The reaction of phenylhydrazine with sterically congested stabilized phosphorus ylides in the presence of silica gel powder in solvent-free conditions: A novel synthesis of fully substituted pyrazole derivatives

Article abstract of DOI:10.1080/10426500701569448

Reactions of sterically congested stabilized phosphorus ylides with phenylhydrazine in the presence of silica gel powder in solvent-free conditions proceed smoothly at 100°C to afford dialkyl 2-(3,5-dimethyl-1-phenyl-1H- pyrazol-4-yl)-2-butenedioates in good yields. The structures of the products were deduced from their IR, 1H NMR, and 13C NMR spectra. The mass spectra of these compounds displayed molecular ion peaks at the appropriate z values. The 1H NMR (CDCl3) spectra of the compounds show the presence of two estereoisomers (E and Z) for each pyrazoles. The relative population of E and Z isomers were determined via their 1H NMR spectra The reaction is fairly stereoselective. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500701569448

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Phosphorus, Sulfur, and Silicon
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The Reaction of
Phenylhydrazine with
Sterically Congested Stabilized
Phosphorus Ylides in the
Presence of Silica Gel
Powder in Solvent-Free
Conditions: A Novel Synthesis
of Fully Substituted Pyrazole
Derivatives
Nader Noshiranzadeh a & Ali Ramazani a
a Department of Chemistry , University of Zanjan ,
Zanjan, Iran
Published online: 09 May 2008.
To cite this article: Nader Noshiranzadeh & Ali Ramazani (2008) The Reaction
of Phenylhydrazine with Sterically Congested Stabilized Phosphorus Ylides in the
Presence of Silica Gel Powder in Solvent-Free Conditions: A Novel Synthesis of Fully
Substituted Pyrazole Derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, 183:5, 1109-1115, DOI: 10.1080/10426500701569448
To link to this article: http://dx.doi.org/10.1080/10426500701569448
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Phosphorus, Sulfur, and Silicon, 183:1109–1115, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701569448
The Reaction of Phenylhydrazine with Sterically
Congested Stabilized Phosphorus Ylides in the Presence
of Silica Gel Powder in Solvent-Free Conditions: A Novel
Synthesis of Fully Substituted Pyrazole Derivatives
Nader Noshiranzadeh and Ali Ramazani
Department of Chemistry, University of Zanjan, Zanjan, Iran
Reactions of sterically congested stabilized phosphorus ylides with phenylhydrazine
in the presence of silica gel powder in solvent-free conditions proceed smoothly at
100◦ C to afford dialkyl 2-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-2-butenedioates
in good yields. The structures of the products were deduced from their IR, 1 H NMR,
and 13 C NMR spectra. The mass spectra of these compounds displayed molecular
ion peaks at the appropriate m/z values. The 1 H NMR (CDCl3 ) spectra of the com-
pounds show the presence of two estereoisomers (E and Z) for each pyrazoles. The
relative population of E and Z isomers were determined via their 1 H NMR spectra
The reaction is fairly stereoselective.
Keywords Phenylhydrazine; phosphorus ylide; pyrazole; silica gel; solvent-free condi-
tions
INTRODUCTION
Pyrazole derivatives are in general well-known nitrogen-containing
heterocyclic compounds, and various procedures have been developed
for their syntheses.1−5 The chemistry of pyrazole derivatives have been
the subject of much interest due to their importance for various ap-
plications and their widespread potential and proven biological and
pharmacological activities such as anti-inflammatory, antipyretic, anal-
gesic, antimicrobial, antiviral, antitumor, antifungal, pesticidal, anti-
convulsant, antihistaminic, antibiotics, anti-depressant, and CNS reg-
ulant properties.2−11
Organophosphorus compounds12,13 have been extensively employed
in organic synthesis as useful reagents as well as ligands in a number
of transition metal catalysts.14 Phosphorus ylides are a class of special
Received 5 June 2007; accepted 6 July 2007.
This work was supported by the Zanjan University.
Address correspondence to Ali Ramazani, Department of Chemistry, University of
Zanjan, P.O. Box 45195-313, Zanjan, Iran. E-mail: aliramazani@yahoo.com
1109

1110
N. Noshiranzadeh and A. Ramazani
type of zwitterions, which bear strongly nucleophilic electron rich car-
banions. The electron distribution around the P+–C− bond and its con-
sequent chemical implications had been probed and assessed through
theoretical, spectroscopic, and crystallographic investigations15; They
are excellent ligands and excel in their ligating functions the unstabi-
lized ylides because of their ambidentate and chemically differentiat-
ing character. Proton affinity of these ylides can be used as a molecular
guide to assess their utility as synthetic reagents and their function as
ligands in coordination and organometallic chemistry.14,16 The nucle-
ophilicity at the ylidic carbon is a factor of essential mechanistic impor-
tance in the use of these ylides as Wittig reagents. Phosphorus ylides
are important reagents in synthetic organic chemistry, especially in the
synthesis of naturally occurring products, compounds with biological
and pharmacological activity.12,13 In recent years, we have established
a one-pot method for the synthesis of stabilized ylides.17−25
Environmentally friendly synthesis of organic compounds without
using of organic solvents has come several steps closer in recent years.26
Organic reactions using conventional organic solvents especially chlo-
rinated hydrocarbons have posed a serious threat to the environment
owing to their toxicity and volatile nature.26 In this regard, solvent free
catalytic organic reaction has received tremendous attention in recent
times.27 Silica gel as an additive promotes many condensation reac-
tions in solvent-free conditions.28,29 As part of our ongoing program
to develop efficient and robust methods for the preparation of hetero-
cyclic compounds,30−32 we sought to develop a convenient preparation
of fully substituted pyrazole derivatives 8a–b (Scheme 1, Scheme 2 and
Scheme 3).
SCHEME 1
RESULTS AND DISCUSSION
Sterically congested stabilized phosphorus ylides 4a-b were prepared
based on previously reported procedure (Scheme 1).25 The phenylhy-
drazine 5 and stabilized phosphorus ylides 4 in the presence of silica

Fully Substituted Pyrazole Derivatives
1111
SCHEME 2
SCHEME 3
gel powder undergo a smooth 1:1 condensation reaction in solvent-
free conditions at 100◦C to produce fully substituted pyrazole deriva-
tives 8 (Scheme 2). TLC indicated the formation of pyrazoles 8 and
triphenylphosphine 1 on the silica gel surface. The reaction proceeds
smoothly and cleanly under reaction conditions and no side reactions
were observed. In the absence of the silica gel powder, the compounds
4 were not reacted with phenylhydrazine 5 under reaction conditions
(100◦C, 5 h) in the solvent-free system. The reaction also was not oc-
1
curred in dichloromethane solutions after several days. The H NMR
(CDCl3) spectra of compounds 8 show the presence of two estereoiso-
mers ( E and Z) for each pyrazoles 8. The relative population of E and
Z isomers were determined via their 1H NMR spectra (See Experimen-
tal section). The reaction is fairly stereoselective. We have also used
electron-poor hydrazine derivatives (such as benzohydrazide, isonicoti-
nohydrazide and 2,4-dinitrophenylhydrazine) in this reaction, but no
corresponding products 8 were observed and in the all cases decomposi-
tion of the starting materials were observed. Fairly week nucleophilicity
of electron-poor hydrazine derivatives relative to the phenylhydrazine
5 may be plausible factor in the reduction of their reactivity toward this
reaction.

1112
N. Noshiranzadeh and A. Ramazani
The mechanism of the reaction between the phenylhydrazine 5 and
stabilized phosphorus ylides 4 in the presence of silica gel powder in
solvent-free conditions has not been established experimentally. How-
ever, a possible explanation is proposed in Scheme 3. The structures
1
of the products were deduced from their IR, H NMR, and 13C NMR
spectra. The mass spectra of these compounds displayed molecular ion
peaks at the appropriate m/z values (See Experimental section).
We have also used Sterically congested stabilized phosphorus
ylides25 10a–b in this reaction (Scheme 4), but no corresponding prod-
ucts 8 were observed and in the all cases decomposition of the starting
materials and formation of 1,3,5-triphenylpyrazole 11 were observed.
SCHEME 4
The presence of fairly bulky phenyl groups in 10a–b relative to the
methyl groups in 4a–b may be plausible factor for the different behav-
ior of their reactivity toward this reaction (Scheme 1, Scheme 2 and
Scheme 4).
CONCLUSIONS
In summary, we have found a new and efficient method for prepar-
ing fully substituted pyrazole derivatives (8) from triphenylphosphine
(1), dialkyl acetylenedicarboxylates (2), acetylacetone (3) and phenyl-
hydrazine (5) in the presence of silica gel powder in solvent-free con-
ditions (Scheme 1, Scheme 2, and Scheme 3). We believe the reported
method offers a simple and efficient route for the preparation of fully
substituted pyrazole derivatives 8a-b (Scheme 2). Its ease of work up

Fully Substituted Pyrazole Derivatives
1113
and good yields make it a useful addition to modern synthetic method-
ologies. Other aspects of this process are under investigation.
EXPERIMENTAL
1H (250 MHz) and 13C (62.5 MHz) NMR measurements were recorded
on a Brucker 250 spectrometer in CDCl3 with tetramethylsilane as
internal standard. IR spectra were measured on a Mattson-1000 FTIR
spectrophotometer. Mass spectra were recorded on a FINNIGAN-MATT
8430 mass spectrometer operating at an ionization potential of 20 eV.
Starting materials and solvents were obtained from Merck (Germany)
and Fluka (Switzerland) and were used without further purification.
Flash chromatography columns were prepared from Merck silica gel
powder.
General Procedure for the Preparation of Compounds 8a-b
Stabilized phosphorus ylides 4a-b were prepared based on previously
reported procedure.25
Homogenous mixture of stabilized phosphorus ylide 4 (1 mmol),
phenylhydrazine 5 (0.1 ml, 1 mmol) and powdered silica gel (0.7 g) were
heated in a oven at 100◦C (5 h for 4a and 4 h for 4b) and then placed over
a column of silica gel (12 g). The column chromatography was washed
using ethyl acetate-light petroleum ether (1:10) as eluent. The solvent
was removed under reduced pressure and the products were obtained
as light yellow oils. The relative population of E and Z stereoisomers
for the compounds 8a-b was determined via their 1H NMR spectra. The
characterization data of the new compounds are given below.
Dimethyl
2-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-yl)-2-butenedioate 8a
Light yellow oil; yield 65%; IR (neat) (υmax , cm−1): 3063, 2954, 1727,
1597, 1504, 1431, 1380, 1249, 1149, 1025, 774, 694. %E=74 and %Z=26.
1H NMR (250 MHz, CDCl3) for E stereoisomer, δH: 2.14 and 2.15 (6 H,
2 s, 2 CH3); 3.71 and 3.84 (6 H,2 s, 2 OCH3); 7.09 (1 H, 1 s, =CH), 7.35–
1
7.51 (5 H, m, arom). H NMR (250 MHz, CDCl3) for Z stereoisomer,
δH: 2.29 and 2.32 (6 H, 2 s, 2 CH3); 3.79 and 3.91 (6 H, 2 s, 2 OCH3);
6.02 (1 H, 1 s, =CH), 7.35–7.51 (5 H, m, arom). 13C NMR (62.5 MHz,
CDCl3) for E stereoisomer, δc: 11.95 and 12.50 (2 CH3); 51.94 and 52.92
(2 OCH3); 125.02, 127.57, 129.02, 129.65 (6 CH); 125.48, 136.90, 138.70,
139.60, 147.84 (5 C); 165.23 and 168.87 (2 C=O). 13C NMR (62.5 MHz,
CDCl3) for Z stereoisomer, δc: 12.02 and 13.42 (2 CH3); 51.89 and 52.56
(2 OCH3); 128.31, 128.82, 129.04 and 129.65 (6 CH); 125.15, 138.98,

1114
N. Noshiranzadeh and A. Ramazani
139.17, 141.99 and 148.08 (5 C); 165.68 and 168.32 (2 C O). MS: m/z
(%) (EI) 314 (M+, 71), 282 (16), 254 (50), 243 (8), 225 (12), 215 (20), 199
(30), 195 (35), 168 (10), 154 (15), 149 (16), 128 (12), 118 (20), 104 (8), 91
(12), 78 (12), 77 (100), 65 (12), 59 (35), 51 (31), 41 (12).
Diethyl
2-(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)-2-butenedioate 8b
Light yellow oil; yield 66%; IR (neat) (υmax , cm−1): 3062, 2985, 2931,
1728, 1596, 1504, 1434, 1380, 1248, 1164, 1033, 786, 694. %E=79 and
1
%Z=21. H NMR (250 MHz, CDCl3) for E stereoisomer, δH: 1.21 and
1.32 (6 H, 2 t, 3JHH = 7.3 Hz, 2 CH3 of 2 OEt); 2.17 and 2.22 (6 H, 2 s, 2
CH3); 4.06 and 4.28 (4 H, 2 q, 3JHH = 7.3 Hz, 2 OCH2 of 2 OEt); 7.08 (1
H, 1 s, =CH), 7.28–7.36 (5 H, m, arom). 1H NMR (250 MHz, CDCl3) for
3
Z stereoisomer, δH: 1.24 and 1.38 (6 H, 2 t, JHH = 7.3 Hz, 2 CH3 of 2
OEt); 2.30 and 2.33 (6 H, 2 s, 2 CH3); 4.25 and 4.37 (4 H, 2 q, 3JHH = 7.3
Hz, 2 OCH2 of 2 OEt); 5.99 (1 H, 1 s, =CH), 7.28-7.36 (5 H, m, arom).
13C NMR (62.5 MHz, CDCl3) for E stereoisomer, δc: 11.99 and 12.58
(2 CH3); 14.06 and 14.18 (2 CH3 of 2 OEt); 60.87 and 60.01 (2 OCH2
of 2 OEt); 124.90, 127.45, 129.00 and 130.09 (6 CH); 125.42, 136.75,
138.45, 139.63 and 147.85 (5 C); 165.04 and 166.50 ( 2 C=O of ester).
13C NMR (62.5 MHz, CDCl3) for Z stereoisomer, δc: 12.15 and 12.25 (2
CH3); 13.51 and 13.95 (2 CH3 of 2 OEt); 61.18 and 61.81 (2 OCH2 of 2
OEt); 125.07, 127.55, 129.21 and 130.07 (6 CH); 125.41, 137.20, 139.00,
139.10 and 147.50 (5 C); 164.00 and 168.09 (2 C=O). MS: m/z (%) (EI)
342 (M+, 100), 313 (8), 296 (34), 271 (50), 268 (50), 250 (12), 241 (34),
229 (14), 225 (25), 199 (55), 195 (45), 173 (29), 154 (22), 149 (10), 128
(16), 118 (25), 104 (9), 91 (11), 77 (81), 65 (10), 51 (22), 42 (11).
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