Published on Web 08/09/2003
A Convenient Method for the Preparation of Inverted tert-Alkyl Carboxylates
from Chiral tert-Alcohols by a New Type of Oxidation-Reduction
Condensation Using 2,6-Dimethyl-1,4-benzoquinone
Teruaki Mukaiyama,* Taichi Shintou, and Kentaro Fukumoto
Center for Basic Research, The Kitasato Institute, 6-15-5 Toshima, Kita-ku, Tokyo 114-0003, Japan, and Kitasato
Institute for Life Sciences, Kitasato UniVersity, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
Received June 25, 2003; E-mail: Mukaiyam@abeam.ocn.ne.jp
Scheme 1. Formation of Inverted tert-Alkyl Carboxylic Esters from
The fundamental concept of oxidation-reduction condensation
Chiral tert-Alcohols
is to perform dehydration condensation by removing H2O as in
2[H] and [O] with the use of a combination of weak reductants
and oxidants. These reactions proceed under “mild and neutral”
conditions without having any assistance of acids or bases.
Examples of these innovative acylation reactions using combinations
of diphenylmercury and tributylphosphine (1963),1 trans-1,2-
dibenzoylethylene and tributylphosphine (1964),2 and 2,2′-dipyridyl
disulfide and triphenylphosphine (1970)3 were reported from our
laboratory. In 1967, phosphoric esters were also prepared by using
triethyl phosphite and diethyl azodicarboxylate (DEAD) in the
presence of alcohols.4 Mitsunobu further developed this concept
to an efficient alkylation method by using a combination of
triphenylphosphine and DEAD (Mitsunobu reaction).5 Recently,
Tsunoda et al. reported an alkylation reaction using alcohols and
cyanomethylenetributylphosphorane or N,N,N′,N′-tetramethylazodi-
ester, followed by treatment with the carboxylic acid and 2,6-
dimethyl-1,4-benzoquinone (Scheme 1).
carboxamide (TMAD)6 which worked out likewise. Shi et al.
described stereospecific synthesis of chiral tertiary alkyl-aryl ethers
via Mitsunobu reaction with complete inversion of configuration
in about 50% chemical yield.7
Results for the present condensations of carboxylic acids with
various chiral tertiary alcohols are shown in Table 1. Alkylation
of carboxylic acids proceeded smoothly in dichloromethane at room
temperature to afford the corresponding tert-alkyl carboxylates in
good yields with almost complete inversion of stereochemistries,
while the corresponding ester was obtained in 83% yield with the
retention of stereochemistry by reaction in a CH2Cl2 solution of
1-adamantanol and benzoic acid for 15 h (Table 1, entry 1). In the
case of using benzoic acid or p-methoxybenzoic acid having an
electron-donating group, the esterifications using various chiral
tertiary alcohols proceeded within 18 h at room temperature to
afford the corresponding alkyl esters in good yields (81-90%) with
almost complete inversion of stereochemistries (98 to >99%) (Table
1, entries 4, 5, 8, 9, and 12-14). When aliphatic carboxylic acid
or p-chlorobenzoic acid having an electron-withdrawing group was
used, on the other hand, the desired esters were obtained in 76-
86% yields with 70-84% inversion (Table 1, entries 6, 7, 10, and
11). By refluxing a CH2Cl2 solution of (-)-terpinen-4-ol and
benzoic acid or 3-phenylpropionic acid for 15 h, the desired esters
were obtained in 78% yield with 98% inversion or 76% yield with
40% inversion, respectively (Table 1, entries 2 and 3), whereas
the corresponding olefin was formed in 81% yield in the case of
2-(4-methoxyphenyl)-2-butanol, and none of the desired esters were
detected (Table 1, entry 15).
The search for a new combination of weak reductant and oxidant
in oxidation-reduction condensation has been a matter of our
continued interest ever since the reaction was first reported. Quinone
compounds have long been anticipated as effective oxidants in this
type of condensation; however, no examples have been shown to
be successful to date. We consider that an interaction of alkoxy-
diphenylphosphine with weak oxidants such as quinone should
provide a key intermediate, phosphonium salt, more smoothly than
triphenylphosphine because of the increased reducing ability.8
It has been shown that oxidation-reduction condensation using
a combination of 2,6-dimethyl-1,4-benzoquinone and alkoxydiphen-
ylphosphines, formed in situ from alcohols and chlorodiphenylphos-
phine or (N,N-dimethylamino)diphenylphosphine, affords alkyl
carboxylates in high yields from the corresponding alcohols and
carboxylic acids by a one-pot procedure.9 The esterification of
various secondary alcohols proceeded similarly to afford the
corresponding esters in high yields with perfect inversion of
stereochemistry.9 Further, it was shown that the reactions of various
carboxylic acids with in situ-formed tertiary alkoxydiphenylphos-
phines, for example, 2,2-dimethylpropionic acid and 2-methyl-1-
phenylpropan-2-ol, or 2-phenylbutyric acid and 1-adamantanol,
afforded the corresponding tert-alkyl carboxylates in 85-96%
yields, respectively.9 The possibility of inversion of the tert-alkyl
alcohol in this ester-forming reaction was then considered.
This Communication describes a new oxidation-reduction
method for converting tertiary alcohols into their corresponding
esters with almost complete inversion of configuration. The method
involves initial conversion of the alcohol to its diphenylphosphinite
Thus, oxidation-reduction condensation using alkoxydiphen-
ylphosphine (i.e., diphenylphosphinite ester) generated in situ 2,6-
dimethyl-1,4-benzoquinone, and carboxylic acids provide a new
and efficient method for the preparation of inverted tert-alkyl
carboxylates from various chiral tertiary alcohols.
9
10538
J. AM. CHEM. SOC. 2003, 125, 10538-10539
10.1021/ja0303844 CCC: $25.00 © 2003 American Chemical Society
Mukaiyama, Teruaki
