First synthesis of 3-aryl-5-dichloromethyl-2-pyrazolines. The electrochemical generation of 2,2-dichlorovinylacetophenones as a key step

Article abstract of DOI:10.1016/j.tetlet.2004.09.101

An efficient synthetic route to the title compounds has been established. Chloralacetophenones 2 were prepared by treatment of acetophenones 1 with anhydrous chloral. Dehydration of intermediates 2 under acidic conditions yielded 2,2,2-trichloroethylidene

Full text of DOI:10.1016/j.tetlet.2004.09.101

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8523–8526
First synthesis of 3-aryl-5-dichloromethyl-2-pyrazolines. The
electrochemical generation of 2,2-dichlorovinylacetophenones as
a key step
Antonio Guirado,* Bruno Martiz and Raquel Andreu
´ ´ ´
Departamento de Quımica Organica, Facultad de Quımica, Universidad de Murcia, Campus de Espinardo, 30071 Murcia,
Apartado 4021, Spain
Received 23 July 2004; revised 10 September 2004; accepted 13 September 2004
Available online 30 September 2004
Abstract—An efficient synthetic route to the title compounds has been established. Chloralacetophenones 2 were prepared by treat-
ment of acetophenones 1 with anhydrous chloral. Dehydration of intermediates 2 under acidic conditions yielded 2,2,2-trichloro-
ethylideneacetophenones 3, which were transformed to 2,2-dichlorovinylacetophenones 5 in nearly quantitative yields by selective
electrochemical monodechlorination at either mercury or graphite electrodes. Finally, 3-aryl-5-dichloromethyl-2-pyrazolines 7 were
efficiently obtained on treatment of compounds 5 with either hydrazine or methylhydrazine.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Scheme 1, we recognized this reaction as the starting
point for preparing 3-aryl-5-dichloromethyl-2-pyrazo-
lines 7, which pertain to a hitherto unknown family of
pyrazolines.
Pyrazolines1 are compounds with noteworthy applica-
tions. One special interest lies in the use as synthetic
intermediates for preparing cyclopropane2 and pyraz-
ole1b,2f,3 derivatives. Certain compounds containing
the 2-pyrazoline moiety have been demonstrated to have
an important therapeutic potential, mainly as anti-
inflammatory,4 antidepressant,5 antipyretic,6 antibacte-
rial,7 antifungal,7a,d,8 and antitumor9 agents.
Given the above, the preparation of compounds 7 itself
shows remarkable interest and highly attractive also is a
promising value arising from the synthetic utility of
geminal dihalide groups. Notwithstanding, the synthesis
of compounds of type 7 has not yet been reported. This
seems to be attributable to incompatibility of pyrazo-
lines with the reagents mostly used to generate dichloro-
methyl groups.15 However, the aim of this approach is
to circumvent the indiscriminate action of these reagents
by utilization of a pre-chlorinated synthon derived from
chloral with the advantageous result of the development
of a general, facile and highly efficient synthesis of prod-
ucts 7 (Table 1). As far as we know, this is the first time
that chloral has been used as starting material for pre-
paring pyrazolines.
Over the years, the synthesis of 2-pyrazolines has
received considerable attention. The most extended
methodologies to generate this ring system involve the
use of either diazoalkanes1b,2a,b,10a–c or a,b-unsaturated
carbonyl compounds1b,2c,d,10d,e,11 as immediate precur-
sors. As a part of our research project on the synthesis
of heterocyclic compounds based on the chemistry and
electrochemistry of chloral derivatives,12 we herein re-
port an efficient approach to the synthesis of dichloro-
methylated pyrazolines. Chloral is an inexpensive
multipurpose starting material for organic synthesis.13
Reaction of chloral with acetophenones 1 provides
chloralacetophenones 2 in high yields.14 As is shown in
2. Results and discussion
In an attempt to prepare the key intermediates 5
chloralacetophenones 2 were treated with zinc in warm
acetic acid. These reactions showed erratic induction
periods and were found to be of little synthetic utility.
The main reaction products were formed along with
Keywords: Pyrazolines; Chloral; Acetophenones; Electrosynthesis;
Reduction; Dechlorination.
*
Corresponding author. Tel.: +34 968367490; fax: +34 968364148;
e-mail: anguir@um.es
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.101

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A. Guirado et al. / Tetrahedron Letters 45 (2004) 8523–8526
O OH
O
O
Cl3CCHO
- H2O
Ar
CCl3
Ar
Ar
CCl3
2
1
3
Zn,AcOH
2e, - Cl
H
∆
O
OH
O
Ar
CHCl2
Ar
Ar
CCl2
CCl2
4
6
5
R-NHNH2
R
N
N
Ar
CHCl2
7
Scheme 1.
Table 1. Preparation of dichlorovinylacetophenones 5 and dichloromethylpyrazolines 7
Entry
Ar
R
Prod. 5 mp°C (%)
Prod. 7 mp°C (%)
a
b
c
C6H5
4-O2NC6H4
2-C10H7
CH3
CH3
CH3
H
50–51 (95)
104–105 (72)
81–82 (96)
72–74 (97)
58–59 (96)
Oil (85)
117–118 dec (78)
156–157 (80)
d
e
4-CH3OC6H4
4-ClC6H4
107–109 dec (96)
126–127 dec (93)
H
numerous unidentified compounds and were isolated in
remarkably low yields and purified only with
considerable difficulty. They were identified as dichlo-
rovinylacetophenones 5. The reduction applied to 2b,
which bears a nitro group, showed a total incapability
to give product 5b. In this case the generation of a very
complex mixture of unidentified products was detected.
All products 5, however, were found to be directly
convertible to the targeted products 7 in near quantita-
tive yields by treatment with hydrazines.
Products 5 reacted easily with hydrazine hydrate as well
as methylhydrazine to give the corresponding 3-aryl-5-
dichloromethyl-2-pyrazolines 7 in high yields (Table
1). The easy and efficient formation of these products
can be explained by participation of intermediates 6.
This is the first time that the synthesis of 3-aryl-5-dichlo-
romethyl-2-pyrazolines 7 has been reported. The struc-
ture of one of these compounds (7c) was determined
by single crystal X-ray diffraction.18
To conclude, a convenient new method for the synthesis
of 3-aryl-5-dichloromethyl-2-pyrazolines 7 is reported.
Versatility, good yields, easy availability of starting
materials, mildness, and simple experimental procedure
are noteworthy advantages of this approach, which
provides access to previously unattainable compounds
of significant interest. It seems feasible that the interme-
diates involved in this synthetic route, particularly
2,2-dichlorovinylacetophenones 5, would also be useful
for preparing a variety of heterocyclic compounds.
Given the high synthetic interest evidenced by inter-
mediates 5 we focused our attention on the search
for an effective preparative procedure. As such, the
compounds 2 could be easily transformed to 2,2,2-tri-
chloroethylideneacetophenones 3 (85–94% yield) by
dehydration with either sulfuric or p-toluenesulfonic
acids.16 A highly efficient generation of the key inter-
mediates 5 was achieved by selective electrochemical
reduction of products 3. These electrolyses provided
single products in near quantitatively yields (Table
1), which were identical to that inefficiently originated
by zinc reduction of compounds 2. Compound 5b
could also be synthesized in good yield in this man-
ner. As far as we know it is the first time that 2,2-
dichlorovinylacetophenones 5 have been prepared.
However, some aliphatic analogues have been de-
scribed.17 The molecular structure of compound 5d
has been determined by X-ray crystallographic
analysis.18
3. Experimental
3.1. Electrogeneration of 2,2-dichlorovinylacetophenones
(5)
Reductive electrolyses of 2,2,2-trichloroethylideneaceto-
phenones 3 were carried out under a constant cathodic
potential in a concentric cylindrical cell with two com-

A. Guirado et al. / Tetrahedron Letters 45 (2004) 8523–8526
8525
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partments separated by a circular glass frit (medium)
diaphragm. A mercury pool (diameter 5cm) was used
as the cathode and a platinum plate as the anode. The
catholyte was magnetically stirred. The temperature
was kept at approximately 18°C by external cooling.
The reductions were performed in MeCN (60mL)–
AcOH (10mL)–LiClO4 (3.5g); 55 and 15mL were
placed in the cathodic and the anodic compartments,
respectively. Sodium acetate (1g) was placed in the ano-
dic compartment. Solutions of 3 (5mmol) were electro-
lyzed under the following cathodic potentials, which
were selected in order to provide operative current inten-
sities (close to 220mA at the beginning and 10mA at the
end): 3a (À0.20); 3b (À0.40); 3c (À0.60); 3d (À0.50); 3e
(À0.72) V versus SCE. The electricity consumption
was 2F/mol in all cases. Isolation of products 3 was car-
ried out by removing the solvent in vacuo,19 adding
water (150mL) and collecting the resulting solid by fil-
tration. These were crystallized from petroleum ether
or cyclohexane (5b).
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using graphite instead of mercury as cathodic material.
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(7)
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To a suspension of compound 5 (7mmol) in EtOH
(15mL) a solution of hydrazine (8.4mmol) in EtOH
(7mL) was added dropwise. The mixture was refluxed
for 10min. Then the solution was concentrated under re-
duced pressure (half of volume) and was kept at À15°C
until the precipitation of a pale yellow solid, which was
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Acknowledgments
We gratefully acknowledge the financial support of the
´
´
´
Consejerıa de Economıa, Industria e Innovacion of the
Comunidad Autonoma de la Region de Murcia (project
´
´
2I04SU005). Author B.M. thanks the Ministerio de
´
Educacion y Cultura for a grant.
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Galvez, J. Tetrahedron Lett. 1998, 39, 1071; (b) Guirado,
A.; Andreu, R.; Galvez, J.; Jones, P. G. Tetrahedron 2002,
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