S. K. Meegalla et al. / Tetrahedron Letters 43 (2002) 8639–8642
8641
cycloalkanones (9) with either organolithium or Grig-
nard reagents in the presence of CuBr·Me2S, followed
by trapping the resulting enolate with chlorotrimethylsi-
lane as silyl enol–ethers (10). The crude enol–ethers
were then reacted with trimethylorthoformate in the
presence of catalytic amounts of iodotrimethylsilane at
−78°C to obtain a-(dimethoxymethyl)cycloalkanone
intermediates (11) regiospecifically (Scheme 4).9
trimethyl-orthoformate promoted by BF3·OEt2 fol-
lowed by a condensation–deprotection–condensation
sequence, to provide rapid access to a number of 3,4-
fused-cycloalkyl-1-arylpyrazoles. This methodology has
been extended to thiocycloalkanones, furnishing a facile
entry into novel 3,4-fused-cycloheteroalkylpyrazoles
and related compounds of potential biological and
medicinal interest. The overall sequence yields are mod-
erate to good, and amenable to multi-gram scale prepa-
rations. In addition this methodology provides specific
regiochemical control in the cyclocondensation step
with specific substitutions on cycloalkyl ring system
from readily available staring materials.
The crude a-(dimethoxymethyl)cycloalkanone (8) or
(11) was reacted with hydrazine in benzene at reflux
temperature for 2 h with azeotropic removal of water to
obtain the corresponding ketimine, which was then
cyclized under acid catalysis to furnish the desired
1-phenylpyrazole 2 in good overall yields (Table 1).
General procedures
Conclusions
Method A. A solution of BF3·OEt2 (7.5 mL, 0.06 mol)
in CH2Cl2 (20 mL) was added dropwise with stirring to
5.5 mL (0.05 mol) of trimethylorthoformate at −30°C
under N2 over a period of 10 min. The reaction mixture
was then allowed to warm to 0°C. After 15 min at this
temperature the reaction mixture was cooled back to
−78°C. A solution of the corresponding ketone (0.025
mol) in CH2Cl2 (10 mL) was then added, followed by
diisopropylethyl amine (0.075 mol) over 30 min. The
resulting mixture was stirred at −78°C for 1 h and
poured into cold NaHCO3 (saturated solution, 500 mL)
and CH2Cl2 (200 mL) with vigorous stirring. The
organic phase was separated, washed with water (3×100
mL), dried and concentrated to obtain the b-
dimethoxymethylketone that was used directly for the
condensation step.
We have combined two regiospecific processes, namely
the a-(dimethoxy)methylation of ketones with
Table 1. 3,4-Fused-cycloalkyl-1-arylpyrazoles prepared by
methods A or B via Scheme 1
Method B. To a solution of CuBr·Me2S in THF (10
mL) at −30°C was added the Grignard or organo-
lithium reagent (2 mmol). The resulting solution was
stirred at −30°C for 1 h and cooled back to −78°C.
HMPA (0.17 mL, 2 mmol) was added dropwise, fol-
lowed by a mixture of a,b-unsaturated cycloalkanone (1
mmol) and TMSCl (0.24 mL, 2.4 mmol). The resulting
mixture was stirred for 30 min at −78°C. and warmed
to −40°C for 30 min. The reaction was quenched by
addition of triethylamine (0.69 mL, 5 mmol), followed
by a mixture of ether–hexane (1:1, 10 mL) and water (1
mL). The resulting mixture was allowed to warm to
room temperature and passed through Celite, eluting
with ether (3×5 mL). The organic fractions were com-
bined, dried and concentrated in vacuo to obtain the
corresponding silyl enol–ether, which was used directly
in the next step. TMSI (0.01 mL, 0.1 mmol) was added
to a solution of silyl enol–ether (1.2 mmol) and
trimethylorthoformate (0.1 mL, 1 mmol) in CH2Cl2 (2
mL) at −78°C under a N2 atmosphere. The resulting
mixture was stirred at −78°C for 1 h and poured into
ice cold saturated NaHCO3 (10 mL). The organic layer
was separated, dried and concentrated to obtain the
corresponding a-(dimethoxymethyl)ketone.
Condensation of h-(dimethoxymethyl)ketones with aryl-
hydrazine for the synthesis of fused 1-arylpyrazoles. b-
(Dimethoxymethyl)ketones (1 mmol) and arylhydrazine
(1 mmol) in benzene (10 mL) was heated at reflux with
azeotropical removal of water. After the starting mate-
Meegalla, Sanath K.
