Synthesis, structure, and in vitro anti-HIV activity of new pyrazole, 1,2,4-thiadiazole, and 1,2,4-triazole derivatives

Article abstract of DOI:10.1080/10426500801968003

α,α'-Dichloroazo compounds 6 react with Lewis acid to furnish 1-(chloroalkyl)-1-aza-2-azoniaallene salts 4. The cations 4 react with acetylenes, isothiocyanates, isocyanates, and carbodiimides under [3+2]-cycloaddition. The cycloadducts undergo consecutiv

Full text of DOI:10.1080/10426500801968003

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Synthesis, Structure, and In
Vitro Anti-HIV Activity of New
Pyrazole, 1,2,4-Thiadiazole,
and 1,2,4-Triazole Derivatives
Y. A. Al-Soud a
a Department of Chemistry, College of Science,
University of Al-al-Bayt, Al-Mafraq, Jordan
Version of record first published: 25 Sep 2008.
To cite this article: Y. A. Al-Soud (2008): Synthesis, Structure, and In Vitro Anti-
HIV Activity of New Pyrazole, 1,2,4-Thiadiazole, and 1,2,4-Triazole Derivatives,
Phosphorus, Sulfur, and Silicon and the Related Elements, 183:10, 2621-2636
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Phosphorus, Sulfur, and Silicon, 183:2621–2636, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500801968003
Synthesis, Structure, and In Vitro Anti-HIV Activity of
New Pyrazole, 1,2,4-Thiadiazole, and 1,2,4-Triazole
Derivatives
Y. A. Al-Soud
Department of Chemistry, College of Science, University of Al-al-Bayt,
Al-Mafraq, Jordan
α,αꢀ-Dichloroazo compounds 6 react with Lewis acid to furnish 1-(chloroalkyl)-1-
aza-2-azoniaallene salts 4. The cations 4 react with acetylenes, isothiocyanates,
isocyanates, and carbodiimides under [3+2]-cycloaddition. The cycloadducts un-
dergo consecutive reactions, e.g., [1,2]-shifts of alkyl groups. The newly synthesized
products were evaluated for their anti-HIV-1 and anti-HIV-2 activity in MT-4 cells.
Keywords 1,2,4-Thiadiazolse; 1,2,4-Triazole; NNRTIs; pyrazoles; synthesis
INTRODUCTION
HIV-1 reverse transcriptase (RT) is a key enzyme in HIV replication
as well as a key target for developing anti-HIV drugs. Two types
of reverse transcriptase inhibitor have been developed;1−3 nucleo-
side reverse transcriptase inhibitors (NRTIs) and non-nucleoside re-
verse transcriptase inhibitors (NNRTIs). Three NNRTIs, nevirapine,4
delaviridine,5,6 and efavirenz7 have been approved by the Food and
Drug Administration (FDA) for the treatment of HIV infection; how-
ever, significant resistance has developed against the current NNRTIs
and there is an urgent need to develop new anti-HIV agents that are ef-
fective against resistant mutants.8,9 Several potent heterocyclic NNR-
TIs have been synthesized with high anti-HIV inhibitory activity, some
of which have an pyrazole scaffold.10 Moreover, numerous examples
of pyrazoles have been reported with a range of biological activities
Received 1 December 2007; accepted 21 January 2008.
This work was supported by the DAAD (Deutscher Akademischer Austausch Dienst).
We thank Professor N. Al-Masoudi, Konstanz, Germany, for helpful discussion, as well
as Professors E. De Clercq and C. Pannecouque, Rega Institute for Medical Research,
Belgium, for the anti-HIV screening.
Address correspondence to Y. A. Al-Soud, Department of Chemistry, Al al-Bayt Uni-
versity, BOX 130090, Al-Mafraq, Jordan. E-mail: alsoud@rocketmail.com
2621

2622
Y. A. Al-Soud
including antipyretic11 and antidepressant12 activities. Important
application of pyrazoles derivatives as antibiotics has also been
reported.13,14 In addition, several 1,3,4-thiadiazole nucleus constitutes
the active part of several biologically active compounds, including
antimycotic15,16 and anti-inflammatory agents.17−19 Moreover, 1,2,4-
triazole moiety is present, for example, in certain antiasthmatic,20
antiviral (ribavirin),21 antifungal (fluconazole),22 antibacterial,23 and
hypnotic (triazolam)24 drugs. Based on the above reports, and in con-
tinuation of our research on the synthesis of biologically active hete-
rocyclic molecules, the synthesis and anti-HIV evaluation of the title
compounds are reported.
RESULTS AND DISCUSSION
Chemistry
Jochims et al.25−29 described synthesis of 1-aza-2-azoniaallene salts
1. These salts undergo cycloaddition to many types of multiple bonds
(alkenes, nitriles, alkynes, isothiocyanates, isocyanates, and carbodi-
imides) to afford heterocyclic salts. Cycloaddition of 1 suffers from the
disadvantage that one ends up with salts. For applications, electrically
neutral to circumvent this problem, we tried to prepare heterocumu-
lenes 1 substituted with a leaving group R3 (e.g., CClR1R2) which can
finally be removed from the cycloadduct 2 and 3 (Figure 1).
Recently, we reported polar [3+2]-cycloadditons of 1-aza-2-
azoniaallene cations, 4 to nitriles, we synthesized a variety of
FIGURE 1 Reagents and conditions: i. t-BuOCl, CHCl3; ii. MCln (SbCl5, TiCl4,
SnCl4), CH2Cl2, −60◦C; iii. X = Y (alkenes, alkynes, nitriles, isocyanates, car-
bodiimides); R1, R2 = alkyl, aryl, CO2R, tert-butyl), −60◦C to 23◦C; iv. R4CN,
−60◦C to 23◦C; and v. NaHCO3, NH3, MeCN, H2O, 0◦C, 2 h.

New Pyrazole, 1,2,4-Thiadiazole, and 1,2,4-Triazole Derivatives
2623
FIGURE 2 Reagents and conditions: i. AlCl3, CH2Cl2, −60◦C; ii. −60◦C to
23◦C; iii. NaHCO3, NH3, MeCN, H2O, 0◦C, 2 h; iv. picric acid in EtOH; and v.
NaClO4 in MeCN.
1,5-dialkyl-1H-1,2,4-triazoles 5 (Figure 1) bearing different precur-
sors such as C-nucleosides,30 acyclic C-nucleosides,31 pyrimidines,32
N-alkylphthalimides,33 D-mannopentitol-1-yl-1,2,4-triazoles,34 1H-
indoles,35 quinolones,35 benzotriazoles,36 3ꢀ -triazolo-thymidines,37
acetic acid alkylidene hydrazides,38 1,4-disubstituted piperazines,39,40
and thiophenes.41
Here, we report that [3+2]-cycloadditons of cations 4 are not limited
to nitriles but can be carried out with many types of multiple bonds.
The reactive intermediates 4ꢀ (Figure 2) were obtained from the
α,αꢀ-di-chloroazo compounds 6a–g42,43 by the treatment with AlCl3 at
−60◦C. At approximately −30◦C, the color changed from orange to
brown, indicating that cumulenes 4ꢀa–g underwent cycloaddition re-
actions with acetylenes 7a–g to give the pyrazolium salts 9 or 10 via
3H-pyrazolium salts 8. With asymmetric acetylenes, the cycloadditions
occurred with complete regioselectivity.
Alkyl and aryl mono- and disubstituted acetylens can be used.
However, electron-deficient acetylenes—e.g., acetylenedicarboxlic acid
dimethylester—did not react with 4ꢀ. The use of antimony pentachlo-
ride as Lewis acid often led to tarry products. Apparently, the acetylenes
were oxidatively destroyed by SbCl5. No such decomposition was en-
countered with AlCl3 as the Lewis acid.

2624
Y. A. Al-Soud
The scope of the reaction is limited by the fact that the primarily
formed 3H-pyrazolium salts 8 rearrange to mixtures of 1H- and 4H-
pyrazolium salts 9 and 10. In situ hydrolysis of 9 and 10 with aqueous
NaHCO3 and aqueous NH3, afforded the pyrazoles 11 and 12 respec-
tively. Thus, from the cumulene 4ꢀa and phenylacetylene (7a), only the
1H-pyrazoles 11a was obtained in 48% yield. However, the cumulenes
4ꢀb–d and diphenylacetylene give a mixture of 11b–d and 12b–d in 84–
91% yield, which separated by column chromatography. Finally, from
the cation 4ꢀe and diphenylacetylene the 3H-pyrazolium salt 8e was
formed exclusively, which hydrolyzed to 3H-pyrazole 13 in 72% yield.
Interestingly, for cation 8e, the [1, 2]-shift of R2 (R2 = methyl) not
observed.
With monosubstituted acetylenes (R3 = H) the intermediate 4H-
pyrazolium salts 10 could not be obtained. Instead, 1H-pyrazolium salts
14 resulting from a [1, 3]-prototropic rearrangement of 10 were isolated
and characterized as their perchlorates or picrates. Again, from the
intermediates 4ꢀf and 4ꢀg only the salts 14f and 14g were isolated,
which hydrolyzed to 1H-pyrazoles 15f and 15g and characterized as
perchlorate and picrate in 85 and 76% yield, respectively.
The constitutions of compounds 11–13 were easily derived from the
NMR spectra. For instance, the 1H NMR spectrum (recorded in CDCl3)
of the pyrazole 11c showed multiplet for NCH2 at δ = 4.36 together
with five multiplets for C-CH2 groups (δ = 1.69–2.71) bound directly
to the heterocyclic ring. The 13C-NMR resonances for C(4) and C =
N of compounds 12a–d appear at δ = 72.3–72.6 and δ = 176.7–184.4,
respectively.
Addition of isothiocyanates 16a,b to the reactive intermediate 4ꢀꢀ,
which prepared from α,αꢀ-di-chloroazo compound 6 (R1= R2= Me)42,43
by the treatment with SbCl5 at −60◦C. By employing the methods of
Jochims et al.,44 lead to a color change of the orange suspension of
4ꢀꢀ between −60◦C and +23◦C indicating a cycloaddition reaction. The
resulting 1,3,4-thiadiazole 17a,b lost its CMe2Cl group and furnished
the moderately stable iminium salts 18a,b (Figure 3), the presence of
traces of moisture in the reaction mixtures is likely to be responsible
for these results. Imine19a,b was obtained by hydrolysis of the salts
18a,b in 85 and 76% yield, respectively. Correspondingly, from allene
4ꢀꢀ the heterocycle 19c were prepared in 77% yield.
The concerted cycloadditions to isothiocyanates are known to occur
both on the C=S and the C=N bond in a competitive manner.44 The
isothiocyanate group of compound 16 reacts as S-nucleophile result-
ing in 2,5-dihydro-1,3,4-thiadiazole 19 and not as N-nucleophile, which
would have resulted in an isomeric 4,5-dihydro-1H-1,3,4-triazole-5-
thione.

New Pyrazole, 1,2,4-Thiadiazole, and 1,2,4-Triazole Derivatives
2625
FIGURE 3 Reagents and conditions: i. CH2Cl2, −60◦C to 23◦C; and ii.
NaHCO3, NH3, MeCN, H2O, 0◦C, 2 h.
1
Compounds 19a–c were identified from the H-NMR and 13C-NMR
spectra, which are in agreement with those of thiadiazole analogous
obtained by Jochims et al.44 The 1H NMR spectrum of 19c (recorded in
CDCl3) is characterized by the presence of singlet at δ = 1.88, which
were attributed to the four methyl groups. The 13C NMR shifts at δ =
107.3 and 175.1 observed for 19c are assigned to the sp3 hybridized
ring carbon atom C(5) and C(2) of the thiadiazole ring, and at δ = 28.3
attributed to the methyl on C(5).
From the hexachloroantimonate 4ꢀꢀ and isocyanate 20 (Figure 4), the
triazolium salts 21 was formed exclusively. It is noteworthy that the
isocyanate acted as a nucleophilic in this reaction,28 the [1, 2]-shift
of R2 (R2 = methyl) not observed. The resulting 1,2,4-triazolium salts
21 lost its CMe2Cl group and afforded salts 22, which hydrolyzed to
furnished the neutral 5-oxo-4,5-dihydro-3H-1,2,4-triazole derivatives
23. The structures of the compounds 23a–c were confirmed by the 1H-,
1
13C-NMR, and mass spectra. The H NMR spectrum of 23c (recorded
in CDCl3) is characterized by the presence of singlet at δ = 1.59, which
were attributed to the two methyl groups. The 13C-NMR shifts at δ =
161.5 observed for 23c is assigned to C O.
Finally, cycloaddition of carbodiimides 24 to heteroallen 4ꢀꢀ provided
the triazolium salts 25, which lost its CMe2Cl group to furnish the
iminium salts26. Neutralization of salts 26 with aqueous NaHCO3
and aqueous NH3, afforded the 3H-1,2,4-triazoles 27 (Figure 5). The
1
structure of 27a–c was determined from the H, 13C NMR and mass
spectrum.

2626
Y. A. Al-Soud
FIGURE 4 Reagents and conditions: i. CH2C12, −60◦C to 23◦C; ii. NaHCO3,
NH3, MeCN, H2O, 0◦C, 2 h.
In-Vitro Anti-HIV Assay
Compounds 11b,c, 13, 15g, 19a, 19c, 23a, and 27a,b were tested for
their in vitro anti-HIV-1 (strain IIIB) and anti-HIV-2 (strain ROD)
activity in human T-lymphocyte (MT-4) cells using the MT-4/MTT
assay.45 The antiviral activity was compared with that of the known
and approved antiviral drugs efavirenz7 and capravirine.46 The results
FIGURE 5 Reagents and conditions: i. CH2C12, −60◦C to 23◦C; ii. NaHCO3,
NH3, MeCN, H2O, 0◦C, 2 h.

New Pyrazole, 1,2,4-Thiadiazole, and 1,2,4-Triazole Derivatives
2627
TABLE I In vitro Anti-HIV-1a and HIV-2b of Some New Heterocycles
Compound
11b
Virus strain
EC50 (µg/mL)c
CC50 (µg/mL)d
SIe
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
IIIB
IIIB
ROD
IIIB
ROD
IIIB
ROD
IIIB
>3.4
>3.7
>2.1
3.88 0.39
3.88 0.39
2.27 0.11
2.27 0.11
12.40 1.72
2.27 1.72
62.60 1.69
62.60 1.69
9.66 0.96
9.66 1.69
57.53 11.10
57.53 11.10
55.80 3.36
55.80 3.36
65.95 4.74
65.95 4.74
68.85 3.64
68.85 3.64
40
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
11c
13
>2.3
>11.7
>11.0
>63.1
>59.8
>10.1
>8.3
>47.0
>56.0
>57.1
>50.8
>65.0
>60.6
>65.2
>65.2
0.003
0.0014
15f
19a
19c
23a
27a
27b
ROD
IIIB
IIIB
IIIB
IIIB
<1
13,333
7,857
Efavirenz7
Capravirine46
11
aAnti-HIV-1 activity measured with strain IIIB.bAnti-HIV-2 activity measured with
strain ROD. cCompound concentration required to achieve 50% protection of MT-4 cells
from the HIV-1- and 2-induced cytopathogenic effect. dCompound concentration that
reduces the viability of mock-infected MT-4 cells by 50%. eSI: Selectivity index
(CC50/EC50).
are summarized in Table I. All tested compounds proved to be less
active than efavirenz and capravirine. None of the tested compounds
was found to inhibit HIV-1 or HIV-2 replication in vitro at EC50 lower
than the cytotoxic concentration (CC50), resulting in a selectivity index
<1. The structure-activity relationship suggested that pyrazoles mani-
fested a higher HIV inhibitory activity than that of the 1,3,4-thiadiazol
or 1,2,4-triazoles. Thus, pyrazole 11c showed the highest activity (EC50
= 2.12 µg/mL), but did not demonstrate selectivity. Such a result would
lead us to modify the structures of the pyrazole residue with more po-
tential groups.
EXPERIMENTAL
Materials and Methods
¨
Chemistry melting points were measured on a Buchi melting
¨
point apparatus B-545 (BUCHI Labortechnik AG, Switzerland) and
are uncorrected. Microanalytical data were obtained with a Vario,

2628
Y. A. Al-Soud
Elementar apparatus (Shimadzu, Japan). NMR spectra were recorded
on 300 and 600 MHz (1H) and on 150.91 MHz (13C) spectrometers
(Bruker, Germany) with tetramethylsilane (TMS) as internal standard
and on d scale in ppm. Mass spectra were measured on a MAT8200
spectrometer on 70 eV EI.
Cycloaddition of the 1-(1-Chloroalkyl)-1-aza-2-azoniaallene
Salts—General Procedures
Method A. solution of SbCl5 (2.99 g, 10 mmol) in CH2Cl2 (15 ml)
is added dropwise to a cold (−70◦C) stirred solution of the azo(1-
chloroalkane) 6 (10 mmol) and the unsaturated compounds (isothio-
cyanates, isocyanates or carbodiimides) in CH2Cl2 (50 ml). After stir-
ring between −60◦C and −10◦C for 2 h and then at 0◦C for 10 min the
solvent is evaporated. Alternatively, the product is precipitated at 0◦C
by addition of pentane. The resulting salt is hydrolyzed to furnish the
neutral heterocycle.
Method B. A solution of 6 (10 mmol) in CH2Cl2 (60 ml) is added
dropwise to a cold (−60◦C) suspension of AlCl3 (1.34 g, 10 mmol) in
CH2Cl2 (20 ml). After 5 min, a solution of the alkyne (10 to 12 mmol) in
CH2Cl2 (20 ml) is added dropwise. The mixture is stirred at −60◦C for 1
h and finally at 23◦C for 10 min. Evaporation of the solvent affords the
very moisture sensitive dark brown oily tetrachloroaluminate, which
is hydrolyzed to the neutral heterocycle, or it is transformed into the
crystalline perchlorate or picrate.
Hydrolysis
At 0◦C a solution of NaHCO3 (8.40 g, 100 mmol) in H2O (100 ml)
containing NH3 (1.70 g, 100 mmol) is added dropwise to the solution
of the crude salts 8e, 9a–d, 10b–d, 14f,g, 18a,b, 18c, 22a–c, 26a–c,
in MeCN (100 ml). After stirring at 0◦C for 2 h, the organic layer is
separated and the aqueous layer is extracted with MeCN (3 × 50 ml).
The combined MeCN extracts are concerted under reduced pressure
to a volume of ca 30 ml. After the addition of CH2Cl2 (100 ml), the
water phase is separated, and the organic phase is dried with Na2SO4.
Filtration after addition of decolorizing carbon and evaporation of the
solvent affords the products 13, 11a–d, 12b–d, 15f,g, 19a,b, 19c, 23a–
c, 27a–c, respectively, which are purified either by crystallization or by
column chromatography.

New Pyrazole, 1,2,4-Thiadiazole, and 1,2,4-Triazole Derivatives
2629
Formation of the Perchlorate from the Tetrachloroaluminate
The crude tetrachloroaluminate 15f is dissolved in MeCN (60 ml).
After addition of NaClO4·H2O (1.41 g, 10 mmol) in MeCN (20 ml) the
mixture is stirred for 3 h. Filtration and concentration of the filtrate
under reduced pressure affords the 15f (perchlorate), which is purified
by recrystallization.
1-Isopropyl-5-methyl-3-phenyl-1H-Pyrazole (11a)
From azo(1-chloro-1,2-dimethylpropane) 6a47,48 (2.39 g, 10 mmol) and
phenylacetylene (1.23 g, 12 mmol) (method B). However, the oily tetra-
chloroaluminate 9a was precipitated from the reaction mixture by ad-
dition of pentane (200 ml). Hydrolysis afforded a yellow foam, which
was crystallized at – 15◦C from pentane to furnish yellow prisms (0.96
1
g, 48%); m.p. 97–99◦C (dec). H NMR (CDCl3): δ 1.51 (d, J = 6.6, 6H),
2.30 (CH3), 4.42 (sept, J = 6.6, CH), 6.28 (H4), 7.21–7.80 (m,s, phenyl).
13C-NMR (CDCl3): δ 11.1, 22.5 (2C) (CH3), 49.9 (CH), 102.3 (C4), 125.5,
127.1, 128.5, 134.2, 138.1, 149.6 (phenyl, C=). Anal. calcd. for C13H16N2
(200.3): C, 77.96; H, 4.81; N, 8.05. Found: C, 77.66; H, 8.18; N, 13.63;
MS: m/z (EI) 200.
1,5-Diethyl-3,4-diphenyl-1H-Pyrazole (11b) and
4,5-Diethyl-3,4-diphenyl-3H-Pyrazole (12b)
From azo(1-chloro-1-ethylpropane) 6b42 (2.39 g, 10 mmol) and dipheny-
1
lacetylene (1.78 g, 10 mmol) (Method B). According to the H NMR
spectrum, the orange oil obtained (2.38, 86%) after hydrolysis con-
sisted of an 1:1 mixture of 11b and 12b. The two products were sepa-
rated by column chromatography (120 g SiO2for flash chromatography;
pentane/Et2O (7:3) as eluent). Evaporation of the solvent of the faster
running product afforded an oil, which crystallized at – 15◦C from pen-
tane to furnish 11b as colorless prisms (1.10 g, 40%); m.p. 79–81◦C
(dec). 1H NMR (CDCl3): δ 1.11 (t, J = 7.5), 1.51 (t, J = 7.2), (CH3), 2.58
(q, J = 7.5), 4.14 (q, J = 7.2) (CH2), 7.14–7.45 (m’s, phenyl). 13C-NMR
(CDCl3): δ 14.4, 16.0, 17.4, 44.0 (CH3, CH2), 117.9, 126.5, 127.0, 127.8,
128.0, 128.4, 130.3, 133.8, 134.5, 142.2, 148.0 (phenyl, C=). Anal. calcd.
for C19H20N2 (276.4): C, 82.57; H, 7.29; N, 10.14. Found: C, 82.25; H,
7.11; N, 10.03; MS: m/z (EI) 276.
Concentration of the second fraction of the column chromatography
1
afforded 12b as orange oil (0.45 g, 16%). H NMR (CDCl3): δ 0.54 (t,
J = 7.4), 1.18 (t, J = 7.2), (CH3), 2.04–2.44 (m’s, 2 CH2), 7.09–7.65 (m’s,
10 H, phenyl). 13C-NMR (CDCl3): δ 7.7, 10.4, 20.1, 24.7 (CH3, CH2),

2630
Y. A. Al-Soud
72.9 (C4), 125.9, 127.8, 128.1, 128.6, 129.5, 130.7, 135.3, 176.7, 183.7
(phenyl, C=). Anal. calcd. for C19H20N2 (276.4): C, 82.57; H, 7.29; N,
10.14. Found: C, 82.32; H, 7.12; N, 9.88; MS: m/z (EI) 276.
5,6,7,8-Tetrahydro-2,3-diphenyl-4H-Pyrazolo[1,5-a]azepine
(11c) and
3a,4,5,6,7,8-Hexahydro-3,3a-diphenylcycloheptapyrazole (12c)
From azo(1-chlorocyclohexane) 6c42,43 (2.63 g, 10 mmol) and dipheny-
lacetylene (1.78 g, 10 mmol) (Method B). For complete hydroly-
sis of the brown tetrachloroaluminates 9c, 10c the mixture in
MeCN/NaHCO3/NH3/H2O had to be stirred at 0◦C for 4 h and at 23◦C
for another 24 h. Workup afforded a mixture of 11c and 12c (ca 2:1
according to the 1H NMR spectrum) as orange oil (2.63, 91%). The
products were separated by column chromatography (150 g SiO2 for
flash chromatography, Et2O as eluent). Evaporation of the solvent of
the faster running product afforded 11c as colorless needles (1.66 g,
58%); m.p. 101–103◦C (dec). 1H NMR (CDCl3): δ 1.69 (m, 2H), 1.87 (m,
4H), 2.71 (m, 2H), 4.36 (m, 2H) (CH2), 7.15–7.43 (m’s, 10H, phenyl). 13
C
NMR (CDCl3): δ 24.6, 27.0, 28.1, 31.0, 53.4 (CH2), 118.6, 126.5, 127.0,
127.9, 128.1, 128.4, 130.5, 133.7, 134.3, 143.0, 146.9 (phenyl, C=). Anal.
calcd. for C20H20N2 (288.4): C, 83.30; H, 6.99; N, 9.71. Found: C, 83.18;
H, 6.96; N, 9.61; MS: m/z (EI) 288.
Concentration of the second fraction of the column chromatography
afforded 12c as orange powder (0.39 g, 14%), which was crystallized
at −15◦C from pentane to furnish a pale yellow crystalline powder;
m.p. 113–114◦C (dec). 1H-NMR (CDCl3): δ 1.03–1.16 (m, 1H), 1.50–1.89
(m, 5H), 2.10 (m, 1H), 2.30 (m, 1H), 2.57 (m, 1H), 2.92 (m, 1H) (CH2),
7.15–7.63 (m’s, 10H, phenyl). 13C NMR (CDCl3): δ 24.4, 27.4, 27.5, 29.4,
30.4 (CH2), 72.3, C3a), 126.5, 128.1, 128.2, 128.5, 129.5, 129.8, 130.5,
134.0 (phenyl), 178.3, 184.4 (C=N). Anal. calcd. for C20H20N2 (288.4):
C, 83.30; H, 6.99; N, 9.71. Found: C, 83.28; H, 6.96; N, 9.76; MS: m/z
(EI) 288.
1-Ethyl-5-methyl-3,4-diphenyl-1H-Pyrazole (11d) and
4-Ethyl-5-methyl-3,4-diphenyl-4H-Pyrazole (12d)
From azo(1-chloro-1-metylpropane) 6d42 (2.11 g, 10 mmol) and dipheny-
lacetylene (1.78 g, 10 mmol) as described for analogues 11c, 12c. Ac-
cording to the 1H NMR spectrum, the orange oil obtained after hydrol-
ysis of the tetrachloroaluminates 9d, 10d consisted of a 3:2 mixture
of 11d and 12d. The products (2.22, 84%) were separated by column

New Pyrazole, 1,2,4-Thiadiazole, and 1,2,4-Triazole Derivatives
2631
chromatography (125 g SiO2for flash-chromatography, pentane/Et2O
(7:2) as eluent). A first fraction consisted of a mixture of compounds.
From the second fraction compound, 11d was obtained as pale yellow
powder (0.62 g, 24%); m.p. 71–73◦C (dec). 1H NMR (CDCl3): δ 1.43 (t, J
= 7.2), 2.27 (CH3), 4.11 (q, J = 7.2) (CH2), 7.13–7.46 (m,s, phenyl). 13C-
NMR (CDCl3): δ 9.8, 15.4, 44.2 (CH3, CH2), 118.5, 126.4, 127.0, 127.9,
128.0, 128.3, 130.2, 133.8, 134.3, 136.3, 147.9 (phenyl, C=). Anal. calcd.
for C18H18N2 (262.4): C, 82.41; H, 6.92; N, 10.68. Found: C, 82.34; H,
7.26; N, 9.60; MS: m/z (EI) 262.
A third fraction of the column chromatography afforded 12d as or-
ange oil (0.39 g, 14%). 1H NMR (CDCl3): δ 0.54 (t, J = 7.4), 1.95 (CH3),
2.36 (m, CH2), 7.08–7.67 (m’s, 10 H, phenyl). 13C NMR (CDCl3): δ 7.6,
12.2, 24,6 (CH3, CH2), 72.8 (C4), 125.8, 127.6, 128.1, 128.6, 129.5, 130.8,
135.1 (phenyl), 176.9, 179.9 (C=N). Anal. calcd. for C18H18N2 (262.4):
C, 82.41; H, 6.92; N, 10.68. Found: C, 82.58; H, 7.21; N, 10.28; MS: m/z
(EI) 262.
3,3-Dimethyl-4,5-diphenyl-3H-Pyrazole (13)
From 6 (R1= R2= Me)42,43 (1.83 g, 10 mmol) and diphenylacetylene (1.78
g, 10 mmol) (method B). Hydrolysis of the brown oily tetrachloroalumi-
nate 8 afforded an orange oil, which crystallized at −15◦C from EtOH
(15 ml) to furnish a pale yellow powder (1.80 g, 72%); m.p. 81–83◦C
(dec). 1H-NMR (CDCl3): δ 1.51 (6H, CH3), 7.14–7.75 (m’s, 10H, phenyl).
13C-NMR (CDCl3): δ 20.6 (CH3), 96.7 (C), 127.7, 128.2, 128.4, 128.5,
129.1, 131.3, 133.3, 149.2, 152.0 (aryl, C=). Anal. calcd. for C17H16N2
(248.3): C, 82.23; H, 6.49; N, 11.28. Found: C, 82.27; H, 6.46; N, 11.25;
MS: m/z (EI) 248.
4,5-Dimethyl-3-phenyl-1H-Pyrazolium Perchlorate (15f)
From 6 (R1= R2= Me) (1.83 g, 10 mmol) and phenylacetylene (1.23 g,
12 mmol) (method B). From the black oily tetrachloroaluminate 14f the
perchlorate 15f was obtained as colorless powder. Yield: 2.32 g (85%)
1
m.p. 110–112◦C (dec). H NMR (CDCl3): δ 2.16, 2.43 (6H, 2CH3); 7.61
(m, phenyl); 12.30 (br, NH). 13C NMR (CDCl3): δ 8.3, 10.1 (CH3); 115.4
(C4); 126.9, 129.4, 130.4, 132.0, 146.3, 146.7 (phenyl, C=). Anal. calcd.
for C11H13NClN2O4 (272.3): C, 48.45; H, 4.81; N, 10.27. Found: C, 48.37;
H, 4.89; N, 10.26; MS: m/z (EI) 272.

2632
Y. A. Al-Soud
3-Butyl-4,5-dimethy-1H-Pyrazolium Picrate (15g)
From 6 (R1= R 2= Me) (1.83 g, 10 mmol) and 1-hexyne (0.99 g, 12 mmol)
(method B). Hydrolysis afforded an orange oil, which was dissolved in
EtOH (12 ml). A saturated solution of picric acid in EtOH (ca 30 ml)
was added. At – 15◦C crystallized as yellow powder (2.12 g, 76%); m.p.
1
122–124◦C (dec). H NMR (CDCl3): δ 0.89 (t, J = 7.4, 3H), 1.25–1.64
(m, 4 H), 2.04, 2.41 (CH3), 2.71 (t, J= 7.4, 2 H), 8.94 (br, NH). 13C
NMR (CDCl3): δ 7.2, 9.8, 13.5, 22.7, 24.2, 30.3 (CH3, CH2), 113.7 (C4);
126.3, 129.5, 130.4, 141.1, 143.1, 147.3, 161.5 (aryl, C=). Anal. calcd.
for C15H19N5O7 (381.1): C, 47.24; H, 5.02; N, 18.37. Found: C, 47.37; H,
4.89; N, 18.26; MS: m/z (EI) 381.
2,5-Dihydro-2,2-dimethyl-5-phenylimino-1,3,4-thiadiazole
(19a)44
From 6 (R1= R2= Me) (1.83 g, 10 mmol) and phenyl isothiocyanate
(1.35 g, 10 mmol). The orange oily hexachloroantimonate 18a was pre-
cipitated from the reaction mixture by addition of pentane (120 ml).
Hydrolysis afforded 19a as a yellow powder, which was crystallized at
−15◦C from Et2O (50 ml) to furnish a pale yellow powder. Yield: 1.50 g
(73%) m.p. 100–102◦C (lit.44] m.p. 100–102◦C). 1H NMR (CDCl3): δ 1.86
(2 CH3); 7.24–7.48 (m, phenyl). 13C NMR (CDCl3): δ 28.3 (2C, 2CH3);
106.9 (C2); 121.0, 126.8, 129.4, 148.2 (phenyl); 174.3 (C=N). Anal. calcd.
for C10H11N3S (205.3): C, 58.51; H, 5.40; N, 20.47. Found: C, 58.02; H,
5.46; N, 20.91; MS: m/z (EI) 205.
5-Benzlimino-2,5-dihydro-2,2-dimethyl-1,3,4-thiadiazol (19b)
From 6 (R1= R2= Me) (1.83 g, 10 mmol) and benzyl isothiocyanate (1.49
g, 10 mmol). The orange oil obtained after hydrolysis was crystallized
at −15◦C from Et2O (50 ml) to furnish an orange semisolid powder.
Yield: 1.40 g (64%) m.p. 39–41◦C. 1H NMR (CDCl3): δ 1.85 (2CH3); 1.64
(2H,CH2); 7.25–7.45 (m, phenyl). 13C NMR (CDCl3): δ 28.4 (2C, 2 CH3);
62.3 (CH2) 106.4 (C2); 127.3, 127.9, 128.6, 137.8 (phenyl); 177.0 (C=N).
Anal. calcd. for C11H13N3S (219.3): C, 60.24; H, 5.97; N, 19.16. Found:
C, 60.14; H, 5.94; N, 19.00; MS: m/z (EI) 219.
1,3-Bis(2,5-dihydro-2,2-dimethyl-1,3,4-thiadiazol-5-
ylideneamino)benzene (19c)
From 6 (R1= R2= Me) (3.66 g, 20 mmol), 1,3-phenylene diisothiocyanate
(1.92 g, 10 mmol) and SbCl5 (5.98 g, 20 mmol). The dark brown oily

New Pyrazole, 1,2,4-Thiadiazole, and 1,2,4-Triazole Derivatives
2633
hexachloroantimonate was precipitate from the reaction mixture by ad-
dition of pentane (150 ml). Hydrolysis afforded 19c as a yellow powder,
which crystallized at -15◦C from Et2O (100 ml) to furnish a pale yellow
1
powder. Yield: 2.56 g (77%) m.p. 124–126◦C (dec). H NMR (CDCl3): δ
1.88 (12 H,CH3); 7.15–7.55 (m, phenyl). 13C NMR (CDCl3): δ 28.3 (4C,
4 CH3); 107.3 (2 C2); 113.1, 119.3, 130.4, 149.4 (phenyl); 175.1 (C=N).
Anal. calcd. for C14H16N6S6 (332.4): C, 50.58; H, 4.85; N, 25.28. Found:
C, 50.22; H, 4.84; N, 24.76; MS: m/z (EI) 332.
4,5-Dihydro-3,3-dimethyl-4-phenyl-3H-1,2,4-triazol-5-one (23a)
From 6 (R1= R2= Me) (1.83 g, 10 mmol) and phenyl isocyanate (1.19 g,
10 mmol). The brown powder obtained after hydrolysis was crystallized
at −15◦C from Et2O (60 ml ) to furnish a brown powder. Yield: 1.59 g
(84%) m.p. 136–138◦C (dec). 1H-NMR (CDCl3): δ 1.63 (6H, 2 CH3);
7.20–7.53 (m, phenyl). 13C NMR (CDCl3): δ 23.4 (CH3); 101.3 (C3);
126.7, 128.9, 130.0 (phenyl); 160.1 (C = O). Anal. calcd. for C10H11N3O
(189.2): C, 63.48; H, 5.86; N, 22.21. Found: C, 63.21; H, 5.93; N, 22.45;
MS: m/z (EI) 189.
4,5-Dihydro-3,3-dimethyl-4-(4-methylphenyl)-3H-1,2,4-triazol-
5-one (23b)
From 6 (R1= R2= Me) (1.83 g, 10 mmol) and p-tolyl isocyanate (1.33 g,
10 mmol). The resulting orange oil obtained after hydrolysis dissolved
in Et2O (140 ml). Filtration and evaporation of the solvent afforded a
pale yellow powder, which was recrystallized at −15◦C from Et2O (50
ml) to furnish a pale yellow powder. Yield: 1.67 g (82%) m.p. 100–102◦C
(dec). 1H NMR (CDCl3): δ 1.60 (s, 2 CH3); 2.39 (3H, CH3); 7.05–7.30 (m,
phenyl). 13C NMR (CDCl3): δ 21.1, 23.3 (2C, 2CH3); 101.2 (C3); 126.6,
130.6, 139.1 (phenyl); 160.1 (C=O). Anal. calcd. for C11H13N3O (203.2):
C, 65.01; H, 6.45; N, 20.68. Found: C, 65.23; H, 6.51; N, 21.30; MS: m/z
(EI) 203.
4,5-Dihydro-3,3-dimethyl-4-(2-tricycl[3.3.13, 7]decyl)-3H-1,2,4-tr-
iazol-5-one (23c)
From 6 (R1= R2= Me) (1.83 g, 10 mmol) and 2-adamantyl isocyanate
(1.77 g, 10 mmol). The resulting colorless powder obtained after hydrol-
ysis was crystallized powder at −15◦C from CHCl3 (20 ml) / pentane
(7 ml) to furnish a colorless powder. Yield: 1.65 g (63%) m.p. sublima-
1
tion above 158◦C. H NMR (CDCl3): δ 1.59 (s, 2 CH3); 1.65–2.30 (m,
12H); 2.53 (br, 2H,CH2); 2.58 (br, 1H,CH). 13C NMR (CDCl3): δ 23.2
(2C, 2CH3); 27.2, 31.4, 32.3, 27.3, 38.3, 61.7 (CH2, CH); 102.1 (C3);

2634
Y. A. Al-Soud
161.5 (C O). Anal. calcd. for C14H21N3O (247.3): C, 67.99; H, 8.56; N,
16.99. Found: C, 68.05; H, 8.71; N, 17.410; MS: m/z (EI) 247.
4,5-Dihydro-3,3-dimethyl-4-phenyl-5-phenylimino-3H-1,2,4-
triazole (27a)
From 6 (R1= R2= Me) (1.83 g, 10 mmol) and diphenyl carbodiimide
(1.94 g, 10 mmol).49 The orange powder obtained after hydrolysis was
dissolved in pentane (100 ml). Filtration from an impurity, evaporation
of the solvent and crystallization of the residue at −15◦C from Et2O
(30 ml) afforded orange prisms. Yield: 1.90 g (72%) m.p. 86–88◦C (dec).
1H-NMR (CDCl3): ca (5:1) mixture of two isomers; major component δ
1.62 (6H, 2 CH3); 7.01–7.49 (m, phenyl); minor component δ 1.56 (very
br, 6H, 2 CH3); 6.63–7.01 (very br, phenyl). 13C-NMR (CDCl3): major
component δ 22.2 (2 CH3); 102.7 (C3); 123.5, 123.7, 126.9, 127.6, 128.5,
129.7, 135.8, 147.3 (phenyl); 156.2 (C=N); minor component δ 24.4 (very
br), 105.6 (very br, C3). Anal. calcd. for C16H16N4 (264.3): C, 72.70; H,
6.10; N, 21.20. Found: C, 72.82; H, 6.31; N, 21.52; MS: m/z (EI) 264.
4,5-Dihydro-4-isopropyl-3,3-dimethyl-5-phenylimino-3H-1,2,4-
triazole (27b)
From 6 (R1= R2= Me) (1.83 g, 10 mmol) and isopropylphenylcarbodi-
imide (1.60 g, 10 mmol).50 The orange oil obtained after hydrolysis was
dissolved in Et2O (150 ml). Filtration from an impurity, evaporation of
the solvent and crystallization of the residue at −15◦C from pentane
(35 ml) afforded an orange powder. Yield: 1.57 g (68%) m.p. 57–59◦C
(dec). 1H NMR (CDCl3): δ 1.47 (d, 6H, J= 6.9, 2CH3); 1.55(6H, 2CH3);
3.84(sept, 1H,CH); 7.01–7.33 (m, phenyl). 13C NMR (CDCl3): δ 19.3, 23.4
(2C, 2 CH3); 45.2 (CH); 102.0 (C3); 122.8, 123.8, 128.6, 148.1 (phenyl);
154.7 (C=N). Anal. calcd. for C13H18N4 (230.3): C, 67.80; H, 7.88; N,
24.33. Found: C, 67.84; H, 8.01; N, 24.20; MS: m/z (EI) 230.
4-Cyclohexyl-5-cyclohexylimino-4.5-dihydro-3,3-dimethyl-3H-
1,2,4-triazole (27c)
From 6 (R1= R2= Me) (1.83 g, 10 mmol) and dicyclohexylcarbodiimide
(2.06 g, 10 mmol). The orange oily hexachloroantimonate 26 was pre-
cipitated from the reaction mixture by addition of pentane (100 ml). Hy-
drolysis afforded 27c as a yellow powder, which was dissolved in Et2O
(150 ml). Filtration from an impurity, evaporation of the solvent and
crystallization of the residue at −15◦C from Et2O (150 ml) afforded a
yellow powder. Yield: 1.85 g (67%) m.p. 95–97◦C (dec). 1H NMR (CDCl3):

New Pyrazole, 1,2,4-Thiadiazole, and 1,2,4-Triazole Derivatives
2635
δ 1.47 (6H, 2CH3);1.13–1.83 (m, 9CH2); 2.17 (m, 2H,CH2); 3.26 (br,CH);
4.49 (br,CH). 13C NMR (CDCl3): δ 24.0, 24,8, 25.4, 26.0, 26.2, 29.1, 35.9
(br, CH3, CH2); 53.0, 56.6 (br,CH); 100.4 (br, C3); 156.1 (C=N). Anal.
calcd. for C16H28N4 (267.4): C, 69.52; H, 10.21; N, 20.27. Found: C,
69.26; H, 10.16; N, 19.97; MS: m/z (EI) 267.
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