A facile one pot synthesis of substituted pyrazole derivatives

Article abstract of DOI:10.3184/174751913X13726128889197

Diazo compounds derived from aromatic aldehydes were reacted with derivatives of (Z)-2-arylidene-2H-benzofuran- 3-ones to give new highly substituted heterocyclic pyrazoles. The structures of the synthesised compounds were determined on the basis of their

Full text of DOI:10.3184/174751913X13726128889197

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 435
JULY, 435–437
A facile one pot synthesis of substituted pyrazole derivatives
Amel Haouas, Naoufel Ben Hamadi, Asma Nsira and Moncef Msadek*
Laboratory of Synthesis heterocyclic and Natural Substances. Department of Chemistry, Faculty of Sciences of Monastir, Boulevard of
Environment, 5000 Monastir, Tunisia
Diazo compounds derived from aromatic aldehydes were reacted with derivatives of (Z)-2-arylidene-2H-benzofuran-
3-ones to give new highly substituted heterocyclic pyrazoles. The structures of the synthesised compounds were
determined on the basis of their elemental analyses and spectroscopic data.
Keywords: benzofuran-3-one, aryldiazomethane, 1,3-dipolar cycloaddition, pyrazoles
Pyrazoles and their variously substituted derivatives are
important biological agents and a significant amount of
research activity has been directed to study these compounds.1
In particular, they are used as anti-tumour, anti-bacterial
and anti-fungal, anti-viral, anti-parasitic, anti-tubercular and
insecticidal agents. Some of these compounds also have anti-
inflammatory, anti-diabetic, anesthetic and analgesic proper-
ties.2–4 Several methods for the synthesis of pyrazoles and their
derivatives have been reported, most of them involving con-
struction of the pyrazole moiety by reaction of α,β-unsaturated
aldehydes or ketones with hydrazines.5–9 In another route, these
products can be obtained by 1,3-dipolar cycloaddition of
diazoalkanes with acetylenes.10–13
proton. Here we can state that, in this case, we have not
isolated the spiranic cycladducts which we were attempting to
prepare but rather we obtained the rearrangement products
possessing the pyrazole structures. In the light of this finding,
we have suggested a mechanism in order to give a plausible
explanation for the observed results. In Scheme 1, 4a–i is able
to undergo 1,3 prototropic rearrangement and opening of the
benzofuranone ring at the 2-position gives fully aromatised
pyrazole derivatives 5a–i.
An additional confirmation of the regiochemistry of the
cycloaddition products was determined from the NOESY
spectrum which allowed us to distinguish a clear spatial
correlation between the hydroxyl proton (11.92 ppm) and the
NH proton (4.69 ppm). Also, the absence of any nOe between
the hydroxyl proton and the aromatic protons of the aryl group
linked to the pyrazole moiety, confirms the structure of the
obtained compounds 5a–i (Scheme 2).
Lévai et al.14 described the addition of diazomethane to
arylidenebenzofuranone as a route to a spiropyrazoline via a
regioselective condensation of the dipole onto the C=C double
bond of the benzofuranone skeleton. Also, Fathi et al.15
studied the reaction of a spiropyrazoline with trifluoroacetic
acid to afford a trisubstitued pyrazole.
We were prompted to study the 1,3-dipolar cycloaddition
reaction of aryldiazomethanes with benzofuranones in order
to synthesise some new highly substituted pyrazoles and we
report here our results.
Conclusion
Here we describe an effective approach to a novel class of
new highly substituted pyrazole systems achieved via the 1,3-
cycloaddition reaction between the (Z)-2-arylidene-2H-benzo-
furan-3-ones with aryldiazomethane. We have shown that these
reactions proceed with excellent regiospecificities.
Results and discussion
The aryldiazomethane was generated in situ by condensation
of p-toluenesulfonyl hydrazide with an aromatic aldehyde
1a–c followed by treatment with an aqueous solution of sodium
hydroxide to give a solution of the sodium salt of the aromatic
aldehyde tosylhydrazone, which upon warming to 50 °C gave
a reddish solution of a diazo compound 2a–c.16,17 The initial
starting compounds (Z)-2-arylidene-2H-benzofuran-3-ones
3a–c were prepared by cyclisation of 2-hydroxychalcones in
the presence of mercury acetate in pyridine according to the
literature procedure.18
Thus we achieved our first aim of reacting the diaryldiazo-
methanes 2a–c with compounds 3a–c to access the spiropyr-
azolinic skeleton 4a–i, but, the unexpected products 5a–i
were obtained. Structures were assigned on the basis of their
spectral data and are new pyrazoles (Scheme 1). The loss of
starting materials was shown by TLC.
Experimental section
Caution: Aryldiazomethane is highly toxic and potentially explo-
sive. All operations should be carried out in an efficient hood
behind a protective screen.
IRspectrawererecordedonaPerkin-ElmerIR-197spectrophotometer.
The mass spectra were acquired with a Kratos MS80RF double
focusing mass spectrometer of Nier-Johnson geometry. Melting points
were determined on a Buchi-510 capillary melting point apparatus
and were not corrected. TLC was performed on silica gel 254 plates
(Merck) with UV (254 nm) visualisation, and preparative chromato-
graphic separations were conducted on silica gel Si-60-7734 (Merck).
NMR spectra were obtained on a Bruker AC 300 spectrometer operat-
ing at 300 MHz for 1H and at 75.64 MHz for 13C. Elemental analyses
were performed on a Perkin-Elmer 240B microanalyser. All reagents
were of commercial quality or purified by standard procedures.
The mass spectra recorded in ES+ mode, of compound 5b
for example, showed a molecular ion m/z = 339.1 [M+H]+.
The 1,3-dipolar cycloaddition of aryldiazomethane is in each
case regiospecific. Unambiguous proof for the obtained cyclo-
adducts came from their spectral data. The 1H NMR spectrum
of compound 5b recorded at 300 MHz in CDCl3, showed a
singlet at 2.27 ppm corresponding to the methyl group, a broad
singlet at 4.69 ppm which corresponds to the NH of the pyr-
azole moiety. Also, the same spectrum showed the aromatics
protons between 6.69 ppm and 8.02 ppm and the presence
of another signal at 11.90 ppm directly linked to a hydroxyl
Synthesis of pyrazoles; typical procedure
Aromatic aldehydes were added to a solution of p-toluenesulfonyl-
hydrazide (1.5 mmol). After stirring for 3 h at room temperature, a
solution of NaOH (5 M, 300 µL, 1.5 mmol) was added and the mixture
was stirred for a further 20 min. The derivatives of the (Z)-2-aryli-
dene-2H-benzofuran-3-ones (7.5 mmol) were added and the mixture
was stirred at 50 °C for 48 h. The volatiles were evaporated under
reduced pressure and the residue was dissolved in a 1:1 mixture of
water:ethyl acetate (70 mL). The organic layer was separated and
dried over MgSO4. After filtration and removal of the solvent under
reduced pressure, the crude material was purified by flash chromato-
graphy (eluent petroleum ether/ethyl acetate 4:1) to afford compounds
5a–i. These products were crystallised from ethanol.
* Correspondent. E-mail: Moncef.Msaddek@fsm.rnu.tn

436 JOURNAL OF CHEMICAL RESEARCH 2013
Scheme 1 Synthesis of pyrazoles using aryldiazomethanes and (Z)-2-arylidene-2H-benzofuran-3-ones.
Scheme 2 Regiochemistry of cycloaddition.

JOURNAL OF CHEMICAL RESEARCH 2013 437
(4,5-Diphenyl-2H-pyrazol-3-yl)-(2-hydroxyphenyl)-methanone
(5a): Yellow solid (75.4%); m.p. 197–199 °C. Anal. Calcd for
C22H16N2O2: C, 77.64; H, 4.70; N, 8.23. Found: C, 77.61; H, 4.58; N,
8.33%; IR (KBr): νcm−1 = 1600 (C=N), 1623 (C=O), 3223 (OH), 3435
OCH3), 4.80 (br s, 1H, NH), 6.76–8.07 (m, 13H-arom), 11.97 (br s,
1H, OH). 13C{1H}NMR (75.47 MHz, CDCl3): δ (ppm) = 55,1 (OCH3),
113.9–136.4 (Carom), 123.6 (C4), 130.0 (C5), 142.9 (C3), 158.9 (OCH3),
163.3 (OH), 193.6 (C=O).
1
(NH); H NMR (300 MHz, CDCl3): δ (ppm) = 4.80 (br s, 1H, NH),
(2-Hydroxyphenyl)-[4-(4-methoxyphenyl)-5-p-tolyl-2H-pyrazol-3-
yl]-methanone (5h): Solid pale white (60.9%); m.p. 231–233 °C.
Anal. Calcd for C24H20N2O3: C, 75.00; H, 5.20; N, 7.29. Found: C,
74.88; H, 5.30; N, 7.25%; IR (KBr): νcm−1 = 1596 (C=N), 1626 (C=O),
3260 (OH), 3440 (NH). 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.38
(s, 3H, CH3), 3.81 (s, 3H, OCH3), 4.80 (br s, 1H, NH), 6.83–8.15 (m,
12-Harom), 12.05 (br s, 1H, OH). 13C{1H}NMR (75.47 MHz, CDCl3):
δ (ppm) = 21.3 (CH3), 55.1 (OCH3), 113.8–136.4 (Carom), 123.6 (C4),
129.6 (C5), 142.8 (C3), 158.8 (COCH3), 163.7 (COH), 191.9 (C=O).
[4,5-Bis-(4-methoxyphenyl)-2H-pyrazol-3-yl]-(2-hydroxyphenyl)-
methanone (5i): Yellow solid (57.6%); m.p. 245–247 °C. Anal. Calcd
for C24H20N2O4: C, 72.00; H, 5.00; N, 7.00. Found: C, 72.04; H, 5.06;
6.73–8.05 (m, 14-Harom), 11.98 (br s, 1H, OH). 13C{1H}NMR (75.47
MHz, CDCl3): δ (ppm) = 117.9–136.4 (Carom), 123.2 (C4), 131.5 (C5),
145.2 (C3), 163.2 (COH), 193.4 (C=O).
(2-Hydroxyphenyl)-(4-phenyl-5-p-tolyl-2H-pyrazol-3-yl)-metha-
none (5b): Pale white solid (46.8%); m.p. 219–221 °C. Anal. Calcd
for C23H18N2O2: C, 77.96; H, 5.08; N, 7.90. Found: C, 78.00; H, 5.15;
N, 8.05%; MS (ES+): m/z = 339.1 [M+H]+, IR (KBr): νcm = 1597
−1
1
(C=N), 1621 (C=O), 3253 (OH), 3440 (NH). H NMR (300 MHz,
CDCl3): δ (ppm) = 2.27 (s, 3H, CH3), 4.69 (br s, 1H, NH), 6.69–8.02
(m, 13-Harom), 11.90 (br s, 1H, OH). 13C{1H}NMR (75.47 MHz,
CDCl3): δ (ppm) = 21,2 (CH3), 116.9–138.9 (Carom), 124.8 (C4), 131.5
(C5), 146.2 (C3), 162.3 (COH), 192.6 (C=O).
−1
N, 7.07%; IR (KBr): νcm = 1595 (C=N), 1624 (C=O), 3254 (OH),
(2-Hydroxyphenyl)-[5-(4-methoxyphenyl)-4-phenyl-2H-pyrazol-3-
yl]-methanone (5c): Yellow solid (55.2%); m.p. 132–134 °C. Anal.
Calcd for C23H18N2O3: C, 74.59; H, 4.86; N, 7.56. Found: C, 74.48; H,
1
3433 (NH). H NMR (300 MHz, CDCl3): δ (ppm) = 3.82 (s, 6H,
2OCH3), 4.77 (br s, 1H, NH), 6.84–8.10 (m, 12-Harom), 12.05 (br s,
1H, OH). 13C{1H}NMR (75.47 MHz, CDCl3): δ (ppm) = 54.6 (OCH3),
54.7 (OCH3), 113.3–135.9 (Carom), 123.3 (C4), 137.8 (C5), 144.1 (C3),
158.2 (COCH3), 159.3 (COCH3), 162.7 (COH), 193.4 (C=O).
−1
4.77; N, 7.53%; IR (KBr): νcm = 1599 (C=N), 1623 (C=O), 3258
(OH), 3446 (NH). 1H NMR (300 MHz, CDCl3): δ (ppm) = 3.83 (s, 3H,
OCH3), 4.79 (br s, 1H, NH), 6.84–8.15 (m, 13-Harom), 12.05 (br s,
1H, OH). 13C{1H}NMR (75.47 MHz, CDCl3): δ (ppm) = 54.7 (OCH3),
113.9–136.3 (Carom), 123.7 (C4), 131.8 (C5), 147.1 (C3), 159.4 (COCH3),
162.1 (COH), 191.8 (C=O).
Received 13 March 2013; accepted 8 May 2013
Paper 1301833 doi: 10.3184/174751913X13726128889197
Published online: 18 July 2013
(2-Hydroxyphenyl)-(5-phenyl-4-p-tolyl-2H-pyrazol-3-yl)-metha-
none (5d): Yellow solid (42.4%); m.p. 200–202 °C. Anal. Calcd for
C23H18N2O2: C, 77.96; H, 5.08; N, 7.90. Found: C, 77.90; H, 5.03; N,
7.85%; IR (KBr): νcm−1 = 1600 (C=N), 1629 (C=O), 3257 (OH), 3396
(NH). 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.32 (s, 3H, CH3), 4.69
(br s, 1H, NH), 6.75–8.07 (m, 13-Harom), 12.00 (br s, 1H, OH).
13C{1H}NMR (75.47 MHz, CDCl3): δ (ppm) = 21.2 (CH3), 117.9–
137.0 (Carom), 123.2 (C4), 130.5 (C5), 143.8 (C3), 163.2 (COH), 193.7
(C=O).
(4,5-Di-p-tolyl-2H-pyrazol-3-yl)-(2-hydroxyphenyl)-methanone
(5e): Yellow solid (55.9%); m.p. 200–202 °C. Anal. Calcd for
C24H20N2O2: C, 78.26; H, 5.43; N, 7.60. Found: C, 78.13; H, 5.48; N,
7.76%; IR (KBr): νcm−1 = 1593 (C=N), 1622 (C=O), 3219 (OH), 3425
(NH). 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.00 (s, 3H, CH3), 2.33
(s, 3H, CH3), 4.67 (br s, 1H, NH), 6.77–8.09 (m, 12-Harom), 11.99 (br
s, 1H, OH). 13C{1H}NMR (75.47 MHz, CDCl3): δ (ppm) = 21.2 (CH3),
29.7 (CH3), 117.9–137.1 (Carom), 121.6 (C4), 129.9 (C5), 142.6 (C3),
163.3 (COH), 193.7 (C=O).
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12-Harom), 11.98 (s, 1H, OH). 13C{1H}NMR (75.47 MHz, CDCl3):
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(OH), 3437 (NH). 1H NMR (300 MHz, CDCl3): δ (ppm) = 3.79 (s, 3H,
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