One-pot synthesis of oxime derivatives of 1,3-diphenylpyrazole-4- carboxaldehydes from acetophenone phenylhydrazones using vilsmeier-haack reagent

Article abstract of DOI:10.1080/00397910600942941

A one-pot synthesis of oxime derivatives 3a-3f of 1-phenyl-3-arylpyrazole- 4-carboxaldehydes has been accomplished by the Vilsmeier-Haack reaction of acetophenone phenylhydrazones 1a-1f under a new workup procedure. Copyright Taylor & Francis Group, LLC.

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One‐Pot Synthesis of Oxime Derivatives of
1,3‐Diphenylpyrazole‐4‐carboxaldehydes
from Acetophenone Phenylhydrazones Using
Vilsmeier–Haack Reagent
Om Prakash a , Kamaljeet Pannu a , Rajesh Naithani a & Harpreet Kaur b
a Department of Chemistry, Kurukshetra University, Kurukshetra, India
b Department of Pharmaceutical Sciences, Wayne State University, Detroit,
Michigan, USA
Version of record first published: 24 Nov 2006
To cite this article: Om Prakash, Kamaljeet Pannu, Rajesh Naithani & Harpreet Kaur (2006): One‐Pot
Synthesis of Oxime Derivatives of 1,3‐Diphenylpyrazole‐4‐carboxaldehydes from Acetophenone
Phenylhydrazones Using Vilsmeier–Haack Reagent, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 36:23, 3479-3485
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Synthetic Communicationsw, 36: 3479–3485, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600942941
One-Pot Synthesis of Oxime Derivatives of
1,3-Diphenylpyrazole-4-carboxaldehydes
from Acetophenone Phenylhydrazones
Using Vilsmeier–Haack Reagent
Om Prakash, Kamaljeet Pannu, and Rajesh Naithani
Department of Chemistry, Kurukshetra University, Kurukshetra, India
Harpreet Kaur
Department of Pharmaceutical Sciences, Wayne State University,
Detroit, Michigan, USA
Abstract: A one-pot synthesis of oxime derivatives 3a–3f of 1-phenyl-3-arylpyrazole-
4-carboxaldehydes has been accomplished by the Vilsmeier–Haack reaction of
acetophenone phenylhydrazones 1a–1f under a new workup procedure.
Keywords: Vilsmeier-Haack reaction, acetophenone phenylhydrazones, 1,3-diphenyl-
pyrazole-4-carboxaldehydes, hydroxylamine, 1,3-diphenylpyrazole-4-carboxaldehyde
oximes
The application of Vilsmeier–Haack (VH) reagent (POCl3/DMF) for
formylation of a variety of both aromatic and heteroaromatic substrates is
well documented.[1] Besides this, the reagent has also been extensively used
for effecting various chemical transformations from other classes of
compounds. Many of these reactions have led to novel and convenient routes
for the synthesis of various heterocyclic compounts.[2] A notable example
that finds significant application in heterocylic chemistry is the synthesis of
Received in the USA April 20, 2006
Address correspondence to Harpreet Kaur, Department of Pharmaceutical Sciences,
Wayne State University, Detroit, MI 48202, USA. E-mail: ay2216@wayne.edu
3479

3480
O. Prakash et al.
Scheme 1.
4-formylpyrazoles (2) from the double formylation of hydrazones 1 with VH
reagent (Scheme 1).[3,4] These observations, coupled with the recent develop-
ments on the simple synthesis of pyrazole derivatives,[5] especially 4-functiona-
lized 1,3-diphenylpyrazoles as antibacterial,[6] anti-inflammatory,[7,8]
antiparasitic,[9] and antidiabetic[10] drugs, prompted us to undertake the
synthesis of pyrazole-4-carboxldehyde derivatives using VH. The study is par-
ticularly aimed at developing a one-pot synthesis of pyrazole-4-carboxaldehyde
oximes (3) starting from acetophenone phenylhydrazones (1).
RESULTS AND DISCUSSION
It has recently been shown that the intermediate iminium salt 4 formed in the
VH formylation of aromatic substrates can be converted into the groups other
than aldehydes, such as oxime, using a modified workup procedure that
involves hydroxylamine.[11] Based on this observation and the presumption
that double formylation of hydrazones 1 outlined in Scheme 1 proceeds
through a similar iminium salt of the type 5, it was anticipated that
changing the workup condition in the reaction might lead directly to desired
pyrazole-4-carboxaldehyde derivative of the type 3 as shown in Method A
of Scheme 2.
To test the feasibility of the proposed scheme, acetophenone
phenylhydrazone (1a) was subjected to standard VH Conditions using POCl3
and N,N-dimethylformamide (DMF) followed by workup under new conditions
.
using NH2OH HCl and NaHCO3. After making several attempts, we were able
to optimize the conditions for obtaining the desired oxime derivative 3a as
colorless solid with mp 168–1708C, in 72% yield.
Encouraged by the successful results, we studied the scope of new method
for the synthesis of variously substituted derivatives 3b–3f. The VH reaction
of hydrazones 1b–1f using new workup conditions indeed afforded the

Oxime Derivatives
3481
Scheme 2.
compounds pyrazole-4-carboxaldehyde oximes (3b–3f) in good yields
Table 1. The structures of oximes were confirmed by elemental analysis and
spectral data (IR, 1H NMR). Further support for the confirmation of
structure of oximes was provided by preparing 3 via isolation of aldehydes
2 (Scheme 2, Method B). The melting points and spectral properties of the
products obtained from the two methods were found to be identical and
were in good agreement with expected data.
It should be noted that the recrystallized products 3a–f obtained from
Methods A and B were found to be a mixture of syn and anti isomers in an
approximately 1 : 1 ratio. The ratio was based on the integration of the
proton singlets of the oximino group in two isomeric forms appearing at
1
d 8.2 and d 8.3 in the H NMR. The other NMR techniques (viz. correlation
spectroscopy (COSY) an heteronuclear multiple quantum coherence
(HMQC)) also established that protons corresponding to these singlets
belong to different molecules rather than being a part of same molecule.
Table 1. Physical data of pyrazole-4-carboxaldehyde oximes 3a–3f prepared
according to Scheme 2
Yield (%)a
Compound
Mp (8C)
Method A
Method B
3a
3b
3c
3d
3e
3f
168–170 (lit.[3] mp 173)
154–155
170–171
75
68
84
72
70
76
52
56
53
40
50
45
136–137
166–167
98–99
aYields of isolated pure products 3 with regard to the quantity of hydrazones 1.

3482
O. Prakash et al.
In conclusion, VH reaction of hydrazones 1 under new workup
conditions provides a convenient and mild one-pot method for the
synthesis of 1-phenyl-3-aryl-pyrazolyl-4-carboxaldehyde oximes. The
yields obtained by the new workup procedure (Method A) are much better
than the method employing the isolation of aldehyde (Method B, Table 1).
It is hoped that the application of this methodology might offer simple
way of synthesizing other 4-functionalized pyrazoles, especially the
synthesis of biologically active compounds. We are investigating the
oxidation of oxime derivatives of pyrazole-4-carboxaldehydes with hyperva-
lent iodine reagents[12] for the synthesis of novel heterocyclic compounds.
Preliminary results indicate the formation of oxadiazole N-oxides of the
type 6.
EXPERIMENTAL
All reagents were purchased from commercial sources and were used without
further purification. Melting points were taken in open capillaries and are
1
uncorrected. HNMR spectra were recorded on a Brucker 300-MHz instru-
ment using TMS as an internal standard. IR spectra were recorded on a
Buck Scientific IR M-500 spectrophotometer.
Preparation of 1-Phenyl-3-arylpyrazolyl-4-oximes (3a–f)
Method A: One-Pot-Synthesis of 3a from 1a
To a cold solution of dimethylformamide (10 ml) and phosphorus oxychloride
(0.5 ml, 6 mmol), acetophenone phenylhydrazone (1a, 0.84 g, 4 mmol) was
added. The mixture was stirred at 50–608C for 5–6 h, cooled to room tempera-
ture, and then poured into a cold saturated solution of hydroxylamine
hydrochloride and sodium bicarbonate. The reaction mixture was stirred
overnight. The solid product thus obtained was filtered, washed with water,
and recrystallized from ethanol to give 1,3-diphenylpyrazole-4-carboxaldehyde
oxime (3a, 0.74 g, yield 75%).

Oxime Derivatives
3483
Similarly, oximes 3b–3f were prepared from the corresponding acetophenone
phenylhydrazones 1b–1f (Table 1).
Method B: Synthesis of 3a from 1a via Isolation of 2a
Step 1: Synthesis of 1,3-diphenylpyrazole-4-carboxaldehyde (2a) from 1a. To
a cold solution of dimethylformamide (10 ml) and phosphorus oxychloride
(0.5 ml, 6 mmol), acetophenone phenylhydrazone (1a, 4 mmol) was added.
The mixture was stirred at 50–608C for 5–6 h, cooled to room temperature,
and then poured into ice-cold water. A saturated solution of sodium bicarbon-
ate was added to neutralize the mixture and give formyl pyrazole 2a, which
was isolated by filtration followed by washing with water (yield 76%).
Step 2: Synthesis of 3a from 2a. To formylpyrazole (2a, 10 mmol) in 25 ml of
ethanol, hydroxylamine hydrochloride (20 mmol) and sodium acetate
(30 mmol) were added. The reaction mixture was refluxed for 2 h. The
reaction mixture was cooled to room temperature and poured into ice-cold
water. The solid thus obtained was filtered, washed with water, and recrystal-
lized from ethanol to get 3a (yield 69%; overall yield of step 1 and step 2:
52%).
Similarly, oximes 3b–3f were prepared from 1b–1f via isolation of
aldehydes 2b–2f (Table 1).
Data
1,3-Diphenylpyrazole-4-carboxaldehyde oxime (3a): IR (Nujol): 3244 cm21
.
1H NMR (CDCl3, 300 MHz): 7.33–7.84 (m, 10H, aromatic protons), 8.27
(s, 0.5H), 8.35 (s, 0.5H), 8.98 (s, 1H, C5-H).
1-Phenyl-3-(4-chlorophenyl)pyrazole-4-carboxaldehyde oxime (3b): IR
(Nujol): 3243 cm21 1H NMR (CDCl3, 300 MHz): 7.37–7.83 (m, 9H,
.
aromatic protons), 8.23 (s, 0.5H), 8.32 (s, 0.5H), 8.97 (s, 1H, C5-H). Anal.
calc. for C16H12N3OCl: C, 64.46; H, 4.04; N, 14.14. Found: C, 64.55; H,
3.94; N, 13.88.
1-Phenyl-3-(4-bromophenyl)pyrazole-4-carboxaldehyde oxime (3c): IR
(Nujol): 3245 cm21 1H NMR (CDCl3, 300 MHz): 7.31–7.73 (m, 9H,
.
aromatic protons), 8.14 (s, 0.5H), 8.23 (s, 0.5H), 8.88 (s, 1H, C5-H). Anal.
calc. for C16H12N3OBr: C, 56.30; H, 3.52; N, 12.32. Found: C, 55.65; H,
3.43; N, 12.11.
1-Phenyl-3-(4-methylphenyl)pyrazole-4-carboxaldehyde oxime (3d): IR
(Nujol): 3250 cm21 1H NMR (CDCl3, 300 MHz): 2.43 (s, 3H, CH3),
.
7.15–7.83 (m, 9H, aromatic protons), 8.27 (s, 0.5H), 8.35 (s, 0.5H), 8.97

3484
O. Prakash et al.
(s, 1H, C5-H). Anal. calc. for C17H15N3O: C, 73.65; H, 5.42; N, 15.16. Found:
C, 73.57; H, 5.12; N, 15.06.
1-Phenyl-3-(4-methoxyphenyl)pyrazole-4-carboxaldehyde oxime (3e): IR
(Nujol): 3267 cm21 1H NMR (CDCl3, 300 MHz): 3.89 (s, 3H, OCH3),
.
7.01–7.83 (m, 9H, aromatic protons), 8.25 (s, 0.5H), 8.33 (s, 0.5H), 8.97
(s, 1H, C5-H). Anal. calc. for C17H15N3O2: C, 69.92; H, 5.12; N, 14.33.
Found: C, 69.53; H, 4.95; N, 13.84.
1-Phenyl-3-(4-nitrophenyl)pyrazole-4-carboxaldehyde oxime (3f): IR
(Nujol): 3350 cm21 1H NMR (CDCl3, 300 MHz): 7.38–8.29 (m, 9H,
.
aromatic protons), 8.31 (s, 0.5H), 8.39 (s, 0.5H), 9.01 (s, 1H, C5-H). Anal.
calc. for C16H14N4O3: C, 61.94; H, 4.52; N, 18.06. Found: C, 61.64;
H, 4.32; N, 17.96.
ACKNOWLEDGMENT
We are thankful to Defense Research & Development Organisation (DRDO)
(ERIP/ER/0303447/M/01), New Delhi, India, for financial support to carry
out the work described.
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