Organic Letters
Letter
performed well using the standard protocol (3ja−3jc, 45%−
63% yield). In addition, secondary α-bromoester 2d was also
found to be a suitable reaction partner, providing 3jd, albeit in
20% yield. Ethyl 4-bromobutanoate 2e was also a competent
substrate, affording 3je in 38% yield. Notably, alkyl bromides
with different functional groups, including 2-bromoacetic acid
and 2-bromoacetonitrile, as well as benzyl bromide (2f−2h),
all allowed the sulfoxide reduction/C−S bond metathesis
cascade to proceed smoothly to deliver 3jf−3jh in yields of
57%−79%.
of 1j gave product 3jg in 72% yield, and 8.0 mmol of 4a led to
sulfide 3ag in 96% yield (Scheme 5). In addition, ionic liquid
could be recycled without a notable decrease in the yield (see
Scheme 5. Gram-Scale Reaction
Encouraged by the above results and postulating that the
cascade initiates by a sulfoxide reduction to a sulfide
intermediate, we wondered if the sulfide could allow C−S
bond metathesis to proceed under our conditions. Indeed,
methyl phenyl sulfide (4a) underwent the metathesis
efficiently with 2a in [Bmim][OTf], providing 3aa in 85%
yield (Scheme 4). Gratifyingly, a slightly higher yield of 3aa
According to the above results, a plausible mechanism is
depicted in Scheme 6. First, the alkyl bromide 2a undergoes a
a b
,
Scheme 4. Scope of Sulfide Metathesis
Scheme 6. Proposed Mechanism
SN2 reaction with nucleophilic O atom of the sulfoxide 7 to
generate alkoxysulfonium salt A, and subsequent deprotona-
tion provides the corresponding alkoxysulfonium ylide B. This
alkoxysulfonium ylide B can undergo a [2,3]-sigmatropic shift
to afford sulfide 10, along with methyl glyoxylate 5, which was
detected by GC-MS. Sulfide 10 can react with alkyl bromide
2a to form sulfonium salt C. Finally, a nucleophilic substitution
of C with the Br− ion leads to the metathesis product 3aa and
benzyl bromide, which was confirmed by GC-MS.
In summary, we have developed a sulfoxide reduction/C−S
bond metathesis cascade between sulfoxides and alkyl
bromides without the use of any catalysts or bases. This
cascade is proven to start with the classical Kornblum
oxidation, which is employed to reduce sulfoxides in ionic
liquid. Moreover, this methodology demonstrates high func-
tional tolerance, mild conditions, and sustainable solvents.
Thus, it would be especially useful for the late-stage
functionalization of sulfoxide and sulfide derivatives.
a
Reaction conditions: 4 (0.3 mmol), 2a or 2g (1.8 mmol) in TFE (1
b
M) at 100 °C for 24 h. Isolated yield. c[Bmim][OTf] as the solvent.
was isolated, when the reaction was conducted in TFE.
Therefore, we explored the scope of sulfides amenable to this
C−S bond metathesis (Scheme 4). The metathesis tolerates a
range of functionalities, including ethers (3ga), chlorides (3ia),
bromides (3ja−3la), ketones (3pa), carboxylic acids (3ua),
nitroarenes (3va), naphthalenes (3ra), benzothiophenes (3sa),
and nitriles (3ag). Furthermore, complex thioethers, such as
photoinitiator derivative 3wa,44 alkyl sulfide 3xg derived from
trans-androsterone, and sulindac sulfide lactone45 3ya, could
be also prepared under the metathesis conditions. Remarkably,
R1 substituent in sulfide 4 could be varied from methyl to ethyl
(9), benzyl (10), and allyl (11), leading to the desired 3aa in
high yield.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
Experimental procedures and characterization data
AUTHOR INFORMATION
Corresponding Authors
■
To further highlight the practicality of these reactions, we
performed two gram-scale reactions. To our delight, 5.0 mmol
Jinyue Luo − Jiangsu Provincial Key Lab for the Chemistry and
Utilization of Agro-Forest Biomass, Jiangsu Co-Innovation
C
Org. Lett. XXXX, XXX, XXX−XXX