General Chemoselective Suzuki-Miyaura Coupling of Polyhalogenated Aryl Triflates Enabled by an Alkyl-Heteroaryl-Based Phosphine Ligand

Article abstract of DOI:10.1021/acscatal.1c02146

This study describes a general chemoselective Suzuki-Miyaura coupling of polyhalogenated aryl triflates with the reactivity order of C-Cl > C-OTf using a Pd/L33 catalyst. The methine hydrogen and the steric hindrance offered by the alkyl bottom ring of L33 were found to be key factors in reactivity and chemoselectivity. With the Pd/ L33 catalyst, a wide range of polyhalogenated (hetero)aryl triflates, which were independent of the substrates and of the relative positioning of the competing reaction sites, coupled well with (hetero)aryl, alkenyl, and alkylboronic acids to obtain the corresponding products with good chemoselectivity and yields. The chemoselective reaction could easily be scaled up to the gram scale, and the use of parts per million levels of Pd catalyst (as low as 10 ppm Pd) was achieved.

Full text of DOI:10.1021/acscatal.1c02146

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Research Article
General Chemoselective Suzuki−Miyaura Coupling of
Polyhalogenated Aryl Triflates Enabled by an Alkyl-Heteroaryl-
Based Phosphine Ligand
Chau Ming So,* On Ying Yuen, Shan Shan Ng, and Zicong Chen
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ABSTRACT: This study describes a general chemoselective Suzuki−Miyaura coupling of polyhalogenated aryl triflates with the
reactivity order of C−Cl > C−OTf using a Pd/L33 catalyst. The methine hydrogen and the steric hindrance offered by the alkyl
bottom ring of L33 were found to be key factors in reactivity and chemoselectivity. With the Pd/L33 catalyst, a wide range of
polyhalogenated (hetero)aryl triflates, which were independent of the substrates and of the relative positioning of the competing
reaction sites, coupled well with (hetero)aryl, alkenyl, and alkylboronic acids to obtain the corresponding products with good
chemoselectivity and yields. The chemoselective reaction could easily be scaled up to the gram scale, and the use of parts per million
levels of Pd catalyst (as low as 10 ppm Pd) was achieved.
KEYWORDS: palladium, phosphine, chemoselectivity, Suzuki−Miyaura coupling, polyhalogenated aryl triflates
alladium-catalyzed cross-coupling reactions are an ex-
Ptremely versatile tool in organic synthesis for connecting
electrophilic and organometallic fragments.1 Among the
electrophiles, aryl bromides, chlorides, and triflates are still
the most widely used electrophiles in the pharmaceutical
industry and routine synthesis, despite the recent discovery of
more attractive alternatives.2 Although the actual chemo-
selectivity of Pd-catalyzed cross-coupling reactions with the
given multiple (pseudo)halides can be affected by multiple
factors, the approximate reactivity order of C−I ≫ C−Br ≈
C−OTf ≫ C−Cl is commonly accepted and used as a general
guideline to predict the chemoselectivity.3 However, it would
be extremely attractive to easily alternate the reactivity order
by changing ligands to align with the ideal synthetic pathways.
Fu reported a single example in the Suzuki coupling of 4-
chlorophenyl triflate with o-tolylboronic acid, in which the
reactivity order between C−Cl and C−OTf could be
alternated by the ligands, where Pt-Bu3 favors a reaction at
C−Cl over C−OTf but PCy3 favors a reaction at C−OTf over
C−Cl (Scheme 1A).4 Further investigations by Schoenebeck,4b
Houk,5 and Sigman6 revealed that the palladium ligation state
(LPd or L2Pd) with the phosphine ligand during the oxidative
addition significantly affects the preference for the oxidative
addition of C−Cl or C−OTf. More recently, Neufeldt reported
that the use of carbene−Pd complexes, which were
presynthesized from (η3-1-t-Bu-indenyl)2(μ-Cl)2Pd2, SIMes,
and SIPr, can allow the chemoselective Suzuki coupling of
chloroaryl triflates (Scheme 1B).7 However, in general, there
are still significant problems that remain unresolved, such as
the limitation of the (1) chemoselectivity of the electronically
biased chloroaryl triflates, (2) chemoselectivity of the highly
sterically congested product formation, (3) high catalyst
loading, and (4) origin of the different chemoselectivities
generated by the catalysts (i.e., the sets of Pd−carbene
complexes)7 as well as influence of the factors of ligand design
on the chemoselectivity.
A previous study suggested that even though the extremely
bulky biaryl monophosphine ligand is usually found to have a
ratio of Pd/L of 1:1, the hemilabile Pd−arene interaction
offered by the aryl bottom ring makes it a “bidentate” ligand
and prefers the oxidative addition of C−OTf over C−Cl
(Scheme 2).6 In contrast to the phosphine ligands bearing the
aryl structure, the use of the alkyl group as the bottom ring in
the ligand design has received less attention and is underex-
Received: May 12, 2021
Revised: May 25, 2021
Published: June 14, 2021
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© 2021 American Chemical Society
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Scheme 1. Chemoselective Suzuki−Miyaura Cross-Coupling Reaction of Polyhalogenated Aryl Triflates
Scheme 2. Chemoselectivity Related to the Palladium
Ligation State
Scheme 3. Proposed Alkyl-Based Phosphine Ligand Design
with High Potential for Tunability
Table S1 for details).4 Among the classical phosphine ligands
tested (L1−L5), only Pt-Bu3 (L3) resulted in selective C−Cl
activation, yet a poor yield was obtained. t-Bu3P-Pd(I)-I dimer
(L3′) was found to be inactive in this reaction. PCy3 (L2)
offered a better overall yield but showed a low selectivity
between 3a and 4a. Buchwald-type biaryl ligands (L6−L11)
showed chemoselective C−OTf activation. The increase in the
ortho-steric bulkiness of the bottom aryl ring (L6 vs L8−L9)
further promoted the C−OTf reaction. Moreover, hetero-
cyclic-based phosphine with a phenyl bottom ring (L12−L13)
and bidentate ligands (L14−L30) also exhibited C−OTf
chemoselectivity. The direct usage of IMes·HCl (L31) and
IPr·HCl (L32) showed a low reactivity and C−OTf chemo-
selectivity. We were delighted to observe that the newly
developed phosphine ligands (L33) with a cyclohexyl bottom
ring provided an inversion of the common selectivity order of
OTf > Cl for the Suzuki reaction in both intra- and
intermolecular coupling reactions (see SI Scheme S5 for
details). A series of ligands with different alkyl bottom groups
and substitution groups on the phosphorous atom were
prepared to probe the structural effect on the reactivity and
chemoselectivity.
plored in coupling reactions. We envision that using the alkyl
group as the bottom ring may offer different interaction and
coordination modes, which may alternate the chemoselectivity.
Herein, we attempted to design and develop a new type of
phosphine ligand with an alkyl bottom group for chemo-
selectivity reactions (Scheme 1C).
In this study, we chose indole as the heterocyclic moiety for
the ligand skeleton, which can offer several advantages: (1)
easy installation of a different alkyl group at the specific
position; (2) the electronic-biased C3-position allows the rapid
regioselective bromination and phosphination; (3) the first and
second advantages can offer an excellent ligand diversity for the
structure−activity relationship investigations; (4) 2-arylindole-
type phosphines have been proven to be effective ligands in
Pd-catalyzed cross-coupling reactions,8 which can offer a direct
and sophisticated reference to evaluate the effectiveness and
the chemoselectivity of the new type of alkyl-based phosphine
ligand (Scheme 3).
Ligands bearing a more electron-rich dialkyl phosphine
group (L33−L34), which may facilitate the oxidative addition
process, offered better activity toward the coupling reaction
compared with the −PPh2 group (L35). The ligand with the
secondary alkyl group (L33−L34) offered the best reactivity
Our initial investigation of the chemoselective Suzuki
coupling of polyhalogenated aryl triflates employed 4-
chlorophenyl triflate and o-tolylboronic acid as the model
substrates with a typical reaction condition (Table 1; see SI
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a
Table 1. Ligand Screening of Chemoselective C−Cl (over C−OTf) Suzuki Coupling at Room Temperature
a
Reaction conditions: 1 (0.20 mmol), o-tolylboronic acid (0.20 mmol), Pd(OAc)2 (4 mol %), L (4 mol %), KF (0.60 mmol), and THF (0.60 mL)
were stirred at r.t. for 1 h. Calibrated GC yields were reported using dodecane as an internal standard.
Scheme 4. Preparation and C−H···Pd Interaction of C1
and chemoselectivity to give product 3a. The poor chemo-
selectivity offered by the ligand with a small methyl group
(L40) may result from the lack of ortho-steric hindrance to
prevent the formation of L2Pd species. Surprisingly, ligands
(L36−L39) with tertiary alkyl bottom groups, which were
intended to further increase the steric hindrance, were found to
be inferior in this reaction. A further increase in steric
hindrance with an adamantyl group or changing the phosphine
group offered no improvement in reactivity, which is
uncommon9 and implies that the methine hydrogen may
play a critical role in the catalyst reactivity. As a direct
comparison, the ligands with an aryl bottom ring (L41−L44)
showed only C−OTf selectivity, irrespective of the substitution
group on the aryl bottom ring.
To investigate the origin of ligand effects on reactivity and
chemoselectivity, the palladium oxidative addition complex C1
was individually prepared10 (Scheme 4), which displayed
essentially the same reactivity and chemoselectivity in the
reaction (see SI Scheme S4 for details). The crystallographic
analysis of the single crystal of C1 showed that it was a
chloride-bridged dimeric Pd(II) complex with a Pd−L ratio of
1:1. The most interesting feature of C1 was the interaction
between the methine hydrogen on the cyclohexyl bottom ring
and the Pd center C13−H12···Pd1. The methine hydrogen
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Scheme 5. Calculated Transition Structures of the Oxidative Addition Step for Pd/L33 and Pd/L41
was in close proximity to the vacant axial position around the
Pd1 center. The distances (2.698 Å) and angles (138.7°) of the
atoms, which lie within a standard range of 2.3−2.9 Å and
110−170° with a downfield shift (5.73 ppm) of the methine
hydrogen, indicate this C−H···Pd interaction as anagostic/
preagostic interactions.11
study suggested that the anagostic/preagostic interaction might
assist the stabilization of the unsaturated complexes in the
catalytic cycle.14 We also performed the calculation for
monoligated Pd−L41, in which the phenyl group was in
place of the cyclohexyl group, to evaluate the effect of the
bottom ring on the chemoselectivity. Consistent with the
experimental results, Pd−L41 favored undergoing the oxidative
addition of C−OTf (TS22) than C−Cl (TS19) by 4.3 kcal
mol−1 (Scheme 5). The phenyl bottom ring had a π-arene
hemilabile interaction/coordination with the palladium cen-
ter,15 and it agrees with the previous finding that the bis-
coordinated palladium complex prefers the C−OTf bond
activation.6
Based on the above observations and studies, we posit that
the methine hydrogen and the steric hindrance offered by the
alkyl bottom group of the ligands might be the key factors
accounting for the reactivity and chemoselectivity. The
preagostic interaction between methine hydrogen and the
palladium center may play a role in stabilizing and affecting the
activity of the unsaturated palladium complex during the
course of the oxidative addition. The steric effect induced by
the cyclohexyl bottom ring may account for the prevention of
the second coordination of the phosphine ligand and the
formation of the L2Pd species.
We then optimized the reaction conditions using alkyl-
indolyl-based ligand SelectPhos L33 for the Suzuki reaction
(see SI Table S2 for details). A series of palladium sources
were screened (Table S2, entries 1−4). Pd(OAc)2 was found
to be the best palladium source in this reaction (Table S2,
entry 1). We attempted to reduce the catalyst loading from 4
to 0.02 mol % Pd(OAc)2 and increase the temperature to 110
°C. The desired product yield 3 was decreased only slightly
(Table S2, entry 6). Efforts were taken to change the ligand
ratio (Table S2, entries 6−9). To our delight, the Pd-to-ligand
ratio of 1:2 resulted in a 99% product yield (Table S2, entry 7).
To further investigate ligand effects on chemoselectivity, we
performed a density functional theory (DFT) study of the
oxidative addition process for the Pd/L33 and Pd/L41
catalytic systems. The calculations were performed at the
SMD(THF) B3PW91-D3(BJ)/6-31G*//B2PLYP-D3(BJ)/
Def2-TZVP level of theory (see the SI for details). The
reaction of monoligated Pd−L33 with 4-chlorophenyl triflate
was used for the oxidative addition study. The DFT result
showed that Pd−L33 was more favorable in reacting with the
C−Cl bond (TS13) than with the C−OTf bond (TS16) with
a difference of 5.8 kcal mol−1, which is consistent with the
experimental results (Scheme 5). The calculation results also
suggested the existence of an agnostic/preagostic interaction
between the palladium center and the methine hydrogen of the
cyclohexyl ring across the oxidative addition process. A
preliminary study of the nature of the C−H···Pd interaction
using the quantum theory of atoms in molecules (QTAIM)
analysis for TS13 indicated a bond path and associated BCP
for the Pd···H separation; the Laplacian of the electron density
at the BCP was positive [∇2ϱ(BCP) = 0.0614 e/bohr5] and
the energy density was negative [H(BCP) = −0.0026 e/bohr3],
which have been used previously as the basis for the preagostic
interaction.11b,12 The natural bond orbital (NBO) analysis
showed that the Pd to antibonding sp3 C−H backdonation at
3.24 kcal mol−1 was of the second-order perturbation energy,
which can be regarded as an attractive component in terms of
electron donation.13 As anagostic interactions involve only
repulsive electrostatics, the Pd···H separation in the complexes
should be described as a preagostic interaction.13 A recent
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Among an array of inorganic bases surveyed, KF was found to
be the best base (Table S2, entry 7 vs entries 10−15). The
presence of water equivalents in K3PO4·H2O led to an increase
in product yield compared with K3PO4 (Table S2, entries 13
and 12). With regard to solvent screening, t-BuOH was found
to be a more effective solvent than THF and the others (Table
S2, entry 20 vs entries 16−19). Hence, Pd(OAc)2/L33 with
KF as the base and t-BuOH as the solvent gave the best results,
in which the catalyst loading could be lowered to 0.02 mol %
Pd at 110 °C. The reaction rate experiment showed that the
Pd(OAc)2/L33 system provided a much higher catalytic
activity than the reported Pd−SIPr system, which was
suspected to suffer from catalyst deactivation at low catalyst
loading (see SI Scheme S1 for details).
Table 2. Palladium-Catalyzed Chemoselective C−Cl (over
a
C−OTf) Suzuki−Miyaura Coupling
In general, in the presence of the 0.02 mol % Pd/L33
catalyst, most of the chloroaryl triflates were completed within
2 h and displayed excellent chloro-selectivity (Table 2). A wide
range of arylboronic acids were examined. Electron-neutral (H,
Me, and t-Bu), electron-deficient (F and CF3), and electron-
rich (OMe) arylboronic acids were coupled smoothly with 4-
chlorophenyl triflate in excellent yields (3a−3i and 3l).
Meanwhile, sterically congested arylboronic acids were found
to be feasible cross-coupling partners (3h−3j and 3k). The use
of heteroarylboronic acids was successful for the first time,
which gave the corresponding products an excellent yield (3o−
3r). Apart from arylboronic acids, alkenylboronic acids were
found to be applicable substrates (3s and 3t). 1-Pyreneboronic
acid and 9-phenanthracenyl boronic acid containing functional
material properties were also feasible cross-coupling partners
(3u, 3y, and 3z).
Particularly noteworthy is that we were able to perform
selective arylation, regardless of whether the C−Cl and C−
OTf bonds were positioned ortho (3w-3ab and 3ad), meta (3v,
3ac, 3ah, 3ai, 3aj, 3al, and 3an), or para (3ae, 3af, 3ag, 3ak,
3am, and 3ao) to each other and whether additional steric
hindrances or functional groups were present. Methoxy (3aa
and 3ah), ester (3n), aldehyde (3ab), nitro (3ad and 3ao),
ketone (3m, 3ac, and 3ag), fluoro (3ai−3am), and nitrile
(3an) moieties were well tolerated. Chloropyridyl triflates were
also feasible cross-coupling partners and produced the
corresponding products smoothly (3ap−3au). The reactivity
of pyridine C−X bonds toward Pd(0) generally follows the
order C2 > C4 > C3/C5.3a Cross-coupling at C−Cl, regardless
of the position, occurred preferentially over the reaction at C−
OTf. The incomplete conversion of chloropyridyl triflates and
the decomposition of starting materials/products account for
the moderate yield of compounds 3ar and 3au. Notably, cross-
coupling at C4−Cl occurred favorably over the reaction at
C2−OTf (3au) using our Pd/L33 catalyst system, a clear
distinction from the study by Neufeldt.7
Sterically hindered chloroaryl triflates furnished the coupling
products in good yields (3av−3ax). The Pd/L33 catalyst also
demonstrated high Cl/OTf chemoselectivity toward the highly
challenging tri-ortho-substituted biaryl synthesis, as with the
first example in Suzuki−Miyaura coupling (3ax). Notably, we
achieved catalyst loading as low as 0.05 mol % Pd. The
challenging alkylboronic acids were also selectively coupled
with 4-chloro-2,6-dimethylphenyl triflate, and 4-chlorophenyl
triflate was coupled with methylboronic acid and n-
butylboronic acid as the first chemoselective alkylation of
C−Cl bonds in the presence of C−OTf bonds with good
yields (3ay−3ba).
a
Reaction conditions: 1 (0.20 mmol), Ar’B(OH)2 (0.20 mmol),
Pd(OAc)2/L33 = 1:2, KF (0.60 mmol), and t-BuOH (0.60 mL) were
stirred at 110 °C for 2 h under a nitrogen atmosphere. Isolated yields
were reported. A selectivity of 95−100% was observed for all
compounds, and the conversion and selectivity ratio of each
b
compound are provided in the SI. <95% selectivity was observed.
c
d
1.2 equiv of Ar’B(OH)2 was used. 1.1 equiv of Ar’B(OH)2 was
e
f
used. 1.5 equiv of Ar’B(OH)2 was used. Toluene was used, and the
reaction time was 4 h. Toluene/t-BuOH at a ratio of 1:1 (total 0.60
mL) was used, and the reaction time was 4 h. The reaction was
g
h
i
conducted for 1 h. Toluene was used, and the reaction time was 3 h.
j
k
1 (0.30 mmol) and Ar’B(OH)2 (0.20 mmol) were used. 3.0 equiv of
Ar’B(OH)2 and toluene were used, and the reaction time was 30 min.
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a
Table 3. Palladium-Catalyzed Chemoselective C−Cl (over C−OTf) Suzuki−Miyaura Coupling at ppm Levels
a
Reaction conditions: 1 (0.20 mmol), Ar’B(OH)2 (0.20 mmol), Pd(OAc)2/L33 = 1:2, KF (0.60 mmol), and t-BuOH (0.60 mL) were stirred at
110 °C for 2 h under a nitrogen atmosphere. Isolated yields were reported. A selectivity of 95−100% was observed for all compounds, and the
b
c
d
conversion and selectivity ratio of each compound are shown in the SI. 18 h. <95% selectivity was observed. 1.5 equiv of Ar’B(OH)2 was used.
Scheme 6. Sequential Functionalization of Polyhalogenated Aryl Triflates
Scheme 7. Large-Scale Chemoselective Suzuki Reaction
To further investigate the effectiveness of the Pd/L33
catalytic system, we attempted to lower the catalyst loading to
the ppm level of Pd. This system effectively converted the
substrates into corresponding products with excellent yields
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and chemoselectivity at 20−50 ppm Pd catalyst (Table 3).
Remarkably, the catalyst loading reached up to 10 ppm Pd
without a significant drop in catalytic activity (3a).
As expected, Pd/L33 catalyzed the coupling of polyhalo-
genated aryl triflates with high Br/OTf and Br/Cl selectivities
(Scheme 6). This highly chemoselective one-pot sequential
method can offer a highly convenient method to access the
novel phenylene triflate building blocks to construct
structurally new PAHs for optoelectronic devices and
materials.16
This reaction can also be directly scaled up 100 times to
produce the coupling product without diminishing the yield
and chemoselectivity. The use of K3PO4·H2O and toluene,
which is one of the most common conditions in the Suzuki−
Miyaura coupling reaction, also works well to successfully
synthesize product 3a (Scheme 7).
Chemical Technology, The Hong Kong Polytechnic
University, Kowloon, Hong Kong SAR, China
Zicong Chen − State Key Laboratory of Chemical Biology and
Drug Discovery and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic
University, Kowloon, Hong Kong SAR, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c02146
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
In summary, we have designed and developed a conceptually
new type of phosphine ligand with an alkyl group as the
bottom ring for chemoselective coupling reactions. This type
of ligand showed high chemoselectivity for Suzuki−Miyaura
coupling of chloroaryl triflates toward a wide range of
substrates, with an inversion of the common reactivity order
of C−Cl > C−OTf in all cases. An excellent reactivity was also
demonstrated, for the first time, by its scale-up ability and the
chemoselective reaction achieved at parts per million levels of
the palladium catalyst.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (21972122), the Research Grants Council of Hong
Kong, Early Career Scheme (ECS 25301819) and General
Research Fund (GRF 15300220), and the Science, Technology
and Innovation Commission of Shenzhen Municipality
(JCYJ20180306173843318) for financial support. The authors
are grateful to Prof. Tamio Hayashi (NTHU) for helpful
discussion on this work, Dr. Siu Cheong Yan, Kenneth for the
assistance in NMR analysis, Dr. Kam-wah Mok, Daniel for the
help in computational study, and Mr. Junyu Wu for preparing
some of the polyhalogenated aryl triflates.
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c02146.
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X-ray crystal structure data for complex C1 (CIF)
Accession Codes
CCDC 2074310 contains the supplementary crystallographic
data for this paper. This data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_-
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, U.K.; Fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Chau Ming So − State Key Laboratory of Chemical Biology
and Drug Discovery and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic
University, Kowloon, Hong Kong SAR, China; The Hong
Kong Polytechnic University Shenzhen Research Institute,
Shenzhen 518057, Guangdong, China; orcid.org/0000-
0001-6268-651X; Email: chau.ming.so@polyu.edu.hk
Authors
On Ying Yuen − State Key Laboratory of Chemical Biology
and Drug Discovery and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic
University, Kowloon, Hong Kong SAR, China
Shan Shan Ng − State Key Laboratory of Chemical Biology
and Drug Discovery and Department of Applied Biology and
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(3) (a) Almond-Thynne, J.; Blakemore, D. C.; Pryde, D. C.; Spivey,
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