Decarboxylative Negishi Coupling of Redox-Active Aliphatic Esters by Cobalt Catalysis

Article abstract of DOI:10.1002/anie.201806799

A cobalt-catalyzed decarboxylative Negishi coupling 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 (±)-preclamol highlight the synthetic potential of this method. Mechanistic studies indicated that a radical mechanism is involved.

Full text of DOI:10.1002/anie.201806799

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Communications
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International Edition: DOI: 10.1002/anie.201806799
German Edition: DOI: 10.1002/ange.201806799
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
Honggen Wang*
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:
https://doi.org/10.1002/anie.201806799.
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Table 1: Scope of the cobalt-catalyzed decarboxylative alkyl–aryl and
alkyl–alkenyl cross-coupling reactions.[a]
catalyst. A number of ligands were screened, but no improve-
ment in the yield was observed.[15]
The scope of the reaction was explored extensively and
found to be quite broad (Table 1). Diaryl zinc reagents
bearing various functional groups were well tolerated,
providing the expected decarboxylative arylation products
7–21 in good yields. Diheteroaryl zinc compounds were also
applicable (products 22, 23). Besides p-toluenesulfonyl (Ts),
other commonly encountered amino protecting groups, such
as benzoyl (Bz; products 4, 8, 10, 12), carboxybenzyl (Cbz;
products 5, 13), and tert-butoxycarbonyl (Boc; products 6, 26)
were compatible. Other heterocyclic (products 24–27) and
cyclic secondary carboxylic acids (product 28), including
those bearing an a-heteroatom (products 26, 27), were all
viable substrates. Interestingly, N-protected phenylalanine
could also be used to deliver the corresponding product 29.
Primary alkyl carboxylic acids yielded the desired products
30–34 as well. In general, the reactions of primary and
secondary alkyl carboxylic acids showed comparable perfor-
mance to the nickel[6a,h] and iron[6h,7] protocols developed by
Baran and co-workers. However, in contrast to the protocol
based on iron catalysis, a tertiary carboxylic acid substrate
gave only a trace amount of product 35, thus demonstrating
a limitation of the current protocol. Product 18 is a valuable
intermediate for the synthesis of Q203, a potent clinical
candidate for the treatment of tuberculosis.[16]
The success of the decarboxylative arylation reaction
promoted us to further examine the feasibility of a similar
olefination reaction by treatment with alkenyl zinc reagents
(Table 1).[6f] Under the above standard reaction conditions,
the decarboxylative olefination reaction proceeded smoothly
with exquisite control of olefin geometry to afford products
36–53. Simple mono- (36–40, 51), di- (41–43, 46–49, 52, 53),
and trisubstituted olefins (44, 45, 50) could be accessed
readily, thus offering a simple and valuable retrosynthetic
strategy for olefin synthesis. Once again, an attempt to couple
a tertiary carboxylic acid substrate failed to give the desired
product 54.
Alkynes are fundamentally important in functional mol-
ecules and organic synthesis. Methods for their synthesis
through the transformation of aliphatic carboxylic acids
should find broad application. We found that the use of
[a] Reaction conditions: redox-active ester (0.2 mmol), R2Zn
(0.66 mmol), CoBr2 (10 mol%), in DMF (0.4m), room temperature;
yields are for the isolated product. [b] CoBr2 (40 mol%). [c] The alkenyl
zinc reagent was derived from a commercial Grignard reagent that exists
as a mixture of olefin isomers. [d] The zinc reagent was prepared from
the alkenyl bromide with a Z/E ratio of 1:1. Boc=tert-butoxycarbonyl,
Bz=benzoyl, Cbz=carboxybenzyl, DMF=N,N-dimethylformamide,
TBS=tert-butyldimethylsilyl, Ts=p-toluenesulfonyl.
dialkynyl zinc reagents as nucleophiles also led to efficient
3
À
C(sp ) C(sp) bond formation (Table 2). Thus, a diverse
arranges of silyl- (products 55–58), aryl- (products 62–73,
75, 76), and alkyl-substituted dialkynyl zinc reagents (prod-
ucts 59–61) were well-suited for the coupling reaction, giving
2
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Table 2: Scope of the cobalt-catalyzed decarboxylative alkyl–alkynyl
Primary carboxylic acids were also viable substrates for
cross-coupling reaction.[a]
coupling (products 78, 79). Likewise, the olefination and
alkynylation reactions could be carried out by following the
same synthetic operations to give 81 and 82, respectively
(Scheme 1a).
Scheme 1. In situ activation protocol and synthetic application.
DMAP=4-(dimethylamino)pyridine, TFA=trifluoroacetic acid.
[a] Reaction conditions: redox-active ester (0.2 mmol), R2Zn
(0.66 mmol), CoBr2 (20 mol%), in DMF (0.4m), room temperature,
15 h; yields are for the isolated product. [b] RZnOPiv (3.0 equiv) was
used. [c] RZnOPiv (4.0 equiv) was used. TES=triethylsilyl, TIPS=trii-
sopropylsilyl, TMS=trimethylsilyl.
To showcase the utility of our method, we attempted the
synthesis of the drug molecule (Æ)-preclamol. By using the in
situ activation protocol, N-Boc-piperidine-3-carboxylic acid
was first converted into the 3-arylated piperidine 83 in 50%
yield. Thereafter, the removal of the N-Boc protecting group
was followed by a reductive amination reaction by treatment
with propanal in the presence of NaBH3CN. Finally, the
methoxy ether was hydrolyzed under acidic conditions to
deliver the final product in 56% yield over three steps
(Scheme 1b).
Mechanistic studies were conducted to shed light on the
reaction mechanism. The involvement of radical intermedi-
ates in cobalt-catalyzed coupling reactions has been suggested
previously.[10] To verify this possibility, we subjected the
cyclopropyl-substituted substrate 1b to the reaction, and
a ring-opening arylation product 85 was produced (Sche-
me 2a). Furthermore, the reaction of 1c with 98% optical
purity led to complete racemization (Scheme 2b). Radical-
trapping experiments with TEMPO shut down the reactivity,
and a TEMPO adduct was detected by HRMS (Scheme 2c).
All these results were in agreement with a radical reaction
pathway.
the corresponding products in moderate to good yields.
Diethynylzinc was also applicable as a reagent, but resulted in
lower yield (product 74). In some cases, the use of alkynyl zinc
pivalates, recently introduced by Knochel and co-work-
ers,[10d,g,14b,17] gave better yields. Baran and co-workers
recently disclosed an elegant nickel-catalyzed decarboxyla-
tive coupling reaction of redox-active esters with alkynyl zinc
chlorides.[6j] Although ethynylzinc worked efficiently in their
method, other substituted alkynyl zinc reagents showed much
less efficiency. Our cobalt protocol is therefore complemen-
tary to the method developed by Baran and co-workers.
An in situ activation protocol was developed to shorten
the synthetic route. Thus, the free carboxylic acid was first
coupled with N-hydroxyphthalimide in the presence of N,N’-
diisopropylcarbodiimide (DIC) and DMAP in dichlorome-
thane (DCM). After evaporation of the volatile components
of the resulting mixture under vacuum, the residue was
subjected to the cobalt-catalyzed Negishi-type decarboxyla-
tive cross-coupling reaction. The arylated product 3 was
obtained in 62% yield, a yield slightly lower than that
observed for the preactivation protocol [75%, Eq. (1)].
On the basis of the above results and literature prece-
dent,[6–9] we propose the reaction mechanism in Scheme 3.
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Acknowledgements
Generous financial support from the Key Project of Chinese
National Programs for Fundamental Research and Develop-
ment (2016YFA0602900), the National Natural Science
Foundation of China (21472250 and 21502242), the National
Science and Technology Major Project of the Ministry of
Science and Technology of China (2018ZX09735010), and the
“1000-Youth Talents Plan” is gratefully acknowledged.
Conflict of interest
The authors declare no conflict of interest.
Scheme 2. Mechanistic studies. TEMPO=(2,2,6,6-tetramethylpiperi-
din-1-yl)oxyl.
À
Keywords: C C bond formation · cobalt · decarboxylation ·
Negishi coupling · redox-active esters
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Manuscript received: June 12, 2018
Version of record online: && &&, &&&&
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
À
C C Coupling
X.-G. Liu, C.-J. Zhou, E. Lin, X.-L. Han,
S.-S. Zhang, Q. Li,
H. Wang*
&&&& — &&&&
Decarboxylative Negishi Coupling of
Redox-Active Aliphatic Esters by Cobalt
Catalysis
Keen to couple: A cobalt-catalyzed
decarboxylative Negishi coupling reac-
tion of N-hydroxyphthalimide (NHPI)
esters with organozinc reagents enabled
efficient alkyl–aryl, alkyl–alkenyl, and
alkyl–alkynyl coupling under mild condi-
tions without an external ligand or addi-
tive (see scheme). The success of an in
situ activation protocol and the facile
synthesis of the drug molecule (Æ)-pre-
clamol highlight the potential of this
method.
6
www.angewandte.org
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2018, 57, 1 – 6
These are not the final page numbers!