Vanadium (V) oxide mediated bromolactonization of alkenoic acids

Article abstract of DOI:10.1016/j.tet.2015.04.029

A full account of our recently communicated method for the V₂O₅ mediated bromolactonization of alkenoic acids is presented. Here we describe the extensive evaluation of the metal oxide catalyst, terminal oxidant, halide source, solvent system, and reaction temperature that resulted in optimal conditions employing 0.05 equiv V₂O₅, 3 equiv urea-hydrogen peroxide complex (UHP), and 3 equiv of NH₄Br in an acetone:H₂O (6:1) solvent system at room temperature. Additionally, we have expanded the substrate scope of the reaction with the aim of evaluating the functional group tolerance of the transformation. Further, we present preliminary data of a related halogenation of β-diketones with our optimal conditions. Finally, we probed the role of urea in the transformation.

Full text of DOI:10.1016/j.tet.2015.04.029

Tetrahedron xxx (2015) 1e8
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Vanadium (V) oxide mediated bromolactonization of alkenoic acids
*
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:
A full account of our recently communicated method for the V2O5 mediated bromolactonization of al-
kenoic acids is presented. Here we describe the extensive evaluation of the metal oxide catalyst, terminal
oxidant, halide source, solvent system, and reaction temperature that resulted in optimal conditions
employing 0.05 equiv V2O5, 3 equiv urea-hydrogen peroxide complex (UHP), and 3 equiv of NH4Br in an
acetone:H2O (6:1) solvent system at room temperature. Additionally, we have expanded the substrate
scope of the reaction with the aim of evaluating the functional group tolerance of the transformation.
Received 13 March 2015
Received in revised form 9 April 2015
Accepted 10 April 2015
Available online xxx
Keywords:
Further, we present preliminary data of a related halogenation of
tions. Finally, we probed the role of urea in the transformation.
b-diketones with our optimal condi-
Haloactonizaton
Vanadium oxide
Bromenium
Ó 2015 Elsevier Ltd. All rights reserved.
Bromine equivalent
1. Introduction
hydrogen peroxide as the terminal oxidant requires strongly acidic
conditions (e.g., H2O2/H2SO410 and H2O2/HBr11) or chalcogen-based
catalysts.12 Additionally, the aerobic oxidation of HBr can be me-
diated by catalytic loadings of sodium nitrite.13
Many groups have invested significant efforts in order to de-
velop synthetically feasible and cost-effective methods to circum-
vent the use of elemental bromine in synthetic operations.1 The
strategy involves the development of means to effect the in situ
oxidation of less corrosive, volatile, and toxic bromide salts to
synthetically competent bromenium (Brþ) equivalents via the in-
corporation of an exogenous oxidant. A number of terminal oxi-
dants are effective including sodium perborate,2 ceric ammonium
nitrate,3 sodium periodate,4 lead acetate,5 and SelectflourÒ.6 More
recently, a superstoichiometric loading of trimethylsilyl triflate
(TMSOTf) and an organic sulfoxide were used to promote the oxi-
dation of sodium bromide.7 While effective, these methods rely on
relatively expensive and environmentally unfriendly oxidants as
compared to an ideal case of using either molecular oxygen or
aqueous hydrogen peroxide as the terminal oxidant.
The most commonly employed method for the in situ oxidation
of bromide relies on treatment of ammonium or sodium bromide
with the peroxysulfate salt, OxoneÒ.8 While generally effective, this
method suffers from the considerable salt waste stream associated
with unpurified OxoneÒ (2KHSO5$KHSO4$K2SO4). Further, OxoneÒ
demonstrates a broad reactivity profile with a number of common
organic functional groups,9 thus presenting the potential for det-
rimental side-reactions with functionalized substrates. Efforts
aimed at employing more idealized co-oxidants such as hydrogen
peroxide, oxygen, or air have met with some success. The use of
From a biological perspective, several algae have evolved the
ability to use the millimolar marine concentration of bromide to
carry out electrophilic halogenation during the course of their
biosynthesis of secondary metabolites. In these organisms, the
critical oxidation of bromide to bromenium is promoted by hal-
operoxidase metalloenzymes harboring a vanadium (V) oxo active
site and relies on hydrogen peroxide as the terminal oxidant.14
Inspired by this biological phenomenon and our on-going in-
terest in vanadium oxide catalysis,15 we sought to develop a reliable
method for the bromolactonization of alkenoic acids hinging on the
in situ oxidation of bromide to a bromenium equivalent catalyzed
by the cheap (w$0.25/g), abundant, and safe vanadium (V) oxide
(i.e., V2O5). We targeted a bromolactonization protocol as our initial
foray into this field based on its historical prominence as a conve-
nient method for the efficient and stereoselective formation of
small and medium sized heterocycles in organic synthesis.16 In-
deed, halolactonizations have received substantial attention from
the synthetic community in the past decade. Several groups have
developed new catalysts that efficiently promote the bromolacto-
nization of alkenoic acids employing N-bromosuccinimide as the
terminal halogen source.17 Additionally, a number of asymmetric
halolactonization methods have appeared.18 Due to the efforts of
a number of groups, chloro,19 bromo,17d,20 and iodo21 lactonizations
have all been rendered enantioselective. Our approach is unique
among these efforts based on the strategy of in situ oxidation of
bromide to bromenium (Brþ) by action of vanadium (V) oxide.
* Corresponding author. E-mail address: dwhiteh@clemson.edu (D.C.
Whitehead).
http://dx.doi.org/10.1016/j.tet.2015.04.029
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
McKenzieL. Campbell et al. / Tetrahedron xxx (2015) 1e8
Vanadium (V) oxide has received some attention as a useful
of bromide (Table 1). We were encouraged by our ability to effect
the desired bromolactonization of 1 in a reasonable 73% yield by
means of the oxidation of ammonium bromide (15 equiv) catalyzed
by 0.5 equiv of V2O5 with 30% aq H2O2 in an acetonitrile:water (6:1)
solvent system (entry 1). A brief survey of other bromide salts, in-
cluding sodium bromide, cesium bromide, lithium bromide, and
potassium bromide returned lactone 2 in yields ranging from 66 to
84% (entries 2e5). Increasing the water portion of the solvent
system from 6:1 (i.e., entry 1) to 1:1 (entry 6) and 1:6 (entry 7)
resulted reduced yields of 71 and 51%, respectively. Conducting the
reaction in the absence of solvent aside from 30% aqueous H2O2
returned 2 in a 68% yield (entry 8). Reducing the loading of halide
salt from 15 equiv to 5 equiv resulted in comparable yields for
ammonium bromide (84% yield, entry 9) and sodium bromide (73%
yield, entry 10). Next, we attempted to reduce the catalyst loading
to more reasonable levels. A 20 mol % loading of V2O5 resulted in
comparable or reduced yields compared to 0.5 equiv loadings (see
entries 11 and 12). The 20 mol % V2O5 loading returned an ac-
ceptable 89% yield of 2 when the reaction mixture was warmed to
65 ꢀC (entry 13). Two experiments with chlorides salts (i.e., NH4Cl
and NaCl, entries 14e15) returned the corresponding chlorolacto-
nization product (not shown) in poor yields ranging from 28 to 36%
yield. Further reduction of the catalyst loading to 10 mol % V2O5
returned bromolactone 2 in poor yields ranging from 40 to 59%
yield, regardless of the bromide source (entries 16e19). This initial
panel of experiments confirmed our hypothesis that V2O5 could
serve as a viable haloperoxidase-like catalyst for the bromolacto-
nization of alkenoic acids. Subsequent efforts, detailed below, were
geared toward optimizing the protocol to one of reasonable syn-
thetic utility.
catalyst for several organic transformations, but it has not achieved
the broad applicability observed for other transition metal oxides of
osmium, ruthenium, chromium, and rhenium. We attribute this
fact to the sparing solubility of the material in most organic sol-
vents and the relatively limited substrate scope of many of the
V2O5-mediated processes. Nonetheless, V2O5 has been used effec-
tively as a catalyst for the oxidation of alcohols to ketones and al-
dehydes with various co-oxidants.22 In alcohol solvents, aldehydes
and ketals can be oxidized directly to esters.23 Other miscellaneous
oxidations mediated by V2O5 include the oxidation of dibenzylth-
iophene,24 the oxidative coupling of naphthols to form biaryls,25
the cyanation of tertiary anilines,26 the aromatization of 1,4-
dihydroxypyridines,27 and the oxidative conversion of the opium
alkaloid thebaine to 14-hydroxycodeinone.28
Additionally, several transformations mediated by V2O5 hinging
on the oxidation of bromide have been reported including the
bromination of arenes,29
b-diketones and b
-ketoesters,30 the
deprotection of dithianes,31 the bromocyclization of 2-
hydroxychalchones,32 and the preparation of organoammonium
perbromide salts.33 The major limitation of these initial efforts has
been the relatively large catalyst loadings (i.e., w0.5 equiv of V2O5
relative to substrate) in some cases. Herein, we provide a full ac-
count of our recently communicated method34 for the V2O5-me-
diated bromolactonization of alkenoic acids mediated by the in situ
oxidation of bromide to bromenium (Brþ).
2. Results and discussion
2.1. Exploratory experiments
2.2. Further optimization: solvent, co-oxidant, temperature
We began our investigation with a series of exploratory
grounding experiments targeting the bromolactonization of 4-
phenylpentenoic acid 1 mediated by the V2O5 catalyzed oxidation
Based on our initial screening efforts, we selected a combination
of 0.2 equiv V2O5 in the presence of 5 equiv NH4Br as the halide
source, in a 6:1:1 ratio of acetonitrile, water, and 30% aq hydrogen
Table 1
Initial exploratory experiments
Table 2
Further optimization
Entry
V2O5
(eq.)
Solvent system
Co-ox.
(eq.)a
Halide source
(eq.)
Yield
(%)b
Entry
V2O5
(eq.)
Solvent system
Co-ox.
(eq.)a
Halide source
(eq.)
Yield
(%)b
1
2
3
4
5
6
7
8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.2
0.2
0.2
0.2
0.2
0.1
0.1
0.1
0.1
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (1:1)
ACN:H2O (1:6)
30% aq H2O2
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (6:1)
ACN:H2O (6:1)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
d
NH4Br (15)
NaBr (15)
CsBr (15)
LiBr (15)
KBr (15)
NH4Br (15)
NH4Br(15)
NH4Br (15)
NH4Br (5)
NaBr (5)
NH4Br (5)
NaBr (5)
NH4Br (5)
NH4Cl (5)
NaCl (5)
73
84
66
76
74
71
51
68
84
73
65
75
89c
36d
28d
59
54
42
40
1
2
3
4
5
6
7
8
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.01
ACN:H2O (6:1)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
UHPc (5)
UHP (5)
UHP (3)
UHP (5)
UHP (5)
UHP (5)
UHP (3)
UHP (3)
UHP (2.5)
UHP (2.5)
UHP (3)
UHP (3)
NH4Br (5)
NH4Br (5)
NH4Br (5)
NH4Br (5)
NH4Br (5)
NH4Br (5)
NH4Br (3)
NH4Br (5)
NH4Br (5)
NH4Br (5)
NH4Br (3)
NaBr (3)
65
67
66
67
87
91d
92
96e
87
36
93
43
84
93d
90
12
EtOAc: H2O (6:1)
PhMe: H2O (6:1)
Acetone:H2O (6:1)
Acetone:H2O (6:1)
Acetone:H2O (6:1)
Acetone:H2O (6:1)
Acetone:H2O (6:1)
Acetone:H2O (12:1)
Acetone:H2O (30:1)
Acetone:H2O (6:1)
Acetone:H2O (6:1)
Acetone:H2O (6:1)
Acetone:H2O (6:1)
Acetone:H2O (6:1)
Acetone:H2O (6:1)
9
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
H2O2 (aq)
10
11
12
13
14
14
16
17
18
19
9
10
11
12
13
14
15
16
NH4Br (2.5)
NH4Br (2.5)
NH4Br (3)
NH4Br (3)
NaBr (5)
NH4Br (5)
CsBr (5)
a
H2O2 (aq) denotes a 30% aqueous solution of hydrogen peroxide employed as
LiBr (5)
a co-solvent in a 6:1:1 ratio with organic solvent and water, respectively.
a
b
H2O2 (aq) denotes a 30% aqueous solution of hydrogen peroxide.
Yields are isolated yields after acid/base extraction.
Reaction warmed to 65 ꢀC.
Yields are isolated yields after acid/base extraction.
b
c
c
UHP¼urea-hydrogen peroxide complex.
d
Reaction warmed to 65 ꢀC.
d
e
Corresponding chlorolactone product was isolated.
Identical yield observed at rt and 65 ꢀC.
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McKenzieL. Campbell et al. / Tetrahedron xxx (2015) 1e8
3
peroxide (i.e., Table 2, entry 1; transcribed from Table 1, entry 11) as
2.3. Metal oxide screen
our starting point for a second round of optimization. We chose
these conditions as a good starting point for subsequent optimi-
zation efforts, despite its disappointing 65% yield of 2, since it
returned a clean sample of the product, free from vicinal dibromi-
nated by-product at room temperature. Changing the organic
component of the solvent system from acetonitrile to ethyl acetate,
toluene, and acetone resulted in comparable yields of 2 ranging
from 66 to 67% (Table 2, entries 2e4). A key breakthrough for our
study was the observation of an increase in yield of bromolactone 2
when the co-oxidant was changed to the commercially available
urea-hydrogen peroxide complex (UHP) in an acetone/water (6:1)
solvent system. In the event, employing 5 equiv of UHP as the co-
oxidant returned 2 in an 87% yield with 0.2 equiv of catalyst (en-
try 5). Otherwise identical conditions at 65 ꢀC returned 2 in an
improved yield of 91% (entry 6). Finally, reducing the loading of
both UHP and NH4Br to 3 equiv each returned 2 in 92% in the
presence of 20 mol % V2O5 (entry 7).
After establishing UHP as the optimal co-oxidant, we embarked
on a systematic screen of reaction conditions with the overall goal
of reducing the loadings of the catalyst, co-oxidant, and terminal
halide source to more reasonable levels. The loading of V2O5 could
be reduced to 0.1 equiv while still returning the desired product 2
in excellent yield at both room temperature and 65 ꢀC (entry 8).
Decreasing the aqueous component of the solvent system from 6:1
acetone/water to 12:1 and 30:1 resulted in a dramatic decline in the
yield of 2 (entries 9 and 10). Reducing the loading of UHP and
NH4Br from 5 equiv to 3 equiv in the presence of 0.1 equiv V2O5
returned 2 in a 93% yield (entry 11). Employing sodium bromide in
lieu of ammonium bromide resulted in a significantly reduced 43%
yield of the desired bromolactone product 2 (entry 12). A signifi-
cant portion of the vicinal dibromination product resulting from
trapping of the initial bromonium intermediate with bromide was
observed. Further reduction of the loading of UHP and NH4Br to
2.5 equiv each resulted in a reduced yield of 84% (entry 13) unless
the reaction was warmed to 65 ꢀC, whereby the yield rose again to
93% (entry 14). Nonetheless, we were able to lower the catalyst
loading to 0.05 equiv while maintaining the co-oxidant and halide
source loading at 3 equiv each and recover bromolactone 2 in only
a slightly reduced 90% isolated yield (entry 15). Unfortunately,
further lowering the catalyst loading to 1 mol % resulted in a very
poor 12% isolated yield of 2 (entry 16).
We also elected to evaluate several other commercially available
metal oxides to ensure that V2O5 was indeed the catalyst of choice
for the desired transformation. In this series of experiments
(Table 3), we screened various metal oxides in a 0.1 equiv catalyst
loading in the presence of 3 equiv of urea-H2O2 and 3 equiv NH4Br
in a 6:1 acetone/H2O solvent system at room temperature for 18 h.
In the absence of metal oxide catalyst (entry 1), no desired bro-
molactone was isolated or detected by 1H NMR analysis, confirming
that uncatalyzed oxidation of NH4Br by UHP alone is not operative
in our system. Entry 2 reiterates the observed 93% yield of the
target bromolactone in the presence of 0.1 equiv of V2O5. Next we
evaluated other commercially available metal oxides to determine
whether V2O5 was uniquely effective at promoting the in situ oxi-
dation of bromide. Oxides of niobium, including niobium pentoxide
and niobium dioxide returned negligible, but still spectroscopically
detectable, amounts of the desired bromolactone, along with
mostly recovered starting material (entries 3e4). Tungsten trioxide
catalysis (entry 5) returned pristine starting material while use of
tungsten dioxide resulted in the isolation of the desired lactone
product in 32% yield (entry 6). Chromium trioxide catalysis also
returned bromolactone 2 in a 29% isolated yield (entry 7). Oxides of
tantalum including lithium tantalate (entry 8) and tantalum pent-
oxide (entry 9) returned trace product and recovered starting
material, respectively. Interestingly, molybdenum trioxide and
molybdenum dioxide returned the desired bromolactone 2 in ac-
ceptable yields of 78% (entries 10e11). This brief evaluation of other
commercially available transition metal oxides confirmed V2O5 as
the catalyst of choice for the desired transformation. Nonetheless,
the corresponding catalytic activity of the molybdenum oxides is
also noteworthy.
2.4. Optimal conditions
Based on the extensive screening process described in the pre-
vious three sections, we arrived at our optimal reaction conditions
for the desired transformation (Scheme 1).
Table 3
Screen of other transition metal oxides
Scheme 1. Optimal reaction conditions for V2O5 catalyzed bromolactonization.
Specifically, urea-hydrogen peroxide complex (3.0 equiv) and
V2O5 (0.05 equiv) were dissolved in acetone/H2O (6:1) (0.08 M
relative to substrate) and stirred at 0 ꢀC for 30 min. Ammonium
bromide (3.0 equiv) was added and stirred for an additional 30 min.
After addition of the substrate (1.0 equiv), the mixture was allowed
to stir for an additional 15 min at 0 ꢀC before gradually warming to
room temperature overnight. Notably, the desired bromolactone
product could be isolated in acceptable purity after a simple acid/
base extraction protocol without recourse to column chromato-
graphic purification. With these optimized conditions in hand, we
set out to evaluate the substrate scope of the transformation.
Entry
Metal oxide
Yield (%)
1
2
3
4
5
6
No catalyst
V2O5
Nb2O5
NbO2
WO3
WO2
0
93
Trace
Trace
0
32
7
CrO3
29
8
9
10
11
LiTaO3
Ta2O5
MoO3
MoO2
Trace
0
78
2.5. Substrate scope
Chart 1 depicts the substrate scope of the method. As mentioned
previously, cyclization of 1 returned bromolactone 2 in 90% isolated
yield. The method was effective for the cyclization of several related
78
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4
McKenzieL. Campbell et al. / Tetrahedron xxx (2015) 1e8
Chart 1. Substrate scope.
para-substituted 4-phenylpentenoic acid substrates including: p-
bromo (3, 83%), p-chloro (4, 85%), p-methoxy (5, 96%), p-methyl (6,
87%), and p-ethyl (7, 82%). The success of the p-ethyl substrate
(returning lactone 7) is noteworthy given that we did not observe
any bromination of the relatively activated 2ꢀ benzylic position,
suggesting that bromine radicals may not be operative in the re-
action. Next, we investigated the effect of extending the linker
between the carboxylate nucleophile and the alkene. The corre-
excellent 93% isolated yield. Finally, we investigated the cyclization
of trans-styrylacetic acid. We were particularly interested in this
transformation due to the predictable lability of the initially formed
bromolactone product 12, which we surmised might rapidly eject
HeBr to form the corresponding unsaturated butenolide. In the
event, our optimal condition with 0.05 equiv of V2O5 proved im-
practically sluggish. Cyclization in the presence of 0.1 equiv V2O5,
however, returned a 58% isolated yield of a 1:1 mixture of bro-
sponding
d
-lactone arising from cyclization of 5-phenyl-5-hexenoic
molactone 12 and the a,b-unsaturated lactone resulting from bro-
acid was initially isolated in a disappointing 26% yield (8a). In-
creasing the catalyst loading to 0.1 equiv resulted in an improved
yield of 50% (8b). In both cases, a significant amount of the un-
desired 5,6-dibrominated uncyclized product was isolated. At-
tempts to promote the desired intramolecular cyclization by
diluting the reaction (i.e., in an effort to preclude the biomolecular
dibromination pathway) failed to improve on the initially observed
yields for this substrate. Nevertheless, the incorporation of a gem-
dimethyl substituent in the linker returned the analogous 3,3-
mide elimination (entry 12a). Conducting the reaction in the
presence of 3 equiv of p-toluenesulfonic acid precluded the for-
mation of the elimination product, thus returning an acceptable
63% yield of the bromolactone product. Presumably, the additive
sufficiently acidifies the reaction medium so as to prevent the
elimination of HBr from the initially formed bromolactone. Un-
fortunately, several attempts to optimize the reaction conditions to
favor the exclusive formation of the butenolide product failed.
dimethyl
of the well-known Thorpe-Ingold effect.35 Cyclization of 4-
pentenoic acid returned the corresponding unsubstituted -lac-
d-lactone 9 in an excellent 97% yield, taking advantage
2.6. Scaled experiments
g
Next we evaluated the ability of the method to perform at larger
tone in yields ranging from 50 to 51% yield (10a and 10b). Further,
the method provides facile access to benzolactones. For example,
cyclization of 2-allylbenzoic acid provided benzolactone 11 in an
scale (Scheme 2).
phenylpentenoic acid 1 was cyclized in excellent yield employing
either 0.1 or 0.05 equiv of V2O5. Specifically, bromolactone 2 was
A one gram portion (5.7 mmol) of 4-
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McKenzieL. Campbell et al. / Tetrahedron xxx (2015) 1e8
5
isolated in acceptable purity in a 95% or 90% yield respectively by
means of a simple acid/base extraction without the need for
chromatographic purification. Similarly, trans-styrylacetic acid 13
was converted to bromolactone 12 in a 66% yield on a 5.7 mmol
scale, indicating that the modified protocol in the presence of the p-
toluenesulfonic acid additive is also reasonably scalable.
Denmark17b groups have also independently detailed significant
rate acceleration in halocyclization reactions in the presence of
exogenous nucleophiles and Lewis bases. In the context of our
methodology, we wondered whether urea might effect a similar
activation by engaging the initially formed bromenium equivalent
to form a complex like 18 (cf. Braddock’s intermediate 19). In order
to probe any potential activating contribution from urea we con-
ducted a set of parallel experiments whereby we employed 30%
aqueous H2O2 as the terminal oxidant instead of urea-H2O2 com-
plex. We compared the yield of this transformation in the presence
or absence of 3 equiv of added urea (Scheme 4, Panel B). Lactoni-
zation of 1 under these modified conditions proceeded in a com-
parable yield with or without added urea (cf. 40% vs 41% yield
respectively). These results suggest that urea does not play a cata-
lytic role in our system similar to the Braddock methodology.
3. Conclusions
We have presented a full account of the development of a novel
method for the bromolactonization of alkenoic acids catalyzed by
vanadium (V) oxide. The method hinges on the biologically-
inspired in situ oxidation of bromide (Brꢁ) to bromenium equiva-
lent (Brþ). The method allows for facile access to bromolactone
products in acceptable purity without recourse to column chro-
matography. Further, we have presented preliminary data that in-
dicates that other transition metal oxides, most notably oxides of
molybdenum, can promote similar reactivity. Preliminary in-
Scheme 2. Gram scale bromolactonization experiments with optimized conditions.
2.7.
a-Halogenation of b-diketone compounds
vestigation of our reaction conditions in the a-bromination of b-
We surmised that our optimal conditions might also represent
a convenient means to effect other useful transformations in-
diketones suggests that the strategy described herein could be
more broadly applicable to other related bromination reactions.
Finally, we have probed the role of urea in the transformation.
Current efforts in our laboratory are focused on further exploiting
this unique method for the generation of reactive halogen species
in organic synthesis. Of particular interest is the possibility of
rendering the protocol asymmetric by means of the incorporation
of appropriate chiral ligands for vanadium. Indeed, the use of va-
nadium oxides for asymmetric catalysis is an emerging area in or-
ganic synthesis.36
cluding the
order to probe this possibility we briefly investigated the
mination of two -diketone substrates (Scheme 3). In the event,
a
-halogenation of activated methylene moieties. In
a-bro-
b
diketones 14 and 15 were mono-brominated in 92% (16) and 94%
(17) yield, in the prescence of 0.05 equiv V2O5 using identical
conditions to our optimized bromolactonization protocol. These
results indicate that our optimal protocol for the in situ oxidation of
bromide to bromenium may provide a convenient route for other
related transformations.
4. Experimental section
4.1. General information
All reagents were purchased from commercial sources and used
without purification. Alkenoic acid substrates were either pur-
chased from commercial sources or prepared following an estab-
lished protocol that included Wittig methylenation followed by
saponification of the terminal ester to the carboxylic acid.19a 1H and
13C NMR spectra were collected on 300 and 500 MHz NMR spec-
trometers using CDCl3 as solvent. Chemical shifts are reported in
parts per million (ppm) and were referenced to the residual solvent
peak. Coupling constants, J, are reported in hertz (Hz). All pre-
viously known products were characterized by 1H and 13C NMR and
are in agreement with samples reported elsewhere. Compounds 3
and 7 are previously unknown compounds, and were characterized
by means of 1H and 13C NMR, IR, and HRMS.
Scheme 3.
a-halogenation of b-diketone compounds.
2.8. Does urea play a role in the transformation?
Finally, since our conditions employed the urea complex of hy-
drogen peroxide in lieu of aqueous H2O2, we wondered whether
the significant concentration of urea (i.e., 3 equiv relative to sub-
strate) might play an activating role in the reaction. We were in-
trigued by a report from Braddock and co-workers that highlighted
the ability of electron-rich nitrogenous nucleophiles to accelerate
the N-bromosuccinimide promoted bromolactonization of alkenoic
acids.17d For instance, Braddock and co-workers disclosed that the
bromolactonization of various alkenoic acids could be significantly
accelerated in the presence of N,N,N0,N0-tetramethylguanidine, ev-
idently by means of the formation of an active species such as 19
(Scheme 4, Panel A). Similar rate enhancements were realized with
other additives including amides like N,N-dimethylformamide and
N,N-dimethylacetamide.17d Additionally, the Tang17a and
4.2. General procedure for bromolactonization and
genation of -diketones
a-halo-
b
Urea-hydrogen peroxide complex (0.851 mmol, 80 mg,
3.0 equiv) and vanadium pentoxide (0.014 mmol, 3 mg, 0.05 equiv)
were dissolved in 3.5 mL acetone/H2O (6:1) and stirred at 0 ꢀC for
30 min. To this ice-cold solution, ammonium bromide (0.851 mmol,
80 mg, 3.0 equiv) was added and stirred for an additional 30 min.
After addition of the substrate (0.284 mmol, 1.0 equiv), the mixture
Please cite this article in press as: Campbell, M. L.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.029

6
McKenzieL. Campbell et al. / Tetrahedron xxx (2015) 1e8
Scheme 4. Probing the role of urea in the V2O5 catalyzed bromolactonization reaction.
was allowed to stir for an additional 15 min at 0 ꢀC before gradually
warming to room temperature overnight. The reaction mixture was
diluted with water (15 mL) and extracted with DCM (3ꢂ15 mL). The
combined organics were washed with saturated aqueous sodium
bicarbonate. The combined aqueous layers were back-extracted
with DCM (15 mL). Finally, all organic extracts were combined
(60 mL total volume), dried over anhydrous sodium sulfate, con-
centrated by rotary evaporation, and dried in vacuo.
2.86e2.70 (m, 2H), 2.61e2.48 (m, 2H); 13C NMR (90 MHz, CDCl3):
175.4, 159.8, 132.6, 126.2, 114.2, 86.3, 55.3, 41.0, 32.2, 29.1.
d
4.7. 5-(Bromomethyl)-5-(4-methylphenyl)dihydrofuran-
2(3H)-one, 620c
Light yellow oil. 1H NMR (300 MHz, CDCl3):
d
7.31 (d, J¼8.4 Hz,
2H), 7.22 (d, J¼8.1 Hz, 2H), 3.76e3.67 (dd, J¼11.4, 17.4 Hz, 2H),
4.3. 5-(Bromomethyl)-5-phenyloxolane-2-one, 217d
2.87e2.75 (m, 2H), 2.61e2.49 (m, 2H), 2.37 (s, 3H); 13C NMR
(90 MHz, CDCl3):
29.0, 21.0.
d 175.5, 138.6, 137.7, 129.5, 124.8, 86.4, 41.0, 32.3,
Light yellow oil, 1H NMR (300 MHz, CDCl3):
d 7.44e7.37 (m, 5H),
3.78e3.70 (dd, J¼10.2, 18.3 Hz, 2H), 2.88e2.79 (m, 2H), 2.62e2.52
(m, 2H); 13C NMR (90 MHz, CDCl3):
124.9, 86.4, 41.0, 32.4, 29.1.
d 175.4, 140.8, 128.9, 128.7,
4.8. 5-(Bromomethyl)-5-(4-ethylphenyl)dihydrofuran-2(3H)-
one, 7
4.4. 5-(Bromomethyl)-5-(4-bromophenyl)dihydrofuran-2-
(3H)-one, 3
Light yellow oil. 1H NMR (300 MHz, CDCl3):
d 7.36e7.24 (m, 4H),
3.78e3.67 (dd, J¼9.3 Hz, 17.4 Hz, 2H), 2.86e2.76 (m, 2H), 2.72e2.51
Light yellow oil; 1H NMR (300 MHz, CDCl3):
d
7.57e7.52 (dt,
(m, 4H), 1.25 (t, J¼7.5 Hz, 3H); 13C NMR (90 MHz, CDCl3):
d 175.6,
J¼2.4, 4.5, 9.3, 11.1, 13.1 Hz, 2H), 7.32e7.28 (dt, J¼2.7, 4.5, 9.3, 11.4,
144.9, 137.9, 128.3, 124.9, 86.5, 41.1, 32.3, 29.1, 28.4, 15.4; IR (DCM):
1786 cmꢁ1; HRMS (ESI-TOF, positive mode): C13H15O2Br; Calculated
(MþH): 283.0334; Found: 283.0328.
14.4 Hz, 2H), 3.73e3.64 (dd, J¼11.4, 13.5 Hz, 2H), 2.85e2.73 (m, 2H),
2.62e2.50 (m, 2H); 13C NMR (90 MHz, CDCl3):
d 175.0, 139.8, 132.0,
126.8, 122.9, 86.0, 40.5, 32.4, 28.9; IR (DCM): 1784 cmꢁ1; HRMS
(ESI-TOF, positive mode):
332.9126; Found: 332.9138.
C11H10O2Br2; Calculated (MþH):
4.9. 6-(Bromomethyl)-6-phenyloxan-2-one, 817d
4.5. 5-(Bromomethyl)-5-(4-chlorophenyl)dihydrofuran-2-
Light yellow oil. 1H NMR (300 MHz, CDCl3):
d 7.58e7.30 (m, 5H),
(3H)-one, 420c
3.72e3.63 (dd, J¼11.1, 15.9 Hz, 1.65H), 2.85e2.32 (m, 3.77),
1.90e1.79 (m, 1H), 1.66e1.52 (m, 1H); 13C NMR (90 MHz, CDCl3):
Light yellow oil. 1H NMR (300 MHz, CDCl3):
d
7.41e7.34 (m, 4H),
d 170.5, 140.2, 129.0, 128.5, 125.39, 85.1, 41.5, 30.0, 29.1, 16.2.
3.74e3.64 (dd, J¼11.4, 16.8 Hz, 2H), 2.86e2.73 (m, 2H), 2.63e2.50
(m, 2H); 13C NMR (90 MHz, CDCl3):
85.9, 40.6, 32.4, 28.9.
d 175.1,139.2,134.7, 129.0,126.4,
4.10. 6-(Bromomethyl)-4,4-dimethyl-6-phenyl)tetrahydro-
2H-pyran-2-one, 920h
4.6. 5-(Bromomethyl)-5-(4-methoxyphenyl)dihydrofuran-
2(3H)-one, 520c
Light yellow oil. 1H NMR (300 MHz, CDCl3):
d 7.48e7.29 (m, 5H),
3.62e3.58 (dd, J¼11.1, 18.0 Hz, 2H), 2.40 (s, 2H), 2.32e2.18 (dd,
Light yellow oil. 1H NMR (300 MHz, CDCl3):
d 7.36e7.31 (dt,
J¼16.5, 27.3 Hz, 2H), 1.09 (s, 3H), 0.75 (s, 3H); 13C NMR (90 MHz,
J¼3.0, 5.1, 9.9, 12.0, 15.0 Hz, 2H), 6.95e6.90 (dt, J¼3.0, 5.1, 9.9, 12.0,
CDCl3):
28.4.
d 170.9, 141.4, 128.9, 128.4, 125.2, 83.9, 43.6, 42.5, 31.6, 30.5,
15.0 Hz, 2H), 3.82 (s, 3H), 3.75e3.64 (dd, J¼11.1, 20.7 Hz, 2H),
Please cite this article in press as: Campbell, M. L.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.029

McKenzieL. Campbell et al. / Tetrahedron xxx (2015) 1e8
7
4.11. 5-(Bromomethyl)oxolan-2-one, 1017d
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Light yellow oil. 1H NMR (300 MHz, CDCl3)
d 4.80e4.72 (m, 1H),
3.61e3.51 (m, 2H), 2.74e2.58 (m, 2H), 2.54e2.40 (m, 1H), 2.19e2.07
(m, 1H); 13C NMR (90 MHz, CDCl3)
d
176.1, 77.8, 34.0, 28.3, 26.2.
4.12. 3-(Bromomethyl)-3,4-dihydro-1H-2-benzopyran-1-one,
1117d
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Light yellow oil. 1H NMR (300 MHz, CDCl3):
d
8.10 (dd, J¼0.9,
7.8 Hz, 1H), 7.58 (td, J¼1.5, 7.5 Hz, 1H), 7.40 (t, J¼7.5 Hz, 1H), 7.30 (d,
J¼7.8 Hz, 1H), 4.79e4.70 (m, 1.0), 3.71e3.57 (m, 1H), 3.25e3.13 (m,
1.0); 13C NMR (90 MHz, CDCl3):
127.7, 124.5, 76.7, 32.5, 31.5.
d 164.3, 137.9, 134.2, 130.4, 128.0,
4.13. 4-(Bromodihydro)-5-phenyl-2-(3H)-furanone, 1220h
Light yellow oil. 1H NMR (300 MHz, CDCl3):
d
7.48e7.36 (m, 5H),
5.68 (d, J¼5.1 Hz, 1H), 4.42e4.36 (ddd, J¼5.4, 6.3, 7.5 Hz, 1H),
3.30e3.21 (dd, J¼7.2, 18.0 Hz, 1H), 3.03e2.95 (dd, J¼6.3, 18.0 Hz,
1H); 13C NMR (90 MHz, CDCl3):
87.8, 45.5, 38.8.
d 173.0, 135.8, 129.3, 129.0, 125.4,
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4.14. 2-Bromo-1-phenyl-1,3-butanedione, 1637
Light yellow oil. 1H NMR (300 MHz, CDCl3):
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8.04 (d, J¼17.4 Hz,
2H), 7.65 (t, J¼9.3, 1H), 7.50 (t, J¼9.0 Hz, 2H), 5.64 (s, 1H), 2.47 (s,
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3H); 13C NMR (90 MHz, CDCl3):
129.0, 52.9, 27.1.
d 198.2, 189.9, 134.5, 133.7, 129.3,
4.15. 2-Bromo-1,3-diphenylpropan-1,3-dione, 1737
Light yellow oil. 1H NMR (300 MHz, CDCl3):
d
8.01 (d, J¼9.0 Hz,
4H), 7.62 (tt, J¼3.0 Hz, 6.0 Hz, 2H), 7.48 (t, J¼15.0 Hz, 4H), 6.60 (s,
1H); 13C NMR (90 MHz, CDCl3):
52.6.
d 189.0, 134.3, 133.8, 129.1, 129.0,
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Supporting Information.
Proton and carbon NMR spectra.
Acknowledgements
The authors gratefully acknowledge Clemson University for
generous start-up funds. The authors wish to thank Rieke Metals,
Inc. and Oakwood Chemical for their generous donation of a sub-
strate precursor in support of this effort.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.04.029.
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