LETTER
3267
Highly Regioselective Synthesis of 1-Aryl-3,4,5-Substituted Pyrazoles
H
ighly Regios
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elective
a
Synthesis
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f
1-Aryl-3, 4
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zoles Gosselin,*a Paul D. O’Shea,*a Robert A. Webster,a Robert A. Reamer,b Richard D. Tillyer,b
Edward J. J. Grabowskib
a
Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 route transcanadienne, Kirkland, Québec,
H9H 3L1, Canada
Fax +1(514)4284936; E-mail: francis_gosselin@merck.com
b
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
Received 10 August 2006
(NMP) and urea solvents such as 1,3-dimethyl-3,4,5,6-
tetrahydro-2-(1H)-pyrimidinone (DMPU) and N,N-tet-
ramethylurea (TMU) provided highest and consistent re-
gioselectivity (>99.8:0.2) of condensation. After
optimization of reaction parameters with amide solvents,
we found that addition of 50 mol% of 10 N aqueous hy-
drochloric acid gave increased yields by presumably fa-
voring the second dehydration reaction of the N-
arylhydrazone intermediate towards the pyrazole hetero-
cycle. For operational convenience and consistency, pyra-
zole syntheses presented in Tables 1– 4 were run on gram-
scale at room temperature for 24 hours and at 0.25 M in
DMAc.
Abstract: A highly regioselective synthesis of 1-aryl-3,4,5-substi-
tuted pyrazoles based on the condensation of 1,3-diketones with
arylhydrazines is described. The reaction proceeds at room temper-
ature in N,N-dimethylacetamide and furnishes pyrazoles in 59–98%
yields.
Key words: 1,3-diketones, arylhydrazines, cyclocondensation, re-
gioselectivity, amide solvents
Pyrazole heterocycles are found as core structural compo-
nents of numerous agrochemicals and pharmaceutical
agents such as antiinflammatories,1 anticoagulants,2 can-
nabinoid receptor ligands,3 and antimicrobials.4 The cy-
clocondensation of 1,3-dicarbonyl compounds with
hydrazine derivatives represents one of the simplest and
most general approaches to the synthesis of pyrazoles.
However, with unsymmetrical 1,3-dicarbonyl substrates
this method often suffers from the formation of regioiso-
meric pyrazoles with generally poor selectivity.5 More-
over, the two pyrazole regioisomers can often be difficult
to separate by chromatography and repeated crystalliza-
tion may be necessary to reject the undesired regioisomer.
This usually results in substantial decrease in isolated
yields of the desired heterocycles. Therefore, various al-
ternative strategies have appeared in the literature as po-
tential solutions to the problem of regioselective synthesis
of pyrazoles.6 We wish to report herein an improved pro-
tocol for the highly regioselective synthesis of 1-aryl-
3,4,5-substituted pyrazoles of pharmaceutical importance.
The reaction proceeds under operationally simple, mild,
safe, volumetrically efficient and readily scaleable condi-
tions.
As illustrated in Table 1, the condensation of 4-substitut-
ed arylhydrazines with 4,4,4-trifluoro-1-arylbutane-1,3-
diones 1a–d proceeded to afford pyrazoles 2a–l in 59–
83% yields with selectivity ranging from 96.7:3.3 to
>99.8:0.2.8 By comparison, reactions run in ethanol at
room temperature generally gave poor selectivity. The cy-
clocondensations of 1,3-diketones with 4-sulfonami-
dophenylhydrazine hydrochloride gave good yields of
pyrazoles 2a–d and were found to be extremely selective
(>99.8:0.2) in many cases.
The 4,4-difluoromethyl-1-arylbutane-1,3-dione 1e–h se-
ries gave pyrazoles 3a–i in 60–98% yields and selectivity
ranging from 86:14 to >99.8:0.2 (Table 2). Although we
observed a slight decrease in regioselectivity in the CF2H-
substituted series relative to the CF3-substituted pyrazoles
2a–l, the reaction remained synthetically useful and gave
results superior to those obtained using ethanol as solvent.
The 4-methyl-1-arylbutane-1,3-dione series 1i–j was
found to exhibit regioselectivity of cyclocondensation
ranging from 93:7 to >99.8:0.2 and provided 3-methyl-
substituted pyrazoles 4a–f in 77–98% yields (Table 3).
We presume that a subtle balance of electronic and steric
effects may be operative and may influence the regiose-
lectivity since the 3-methyl-substituted series gave levels
of regioselectivity intermediates between the CF3- and
CF2H-substituted pyrazole series.
We have found that in the cyclocondensation of arylhy-
drazine hydrochlorides with 1,3-diketones, aprotic sol-
vents with strong dipole moments and dielectric constants
consistently gave much improved results relative to polar,
protic solvents such as ethanol and acetic acid which are
typically used for this type of reaction.7 Our initial evalu-
ation of solvents for the condensation of aryl-1,3-dike-
tones with phenylhydrazine hydrochloride indicated that
amide solvents such as N,N-dimethylacetamide (DMAc),
N,N-dimethylformamide (DMF), N-methylpyrrolidinone
Finally, we explored the use of 2-alkyl-substituted 1,3-
diketones in condensation reactions (Table 4). Gratifying-
ly, we found that condensation of 4,4,4-trifluoro-1-
phenyl-2-ethylbutane-1,3-dione (1k) with arylhydrazines
gave 1-aryl-3,4,5-trisubstituted pyrazoles 5a–c in 79–
89% yields and regioselectivity >99.8:0.2 in all cases. In
SYNLETT 2006, No. 19, pp 3267–3270
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Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-956487; Art ID: S15906ST
© Georg Thieme Verlag Stuttgart · New York