Aaron VanZanten, Ryan Harrington, Adam Kiefer, Julie Pigza, David Carlson, Bill Andrews, Claude Ogoe

1
2,3-Dibromo-1-(phenylsulfonyl)propene (DBP) as a
Versatile Reagent for the Preparation of
2,4-Disubstituted Furans
Aaron VanZanten, Ryan Harrington, Adam Kiefer,
Julie Pigza, David Carlson, Bill Andrews, Claude
Ogoe, and S. Shaun Murphree Allegheny College,
Meadville, PA 16335
Abstract
Results and Discussion
Sulfonyl carbanions can also be acylated with
esters or acyl halides14, but treatment of acyl
chlorides with the monolithiate of furan 4 gave
yields that were consistently lower than 50,
with a large amount of recovered starting
material, a result presumably due to a facile
proton transfer between the initially formed
intermediate (19) and the starting anion 17.
This problem could be overcome, however, through
the generation of a dianion.15 Thus, a THF
solution of furan 4 was treated with 2.0
equivalents of n-BuLi at -78C and allowed to
stir for 15 minutes, after which 1.05 equivalents
of pivaloyl chloride was added. The reaction was
warmed to room temperature, worked up, and
subjected to flash chromatography to yield 79 of
the acyl sulfonyl furan 19a as a white solid.
1,3-dicarbonyl compounds (3) add to the vinylic
position of 2,3-dibromo-1-(phenylsulfonyl)propene
(DBP, 2) to form Michael adducts (5), which
cyclize under basic conditions to afford
2,4-disubstitued furans (4). Deprotonation at
the a-sulfonyl position furnishes a stabilized
carbanion, which may be captured by a variety of
electrophiles (E) to give the elaboration at
the 4-position. Generality at the 2-position can
be introduced by using t-butyl ketoesters (16),
which are readily available from carboxylic acids.
Generality at the 2-Position. When furan 4 is
prepared from DBP and 2,4-pentanedione (3), the
2-methyl group is derived from the half of the
diketone left after deacylation of intermediate
5. In terms of generality of the protocol,
relying upon symmetrical diketones for the
2-substituent suffers from obvious setbacks in
terms of accessibility and atom economy.
Unfortunately, the use of simple enolates leads
to severe decomposition of DBP due to eliminative
side-reactions.
Therefore, a method is needed that offers
generality of the R-group, but does not suffer
from the basicity issues of simple enolates. One
approach is available through the use of t-butyl
ketoesters. Thus, the commercially available
t-butyl acetoacetate (11) affords the
corresponding adduct 12. Selective
decarboxylation in the presence of
p-toluenesulfonic acid gives enone 6, which
cyclizes to the furan 4 under basic conditions as
previously described.
Scheme 6. Proton transfer of a-sulfonyl ketones
Scheme 3. Selective deacylation of
DBP/keto-ester intermediates
Introduction and Background
Table 2. Acylation of phenylsulfonyl carbanions
Sulfonyl containing compounds (RSO2R)
represent an ever expanding cadre of organic
intermediates for the synthesis of complex
targets, and their agency in the preparation of
biologically active compounds is significant.1
The phenylsulfonyl (PhSO2) and tolylsulfonyl
(p-TolSO2) substituents are particularly
attractive, since they are easily accessible,
they impart many practically beneficial
characteristics (e.g., crystalline nature), and
their subsequent chemistry is versatile and
well-defined.2 Moreover, the removal
removal of these groups can be effected under
mild conditions.3 As an outgrowth of our studies
on phenylsulfonyl allene (1)4, we developed a
versatile multifunctional sulfone, namely
2,3-dibromo-1-phenylsulfonyl-1-propene (DBP, 2)5,
which contains a vinyl sulfone, a vinyl bromide,
and an allylic bromide in a compact three-carbon
array (Scheme 1). DBP is a stable, crystalline
solid with a long shelf life, and requiring no
special storage or handling procedures.
In terms of generality, this option is
particularly attractive, since t-butyl ketoesters
of this type can be prepared from carboxylic
acids using carbonyldiimidazole (CDI) according
to the method of Hoffman11 (Scheme 4).
Thus, the 2-alkyl position of the product furans
is theoretically limited only by the availability
of the corresponding carboxylic acid. Studies
into the scope and limitations of this approach
is ongoing.
In conclusion, the reaction of t-butyl ketoesters
with DBP, followed by decarboxylation and ring
closure, gives (phenylsulfonyl)methyl furans with
variable substitution at the 2-position.
Alkylation or acylation at the a-sulfonyl site
then provides for modification at the 4-position.
This methodology therefore represents a flexible
approach to the synthesis of 2,4-disubstituted
furans.
Further exploration into the scope and
limitations of this protocol, as well as studies
into the mechanistic underpinnings of the
transformations, is a subject of continuing
investigation in our laboratories.
Scheme 4. Availability of t-butyl ketoesters
Generality at the 4-position. The presence of
the (phenylsulfonyl)methyl substituent allows us
to take advantage of well-known a-sulfonyl
carbanion chemistry12 to elaborate the
4-position. Thus, furan 4 is smoothly
deprotonated in the presence of n-butyllithium,
and the resulting carbanion (17) can be
efficiently trapped with a variety of
electrophiles (Table 1).
The methodology is tolerant to a wide array of
alkyl halides, from simple alkyl halides (18a) to
a-bromoesters (18e). Sulfonyl anions are also
known to undergo addition to carbonyls.13
Indeed, the lithiate of furan 4 engaged in the
smooth attack of cyclohexanone to provide the
corresponding tertiary alcohol 18f.
Scheme 1. Furans from DBP and dicarbonyls
References Cited
When DBP is allowed to react with
2,4-pentanedione (3) under basic conditions in
polar protic solvent (e.g., methoxide in
methanol), the 2,4-disubstituted furan 4 is
produced. This reaction proceeds via initial
Michael addition-elimination to form the
substituted dicarbonyl 5. This adduct suffers
deacylation under the reaction conditions to
provide sulfonyl b,g-enone 6, which rapidly
cyclizes to the (phenylsufonyl)methyl furan 4.
This methodology can be applied to other
dicarbonyl compounds as well. For example,
2-formyl-5-methylcyclohexanone (7)6 reacts with
DBP to give adduct 8, which then undergoes
selective deformylation in the presence of excess
methoxide to provide the elaborated cyclohexanone
derivative (9). Subsequent in situ cyclization
completes a short synthesis of racemic
menthofuran (10).7

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Scheme 5. Elaboration of the 4-position by
alkylation
Scheme 2. Mechanistic detail and synthesis
of menthofuran
Table 1. Alkylation of phenylsulfonyl carbanions
Acknowledgements
We gratefully acknowledge Allegheny College for
support of this research, as well as the Shanbrom
Fund for generous support of summer research
students.
There are many intriguing aspects to this
chemistry. For example, certain substituents
situated between the two carbonyl functionalities
can cause a mechanistic crossover so that
cyclopentenones are produced in preference to
furans. The practical application of this
anomaly has been demonstrated by the synthesis of
cis-jasmone8, however the mechanistic
underpinnings are not yet entirely understood and
are the subject of ongoing study.
The current work is aimed specifically at
enhancing the scope of the synthesis of furans
using DBP by introducing generality at both the
2- and the 4-positions of the product. The
availability of such a general method will
supplement existing syntheses of
2,4-disubstituted furans9, a structural subunit
widely distributed in naturally occurring and
synthetic compounds of biological interest.10