A general direct arylation of polyfluoroarenes with heteroaryl and aryl chlorides catalyzed by palladium indolylphosphine complexes

Article abstract of DOI:10.1002/asia.201500048

The first general examples of direct coupling of heteroaryl chlorides, especially substituted 2-pyridyl chlorides which were previously found to be problematic, with electron-deficient polyfluoroarenes are reported. Pd(OAc)₂ associated with 3-(

Full text of DOI:10.1002/asia.201500048

CHEMISTRY
AN ASIAN JOURNAL
Accepted Article
Title: A General Direct Arylation of Polyfluoroarenes with Heteroaryl and Aryl Chlo-
rides Catalyzed by Palladium Indolylphosphine Complexes
Authors: On Ying Yuen; Mueangkaew Charoensak; Chau Ming SO; Chutima Kuha-
karn; Fuk Yee Kwong
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Chemistry - An Asian Journal
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COMMUNICATION
A General Direct Arylation of Polyfluoroarenes with Heteroaryl
and Aryl Chlorides Catalyzed by Palladium Indolylphosphine
Complexes
On Ying Yuen,[a] Mueangkaew Charoensak,[b] Chau Ming So,[a] Chutima Kuhakarn[b] and Fuk Yee
Kwong*[a]
In celebrating the 10th year Anniversary of Cutting-Edge Organic Chemistry in Asia Core Program (ACP)
Abstract: The first general examples of direct coupling of heteroaryl
chlorides, especially substituted 2-pyridyl chlorides in which they
were previously found to be problematic, with electron deficient
polyfluoroarenes are reported. Pd(OAc)2 associated with L1 serves
as the effective catalyst which allows the challenging direct coupling
of heteroaryl chlorides and polyfluoroarenes to be succeeded. In
addition to heterocycles, a wide range of non-activated and activated
aryl chlorides and alkenyl chloride were also applicable under this
catalyst system. The catalyst loading down to 1 mol% Pd can be
achieved.
Transition metal-catalyzed cross-coupling constitutes as
useful method for connecting two aromatic building blocks
together. However, integrating an electron-deficient aromatic
fragment to the target molecule has encountered difficulty. For
instance, the general use of highly electron-deficient nucleophilic
partners (e.g. C6F5B(OH)2) are still problematic.
Those
challenges may arise from: (1) the preparation of highly electron-
5
deficient nucleophiles is not straightforward; (2) electron-
deficient heteroaryl and polyfluoroaryl nucleophiles often
undergo transmetallation process at a relatively slower rate; and
(3) electron-deficient arylboronic acids are moderately stable
and usually decompose via rapid protodeboronation during the
course of coupling reactions. Indeed, these problematic issues
must be tackled in order to afford target product in a better
yield.5,6 One of the usual solutions is to circumvent the selection
of relatively electron-deficient arene as the nucleophilic partner
between two coupling components (Scheme 1A). Nevertheless,
this strategy would become a challenge, if both of the coupling
partners are electron-deficient aromatics (Scheme 1B). Hence,
effort in seeking efficient protocol for obtaining electron-deficient
biaryls is indeed demanded.
Heterobiaryl motifs are commonly found in biologically active
compounds, natural products, pharmaceutically effective
molecules and functional materials. Particularly, 2-substituted
nitrogen-containing compounds constitute high relevance in
pharmaceutical chemistry and material sciences.1 For examples,
polymer and hybrid electron accepting materials based on
2
semiconducting
perfluorophenylquinoline
(P5FQ),
the
sensitization of TiO2 nanoparticles and electrodes with
perfluoroaryl motif in organic semioconducting dye for
photochemical applications (Ph5FQ-TiO2)3, and betaine dyes for
determination of solvent polarity (eicosanfluoro (F20)-substituted
betaine dye).4
Figure 1. Examples of useful heteroaryl-perfluoroaryl-containing molecules
Scheme 1. Advantages and limitations of interchanging nucleophile strategy
[a]
[b]
Ms. O. Y. Yuen, Dr. C. M. So, Prof. Dr. F. Y. Kwong*
State Key Laboratory of Chirosciences and Department of Applied
Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hung Hom, Kowloon, Hong Kong
E-mail: fuk-yee.kwong@polyu.edu.hk
Mr. M. Charoensak, Prof. Dr. C. Kuhakarn
Department of Chemistry and Center of Excellence for Innovation in
Chemistry (PERCH-CIC), Faculty of Science, Mahidol University,
Rama VI Road, Bangkok 10400, Thailand
Direct C-H arylation of polyfluoroarenes is an excellent
alternative to conventional cross-coupling reactions when
heteroaryl and polyfluoroaryl components are used. 7 This
synthetic route allows a better atom economy and more
streamlined chemical synthesis. For instance, the direct usage
of polyfluoroaryl could avoid the multi-step synthesis of unstable
heteroarylboronic acid8 or polyfluoroarylboronic acid and thus
eventually improves the step-economy.9
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))

Chemistry - An Asian Journal
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COMMUNICATION
Scheme 3. Two step synthesis of indolyl phosphine L1 from commercially
available materials.
To evaluate the effectiveness of L1 for direct arylation of
polyfluorobenzenes with heteroaryl chlorides, 2-chloroquinoline
and pentafluorobenzene were used as benchmark substrates
(Table 1). Catalyst loading of 2.0 mol% Pd was initially applied
in probing the ligand efficacy. Pd(OAc)2 was found to be
superior among Pd2(dba)3, PdCl2(CH3CN)2, Pd(TFA)2 and
Pd(OAc)2 screened (Table 1, entries 1-4). Addition of 10 mol%
PivOH improved the desired product yield from 43% to 84%
(Table 1, entries 1 vs 5). Na3PO4, KOAc and Na2CO3 provided
comparable product yields among the common inorganic bases
examined (Table 1, entries 6-10). DMA was found to be the
best choice of solvent (Table1, entries 1 vs 11-13).
Scheme 2. Transition metal-catalyzed direct arylation of polyfluoroarenes with
substituted 2-pyridyl halides and sulfonates
Despite the advantages of using direct arylation method,
there have been only a few reports regarding the successful
direct C-H arylation of polyfluoroarenes with heteroaryl halides
and sulfonates, in particular 2-substituted-pyridyl halides and
sulfonates (Scheme 2). In 2008, Daugulis initially reported a
copper-catalyzed arylation of polyfluorobenzenes with aryl and
heteroaryl iodides and bromides.10 One example concerning the
coupling of 2-bromopyridine was demonstrated. Later, they
employed the same catalyst system and similar reaction
conditions for 2-pyridyl chloride coupling.11 Nevertheless, even
Table 1. Initial Screening of Palladium-Catalyzed Direct Arylation of
Polyfluoroarenes with Heteroaryl Chlorides.[a]
Entry
Pd source (mol %)
Base
Solvent
Yield %[b]
1
Pd(OAc)2 (2)
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na3PO4
NaOAc
KOAc
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
Toluene
DMF
43
2
Pd(TFA)2 (2)
trace
5
o
under the harsh reaction conditions (120–150 C), the yield of
3
PdCl2(CH3CN)2 (2)
Pd2(dba)3 (2)
Pd(OAc)2 (2)
the corresponding coupling product from 2-chloropyridine and
pentafluorbenzene was moderate. In 2011, Zhang reported a
palladium-catalyzed direct arylation of polyfluoroarenes with
heteroaryl tosylates. 12 Indeed, aryl sulfonates are the most
versatile complementary substrates to aryl halides for various
coupling reactions. Yet, the cost of substituted hydroxypyridines
(as the precursors for the corresponding tosylates) is
exceptionally higher when compared to the direct usage of
substituted pyridyl chlorides.13 Moreover, additional tosylation
4
trace
84[c]
82[c]
56[c]
82[c]
79[c]
21[c]
32
5
6
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.5)
Pd(OAc)2 (2)
7
8
9
Na2CO3
K2CO3
10
11
12
13
Na3PO4
Na3PO4
Na3PO4
Pd(OAc)2 (2)
41
34[c]
step of hydroxypyridines is required too.
Therefore, the
Pd(OAc)2 (0.5)
i-PrOAc
development of a new catalytic system for direct usage of
inexpensive and versatile heteroaryl chlorides is still highly
desirable.
[a] Reaction conditions: 2-Chloroquinoline (0.5 mmol), pentafluorobenzene
(1.0 mmol), Pd source (2 mol%), L1 (8 mol%), base (0.75 mmol) and solvent
(1.0 mL) were stirred at 100 oC for 18 h under N2. [b] Calibrated GC yields
were reported using dodecane as internal standard. [c] 10 mol% PivOH was
added.
In view of current drawbacks and our persisting interests in
14
palladium-catalyzed direct C-H arylation reaction
and
phosphine ligand synthesis and applications, 15 we aim to
develop an efficient protocol for coupling of electron-deficient
polyfluoroarenes with heteroaryl chlorides, and especially
With these encouraging results in hand, we next investigated
the effect of phosphine ligands in this reaction (Scheme 4).
Previously reported indolylphosphine ligands where the
phosphino group is attached to different positions of the indole
ring were examined (L1–L4). Ligand L1 was found to be the
best ligands for this reaction. A list of commercially available
and well-recognized effective phosphine ligands were further
evaluated (L5–L12), such as PCy3, PPh3, CataCXium®A,
CataCXium®PCy, cataCXium®PInCy, SPhos, XPhos and Cy-
substituted 2-pyridyl chlorides.
We initially chose the 3-
(dicyclohexylphosphino)-2-phenylindole (PCy2 Phendole-Phos)
L1 to test the feasibility of direct arylation of polyfluoroarenes
with heteroaryl chlorides. This ligand features of commercially
available and inexpensive starting materials and can be easily
prepared in large scale in 2 steps (Scheme 3).

Chemistry - An Asian Journal
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COMMUNICATION
JohnPhos. Surprisingly, other than XPhos (L6) could give a
better yield among the ligands examined, poor substrate
conversions and product yields were observed from L5 and L7-
L12. Therefore, catalyst system comprising Pd(OAc)2 and L1
was employed to test the scope of this reaction.
reaction conditions (Table 3, 5iu – 5ou). Particularly, the free
amino groups remained intact during the course of the reaction
(Table 3, 5qu and 5ru). Alkenyl chloride could also serve as an
effective substrate for direct arylation of pentafluorobenzene
(Table 3, 5su). To the best of our knowledge, it is the lowest
palladium catalyst loading reported to date for this reaction.
Table 2. Palladium-Catalyzed Direct Arylation of Polyfluoroarenes with
Heteroaryl Chlorides. [a, b]
Scheme 4. Investigation of Phosphine Ligands in Pd-catalyzed Direct
Arylation of Perfluorobenzene with 2-Quinolyl Chlorides. Reaction conditions:
2-chloroquinoline (0.50 mmol), pentafluorobenzene (1.0 mmol), Pd(OAc)2 (2
mol%), L (8 mol%), Na3PO4 (0.75 mmol) and DMA (1.0 mL) were stirred at
100 oC for 18 h under nitrogen. Calibrated GC yields were reported using
dodecane as internal standard.
A wide range of heteroaryl chlorides were probed in order to
test the efficacy of the new catalytic system (Table 2). 2-
Chloropyridine, in which it is the most challenging cross-coupling
11
partner
showed excellent product yield under these reaction
conditions (Table 2, 3au). 6-Substituted-2-chloropyridines were
efficiently coupled smoothly with pentafluorobenzene in good
yields (Table 2, 3cu–3gu). Diphenylation could be done when
2,6-dichloropyridine was used (Table 2, 3hu). Other
polyfluoroarenes were also applicable coupling partners (Table 2,
3cv–3cz). It should be noted that 10 new compounds were
synthesized among the 13 entries which may implies the lack of
current effective methods for accessing pyridyl/polyfluoro biaryl
compounds, in spite of the usefulness of polyfluoroarene
compounds.
[a] Reaction conditions: Heteroaryl chlorides (0.5 mmol), polyfluorobenzenes
(1.0 mmol), Pd(OAc)2 : L1 (1 : 4), Na3PO4 (0.75 mmol), PivOH (10 mol%) and
DMA (1.0 mL) were stirred at 100 oC for 24 h under nitrogen. [b] Isolated
yields. [c] Dioxane (1.0 mL) was used and stirred at 110 oC. [d] Dioxane : DMA
(1 : 1, total 1.0 mL) was used and stirred at 110 oC. [e] Dioxane : DMA (4 : 1,
total 1.0 mL) was used and stirred at 110 oC. [f] 4 equiv. polyfluorobenzene
was used. [g]
3 equiv. polyfluorobenzene was used. [h] 5 equiv.
polyfluorobenzene was used.
In order to probe the generality of the Pd-L1 catalyst system,
a series of the electron neutral, electron rich and functionalized
aryl chlorides were further examined (Table 3). Electron rich
aryl chlorides were coupled with pentafluorobenzene in excellent
yields (Table 3, 5eu – 5hu). Functional groups, such as –CHO,
–COMe, –COOMe, –COPh, –CN, were compatible under these

Chemistry - An Asian Journal
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COMMUNICATION
Table 3. Palladium-Catalyzed Direct Arylation of Polyfluoroarenes with Aryl
Pd could be achieved. Moreover, the substrate scope can be
extended to non-activated and activated aryl chlorides and
alkenyl chloride without difficulty. General functional groups
such as –CHO, –C(O)Me, –COOMe, –C(O)Ph, –NHC(O)Me, –
CN, –NH2 were compatible under these reaction conditions. We
believe that this direct heteroarylation protocol provides a useful
and facile access to polyfluoro/hetero biaryl compounds that are
important in pharmaceutical chemistry and material sciences.
Chlorides. [a, b]
Experimental Section
General Procedure for direct arylation of polyfluoroarenes with aryl
chlorides (Pd catalysts loading equal to or larger than 2.0 mol%):
Pd(OAc)2 (Pd loading indicated in the entry table) and L1 (Pd : L = 1 : 4)
were loaded into a Schlenk tube equipped with a Teflon-coated magnetic
stir bar. The tubes were evacuated and backfilled with nitrogen (3
cycles).
Precomplexation was applied by adding freshly distilled
dichloromethane (1.0 mL) and Et3N (0.1 mL) into the tube. The
palladium complex stock solution was stirred and warmed using a hair
drier for 1 to 2 minutes until the solvent started boiling. The solvent was
then evaporated under high vacuum. Na3PO4 (0.164 g, 0.75 mmol) and
solid aryl chlorides (0.50 mmol) were loaded into the tube, and the
system was further evacuated and flushed with nitrogen for three times.
Polyfluoroarenes (1.0 mmol), aryl chlorides (if liquid, 0.5 mmol), pivalic
acid (5.1 mg, 0.050 mmol) and DMA (1.0 mL) were added into the tube
via syringe and the mixtures were stirred at room temperature for 3-5
minutes. The tube was then placed into a preheated oil bath (100 °C)
and stirred for 24 h. After the completion of the reaction, the reaction
tube was allowed to reach room temperature. Ethyl acetate (~10 mL)
and water (~3 mL) were added. The organic layer was subjected to GC
analysis. The filtrate was concentrated under reduced pressure. The
crude products were purified by flash column chromatography on silica
gel (230-400 mesh) to afford the desired product.
Acknowledgements
We thank the Research Grants Council of Hong Kong (GRF:
PolyU5014/10P), PolyU Development Grant (1BD07) and State
Key Laboratory of Chirosciences for financial support. F.Y.K is
grateful to the Croucher Foundation for the Croucher Senior
Research Fellowship 2013.
Keywords: Palladium • C-H arylation • Phosphine • Aryl
Chlorides • Polyfluoroarenes
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[a] Reaction conditions: Aryl chlorides (0.5 mmol), polyfluorobenzenes (1.0
mmol), Pd(OAc)2 : L1 (1 : 4), Na3PO4(0.75 mmol), PivOH (10 mol%) and DMA
(1.0 mL) were stirred at 100 oC for 24 h. [b] Isolated yields. [c] without 10 mol%
PivOH.
In conclusion, we reported the first general palladium-
catalyzed direct arylation of polyfluorobenzenes with heteroaryl
chlorides especially substituted 2-pyridyl chlorides using the
combination of Pd(OAc)2 and indolylphosphine ligand L1 as
catalyst system. Particularly noteworthy is that the reaction
conditions were mild and the catalyst loading down to 1 mol%

Chemistry - An Asian Journal
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Chemistry - An Asian Journal
COMMUNICATION
COMMUNICATION
10.1002/asia.201500048
On Ying Yuen, Mueangkaew
Charoensak, Chau Ming So, Chutima
Kuhakarn and Fuk Yee Kwong*
Page No. – Page No.
A General Direct Arylation of
Polyfluoroarenes with Heteroaryl and
Aryl Chlorides Catalyzed by
Palladium Indolylphosphine
Complexes
The first general examples of direct coupling of heteroaryl chlorides, especially
substituted-2-pyridyl chlorides in which they were previously found to be
problematic, with electron deficient polyfluoroarenes are reported.