Bimetallic Cooperative Catalysis for Decarbonylative Heteroarylation of Carboxylic Acids via C-O/C-H Coupling

Article abstract of DOI:10.1002/anie.202100949

Cooperative bimetallic catalysis is a fundamental approach in modern synthetic chemistry. We report bimetallic cooperative catalysis for the direct decarbonylative heteroarylation of ubiquitous carboxylic acids via acyl C-O/C-H coupling. This novel catalytic system exploits the cooperative action of a copper catalyst and a palladium catalyst in decarbonylation, which enables highly chemoselective synthesis of important heterobiaryl motifs through the coupling of carboxylic acids with heteroarenes in the absence of prefunctionalization or directing groups. This cooperative decarbonylative method uses common carboxylic acids and shows a remarkably broad substrate scope (>70 examples), including late-stage modification of pharmaceuticals and streamlined synthesis of bioactive agents. Extensive mechanistic and computational studies were conducted to gain insight into the mechanism of the reaction. The key step involves intersection of the two catalytic cycles via transmetallation of the copper–aryl species with the palladium(II) intermediate generated by oxidative addition/decarbonylation.

Full text of DOI:10.1002/anie.202100949

Angewandte
Research Articles
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 10690–10699
International Edition:
German Edition:
doi.org/10.1002/anie.202100949
doi.org/10.1002/ange.202100949
Cooperative Catalysis Very Important Paper
Bimetallic Cooperative Catalysis for Decarbonylative Heteroarylation
of Carboxylic Acids via C-O/C-H Coupling
Chengwei Liu, Chong-Lei Ji, Tongliang Zhou, Xin Hong,* and Michal Szostak*
Abstract: Cooperative bimetallic catalysis is a fundamental
approach in modern synthetic chemistry. We report bimetallic
cooperative catalysis for the direct decarbonylative heteroar-
ylation of ubiquitous carboxylic acids via acyl C-O/C-H
coupling. This novel catalytic system exploits the cooperative
action of a copper catalyst and a palladium catalyst in
decarbonylation, which enables highly chemoselective syn-
thesis of important heterobiaryl motifs through the coupling of
carboxylic acids with heteroarenes in the absence of prefunc-
tionalization or directing groups. This cooperative decarbon-
ylative method uses common carboxylic acids and shows
a remarkably broad substrate scope (> 70 examples), including
late-stage modification of pharmaceuticals and streamlined
synthesis of bioactive agents. Extensive mechanistic and
computational studies were conducted to gain insight into the
mechanism of the reaction. The key step involves intersection
have had a major impact on the advancement of organic
chemistry (Figure 1B). Methods such as Paal-Knorr syn-
thesis,[6,7] Hantzsch pyridine synthesis[8] and Fischer indole
synthesis[9] are utilized on daily basis in the repertoire of
practicing synthetic chemists. Modern academic and indus-
trial studies on heterocyclic chemistry have been focused on
the development of strategies for the synthesis of heterobiaryl
motifs owing to the privileged nature of biaryls[4,5] and their
pervasive presence in many pharmaceuticals, agrochemicals,
natural products, organic materials and ligands for transition-
metal-catalysis (Figure 1B).[10]
The most straightforward and efficient approach for the
synthesis of heterobiaryls hinges upon transition-metal-cata-
lyzed cross-coupling between haloarene/heteroarene or
equivalent and metalated arene/heteroarene (Figure 1C,
top).[4,5] Later, significant progress has been made by enabling
À
of the two catalytic cycles via transmetallation of the copper– direct C H bond arylation of heteroarenes.[11] Carboxylic acid
aryl species with the palladium(II) intermediate generated by
oxidative addition/decarbonylation.
derivatives can be employed as electrophiles in the cross-
coupling with heterocycles, including acyl fluorides,[12] acyl
chlorides,[13] esters,[14] and amides[15] (Figure 1C, top).[16–20]
In the past years, the field of decarbonylative cross-
coupling has experienced a rapid growth, in part owing to the
high efficiency of generating aryl-metal intermediates.[21] Due
to the undesired generation of activated starting materials in
an additional synthetic step, the direct use of ubiquitous
carboxylic acids has the major advantage over other precur-
sors.[21] In recent years, elegant studies on decarboxylative
cross-coupling of carboxylic acids have been disclosed, which
employ carboxylic acids as nucleophilic coupling part-
ners.[21–23] However, in many cases, steric and electronic
effects limit the development and application of this platform,
which is favored for electron-deficient or sterically-hindered
carboxylic acids.[23] As a result, there is high demand for
general and broadly applicable cross-coupling methods of
carboxylic acids.
Decarbonylative cross-coupling of carboxylic acids can be
traced to the work by de Vries in 1998 in the decarbonylative
Heck reaction after conversion to symmetrical anhydrides,[24]
followed by several studies demonstrating the utility of this
attractive cross-coupling platform.[21–25] However, despite the
distinct advantages of carboxylic acids as cross-coupling
partners and the urgent demand for the efficient methods
for the construction of valuable biaryl heterocycles, the
decarbonylative synthesis of heterobiaryls from carboxylic
acids is unknown.
Introduction
Heterocyclic compounds are molecular structures that
contain at least two different elements in the ring, and are
used as indispensable motifs across various facets of chemis-
try.[1] Heterocyclic chemistry is crucial in the preparation of
new pharmaceutical agents, myriad of industrial products and
polymers.[2,3] In comparison to the carbon-only backbone,
heteroatoms engender the unique electronic and steric
properties that have been particularly attractive in various
fields of life sciences and technology, including pharmaceut-
icals, natural products, agrochemicals and functional materi-
als.[4,5] It is noteworthy that a major percentage of commercial
drugs relies on heterocyclic compounds (Figure 1A).[2a]
The widespread application of heterocycles as the back-
bone of a broad range of biologically active compounds has
accelerated the demand for new technologies. Over the last
decades, classic approaches for the synthesis of heterocycles
[*] Dr. C. Liu, T. Zhou, Prof. Dr. M. Szostak
Department of Chemistry, Rutgers University
73 Warren Street, Newark, NJ 07102 (USA)
E-mail: michal.szostak@rutgers.edu
Homepage: http://chemistry.rutgers.edu/szostak/
C.-L. Ji, Prof. Dr. X. Hong
Department of Chemistry, Zhejiang University
Hangzhou, 310027 (China)
We proposed that the palladium-catalyzed decarbonyla-
tive heteroarylation of carboxylic acids for the synthesis of
heterobiaryls will offer a general and practical methodology
for the synthesis of biaryl motifs from carboxylic acids, while
at the same time exploiting the utility of the powerful
E-mail: hxchem@zju.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.202100949.
10690
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 10690 –10699

Angewandte
Research Articles
Chemie
Figure 1. Cooperative decarbonylative heteroarylation of carboxylic acids via C-O/C-H coupling.
decarbonylative activation mode of carboxylic acids (Fig-
ure 1C, bottom).
scope, prefunctionalization to form boronic acids is required
for the cross-coupling.[41–43] With the continuous evolution of
In the context of biaryl synthesis, rhodium catalysis has
represented a particularly robust strategy for the construction
the field and the high demand for biaryl heterocycles, we
anticipated that the direct implementation of heteroarenes as
nucleophiles without prefunctionalization or directing groups
in decarbonylative cross-coupling of carboxylic acids via
À
of C C bonds via direct C-H activation with the assistance of
directing groups.[26–29] Rhodium-catalyzed decarbonylative
arylation of carboxylic acids via C-H coupling with the
assistance of directing groups has been reported (Fig-
ure 1D).[30,31] However, N-heterocyclic directing groups are
necessary for coordination of the rhodium catalyst. Palladium
and nickel catalysis have been considered as versatile catalytic
systems for arylation reactions.[32–39] In 2019, we reported the
palladium-catalyzed decarbonylative Suzuki–Miyaura cross-
coupling of carboxylic acids with boronic acids as arylating
reagents (Figure 1D).[40] While the protocol showed broad
À
À
C O/C H bond activation would allow for a broad range of
heterobiaryls to be accesses from abundant carboxylic acid as
electrophilic cross-coupling partners (Figure 1D, bottom).
As a critical advantage, the bimetallic cooperative catal-
ysis was proposed via two catalytic cycles (Figure 1E): (i) a
copper catalyst would first coordinate to the Lewis-basic
group on heterocycle, leading to the heterocycle-Cu species
by C-H activation; (ii) a palladium catalyst would insert into
À
the acyl C O bond of the carboxylic acids that has been
Angew. Chem. Int. Ed. 2021, 60, 10690 –10699
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org 10691

Angewandte
Research Articles
Chemie
activated in situ to give ArCOOPiv. The acyl-Pd-OPiv
intermediate would next undergo decarbonylation to form
Ar-Pd-OPiv intermediate. Finally, the two catalytic cycles
electron-donating (3d) and electron-deficient carboxylic
acids (3e–3 f) underwent the coupling in excellent yields. It
is noteworthy that electrophilic groups that would be
would intersect during the transmetallation of the copper– problematic in classical addition of highly nucleophilic
aryl species with the palladium(II) intermediate to generate
the final heterobiaryl product after reductive elimination. The
transformation is distinct from previous studies by engaging
cooperative cycle and decarbonylative acyl coupling of
carboxylic acid anhydrides, which permits readily available
carboxylic acids to be coupled with heteroarenes by direct
deprotonation.
organomagnesium or organolithium organometallics, such
as esters (3g), ketones (3h), aldehydes (3i) and nitriles (3j)
could be readily employed. Remarkably, synthetic handles for
further functionalization by cross-coupling, such as tosyl (3k)
and chloride (3l) are well-compatible, resulting in 97% and
77% yields. Furthermore, sterically-hindered carboxylic acids
(3m–3p) are well-tolerated. Moreover, unbiased substrates
functionalized at the meta position, including esters (3q),
ketones (3r), nitriles (3s), chlorides (3t) and alkyl groups
(3u) are perfectly compatible in this cooperative transforma-
tion. Importantly, cinnamic acids (3v–3x) could also be used
in this decarbonylative platform to deliver styryl-heterocyclic
motifs in good to excellent yields. Likewise, this approach
permits for the synthesis of the challenging bis-heterocylic
biaryls directly from heterocycles and heterocyclic carboxylic
acids (3y–3ab). Finally, this catalytic system can also accom-
modate the synthesis of hetero-terphenyls (3ac) and ex-
tremely hindered carboxylic acids, such as mesityl (3ad),
demonstrating high level of compatibility in decarbonylative
transfer via C-O/C-H activation.
Noteworthy features of our study include: (1) direct use of
À
À
ubiquitous carboxylic acids via robust C O/C H bond
activations; (2) high chemoselectivity in the absence of
prefunctionalization or directing groups; (3) bimetallic coop-
erative catalysis under decarbonylative regimen; (4) remark-
ably broad substrate scope, including late-stage modification
of pharmaceuticals and streamlined synthesis of bioactive
agents; (5) mechanistic studies providing key insights into the
mechanism of the bimetallic decarbonylative catalysis plat-
form.
Results and Discussion
To demonstrate the functional group compatibility of the
heterocyclic component, we next investigated the scope of
heterocycles amenable to this cooperative coupling (Fig-
ure 2B). To our delight, various five-membered heterocycles
containing nitrogen, oxygen and sulfur, such as benzothia-
zoles (3ae, 3ak, 3aq), benzimidazoles (3af, 3al, 3ar),
oxazoles (3ag, 3am, 3as), thiazoles (3ah–3ai, 3an-3ao, 3at-
3au) and imidazoles (3aj, 3ap, 3av) are compatible with this
method, offering direct access to various heterobiaryl motifs.
As a further demonstration of this strategy, we applied
this cooperative decarbonylative coupling to the direct, late-
stage functionalization of pharmaceuticals (Figure 3). The
synthesis of heterobiaryls from (Adapalene, 3aw), (Bexar-
otene, 3ax), (Tamibarotene, 3ay), (Repaglinide, 3az), (Di-
flufenican, 3ba), (Probenecid, 3bb), (Febuxostat, 3bc),
(Tocopherol, 3bd), (Menthol, 3be) and (Cholosterol, 3bf)
using various heterocycles, such as benzoxazole (3be–3bf),
benzimidazole (3bg), imidazole (3bh), 4-carboethoxyoxazole
(3bi), oxadiazole (3bj), oxazole (3bk), benzothiazole (3bl),
benzimidazole (3bm), thiazole (3bn), 4-carbo-tert-butoxy-
thiazole (3bo) and 1,3,7-trimethylxanthine (3bp) demon-
strates the excellent functional group tolerance of this
cooperative platform and strongly emphasizes the synthetic
utility of the coupling approach directly exploiting readily
available carboxylic acids as electrophilic synthetic handles.
At the present stage, electron-withdrawing substituents on
the heterocycle component are well-tolerated (Adapalene,
3bi), while electron-donating groups lead to lower yields.
The proposed palladium/copper catalyzed decarbonyla-
tive heteroarylation of carboxylic acids was examined using
benzoxazole (1a) and benzoic acid (2a) as model substrates
(Supporting Information). To our delight, after very extensive
optimization, we identified the combination of Pd(OAc)2
(2.5 mol%), CuF2 (10 mol%) and dppb (5 mol%) in the
presence of DMAP (1.5 equiv) and Piv2O (1.5 equiv) in
dioxane at 1608C as the optimum system to deliver the
desired heterobiaryl product (3a) in 92% isolated yield
(Figure 2).
A summary of the optimization results is shown in the
Supporting Information. Several optimization results are
worth noting: (1) the use of either palladium or copper alone
results in negligible conversion (< 5%); (2) Dppb is the
preferred ligand (96% yield); however, dppe (87%), dppp
(72%), DPEPhos (61%) and dppf (93%) are also effective;
(3) Among various copper salts examined, CuF2 is the
preferred catalyst; however CuBr (61%), CuCl (63%),
CuCN (58%), CuSO4 (43%), Cu(OAc)2 (56%) and
Cu(OTf)2 (71%) also gave good to high yields; (4) The
reaction is performed in the absence of an external inorganic
base with pivalate acting as an internal base; (5) DMAP is the
preferred Lewis base; however, the coupling is possible in the
absence of DMAP (40% yield); (6) In all cases examined, the
formation of heterobiaryl ketones (acyl coupling) was not
observed, consistent with the high capacity of the cooperative
system to facilitate decarbonylation.
À
With optimized conditions in hand, we next investigated
the scope of carboxylic acids in this cooperative methodology
for the synthesis of heterobiaryls using readily available
carboxylic acids and heterocyclic substrates (Figure 2A). As
shown, the scope of this approach is very broad, including
excellent functional group tolerance to various sensitive
electrophilic groups. Thus, various electron-neutral (3a–3c),
Moreover, considering the similarity of the acidic C H
bond character between heterocycles and polyfluorinated
arenes,[44] we investigated the decarbonylative arylation of
pentafluorobenzene using carboxylic acids as electrophiles
(Figure 4A). To our delight, a range of carboxylic acid
substrates could be converted to the polyfluorinated biaryl or
10692 www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 10690 –10699

Angewandte
Research Articles
Chemie
Figure 2. Scope of cooperative decarbonylative heteroarylation of carboxylic acids via C-O/C-H coupling. [a] Conditions: Pd(OAc)2 (2.5 mol%),
CuF2 (10 mol%), dppb (5 mol%), DMAP (1.5 equiv), piv2O (1.5 equiv). [b] Pd(OAc)2 (5.0 mol%), CuF2 (20 mol%), dppb (10 mol%), DMAP
(3.0 equiv), piv2O (3.0 equiv). For details, see the Supporting Information.
styrenyl products without modification of the reaction con-
ditions.
To illustrate the utility of this cooperative decarbonylative
method in the synthesis of biologically active agents, we
applied this protocol to the synthesis of hetero-terphenyl 3bh,
a selective COX-2 inhibitor with the activity comparable to
that of Celecoxib (Figure 4E, IC50 = 0.67).[48] Thus, the
Suzuki–Miyaura coupling followed by cooperative decarbon-
ylative heteroarylation permits for a convergent approach to
introduce the heterocyclic biaryl scaffold without modifica-
tion of the reaction conditions. Furthermore, the cooperative
decarbonylative heteroarylation of 4-oxo-4H-chromene-2-
carboxylic acid delivered the bis-heterobiaryl chromenone
derivative 3bi, a class of bis-heterocycles that are used for the
diagnosis of amyloid related disease as specific PET imaging
probes (Figure 4F).[49]
Considering the remarkably broad scope and prospective
applications of the cooperative decarbonylative coupling of
carboxylic acids, we sought to gain insight into the reaction
mechanism of this intriguing process. Consequently, we
conducted a series of stoichiometric and DFT studies (vide
infra). Stoichiometric studies are summarized in Figure 5.
To demonstrate the utility of this robust cooperative
decarbonylative platform, we performed a series of sequential
transformations deploying the carboxylic acid functional
group as a directing handle (Figure 4B–D). Thus, the ortho-
C-H arylation directed by the carboxylic acid group,[45]
followed by cooperative decarbonylative heteroarylation
under standard reaction conditions delivered ortho-hetero-
terphenyls, which are used as heat storage agents (Figure 4B).
Next, traceless toluene oxidation/cooperative heterobiaryl
coupling delivered the para-heteroterphenyl product exploit-
ing an alkyl group as a carboxylic acid equivalent in a formal
[46]
À
C C bond activation (Figure 4C). Furthermore, electro-
philic meta-C-H functionalization of benzoic acids is readily
achieved by SNAr, which enables for orthogonal sequential
couplings on the benzoic acid template as exemplified in the
Suzuki–Miyaura cross-coupling/heterobiaryl coupling under
standard conditions (Figure 4D).[47]
Angew. Chem. Int. Ed. 2021, 60, 10690 –10699
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org 10693

Angewandte
Research Articles
Chemie
Figure 3. Late-stage functionalization of pharmaceuticals via cooperative decarbonylative C-O/C-H coupling. [a] Conditions: Pd(OAc)2 (2.5 mol%),
CuF2 (10 mol%), dppb (5 mol%), DMAP (1.5 equiv), piv2O (1.5 equiv). For details, see the Supporting Information.
(1) To rule out the pathway by ketone decarbonylation,[50] we
prepared heterobiaryl ketone 3a’ and subjected this
substrate to the standard coupling conditions, resulting
in close to quantitative recovery of starting material; the
decarbonylative product was not formed under the
reaction conditions (< 2%) (Figure 5A). This experi-
ment is also consistent with decarbonylation prior to
transmetallation (vide infra).
(2) To gain insight into the proposed transmetallation step,
we prepared 2-benzoxazolyl copper,[12] and subjected this
compound to the coupling conditions in the presence of
benzoic acid, Piv2O and a palladium catalyst, which
resulted in the formation of the desired heterobiaryl
product in 97% yield (Figure 5B). This experiment is
consistent with copper to palladium transmetallation in
the reaction mechanism.
(3) To investigate the effect of the copper catalyst, we
performed the coupling using well-defined [Cu(IPr)Cl]
and [Cu(dppb)I] catalysts, which resulted in 51% and
30% yield of the heterobiaryl product (Figure 5C). These
experiments indicate that well-defined sources of copper
could catalyze the reaction, consistent with heterocycle
C-H activation by the copper catalyst.[11a,44]
(4) To investigate the active species formed from the
carboxylic acid, we prepared ArCO2Piv as the proposed
intermediate and subjected this substrate to the reaction
conditions, resulting in 90% yield of the heterobiaryl
product (Figure 5D). This experiment is consistent with
10694 www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 10690 –10699

Angewandte
Research Articles
Chemie
Figure 4. Synthetic applications of cooperative decarbonylative heteroarylation of carboxylic acids via C-O/C-H coupling.
activation of the carboxylic acid to give ArCO2Piv as the
active intermediate.
more reactive than unsubstituted benzoic acids (Fig-
ure 5H). The increased steric demand of acyl-metal
(5) Next, in order to gain insight into the copper catalyst, we
performed the coupling using CuCl and CuCl2 under the
standard conditions (Figure 5E). The reaction resulted in
a similar conversion (CuCl: 63%; CuCl2: 66%) demon-
strating that copper catalysts at both I and II oxidation
state are suitable.
(6) To investigate the observed selectivity in the coupling, we
performed a series of stoichiometric competition experi-
ments (Figure 5F–H). Thus, competition experiments
between different heterocycles revealed the following
order of reactivity: benzoxazole > oxazole > benzothia-
zole > benzimidazole > imidazole (Figure 5F–G), which
complexes favors decarbonylation[21] (vide infra).
Computational studies. To further understand this coop-
erative decarbonylative coupling, we performed DFT calcu-
lations on the catalytic cycle. The DFT-computed free energy
profile of the operative pathway is shown in Figure 6A. From
the anhydride-coordinated complex int1, the oxidative addi-
À
tion via TS2 cleaves the acyl C O bond and generates the
acylpalladium(II) intermediate int3. Subsequent decarbon-
ylation via TS4 leads to the CO-coordinated species int5, and
CO dissociates to generate the arylpalladium(II) intermedi-
ate int6. int6 complexes with the arylcopper intermediate int7
to form the bimetallic complex int8. This complexation from
int6 to int8 is endergonic by 11.3 kcalmolÀ1 because the
15.1 kcalmolÀ1 endergonicity of the arylcopper generation
(int15 to int7) is included; the energy reference for the
arylcopper intermediate int7 is the stable LCuF(oxazole)
species int15. From int8, the transmetallation via TS9 leads to
the biarylpalladium(II) intermediate int10. int10 dissociates
the copper(I)pivalate int11, and subsequent C-C reductive
À
is consistent with the relative C H bond acidity (benzox-
azole, pKa = 24.8; oxazole, pKa = 27.7; benzothiazole,
pKa = 27.8; thiazole, pKa = 29.4; N-Me-benzimidazole,
pKa = 32.1; N-Me-imidazole, pKa = 33.7).[44] Competition
experiments between differently substituted benzoic
acids revealed that electron-deficient carboxylic acids
are inherently more reactive than their electron-rich
counterparts, while sterically-hindered benzoic acids are
Angew. Chem. Int. Ed. 2021, 60, 10690 –10699
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org 10695

Angewandte
Research Articles
Chemie
Figure 5. Mechanistic studies in cooperative decarbonylative heteroarylation of carboxylic acids via C-O/C-H coupling.
elimination via TS13 produces the product-coordinated com-
plex int14. int14 eventually liberates the cross-coupling
product and regenerates the catalytic active species int1.
Based on the computed free energy profile, the on-cycle
resting state is the acylpalladium(II) intermediate int3. The
rate-determining step is the transmetallation via TS9, which
requires an overall barrier of 28.7 kcalmolÀ1 comparing with
the resting state int3.
(I) int7 generation, which are summarized in Figure 6B. The
out-sphere and inner-sphere deprotonations with copper-
(I)pivalate are both less favorable via TS20 and TS23
respectively. On the basis of mechanistic and DFT studies
we proposed the catalytic cycle shown in Figure 7.
Conclusion
The DFT-computed free energy changes of the
arylcopper(I) int7 generation is presented in Figure 6A.
From the LCuF(oxazole) species int15, the out-sphere
deprotonation by pivalate anion occurs through TS16, which
generates the anionic arylcopper intermediate int17. Int17 has
the coordinated pivalic acid quenched by DMAP, and the
anionic arylcopper(I)F species dissociates the fluoride anion
to produce the arylcopper(I) int7. This fluoride dissociation is
necessary to provide the required coordination site of the
arylcopper species int7 in the complexation with arylpalla-
dium intermediate int6. Our calculations suggest that the
generation of int7 is quite facile, requiring a 14.9 kcalmolÀ1
barrier for the out-sphere deprotonation via TS16. This
In conclusion, we have reported a bimetallic cooperative
system for the direct decarbonylative heteroarylation of aryl
À
À
carboxylic acids via C O/C H bond activation. Thus, a coop-
erative action of palladium and copper catalysts in decarbon-
ylation permits for the synthesis of privileged heterobiaryls
with a broad substrate scope and excellent functional group
tolerance. The prospective impact of this synthetic platform
was showcased in the late-stage modification of pharmaceut-
icals and streamlined synthesis of bioactive motifs, directly
exploiting the pervasive presence of the carboxylic acid
moiety in drugs and common synthetic motifs. Extensive
mechanistic studies and DFT provided insight into the
catalytic mechanism, whereby the two catalytic cycles merge
via transmetallation of the copper–aryl species with the
palladium(II) intermediate. The power of this bimetallic
À
indicates that the Cu-catalyzed C H bond activation is not
rate-determining in the cooperative catalysis. We also con-
sidered a number of alternative pathways for the arylcopper-
10696 www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 10690 –10699

Angewandte
Research Articles
Chemie
Figure 6. DFT calculations of cooperative decarbonylative heteroarylation of carboxylic acids via C-O/C-H coupling.
advantage of carboxylic acids as electrophilic components in
cross-coupling reactions,[51] this method should have broader
implications for the development of decarbonylative cou-
plings and the rapid synthesis of heterobiaryl building blocks.
Further studies on cooperative decarbonylative catalysis are
currently underway and will be reported in due course.
Acknowledgements
We thank the NIH (1R35GM133326, M.S.), the NSF (CA-
REER CHE-1650766, M.S.), Rutgers University (M.S.),
NSFC (21702182 and 21873081, X.H.), Fundamental Re-
search Funds for the Central Universities (X.H.), and
Zhejiang University (X.H.) for generous financial support.
The Bruker 500 MHz spectrometer used in this study was
supported by the NSF-MRI (CHE-1229030). Additional
support was provided by the Rutgers Graduate School in
the form of a Deanꢀs Dissertation Fellowship (C.L.). Calcu-
Figure 7. Proposed catalytic cycle.
decarbonylative coupling approach is reflected by efficient
couplings across a range of heteroarenes and benzoic acids as
electrophiles that are beyond decarboxylative generation of
aryl nucleophiles from carboxylic acids. Considering the great
Angew. Chem. Int. Ed. 2021, 60, 10690 –10699
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org 10697

Angewandte
Research Articles
Chemie
[15] For decarbonylative heteroarylation of amides, see: P.-X. Zhou,
S. Shi, J. Wang, Y. Zhang, C. Li, C. Ge, Org. Chem. Front. 2019, 6,
1942 –1947.
lations were performed on the high-performance computing
system at the Department of Chemistry, Zhejiang University.
[16] For reviews on cross-coupling of amides, see: a) C. Liu, M.
Szostak, Chem. Eur. J. 2017, 23, 7157 –7173; b) G. Li, S. Ma, M.
Szostak, Trends Chem. 2020, 2, 914 –928.
Conflict of interest
[17] a) C. Liu, G. Meng, Y. Liu, R. Liu, R. Lalancette, R. Szostak, M.
Szostak, Org. Lett. 2016, 18, 4194 –4197; b) C. Liu, G. Li, S. Shi,
G. Meng, R. Lalancette, R. Szostak, M. Szostak, ACS Catal.
2018, 8, 9131 –9139; c) C. Liu, S. Shi, Y. Liu, R. Liu, R.
Lalancette, R. Szostak, M. Szostak, Org. Lett. 2018, 20, 7771 –
7774; d) C. Liu, R. Lalancette, R. Szostak, M. Szostak, Org. Lett.
2019, 21, 7976 –7981.
The authors declare no conflict of interest.
À
À
Keywords: bimetallic catalysts ·carboxylic acids ·C O/C
H bond activation ·decarbonylation ·heteroarylation
[18] G. Meng, M. Szostak, Angew. Chem. Int. Ed. 2015, 54, 14518 –
14522; Angew. Chem. 2015, 127, 14726 –14730.
[19] S. Shi, G. Meng, M. Szostak, Angew. Chem. Int. Ed. 2016, 55,
6959 –6963; Angew. Chem. 2016, 128, 7073 –7077.
[20] C. Liu, M. Szostak, Angew. Chem. Int. Ed. 2017, 56, 12718 –
12722; Angew. Chem. 2017, 129, 12892 –12896.
[1] a) J. A. Joule, K. Mills, Heterocyclic Chemistry, Wiley-Blackwell,
Oxford, 2013; b) S. Noel, S. Cadet, E. Gras, C. Hureau, Chem.
Soc. Rev. 2013, 42, 7747 –7762; c) Z. Jin, Nat. Prod. Rep. 2013,
30, 869 –915; d) D. C. Palmer, Oxazoles: Synthesis Reactions and
Spectroscopy, Part A, Wiley, Hoboken, 2003; e) D. C. Palmer,
Oxazoles: Synthesis Reactions and Spectroscopy, Part B, Wiley,
Hoboken, 2004; f) L. D. Luca, Curr. Med. Chem. 2006, 13, 1 –23;
g) M. R. Grimmett, Imidazole and Benzimidazole Synthesis,
Academic Press, London, 1997.
[2] a) N. A. McGrath, M. Brichacek, J. T. Njardarson, J. Chem.
Educ. 2010, 87, 1348 –1349; b) C. Cabrele, O. Reiser, J. Org.
Chem. 2016, 81, 10109 –10125; c) T. Cernak, K. D. Dykstra, S.
Tyagarajan, P. Vachal, S. W. Krska, Chem. Soc. Rev. 2016, 45,
546 –576; d) D. C. Blakemore, L. Castro, I. Churcher, D. C.
Rees, A. W. Thomas, D. M. Wilson, A. Wood, Nat. Chem. 2018,
10, 383 –394.
[3] a) S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451 –
3479; b) D. G. Brown, J. Bostrçm, J. Med. Chem. 2016, 59, 4443 –
4458; c) E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem.
2014, 57, 10257 –10274.
[4] For reviews, see: a) K. C. Nicolaou, P. G. Bulger, D. Sarlah,
Angew. Chem. Int. Ed. 2005, 44, 4442 –4489; Angew. Chem.
2005, 117, 4516 –4563; b) J. Hassan, M. Sevignon, C. Gozzi, E.
Schulz, M. Lemaire, Chem. Rev. 2002, 102, 1359 –1470; c) D.
Alberico, M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174 –
238.
[5] For reviews on direct C-H functionalization of heteroaromatic
compounds, see: a) L.-C. Campeau, K. Fagnou, Chem. Commun.
2006, 1253 –1264; b) D. A. Colby, R. G. Bergman, J. A. Ellman,
Chem. Rev. 2010, 110, 624 –655; c) L. Ackermann, R. Vicente,
A. R. Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792 –9826;
Angew. Chem. 2009, 121, 9976 –10011; d) X. X. Guo, D. W. Gu,
Z. Wu, W. Zhang, Chem. Rev. 2015, 115, 1622 –1651.
[6] C. Paal, Ber. Dtsch. Chem. Ges. 1884, 17, 2756 –2767.
[7] L. Knorr, Ber. Dtsch. Chem. Ges. 1884, 17, 2863 –2870.
[8] A. Hantzsch, Chem. Ber. 1881, 14, 1637 –1638.
[9] E. Fischer, F. Jourdan, Ber. Dtsch. Chem. Ges. 1883, 16, 2241 –
2245.
[10] For a recent study, see: S. Lee, S. B. Park, Org. Lett. 2009, 11,
5214 –5217.
[11] a) J. Huang, J. Chan, Y. Chen, C. J. Borths, K. D. Baucom, R. D.
Larsen, M. M. Faul, J. Am. Chem. Soc. 2010, 132, 3674 –3675;
b) J. Canivet, J. Yamaguchi, I. Ban, K. Itami, Org. Lett. 2009, 11,
1733 –1736; c) K. Muto, J. Yamaguchi, K. Itami, J. Am. Chem.
Soc. 2012, 134, 169 –172.
[21] For reviews on decarbonylative cross-coupling, see: a) H. Lu,
T. Y. Yu, P. F. Xu, H. Wei, Chem. Rev. 2021, 121, 365 –411;
b) W. I. Dzik, P. P. Lange, L. J. Gooßen, Chem. Sci. 2012, 3,
2671 –2678; For reviews on decarboxylative cross-coupling of
carboxylic acids, see: c) L. J. Gooßen, N. Rodriguez, K. Gooßen,
Angew. Chem. Int. Ed. 2008, 47, 3100 –3120; Angew. Chem.
2008, 120, 3144 –3164; d) N. Rodríguez, L. J. Gooßen, Chem.
Soc. Rev. 2011, 40, 5030 –5048; e) Y. Wei, P. Hu, M. Zhang, W.
Su, Chem. Rev. 2017, 117, 8864 –8907.
[22] For decarboxylative heteroarylation, see: a) F. Zhang, M. F.
Greaney, Angew. Chem. Int. Ed. 2010, 49, 2768 –2771; Angew.
Chem. 2010, 122, 2828 –2831; b) P. Hu, M. Zhang, X. Jie, W. Su,
Angew. Chem. Int. Ed. 2012, 51, 227 –231; Angew. Chem. 2012,
124, 231 –235; c) Y. Zhang, H. Zhao, M. Zhang, W. Su, Angew.
Chem. Int. Ed. 2015, 54, 3817 –3821; Angew. Chem. 2015, 127,
3888 –3892; d) J. Kan, S. Huang, J. Lin, M. Zhang, W. Su, Angew.
Chem. Int. Ed. 2015, 54, 2199 –2203; Angew. Chem. 2015, 127,
2227 –2231.
[23] For recent studies on decarboxylative heteroarylation, see:
a) R. A. Crovak, J. M. Hoover, J. Am. Chem. Soc. 2018, 140,
2434 –2437; b) L. Chen, L. Ju, K. A. Bustin, J. M. Hoover, Chem.
Commun. 2015, 51, 15059 –15062.
[24] M. S. Stephan, A. J. J. M. Teunissen, G. K. M. Verzijl, J. G.
de Vries, Angew. Chem. Int. Ed. 1998, 37, 662 –664; Angew.
Chem. 1998, 110, 688 –690.
[25] a) X. Zhang, F. Jordan, M. Szostak, Org. Chem. Front. 2018, 5,
2515 –2521; b) L. J. Gooßen, J. Paetzod, Angew. Chem. Int. Ed.
2002, 41, 1237 –1241; Angew. Chem. 2002, 114, 1285 –1289;
c) L. J. Gooßen, N. Rodriguez, Chem. Commun. 2004, 724 –725;
d) G. A. Kraus, S. Riley, Synthesis 2012, 44, 3003 –3005; e) Y.
Liu, K. E. Kim, M. B. Herbert, A. Fedorov, R. H. Grubbs, B. M.
Stoltz, Adv. Synth. Catal. 2014, 356, 130 –136; f) A. John, L. T.
Hogan, M. A. Hillmyer, W. B. Tolman, Chem. Commun. 2015,
51, 2731 –2733.
[26] K. Fagnou, M. Lautens, Chem. Rev. 2003, 103, 169 –196.
[27] Y. J. Jang, E. M. Larin, M. Lautens, Angew. Chem. Int. Ed. 2017,
56, 11927 –11930; Angew. Chem. 2017, 129, 12089 –12092.
[28] M. Sidera, S. P. Fletcher, Nat. Chem. 2015, 7, 935 –939.
[29] F. W. Goetzke, M. Mortimore, S. P. Fletcher, Angew. Chem. Int.
Ed. 2019, 58, 12128 –12132; Angew. Chem. 2019, 131, 12256 –
12260.
[12] For heteroarylation of acyl fluorides, see: Y. Ogiwara, Y. Iino, N.
Sakai, Chem. Eur. J. 2019, 25, 6513 –6516.
[13] For heteroarylation of acyl chlorides, see: N. K. Harn, C. J.
Gramer, B. A. Anderson, Tetrahedron Lett. 1995, 36, 9453 –9456.
[14] For decarbonylative heteroarylation of esters, see: a) K.
Amaike, K. Muto, J. Yamaguchi, K. Itami, J. Am. Chem. Soc.
2012, 134, 13573 –13576; b) L. Meng, Y. Kamada, K. Muto, J.
Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 2013, 52, 10048 –
10051; Angew. Chem. 2013, 125, 10232 –10235.
[30] F. Pan, Z.-Q. Lei, H. Wang, H. Li, J. Sun, Z.-J. Shi, Angew. Chem.
Int. Ed. 2013, 52, 2063 –2067; Angew. Chem. 2013, 125, 2117 –
2121.
[31] Z.-Q. Lei, F. Pan, H. Li, Y. Li, X.-S. Zhang, K. Chen, H. Wang,
Y.-X. Li, J. Sun, Z.-J. Shi, J. Am. Chem. Soc. 2015, 137, 5012 –
5020.
10698 www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 10690 –10699

Angewandte
Research Articles
Chemie
[32] For palladium-catalyzed hydroarylation, see: A. M. Vasquez,
[44] I. I. F. Boogaerts, G. C. Fortman, M. R. L. Furst, C. S. J. Cazin,
J. A. Gurak, C. L. Joe, E. C. Cherney, K. M. Engle, J. Am. Chem.
Soc. 2020, 142, 10477 –10484.
S. P. Nolan, Angew. Chem. Int. Ed. 2010, 49, 8674 –8677; Angew.
Chem. 2010, 122, 8856 –8859.
[33] For nickel-catalyzed 1,2-diarylation, see: J. Derosa, R. Klein-
mans, V. T. Tran, M. K. Karunananda, S. R. Wisniewski, M. D.
[45] S. De Sarkar, W. P. Liu, S. L. Kozushkov, L. Ackermann, Adv.
Synth. Catal. 2014, 356, 1461 –1479.
Eastgate, K. M. Engle, J. Am. Chem. Soc. 2018, 140, 17878 – [46] J. Ni, J. Li, Z. Fan, A. Zhang, Org. Lett. 2016, 18, 5960 –5963.
17883.
[47] a) J. Mortier, Arene Chemistry: Reaction Mechanisms and
Methods for Aromatic Compounds, Wiley, Hoboken, 2016;
b) L. Kraszkiewicz, M. Sosnowski, L. Skulski, Synthesis 2006,
7, 1195 –1199.
[34] For Co/Ni-catalyzed hydroarylation, see: S. L. Shevick, C.
Obradors, R. A. Shenvi, J. Am. Chem. Soc. 2018, 140, 12056 –
12068.
[35] For Fe/Ni-catalyzed hydroarylation, see: S. A. Green, S. Vas-
quez-Cespedes, R. A. Shenvi, J. Am. Chem. Soc. 2018, 140,
11317 –11324.
[36] For Ni-catalyzed alkylarylation, see: K. C. Shekhar, R. K.
Dhungana, B. Shrestha, S. Thapa, N. Khanal, P. Basnet, R. W.
Lebrun, R. Giri, J. Am. Chem. Soc. 2018, 140, 9801 –9805.
[37] For Ni-catalyzed difunctionalization, see: B. Shrestha, P. Basnet,
R. K. Dhungana, K. C. Shekhar, S. Thapa, J. M. Sears, R. Giri, J.
Am. Chem. Soc. 2017, 139, 10653 –10656.
[38] For Ni-catalyzed arylboration, see: S. R. Sardini, A. L. Lam-
bright, G. L. Trammel, H. M. Omer, P. Liu, M. K. Brown, J. Am.
Chem. Soc. 2019, 141, 9391 –9400.
[39] For Ni-catalyzed diarylation, see: P. Gao, L.-A. Chen, M. K.
Brown, J. Am. Chem. Soc. 2018, 140, 10653 –10657.
[40] C. Liu, C. L. Ji, Z. X. Qin, X. Hong, M. Szostak, iScience 2019,
19, 749 –759.
[48] a) K. Seth, S. K. Garg, R. Kumar, P. Purohit, V. S. Meena, R.
Goyal, U. C. Banerjee, A. K. Chakraborti, ACS Med. Chem.
Lett. 2014, 5, 512 –516; b) T. E. Barder, S. D. Walker, J. R.
Martinelli, S. L. Buchwald, J. Am. Chem. Soc. 2005, 127, 4685 –
4696.
[49] T. Fuchigami, M. Nakayama, S. Yoshida, F. Katayama, M.
Makaie, WO 2019168170, Mar 1, 2019.
[50] C. L. Ji, X. Hong, J. Am. Chem. Soc. 2017, 139, 15522 –15529.
[51] For further pertinent studies on decarboxylative coupling of
carboxylic acids, see: a) T. Patra, D. Maiti, Chem. Eur. J. 2017, 23,
7382 –7401; b) S. Agasti, T. Pal, T. K. Achar, S. Maiti, D. Pal, S.
Mandal, K. Daud, G. K. Lahiri, D. Maiti, Angew. Chem. Int. Ed.
2019, 58, 11039 –11043; Angew. Chem. 2019, 131, 11155 –11159;
c) S. Agasti, S. Maity, K. J. Szabo, D. Maiti, Adv. Synth. Catal.
2015, 357, 2331 –2338; d) T. Patra, S. Nandi, S. K. Sahoo, D.
Maiti, Chem. Commun. 2016, 52, 1432 –1435.
[41] C. Liu, C. L. Ji, X. Hong, M. Szostak, Angew. Chem. Int. Ed.
2018, 57, 16721 –16726; Angew. Chem. 2018, 130, 16963 –16968.
[42] C. Liu, Z. X. Qin, C. L. Ji, X. Hong, M. Szostak, Chem. Sci. 2019,
10, 5736 –5742.
[43] C. Liu, C. L. Ji, T. Zhou, X. Hong, M. Szostak, Org. Lett. 2019,
21, 9256 –9261.
Manuscript received: January 20, 2021
Accepted manuscript online: February 17, 2021
Version of record online: April 6, 2021
Angew. Chem. Int. Ed. 2021, 60, 10690 –10699
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org 10699