Communications
À
C C Coupling
Decarboxylative Negishi Coupling of Redox-Active Aliphatic Esters by
Cobalt Catalysis
Xu-Ge Liu, Chu-Jun Zhou, E. Lin, Xiang-Lei Han, Shang-Shi Zhang, Qingjiang Li, and
Abstract: A cobalt-catalyzed decarboxylative Negishi cou-
pling reaction of redox-active aliphatic esters with organozinc
reagents was developed. The method enabled efficient alkyl–
aryl, alkyl–alkenyl, and alkyl–alkynyl coupling reactions
under mild reaction conditions with no external ligand or
additive needed. The success of an in situ activation protocol
and the facile synthesis of the drug molecule (Æ)-preclamol
highlight the synthetic potential of this method. Mechanistic
studies indicated that a radical mechanism is involved.
tive catalyst enabling the effective coupling of aryl,[10]
alkenyl,[11] and alkynyl halides[12] (or their pseudohalides)
with organozinc compounds (Figure 1a). Nevertheless, the
use of unactivated alkyl electrophiles[13] in cobalt-catalyzed
Negishi coupling reactions is only recent.[14] In 2015, Knochel
T
ransition-metal-catalyzed cross-coupling reactions to forge
À
C C bonds are of vital importance in modern organic
synthesis.[1] While organohalides have enjoyed a success as
the electrophilic coupling partners, recent years have wit-
nessed a growing interest in the use of aliphatic carboxylic
acids (or their derivatives) as alkyl halide surrogates in such
reactions.[2] Advantages are apparent not only in the wide
availability of carboxylic acids, but also in that alkyl halides
are typically unstable, challenging to prepare, and undergo
oxidative addition to transition metals with difficulty. By
activating the carboxylic acid to the corresponding redox-
active ester, single-electron-transfer reduction is feasible to
generate an alkyl radical through the extrusion of CO2. This
radical-generation process has been involved in diverse
carbon–carbon and carbon–heteroatom bond forming reac-
tions based on single photocatalytic systems[3] or dual catalytic
systems[4] combining photoredox catalysis with transition-
metal catalysis.[5] Advances by the Baran research group
showed that low-valent first-row transition metals, including
nickel[6] and iron,[6h,g,7] were also effective in a broad range of
decarboxylative cross-coupling reactions without the need for
light irradiation. Very recently, a copper-catalyzed decarbox-
ylative radical silylation of redox-active aliphatic esters was
also developed.[8] Inspired by these elegant studies, we
reasoned that a low-valent cobalt catalyst could also donate
an electron to the redox-active ester,[9] thereby triggering
alkyl radical formation and a follow-up cross-coupling
reaction.
Figure 1. Cobalt-catalyzed Negishi cross-coupling reactions. Piv=piva-
loyl.
and co-workers reported an elegant cobalt-catalyzed cross-
coupling reaction of (hetero)aryl zinc reagents with primary
and secondary alkyl iodides; alkyl bromides were also
applicable but with lower efficiency.[14a] We report herein
a cobalt-catalyzed decarboxylative Negishi coupling of acti-
vated aliphatic carboxylic acids under mild reaction condi-
tions (Figure 1b). The reaction allowed the synthesis of
a broad range of alkylated arenes, alkenes, and alkynes by
reactions with aryl zinc, alkenyl zinc, and alkynyl zinc
reagents, respectively. In a decarboxylative alkynylation
study reported by Baran and co-workers, Co(acac)2 was
shown to provide the desired product in 30% yield.[6j]
Cobalt, as an earth-abundant and low-toxic first-row
transition metal, has been previously identified as an attrac-
We initiated our study by focusing on the coupling
reaction of piperidine N-hydroxyphthalimide (NHPI) ester
1 with diaryl zinc reagent 2. Systematic examination of
different reaction parameters revealed that with CoBr2
(10 mol%) as the catalyst in DMF at room temperature, the
desired coupling product 3 could be formed in 75% yield
[Eq. (1)].[15] The use of the tetrachloro-substituted NHPI
ester TCNHP was also effective, but resulted in lower yield
(44%). While the use of ultrapure CoBr2 (99.99% purity)
gave a similar yield, the omission of the catalyst led to no
reaction, thus confirming that the cobalt salt is the active
[*] Dr. X.-G. Liu, C.-J. Zhou, E. Lin, X.-L. Han, S.-S. Zhang, Dr. Q. Li,
Prof. H. Wang
School of Pharmaceutical Sciences, Sun Yat-sen University
Guangzhou 510006 (China)
E-mail: wanghg3@mail.sysu.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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