Direct Arylation of Azoles Enabled by Pd/Cu Dual Catalysis

Article abstract of DOI:10.1021/acs.orglett.1c00100

A practical approach toward the synthesis of 2-arylazoles via direct arylation is described. The transformation relies on a Pd/Cu cocatalyst system that operates with low catalyst loadings. The reaction conditions were found to be tolerant of a wide range of functional groups and nitrogen-containing heterocycles commonly employed in a drug discovery setting.

Full text of DOI:10.1021/acs.orglett.1c00100

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Letter
Direct Arylation of Azoles Enabled by Pd/Cu Dual Catalysis
Tiffany Piou,* Yuriy Slutskyy,* Nancy J. Kevin, Zhongxiang Sun, Dong Xiao, and Jongrock Kong
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ABSTRACT: A practical approach toward the synthesis of 2-
arylazoles via direct arylation is described. The transformation
relies on a Pd/Cu cocatalyst system that operates with low catalyst
loadings. The reaction conditions were found to be tolerant of a
wide range of functional groups and nitrogen-containing hetero-
cycles commonly employed in a drug discovery setting.
irect functionalization of C−H bonds is an attractive
D
approach for the efficient preparation and late-stage
diversification of complex natural products and pharmaceuti-
cally relevant molecules.1 Compared to traditional methods
that rely on prefunctionalized starting materials, C−H bond
functionalization approaches are inherently advantageous in
terms of atom, redox, and step economies.2 Despite the
aforementioned advantages, the general applicability of direct
C−H arylation protocols in a drug discovery setting remains
challenging because of the common limitations that include
site selectivity, functional group tolerance, and the need for
large excesses of reagents and catalysts.3,4
Biaryl scaffolds, including 2-aryloxazoles, are commonly
found in pharmaceutically relevant molecules, such as the ones
shown in Figure 1.5 Given their prevalence, a general, reliable,
Figure 2. Inspiration for the development of Pd/Cu cocatalyzed C−
H arylation of azoles.
for harsh conditions that significantly limit the scope of the
transformations (Figure 2A).8−11
In 2010, Amgen disclosed the use of a novel Pd/Cu
cocatalyst12 for the direct C−H arylation of benzoazoles using
just 0.25 mol % Pd loadings (Figure 2B).13 However, to the
best of our knowledge, a similar highly efficient catalytic system
for C−H arylation of azoles has not been reported. The
presence of an additional potentially reactive C−H bond in
azoles can render couplings unselective.14 Thus, the use of an
excess of the azole partner is often required to limit the
formation of the undesired bis-arylated oxazole side product.
Herein, we report an efficient Pd/Cu dual-catalytic system that
enables C-2 selective arylation of azoles with low catalyst
Figure 1. Examples of 2-aryloxazoles in biologically active molecules.
and highly efficient method for C−H functionalization of
azoles would be of a significant interest (Figure 2).
Furthermore, direct C−H arylation approaches take advantage
of widely available aryl halide monomers, offering an attractive
strategy for various classes of coupling partners.6
Received: January 11, 2021
Published: March 5, 2021
Despite numerous protocols for metal-catalyzed direct C−H
arylations of azoles,7 their applications in the pharmaceutical
industry, especially in a development stage, are rare because of
the high catalyst loadings (5−10 mol %) and the requirement
https://dx.doi.org/10.1021/acs.orglett.1c00100
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1996−2001
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Letter
loadings, employing a mild base to ensure the tolerability of a
broad range of pharmaceutically relevant heterocyclic coupling
partners (Figure 2C). The salient results of our optimization
study, the scope of the transformation, and preliminary
mechanistic experiments are detailed below.
The results of our optimization study for the direct C−H
arylation of ester oxazole 1a with bromopyridine 2a are
summarized in Table 1. After an extensive screening
Table 1. Optimization of C−H Arylation Conditions
a
b
entry
deviation from standard conditions
no change
CuBr instead of Cu(Phen)PPh3Br
CuI instead of Cu(Phen)PPh3Br
CuCl instead of Cu(Phen)PPh3Br
yield (%)
c
1
2
3
4
5
6
7
84 (87 )
66
74
55
73
25
54
Cu(NCMe)4PF6 instead of Cu(Phen)PPh3Br
K2CO3 instead of DBU
DMAc instead of 1,4-dioxane
a
b
Scale: 0.70 mmol. Assay yields were determined on the basis of the
UPLC area percent at 210 nm with a calibrated UPLC instrument.
c
Isolated yield.
campaign,15 we found that commercially available Pd(OAc)2
(0.5 mol %), PCy3·HBF4 (1.0 mol %), and Cu(Phen)(PPh3)Br
(1.0 mol %) formed a dual catalytic system to produce the
desired coupling product 3aa in 87% isolated yield. The
identity of the Cu source was critical to realize the desired
transformation with low catalyst loadings. Reactions that
employed alternate Cu cocatalysts, such as CuI, CuBr, CuCl,
or Cu(NCMe)4PF6, led to inferior levels of reactivity (entries
2−5). Couplings that utilized K2CO3 as base led to bis-
arylation of the oxazole 1aa, resulting in poor yields of the
desired product 3aa (entry 6).14c Notably, similar side
products arising from unselective C-5 arylation were not
observed with DBU.16 Finally, 1,4-dioxane was found to be the
optimal solvent, as reactions that were performed in other
media, such as DMAc, resulted in lower yields of the product
3aa (entry 7).
a
Figure 3. Scope studies of aryl bromides. Reactions were run using
standard reaction conditions: aryl bromide 2 (1.0 equiv), oxazole 1a
(1.1 equiv), Pd(OAc)2 (0.5 mol %), PCy3·HBF4 (1.0 mol %),
Cu(Phen)(PPh3)Br (1.0 mol %), DBU (2.0 equiv), 1,4-dioxane (0.3
M), 110 °C. Isolated yields are reported. bThe reaction was conducted
utilizing 2.0 g of 1a. Isolated yield is reported. Boc = tert-
butyloxycarbonyl, Cbz = benzyloxycarbonyl, DBU = 1,8-
diazabicyclo(5.4.0)undec-7-ene, and Phen = phenanthroline.
With an optimized set of conditions in hand, the scope of
the transformation with respect to the aryl halide coupling
partner was explored next (Figure 3). Substituents at the para
or meta positions of the pyridine rings, irrespective of their
electronic nature (−CF3, −CO2Et, −OMe), had no influence
on the efficiency of the coupling, delivering the corresponding
biaryl products 3aa−ac in high yields. Unsurprisingly, using
aryl iodide instead of aryl bromide afforded the product 3aa in
a similar yield. Functionalization of the oxazole 1a with an
ortho-substituted bromo-pyridine led to the desired product
3ad in 88% yield. Furthermore, a strongly coordinating
functional group at the ortho position of the aryl halide
monomer, such as an unprotected amine, was tolerated,
producing amino-pyridine 3ae in 66% isolated yield. Gratify-
ingly, chemoselective oxidative addition of the Ar−Br bond
was observed when 3-bromo-5-chloropyridine (2f) was used as
a coupling partner, delivering chloride-containing 2-aryloxazole
3af in excellent yield, enabling further downstream diversifi-
cation of the product. The reactions that used medicinally
relevant nitrogen-containing heterocycles, 2-bromopyridines
and 2-bromopyrazines, furnished the corresponding products
3ag and 3ah in 84% and 67% yields, respectively. The
couplings of oxazole 1a with electron-rich 5-membered aryl
halides were more challenging, with modest reactivity observed
for bromopyrazoles, leading to products such as 3ai in reduced
yields. The ability to functionalize oxazole 1a with 2-
bromopyridines, pyrazines, and pyrazoles serves to underscore
the complementarity of the C−H arylation approach to the
traditional Suzuki-Miyaura coupling, as corresponding aryl
boronates either are not commercially available or are
significantly less stable.17 Apart from a broad aryl substrate
scope, the reaction also displayed good functional group
tolerance. Couplings with substrates that contained ketone,
nitrile, Boc (tert-butyloxycarbonyl)-protected amine, and α-
tertiary amine functional groups proceeded smoothly to afford
the desired biaryl products 3aj−am ranging from 74% to 95%
yield. Aryl bromides containing fused nitrogen heterocycles,
found in products 3an and 3ao, performed well under the
reaction conditions, further demonstrating the utility of the
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developed transformation in a drug discovery setting. Finally,
the reaction was found to be readily scalable, delivering biaryl
product 3aa in 79% yield on gram scale. In general, poor
reaction outcomes were observed when aryl chlorides 2ap and
2-bromopyrimidines 2aq were subjected to the coupling
conditions, delivering only trace amounts of the expected
products.18,19
Inspired by the broad substrate scope observed with respect
to both coupling partners, we set out to further explore the
applicability of the developed conditions toward late-stage
functionalization of pharmaceutically relevant compounds. To
this end, an “informer” set of druglike halides was used to
benchmark the robustness of the reaction conditions.23 We
elected to leverage high-throughput experimentation (HTE) to
evaluate reaction performance across 18 complex aryl halides
using two sets of coupling conditions.24 We were delighted to
see successful late-stage functionalization of a variety of
complex aryl halides with selected couplings shown in Figure
5.25 For example, imidazole-containing aryl bromide under-
Next, the scope of the transformation with respect to the
azole coupling partner was explored (Figure 4). Conducting
Figure 4. Scope studies of azoles. aConditions A: aryl bromide 2a (1.0
equiv), azole 1 (1.1 equiv), Pd(OAc)2 (0.5 mol %), PCy3·HBF4 (1.0
mol %), Cu(Phen)(PPh3)Br (1.0 mol %), DBU (2.0 equiv), 1,4-
dioxane (0.3 M), 110 °C. bConditions B: aryl bromide 2a (1.0 equiv),
azole 1 (1.1 equiv), Pd(OAc)2 (2.0 mol %), PCy3·HBF4 (4.0 mol %),
CuBr·DMS (4.0 mol %), KOPiv (2.0 equiv), toluene (0.30 M), 110
°C. DBU = 1,8-diazabicyclo(5.4.0)undec-7-ene, DMS = dimethyl
sulfide, and Phen = phenanthroline.
Figure 5. Selected examples for coupling of ethyl oxazole-4-
carboxylate with informer halides. aReactions were run using standard
reaction conditions: aryl bromide 2 (1.0 equiv), oxazole 1a (1.1
equiv), Pd(OAc)2 (0.5 mol %), PCy3·HBF4 (1.0 mol %), Cu(Phen)-
(PPh3)Br (1.0 mol %), DBU (2.0 equiv), 1,4-dioxane (0.3 M), 110
°C. Boc = tert-butyloxycarbonyl, DBU = 1,8-diazabicyclo(5.4.0)-
undec-7-ene, and Phen = phenanthroline.
the reaction with the isomer of the model substrate, ethyl
oxazole-5-carboxylate (1ba), led to the desired product 3ba in
84% yield, similar to the 87% yield observed for 3aa
(conditions A).20 However, when oxazoles containing a less
acidic hydrogen at the C-2 position were employed, in addition
to increasing Pd and Cu loadings to 2.0 mol % and 4.0 mol %
to improve conversion, a carboxylate base, KOPiv, was
essential to achieve high levels of reactivity (conditions B).21
Despite the increase in catalyst loadings, near equimolar
amounts of the coupling partners were retained. Utilizing this
modified protocol, we were pleased to observe that both fully
substituted oxazole isomers 3bb and 3bc were formed in 66%
and 75% yields, respectively.22 Oxazoles containing phenyl
substituents, either at the 4- or the 5-position, were also found
to be competent substrates under the developed reaction
conditions, furnishing products 3bd and 3be. Furthermore, the
modified reaction conditions B performed well with sub-
stantially less acidic C−H bonds found in alkyl-substituted
oxazoles 3bf−3bh. Strongly coordinating substituents, such as
primary hydroxyl groups, were tolerated, enabling the
preparation of alcohol-containing products 3bg and 3bh in
72% and 67% yields, respectively. Finally, the applicability of
the developed method was expanded to thiazoles, delivering
the biaryl product 3bi in 61% yield.
went chemoselective coupling with ester oxazole 1a to deliver
the corresponding product 3ca in 57% isolated yield.26
Gratifyingly, the coupling of 1a delivered the biaryl product
3cb in excellent yield. Other complex aryl halides, bearing
conjugated olefins and sulfonamide functionalities, furnished
the desired products 3cc and 3cd in 66% and 83% yields,
respectively. Noteworthy, the aforementioned transformations
were carried out in the presence of just 0.5 mol % Pd and 1.0
mol % Cu, underscoring the efficiency of the discovered
cocatalyst system.
To gain a better mechanistic understanding of the C−H
arylation, we carried out key control experiments (Figure 6).
Reactions performed in the absence of the copper complex led
to low conversion with the coupling product 3aa formed in
only 34% yield (Figure 6A). No reactivity was observed with
the Cu(Phen)(PPh3)Br catalyst in the absence of a Pd source
in the reaction. These experimental findings emphasize the
crucial role of the Pd/Cu cocatalyst system to achieve high
levels of reaction efficiency and indicate that both metallic
species are involved in the catalytic cycle. Finally, when the
reaction was conducted with PdCl2 in place of Pd(OAc)2, the
reactivity was not affected, affording the desired product 3aa in
comparable yields. This observation suggests that the C−H
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pubs.acs.org/OrgLett
Letter
Detailed experimental procedures, analytical data, and
copies of spectra (1H NMR and 13C NMR) of all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Tiffany Piou − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States; orcid.org/0000-0003-4923-9138;
Email: tiffany.piou@merck.com
Yuriy Slutskyy − Department of Discovery Chemistry, Merck
& Co., Inc., Kenilworth, New Jersey 07033, United States;
orcid.org/0000-0002-3059-5362;
Email: yuriy.slutskyy@merck.com
Authors
Nancy J. Kevin − Department of Discovery Chemistry, Merck
& Co., Inc., Kenilworth, New Jersey 07033, United States
Zhongxiang Sun − Department of Discovery Chemistry, Merck
& Co., Inc., Kenilworth, New Jersey 07033, United States
Dong Xiao − Department of Discovery Chemistry, Merck &
Co., Inc., Kenilworth, New Jersey 07033, United States;
orcid.org/0000-0001-8936-0448
Jongrock Kong − Department of Process Research and
Development, Merck & Co., Inc., Rahway, New Jersey 07065,
United States
Figure 6. Proposed mechanism for Pd/Cu catalyzed C−H arylation
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00100
of oxazoles. Ligands were omitted for the sake of clarity. aAssay yield.
Notes
The authors declare no competing financial interest.
bond cleavage is likely not going through a carboxylate
mediated concerted metalation-deprotonation process.27
On the basis of the control experiments and previous
literature reports,28 a proposed mechanism is depicted in
Figure 6B that features a bimetallic catalytic system in which
Pd(0) and Cu(I) operate concomitantly.29 First, the azaphilic
Cu(I) catalyst coordinates to the nitrogen atom of the oxazole
ring I, increasing C−H bond acidity to facilitate deprotonation
and produce organocopper species II. The resulting Cu
intermediate undergoes transmetalation with Ar−Pd(II)
complex III (formed via oxidative addition of Pd(0) to
bromopyridine 2a) to release Cu(I) catalyst. Subsequent
reductive elimination liberates product 3aa and regenerates the
Pd(0) cocatalyst. Further mechanistic studies are ongoing in
our laboratory, and the results will be reported in due course.
In summary, we have identified a general and efficient set of
reaction conditions utilizing Pd and Cu catalysis for the direct
C−H arylation of azoles with aryl bromides. The reported
dual-catalytic approach enables high catalyst turnover,
requiring the use of just 0.5−2 mol % Pd. During our
exploratory studies, the transformation was found to be robust,
scalable, and applicable to a diverse range of aryl bromides and
azoles. As a result, we believe these conditions will benefit the
broader synthetic community and encourage wider implemen-
tation of direct arylation approaches overall.
ACKNOWLEDGMENTS
■
The work was supported by Merck Sharp & Dohme Corp., a
subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. We
thank Benjamin Sherry, Louis-Charles Campeau, Marion
Emmert, and Shawn Walsh (all employees of Merck Sharp &
Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth,
NJ, USA) for helpful discussions.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
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results with 18 informers under both coupling conditions A and B.
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(29) At this point, we cannot exclude the possibility of two catalytic
cycles operating concomitantly: a monometallic Pd-catalyzed pathway
and a Pd/Cu dual catalytic process. Further studies are ongoing and
will be reported in due course.
(16) In addition to high regioselectivity for C-2 arylation, the use of
a soluble organic base, such as DBU, was deemed to be attractive for
several reasons: homogeneous reaction conditions, beneficial for
scale-up applications (particle size uniformity, stirring consistency),
and parallel dosing in a library setting. Please see the Supporting
Information for other bases surveyed during the optimization studies.
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DOI: 10.1002/anie.202010631.
(18) The use of an inorganic base in place of DBU appears to be
beneficial for couplings that utilize Ar−Cl monomers. Please see the
HTE Reaction Screen with Informer Halides section in the
Supporting Information for details.
(19) LCMS analyses of the crude mixtures containing 2-
bromopyrimidines indicated protodehalogenation of these coupling
partners in under 2 h when subjected to the reaction conditions.
(20) The coupling partner 4-bromopyridine 2a was used to
investigate the azole scope because it was employed during the
reaction optimization studies. Arylation of oxazole 1ba with 4-
bromotoluene led to the formation of the corresponding product in
96% isolated yield. Please see the Supporting Information for details.
(21) The origins of the observed reactivity improvements with the
inorganic bases for arylations of oxazoles bearing less acidic hydrogens
at the C-2 position are not well understood at this time. Current
investigations are focused on understanding the roles of each
component and their contributions to the mechanistic pathway for
the reported transformation. The results of the ongoing efforts will be
published in due course.
(22) The couplings that utilized oxazoles 1bb and 1bc led to low
conversions (∼20−30% assay yield) under conditions A. Unreacted
starting material accounted for the majority of the remaining mass
balance.
(23) Kutchukian, P. S.; Dropinski, J. F.; Dykstra, K. D.; Li, B.;
DiRocco, D. A.; Streckfuss, E. C.; Campeau, L.-C.; Cernak, T.;
Vachal, P.; Davies, I. W.; Krska, S. W.; Dreher, S. D. Chemistry
Informer Libraries: A Chemoinformatics Enabled Approach to
2001
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