Synthesis of α-acetoxy and formyloxy ketones by thallium(III) promoted α-oxidation

Article abstract of DOI:10.1039/b102192n

Treatment of ketones with thallium(III) triflate in amide solvents at 60°C for 30 min followed by addition of small amounts of H₂O cleanly provided the corresponding α-acyloxy ketones.

Full text of DOI:10.1039/b102192n

Synthesis of a-acetoxy and formyloxy ketones by thallium(III
)
promoted a-oxidation
Jong Chan Lee,* Yong Suk Jin and Ju-Hee Choi
Department of Chemistry, Chung-Ang University, Seoul 156-756, Korea. E-mail: jclee@cau.ac.kr;
Fax: +82-2-825-4736; Tel: +82-2-824-7863
Received (in Cambridge, UK) 7th March 2001, Accepted 17th April 2001
First published as an Advance Article on the web 9th May 2001
Treatment of ketones with thallium(III) triflate in amide
solvents at 60 °C for 30 min followed by addition of small
amounts of H2O cleanly provided the corresponding a-
acyloxy ketones.
cyclopentanone by column chromatographic separation failed
owing to the decomposition of the compounds. When the
present reaction conditions were applied to cyclohexanone, a
mixture of a-hydroxy cyclohexanone and a-formyloxy cyclo-
hexanone was obtained in a ratio of 84+16 as indicated by GC,
probably due to the highly unstable preformed a-formyloxy
cyclohexanone undergoing further hydrolysis.
When the same reaction protocol used in a-formyloxylation
of ketones was conducted in N,N-dimethylacetamide instead of
DMF, a-acetoxylation of ketones took place remarkably well to
give uniformly high yields of a-acetoxy ketones with all of the
ketones examined. The representative results are summarized in
Table 1. It is important to note that the solvolytic reaction of
iminium salts in DMF was carried out at 60 °C to obtain the best
results. Elevated temperature gave a number of side products.
The intermediates iminium salts 3 were not stable enough to be
isolated.
We have also studied the cleavage reactions of a-formyloxy
and a-acetoxy ketones to their corresponding a-hydroxy
ketones. We found the lithium hydroxide in aqueous solution to
be suitable for the cleavage of the formyl and acetyl groups.
Treatment of isolated a-formyloxy ketones or a-acetoxy
ketones in THF–H2O (3+1, v/v) solution of lithium hydroxide at
room temperature for 2 min afforded the corresponding a-
hydroxy ketones 5 in excellent yields ranging from 95 to
98%.
In conclusion, the facile conversion of ketones to the a-
formyloxy ketones and a-acetoxy ketones has been accom-
plished in excellent yield. The present approach provides
efficient entry for installation of a-acyloxy moieties into
ketones and their clean deprotection should find wide applica-
The a-hydroxy ketone subunit is found in a variety of
biologically interesting natural products.1 The formate and
acetate groups can serve as useful protective groups for the
hydroxy functions in a-hydroxy ketones.2,3 The a-acetoxy
ketones can be prepared via various ways which include the
reaction of a-bromo ketones with carboxylate ions,4 the
oxidation of morpholine enamine with thallium(III) triacetate,5
anodic oxidation of enol acetates in acetic acid,6 and Cu(acac)2
catalyzed insertion reactions of a-diazo ketones with carboxylic
acids.7 In addition, it has been reported that the solvolytic
reaction of a-keto triflate in acetic acid or formic acid can
provide corresponding a-acyloxy ketones,8 but potential diffi-
culties in preparing a-triflyloxy ketone precursors (e.g. a-
triflyloxy propiophenone) limits their further synthetic applica-
tions. There exist only a few methods that deal with the direct
preparation of a-acetoxy ketones from ketones. These involve
the oxidation of ketones with lead tetraacetate,9 the oxidation of
ketones with manganese(III) acetate in acetic acid,10 and the
oxidation of aromatic ketones with hypervalent iodine reagent
followed by solvolysis in acetic acid in the presence of silver
carbonate.11 Although many procedures have been reported for
the preparation of a-acetoxy ketones, relatively little is known
for the preparation of a-formyloxy ketones. The only reported
method involves anodic oxidation of enol carbonate in DMF–
LiClO4.12 To the best of our knowledge, no general method for
the one-pot conversion of ketones to their corresponding a-
formyloxy ketones has been reported.†
We now report a new and highly efficient preparation method
for the a-formyloxy ketones and a-acetoxy ketones. This
methodology is based on the hydrolysis of iminium salt
intermediates 3 formed by the reaction of a-triflyloxy ketone
with amide solvent. Initial treatment of ketones with thallium-
(
III) triflate, formed in situ by the reaction of thallium(III) acetate
with trifluoromethanesulfonic acid, in DMF at 60 °C followed
by addition of small amounts of H2O cleanly provided the a-
formyloxy ketones in excellent yields. The probable mechanism
is shown in Scheme 1. The thallium(III) organosulfonate
mediated a-sulfonyloxylation of ketones is well established.13
Therefore, the reaction of ketones with thallium(III) triflate at
room temperature for 10 min should provide a-triflyloxy ketone
intermediates 2 which undergoes rapid solvolytic reaction with
DMF at 60 °C for 20 min to give iminium salts 3. These
intermediates are instantaneously hydrolysed to give desired a-
formyloxy ketones in the presence of H2O. Although the utility
of DMF as a formate anion equivalent for the preparation of
alkyl formates has been reported,14 application of this method
for the a-formyloxylation of ketones is unprecedented. Among
the ketones examined, aliphatic ketones such as acetone and
pentan-3-one gave complex product mixtures under the present
reaction conditions. In the case of cyclopentanone, a-formyloxy
cyclopentanone was detected in 98% yield as judged by GC
analysis but a number of attempts to isolate pure a-formyloxy
Scheme 1
956
Chem. Commun., 2001, 956–957
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b102192n

View Article Online
Table 1 Conversion of ketones to a-formyloxy ketones
for 20 min. After reaction, the temperature was brought down to rt, H2O (1
mL) was added and stirred for an additional 10 min. The reaction mixture
was diluted with CH2Cl2 (30 mL), washed with saturated NaHCO3 aqueous
solution, water, and dried over MgSO4. Evaporation of solvent, followed by
short column chromatography on silica gel (ethyl acetate–hexane 1+2)
yielded the a-formyloxy acetophenone.
% Yielda of
% Yielda of
a-formyloxy a-acetoxy
ketones
Entry
Ketones
ketones
1
2
3
4
5
6
7
8
9
10
11
12
13
PhCOCH3
94
92
97
90
96
91
97
99
99b
99c
96
92
98
90
97
93
98
99
99b
99
99
99
98
p-CH3C6H4COCH3
p-CH3OC6H4COCH3
p-ClC6H4COCH3
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PhCOCH2CH3
p-CH3C6H4COCH2CH3
p-CH3OC6H4COCH2CH3
p-PhCH2OC6H4COCH2CH3
Cyclopropyl methyl ketone
Cyclopentanone
Cyclohexanone
Indan-1-one
2-Acetylthiophene
d
—
98
97
a Isolated yields. b The acyloxylation occurred at methyl position. c GC
yield. d a-Hydroxy ketone was obtained as a major product.
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product synthesis.
The authors would like to thank the KOSEF
(1999-2-121-001-5) for financial support.
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Notes and references
† Caution: Thallium compounds are highly toxic; they should therefore be
handled with extreme caution and all operations must be carried out in an
efficient fume hood. The experimental procedure for the preparation of a-
formyloxy acetophenone is representative. To thallium(III) acetate (0.572 g,
1.5 mmol) in DMF (5 mL) was added trifluoromethanesulfonic acid (0.675
g, 4.5 mmol) at rt under nitrogen with stirring for 10 min. To the reaction
mixture acetophenone (0.120 g, 1.0 mmol) was added and stirred at 60 °C
Chem. Commun., 2001, 956–957
957