Synthesis of 1-(2,3-dimethyl-1-phenyl-pyrazolone-5-yl-4)-2-mercapto-1′,5- cycloalkane-spiro[1,3]thiazolo[3,4-b]-1,2,4-triazole derivatives

Article abstract of DOI:10.1080/10426500307854

New thiosemicarbazone derivatives 3a-c, obtained by the condensation of 4-(2,3-dimethyl-1-phenyl-pyrazolone-5-yl-4)-thiosemicarbazide (1) with cycloalkanones 2a-c, on reaction with mercaptoacetic acid (4) yields the corresponding spiro thiazolidin-4-ones 5a-c. Compound 5 undergo intramolecular heterocyclization to the corresponding 1-(2,3-dimethyl-1-phenyl-pyrazolone-5-yl-4)-2-mercapto-1′,5- cycloalkane-spiro[1,3]thiazolo[3,4-b]-1,2,4-triazoles 6a-c with NaOH.

Full text of DOI:10.1080/10426500307854

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Phosphorus, Sulfur, and Silicon and the Related
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Synthesis of 1-(2,3-Dimethyl-1-phenyl-
pyrazolone-5-yl-4)-2-mercapto-1′,5-cycloalkane-
spiro[1,3]thiazolo[3,4-b]-1,2,4-triazole Derivatives
R. M. Shaker a
a El-Minia University , El-Minia, Egypt
Published online: 27 Oct 2010.
To cite this article: R. M. Shaker (2003) Synthesis of 1-(2,3-Dimethyl-1-phenyl-pyrazolone-5-yl-4)-2-mercapto-1′,5-
cycloalkane-spiro[1,3]thiazolo[3,4-b]-1,2,4-triazole Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements,
178:5, 1175-1182, DOI: 10.1080/10426500307854
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:1175–1182
C
Copyright 2003 Taylor & Francis
1042-6507/03 $12.00 + .00
DOI: 10.1080/10426500390209009
SYNTHESIS OF 1-(2,3-DIMETHYL-1-PHENYL-
PYRAZOLONE-5-yl-4)-2-MERCAPTO-10,5-
CYCLOALKANE-SPIRO[1,3]THIAZOLO[3,4-b]-1,2,4-
TRIAZOLE DERIVATIVES
R. M. Shaker
El-Minia University, El-Minia, Egypt
(Received October 29, 2002; accepted November 23, 2002)
New thiosemicarbazone derivatives 3a–c, obtained by the condensation
of 4-(2,3-dimethyl-1-phenyl-pyrazolone-5-yl-4)-thiosemicarbazide (1)
with cycloalkanones 2a–c, on reaction with mercaptoacetic acid
(4) yields the corresponding spiro thiazolidin-4-ones 5a–c. Com-
pound 5 undergo intramolecular heterocyclization to the corre-
sponding 1-(2,3-dimethyl-1-phenyl-pyrazolone-5-yl-4)-2-mercapto-10,5-
cycloalkane-spiro[1,3]thiazolo[3,4-b]-1,2,4-triazoles 6a–c with NaOH.
Keywords: Spiro thiazolidin-4-ones; synthesis; thiazolo-[3,4-b]-1,2,4-
triazoles; thiosemicarbazones
Spiroheterocyclic derivatives have considerable importance as drugs
and a wide scope of applications.1–5 The pharmaceutical activities
of 1,2,4-triazoles6–9 and thiazole derivatives10–12 have been studied
extensively. Prompted by the aforesaid biological and pharmaceuti-
cal activities, and in continuation of our previous work aimed at
Address correspondence to R. M. Shaker, Chemistry Department, Faculty of Science,
El-Minia University, El-Minia, Egypt.
1175

1176
R. M. Shaker
developing new approaches for the synthesis of polyfunctionally sub-
stituted heterocyclic compounds of expected biological activity,12–17 we
report here the synthesis of the versatile and hitherto unreported, oth-
erwise difficult accessible bicyclic system 2-mercapto-10,5-cycloalkane-
spiro[1,3]thiazolo[3,4-b]-1,2,4-triazoles 6a–c in order to study their
biological activity.
RESULTS AND DISCUSSION
Thus, 1-cycloalkylidene-4-(2,3-dimethyl-1-phenylpyrazolone-5-yl-4)-
thiosemicarbazones 3a–c were synthesized by condensation of 4-
(2,3-dimethyl-1-phenyl-pyrazolone-5-yl-4)-thiosemicarbazide (1) with
cycloalkanones 2a–c in butanol containing a catalytic amount of gl.
acetic acid (Scheme 1). The structural assignments of compound 3
SCHEME 1

Synthesis of Triazolo Derivatives
1177
1
was confirmed by elemental analysis as well as by IR, MS, H NMR,
and 13C NMR spectra. The resonance peak of NH2 group appearing
1
1
at 4.72 ppm in the H NMR of 1 disappeared in the H NMR of 3
supporting the participation of this group in the hydrazone formation
(see Experimental). The 13C NMR spectrum of 3a confirmed the
proposed structural feature (Figure 1).
Addition-condensation of thiosemicarbazones 3 to mercaptoacetic
acid (4) furnished the corresponding cycloalkane spirothiazolidin-4-
ones 5a–c (Scheme 1). The products were fully characterized through
spectral and elemental analysis (see Experimental), the structure of 5
1
was indicated by broad IR bands around 3320 cm corresponding to
NH group, at 1685, 1650 cm 1corresponding to the carbonyl group of
1
the thiazole and pyrazole rings, and a band around 1220 cm corre-
sponding to C S group. The structure elucidation for the system 5 shall
be discussed here in detail for 5a. The 1H NMR spectrum in DMSO-d6
contained a two protons singlet at 3.52 due to thiazolidinone protons, a
two sharp singlet at (2.15 and 3.09) for the two methyl groups, a broad
FIGURE 1 13C NMR spectral data.

1178
R. M. Shaker
singlet at 11.9 for the two NH groups, a ten-protons multiplet in the
region of 1.15–2.10 due to the cyclohexyl protons and a multiplet at
7.2–7.4 ppm for the aromatic protons. The structure 5a was further
confirmed by 13C NMR spectrum which revealed resonance at 53.5
and 164.6 ppm. The resonances were consistent with the quaternary
sp3 carbon (spiro carbon) and the carbonyl group of the thiazole ring
respectively (Figure 1). Furthermore, the mass spectrum of 5a gave the
molecular ion peak at m/z 431 (M+, 78%) which found to be in good
agreement with the assigned structure (see Experimental).
The compound 5a on treatment with sodium hydroxide un-
derwent cyclization to 1-(2,3-dimethyl-1-phenyl-pyrazolone-5-yl-4)-2-
mercapto-10,5-cyclohexane-spiro[1,3]thiazolo[3,4-b]-1,2,4-triazole (6a)
(Scheme 1). The structural assignment of 6a was established by spec-
troscopic studies and elemental analysis. Thus, the mass spectrum of
6a was compatible with the molecular formula C20H23N5OS2 (M+
413). Its IR spectrum indicated that it exist in the iminothiol-form 6 :
=
There is no absorption of the N C S group, NH group, and C O of thi-
1
azol ring, but band due to the SH group at 2560 cm is observed. The
tautomeric equilibrium between iminothiol-6 and thioamide-form 6
seems to be widely shifted toward the iminothiol form as indicated by
the 1H NMR spectrum which revealed a signlet at 7.85 ppm assigned
to the N (C N ) SH group and this peak disappear on addition of
deuterium oxide. Structure 6a was further confirmed by 13C NMR spec-
trum which gave conclusive evidence for iminothiol-form 6 . The spec-
trum reveals low-field signal at 154.4 (triazole C-2), 59.2 ppm (spiro
carbon) and the other signals appeared at expected field (Figure 1). If
the thioamide-form 6 is the reaction product, one would expect a sig-
nal for the triazole C-2 to appeare at higher values (see Experimental).
The formation of 6a involves intramolecular heterocyclization of 5, thus
the reaction of 5 with NaOH furnishes18 the ambident N,S anion, the
terminal nitrogen of which attacks the carbonyl carbon of 1,3-thiazole
ring to yield the corresponding 6. Compounds 6b,c were prepared in
similar way (Scheme 1). The structure of 6b,c were confirmed on the
same line as 6a (see Experimental).
EXPERIMENTAL
All mps were recorded on a Gallen Kamp apparatus and are uncor-
rected. IR spectra (cm 1) were recorded (as KBr pellets) on a Shimadzu
480 spectrophotometer. The 1H NMR spectra were measured in DMSO-
d6 with a Bruker AM 400 ( 400 MHz) spectrometer using TMS as an
internal standard; the 13C NMR spectra were recorded at 100 MHz.

Synthesis of Triazolo Derivatives
1179
The chemical shifts are expressed as values (ppm). Mass spectra were
determined on a Finnigan Mat 8430 mass spectrometer operating at
70 eV. Microanalytical data were obtained from Microanalytical unit
at Cairo University. Compound 1 was prepared by literature19 and the
starting materials were obtained commercially.
General Procedure for the Synthesis of
1-Cycloalkylidene-4-(2,3-dimethyl-1-phenyl-pyrazolone-
5-yl-4)-thiosemicarbazones 3a–c
The thiosemicarbazide 1 (0.01 mmol) was dissolved in 20 ml of hot
butanol, then cycloalkanones 2a–c (0.01 mmol) and 1 ml of acetic acid
were added and the mixture was refluxed for about 4–6 h. After cooling,
the resulting product was filtered off, washed with butanol and diethyl
ether, and recrystallized from AcOH/H2O (1:1).
1-Cyclohexaylidene-4-(2,3-dimethyl-1-phenyl-pyrazolone-
5-yl-4)-thiosemicarbazone (3a)
Obtained in 80% yield, m.p. 214–216 C; (found: C, 60.40; H, 6.50;
N, 19.60; S, 8.90. C18H23N5OS requires C, 60.48; H, 6.49; N, 19.59;
1
S, 8.97%); max/cm 3320–3150 (NH) 2900,2850 ( CH2 ), 1650 (CO),
1620 (C N), 1220 (C S);
1.41–2.10 (m, 10H, cyclohexyl protons),
H
2.17 (s, 3H,CH3), 3.09 (s, 3H, N CH3), 7.2–7.6 (m, 5H, Ar H), 9.3 (s,
1H, NH), 11.90 (s, 1H, NH);
15.7, 26.2, 27.0, 32.2, 33.1, 35.5, 112.2,
C
116.5, 118.8, 129.0, 131.6, 142.4, 156.0, 160.8, 178.4; m/z 357 (M+, 74%).
1-(2-Methyl-cyclohexaylidene)-4-(2,3-dimethyl-1-
phenylpyrazolone-5-yl-4)-thiosemicarbazone (3b)
Obtained in 78% yield, m.p. 206–208 C; (found: C, 61.50; H, 6.80;
N, 18.90; S, 8.50. C19H25N5OS requires C, 61.43; H, 6.78; N, 18.85; S,
1
8.63%); max/cm 3300–3150 (NH), 2900,2850 ( CH2 ), 1650 (CO),
1620 (C N), 1220 (C S);
0.78 (d, J 6.5 Hz, 3H, CH3), 1.43–2.11 (m,
H
8H, cyclohexyl protons), 2.19 (s, 3H, CH3), 2.23 (m, 1H, CH), 3.10 (s, 3H,
N CH3), 7.2–7.5 (m, 5H, Ar H), 9.40 (s, 1H, NH), 11.80 (s, 1H, NH);
m/z 371 (M+, 89%).
1-Cycloheptaylidene-4-(2,3-dimethyl-1-phenyl-pyrazolone-
5-yl-4)-thiosemicarbazone (3c)
Obtained in 68% yield, m.p. 208–210 C; (found: C, 61.50; H, 6.80;
N, 18.80; S, 8.60. C19H25N5OS requires C, 61.43; H, 6.78; N, 18.85;
1
S, 8.63%); max/cm 3320–3150 (NH) 2900,2850 ( CH2 ), 1650 (CO),
1620 (C N), 1220 (C S);
1.61–2.10 (m, 12H, cycloheptyl protons),
H

1180
R. M. Shaker
2.15 (s, 3H,CH3), 3.10 (s, 3H, N CH3), 7.2–7.5 (m, 5H, Ar H), 9.3 (s,
1H, NH), 11.8 (s, 1H, NH); m/z 371 (M+, 72%).
Synthesis of Spirothiazolidinones 5a–c
To a well stirred solution of 3a–c (0.05 mmol) in dry dioxane (50 ml) was
added mercaptoacetic acid (4) (0.075 mmol). The reaction mixture was
refluxed for 6–8 h (monitored by TLC). The clear solution thus obtained
was allowed to cool, poured into ice-cold water, and neutrallized with
NaHCO3. The crystalline product thus formed was filtered off, washed
with water, and recrystallized from dioxane.
4-[3-(2,3-Dimethyl-1-phenyl-pyrazolone-5-yl-4))-
thioureido]-1-thia-4-azaspiro-[4.5]-decan-3-one (5a)
Obtained in 64% yield, m.p. 262–263 C; (found: C, 55.70; H, 5.90; N,
16.30; S, 14.80. C20H25N5O2S2 requires C, 55.66; H, 5.84; N, 16.23; S,
1
14.86%); max/cm 3320–3150 (NH) 2900, 2850 ( CH2 ), 1685, 1650
(CO), 1620 (C N), 1220 (C S);
1.15–2.10 (m, 10H, cyclohexyl pro-
H
tons), 2.15 (s, 3H, CH3), 3.09 (s, 3H, N CH3), 3.52 (s, 2H, thiazolidinone
protons), 7.2–7.4 (m, 5H, Ar H), 11.9 (br, s, 2 NH); 15.8, 19.5, 27.4,
C
34.5, 35.5, 43.6, 53.5, 112.2, 116.4, 118.8, 128.8, 131.6, 142.4, 160.8,
164.6, 178.4; m/z 431 (M+, 78%).
4-[3-(2,3-Dimethyl-1-phenyl-pyrazolone-5-yl-4))-
thioureido]-6-methyl-1-thia-4-aza-spiro[4.5]decan-3-one
(5b)
Obtained in 65% yield, m.p. 242–243 C; (found: C, 56.50; H, 6.20; N,
15.80; S, 14.30. C21H27N5O2S2 requires C, 56.60; H, 6.11; N, 15.72; S,
1
14.39%); max/cm 3320–3150 (NH) 2900, 2850 ( CH2 ), 1685, 1650
(CO), 1620 (C N), 1220 (C S); H 0.80 (d, J 6.5 Hz, 3H, CH3), 1.15–2.10
(m, 8H, cyclohexyl protons), 2.15 (s, 3H, CH3), 2.25 (m, 1H, CH), 3.15
(s, 3H, N CH3), 3.46 (s, 2H, thiazolidinone protons), 7.2–7.6 (m, 5H,
Ar H), 11.8 (br, s, 2 NH); m/z 445 (M+, 80%).
4-[3-(2,3-Dimethyl-1-phenyl-pyrazolone-5-yl-4))-
thioureido]-1-thia-4-azaspiro-[4.6]-undecan-3-one (5c)
Obtained in 61% yield, m.p. 252–254 C; (found: C, 56.50; H, 6.00; N,
15.70; S, 14.40. C21H27N5O2S2 requires C, 56.60; H, 6.11; N, 15.72; S,
1
14.39%); max/cm 3320–3150 (NH) 2900, 2850 ( CH2 ), 1680, 1650
(CO), 1620 (C N), 1220 (C S);
1.61–2.10 (m, 12H, cycloheptyl pro-
H
tons), 2.17 (s, 3H, CH3), 3.10 (s, 3H, N CH3), 3.49 (s, 2H, thiazolidinone
protons), 7.2–7.6 (m, 5H, Ar H), 11.9 (br, s, 2 NH); m/z 445 (M+, 82%).

Synthesis of Triazolo Derivatives
1181
Synthesis of 1-(2,3-Dimethyl-1-phenyl-pyrazolone-5-yl-4)-
2-mercapto-10,5-cycloalkane-spiro[1,3]thiazolo[3,4-b]-1,2,4-
triazoles 6a–c
To a solution of NaOH (0.01 mmol) in methanol (30 ml), spirothiazo-
lidinone 5a–c (0.01 mmol) was added and the mixture was refluxed
for 5–6 h. The solid was then collected while hot, and poured in water
(50 ml), the mixture was acidified with concentrated hydrochloric acid
and stirred for 1 h. The precipitated solid was filtered off, washed with
water, and disolved in the minimum volume of acetone. The residue
was sujected to PLC chromatography using tolune-ethylacetate (3:2)
as eluent. The pure products were recrystallized from dioxane.
1-(2,3-Dimethyl-1-phenyl-pyrazolone-5-yl-4)-2-mercapto-
10,5-cyclohexane-spiro[1,3]thiazolo-[3,4-b]-1,2,4-triazole
(6a)
Obtained in 64% yield, m.p. 276–278 C; (found: C, 58.20; H, 5.50; N,
17.00; S, 15.40. C20H23N5OS2 requires C, 58.09; H, 5.61; N, 16.93; S,
1
15.51%); max/cm 2900, 2850 ( CH2 ), 2560 (SH), 1650 (CO), 1620
(C N);
1.12–2.10 (m, 10H, cyclohexyl protons), 2.15 (s, 3H, CH3),
H
3.20 (s, 3H, N CH3), 7.2–7.7 (m, 6H, Ar H and CH), 7.85 (s, 1H, SH);
15.8, 18.8, 26.6, 35.5, 37.2, 59.2, 84.2, 106.1, 112.2, 118.8, 129.0,
C
131.8, 137.4, 142,4, 154.4, 160.8; m/z 413 (M+, 72%).
1-(2,3-Dimethyl-1-phenyl-pyrazolone-5-yl-4)-2-mercapto-
10,5-(20-methyl-cyclohexane)-spiro[1,3]thiazolo[3,4-b]-
1,2,4-triazole (6b)
Obtained in 60% yield, m.p. 266–268 C; (found: C, 59.00; H, 5.80; N,
16.50; S, 14.90. C21H25N5OS2 requires C, 58.99; H, 5.89; N, 16.38; S,
1
15.00%); max/cm 2900, 2850 ( CH2 ), 2565 (SH), 1650 (CO), 1620
(C N);
0.79 (d, J 6.5 Hz, 3H, CH3), 1.23–2.13 (m, 8H, cyclohexyl
H
protons), 2.15 (s, 3H, CH3), 2.29 (m, 1H, CH), 3.15 (s, 3H, N CH3),
7.2–7.7 (m, 6H, Ar H and CH), 7.85 (s, 1H, SH); m/z 427 (M+, 76%).
1-(2,3-Dimethyl-1-phenyl-pyrazolone-5-yl-4)-2-mercapto-
10,5-cycloheptane-spiro[1,3]-thiazolo-[3,4-b]-1,2,4-triazole
(6c)
Obtained in 60% yield, m.p. 270–272 C; (found: C, 58.90; H, 6.00; N,
16.40; S, 15.00. C21H25N5OS2 requires C, 58.99; H, 5.89; N, 16.38; S,
1
15.00%); max/cm 2900, 2850 ( CH2 ), 2560 (SH), 1650 (CO), 1620
(C N);
1.61–2.20 (m, 12H, cycloheptyl protons), 2.15 (s, 3H, CH3),
H
3.20 (s, 3H, N CH3), 7.2–7.7 (m, 6H, Ar H and CH), 7.85 (s, 1H, SH);
m/z 427 (M+, 82%).

1182
R. M. Shaker
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