Palladium-catalyzed ortho-selective c-f activation of polyfluoroarenes with triethylsilane: A facile access to partially fluorinated aromatics

Article abstract of DOI:10.1002/anie.201300400

PdF: A simple catalytic system, broad substrate scope, and high versatility provide a useful and facile access to partially fluorinated aromatics (see scheme). Tuning the reaction conditions enables a diverse range of product structures to be prepared. Copyright

Full text of DOI:10.1002/anie.201300400

Angewandte
Chemie
DOI: 10.1002/anie.201300400
À
Catalytic C F Activation
À
Palladium-Catalyzed Ortho-Selective C F Activation of
Polyfluoroarenes with Triethylsilane: A Facile Access to Partially
Fluorinated Aromatics**
Zhao Chen, Chun-Yang He, Zengsheng Yin, Liye Chen, Yi He, and Xingang Zhang*
Owing to the unique characteristics of fluorine that often lead
to profound changes in physical, chemical, and biological
properties of organic molecules when it is incorporated,[1]
partially fluorinated aromatics play an important role in life
and materials sciences.[2] However, synthetic access to these
fluorinated compounds is difficulties[3] and there is only
limited commercial availability of fluoroaromatic sources.
One attractive approach to partially fluorinated aromatics is
Azine/diazine (e.g., pyridine, quinoline, quinoxaline)
substituted fluorinated aromatics bearing a hydride ortho to
the heteroaryl group are an important structural motif in
light-emitting devices[10] and photocatalysts.[11] However, the
limited synthetic methods and commercial availability of
fluoroaryl patterns significantly limits the structural and
functional diversity of this structural motif in further appli-
cations. Continuing our study in palladium-catalyzed poly-
fluoroarene chemistry,[12] herein, we describe the first exam-
ple of palladium-catalyzed, chelation-assisted ortho-selective
À
selective substitution of polyfluoroarenes through C F bond
activation, as polyfluoroarenes are more readily available and
cheaper than their mixed halo or organometallic counter-
parts. In the past few years, important progress has been made
À
C F activation of polyfluoroarenes with triethylsilane, in
which N-containing heterocycles were employed as directing
groups. This method provides a useful and facile access to
a wide range of azine/diazine substituted fluoroaromatics that
are difficult to synthesize otherwise.
in this field,[4] and the reduction of C F bonds (hydro-
À
defluorination, HDF) in polyfluoroarenes has become
a useful approach to access partially fluorinated aromatics
that are difficult to obtain otherwise.[5] However, compared to
some aromatic nucleophilic substitution (SNAr) reactions of
polyfluoroarenes that can regioselectively lead to substituted
polyfluoroarenes with strong nucleophiles,[4d] the transition-
metal-catalyzed chemo- and regioselective transformations of
We began this study on the basis of the hypothesis that
with the aid of a directing group, such as N-containing
heterocycles, ortho to the fluorine to chelate and direct
delivery of palladium catalyst, the oxidative addition of the
0
[13]
À
C F bond to Pd would be facilitated. Subsequently, the
Pd-catalyzed ortho-selective hydrodefluorination of poly-
fluoroarenes would be possible in the presence of a reductant,
À
C F bonds remain a challenge owing to the robustness of the
À
C F bond and difficulty in adjusting reaction selectivity of
[6]
À
À
different C F bonds on an aromatic ring. Although
such as silane (Scheme 1). The formation of thermostable Si
F[14] bond between the newly formed Pd F complex (I or II)
À
examples of selective transition-metal-catalyzed HDF of
polyfluoroarenes have been reported, most of them focus
on the mechanistic understanding of the HDF cycle.[7,8] In
particular, for the palladium-catalyzed HDF reaction, only
hydrodefluorination of pentafluoropyridine at the para posi-
tion has been reported to date, in which palladium fluoro or
palladium hydrido complexes were used as precatalysts.[9]
Therefore, developing a new simple catalytic system with
broad substrate scope and high regioselectivity for wide-
spread synthetic applications is appealing.
and silane 2 would be a driving force to promote the
generation of palladium hydrido complex (III or IV) that
would release ortho hydrodefluorinated aromatics V after
reductive elimination.
[*] C.-Y. He, Z. Yin, L. Chen, Prof. Dr. X. Zhang
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Science
345 Lingling Lu, Shanghai 200032 (China)
E-mail: xgzhang@mail.sioc.ac.cn
Z. Chen, Y. He
School of Chemistry and Chemical Engineering
Southwest Petroleum University
8 Xindu Avenue, Chendu, Sichuan 610500 (China)
[**] This work was financially supported by the National Basic Research
Program of China (973 Program) (No. 2012CB821600), the NSFC
(No 21172242), and SIOC.
Scheme 1. Mechanism for the palladium-catalyzed, chelation-assisted
À
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201300400.
ortho-selective C F activation of polyfluoroarenes with silane. DG=dir-
ecting group
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Accordingly, 2-(perfluorophenyl)pyridine 1a was chose as
the model substrate for this study, as the resulting hydro-
defluorinated product 3a is an important structural motif in
photoelectronic materials and compound 1a can be easily
accessed by the reaction of cheap and commercially available
pentafluorobenzene with 2-bromopyridine.[3b,c] Initially, the
reaction of 1a with triethylsilane 2 was investigated in the
presence of [Pd(PPh3)4] (10 mol%) in DMF at 1008C,
providing 3a in 11% yield along with 89% starting material
1a (Table 1, entry 1). Because the base can be functionalized
showed the best catalytic effect (Table 1, entry 6) (for details
see Supporting Information). Among the tested ligands,
bidentate ligands dppe and dppb benefited the reaction
(Table 1, entries 10 and 12), but a 13% yield of di-hydro-
defluorinated product 4a was observed for dppe (Table 1,
entry 10), suggesting that the catalytic system with dppe is
more reactive for di-hydrodefluorination. The reaction was
also found to be sensitive to the solvents and bases. DMF and
Na2CO3 were the optimum ones. Other solvents or bases were
less or not effective (for details see Supporting Information).
Finally, an optimum yield of isolated product (91%)
À
Table 1: Palladium-catalyzed ortho-selective C F activation of 2-(perfluorophenyl)-
was obtained with utilization of [{PdCl(C3H5)}2]
(2.5 mol%), dppb (5 mol%), and Na2CO3
(0.2 equiv) in DMF at 908C (Table 1, entry 15).
Without Pd catalyst or phosphane ligand no desired
product was obtained, thus demonstrating that a Pd-
(0/II) catalytic cycle is involved in the reaction
(Table 1, entries 17, 18). Additionally, the di-hydro-
defluorinated 4a can also be obtained in good yield
(77%) by using [{PdCl(C3H5)}2] (3.75 mol%), dppe
(7.5 mol%), and Et3SiH (2.5 equiv) at 1208C
(Table 1, entry 19).
To explore the substrate scope of this method,
a variety of N-containing heterocyclic pentafluoro-
benzenes 1[16] were investigated. We found that the
optimum reaction conditions for 1a were not always
ideal for other substrates owing to their relatively
“inertness”. Accordingly, on the basis of the above
results (Table 1, entries 10 and 19), a more reactive
catalytic system using [{PdCl(C3H5)}2] (3.75 mol%),
dppe (7.5 mol%), Na2CO3 (2.0 equiv),[17] and Et3SiH
(2.0 equiv) was identified, which allowed hydrode-
fluorination of a wide range of N-heterocyclic-
substituted pentafluorobenzenes 1 in high efficiency
and ortho selectivity (Table 2).
pyridine 1a with triethylsilane.[a]
Entry
Pd complex, x [mol%]
L, y [mol%]
additive [equiv]
3a Yield [%][b]
1
[Pd(PPh3)4], 10
–
–
11
2
3
4
5
6
7
8
9
10
11
12
13[d]
14[d]
15[d]
16[d]
17[d]
18[d]
19
[Pd(PPh3)4], 10
[Pd(PPh3)4], 10
[Pd(PPh3)4], 10
[Pd(PPh3)4], 10
–
–
–
Cs2CO3 [2.0]
Na2CO3 [2.0]
NaHCO3[2.0]
Na2CO3 [2.0]
Na2CO3 [2.0]
Na2CO3 [2.0]
Na2CO3 [2.0]
Na2CO3 [2.0]
Na2CO3 [2.0]
Na2CO3 [2.0]
Na2CO3 [2.0]
Na2CO3 [2.0]
Na2CO3 [1.0]
Na2CO3 [0.2]
–
34
32
24
75
89
66
14
6
L1, 20
L1, 20
L1, 10
SPhos, 10
XPhos, 10
dppe, 5
dppp, 5
dppb, 5
dppb, 5
dppb, 5
dppb, 5
dppb, 5
–
[{PdCl(C3H5)}2], 5
[{PdCl(C3H5)}2], 2.5
[{PdCl(C3H5)}2], 2.5
[{PdCl(C3H5)}2], 2.5
[{PdCl(C3H5)}2], 2.5
[{PdCl(C3H5)}2], 2.5
[{PdCl(C3H5)}2], 2.5
[{PdCl(C3H5)}2], 2.5
[{PdCl(C3H5)}2], 2.5
[{PdCl(C3H5)}2], 2.5
[{PdCl(C3H5)}2], 2.5
[{PdCl(C3H5)}2], 2.5
–
73[c]
68[e]
87 (69)[f]
90 (81)[f]
89[f]
99 (91)[e]
63[e]
NR
Na2CO3 [0.2]
Na2CO3 [0.2]
Na2CO3 [2.0]
dppb, 5
dppe, 7.5
NR
Substrates bearing functionalized pyridyl or
quinolinyl groups underwent the reaction smoothly
(Table 2, 3a–3g). In particular, the ester group,
which is useful during the downstream transforma-
tions, was stable under the reaction conditions
(Table 2, 3g). Good chemo- and regio-selectivity
[{PdCl(C3H5)}2], 3.75
(13)[g]
[a] Reaction conditions (unless otherwise specified): 1a (0.2 mmol), Et3SiH
(2.0 equiv), DMF (1.0 mL). L1, P(biphenyl-2-yl)Cy2. [b] NMR yield determined by
19F NMR using fluorobenzene as internal standard, yield of isolated product is in
parenthesis. [c] 13% yield of 4a was observed. [d] Reaction conducted at 908C.
[e] No 4a was observed. [f] Less than 5% of 4a were observed. [g] Using 2.5 equiv of
Et3SiH, and reaction conducted at 1208C for 8 h. 77% yield of 4a was isolated.
À
was observed for 3b in which the ortho C F bond on
the pyridine ring was intact (Table 2, 3b), while
À
a reduction of C Cl bond was observed for 2-chloro
pyridyl pentafluorobenzene, demonstrating the higher bond
as an activator for the silicon-based cross-coupling reaction,[15]
we envisioned that the addition of Cs2CO3 may activate
À
À
dissociation energies of the C F bond than the C Cl bond
(Table 2, 3a’). It should be pointed out that benzothiazole and
oxazoline functionalities were also applicable (Table 2, 3j and
3k), thus providing an efficient way to diverse structures for
further applications. However, for 2-quinaxolinyl-substituted
substrates, using [Pd(PPh3)4] instead of [{PdCl(C3H5)}2]
furnished the corresponding products more effective with
moderate to good yields (Table 2, 3h and 3i). The usefulness
of this method is also shown by facile access of 3a in a 1-gram
scale synthesis, thus indicating the good reliability of the
process (Table 2, 3a). To further demonstrate the versatility
of this method, the di-hydrodefluorinated products 4d and 4 f
can also be obtained from 1d and 1 f, respectively, in high
efficiency (Table 2, 4d and 4 f). Thus, through this strategy,
À
triethylsilane 2 and aid the F H exchange between the newly
À
formed Pd F complex (I or II) and Et3SiH. As a result the
conversion of 1a into the desired product 3a would be
promoted. To our delight, the yield was improved to 34%
albeit significant formation of by-product (43% of hydro-
defluorinated product at the para position was observed)
when using Cs2CO3 (Table 1, entry 2). The side reactions can
be inhibited by switching Cs2CO3 to a weaker base, such as
Na2CO3 (Table 1, entry 3). To further improve the reaction
efficiency, a series of reaction parameters, such as different Pd
salts, phosphane ligands, solvents, bases, and reaction temper-
ature were examined (Table 1, entries 5–12) (for details see
Supporting Information). It turned out that [{PdCl(C3H5)}2]
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Table 2: Palladium-catalyzed ortho-selective C F activation of N-containing-heterocycle pentafluoro-
sively afforded 6e. The isomer
generated from the reduction of
benzenes 1 with triethylsilane.[a]
À
the other C F bond ortho to the
quinolinyl group was not observed
(Table 3, 6e). This result may be
attributed to the electron-with-
drawing effect of an additional
fluorine atom attached to C-3,
À
which activates the C F bond at
the 2-position so that oxidative
0
À
addition of Pd to the C F bond
occurs preferentially at this site.
The X-ray crystallographic analysis
of 6e further confirmed its struc-
ture.[18] It was also possible to
efficiently generate di-hydrode-
fluorinated products by a sequen-
À
tial C F bond activation strategy.
For example, partially fluorinated
aromatics 4a and 6g were effi-
ciently synthesized from com-
pounds 3a and 6c, respectively
(Table 3, 4a and 6g).
In an attempt to understand the
proposed mechanism illustrated in
Scheme 1, the following experi-
ments
were
performed
(Scheme 2). Unexpectedly, when
the reaction of 1e with [{PdCl-
(C3H5)}2] (0.5 equiv) and dppe
(1.0 equiv) in the presence of
Et3SiH and Na2CO3 was conducted
at room temperature, formation of
À
the Pd Cl complex II-2 instead of
À
Pd F complex II-1 or
I (see
Scheme 1) was observed (Sche-
me 2a). Further investigation
revealed that only trace amount
of desired product 3e was observed
under catalytic reaction conditions
(Scheme 2b). These findings indi-
cated that an active Pd0 species was
generated in the reaction, which
facilitated the oxidative addition of
[a] Reaction conditions (unless otherwise specified): 1 (0.4 mmol), Et3SiH (2.0 equiv), DMF (2.0 mL),
8 h. All reported reaction yields are of isolated products. [b] Using 2.5 mol% [{PdCl(C3H5)}2], 5 mol%
dppb, 0.2 equiv of Na2CO3, 908C, 8 h. [c] Reaction conducted at 908C. [d] Using 1.5 equiv of Et3SiH and
reaction run for 3–4 h. [e] Using 10 mol% [Pd(PPh3)4] and reaction conducted at 1208C for 13 h.
[f] 1 gram scale reaction using 2.5 mol% [{PdCl(C3H5)}2], 5 mol% dppb, and 0.2 equiv of Na2CO3 at
908C. [g] Using 2.5 equiv of Et3SiH.
0
À
a series of partially fluorinated arenes, which are difficult to
prepare otherwise, can be rapid access from simple and
readily available starting materials.
the C F bond to Pd . As to the formation of II-2, we reasoned
that when [{PdCl(C3H5)}2] was treated with Et3SiH and dppe,
besides the formation of Pd0 species, Et3SiCl was also
The hydrodefluorination of various fluoroarenes 5[16]
containing 3–4 fluorine atoms with Et3SiH were also tested
and representative results are illustrated in Table 3.Generally,
compared to pentafluorobenzene derivatives 1, higher yields
were obtained for substrates 5. Importantly, even for trifluor-
obenzene derivatives 5h and 5i, almost quantitative yields of
the corresponding products 6h and 6i were obtained (Table 3,
6h and 6i), providing a highly efficient way to access these
important structural motifs for photoelectronic materials.[10,11]
Fluorinated pyridine was also a suitable substrate with
reasonable yield obtained (Table 3, 6 f). It was noteworthy
that unsymmetrical tetrafluorobenzene derivative 5e exclu-
generated.[19] Subsequently, Et3SiCl reacted with Pd F com-
À
0
À
plex II-1 generated by the oxidative addition of C F to Pd to
provide Pd Cl complex II-2 (Scheme 2c).[9a] The structure of
À
II-2 was confirmed by X-ray crystallographic analysis (see
Supporting Information Figure S2).[18] Subjecting of a solution
of II-2 in DMF, in the presence of Et3SiH and Na2CO3, to
heating at 908C indeed afforded the final product 3e
(Scheme 2d). Thus, these results demonstrate that the
catalytic cycle involves the N-containing directing group
À
chelation-assisted ortho-selective oxidative addition of the C
F bond to Pd0 and reductive elimination of the hydrode-
fluorinated products.
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Table 3: Palladium-catalyzed ortho-selective C F activation of N-containing-heterocycle fluoroarenes 5
To illustrate the potential appli-
cations of this method, the con-
with triethylsilane.[a]
À
À
struction of C C bond by C F bond
activation has also been exam-
ined.[20] As shown in Scheme 3,
compounds 7 and 8 can be easily
prepared by palladium-catalyzed
cross-coupling of 1 or 5 with various
aryl and alkenyl species including
boronic acids, borates and silanes.
In conclusion, we have devel-
oped an efficient and versatile
method for preparation of partially
fluorinated aromatics by Pd-cata-
lyzed, chelation-assisted, ortho-
À
selective C F bond activation of N-
heterocycle-substituted polyfluor-
oarenes with Et3SiH. Additionally,
this method can also be extended to
À
À
C C bond formation by C F bond
activation. The simple catalytic
system, broad substrate scope,
operational simplicity, high reaction
efficiency, and excellent regioselec-
tivity of this route make it a useful
method to access a series of interest-
ing azine/dizine-substituted fluo-
roarenes for drug discovery and
photoelectronic devices. Further
studies to uncover the detailed
mechanism as well as other deriva-
tive reactions are now in progress.
[a] Reaction conditions (unless otherwise specified): 1 (0.4 mmol), Et3SiH (2.0 equiv), DMF (2.0 mL), 8–
13 h. All reported reaction yields are of isolated product. [b] Reaction conducted at 908C. [c] Using
2.5 mol% [{PdCl(C3H5)}2], 5 mol% dppb, 0.2 equiv of Na2CO3 at 908C, 6 h.
À
Scheme 3. Synthesis of compounds 7 and 8 by C F bond activation.
[a] [PdCl2(dppf)] (5 mol%), X-phos (10 mol%), K2CO3 (1.0–2.0 equiv),
DMF, 1008C. X-phos, dicyclohexyl(2’,4’,6’-triisopropyl-[1,1’-biphenyl]-2-
yl)phosphine.
Received: January 16, 2013
Revised: February 27, 2013
Published online: April 19, 2013
À
Keywords: C F activation · homogeneous catalysis ·
hydrodefluorination · palladium · polyfluoroarenes
.
Scheme 2. Experiments for mechanistic studies.
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À
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À
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and [12d].
[17] Using less than 2.0 equiv of Na2CO3 led to lower yields.
[18] CCDC 915389 (6e), 918117 (II-2) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[19] U. S. Mahajan, R. R. Godinde, P. N. Mandhare, Synth. Commun.
2011, 41, 2195.
[8] For other examples of hydrodefluorination, see: a) C. Douvris,
O. V. Ozerov, Science 2008, 321, 1188; b) M. F. Kꢀhnel, D. Lentz,
Angew. Chem. 2010, 122, 2995; Angew. Chem. Int. Ed. 2010, 49,
[20] a) K. Kawamoto, T. Kochi, M. Sato, E. Mizushima, F. Kakiuchi,
Tetrahedron Lett. 2011, 52, 5888; b) D. Yu, Q. Shen, L. Lu, J. Org.
Chem. 2012, 77, 1798.
À
2933. For C F bond activation of unactivated aliphatic fluorides,
Angew. Chem. Int. Ed. 2013, 52, 5813 –5817
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