Synthesis of a new series of biphenyl-substituted, fused 1,2,4-triazoles by oxidative cyclisation and Dimroth rearrangement

Article abstract of DOI:10.3184/174751913X13570601346457

A new series of 3-substituted-9-(1,1′-biphenyl-4-yl)-7-phenyl-7H- pyrazolo[4,3-e][1,2,4]triazolo [4,3-c]pyrimidines and 2-substituted-9-(1, 1′-biphenyl-4-yl)-7-phenyl-7H-pyrazolo[4,3-e][1,2,4] triazolo[1,5-c] pyrimidines were synthesised, as a new class of potent xanthine oxidase inhibitors, by oxidative cyclisation of 4-[2-(arylidene)hydrazinyl]-3-(1,1- biphenyl-4-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidines with FeCl3 in ethanol and Dimroth rearrangement. Keywords: hydrazones, nitrilimines, 1,5- electrocyclisation, heterocycles, Dimroth rearrangement.

Full text of DOI:10.3184/174751913X13570601346457

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 91
FEBRUARY, 91–94
Synthesis of a new series of biphenyl-substituted, fused 1,2,4-triazoles by
oxidative cyclisation and Dimroth rearrangement
Nabil Kh. Shurrab, Ali K. El-Louh, Iyad M. Al-Meghari and Abed El Rahman Ferrwanah*
Department of Chemistry, Faculty of Science, Al-Azhar University of Gaza, PO Box 1277 Gaza, Palestine
A new series of 3-substituted-9-(1,1′-biphenyl-4-yl)-7-phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo [4,3-c]pyrimidines and
2-substituted-9-(1,1′-biphenyl-4-yl)-7-phenyl-7H-pyrazolo[4,3-e][1,2,4] triazolo[1,5-c]pyrimidines were synthesised,
as a new class of potent xanthine oxidase inhibitors, by oxidative cyclisation of 4-[2-(arylidene)hydrazinyl]-3-(1,1-
biphenyl-4-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidines with FeCl3 in ethanol and Dimroth rearrangement.
Keywords: hydrazones, nitrilimines, 1,5-electrocyclisation, heterocycles, Dimroth rearrangement
Fused 1,2,4-triazoles have interesting biological properties such
as antimicrobial1 and anxiolytic activities,2 and can act also as
adenosine3,4 and benzodiazepine receptor antagonists.5 In addi-
tion, some derivatives of pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]
pyrimidine and pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimi-
dines exhibit pharmacological activities.6 For example, several
3-and/or 5-substituted-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]-
pyrimidines have been reported to be potent xanthine oxidase
(XO) inhibitors.6 Moreover, the introduction of a 1,1-biphenyl-
4-yl group provides the heterocyclic nucleus with improved
biological activity. For example, the 1,1-biphenyl-4-yl substi-
tuted compounds have been reported to be antimicrobial,7,8
antihypertensive,9,10 antidiabetic,11 anti-inflammatory,12–14
antiviral,15 anticancer,16 agents in addition to other activities.
We now report the synthesis of the title compounds by a simple
and convenient route. This route involves 1,5-electrocyclisa-
tion of nitrilimines generated in situ from N-(pyrazolo[3,4-
d]pyrimidin-4-yl)hydrazones 7a–f to give the respective pyr-
azolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine derivatives 8a–f.
Dimroth rearrangement of the latter afforded the respective
isomers, namely pyrazolo[4,3-e] [1,2,4]triazolo[1,5-c]pyrimi-
dines 9a–f.
triazolo[1,5-c]pyrimidines 9a–f (Scheme 2). A variety of com-
mercially available benzaldehydes and heteroaromatic alde-
hydes allow the introduction of chemical diversity at positions
2 and 3 of the heterocyclic nucleus.
The key starting material for the title compounds i.e.
3-(1,1-biphenyl-4-yl)-4-hydrazino-1-phenyl-1H-pyrazolo-
[3,4-d]pyrimidine 6 was obtained from N-phenyl-1,1-biphe-
nyl-4-carbohydrazide 1 as outlined in Scheme 1.
Hydrazide derivative 1 was converted to hydrazonoyl chlo-
ride 2 according to the method of Wolkoff.17 Thus, CCl4 was
added dropwise to a refluxing solution of 1 and Ph3P in dry
acetonitrile to afford the expected product 2. The structure
1
of 2 was established on the basis of its spectral (MS, IR, H
NMR) data and elemental analysis. For example, the mass
spectrum of 2 showed the molecular ion peak (M+) at m/z 306,
whilst the IR spectrum revealed the presence of the character-
istic absorption bands for C=N– and N–H stretch at 1668 and
3305 cm−1 respectively. A singlet for the NH proton appeared
at 9.90 ppm. Treatment of 2 with malononitrile in ethanol in
the presence of sodium ethoxide at room temperature yielded
the corresponding 5-amino-3-(1,1-biphenyl-4-yl)-1-phenyl-
1H-pyrazole-4-carbonitrile 3. Refluxing 3 with triethyl ortho-
formate in acetic anhydride for 7 h gave the imidoformate
derivative 4. Finally, treatment of 4 with an equivalent amount
of hydrazine hydrate in ethanol at room temperature afforded
the 4-iminopyrazolopyrimidine derivative 5 that rearranged to
hydrazino derivative 6 upon treatment with excess hydrazine
hydrate for 12 h. Also, 6 was accessible from a one-pot reac-
tion by refluxing 4 with excess hydrazine hydrate for 3 h. The
structures of the latter compounds were confirmed on the basis
Results and discussion
We hypothesised that the reaction of 3-(1,1-biphenyl-4-yl)-
4-hydrazino-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine 6 with
aromatic aldehydes followed by oxidation and Dimroth
rearrangement might be a potential approach for the synthesis
of 3-substituted-9-(1,1-biphenyl-4-yl)-7-phenyl-7H-pyrazolo-
[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines 8a–f and 2-substituted-
9-(1,1-biphenyl-4-yl)-7-phenyl-7H-pyrazolo[4,3-e][1,2,4]
Scheme 1
* Correspondent. E-mail: nabilkhsh139@yahoo.com

92 JOURNAL OF CHEMICAL RESEARCH 2013
of their elemental analysis and spectral data (see Experimen-
tal). The IR spectra of 3 and 4 exhibited absorption bands
at 2210 and 2213 cm−1 assignable to C≡N stretch which
disappeared in the IR spectrum of compound 6. The 1H NMR
spectrum of compound 4 revealed the presence of a singlet at
8.65 ppm assignable to the N=CHO– proton which disap-
refluxing ethanol yielded, in each case, a single product that
was identified as the respective 2-aryl-7H-pyrazolo[4,3-e][1,2,4]-
triazolo[1,5-c]pyrimidines 9a–f (Scheme 2). The structures
assigned to the latter products 9a–f were consistent with their
1
analytical and spectral (MS, H NMR, IR) data (see Experi-
mental). Rearrangement of 8 into 9 was evidenced by com-
1
1
peared in the H NMR spectrum of 6. On the basis of these
parison of the H NMR spectra of 8a–f with those of 9a–f.
findings compound 6 was assigned a 4-hydrazino-1H-
pyrazolo[3,4-d]pyrimidine structure. The rearrangement of 5
into 6 could be due to a Dimroth rearrangement which seems
to occur through base-catalysed tandem ring opening and
ring closure. This is consistent with a similar rearrangement
that was reported recently.18 Condensation of equimolar quan-
tities of the hydrazino derivative 6 with a series of (hetero)aro-
matic aldehydes gave the corresponding hydrazones 7a–f
(Scheme 2).
For example, the spectrum of 8a revealed the pyrimidine
H-5 proton signal as a singlet at δ 9.35, whereas the similar
signal from 9a was observed further downfield at δ 9.78. The
downfield shift of the pyrimidine proton in 9a can be attributed
to proximity of the nitrogen atoms in the rearranged triazole
ring. This feature is consistent with literature reports which
indicate that the pyrimidine ring proton (H-5) in thieno[3,2-e]
[1,2,4]triazolo[1,5-c]pyrimidine is more deshielded than H-5
in thieno[3,2-e][1,2,4]triazolo[4,3-c]pyrimidine.20
The elucidation of structures 7a–f was based on spectral evi-
dence and microanalysis (see Experimental). The mass spectra
showed, in each case, the correct molecular ion peak. The
IR spectra of 7a–f revealed absorption bands in the 3100–
The conversion of 8a–f into 9a–f is analogous to the rear-
rangement of 1,2,4-triazolo[4,3-a] pyrimidines in alkali to
the isomeric 1,2,4-triazolo[1,5-a]pyrimidines.20–25 To provide
decisive evidence for this rearrangement, one of the products
namely 9a, was compared with an authentic sample prepared
by alternate synthesis.26 Thus, treatment of 5 with an equiva-
lent quantity of benzoyl chloride in pyridine gave a single
product which proved to be identical in all respects (m.p.,
mixed m.p., IR and 1H NMR spectra) with that obtained above
from the base-catalysed rearrangement of 8a (Scheme 2).
In conclusion, we have successfully accomplished the facile
and general synthesis of 3-substituted-9-(1,1-biphenyl-4-yl)-
7-phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines
8a–f and the isomeric 2-substituted-9-(1,1-biphenyl-4-yl)-7-
phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c] pyrimidines
9a–f through heterocyclisation of hydrazones 7, derived
from 6 and aromatic aldehydes, and a subsequent Dimroth
rearrangement.
1
3400 cm−1 region due to NH stretching absorptions. Their H
NMR spectra showed the presence of the hydrazone (–C=
N–NH–) protons as singlets in the range 11.76–12.12 ppm.
In addition, they exhibited multiplets in the 6.61–8.61 ppm
region due to the aromatic protons as well as singlets at
8.36–8.67 ppm due to the hydrazone azomethine protons
(–CH=N–). Subsequent oxidative intramolecular cyclisation
of the hydrazones 7a–f with FeCl3 (4 equiv.) in ethanol at
45 °C provided the desired 3-substituted-9-(1,1-biphenyl-4-yl)-
7-phenyl-7H-pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidines
8a–f in 40–75% yields. Characterisation of the products 8a–f
1
was based upon careful comparison of their IR and H NMR
spectra with those of the starting materials 7a–f. Thus the IR
spectra of 8a–f showed the absence of NH bands that were
present in the starting materials 7a–f. An important character-
istic feature in the 1H NMR spectra of 8a–f was the disappear-
ance of the signals at δ 8.36–8.67 and 11.76–12.12 for the
hydrazone and NH protons respectively that were present in
the spectra of the intermediate hydrazones 7a–f. The cyclisa-
tion of 7a–f is reminiscent of related oxidative cyclisations of
N-heteroarylaldehyde hydrazones with FeCl3, which were
reported to proceed by generation of the respective nitrilimines
that undergo in situ 1,5-electrocyclisation to give the respec-
tive fused heterocycles.19 Next, the Dimroth rearrangement of
the 3-aryl-7H-pyrazolo[4,3-e][1,2,4]triazolo [4,3-c]pyrimidines
8a–f was examined. Treatment of 8a–f with sodium acetate in
Experimental
An electrothermal or Gallenkamp apparatus was used for melting
point determinations. All synthesised compounds were dried over
CaCl2 in a desiccator. The IR spectra were measured on a Pye-Unicam
SP300 instrument (KBr discs). The 1H NMR spectra were recorded on
a Varian Mercury VXR-300 spectrometer (300 MHz) in DMSO-d6.
MS were run on a GCMS-Q1000-EX Shimadzu and GCMS 5988-A
HP spectrometer at 70 eV. Elemental analyses were carried out by the
Microanalytical Centre of Cairo University, Giza, Egypt. The starting
biphenyl-4-carbonyl chloride was obtained from Aldrich Chemical
Company.
Scheme 2

JOURNAL OF CHEMICAL RESEARCH 2013 93
N-Phenyl-1,1-biphenyl-4-carbohydrazide (1): Biphenyl-4-carbonyl
chloride (21.66 g, 0.1 mol) was added portionwise to a stirred solution
of freshly distilled phenylhydrazine (19 mL, 0.1 mol) in pyridine
(100 mL) over 30 min. When the addition was complete, the mixture
was stirred for 3 h then poured onto cold HCl (300 mL, 10%). The
precipitated solid was filtered, washed with dilute HCl and water. The
product was crystallised from acetic acid and dried to give 1 as a white
solid, yield 16.7 g (58%), m.p. 209–211 °C. IR νmax (KBr): 3366,
3245, 3046, 1648, 1596, 744, 685 cm−1; 1H NMR (DMSO-d6): δ 6.71–
8.04 (m, 14 H, ArH), 10.40,10.41 (2s, 2H, –CONH–NH–Ph); MS m/z
(%): 290 (M++2, 1), 289 (M++1, 10), 288 (M+, 42), 181 (100), 153
(23), 152 (40), 77 (11). Anal. Calcd for C19H16N2O (288.35): C, 79.14;
H, 5.59; N, 9.71. Found: C, 79.11; H, 5.62; N, 9.74%.
N-Phenyl-1,1-biphenyl-4-ylcarbohydrazonoyl chloride (2): CCl4
(1.95 mL, 20 mmol) was added to a refluxing mixture of N-phenyl-
1,1-biphenyl-4-carbohydrazide 1 (5.76 g, 20 mmol) and Ph3P (6.55 g,
25 mmol) in acetonitrile (40 mL) that had been dried by passage
through alumina column and introduced directly from the column into
the reaction flask. The reaction mixture was refluxed for 2 h and after
that stirred at room temperature for 12 h. The solid product was
filtered, washed with water, crystallised from acetonitrile and dried to
give 2 as yellow crystals yield 5.8 g (94.9%), m.p. 205–207 °C. IR νmax
(KBr): 3305, 3041, 1668, 1592, 754, 687 cm−1; 1H NMR (DMSO-d6):
δ 6.85–7.98 (m, 14 H, ArH), 9.90 (s, 1H, =NNH–); MS m/z (%): 309
(M++3, 5), 308 (M++2, 21), 307 (M++1, 16), 306 (M+, 63), 270 (65),
179 (26), 91 (100), 77 (5). Anal. Calcd for C19H15ClN2 (306.80): C,
74.39; H, 4.93; N, 9.13. Found: C, 74.44; H, 4.95; N, 9.21%.
5-Amino-3-(1,1-biphenyl-4-yl)-1-phenyl-1H-pyrazole-4-carbonitrile
(3): Malononitrile (0.33 g, 5 mmol) was added to an ethanolic solution
of sodium ethoxide, prepared from sodium metal (0.11 g, 5 mmol) and
absolute ethanol (15 mL), N-phenyl-1,1-biphenyl-4-ylcarbohydra-
zonoyl chloride 2 (1.53 g, 5 mmol) was added portionwise and the
mixture was stirred for overnight. During this period the halide
dissolved and the crude pyrazole derivative precipitated. The solid
product was filtered, washed with water, crystallised from ethanol and
dried to give 3 as a pale yellow solid, yield 1.42 g (85%), m.p. 188–
190 °C. IR νmax (KBr): 3430, 3394, 3024, 2210, 1626, 1598, 726, 689
cm−1; 1H NMR (DMSO-d6): δ 6.82 (s, 2H, NH2); 7.39–7.98 (m, 14H,
ArH); MS m/z (%): 338 (M++2, 4), 337 (M++1, 27), 336 (M+, 100),
335 (20), 153 (4), 152 (10), 77 (34).Anal. Calcd for C22H16N4 (336.40):
C, 78.55; H, 4.79; N, 16.65. Found: C, 78.63; H, 4.74; N, 16.85%.
Ethyl [3-(1,1-biphenyl-4-yl)-4-cyano-1-phenyl-1H-pyrazol-5-yl]imido-
formate (4): Triethyl orthoformate (0.74 g, 5 mmol) was added to a
solution of 5-amino-3-(1,1-biphenyl-4-yl)-1-phenyl-1H-pyrazole-4-
carbonitrile 3 (1.68 g, 5 mmol) in acetic anhydride (3 mL); the
mixture was refluxed for 7 h, then cooled. Methanol was added, the
product solidified and was filtered, washed with water then crystal-
lised from ethanol and dried to give the title compound as a white
solid, yield 1.63 g (83%), m.p. 157–159 °C. IR νmax (KBr): 3025,
2982, 2213, 1629, 732, 691 cm−1; 1H NMR (DMSO-d6): δ 1.29–1.34
(t, 3H, CH3); 4.31–4.38 (q, 2H, CH2); 7.38–8.06 (m, 14 H, ArH); 8.65
(s, 1H, N=CHO-); MS m/z (%): 395 (M++3, 1), 394 (M++2, 5), 393
(M++1, 30), 392 (M+, 100), 336 (33), 335 (21), 152 (14), 77 (41). Anal.
Calcd for C25H20N4O (392.46): C, 76.51; H, 5.14; N, 14.28. Found: C,
76.60; H, 4.98; N, 14.32%.
δ 4.85 (s, 3H, br. NH and NH2), 7.35–8.25 (m, 14H, ArH), 7.92 (s, 1H,
H-6); MS m/z (%): 379 (M++1, 30), 378 (M+, 100), 377 (57), 348 (47),
347 (15), 336 (13), 333 (10), 77 (74). Anal. Calcd for C23H18N6
(378.44): C, 73.00; H, 4.79; N, 22.21. Found: C, 72.92; H, 4.78; N,
22.25%.
Synthesis of 3-(1,1-biphenyl-4-yl)-4-{2-[(hetero)arylidene]hydrazinyl}-
1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)hydrazones 7a–f; general
procedure
Two drops of acetic acid were added to a mixture of 3-(1,1-biphenyl-
4-yl)-4-hydrazino-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine 6 (1.88 g,
5 mmol) and the appropriate aromatic aldehyde (5 mmol) in ethanol
(50 mL), and the reaction mixture was refluxed for 2 h then cooled.
The precipitate formed was filtered, washed with water, ethanol
and finally crystallised from the appropriate solvent to give the
corresponding hydrazone derivative 7a–f. The various hydrazone
derivatives 7a–f prepared are listed below together with their physical
constants and spectral data.
4-[2-(Benzylidene)hydrazinyl]-3-(1,1-biphenyl-4-yl)-1-phenyl-1H-
pyrazolo[3,4-d]pyrimidine (7a): Yellow crystals, 71% yield, m.p.
226–228 °C; IR νmax (KBr): 3341, 3050, 1639, 1584, 723, 683 cm−1;
1H NMR (DMSO-d6): 7.41–8.59 (m, 19 H, ArH,), 8.13 (s, 1H, H-6),
8.51 (s, 1H, –N=CH); 12.07 (s, 1H, NH); MS m/z (%): 468 (M++2, 6),
467 (M++1, 7), 466 (M+, 9), 465 (39), 464 (100), 388 (25), 91 (58), 77
(66). Anal. Calcd for C30H22N6 (466.55): C, 77.23; H, 4.75; N, 18.01.
Found: C, 77.18; H, 4.66; N, 18.10%.
3-(1,1-Biphenyl-4-yl)-4-[2-(4-chlorobenzylidene)hydrazinyl]-1-
phenyl-1H-pyrazolo[3,4-d]pyrimidine (7b): Yellow crystals, 85%
yield, m.p. 235–237 °C; IR νmax (KBr): 3309, 3037, 1636, 1589, 758,
686 cm−1; 1H NMR (DMSO-d6): δ 7.40–8.57 (m, 18 H, ArH), 8.05 (s,
1H, H-6), 8.49 (s, 1H, –N=CH); 12.12 (s, 1H, NH); MS m/z (%): 502
(M++1, 9), 501 (M+, 66), 499 (57), 385 (100), 306 (90), 265 (94), 204
(95), 101 (90). Anal. Calcd for C30H21ClN6 (501.00): C, 71.92; H,
4.23; N, 16.77. Found: C, 71.81; H, 4.18; N, 16.69%.
3-(1,1-Biphenyl-4-yl)-4-[2-(3,4-dimethoxybenzylidene)hydrazinyl]-
1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (7c): Yellow crystals, 86%
yield, m.p. 250–252 °C; IR νmax (KBr): 3333, 3034, 2952, 1637, 726,
1
687 cm−1; H NMR (DMSO-d6): δ 3.83 and 3.88 (2s, 6H, 2OCH3),
7.03–8.61 (m, 17 H, ArH), 8.02 (s, 1H, H-6); 8.44 (s, 1H, –N=CH);
11.96 (s, 1H, NH); MS m/z (%): 529 (M++3, 26), 528 (M++2, 25), 527
(M++1, 43), 526 (M+, 36), 524 (25), 496 (39), 296 (36), 80 (100). Anal.
Calcd for C32H26N6O2 (526.60): C, 72.99; H, 4.98; N, 15.96. Found: C,
73.06; H, 4.81; N, 16.03. %.
4-[2-(1,3-Benzodioxolan-5yl)hydrazinyl]-3-(1,1-biphenyl-4-yl)-1-
phenyl-1H-pyrazolo[3,4-d]pyrimidine (7d): Yellow crystals, 87%
yield, m.p. 242–244 °C; IR νmax (KBr): 3350, 3037, 2896, 1641, 1592,
716, 682 cm−1; 1H NMR (DMSO-d6): δ 6.10 (s, 2H, –CH2), 6.64–8.59
(m, 17H, ArH), 7.83 (s, 1H, H-6), 8.40 (s, 1H, –N=CH); 12.03 (s, 1H,
NH); MS m/z (%): 512 (M++2, 6), 510 (M+, 6), 98 (24), 82 (10), 81
(31), 80 (100). Anal. Calcd for C31H22N6O2 (510.56): C, 72.93; H,
4.34; N, 16.46. Found: C, 72.99; H, 4.31; N, 16.51%.
3-(1,1-Biphenyl-4-yl)-4-[2-(2-furyl)hydrazinyl]-1-phenyl-1H-pyr-
azolo[3,4-d]pyrimidine (7e): Yellow -brown crystals, 80% yield, m.p.
231–233 °C; IR νmax (KBr): 3319, 3049, 1641, 1590, 740, 682 cm−1; 1H
NMR (DMSO-d6): δ 6.68–8.57 (m, 17 H, ArH), 7.89 (s, 1H, H-6),
8.36 (s, 1H, –N=CH); 11.89 (s, 1H, NH); MS m/z (%): 456 (M+, 27),
455 (21), 454 (33), 363 (49), 154 (23), 77 (28), 64 (100), 51 (25).
Anal. Calcd for C28H20N6O (456.51): C, 73.67; H, 4.42; N, 18.41.
Found: C, 73.53; H, 4.37; N, 18.42%.
3-(1,1-Biphenyl-4-yl)-4-[2-(2-thienyl)hydrazinyl]-1-phenyl-1H-
pyrazolo[3,4-d]pyrimidine (7f): Yellow crystals, 80% yield, m.p.
252–254 °C; IR νmax (KBr): 3325, 3052, 1633, 1563, 726, 695 cm−1;
1H NMR (DMSO-d6): δ 7.16–8.57 (m, 17 H, ArH), 8.02 (s, 1H, H-6),
8.67 (s, 1H, –N=CH); 11.76 (s, 1H, NH); MS m/z (%): 474 (M++2,
58), 473 (M++1, 66), 472 (M+, 56), 395 (63), 389 (77), 279 (100), 242
(58), 236 (77). Anal. Calcd for C28H20N6S (472.58): C, 71.17; H, 4.27;
N, 17.78. Found: C, 71.13; H, 4.22; N, 17.90%.
3-(Biphenyl-4-yl)-4-imino-1-phenyl-1,4-dihydro-5H-pyrazolo[3,4-d]
pyrimidin-5-amine (5): Hydrazine hydrate 80% (1.5 mL) was added
dropwise to a stirred mixture of ethyl [3-(1,1-biphenyl-4-yl)-4-cyano-
1-phenyl-1H-pyrazol-5-yl] imidoformate 4 (1.96 g, 5 mmol) in etha-
nol (30 mL). The mixture was stirred at room temperature for 2 h. The
precipitated solid was filtered, washed with water and crystallised
from 1,4-dioxane to give 5 as a white solid, yield 1.79 g (95%), m.p.
203–204 °C. IR νmax (KBr) 3424, 3314, 3139, 3050, 1640, 1600, 760,
1
687 cm−1; H NMR (DMSO-d6): δ 5.72 (s, 2H, NH2); 7.38–8.09 (m,
14H, ArH), 8.19 (s, 1H, H-6), 8.47 (s, 1H, NH); MS m/z (%): 378 (M+,
7), 316 (8), 98 (17), 81(23), 80 (100), 79 (10). Anal Calcd for C23H18N6
(378.44): C, 73.00; H, 4.79; N, 22.21. Found: C, 72.90; H, 4.71; N,
22.28%.
Synthesis of 3-(hetero)aryl-9-(1,1-biphenyl-4-yl)-7-phenyl-7H-pyr-
azolo[4,3-e][1,2,4]triazolo [4,3-c]pyrimidines 8a–f; general procedure
A solution of FeCl3 (2 M, 10 mL) was added to a solution of the
appropriate hydrazone 7a–f (5 mmol) in ethanol (125 mL) and the
mixture was stirred at 45 °C for 12 h. The precipitated solid was
filtered, washed with water, ethanol and finally crystallised from
DMF–EtOH to give the title compounds. The various derivatives 8a–f
prepared are given below together with their physical constants and
spectral data.
3-(1,1-Biphenyl-4-yl)-4-hydrazino-1-phenyl-1H-pyrazolo[3,4-d]pyri-
midine (6): hydrazine hydrate (10 mL, 80%) was added to ethyl
(3-(biphenyl-4-yl)-4-cyano-1-phenyl-1H-pyrazol-5-yl)imidoformate
4 (1.96 g, 5 mmol) in ethanol. The mixture was refluxed for 3 h, the
precipitated solid was filtered and crystallised from 1,4-dioxane to
give3-(biphenyl-4-yl)-4-hydrazino-1-phenyl-1H-pyrazolo[3,4-d]pyri-
midine 6, yield 1.52 g (81%) as a white solid, m.p. 216–218 °C. IR
1
νmax (KBr): 3426, 3194, 3030, 687, 759 cm−1; H NMR (DMSO-d6):

94 JOURNAL OF CHEMICAL RESEARCH 2013
9-(1,1-Biphenyl-4-yl)-3,7-diphenyl-7H-pyrazolo[4,3-e][1,2,4]tria-
zolo[4,3-c]pyrimidine (8a): White crystals, 67% yield, m.p. 274–
275 °C; IR νmax (KBr): 3051, 1623, 763, 690 cm−1; 1H NMR (DMSO-
d6): δ 7.39–8.96 (m, 19 H, ArH), 9.35 (s, 1H, H-5); MS m/z (%): 467
(M++3, 9), 466 (M++2, 15), 465 (M++1, 41), 464 (M+, 100), 387 (15),
234 (12), 153 (11) 77 (45). Anal. Calcd for C30H20N6 (464.53): C,
77.57; H, 4.34; N, 18.09. Found: C, 77.53; H, 4.31; N, 18.11%.
9-(1,1-Biphenyl-4-yl)-3-(4-chlorophenyl)-7-phenyl-7H-pyr-
azolo[4,3-e][1,2,4]triazolo [4,3-c]pyrimidine (8b): Yellow crystals, 52%
yield, m.p. 236–237 °C; IR νmax (KBr): 3055, 1621, 758, 688 cm−1;
1H NMR (DMSO-d6): δ 7.42–8.95 (m, 18 H, ArH), 9.36 (s, 1H, H-5);
MS m/z (%): 501 (M++3, 14), 500 (M++2, 50), 499 (M++1, 43), 498
(M+, 100), 421 (16), 345 (16), 152 (20), 77 (40). Anal. Calcd for
C30H19ClN6 (498.98): C, 72.21; H, 3.84; N, 16.84. Found: C, 72.12; H,
3.76; N, 16.90%.
2-(1,3-Benzodioxol-5-yl)-9-(1,1′-biphenyl-4-yl)-7-phenyl-7H-pyr-
azolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (9d): Pale yellow crys-
tals, 78% yield, m.p. 309–311 °C; IR νmax (KBr): 3064, 2908, 1632,
757, 684 cm-1; 1H NMR (DMSO-d6): δ 6.16 (s, 2H, –CH2), 7.12–8.93
(m, 17H, ArH), 9.72 (s, 1H, H-5); MS m/z (%): 510 (M++2, 75), 509
(M++1, 47), 508 (M+, 49), 475 (100), 386 (67), 199 (78). Anal. Calcd
for C31H20N6O2 (508.54): C, 73.22; H, 3.96; N, 16.53. Found: C, 73.15;
H, 4.03; N, 16.42%.
9-(1,1′-Biphenyl-4-yl)-2-(2-furyl)-7-phenyl-7H-pyrazolo[4,3-e]
[1,2,4]triazolo[1,5-c]pyrimidine (9e): Brown crystals, 80% yield,
1
m.p. 279–281 °C; IR νmax (KBr): 3078, 1628, 760,733, 688 cm−1; H
NMR (DMSO-d6): δ 6.79–8.85 (m, 17H, ArH), 9.72 (s, 1H, H-5); MS
m/z (%): 454 (M+, 13), 376 (13), 154 (14), 80 (62), 73 (100). Anal.
Calcd for C28H18N6O (454.50): C, 74.00; H, 3.99; N, 18.49. Found: C,
74.06; H, 3.95; N, 18.58%.
9-(1,1′-Biphenyl-4-yl)-7-phenyl-2-(2-thienyl)-7H-pyrazolo[4,3-e]
[1,2,4]triazolo[1,5-c]pyrimidine (9f): Yellow crystals, 88% yield,
m.p. 310–312 °C; IR νmax (KBr): 3056, 1630, 766, 692 cm−1; 1H NMR
(DMSO-d6): δ 7.29–8.89 (m, 17H, ArH), 9.72 (s, 1H, H-5); MS m/z
(%): 472 (M++2, 18), 471 (M++1, 42), 470 (M+, 100), 152 (15), 77
(22). Anal. Calcd for C28H18N6S (470.56): C, 71.47; H, 3.86; N, 17.86.
Found: C, 71.59; H, 3.94; N, 17.75%.
9-(1,1′-Biphenyl-4-yl)-3-(3,4-dimethoxyphenyl)-7-phenyl-7H-
pyrazolo[4,3-e][1,2,4]triazolo[4,3-c]pyrimidine (8c): White crystals,
76% yield, m.p. 239–240 °C; IR νmax (KBr): 3057, 2968, 1620, 735,
1
690 cm−1; H NMR (DMSO-d6): δ 3.88 and 3.89 (2s, 6H, 2OCH3);
7.20–8.93 (m, 17 H, ArH), 9.33 (s, 1H, H-5); MS m/z (%): 527 (M++3,
25), 526 (M++2, 30), 525 (M++1, 52), 524 (M+, 100), 509 (33), 493
(32), 340 (25), 310 (29). Anal. Calcd for C32H24N6O2 (524.59): C,
73.27; H, 4.61; N, 16.02. Found: C, 73.21; H, 4.54; N, 16.10%.
3-(1,3-Benzodioxol-5-yl)-9-(1,1′-biphenyl-4-yl)-7-phenyl-7H-pyr-
azolo-[4,3-e][1,2,4]triazolo [4,3-c]pyrimidine (8d): White crystals,
73% yield, m.p. 264–266 °C; IR νmax (KBr): 3057, 2910, 1621, 735,
691 cm−1; 1H NMR (DMSO-d6): δ 6.18 (s, 2H, –CH2), 7.17–8.93 (m,
17H, ArH), 9.29 (s, 1H, H-5); MS m/z (%): 508 (M+, 100), 468 (63),
181 (75), 77 (77). Anal. Calcd for C31H20N6O2 (508.54): C, 73.22; H,
3.96; N, 16.53. Found: C, 73.18; H, 3.87; N, 16.61%.
Received 6 October 2012; accepted 14 December 2012
Paper 1201558 doi: 10.3184/174751913X13570601346457
Published online: 13 February 2013
References
9-(1,1′-Biphenyl-4-yl)-3-(2-furyl)-7-phenyl-7H-pyrazolo[4,3-e]
[1,2,4]triazolo[4,3-c]pyrimidine (8e): Pale brown crystals, 42% yield,
m.p. 269–271 °C; IR νmax (KBr): 3054, 1617, 760, 689 cm−1; 1H NMR
(DMSO-d6): δ 6.86–8.92 (m, 17H, ArH), 9.60 (s, 1H, H-5); MS m/z
(%): 456 (M++2, 12), 455 (M++1, 44), 454 (M+, 100), 377 (14), 301
(14), 152 (15), 77 (29). Anal. Calcd for C28H18N6O (454.50): C, 74.00;
H, 3.99; N, 18.49. Found: C, 73.96; H, 3.93; N, 18.60%.
9-(1,1′-Biphenyl-4-yl)-7-phenyl-3-(2-thienyl)-7H-pyrazolo[4,3-e]
[1,2,4]triazolo[4,3-c]pyrimidine (8f): Yellow crystals, 51% yield,
m.p. 261–263 °C; IR νmax (KBr): 3053, 1621, 755, 690 cm−1; 1H NMR
(DMSO-d6): δ 7.36–8.92 (m, 17H, ArH), 9.54 (s, 1H, H-5); MS m/z
(%): 472 (M++2, 16), 471 (M++1, 36), 470 (M+, 100), 235 (10), 153
(8), 83 (7), 77 (32). Anal. Calcd for C28H18N6S (470.56): C, 71.47; H,
3.86; N, 17.86. Found: C, 71.42; H, 3.78; N, 17.93%.
1
2
N.S. Habib and S.A. El-Hawash, Pharmazie, 1997, 52, 594.
G. Tarzia, E. Ocelli, E. Toja, D. Barone, N. Corsico, L. Gallico and
F. Luzzani, J. Med. Chem., 1988, 31, 1115.
P. Bhattacharya, Bioorg. Med. Chem. Lett., 2005, 15, 3737.
B.B. Fredholm and K. Lindsrtrom, Eur. J. Pharm., 1999, 197.
V. Colotta, D. Catarzi, F. Varano, L. Cecchi, G. Filacchioni, A. Galli and
C. Costagli, Arch. Pharm., 1997, 330, 387.
T. Nagamatsu and T. Fujita Chem. Commun., 1999, 1461.
B.D. Palmer, A.M. Thompson, H.S. Sutherland, A. Blaser, I. Kmentova,
S.G. Franzblau, B. Wan, Y. Wang, Z. Ma, and W.A. Denny, J. Med. Chem.
2010, 53, 282.
A.O. de Souza, F.P. Hemerly, A.C. Busollo, P.S. Melo, G.M.C. Machado,
C.C. Miranda, R.M. Santa-Rita, M. Haun, L.L. Leon, D.N. Sato, S.L. de
Castro and N. Duran, J. Antimicrob. Chemother., 2002, 50, 629.
R.R. Kamble, D.B. Biradar, G.Y. Meti, T. Taj, T. Gireesh, I.A.M. Khazi,
S.T. Vaidyanathan, R. Mohandoss, B. Sridhar andV. Parthasarathi, J. Chem.
Sci., 2011, 123, 393.
3
4
5
6
7
8
9
Synthesis of 2-substituted-9-(1,1′-biphenyl-4-yl)-7-phenyl-7H-pyr-
azolo[4,3-e][1,2,4]triazolo[1,5-c] pyrimidines 9a–f; general procedure
To a solution of the appropriate 8a–f derivative (5 mmol) in ethanol
(250 mL) was added NaOAc (1.64 g, 10 mmol) and the mixture was
refluxed for 6 h then cooled. The precipitated solid was filtered,
washed with water, ethanol and finally crystallised from DMF to give
the title compounds 9a–f. The various derivatives prepared are given
below:
9-(1,1′-Biphenyl-4-yl)-2,7-diphenyl-7H-pyrazolo[4,3-e][1,2,4]tria-
zolo[1,5-c]pyrimidine (9a): White crystals, 73% yield, m.p. 304–
305 °C; IR νmax (KBr): 3061, 1633, 758, 688 cm−1; 1H NMR (DMSO-
d6): δ 7.51–8.96 (m, 19 H, ArH), 9.78 (s, 1H, H-5); MS m/z (%): 464
(M+, 100), 153 (25) 77 (58). Anal. Calcd for C30H20N6 (464.53): C,
77.57; H, 4.34; N, 18.09. Found: C, 77.48; H, 4.44; N, 18.18%.
9-(1,1′-Biphenyl-4-yl)-2-(4-chlorophenyl)-7-phenyl-7H-pyr-
azolo[4,3-e][1,2,4]triazolo[1,5-c] pyrimidine (9b): White crystals,
61% yield, m.p. >310 °C; IR νmax (KBr): 3054, 1630, 753, 684 cm−1;
1H NMR (DMSO-d6): δ 7.43–8.94 (m, 18 H, ArH), 9.79 (s, 1H, H-5);
MS m/z (%): 498 (M+, 79), 421 (82), 343 (79), 115 (91). Anal. Calcd
for C30H19ClN6 (498.98): C, 72.21; H, 3.84; N, 16.84. Found: C, 72.32;
H, 3.78; N, 16.93%.
10 R.D. Larsen, A.O. King, C.Y. Chen, E.G. Corley, B.S. Foster, F.E. Roberts,
C. Yang, D.R. Lieberman and P.J. Reider, J. Org. Chem., 1994, 59, 6391.
11 N. Sachan, S. Thareja, R. Agarwal, S.S. Kadam and V.M. Kulkarni, Int. J.
PharmTech Res., 2009, 1, 1625.
12 B.P. Imbimbo, E.D. Giudice, D. Colavito, A. D’Arrigo, M.D. Carbonare,
G. Villetti, F. Facchinetti, R. Volta, V. Pietrini, M.F. Baroc, L. Serneels,
B.D. Strooper and A. Leon, J. Pharmacol. Exp. Ther., 2007, 323, 822.
13 G. Lu, R. Franzen, X.J. Yu and Y. J Xu, Chin. Chem. Lett., 2006, 17, 461.
14 M. Amir, H. Kumar and S.A. Kan, Bioorg. Med. Chem. Lett., 2008, 18,
918.
15 G. Vitale, P. Corona, M. Loriga, A. Carta, G. Paglietti, P.L. Colla,
B. Busonera, E. Marongiu, D. Collu and R. Loddo, Med. Chem., 2009, 5,
507.
16 S.F. Chen, R.L. Ruben and D.L. Dexter, Cancer Res. 1986, 46, 5014.
17 P. Wolkoff, Can. J. Chem. 1975, 53, 1333.
18 A.E. Rashad, O.A. Heikel, A.O.H. El-Nezhawy and F.M.E. Abdel-Megeid,
Heteroatom Chem. 2005, 16, 226.
19 M.A. Shaban and A.Z. Nasr, Adv. Heterocycl. Chem. 1999, 49, 277.
20 H.Y. Son and Y.H. Song, J. Korian Chem. Soc., 2010, 54, 350.
21 D.J. Brown and T. Nagamatsu, Aust. J. Chem., 1977, 30, 2515.
22 C.A. Lovelette and K. Geagan, J. Heterocycl. Chem., 1982, 19, 1345.
23 S.P. Langdon, R.J. Simmonds, and M.F.G. Stevens, J. Chem. Soc., Perkin
Trans 1, 1984, 993.
24 M. Cabre, J. Farras, J.F. Sanz and J. Vilarrasa, J. Chem. Soc., Perkin Trans.
2, 1990, 1943.
25 D. Loakes, D.M. Brown and S.A. Salisbury, Tetrahedron Lett., 1998, 39,
3865.
9-(1,1′-Biphenyl-4-yl)-2-(3,4-dimethoxyphenyl)-7-phenyl-7H-pyr-
azolo[4,3-e][1,2,4]triazolo [1,5-c]pyrimidine (9c): White crystals,
71% yield, m.p. 276–278 °C; IR νmax (KBr): 3062, 2953, 1638, 758,
691 cm−1; 1H NMR (DMSO-d6): δ 3.84 and 3.88 (2s, 6H, 2 × OCH3);
7.10–8.90 (m, 17 H, ArH), 9.67 (s, 1H, H-5); MS m/z (%): 526 (M++2,
17), 525 (M++1, 39), 524 (M+, 100), 506 (40), 152 (42), 77 (25). Anal.
Calcd for C32H24N6O2 (524.59): C, 73.27; H, 4.61; N, 16.02. Found: C,
73.14; H, 4.57; N, 15.93%.
26 A.A. Fahmi, S.T. Mekki, H.A. Albar, A.S. Shawali, H.M. Hassaneen and
H. Abdelhamid, J. Chem. Res., 1994 (S) 6, (M) 140.

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.