Pd/Cu-Catalyzed C-H/C-H Cross Coupling of (Hetero)Arenes with Azoles through Arylsulfonium Intermediates

Article abstract of DOI:10.1021/acs.orglett.1c01322

A highly efficient method for the selective formal C-H/C-H cross-coupling of azoles and (hetero)arenes was established through arylsulfonium intermediates under transition-metal catalysis, which produced a variety of 2-(hetero)aryl azoles in good to excellent yields. Advantages of the reaction included mildness, a good functional group tolerance, a wide range of substrates, a high regio- and chemoselectivity, one-pot procedures, and the late-stage functionalization of complex molecules without the use of oxidants, offering a promising strategy for the transition-metal-catalyzed C-H arylation of azoles.

Full text of DOI:10.1021/acs.orglett.1c01322

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Letter
Pd/Cu-Catalyzed C−H/C−H Cross Coupling of (Hetero)Arenes with
Azoles through Arylsulfonium Intermediates
Ze-Yu Tian, Zeng-Hui Lin, and Cheng-Pan Zhang*
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ABSTRACT: A highly efficient method for the selective formal C−H/C−H cross-coupling of azoles and (hetero)arenes was
established through arylsulfonium intermediates under transition-metal catalysis, which produced a variety of 2-(hetero)aryl azoles in
good to excellent yields. Advantages of the reaction included mildness, a good functional group tolerance, a wide range of substrates,
a high regio- and chemoselectivity, one-pot procedures, and the late-stage functionalization of complex molecules without the use of
oxidants, offering a promising strategy for the transition-metal-catalyzed C−H arylation of azoles.
2-Aryl azole scaffolds are widely prevalent in drug molecules
and natural products (e.g., COX-2 and PDE4 inhibitors,
Febuxostat, Balsoxin, and Texamine) (Scheme 1) and possess
of the C−H bond activation, and the need for the installation
or removal of directing groups on arenes for the ortho-metal-
mediated C−H arylation.2,4−9 Therefore, developing efficient,
mild, and selective approaches for the production of 2-aryl
azoles with a broad functional group tolerance and no use of
directing groups via C−H functionalization is highly sought
after.
Scheme 1. Representative Examples of 2-Aryl Azoles with
Biological Activities
Arylsulfonium salts have been widely used as versatile agents
in organic chemistry and materials science due to their
nonvolatility, nontoxicity, easy preparation, good thermal
stability, modest reactivity, and broad structural diversity.10
A
number of arylsulfonium salts have been exploited as powerful
arylation reagents in transition-metal-catalyzed cross-coupling
reactions, such as Suzuki, Heck, Sonogashira, Negishi,
sulfonylation, carbonylation, amination, silylation, borylation,
and germylation reactions,11 as well as in the transition-metal-
free arylation of heteroatom nucleophiles via aryne inter-
mediates or the SNAr mechanism.12 Moreover, photoredox
catalysis with or without transition metals has enabled the
significant biological activities, such as anticancer, anti-
inflammatory, antibacterial, antitrypanosomal, and neuro-
protection properties.1 Various methods have been developed
for the construction of 2-aryl azoles via the C−H bond
functionalization of simple azoles at the C2-position with the
aid of their specific acidity.2−9 In particular, the C−H/C−H
cross-coupling between two (hetero)arenes has been con-
firmed as a convenient access to 2-aryl azoles, which has
attracted great attention.8,9 However, challenges exist in these
conversions, such as harsh reaction conditions, a large excess of
oxidants, homocoupling byproducts, the poor regioselectivity
Received: April 19, 2021
Published: May 19, 2021
https://doi.org/10.1021/acs.orglett.1c01322
© 2021 American Chemical Society
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homolytic cleavage of C−S bonds and the coupling of
triarylsulfonium, arylthianthrenium, or dibenzothiophenium
salts with alkenes, halides, cyanide, trifluoromethylthiolate,
triphenylphosphite, [CuCF3], water, and others to form
complex small molecules.13 The site-selective C−H sulfenyla-
tions of arenes with thianthrene (S)-oxides (TTO) and
dibenzothiophene (S)-oxide in the presence of an activator
are elaborately included in some of the reactions reported by
Ritter, Procter, Wang and etc., previously generating stable and
tamable arylsulfonium salts for the next arylation that have
provided useful platforms for indirect aromatic C−H
functionalization.11,13
Scheme 2. Pd/Cu-Catalyzed C−H Phenylation of
Benzo[d]oxazole (1a) with Diverse Arylsulfonium Salts (2)
a
Procter and co-workers described a metal-free photoredox-
catalyzed formal C−H/C−H coupling of different arenes for
the preparation of (hetero)biaryls via interrupted Pummerer
activation and subsequent photoredox-catalyzed radical
arylation.13f Unfortunately, when a preliminary C−H/C−H
cross-coupling of phenylbenzo[d]oxazole with 1-phenylpyrro-
lidin-2-one was performed following their method, the desired
2-aryl azole was formed in only a trace amount (<1% HPLC
yield) (see the Supporting Information for more examples).
These results implied the incompatibility of this approach for
an azole system. As a part of our continuous interest in
advancing arylations with arylsulfonium salts,11c−e,g,12a,c we
endeavor to utilize transition-metal catalysis and the isolated or
in situ-formed arylsulfonium salts from (hetero)arenes to build
2-(hetero)aryl azoles by a formal C−H/C−H cross-coupling
with azoles.
Since Pd/Cu/phosphine systems have achieved great
success in transition-metal-catalyzed C−H arylation of azoles
with aryl halides,4 a combination of Pd[P(tBu)3]2 (10 mol %),
CuBr (10 mol %), and xantphos (10 mol %) was used as a
tentative catalyst for the phenylation of benzo[d]oxazole (1a)
with butyl(mesityl)(phenyl)sulfonium triflate (2a). Luckily,
when 1a reacted with 2a (1.5 equiv), K3PO4 (1.5 equiv), and
the catalyst in DMF at 60 °C under N2 for 16 h, 2-
phenylbenzo[d]oxazole (3a) was formed in an 18% yield
(Table S1). A survey of the reaction conditions showed that
DMAc was a better solvent and K3PO4 was a better base than
those tested for the conversion, supplying 3a in a 36% yield
(Tables S1 and S2 and Scheme 2). The phenylation with Cu
salts, e.g., CuI, CuCl, CuOAc, CuOTf, Cu(MeCN)4PF6,
CuTc, CuSCN, Cu(OTf)2, Cu(OAc)2, and CuBr2, gave 3a
in 24−36% yields, which were comparable to that using CuBr
(Table S4). Decreasing or elevating the reaction temperature
of 1a and 2a from 60 °C to 40−50 °C or 70−80 °C,
respectively, did not obviously change the yield of 3a (Table
S5). It should be mentioned that the nature of the
arylsulfonium salts had a large influence on the phenylation
(Scheme 2). Butyl(mesityl)(phenyl)-, methyl(diphenyl)-, and
ethyl(diphenyl)sulfonium triflates (2a−c, respectively) reacted
with 1a in the presence of K3PO4 (1.5 equiv), Pd[P(tBu)3]2
(10 mol %), CuBr (10 mol %), and xantphos (10 mol %) at 60
or 80 °C for 16 h to afford 3a in 5−36% yields, while the same
reactions of 1a and triphenylsulfonium triflate (2f) provided 3a
in 35−80% yields (Table S5 and Scheme 2). Further
optimization revealed that a mixture of 1a, 2f (1.5 equiv),
K3PO4 (1.5 equiv), Pd(dba)2 (5 mol %), CuBr (5 mol %),
nixantphos (10 mol %), and DMAc at 80 °C for 24 h formed
3a in an excellent yield (91% isolated yield) (Table S6 and
Scheme 2). Nonetheless, the treatment of 1a with 2b, 2c,
dimethyl(phenyl)sulfonium triflate (2d), and 1-phenyltetrahy-
dro-1H-thiophen-1-ium triflate (2e) under these optimized
a
Reaction conditions are as follows: 1a (0.2 mmol), 2 (0.3 mmol),
K3PO4 (0.3 mmol), xantphos (10 mol %), Pd[P(tBu)3]2 (10 mol %),
CuBr (10 mol %), DMAc (2.0 mL), 60 °C, N2, and 16 h. Yields
b
c
shown are HPLC yields. Performed at 80 °C. Reaction conditions
are as follows: 1a (0.2 mmol), 2 (0.3 mmol), K3PO4 (0.3 mmol),
nixantphos (10 mol %), Pd(dba)2 (5 mol %), CuBr (5 mol %), DMAc
(2.0 mL), 80 °C, N2, and 24 h. The isolated yields are depicted in the
parentheses.
conditions (for 2f) did not improve the yields of 3a. To our
delight, the reactions using 5-phenyl-5H-dibenzo[b,d]-
thiophen-5-ium (2g), phenylxanthenium (2h), and phenyl-
thianthrenium (2i) triflates as phenylation sources furnished
3a in 55−90% isolated yields (Scheme 2). The results
indicated that triarylsulfonium salts were more efficient
phenylation reagents than alkyl(diphenyl)- and dialkyl-
(phenyl)sulfonium salts in the Pd/Cu-catalyzed couplings
with 1a.
An assembly of the azole (1), 2f (1.5 equiv), K3PO4 (1.5
equiv), Pd(dba)2 (5 mol %), CuBr (5 mol %), and nixantphos
(10 mol %) in DMAc at 80 °C under a N2 atmosphere for 24 h
was employed as the standard conditions to probe the
substrate scope of the reaction. As shown in Scheme 3,
numerous benzo[d]oxazoles bearing either electron-donating
or electron-withdrawing groups on the phenyl rings (1b−j)
were smoothly converted under the standard conditions to give
the 2-phenylated products (3b−j, respectively) in good to
almost quantitative yields. Naphtho[2,3-d]oxazole (1k)
reacted similarly with 2f and K3PO4 in the presence of
Pd(dba)2, CuBr, and nixantphos to afford 3k in a 99% yield.
This protocol was also applicable to other azoles. The reaction
of benzo[d]thiazole (1l) with 2f under the standard conditions
provided 3l in an 82% yield, and elevating the reaction
temperature from 80 to 100 °C could further improve the
phenylation (99%). The treatment of 5-phenyloxazole (1m),
5-(furan-2-yl)oxazole (1n), 5-(pyridin-3-yl)oxazole (1o), and
(E)-5-styryloxazole (1p) with 2f in the presence of CsOH (1.5
equiv), Pd(dba)2 (5 mol %), CuBr (5 mol %), and nixantphos
(10 mol %) at 80 °C under N2 for 24 h supplied 3m−p,
respectively, in 71−84% yields. The choice of a stronger base
(e.g., CsOH) instead of K3PO4 benefited the phenylation of
these oxazoles. Again, the reaction at a higher temperature
(100 °C) gave an enhanced yield of the product (e.g., 3o).
When 5-(3,4-dimethoxyphenyl)oxazole (1q) and 5-(benzo[d]-
[1,3]dioxol-5-yl)oxazole (1r) were reacted with 2f and CsOH
under the standard conditions, balsoxin (3q) and texamine
(3r) were obtained in 61% and 62% yields, respectively.
Analogously, reactions of 2-(4-methylthiazol-5-yl)ethan-1-ol
(1s), ethyl 4-methylthiazole-5-carboxylate (1t), 2-phenyl-1,3,4-
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Scheme 3. Phenylation of Different Types of Azoles (1) with
Triphenylsulfonium Triflate (2f)
Scheme 4. Pd/Cu-Catalyzed C−H/C-H Cross-Couplings of
Benzo[d]oxazole (1a) with Different (Hetero)Arenes via
Arylthianthrenium Salts (2).
a
a
a
Reaction conditions are as follows: 1 (0.2 mmol), 2f (0.3 mmol),
K3PO4 (0.3 mmol), nixantphos (10 mol %), Pd(dba)2 (5 mol %),
CuBr (5 mol %), DMAc (2.0 mL), 80 °C, N2, and 24 h. Yields shown
b
c
are isolated yields. Performed at 100 °C. Using CsOH instead of
a
K3PO4.
Reaction conditions are as follows: 1a (0.2 mmol), 2 (0.3 mmol),
K3PO4 (0.3 mmol), nixantphos (10 mol %), Pd(dba)2 (5 mol %),
CuBr (5 mol %), DMAc (2.0 mL), 80 °C, N2, and 24 h. Yields shown
oxadiazole (1u), and 1,3,7-trimethyl-3,7-dihydro-1H-purine-
2,6-dione (1v) with 2f at 80 or 100 °C in the presence of
either K3PO4 or CsOH formed 3s−v, respectively, in up to a
95% yield. Functional groups in the azoles, such as nitro
groups, cyano groups, esters, a ketone, heterocycles, a carbon−
carbon double bond, active methylene, an alcohol, and an
amide, were well tolerated in the reactions. Remarkably, even
nonaromatic 4,4-dimethyl-4,5-dihydrooxazole (1w) was a
suitable substrate in the phenylation, producing 3w in a 36%
yield under the standard conditions. All these data demonstrate
that the Pd/Cu-catalyzed C−H arylation had a wide range of
azole substrates and a good functional group tolerance,
exhibiting a broad application prospect in the direct C−H
functionalization of azoles.
b
c
d
are isolated yields. Performed at 100 °C. Performed at 60 °C.
A
combination of nixantphos (5 mol %), CuBr (5 mol %), and
e
Pd[P(tBu)3]2 (5 mol %) was used as the catalyst. Using NMP
f
g
instead of DMAc. i-PrCO2H (20 mol %) was added. The molar ratio
h
of regioisomers of 2x was >5.7:1. The molar ratio of regioisomers of
5o was >12:1.
arylthianthrenium triflates (2, 1.5 equiv) assembled with the
azole, K3PO4 (1.5 equiv), Pd(dba)2 (5 mol %), CuBr (5 mol
%), and nixantphos (10 mol %) in DMAc at 80 °C under a N2
atmosphere for 24 h as the standard conditions with which to
explore the substrate scope of this formal C−H/C−H coupling
(Scheme 4).
Next, the formal C−H/C−H cross-coupling between arenes
and benzo[d]oxazole (as an example) was harnessed by C−H
sulfenylation and a subsequent Pd/Cu-catalyzed C−H
arylation (Scheme 4). Although acyclic triarylsulfonium
triflates can be easily synthesized from acyclic diaryl sulfoxides
and arenes and used as reliable coupling partners, their
arylations suffered from low chemoselectivities because of the
small differences among the three aryl groups of the
asymmetric triarylsulfonium salts.10−12 These circumstances
retarded the use of acyclic triarylsulfonium salts as the key
intermediates in the C−H/C−H cross-coupling reactions. In
contrast, the preparation and applications of 5-aryl-5H-
dibenzo[b,d]thiophen-5-ium, arylxanthenium, and arylthian-
threnium triflates from dibenzo[b,d]thiophene-5-oxide, phe-
noxathiine-10-oxide, and thianthrene-5-oxide (TTO) via the
C−H sulfenylation of arenes showed very high regioselectiv-
ities, which are very helpful for site-selective C−H/C−H cross-
couplings.10,11,13 Since phenylthianthrenium triflate (2i)
appeared to be the best Ph source among 2g−i, as it not
only exhibited a high chemoselectivity but also gave the highest
yield of 3a when coupled with 1a (Scheme 2), we chose
Pleasingly, a wide range of arenes with electron-donating or
electron-withdrawing groups on the aryl rings (4a−k)
underwent highly regioselective C−H thianthrenation with
thianthrene 5-oxide to form arylthianthrenium intermediates
(2j−t), which then reacted with benzo[d]oxazole (1a) under
the standard condition to afford the corresponding 2-aryl
benzo[d]oxazoles (5a−k) in good yields (Scheme 4). The
functionalities in the arene compounds, such as ethers, amides,
chloride, formaldehyde, cyano, and nitro groups, were very
compatible in this transformation. It seemed that the ortho-
steric hindrance of the arylsulfonium salt had an influence on
the C−H arylation of 1a, e.g., the reaction of 5-(p-tolyl)-5H-
thianthren-5-ium triflate (2j) (derived from toluene (4a)) with
1a under the standard conditions provided 5a in a 99% yield,
while the same reaction of 5-(2,4-dimethylphenyl)-5H-
thianthren-5-ium triflate (2k) (from m-xylene (4b)) and 1a
furnished 5b in only a 37% yield. Elevating the reaction
temperature from 80 to 100 °C could greatly increase the yield
of 5b (74%). In some cases, the reaction temperature could be
favorably decreased (to 60 °C), achieving comparable or even
better yields of the products compared to those at 80 °C (e.g.,
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5c, 5g, 5j, and 5k). The addition of i-PrCO2H (20 mol %) to a
reaction mixture of 5-(3-cyano-4-isobutoxyphenyl)-5H-
thianthren-5-ium triflate (2q) and 1a in NMP at 80 °C
under similar conditions formed 5h in a higher yield (58% vs
25%). The formal C−H/C−H cross coupling was also
applicable to complex molecules. The late-stage functionaliza-
tion of pyriproxyfen (4l, pesticide) under the standard
conditions through 2u provided the desirable product (5l) in
an 86% yield. Heteroarenes such as 2-phenylthiophene (4m),
2,2′-bithiophene (4n), dibenzo[b,d]furan (4o), and 2-methox-
ypyridine (4p) reacted with 1a under the standard or modified
conditions to afford 5m−p, respectively, in up to >99% yields.
Regioisomers of 2x and 5o were observed in the conversion of
4o, which could not be isolated by either crystallization or
column chromatography. In addition, Febuxostat (gout
drug)1c was readily synthesized by this method from cheap
2-fluorobenzonitrile via four steps, including C−H thianthre-
nation (2q) and C−H arylation (5q), to give a 71% total yield.
This C−H/C−H cross-coupling strategy showed a good
functional group tolerance and an excellent compatibility for
complex arenes, boding well for its application in the
preparation or late-stage modification of pharmaceuticals,
agrochemicals, and natural products.
catalyzed formal C−H/C−H cross-couplings with isolated or
in situ-formed arylsulfonium salts. A variety of azoles and
complex (hetero)arenes were readily converted under the
standard conditions to form the respective 2-(hetero)arylated
azoles in good to almost quantitative yields. The reaction
displayed advantages such as a wide range of substrates, a good
functional group tolerance, a high regio- and chemoselectivity,
mild conditions, ease of handling and scale up, the feasibility of
the one-pot procedure, and the intermediacy of readily
accessible and structurally diversified arylsulfonium salts
using diaryl sulfoxides as transient mediators without the use
of oxidants. This protocol was also applicable to the late-stage
arylation of complex molecules, including the synthesis and
modification of drugs or drug candidates, natural products, and
other useful compounds, showcasing its great potential in
synthetic organic chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01322.
Survey of reaction conditions, general procedures,
characterization data of the products, and copies of
NMR spectra (PDF)
Additionally, the one-pot C−H/C−H cross-coupling
reaction between an arene and an azole was examined
(Scheme 5). The thianthrenation of 4a at the para-position
AUTHOR INFORMATION
Corresponding Author
■
Scheme 5. One-Pot and Scale-up Synthesis of 2-Arylated
Azoles
Cheng-Pan Zhang − School of Materials Science and
Engineering and School of Chemistry, Chemical Engineering
and Life Science, Wuhan University of Technology, Wuhan
430070, China; orcid.org/0000-0002-2803-4611;
Email: cpzhang@whut.edu.cn, zhangchengpan1982@
hotmail.com
Authors
Ze-Yu Tian − School of Materials Science and Engineering and
School of Chemistry, Chemical Engineering and Life Science,
Wuhan University of Technology, Wuhan 430070, China
Zeng-Hui Lin − School of Chemistry, Chemical Engineering
and Life Science, Wuhan University of Technology, Wuhan
430070, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01322
by thianthrene 5-oxide (TTO) in the presence of Tf2O without
any workup, followed by the C−H arylation of 1a with excess
K3PO4 (4.5 equiv) under the standard conditions, afforded 5a
in an 89% yield (Scheme 5a), which was comparable to the
total yield obtained from the stepwise method through isolated
2j (87%, Scheme 4). Moreover, the reaction was easily scaled
up. The treatment of 1a (5 mmol) with 2f (7.5 mmol) under
the standard conditions formed 3a (0.92 g) in a 94% yield
(Scheme 5b). Significantly, the scaled-up one-pot C−H/C−H
cross coupling of 4j (7.5 mmol) and 1a (5.0 mmol) proceeded
successfully via the consecutive C−H thianthrenation of 4j
with TTO and the Pd/Cu-catalyzed C−H arylation of 1a to
give 5j in a 92% yield (1.42 g) (Scheme 5c). These results
demonstrated the good practicality and availability of one-pot
procedures in the transition-metal-catalyzed C−H/C−H cross-
coupling of two different arenes.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Wuhan University of Technology, the “Hundred
Talent” Program of Hubei Province (China), and the
Fundamental Research Funds for the Central Universities
(2019-YB-002 and 2020-YB-003) for financial support.
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