A Monophosphine Ligand Derived from Anthracene Photodimer: Synthetic Applications for Palladium-Catalyzed Coupling Reactions

Article abstract of DOI:10.1021/acs.orglett.9b02414

Herein, we present an air-stable dianthracenyl monophosphine ligand (diAnthPhos) which can be prepared in two steps from commercially available anthracene derivatives. The ligand exhibits excellent efficiency for palladium-catalyzed coupling reactions. In particular, Miyaura borylation of heterocycle-containing electrophiles can be facilitated employing the diAnthPhos ligand with a broad substrate scope and low catalyst loading. The valuable synthetic utility of the new ligand is further demonstrated by a one-pot Miyaura borylation/Suzuki coupling protocol for heteroaryl-containing substrates.

Full text of DOI:10.1021/acs.orglett.9b02414

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Monophosphine Ligand Derived from Anthracene Photodimer:
Synthetic Applications for Palladium-Catalyzed Coupling Reactions
Xin Wang, Wei-Gang Liu, Chen-Ho Tung, Li-Zhu Wu, and Huan Cong*
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry & School
of Future Technology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, 100190, China
S
* Supporting Information
ABSTRACT: Herein, we present an air-stable dianthracenyl monophosphine ligand (diAnthPhos) which can be prepared in
two steps from commercially available anthracene derivatives. The ligand exhibits excellent efficiency for palladium-catalyzed
coupling reactions. In particular, Miyaura borylation of heterocycle-containing electrophiles can be facilitated employing the
diAnthPhos ligand with a broad substrate scope and low catalyst loading. The valuable synthetic utility of the new ligand is
further demonstrated by a one-pot Miyaura borylation/Suzuki coupling protocol for heteroaryl-containing substrates.
ew ligand design is one of the long-lasting research
themes in the development of transition metal-catalyzed
Scheme 1. Monophosphine Ligand diAnthPhos (1) and Its
Preparation
a
N
reactions, since ligands can tune the properties of metal centers
by coordination, thereby enabling efficient catalyst turnover
with desirable selectivity and substrate scope.1 Among the
successful ligands known to date, the family of monophosphine
ligands is particularly effective for palladium-catalyzed coupling
reactions,2 featuring sterically demanding substituents on
phosphine to increase catalyst durability as well as to facilitate
reductive elimination steps (Scheme 1a).3 We speculate that
the unique structure of the anthracene [4 + 4] photodimer4
not only could serve as useful synthetic building blocks5 but
also provide an attractive opportunity for new monophosphine
ligand design because of its rigid and bulky scaffold.
Here we report a dianthracenyl monophosphine ligand,
diAnthPhos (1), which exhibits versatile applications for a
number of palladium-catalyzed coupling reactions of a broad
range of heterocycle-containing substrates with a low catalyst
loading. Designing and synthesizing ligands by means of
photochemical approaches is an important strategy to establish
distinct properties, but remains underdeveloped in the
literature.6 We expect that the introduction and utility of
ligand 1 would open the door toward the development of the
dianthracene core as a new type of privileged scaffold for new
ligand/reaction discovery.
a
Reagents and conditions: (i) 2 (1.0 equiv), anthracene (10 equiv),
toluene, xenon lamp, 110 °C, 24 h; (ii) 3 (1.0 equiv), n-BuLi (1.25
equiv), THF, −78 °C, 1.5 h; then PPh2Cl (2.0 equiv), 25 °C, 15 h.
The ligand 1 features concise preparation, with two steps
from the commercially available 1-bromoanthracene (2) and
an overall 42% isolated yield. The [4 + 4] photocycloaddition
between 2 and excess unsubstituted anthracene under
ultraviolet light furnished the heterodimer 3. Treatment of 3
with n-butyllithium provided an aryl lithium intermediate
which then reacted with diphenylphosphine chloride, affording
the diAnthPhos (1) as an air-stable, free-flowing solid (Scheme
1b). The all-aryl substitutions on the phosphine endow the
ligand with good stability and ease of use in air. By design, the
placement of the phosphine moiety next to the bridge-head
position should maximize the steric effects of the dianthracene
Received: July 12, 2019
© XXXX American Chemical Society
A
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Letter
scaffold7 when ligand 1 coordinates with a transition metal
catalyst (cf. Figure 1).
Notably, compound 4y contains an unprotected labile amino
group that may complicate transition-metal-catalyzed reac-
tions. As summarized in Scheme 2, we were delighted to
identify that the monophosphine ligand 1, when complexed
with the Pd G4 dimer,10 could efficiently promote the
borylation of all three substrates with excellent yields under
a low catalyst loading (0.5 mol % Pd). Control experiments
showed that the absence of 1 led to much less product
formation. Inferior results to various extents were obtained
when replacing 1 with a series of phosphine-based ligands,
including simple triaryl- or trialkylphosphine ligands, Buchwald
monophosphine ligands,11 AntPhos,9b and chelating bis-
(phosphine) ligands.8,12 It should be noted that compared
with the diphenylphosphine moiety of 1, many of the above
ligands contain more electron-donating and sterically demand-
ing alkyl substituents on phosphines. Indeed, these results
highlighted the effectiveness of ligand design based on the
unique dianthracene scaffold.
Figure 1. X-ray crystallographic structure (ORTEP) of the precatalyst
1-Pd G4 with the thermal ellipsoids shown at a 50% probability.
Hydrogen atoms were omitted for clarity.
Pd-catalyzed Miyaura borylation is a widely used method-
ology with numerous important applications in medicinal and
material chemistry.8 In particular, general methods to convert
heterocycle-containing electrophiles to the corresponding
boronic esters are highly desirable, but remain challenging
likely due to the nucleophilicity and/or side reactions
originated from the heterocycles.9 In order to establish the
utility of ligand 1, we set out with a comprehensive evaluation
of three selected heteroaryl substrates to develop a generalized
condition (Scheme 2 and Supporting Information (SI) Tables
S1−S4). Specifically, 1-benzylpyrazole (4a), 4-bromoquinoline
(4r), and 5-bromo-2-aminopyrimidine (4y) represent struc-
tural diversity with regard to heterocycle scaffolds and electron
density.
In order to unambiguously characterize the Pd precatalyst
containing ligand 1, single crystals suitable for X-ray crystallo-
graphic analysis were obtained by slow diffusion of n-pentane
into a dichloromethane solution of the 1-Pd G4 complex at
−20 °C (Figure 1).13 The solid-state structure of 1-Pd G4
exhibits some similar features (e.g., bond lengths and bond
angles surrounding the Pd center) compared to the previously
reported structure of XPhos-Pd G4.10 The tetracoordinated
Pd(II) center is observed with a slightly distorted square planar
geometry, and the phosphine is bound to the palladium trans
to the Pd−N bond. Additionally, when complexed with Pd G4,
ligand 1 adopts a conformation that lays the two phenyl
substituents on the phosphine away from the bulky
dianthracene core.
Employing the standard conditions, we explored the reaction
scope with regard to the heterocycle-containing electrophiles
(Scheme 3a) and observed excellent method generality and
functional group tolerance.14 More than a dozen (hetero)aryl
moieties, which are frequently used pharmacophores, prove to
be suitable substrates with good efficiency and compatibility
regardless of the electronic effects, including pyrazole,
thiophene, isoxazole, pyridine, pyrimidine, indole, benzofuran,
benzothiophene, 7-azaindole, benzo[1,3]dioxoles, benzoxazole,
benzothiazole, benzothiadiazole, carbazole, dibenzothiophene,
quinoline, and dihydropyrimidinone (5a−5t). Notably, sub-
strates with steric hindrance (5c) or in the absence of
protecting groups (5f, 5j, and 5p) smoothly afforded the
desired products, showcasing the reaction robustness using the
monophosphine 1 as the ligand. Since some of the boronic
ester products (such as 5c, 5d, 5e, and 5r) are either unstable
during silica gel chromatography or difficult to separate from
minor impurities, we have further devised a one-pot Miyaura
borylation/Suzuki coupling protocol (see Scheme 7) to isolate
the corresponding C−C bond coupling products.
a
Scheme 2. Reaction Optimization by Evaluation of Ligands
To highlight the reaction utility featuring heterocycle-
containing substrates, late-stage borylations of pharmaceutical
derivatives were investigated (Scheme 3b). Starting from the
corresponding bromides or iodides, Celecoxib- and Trameti-
nib-derived boronic esters (5u and 5v, respectively) were
obtained with good to excellent yields, indicating profound
potential for applications in medicinal chemistry.
Heterocyclic boronic esters are highly important synthetic
building blocks which can serve as linchpin compounds to
access a variety of functionalized heterocycles.15 We next
applied the standard conditions to access the key synthetic
a
The yields were determined by 1H NMR using an internal standard.
B
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Scheme 3. Substrate Scope
Scheme 4. Synthetic Applications toward Pharmacologically
Active Molecules
a
b
With 0.5 mol % Pd G4 dimer and 1.2 mol % ligand 1. With 1.0 mol
c
% Pd G4 dimer and 2.4 mol % ligand 1. The yield was determined by
1H NMR using an internal standard. See Scheme 7 for the isolated
a
The reaction was conducted using THF as solvent at 80 °C.
yield of the corresponding C−C bond coupling product employing
d
the one-pot Miyaura borylation/Suzuki coupling protocol. The
inhibitor19 and a five-lipoxygenase activating protein (FLAP)
inhibitor.20
crude boronic ester 5l was further oxidized to the corresponding
hydroxy-containing product prior to purification, with the yield
referring to the final product (over two steps). See SI for details.
The Miyaura borylation reaction of heteroaryl substrates
also shows good potential for scaling-up under an even lower
catalyst loading. As shown in Scheme 5, the boronic ester
product 5i can be isolated in gram scale using a 0.05 mol %
loading of Pd G4 dimer and 0.12 mol % loading of ligand 1.
Encouraged by the successful Miyaura borylation reactions,
we then sought to expand the use of ligand 1 in a broader
e
f
With 0.5 mol % Pd2dba3 and 1.2 mol % ligand 1. Starting from aryl
iodide.
precursors of pharmacologically active molecules (Scheme 4).
Pleasingly, 5-bromopyrimidine derivative 4w could be
converted into product 5w, an intermediate toward a GPR
119 agonist.16 Pyrazolyl bromide 4x proceeded smoothly to
furnish the boronic ester 5x, which can be further carried
through the synthetic routes to access the anticancer drug
Crizotinib17 and a c-Met kinase inhibitor.18 Moreover,
excellent yield could be obtained for unprotected amino-
pyrimidine substrate 4y with the desired boronic ester 5y being
an key precursor en route to a phosphoinositide-3-kinase
Scheme 5. Gram-Scale Reaction
C
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range of Pd-catalyzed couplings. It was revealed that the same
combination of Pd G4 dimer and ligand 1 is a versatile and
effective catalyst. With minor alternations from the afore-
mentioned standard conditions (cf. Scheme 2), productive
applications included Suzuki−Miyaura coupling3a,21 between
1-nathphyl boronic acid and sterically demanding aryl
electrophiles (Scheme 6a, products 6a−6c), Negishi aryla-
tion22 of 2-bromopyrazine (Scheme 6b, product 7), and the
arylation of a 1-indanone derivative23 affording the tertiary
fluoride 8 (Scheme 6c).
Scheme 7. Applications of diAnthPhos (1) in One-Pot
Miyaura Borylation/Suzuki Coupling Reactions
a
Scheme 6. Applications of diAnthPhos (1) in Pd-Catalyzed
Coupling Reactions
a
b
All yields refer to the overall isolated yields over two steps. Reaction
time for the Suzuki coupling step was 48 h.
The utility of ligand 1 is further demonstrated by a one-pot
Miyaura borylation/Suzuki coupling protocol11a,24 for hetero-
aryl-containing substrates, affording various C−C coupling
products with high yields in an operation-efficient manner
(Scheme 7). After the Pd-catalyzed borylation step, base,
deoxygenated water, and the second electrophile were added
to the crude reaction mixture. Then the Suzuki coupling step
could proceed smoothly at elevated temperature, without the
need for workup procedures or any additional Pd catalyst/
ligand. On one hand, this one-pot protocol could enable facile
synthesis of heterocycle-derived coupling products from two
distinct electrophiles without the isolation of boronic esters
which may be unstable or time-consuming to separate
(Scheme 7a). On the other hand, the productive formation
of various heteroaryl-heteroaryl coupling products opens a new
pathway for the rapid construction of functionalized hetero-
cycle-rich compounds, and concurrently establishes the
robustness of the Pd/ligand 1 catalyst (Scheme 7b).
containing electrophiles at a low catalyst loading, among other
versatile applications. The straightforward two-step synthesis of
1 should allow scalable access and diverse derivatizations for
new ligand development. Considering the productive chem-
istry involving phosphine-based ligands and reagents, we
expect a profound opportunity to explore the unique
dianthracene core as the key feature for new molecule designs.
Continuing investigation in this direction is currently under-
way and will be reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
In summary, a novel anthracene photodimer-derived mono-
phosphine diAnthPhos (1) has been prepared in two steps as
an effective ligand for Pd-catalyzed coupling reactions. In
particular, the combination of Pd G4 dimer and ligand 1 is a
highly efficient catalyst to facilitate Miyaura borylation and
one-pot Miyaura borylation/Suzuki coupling of heterocycle-
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02414.
Experimental procedures and spectroscopic data for new
compounds (PDF)
D
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Accession Codes
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CCDC 1919887 contains the supplementary crystallographic
data for this paper. These 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hcong@mail.ipc.ac.cn.
ORCID
Chen-Ho Tung: 0000-0001-9999-9755
Li-Zhu Wu: 0000-0002-5561-9922
Huan Cong: 0000-0003-1687-2404
Author Contributions
X.W. and W.-G.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Strategic Priority Research Program
of Chinese Academy of Sciences (XDB17000000), the
National Key Research and Development Program of China
(2017YFA0206903), the National Natural Science Foundation
of China (21672227), the Recruitment Program of Global
Experts, K. C. Wong Education Foundation, and the TIPC
Director’s Fund is gratefully acknowledged. We thank Dr.
Chong Han (Genentech) for helpful discussions. Prof.
Congyang Wang (Institute of Chemistry, CAS) and Drs.
Xiaodi Yang (Shanghai University of Traditional Chinese
Medicine), Jie Su, and Wen Zhou (Peking University) are
acknowledged for assistance with compound characterizations.
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under the standard conditions.
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DOI: 10.1021/acs.orglett.9b02414
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