for C(sp^2 )–H activation of nicotinic acids ( 26 );
cognizant of this, we examined five-membered
chelate analogs ofL5toL7to investigate
whether they could promote dehydrogenation
reactions through C(sp^3 )–H activation while
avoiding undesiredb-vinyl C–H activation. We
found that the yield of the dehydrogenation
reaction carried out with ligandL8increased
considerably to 71%. A deuterium exchange
experiment with the olefin product using this
five-membered chelating ligand did not incor-
porate deuterium at theb-vinyl position of the
olefin product in the presence of AcOH-d 4.
This suggests that activation of theb-vinyl
C(sp^2 )–H bond of 2-hexenoic acid is unfavorable
with ligandL8. On the basis of these observa-
tions and comparative DFT studies (detailed in
the supplementary materials), we propose that
although both five- and six-membered chelating
ligands are capable of enabling C(sp^3 )–H activa-
tion, the bite angle of the former (78.7°) disfavors
subsequent C(sp^2 )–H activation of the olefin
products compared with the latter (88.2°). Such
a difference in reactivity could be attributed to
the increased structural distortion withL8in
the corresponding C(sp^2 )–H cleavage transition
state (TS). Substituent effects on the ligands
were also surveyed (L8toL19), revealing that
ligands bearing a quinoline or isoquinoline
moiety (L8andL17) were superior, andL8
was chosen for subsequent investigations. Using
tert-amyl alcohol as a cosolvent, we were also
able to decrease Pd loading from 10 to 4% and
retain an 81% isolated yield for the desaturation
of hexanoic acid to 2-hexenoic acid.
Subsequently, dehydrogenation of a wide
range of free carboxylic acids withb-methylene
C–H bonds was carried out under optimizedconditions (Fig. 2). Simple linear and branched
aliphatic acids, such as butyric acid and 4-
methyloctanoic acid, provided the correspond-
inga,b-unsaturated acids in >75% yield with
exclusive generation of theE-isomer (2ato2f).
Carboxylic acids bearing ring systems also
produced the correspondinga,b-unsaturated
acids (2gto2k)inupto87%yield.tert-
butoxycarbonyl (Boc)–and toluenesulfonyl
(tosyl)–protected amines and various ethers
were all tolerated, giving the corresponding
products in good yields (2lto2p). Phenyl-
propanoic acids bearing bromo-, chloro-,
methylthio-, and Boc-protected amino sub-
stituents were successfully desaturated to the
corresponding enoic acids (2qto2u); a sub-
strate containing pyridine was also converted
to product in high yield (2v). Additionally,
phenylvaleric acid underwent smooth de-
hydrogenation to provide the corresponding
a,b-unsaturated acid (2w) in good yield.
Additionally, we found that the reaction was
effective for the dehydrogenation ofa-branched
carboxylic acid substrates, offering a comple-
mentary strategy to approaches on the basis
of enolate oxidation. Dehydrogenation of
2-phenylbutanoic acid and 2-ethylbutanoic
acid gave their corresponding dehydrogen-
ated products in 65 and 51% yield, respectively
(2xand2y).a,b-unsaturated acid2ygenerated
from 2-ethylbutanoic acid predominantly gave
theE-isomer. Isobutyric acid, a substrate with
only methyl C–Hbondsaccessible,gavemeth-
acrylic acid in 42% yield (2z). For carboxylic
acids bearing bothb-methyl andb-methylene
C–H bonds, we observed a slight preference
for reactivity at the methylene C–H bonds over
the methyl C–H bonds (2aa). Cyclopentane-
carboxylic acid and cyclohexanecarboxylic acid
were also viable substrates (2abto2ac). In a
complex setting, acetyl-protected lithocholic
acid was dehydrogenated in 56% yield (2ad).
Thesea,b-unsaturated acids are common build-
ing blocks and functional handles in synthetic
chemistry that are amenable to a wide range of
downstream derivatization, such as conjugate
addition, epoxidation, and dihydroxylation.
Notably, the dehydrogenation reaction was
also found to be selective for carboxylic acids
in the presence of enolizable ketones (2aeto
2ag) and esters (2ahto2ai), thus providing
orthogonal chemoselectivity to enolate-based
desaturation reactions ( 2 – 14 ). Ana-quaternary
substrate, 1-propylcyclohexane-1-carboxylic acid,
was also dehydrogenated and subsequently
coupledwithanacrylatetogiveacomplex
fused lactone (2aj). Upon further optimiza-
tion, this dehydrogenation reaction by means
ofb-C–H activation could lead to a synthetic
disconnection that is not possible using the
enolate pathway. Finally, we found that re-
placement of Ag 2 CO 3 by other practical oxi-
dants was also feasible. Several classes of
representative substrates afforded moderate1282 3 DECEMBER 2021•VOL 374 ISSUE 6572 science.orgSCIENCE
Fig 1. Dehydrogenation through CÐH activation.(A) Two pathways for dehydrogenation reactions.
(B) Limitations inb-C–H functionalization of free carboxylic acids. (C) Ligand-controlleda,b-dehydrogenation or
C–C coupling of aliphatic acids. R 1 ,R 2 ,R 3 , alkyl or aryl; M, metal; cat, catalyst; Ar, aryl; OAc, acetate; Me (methyl).
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