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A. F. C. Flores et al. / Tetrahedron Letters 43 (2002) 5005–5008
Scheme 2.
trichloro-4-alkoxyalk-3-en-2-ones or 2-trichloroacetyl
cyclohexanone with hydroxylamine is regiospecific
within a pH between 1 and 13 leading always to the
obtaining of 5-trichloromethyl-substituted isoxazoles,
independent of the reaction conditions used.8 However,
for the cyclocondensation of the same set of
ride and potassium hydroxide in methanol under reflux
to furnish 1-methyl-3-isoxazolones 3a–d in good yields
(Scheme 2). In this series, for reactions carried out in
methanol the products 3a–d were isolated in higher
purity and in better yields than the reactions carried out
in acetonitrile. The reaction of compounds 1e and 1f
with N-methylhydroxylamine hydrochloride carried out
in methanol/potassium carbonate, acetonitrile/potas-
sium hydroxide, and acetonitrile/triethylamine fur-
nished complex mixtures of unidentified compounds.
trichloromethyl-substituted
1,3-electrophiles
with
hydrazine, a direct relationship between the solvent
used and the structure of the resulting pyrazole was
observed.9–11 It has been shown that the reactions car-
ried out in polar solvents (DMSO,10 ethanol,9
methanol,10 and water10) furnished preferentially 3(5)-
carboxylpyrazole derivatives, whereas reactions in less
polar solvents (chloroform) 5-trichloromethyl-substi-
tuted pyrazoles were obtained.11
The synthesis of 2-trichloroacetylcycloalcanones 1a–d,
3-trichloroacetyl-4,5-dihydrofuran
(1e),
and
3-
trichloroacetyl-5,6-dihydro-4H-pyran (1f) has been
reported elsewhere.8,14 Anhydrous hydrazine was
obtained from successive distillations of hydrazine
monohydrate (Merck art. 804608) over KOH. Acetoni-
trile p.a. (Fluka 00700) was used as obtained from
commercial suppliers. All melting points were deter-
mined on a Reichert Thermovar apparatus and are
In addition, it has been reported that the
trichloromethyl group in ketones such as 1,1,1-
trichloroacetone or 1,1,1-trichloroacetophenone can be
substituted by amines furnishing acetamides and benza-
mides, respectively.12 It has been reported that the
mechanism of this reaction, which undergoes with sub-
stitution of the trichloromethyl group, is favored by
polar solvents such as water or acetonitrile.13
1
uncorrected. H and 13C NMR spectra were acquired
on a Bruker DPX400 spectrometer in a 5 mm probe in
10−3 M CDCl3 solutions, TMS was used as internal
reference.
In this work, we wish to report a new aspect of the
cyclocondensation of trichloromethyl-substituted 1,3-
dielectrophiles 1a–f with dry hydrazine (Scheme 1) and
N-methylhydroxylamine (Scheme 2) which has been
Hydroxy-1H-pyrazoles 2a–f. General Procedure: To a
solution of 2-trichloroacetylcycloalcanones (1a–c),
1,1,1-trichloro-3-methyl-4-phenyl-2,4-butenodione (1d),
3-trichloroacetyl-4,5-dihydrofuran
(1e),
or
5-
accomplished
with
the
substitution
of
the
trichloroacetyl-3,4-dihydro-2H-pyran (1f) (5 mmol) in
acetonitrile (5 ml) were added dropwise to a stirred
solution of anhydrous hydrazine (0.25 g, 7.5 mmol) in
acetonitrile (2 ml). The resulting mixture was stirred for
2 h at 25–30°C and the acetonitrile was removed using
a rota-evaporator. The excess hydrazine was removed
by washing with water, resulting in a white solid that
was dried in a desiccator. The products were identified
as hydroxypyrazoles 2a–f. Yields and selected physical
and spectroscopic data are reported in Table 1.
trichloromethyl group leading to a series of 3-hydroxy-
pyrazoles 2a–f and 2-methylisoxazol-3-ones 3a–d,
respectively.
The reaction of the enones 1a–f and hydrazine in
acetonitrile (Scheme 1) led to the quantitative isolation
of 3-hydroxypyrazoles derivatives 2a–f. The reaction of
4-methoxy-1,1,1-trichloropent-3-en-2-one or the respec-
tive dicarbonyl derivative† with dry hydrazine under the
same reaction conditions used for the substrates 1a–f
furnished the 3-methyl-5-carboxy-1H-pyrazole‡ where
the trichloromethyl group was hydrolyzed to carboxylic
acid instead of undergoing substitution.10
2-Methyl-3-isoxazolones 3a–d. General procedure: To a
solution of 2-trichloroacetylcycloalcanones (1a–c) or
1,1,1-trichloro-3-methyl-4-phenylbutan-2,4-dione (1d)
(5 mmol) in methanol (5 ml) was added to a stirred
solution of N-methylhydroxylamine hydrochloride
(0.47 g, 5.5 mmol), potassium hydroxide (0.31 g, 5.5
mmol) in methanol (5 ml). The resulting mixture was
stirred for 2 h at 25–30°C. The solution was filtered to
remove KCl and the methanol was removed under
vacuum. Purification of products was done by column
chromatography on silica gel and eluted with 3:1 chloro-
form/hexane. The products were obtained as oils iden-
tified as 1-methyl-3-isoxazolones 3a–d. Yields and
selected physical and spectroscopic data are reported in
Table 2.
The reaction of compounds 1a–d were carried out in
equimolar ratios of N-methylhydroxylamine hydrochlo-
† The 4-methoxy-1,1,1-trichloropent-3-en-2-one was synthesized
according to procedures in Ref. 8. The respective b-dicarbonyl
compound was obtained by hydrolysis in H2SO4 50%, 60°C, 4 h.
‡ C5H6N2O2, mol. wt. 126.12; 1H NMR (400 MHz, DMSO) l 6.5 (s,
1H), 2.2 (s, 3H); 13C NMR (100 MHz, DMSO) l 162.8 (CO2H),
142.4 (C3), 141.5 (C5), 107.1 (C4), 11.2 (Me). Anal. calcd: C, 47.62;
H, 4.8. Found: C, 48.0; H, 4.90%.
Flores, Alex F.C.
