diketone.15 Nonetheless, this last source helped to inspire a
starting point.
distribution is displayed in Scheme 1. The difference in yield
between bases shown in Table 1 is mostly attributable to
this scrambling effect.
By employing a hydrocarbon solvent, we thought that side
reactions might be slowed by disfavoring a charged inter-
mediate, only allowing the enolate to react with the very
electrophilic acid chloride. We tested our hypothesis by
reacting 4-bromoacetophenone enolate with 4-methoxyben-
zoyl chloride.16
Scheme 1. Regiochemical Scrambling via Triketone
Intermediates
When toluene was used as a solvent and LDA or MHMDS
was used as the base, no homocondensation was observed
and the generated diketone did not react to form a vinylogous
species. However, Table 1 shows a trend based on the ionic
Table 1. Effect of Base and Solvent on the Yield of 5
base
solvent
yielda (%)
LiHMDS (1.0 M THF)
LiHMDS (1.0 M THF)
NaHMDS (0.6 M toluene)
KHMDS (0.5 M toluene)
LDA (2.0 M THF)
toluene
toluene
toluene
toluene
toluene
toluene
THF
89
47b
77c
60c
64
trace
27
KOtBu
LiHMDS (1.0 M THF)
a Isolated yield of 5. b 1 equiv of 4-bromoacetophenone. c Isolated by
column chromatography (acetone/DCM, 1:1).
nature of the enolate. When NaHMDS or KHMDS were
used, 15 and 20%17 of the detected diketone intermediate 1
was actually a triketone 2 arising from the metal diketonate
reacting with another equivalent of acid chloride. Lithium
bases gave no detectable amount of 2 and so were employed
for further experimentation.
When hydrazine was added to this mixture, the unsym-
metrical 3,5-disubstituted pyrazole 3 was formed along with
some symmetrical product 4 containing two anisyl groups.
This implies that one of the benzoyl groups is actually a
leaving group, an idea further backed by the isolation of a
small amount of 4-methoxybenzoic hydrazide and 4-bro-
mobenzoic hydrazide. A suggested mechanism for this
elimation giving rise to the two products in a statistical
We then attempted to synthesize a variety of pyrazoles
derived from diketone intermediates to test the generality of
the method. The results of our efforts are displayed in Table
2. Yields were generally good to excellent, though we made
no attempt to optimize the conditions for each reaction.
Electronic effects on the aromatic coupling partners did not
affect reaction yields or purity systematically, although steric
effects could be observed in the case of 10 and the sterically
demanding 11.
A wide range of functional groups were tolerated in both
coupling partners. Of particular interest is the cyano func-
tionality carried through in 9 and 13. As expected, aldehydes
did not survive the enolization step. Electrophiles containing
enolizable R-protons were successfully coupled to the enolate
to form 1,3-diketones. Finally, primary halides were tolerated
without any observed elimination. Although esters were also
tolerated in the enolate condensation step, the addition of
hydrazine was problematic.
Substituted hydrazines typically gave a mixture of regio-
isomers that was dependent on the aryl substitution. Com-
pound 21 is essentially symmetrical electronically; thus, a
1:1 mixture was formed. Compounds 6 (∼3:1, a:b) and 17,
which gave only a single isomer, further elaborate this trend.
The conditions used gave rise to kinetic control of enolate
formation as witnessed by 7, which was isolated almost
exclusively as the kinetic product. It is likely that the short
time frame of the reaction combined with a high barrier of
activation between enolates caused by the nonpolar solvent
and lithium base add to the kinetic selectivity in the face of
relatively high temperature.
(15) Vavon, G.; Conia, J. M. C. R. Acad. Sci. 1951, 233, 876.
(16) Representative Proecedure. Preparation of 5. 4′-Bromoacetophe-
none (0.3981 g, 2 mmol) was dissolved in 5 mL of dry toluene in a screw
cap vial (with septum), and then the solution was cooled to 0 °C under
nitrogen. LiHMDS (2.1 mL, 1.0 M in THF, 2.1 mmol) was added quickly
via syringe with stirring, and the formed anion was allowed to sit for
approximately 1 min before the addition of 4-methoxybenzoyl chloride
(0.1706 g, 1.354 mL, 1 mmol) in one portion with stirring. The vial was
then removed from the ice bath and allowed to stand for 1 min, and then
2 mL of AcOH was added with stirring. EtOH (10 mL) and THF (5 mL)
were added to form a homogeneous mixture, then hydrazine hydrate (2
mL, 1.1 g, 34.3 mmol) was added. The mixture was allowed to auto-reflux
and was held at that temperature for 5 min, when LCMS showed that all
diketone had reacted. The resulting solution was added to 1.0 M NaOH
solution and extracted with EtOAc. The organic fraction was then washed
with brine, dried over Na2SO4, and evaporated under reduced pressure. The
resulting residue was recrystallized from 2-propanol/water to afford white
crystalline product 5 (0.293 g, 89%): 1H NMR (400 MHz, d6-DMSO) δ
13.30 (s, 1H), 7.80 (d, J ) 7.6 Hz, 2H), 7.75 (d, J ) 8 Hz, 2H), 7.64 (d,
J ) 7.6 Hz, 2H), 7.11 (s, 1H), 7.03 (d, J ) 8 Hz, 2H), 3.80 (s, 3H).
(17) Approximate values from LCMS characterization. NaHMDS yielded
4% and KHMDS yielded 7% 3,5-bis(4-methoxyphenyl)-1H-pyrazole after
chromatography.
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Org. Lett., Vol. 8, No. 13, 2006