Journal of the American Chemical Society
Article
demonstrating that DMS influences the structure of AcOH and
MeOH. The interaction among these compounds are
summarized in Figure 2d. Clusters of AcOH would be formed
in liquid DMS, as observed in aqueous acetonitrile solution.13
On the other hand, AcOH is mixed with MeOH on a
microscopic scale owing to the strong interaction of AcOH
with MeOH. These soft X-ray absorption experiments led us to
conclude that MeOH would break the interaction of AcOH−
AcOH pairs in the AcOH clusters and help the formation of
the AcOH−DMS pairs on a microscopic scale, which could
accelerate the reaction of AcOH and DMS.
Reversibility of C−H Bond Cleavage and KIE Experi-
ments. Subsequently, the reversibility of C−H bond cleavage
was examined, and we found that no D/H exchange occurred
in the reaction, revealing irreversible cleavage of the C−H
KIE (kinetic isotope effects) experiments were performed. As
shown in Figure S3, the KIE value of 1.2 in the presence of
MeOH indicated that the cleavage of the α-C(sp3)−H bond is
not the rate-determining step. In contrast, the cleavage of the
α-C(sp3)−H bond is the rate-determining step in the absence
of MeOH (KIE = 5), revealing that MeOH plays an important
role in the C−H bond activation step (Figure S4).
Proposed Mechanism. On the basis of the above results,
we proposed a mechanism, as shown in Figure 2e. With the
assistance of MeOH, clusters of AcOH (I) would separate.
Then, sulfide, AcOH, and MeOH assemble into new models as
illustrated by structure II in Figure 2. Hydrogen bonding
between a sulfur atom and AcOH can facilitate the oxidation of
sulfide, which accelerates the formation of a sulfur radical
cation (III) through a single-electron transfer. Subsequently,
self-assembly of these compounds allows MeOH to favorably
capture the proton from the sterically less hindered side (R1 >
R2CH2), forming the state IV with high regioselectivity. A
thionium ion is generated via loss of a proton and an electron
from the sulfur radical cation. Due to its strongly electrophilic
character, a thionium ion is susceptible to CH3COOH by
nucleophilic attack to form the desired product along with
hydrogen evolution at the cathode. In this transformation,
MeOH serves as a base to abstract hydrogen.
Substrate Scope for Carboxylic Acids. On the basis of
an understanding of this protocol, we sought to examine the
substrate scope with respect to acids. As is shown in Figure 3,
primary, secondary, and tertiary carboxylic acids were found to
be viable coupling partners (1−7). Functional groups that are
sensitive to nucleophilic substitution by CH3COO−, such as
cyclopropyl (8 and 10), cyclobutyl (9), alkyl chloride (11),
and alkyl bromide (77), were amenable to this protocol. To
our delight, fluorides with important applications in biological
detection, such as a fluoroalkyl substrate (9) and aryl fluorides
(20, 42, and 51) were also smoothly transformed into the
corresponding products. Moreover, reductively labile groups,
such as alkenyl, alkynyl, cyano, ester, sulfones, and
ketocarbonyl groups, were well tolerated, to chemoselectively
afford the desired products without the reduction byproducts
under electrochemical conditions (12−31). It is worth
mentioning that cinnamic acid and phenylpropiolic acid as
coupling partners performed well and afforded the correspond-
ing products (13 and 15) without the formation of unsaturated
addition products or hydrogenation products. Most impor-
tantly, highly regioselective C−H bond acyloxylation was
achieved instead of the C−H bond adjacent to the S(O)2
group, providing the desired products in high yield (30 and
31). On the other hand, the synergistic effect of this self-
assembly strategy was also amenable to various oxidatively
labile groups, such as alkenes, hydroxyl, electron-rich aromatic
rings, electron-rich heterocycles, etc. Mandelic acids reacted
smoothly with 1a, achieving the reaction of the carboxyl acid
rather than the hydroxyl group (32−34). Additionally, the
scope of this C−H bond acyloxylation protocol could be
extended to alkyl carboxylic acids which contain various
heterocycles (35−38). Subsequently, the scope of this
approach also included the classes of aryl carboxylic acids.
Steric and electronic effects have no obvious impact on the
efficiency of this protocol, delivering the corresponding
products in moderate to good yields (39−51). 2-Naphthoic
acid was successfully used to access the product of
acyloxylation (52). Furthermore, a series of heterocyclic
acids proved to be competent coupling products, as
exemplified by isoxazole carboxylic acid (53), thiophene
carboxylic acids (54−57) and furoic acids (58−62), further
highlighting the broader adaptability of this protocol.
Late-Stage Modification of Amino Acids and Phar-
maceutical Molecules. With the success of the unusually
broad scope, this method was applied to a more challenging
task. As shown in Figure 4, a series of α-amino acid derivatives
were amenable to this C−H bond acyloxylation at room
temperature (65−73). Moreover, β- and γ-amino acids proved
compatible as well to form the corresponding products in good
yields (74−76). As is known, carboxyl groups are widely found
in natural products, pharmaceuticals, and agrochemical
compounds. Interestingly, ibuprofen, ioxoprofen, and flurbi-
profen (used for the treatment of inflammation) reacted
smoothly with 1a to give the desired products in good yields at
room temperature (80−82). Lipid regulators, such as
ciprofibrate and bezafibrate, also proved to be suitable coupling
partners (83 and 88). Compound 86 can be accessed from
mycophenolate mofetil, which serves as a major immunosup-
pressive agent to prevent and treat the acute rejection of
transplanted organs. Additionally, N-Boc gabapentin, a novel
antiepileptic, was also examined under the standard conditions
and exhibited good efficiency (87). Other drugs containing
carboxyl groups such as levulinic acid, aspirin, probenecid, and
dehydrocholic acid were also evaluated (78, 79, 83, and 85),
further highlighting the utility of our methodology in modern
drug research.
Substrate Scope for Thioethers. The precise control of
regioselectivity is an important issue in the field of C−H bond
activation.14 The substrate scope for thioethers was then
evaluated (Figure 5). Satisfactorily, a high site selectivity of this
self-assembly protocol was shown among C(sp3)−H bonds
with comparable properties. First, sulfur-containing cyclic
ethers, alcohols, and N-Ts-thiomorpholine underwent C−H
bond acyloxylation exclusively at the α-sulfur C−H bond in
high yield, demonstrating precise site selectivity (89−92).
Moreover, acyloxylation of a terminal α-C−H bond to forge a
C−O bond was generally preferred over that of an internal α
C−H bond (93−97). Importantly, the reaction of aryl and
alkyl carboxylic acids with dimethyl sulfide (DMS) proceeded
smoothly to form the corresponding products (98−100) with
excellent efficiency, opening practical avenues for the
protection of carboxylic acids.15 Fortunately, this protocol
was also found to effectively functionalize various symmetrical
cyclic and chain sulfides, affording single site-selective C−H
bond acyloxylation products (101−105).
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J. Am. Chem. Soc. 2021, 143, 3628−3637