Tetrahedron Letters
Bromolactonization of alkenoic acids mediated by V2O5 via bromide
to bromenium in situ oxidation
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McKenzie L. Campbell , Samuel A. Rackley , Lauren N. Giambalvo, Daniel C. Whitehead
Department of Chemistry, Clemson University, Clemson, SC 29634, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient protocol for the bromolactonization of alkenoic acids is presented that obviates the use of
molecular bromine or exogenous bromenium sources. Vanadium (V) oxide catalyzes the in situ oxidation
of bromide salts to bromenium (Br+) in a process mediated by urea–hydrogen peroxide complex. Initial
mechanistic investigations indicate that the presence of urea does not accelerate the halolactonization
reaction.
Received 23 July 2014
Revised 12 August 2014
Accepted 18 August 2014
Available online 28 August 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Bromolactonization
Halenium equivalent
Alkenoic acid
Vanadium oxide
Marine algae have evolved impressive metalloenzymes that
make use of the mM concentration of bromide in ocean water as
a terminal halogen source for the electrophilic bromination of sec-
ondary metabolites. The so-called haloperoxidase enzymes feature
a vanadium (V) oxo active site that promotes the oxidation of bro-
mide to bromenium (Br+) mediated by hydrogen peroxide as the
terminal oxidant.1 Building on our previous work on vanadium
(V) oxide-mediated oxidations,2 we present here a bio-inspired
approach toward the bromolactonization of alkenoic acids medi-
ated by a similar V2O5-catalyzed in situ oxidation of bromide to
bromenium. Previous attempts at exploiting haloperoxidase-like
chemistry with V2O5 in different transformations have been sty-
mied by very high catalyst loadings (i.e., >0.5 equiv relative to sub-
strate).3 In the case of our method, V2O5 (ꢀ$0.25/g) is employed in
a reasonable 0.05 equiv loading with 3 equiv of urea–hydrogen
peroxide complex as the terminal oxidant. The protocol is opera-
tionally simple, often returning products after acid–base extraction
without the need for column chromatography. This method repre-
sents an attractive alternative to bromolactonizations that employ
molecular bromine or other exogenous bromenium sources (i.e.,
NBS, 1,3-dibromo-5,5-dimethylhydantoin, etc.), particularly in
light of instances such as the 2011 accidental release of approxi-
mately 50 L of molecular bromine in Chelyabinsk, Russia that
resulted in the hospitalization of 40 people.4
our ability to effect the desired bromolactonization to return
-bromolactone 2 in 84% yield mediated by 0.5 equiv of V2O5 in
an ACN/H2O/H2O2 (6:1:1) solvent system with NH4Br as the termi-
c
nal bromine source (Table 1, entry 1).
Similar conditions with NaBr as the bromine source returned 2 in
a reduced 73% yield (entry 2). Reducing the catalyst loading to 0.2 or
0.1 equiv V2O5 (entries 3–7) resulted in reduced yields with both
NH4Br and NaBr. A notable exception was the acceptable 89% yield
with 0.2 equiv V2O5 and 5 equiv NH4Br that resulted from warming
the reaction mixture to 65 °C (entry 5). An extensive solvent and co-
oxidant screen finally returned conditions whereby lactone 2 was
isolated in 93% yield with as low as 0.1 equiv of V2O5 (entries 8
and 9). Ammonium bromide was confirmed as the halide source of
choice, given that NaBr returned bromolactone in an unacceptable
43% yield coupled with significant formation of the corresponding
dibromo carboxylic acid product resulting from the rupture of the
bromonium intermediate with bromide (entry 10). In all cases,
regardless of conditions, the reactions were homogenous.
The catalyst loading could be further lowered to 0.05 equiva-
lents with only a marginal decrease in yield of 2 to 90% (entry
11). In the event, the optimal conditions were found to be
0.05 equiv V2O5, 3 equiv of urea–hydrogen peroxide complex
(UHP), and 3 equiv of NH4Br in a 6:1 mixture of acetone and water
at room temperature (entry 11, highlighted in bold). Further reduc-
tion in the catalyst loading to 0.01 equiv V2O5 resulted in a poor
yield of 12% of lactone 2 coupled with significant formation of
the vicinal dibromo by-product (entry 12). Conducting the reaction
in the absence of V2O5 confirmed that any background reaction
resulting from direct H2O2-mediated oxidation of bromide was
negligible (entry 13).
We began our investigation by evaluating the bromolactoniza-
tion of 4-phenyl-4-pentenoic acid (1). We were encouraged by
⇑
Corresponding author.
These authors contributed equally.
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.