COMMUNICATION
Organic synthesis using a hypervalent iodine reagent: unexpected and
novel domino reaction leading to spiro cyclohexadienone lactonesw
Hiromichi Fujioka,*a Hideyuki Komatsu,a Taeko Nakamura,a Akihito Miyoshi,a
Kayoko Hata,a Jnashuara Ganesh,a Kenichi Muraia and Yasuyuki Kita*b
Received (in Cambridge, UK) 8th December 2009, Accepted 19th February 2010
First published as an Advance Article on the web 24th March 2010
DOI: 10.1039/b925687c
The reaction of 1-(p-hydroxyaryl)cyclobutanols and phenyl
iodide(III) diacetate in hexafluoroisopropanol and water produced
spiro cyclohexadienone lactones via a domino reaction.
Hypervalent iodine reagents are widely recognized as non-
toxic oxidizing agents for use in the place of highly toxic heavy
metal oxidizing reagents, and many such oxidation methods
have been developed.1 We have also been developing many
synthetic reactions using hypervalent iodine reagents.2 As a
part of our studies into the use of hypervalent iodine reagents,
we found that the reaction of phenol compounds with benzylic
tert-alcohol and phenyliodine diacetate (PIDA) produced a
Scheme 2
novel one-pot transformation to afford spiro cyclohexadienone
lactones in good yields (Scheme 1). We now describe the study
hexafluoroisopropanol (HFIP) was carried out. As a result,
although a complex mixture was obtained in the case of PIFA,
the reaction with PIDA gave the spiro[5.5]dienone lactone 2a,
but in low yield (Scheme 2, eqn (2)).4,5 This was an unexpected
and unprecedented result. We then studied this reaction in
detail (Table 1). As a hypervalent iodine reagent, PIDA was
much better than PIFA (entry 2 vs. entry 1). As a reaction
solvent, HFIP–H2O (9 : 1) was the solvent of choice (entry 4 vs.
entries 2, 3, and 9). This transformation needed 2 equivalents of
PIDA (entries 5, 7, 8 vs. entries 4, 6). The addition of NaHCO3 as
an additive improved the yield of 2a (entries 7 and 8 vs. entry 5).
The optimized conditions were the reaction with 1a, PIDA
(2 eq.), NaHCO3 (4 eq.) in HFIP–H2O (9:1), and 2a was
obtained in 75% yield (entry 8).
of this novel domino transformation.
Since phenols having a p-substituent with a nucleophilic
function, such as hydroxyl or carboxylic acid groups, are
known to produce spiro cyclohexadienones on reaction with
hypervalent iodine reagents, such as phenyliodine bistrifluor-
oacetate (PIFA) or PIDA,3 we theorized that the treatment of
phenol compounds with a benzylic tert-alcohol would afford
the spiro cyclohexadienone ketone through a rearrangement
reaction (Scheme 2, eqn (1)). 1a was then prepared in a three-
step sequence from p-bromophenol and cyclobutanone: (1)
tert-butyldimethylsilylation of p-bromophenol, (2) condensation
of the lithio compound, obtained by the treatment of p-bromo-
phenol-TBDMS ether with n-BuLi, and cyclobutanone, and (3)
desilylation of the coupling product. Next, the reaction of the
phenol 1a and 1 equivalent of PIFA or PIDA in just-purchased
Scheme 3 shows the reaction of the 1a derivative, 1a-Me,
whose benzylic tert-alcohol was protected as a methyl ether. In
this case, the spirolactone 2a was also obtained, although its
yield was slightly low. This result means that the contribution
of the benzylic alcohol to this transformation does not occur
during the initiation step of the reaction.
To clarify the reaction mechanism, the reaction of 1a to 2a
was carried out in the same manner except for the H2O
(Scheme 4). In this case, 18O labeled water was used in
place of H2O, and 18O-introduced spirolactone 2a[18O] and
16O-introduced spirolactone 2a[16O] were obtained in 83%
yield in the ratio of 2 to 1. 16O must be derived from H216O
formed by the reaction of AcOH from PIDA and NaHCO3.
The formation of 2a[18O] meant that one of the two oxygen
atoms of the lactone moiety came from water. LiAlH4 reduction
of the mixture of 2a[18O] and 2a[16O] gave a mixture of 3[18O],
whose oxygen atom of the primary alcohol is the 18O labeled
one, and 3[16O], whose oxygen atom of the primary alcohol is
the normal one, in the ratio of 1 to 2 in a total 71% yield. That
Scheme 1
a Graduate School of Pharmaceutical Sciences, Osaka University,
1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
E-mail: fujioka@phs.osaka-u.ac.jp; Fax: +81 668798229;
Tel: +81 668798225
b College of Pharmaceutical Sciences, Ritsumeikan University,
1-1-1 Nojihigashi, Kusatsu, Shiga 525-8577, Japan.
E-mail: kita@ph.ritsumei.ac.jp; Fax: +81 775615829;
Tel: +81 775615829
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for the compounds. See DOI:
10.1039/b925687c
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 4133–4135 | 4133