Organic Letters
Letter
Scheme 2. Dehydrative Alkylation of 1,3-Diektone Derivatives
a
b
c
Using 1,3-diketone (5 equiv). Using benzhydrol (2 equiv) and 1,3-diketone (1 equiv). Reaction performed on a 4 mmol scale.
scope of reactions promoted by these readily available catalytic
systems.
demonstrated by performing the reaction on gram scale (4
mmol of alcohol) to give 1.25 g of 9 in 93% yield. Halogen
substitution on the aryl ring was also possible with 4-fluoro-
and 4-bromophenyl ethanol reacting to give 12 and 13 in 90%
and 71% yield, respectively. Altering the substitution pattern
affected the reactivity, with 1-(2-bromo- and 1-(3-
bromophenyl)ethanol giving products 14 and 15 in slightly
reduced yields. The presence of an alkyne on the reacting
carbinol center was well tolerated, giving 16 in 98% yield.
Limitations included the use of a sterically demanding
secondary and tertiary alcohols, which are unreactive, while
primary benzylic alcohols preferentially form the symmetric
ether product.13
The use of 1,3-ketoesters as pro-nucleophiles was possible
under the standard conditions (Scheme 3). For example,
reacting ethyl benzoylacetate 17 with benzhydrol (2 equiv)
gave product 18 in an excellent 97% yield after heating at 90
°C overnight. In this case, an excess of the alcohol was used to
aid purification, with the symmetrical ether of benzhydrol
formed as a side product. The use of 1-arylethanol derivatives
bearing either electron-donating or halogen substituents as the
electrophile gave C-alkylation products 19−22 in generally
good yield as a mixture of diastereoisomers. Resubjecting an
isolated sample of diastereomerically enriched product 21
(63:37 dr) to the reaction conditions led to equilibration of the
diastereoisomers into the observed 53:47 dr, suggesting
formation of a thermodynamic mixture. The product
epimerization presumably occurs via catalyst-promoted enoli-
zation and protonation of the 1,3-ketoester stereocenter. The
C-alkylation of 1,3-ketoesters could also be performed on gram
scale (3.2 mmol of alcohol), giving 0.97 g of product 20 in 97%
yield.
First, the use of enolizable 1,3-diketones as potential pro-
nucleophiles was investigated with the reaction of benzhydrol
with dibenzoylmethane. Reaction optimization showed that a
combination of pentafluorophenylboronic acid 1 (5 mol %)
and oxalic acid 2 (10 mol %) in MeNO2,13 a catalytic system
first reported by Moran for a dehydrative Friedel−Crafts
alkylation reaction,7f gave the desired C-alkylation product 3 in
76% yield after 3 h at room temperature. In the absence of any
catalyst or with pentafluorophenylboronic acid 1 alone, no
reaction was observed, while using only oxalic acid 2 (10 mol
%) gave 5% conversion into 3 over 3 h.13 The reaction scope
was first investigated through variation of the 1,3-diketone
component (Scheme 2). Symmetrical diketones bearing both
electron-donating and electron-withdrawing substituents were
tolerated under the standard reaction conditions, forming
products 4 and 5 in good yields. Heterocycle containing acyl
benzothiazoles and acyl benzoxazoles were also competent
pro-nucleophiles, forming products 6 and 7 after extended 48 h
reaction times at 90 °C, although the analogous acyl
benzimidazole was unreactive under these conditions. The
use of a cyclic 1,3-diketone was also possible, forming product
8 bearing a new quaternary carbon center in an excellent 93%
yield. In contrast, the reaction of benzhydrol with 1,3-
cyclohexanedione gave selective O-alkylation into the corre-
sponding β-keto enol ether.13,14 Attempts to extend the scope
to alternative enolizable ketones such as 2-phenylacetophe-
none or benzoylacetonitrile were unsuccessful, with only
starting materials returned at room temperature. Using
dibenzoylmethane (2 equiv) as standard, the use of various
secondary benzylic alcohols as the electrophilic component
was trialed. 1-Arylethanol derivatives bearing either neutral or
electron-donating substituents were well tolerated, forming
products 9−11 in excellent yields. The synthetic potential was
Furthermore, the isolated diastereomeric mixtures of
products 19−21 could be derivatized into the corresponding
B
Org. Lett. XXXX, XXX, XXX−XXX