5-fluoro-6ꢀ-(4-fluorophenyl)-2ꢀ-oxido-spiro{indole-3,5ꢀ-[1,2]oxaphospholo[5,4-d]thiazol}
-2-one (7) (Scheme 5). The proposed mechanism involved an initial Michael-type addition of the
phosphorus atom of diethyl phosphite to the activated double bond in compound 5 to give the non-
isolable phosphonate C, which underwent cyclization by elimination of ethanol to give the product

Journal of Sulfur Chemistry 403
H-P(O)(OEt)2
HSCH2COOH
5
Dioxane
BF3·Et2O
80–90oC
anhydrous K2CO3
OH
F
F
O
H
OEt
O
P
S
H
H
S
OEt
Cl
H
S
Cl
O
O
F
F
N
N
O
N
H
O
N
H
F
F
A
C
- H2O
F
F
H
O
OEt
S
P
Cl
H
S
H
S
OEt
Cl
COOH
OH
F
F
N
N
O
N
H
O
N
H
F
F
B
D
- CO2
- EtOH
aromatization
F
S
F
O
OEt
P
Cl
Cl
H
O
S
S
F
F
N
O
N
N
H
N
O
H
F
F
6
7
Scheme 5. The reaction of compound 5 with thioglycolic acid and diethyl phosphite.
1
7 (Scheme 5).[26] The H-NMR spectrum of compound 7 displayed a doublet at δ 5.18 ppm
(J = 22.2 Hz) assignable to proton C3–H of the oxaphosphole ring, while the ethoxy protons
appeared as a triplet and quartet at δ 1.20 and 3.85 ppm (J = 7.2 Hz), respectively. Its 13C-NMR
spectrum revealed characteristic peaks at δ 16.8 (CH3), 62.3 (CH2), 42.6 (C3–Hoxaphosphole) and
165.2 (C5–Hoxaphosphole) ppm. Also, its IR spectrum confirmed the disappearance of the carbonyl
group of compound 5, which supports the cyclized state.

404 T.E. Ali and R.M. Abdel-Rahman
Reaction of compound 1 with hydrazine hydrate in refluxing absolute ethanol produced the
corresponding hydrazone 8 in high yield (Scheme 6). The structure of compound 8 was established
on the basis of its elemental analysis, IR, 1H-NMR and mass spectral data (see Section 4).
NH2
O
N
S
S
F
NH2NH2·H2O
EtOH
F
N
N
N
H
O
N
O
H
F
1
F
8
Scheme 6. Condensation reaction of compound 1 with hydrazine hydrate.
It is known that hydrazones could be used as a precursor for the synthesis of a variety of
bioactive heterocyclic systems.[27,28] Thus, treatment of the hydrazone 8 with thionyl chloride
and phosphorus oxychloride in dry dioxane containing triethylamine as a catalyst produced the
corresponding thiazolothiadiazole 9 and thiazolodiazaphosphole 10 derivatives, respectively, in
moderate yields (Scheme 7). The chemical structures of 9 and 10 were established on the basis
of spectral data. Their IR spectra showed the presence of NHNH groups in the 3145–3354 cm−1
region, while their 1H-NMR spectra revealed broad singlets at δ 5.09 and 6.29 ppm, respectively,
=
assignable to NHNH protons. In addition, a broad singlet at δ 8.45 ppm due to the HO–P O group
in compound 10 was observed. The 13C-NMR spectra of compounds 9 and 10 were also supportive
of the proposed structures exhibiting characteristic signals at δ 98.0 (C–5thiadiazole) and 158.3
(C–4thiadiazole) for compound 9 and at δ 90.0 (C–4diazaphosphole) and 155.0 (C–5diazaphosphole) ppm for
compound 10. The 1H- and 13C-NMR spectra of 9 and 10 confirmed localization of the protons
on the nitrogen atoms and not on the carbon atoms of the thiadiazole and diazaphosphole rings.
2.2. Antioxidant activity
All the synthesized compounds were tested for antioxidant activity by the 1,1-diphenyl-2-
picrylhydrazyl (DPPH) method.[29,30] The results of scavenging the stable DPPH radical are
tabulated in Table 1 and illustrated in Figure 1, where it is documented that at 150, 300 and
450 μmol L−1 of the synthesized compounds under study scavenged between 49% and 78% of
the DPPH radicals. This increase in the % DPPH inhibition is caused by the reaction between
the compounds under study with DPPH radicals. Hence, DPPH radical is an important substrate
to evaluate the antioxidant activity.[31] The results suggested that compounds 1, 2, 5, 6, 8 and 9
showed moderate activities in the range of 49–60% at different concentrations, while compounds 7
and 10showedverygoodactivitiesinrangeof63–71%. Furthermore, compounds3and 4proved to
exhibit potent antioxidative activities in range of 70–78%. The presence of trifluoromethyl group
and oxindole moiety incorporated with thiazolopyrimidinethione or thiazolodiazaphosphorine
enhanced the antioxidant activity.
3. Conclusion
Facile routes were achieved to synthesize novel fluorinated spiro[oxindole-thiazolidinone]
fused with some sulfur and phosphorus heterocycles in two steps starting from 5-fluoro-
3ꢀ-(4-fluorophenyl)-4ꢀH-spiro[indole-3,2ꢀ-thiazolidine]-2,4ꢀ-(1H)-dione (1). Some of the novel

Journal of Sulfur Chemistry 405
O
H
N
S
H
N
S
SOCl2
F
8
N
Dry dioxane
Et3N
N
O
H
F
G
Dry dioxane
Et3N
POCl3
O
P
H
Cl
H
N
O
H
N
N
S
S
F
NH
N
S
F
N
N
O
H
N
O
F
H
F
F
9
H2O
O
O
H
H
HO
HO
H
N
N
P
P
NH
N
S
S
F
F
N
N
N
O
N
O
H
H
F
F
10
G
Scheme 7. The reaction of compound 8 with thionyl chloride and phosphorus oxychloride.
products recorded good antioxidant properties. We hope that this approach may be value to others
seeking novel synthetic fragments with unique properties for medicinal chemistry.
4. Experimental
4.1. General remarks
Melting points of the products were determined on Stuart SMP3. A Perkins Elmer model
RXI-FT-IR system 55529 was used for recording the IR spectra of the prepared compounds.
1H- and 13C-NMR spectra were recorded on a Bruker 600 MHz spectrometer operating at 600
and 150 MHz, respectively. The chemical shifts in NMR spectra are reported in ppm with respect
to the references and were stated relative to tetramethylsilane. Mass spectra were recorded on a
Gas Chromatographic DI analysis Shimadzu instrument Q-2010 Plus at 70 eV. Elemental micro-
analyses were performed with Perkin-Elmer 2400II at the Chemical War Department, Ministry of
Defense. The purity of the synthesized compounds was checked by thin layer chromatography.

406 T.E. Ali and R.M. Abdel-Rahman
Table 1. DPPH radical scavenging activities (%) of the synthesized com-
pounds 1–10 at 150, 300 and 450 μmol L−1
.
DPPH % inhibition antioxidant SD
Compd no.
150 (μmol L−1
)
300 (μmol L−1
)
450 (μmol L−1
)
1
2
3
4
5
6
7
8
54.12 0.13
51.59 0.12
70.35 0.12
72.67 0.18
52.83 0.06
53.92 0.06
62.68 0.18
49.23 0.06
55.30 0.06
65.54 0.18
43.00
56.54 0.12
53.78 0.18
74.55 0.18
75.01 0.18
54.12 0.18
55.87 0.06
65.37 0.06
51.29 0.38
57.34 0.38
68.20 0.06
50.70
58.95 0.13
56.47 0.12
77.45 0.12
77.78 0.12
58.32 0.18
58.02 0.06
68.12 0.06
56.75 0.06
59.71 0.38
70.65 0.18
55.20
9
10
Ascorbic acid
90
80
70
60
50
40
30
20
10
0
150 300 450
1
2
3
4
5
6
7
8
9
10
Ascorbic
acid
The tested compounds
Figure 1. The DPPH radical scavenging activity (%) for the tested compounds.
4.2. 5-Fluoro-3ꢀ-(4-fluorophenyl)-4ꢀH-spiro[indole-3,2ꢀ-thiazolidine]-2,4ꢀ(1H)-dione (1)
A mixture of 4-fluoroaniline (2.5 mmol, 0.28 g) and 5-fluoroisatin (2.5 mmol, 0.41) was heated in
dry dioxane (15 ml) under reflux for 30 min, followed by the addition of a solution of thioglycolic
acid (3 mmol, 0.20 ml) in dry dioxane (5 ml) and 1.0 g freshly fused zinc chloride. The reaction
mixture was heated under reflux for additional 20 h. The mixture was cooled then neutralized
with aqueous NaHCO3 (10%, 20 ml). The formed solid was filtered off, washed with water three
times and crystallized from ethanol to give yellow crystals in 72% yield; mp 184–186◦C [Lit. [23]
182◦C]. IR (KBr) (νmax, cm−1): 3277 (NH), 1728 (C Ooxindole), 1682 (C Othiazolidinone), 1618
=
=
1
=
(C C), 1219 (C–F). H-NMR (DMSO, δ ppm): 3.85, 4.29 (dd, 2H, J = 15 Hz, CH2 AB system),
6.76 (d, 1H, J = 7.2 Hz,Ar–H), 6.90–7.07 (m, 4H,Ar–H), 7.19 (t, 1H, J = 7.8 Hz,Ar–H), 7.40 (d,
1H, J = 7.8 Hz, Ar–H), 10.34 (s, 1H, NHoxindole). 13C-NMR (DMSO, δ ppm): 32.7, 70.3, 111.1,
116.2, 117.9, 122.9, 124.6, 130.2, 137.8, 141.8, 161.1, 162.7, 172.4, 176.5. MS (m/z, I%): 332
(M+, 42%).Anal. Calcd for C16H10F2N2O2S (332.33): C, 57.83; H, 3.03; N, 8.43; S, 9.65. Found:
C, 57.59%; H, 2.87%; N, 8.10%; S, 9.32%.

Journal of Sulfur Chemistry 407
4.3. 5-Fluoro-3ꢀ-(4-fluorophenyl)-5ꢀ-(trifluoroacetyl)-spiro[indole-3,2ꢀ-thiazolidine]-
2,4ꢀ(1H)-dione (2)
A mixture of 5-fluoro-3ꢀ-(4-fluorophenyl)-4ꢀH-spiro[indole-3,2ꢀ-thiazolidine] -2,4ꢀ(1H)-dione (1)
(2.5 mmol, 0.83 g)andtrifluoroacetamide(2.5 mmol, 0.28 g)inthepresenceoffewdropsofglacial
acetic acid was fused at 120◦C for 1 h.The cooled reaction mixture was poured onto 50 g of crushed
ice.Theformedsolidwasfilteredoff, washedwithwaterthreetimesthencrystallizedfromaqueous
ethanol to give beige crystals; 68% yield; mp 112–114◦C. IR (KBr) (νmax, cm−1): 3247 (NH),
=
=
=
=
1748 (C Otrifluoroacetyl), 1717 (C Ooxindole), 1650 (C Othiazolidinone), 1620 (C C), 1230 (C–F).
1H-NMR (DMSO, δ ppm): 4.68 (s, 1H, CH), 6.76 (d, 1H, J = 7.8 Hz, Ar–H), 6.90–6.97 (m,
2H, Ar–H), 7.00–7.08 (m, 2H, Ar–H), 7.19 (t, 1H, J = 7.2 Hz, Ar–H), 7.41 (d, 1H, J = 7.2 Hz,
Ar–H), 10.31 (s, 1H, NHoxindole). 13C-NMR (DMSO, δ ppm): 66.9, 70.3, 111.0, 113.6, 116.2,
117.8, 122.9, 124.6, 130.2, 137.8, 141.8, 161.0, 162.7, 172.3, 172.6, 176.5. MS (m/z, I%): 428
(M+, 62%). Anal. Calcd for C18H9F5N2O3S (428.34): C, 50.47; H, 2.12; N, 6.54; S, 7.49. Found:
C, 50.09%; H, 2.00%; N, 6.19%; S, 7.12%.
4.4. 5-Fluoro-3ꢀ-(4-fluorophenyl)-5ꢀ-thioxo-7ꢀ-(trifluoromethyl)-
spiro{indole-3,2ꢀ-thiazolo[4ꢀ,5ꢀ-d]pyrimidin}-2-one (3)
A mixture of compound 2 (1 mmol, 0.43 g) and thiourea (1 mmol, 0.08 g) in absolute ethanol
(15 ml) containing few drops of piperidine was heated under reflux for 10 h. After cooling, the
formed solid was filtered off and crystallized from ethanol to give yellow crystals; 56% yield; mp
226–228◦C. IR (KBr) (νmax, cm−1): 3289 (NH), 1761 (C Ooxindole), 1219 (C–F), 1155 (C S).
1H-NMR (DMSO, δ ppm): 6.91 (t, 1H, J = 8.4 Hz, Ar–H), 6.99–7.11 (m, 4H, Ar–H), 7.70–7.76
(m, 2H, Ar–H), 10.33 (s, 1H, NHoxindole), 10.65, 10.77 (ss, 1H, NHpyrimidine). 13C-NMR (DMSO,
δ ppm): 70.3, 111.5, 112.2, 115.5, 117.2, 118.6, 122.1, 125.9, 133.0, 136.5, 138.0, 156.7, 161.1,
162.7, 169.3, 174.9, 190.3. MS (m/z, I%): 468 (M+, 13%). Anal. Calcd for C19H9F5N4OS2
(468.43): C, 48.72; H, 1.94; N, 11.96; S, 13.69. Found: C, 48.39%; H, 1.63%; N, 11.69%; S,
13.40%.
=
=
4.5. 5-Fluoro-7ꢀ-(4-fluorophenyl)-4ꢀ-(trifluoromethyl)-2ꢀ-methyl-2ꢀ-oxido-1ꢀ,
2ꢀ-dihydro-spiro{indole-3,6ꢀ-thiazolo[4ꢀ,5ꢀ-d][1,3,2]diazaphosphinin}-2-one (4)
A mixture of compound 2 (1 mmol, 0.43 g) and methyl phosphoric diamide (1 mmol, 0.1 g) in
absolute ethanol (15 ml) containing few drops of piperidine was heated under reflux for 10 h.
After cooling, the formed solids were filtered off and crystallized from ethanol to brown crystals;
61% yield; mp 196–198◦C. IR (KBr) (νmax, cm−1): 3266 (NH), 1738 (C Ooxindole), 1212 (C–F),
=
1
=
1180 (P O). H-NMR (DMSO, δ ppm): 2.14 (d, 3H, J = 8.4 Hz, P–CH3), 6.79–6.89 (m, 3H,
Ar–H), 6.97 (t, 1H, J = 8.4 Hz, Ar–H), 7.13 (dd, 1H, J = 8.4 and 2.4 Hz, Ar–H), 7.53–7.58 (m,
2H, Ar–H), 9.47, 10.66 (ss, 1H, NHdiazaphosphorine), 10.14 (s, 1H, NHoxindole). 13C-NMR (DMSO,
δ ppm): 29.6, 69.8, 110.0, 110.8, 112.1, 113.3, 115.0, 121.4, 123.7, 134.9, 137.0, 139.5, 157.9,
159.4, 163.8, 168.9, 176.9. MS (m/z, I%): 486 (M+, 21%). Anal. Calcd for C19H12F5N4O2PS
(486.36): C, 46.92; H, 2.49; N, 11.52; S, 6.59. Found: C, 46.68%; H, 2.11%; N, 11.19%; S, 6.23%.
4.6. 5ꢀ-(2-Chloro-6-fluorobenzylidene)-5-fluoro-3ꢀ-(4-fluorophenyl)-
4ꢀH-spiro[indole-3,2ꢀ-thiazolidine]-2,4ꢀ-(1H)-dione (5)
A mixture of compound 1 (2.5 mmol, 0.83 g) and 2-chloro-6-fluorobenzaldehyde (2.5 mmol,
0.39 g) in absolute ethanol (20 ml) containing few drops of piperidine was heated under reflux for
10 h. After cooling, the formed solid was filtered off and crystallized from ethanol to give beige

408 T.E. Ali and R.M. Abdel-Rahman
crystals; 73% yield; mp 148–150◦C. IR (KBr) (νmax, cm−1): 3359 (NH), 1719 (C Ooxindole), 1653
=
1
=
=
(C Othiazolidinone), 1605 (C C), 1215 (C–F). H-NMR (DMSO, δ ppm): 6.74–6.76 (m, 2H, Ar–
H), 6.91–6.98 (m, 4H,Ar–H), 7.05–7.07 (m, 3H,Ar–H), 7.16 (dd, 1H, J = 7.8 and 3.0 Hz,Ar–H),
7.53 (s, 1H, CH C), 10.40 (s, 1H, NHoxindole). 13C-NMR (DMSO, δ ppm): 70.3, 112.0, 113.5,
113.7, 116.3, 117.9, 120.0, 122.0, 126.2, 127.3, 128.0, 130.2, 131.7, 135.0, 137.8, 142.0, 159.6,
161.1, 162.8, 172.4, 176.5. MS (m/z, I%): 473 (M+, 76%). Anal. Calcd for C23H12ClF3N2O2S
(472.88): C, 58.42; H, 2.56; N, 5.92; S, 6.78. Found: C, 58.09%; H, 2.34%; N, 5.73%; S, 6.53%.
=
4.7. 6ꢀ-(2-Chloro-6-fluorophenyl)-5-fluoro-3ꢀ-(4-fluorophenyl)-2ꢀ,3ꢀ-dihydro-spiro
{indole-3,2ꢀ-thieno[3,4-d]thiazol}-2-one (6)
A mixture of chalcone 5 (1 mmol, 0.47 g) and thioglycolic acid (3 mmol, 0.2 ml) in dry dioxane
(15 ml) in the presence of anhydrous potassium carbonate (1 g) was refluxed for 8 h.After cooling,
the resulting precipitate was filtered off, washed with water several times and crystallized from
ethanol to give pale yellow crystals in 78% yield; mp 222–224◦C. IR (KBr) (νmax, cm−1): 3231
1
=
=
(NH), 1731 (C Ooxindole), 1605 (C C), 1217 (C–F). H-NMR (DMSO, δ ppm): 6.20 (s, 1H, C2–
H
thiophene), 6.74–6.76 (m, 2H, Ar–H), 6.91–6.98 (m, 4H, Ar–H), 7.05–7.08 (m, 3H, Ar–H), 7.17
(dd, 1H, J = 7.8 and 2.4 Hz, Ar–H), 10.44 (s, 1H, NHoxindole). 13C-NMR (DMSO, δ ppm): 70.3,
111.1, 114.0, 116.1, 116.2, 117.9, 121.0, 122.0, 123.0, 124.6, 126.2, 127.0, 130.3, 131.1, 131.9,
133.0, 134.0, 138.0, 158.0, 161.0, 162.7, 176.9. MS (m/z, I%): 501 (M+, 7%). Anal. Calcd for
C24H12ClF3N2OS2 (500.95): C, 57.54; H, 2.41; N, 5.59; S, 12.80. Found: C, 57.19%; H, 2.21%;
N, 5.21%; S, 12.52%.
4.8. 3ꢀ-(2-Chloro-6-fluorophenyl)-2ꢀ-ethoxy-5-fluoro-6ꢀ-(4-fluorophenyl)-
2ꢀ-oxido-spiro{indole-3,5ꢀ-[1,2]oxaphospholo [5,4-d]thiazol}-2-one (7)
A mixture of chalcone 5 (1 mmol, 0.47 g) and diethyl phosphite (1.5 ml) in the presence of boron
trifluoride etherate (0.2 ml) was heated on water bath for 16 h. The excess of diethyl phosphite was
removed under reduced pressure. The formed precipitate was filtered off and crystallized from
ethanol to give pale brown crystals in 79% yield; mp 110–112◦C. IR (KBr) (νmax, cm−1): 3246
1
=
=
=
(NH), 1731 (C Ooxindole), 1619 (C C), 1216 (C–F), 1189 (P O). H-NMR (DMSO, δ ppm):
1.20 (t, 3H, J = 7.2 Hz, CH3), 3.85 (q, 2H, J = 7.2 Hz, CH2), 5.18 (d, 1H, J = 22.2 Hz, CH–P),
6.76 (d, 2H, J = 7.8 Hz, Ar–H), 6.91–6.95 (m, 3H, Ar–H), 7.00–7.07 (m, 3H, Ar–H), 7.19 (t, 1H,
J = 7.8 Hz, Ar–H), 7.40 (d, 1H, J = 7.8 H, Ar–H), 10.32 (s, 1H, NHoxindole). 13C-NMR (DMSO,
δ ppm): 16.8, 42.6 (d, J = 150.4 Hz, CH–P), 62.3, 70.3, 111.1, 115.0, 116.0, 116.2, 122.9, 124.6,
126.0, 127.0, 128.0, 130.2, 131.2, 131.9, 135.0, 141.8, 160.0, 161.0, 162.7, 165.2, 172.6. MS
(m/z, I%): 565 (M+, 10%). Anal. Calcd for C25H17ClF3N2O4PS (564.91): C, 53.16; H, 3.03; N,
4.96; S, 5.66. Found: C, 52.93%; H, 2.84%; N, 4.71%; S, 5.29%.
4.9. 5-Fluoro-3ꢀ-(4-fluorophenyl)-4ꢀ-hydrazinylidene-spiro[indole-3,2ꢀ-thiazolidin]-
2(1H)-one (8)
A mixture of compound 1 (2.5 mmol, 0.83 g) and hydrazine hydrate (4 mmol, 0.2 ml) in absolute
ethanol (15 mL) was heated under reflux for 10 h. After cooling, the formed solid was filtered off
and crystallized from DMF–EtOH to give white crystals; 85% yield; mp 226–227◦C. IR (KBr)
1
(νmax, cm−1): 3246 (NH), 1731 (C Ooxindole), 1636 (C N), 1216 (C–F). H-NMR (DMSO,
δ ppm): 3.83, 4.33 (dd, 2H, J = 15 Hz, CH2 AB system), 5.37 (br, 2H, NH2), 6.76 (d, 1H,
J = 7.2 Hz,Ar–H), 6.92–7.05 (m, 4H,Ar–H), 7.20–7.41 (m, 2H,Ar–H), 10.02 (s, 1H, NHoxindole).
=
=

Journal of Sulfur Chemistry 409
MS (m/z, I%): 346 (M+, 4%). Anal. Calcd for C16H12F2N4OS (346.36): C, 55.48; H, 3.49; N,
16.18; S, 9.26. Found: C, 55.12%; H, 3.13%; N, 15.80%; S, 8.98%.
4.10. 5-Fluoro-4ꢀ-(4-fluorophenyl)-1ꢀ-oxido-2ꢀ, 3ꢀ,
4ꢀ,5ꢀ-tetrahydro-spiro{indole-3,5ꢀ-thiazolo[4,5-d][1,2,3]thiadiazol}-2-one (9)
A mixture of hydrazone 8 (0.57 g, 1.66 mmol) in dry dioxane (15 ml) containing triethylamine
(4 mmol, 0.4 ml) was kept with constant magnetic stirring, maintaining the temperature below
0◦C. A solution of thionyl chloride (2 mmol, 0.15 ml) in dry dioxane (10 ml) was added to the
above mixture with constant magnetic stirring, maintaining the temperature below 0◦C. After
the complete addition, the temperature was allowed to rise to room temperature for 2 h. The
mixture was heated under reflux for a further 3 h. After cooling, the mixture was poured into ice.
The resulting product 9 was isolated using an extraction isolation technique and recrystallized
from ethanol as brown crystals; 60% yield; mp 170–172◦C. IR (KBr) (νmax, cm−1): 3354, 3145
1
=
=
=
(NHNH), 1736 (C Ooxindole), 1587 (C C), 1210 (C–F), 1080 (S O). H-NMR (DMSO, δ ppm):
5.09 (br, 2H, NHNH), 7.04 (t, 2H, J = 8.4 Hz, Ar–H), 7.16 (t, 2H, J = 8.4 Hz, Ar–H), 7.73 (t, 2H,
J = 7.2 Hz, Ar–H), 8.01 (t, 1H, J = 7.2 Hz, Ar–H), 9.71 (s, 1H, NHoxindole). 13C-NMR (DMSO,
δ ppm): 66.9, 98.0, 110.0, 115.1, 115.3, 122.5, 125.0, 130.2, 134.9, 140.0, 158.3, 159.9, 163.8,
172.6. MS (m/z, I%): 392 (M+, 3%). Anal. Calcd for C16H10F2N4O2S2 (392.41): C, 48.97; H,
2.57; N, 14.28; S, 16.34. Found: C, 48.61%; H, 2.13%; N, 13.91%; S, 16.09%.
4.11. 5-Fluoro-6ꢀ-(4-fluorophenyl)-3ꢀ-hydroxy-2ꢀ,3ꢀ,5ꢀ,6ꢀ-
tetrahydro-1H-spiro{indole-3,5ꢀ-thiazolo[5,4-d][1,2,3]diazaphosphol}-2-one (10)
A mixture of hydrazone 8 (0.57 g, 1.66 mmol) in dry dioxane (15 ml) containing triethylamine
(4 mmol, 0.4 ml) was kept with constant magnetic stirring, maintaining the temperature below
0◦C. A solution of phosphorus oxychloride (2 mmol, 0.19 ml) in dry dioxane (10 ml) was added
to the above mixture with constant magnetic stirring, maintaining the temperature below 0◦C.
After the complete addition, the temperature was allowed to rise to room temperature for 2 h. The
mixture was heated under reflux for a further 3 h. After cooling, the mixture was poured into ice.
The resulting product 9 was isolated using an extraction isolation technique and recrystallized
from ethanol as beige crystals; 58% yield; mp 230–232◦C. IR (KBr) (νmax, cm−1): 3247 (br, OH,
1
=
=
=
NH), 1729 (C Ooxindole), 1619 (C C), 1217 (br, C–F and P O). H-NMR (DMSO, δ ppm): 6.29
(br, 2H, NHNH), 6.85 (d, 2H, J = 7.8 Hz, Ar–H), 6.97 (t, 2H, J = 7.2 Hz, Ar–H), 7.13 (t, 2H,
J = 7.8 Hz, Ar–H), 7.41 (d, 1H, J = 7.2 Hz, Ar–H), 8.45 (br, 1H, OH), 9.74 (s, 1H, NHoxindole).
13C-NMR (DMSO, δ ppm): 67.9, 90.0, 110.2, 115.2, 118.3, 121.8, 127.4, 135.0, 138.9, 140.0,
155.0, 160.0, 162.0, 172.5. MS (m/z, I%): 408 (M+, 45%). Anal. Calcd for C16H11F2N4O3PS
(408.33): C, 47.06; H, 2.72; N, 13.72; S, 7.85. Found: C, 46.87%; H, 2.43%; N, 13.49%; S, 7.56%.
4.12. Antioxidant activity
The nitrogen-centered stable free radical DPPH has often been used to characterize antioxidants.
It is reversibly reduced and the odd electron in the DPPH free radical gives a strong absorption
maximum at λ 517 nm, which is purple in color. This property makes it suitable for spectrophoto-
metric studies.A radical scavenging antioxidant reacts with DPPH stable free radical and converts
into 1,1-diphenyl-2-picrylhydrazine. The resulting decolorization is stoichiometric with respect
to the number of electrons captured. The change in the absorbance produced in this reaction
has been used to measure antioxidant properties. The solutions of test compounds (150, 300 and

410 T.E. Ali and R.M. Abdel-Rahman
450 μmol L−1) were added to DPPH (100 μM) in DMSO/ethanol. The tubes were kept at an ambi-
ent temperature for 20 min and the absorbance was measured at λ 517 nm.[29,30] The difference
between the test and the control experiments was taken and expressed as the percent scavenging of
the DPPH radical using the following formula % inhibition = (AB - AA/AB) × 100, where AB
is the absorption of blank and AA the absorption of the tested compound. The radical scavenging
activity of ascorbic acid was also measured and compared with that of the different synthesized
compounds.
Acknowledgement
The authors are thankful to Dr Engy Mahmoud for evaluation of the antioxidant properties in Department of Flavour and
Aroma Chemistry, National Research center (NRC), Egypt.
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