SCHEME 1
Hyd r oxya lk yla tion of r-C-H Bon d s of
Tetr a h yd r ofu r a n w ith Ald eh yd es in th e
P r esen ce of Tr ieth ylbor a n e a n d ter t-Bu tyl
Hyd r op er oxid e
Takehiko Yoshimitsu,* Yoshimasa Arano, and
Hiroto Nagaoka*
SCHEME 2
Meiji Pharmaceutical University, 2-522-1 Noshio,
Kiyose, Tokyo 204-8588, J apan
takey@my-pharm.ac.jp
Received September 10, 2002
We recently reported an R-hydroxyalkylation of tet-
rahydrofuran (THF) with aldehydes that occurred via the
R-C-H abstraction of THF by ethyl radicals from trieth-
ylborane in the presence of air (Scheme 1).9,10 The use of
air as a safe, inexpensive ethyl-radical generator11 is
generally time-consuming, even with continuous applica-
tion to the reaction mixture. Various new reagent sys-
tems were thus devised and evaluated for the promotion
of the above reactions.12 This study shows triethylborane
and tert-butyl hydroperoxide (TBHP) used in combination
to be quite effective for promoting the R-C-H hydroxy-
alkylation of THF with aldehydes, and, accordingly, this
combination may be used to replace the triethylborane/
air system (Scheme 2).13,14
The oxidation of organoboranes with neutral hydrogen
peroxides proceeds via a free-radical process.15 It should
follow then that certain hydroperoxides under neutral
conditions may initiate alkyl-radical generation from
trialkylboranes, thus facilitating the radical R-C-H
abstraction of THF (Table 1).
Abstr a ct: The R-hydroxyalkylation of tetrahydrofuran with
aldehydes via radical C-H abstraction was conducted using
triethylborane in the presence of tert-butyl hydroperoxide.
This study presents a rare instance of direct intermolecular
radical addition of unactivated cyclic ether to aldehydes.
C-H functionalization of organic molecules is presently
a focal point of intensive research.1-3 Carbon-carbon
bond formation at the otherwise unreactive R-C-H
position of cyclic ethers is generally carried out by free-
4,5
radical
and carbenoid C-H insertion reactions.6,7
These methods have a significant potential for providing
rapid access to R-substituted cyclic ethers, ubiquitous
structural motifs of bioactive molecules.8 However, direct
assembly between unactivated cyclic ethers and alde-
hydes through R-C-H functionalization remains unex-
ploited despite its significant synthetic challenge.
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10.1021/jo020590e CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/12/2002
J . Org. Chem. 2003, 68, 625-627
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