Direct Pd-catalyzed benzylation of highly electron-deficient perfluoroarenes

Article abstract of DOI:10.1039/c0cc00598c

An efficient and practical method to a wide range of perfluorinated unsymmetrical diarylmethanes with good to excellent yields and high regioselectivities has been developed by Pd-catalyzed direct benzylation of highly electron-deficient perfluoroarenes; excellent compatibility of functional groups has also been established.

Full text of DOI:10.1039/c0cc00598c

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Direct Pd-catalyzed benzylation of highly electron-deficient
perfluoroareneswz
Shilu Fan, Chun-Yang He and Xingang Zhang*
Received 26th March 2010, Accepted 12th May 2010
First published as an Advance Article on the web 4th June 2010
DOI: 10.1039/c0cc00598c
An efficient and practical method to a wide range of perfluorinated
unsymmetrical diarylmethanes with good to excellent yields and
high regioselectivities has been developed by Pd-catalyzed direct
benzylation of highly electron-deficient perfluoroarenes; excellent
compatibility of functional groups has also been established.
using a Pd catalyst.9 To continue our research, herein, we
disclosed an efficient and practical Pd-catalyzed protocol for
Csp2-Csp3 direct benzylation of perfluoroarenes.
We began our studies of direct benzylation of pentafluoro-
benzene 1 by choosing benzyl chloride 2a as substrate because
it is inexpensive, readily available and reluctant to the reductive
dehalogenation when compared to the bromo and iodo counter-
parts (Table 1). Although, initially, a negative result was
provided when the reaction was carried out with 1 (2.0 equiv),
2a (1.0 equiv.) and K2CO3 (1.2 equiv.) in the presence of
Pd(OAc)2 (10 mol%) at 135 1C for 24 h in the absence of a
ligand (Table 1, entry 1), we were pleased to observe the
formation of desired product 3a when 20 mol% of bulky
biaryldialkylphosphine L1 was used, albeit in a low yield
(30%) (Table 1, entry 2). With this preliminary result in hand,
different bases were examined and Cs2CO3 was found to be the
optimum base, providing 3a in 80% yield (Table 1, entry 6).
Other bases, such as K3PO4, KOAc, and Na2CO3 proved to be
ineffective (Table 1, entries 3–5). The reaction was found to be
sensitive to the reaction temperature and the nature of solvents
(Table 1, entries 7–12). A lower reaction temperature (120 1C)
or employing polar solvents (such as DMF, DMI, NMP) led
to a much lower yield than the reaction run at 140 1C in
toluene (Table 1, entry 8).
Diarylmethanes have recently received great synthetic interests
due to the presence of such a motif in a range of biologically
active compounds1 and supramolecular structures.2 The most
widely used approaches to this functional group array rely on
cross-couplings of a stoichiometric amount of organometallic
aryl with electrophiles (aldehydes or benzyl halides).3 However,
this ‘‘prefunctionalization’’ process suffers from the requirement
of additional steps for preparation of organometallic reagents
and the incompatibility of functional groups. In this regard,
direct benzylation of arenes and heteroarenes have been
successfully developed recently.4 These impressive metal-catalyzed
direct C–H functionalizations provide a more effective and
straightforward method to this class of compounds since the
preactivation step of arenes can be avoided. However, unlike
the direct benzylation of electron-rich arenes, reactions of
highly electron-deficient perfluoroarenes remain a synthetic
challenge. The main reason is that the pentafluorophenyl
metals (C6F5-M) bond is particularly strong and hard to utilize
due to its ionic character,5 as a result the metal catalyzed cross-
couplings of C6F5-M with aliphatic halides lead to undesired
products.6 Therefore, to develop an effective methodology for
the direct benzylation of electron-deficient perfluoroarenes to
meet these challenges is of great importance.
It has been demonstrated that besides trialkylphosphine and
biphenyldialkylphosphine, less reactive triarylphosphine
ligands may also accelerate the oxidative addition of aliphatic
carbon-halogen bonds to low-valent palladium.10 Thus, from
the viewpoint of synthetic convenience and cost effectiveness,
we examined the reactivity of PPh3 in the catalytic benzylation
of pentafluorobenzene. To our delight, 89% isolated yield of
3a was afforded (Table 1, entry 16). Other ligands such as
tricyclohexylphosphine, bidentate ligand, dppf, and P(o-Tol)3
were less effective than PPh3 (Table 1, entries 13–15). Further
investigation of the reaction time showed that the best yield
(92%) could be obtained by shortening the reaction time to
12 h (Table 1, entry 17). An attempt to decrease the Pd(OAc)2
to 5 mol% resulted in the yield dramatically dropping to 53%
(Table 1, entry 19). As expected, employment of benzyl
bromide led to a moderate yield (Table 1, entry 18), indicative
of the essentiality of benzyl chlorides to the direct benzylation
of pentafluorobenzene 1.
On the other hand, perfluoroarenes constitute a distinct
class of fluorinated compounds due to their importance in
materials and life science.7 However, comparing to C–C bond
formation between perfluorinated aromatic rings and
arenes,8 only a few cross-coupling methods (including C–H
functionalization8d and traditional cross-coupling methods6)
for connecting perfluoroarenes with alkyl (Csp3) side chains
have been reported so far. Thus, development of effective
transition metal catalyzed reactions for installing various
fluorinated aryl groups onto organic structures is highly
desirable. Very recently, we successfully developed a straight-
forward method for direct olefination of perfluoroarenes by
Under the optimum reaction conditions (Table 1, entry 17),
the substrate scope of the direct benzylation of pentafluoro-
benzene 1 was tested and the representative results were
illustrated in Table 2. Generally, the reaction efficiency depends
on the nature of the substituents on the benzylchlorides.
Substrates bearing an electron-donating group furnished
the reaction smoothly in good yields (3b–d), while for
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China. E-mail: xgzhang@mail.sioc.ac.cn;
Fax: (+86)-21-6416-6128; Tel: (+86)-21-5492-5333
w In memory of Professor Keith Fagnou.
z Electronic supplementary information (ESI) available: Detailed
experimental procedures and analytical data for all new compounds.
See DOI: 10.1039/c0cc00598c
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Table 1 Selected results for optimization of direct benzylation of
pentafluorobenzene 1a
Table 2 Pd-catalyzed direct benzylation of pentafluorobenzene 1
with various benzylchlorides 2a
Entry
L
Base
Solvent
T/1C
Yield (%)b
1
2
3
4
5
6
7
8
None
L1
L1
L1
L1
L1
L1
L1
L1
K2CO3
K2CO3
K3PO4
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
DMF
DMI
NMP
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
135
135
135
135
135
135
120
140
140
140
140
140
140
140
140
140
140
140
140
5
30
13
23
8
80
53
95 (87)
70
8
14
41
57
63
46
100 (89)
100 (92)
56
KOAc
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14
15
16
17c
18d
19e
L1
L1
L1
PCy3.HBF4
dppf
P(o-Tol)3
PPh3
PPh3
PPh3
PPh3
53
a
Conditions: 1 (0.4 mmol), 2a (0.2 mmol), Pd(OAc)2 (10 mol%), L (20
mol%), Base (1.2 equiv.), in solvent (1 mL), 24 h. L1: biphenyl-2-
b
yldi-tert-butylphosphine. NMR yield determined by 19F NMR using
fluorobenzene as internal standard and number in parentheses is
a
Conditions: 1 (1.2 mmol, 2.0 equiv.), 2 (0.6 mmol, 1.0 equiv.),
Pd(OAc)2 (10 mol%), PPh3 (20 mol%), Cs2CO3 (1.2 equiv.), toluene
c
isolated yield. Reaction run for 12 h. Using benzylbromide.
d
b
c
(2.5 mL), 140 1C, 12 h. 1 gram scale reaction. Using 1.2 equiv. of
PivOH and 2.4 equiv. of Cs2CO3.
e
Using 5 mol% Pd(OAc)2 and reaction run for 36 h.
electron-withdrawing substituted benzylchlorides (3h–m),
unsatisfied yields were afforded (see ESI Table S1z). For
further improvement of the reaction efficiency, we found that
good to excellent yields were provided by employment of
1.2 equiv. of pivalic acid (PivOH).9,11 It is noteworthy that
versatile functional groups such as ester, methyl ketone,
amide, nitro, nitrile and heterocycle, pyridine are compatible
to the reaction conditions, providing opportunities for further
functionalization without the need for protection/deprotection
sequences. Importantly, product 3e also revealed an excellent
chemical selectivity at benzyl chloride over aryl chloride. A
1-g-scale synthesis of 3d was also performed without difficulty
(89%), indicating the good reliability of this process.
acidic C–H bond located between two fluorines is the primary
reaction site (5k). The low reactivity of difluoroarenes is
probably due to the low acidity of the C–H bond to be
activated.12
It was also possible to direct benzylation of alkenylated
fluoroarene 4l that was prepared via Pd-catalyzed oxidative
olefination of 1,2,4,5-tetrafluorobenzene (Scheme 1).9 The
a,b-unsaturated ester was compatible with the reaction system,
featuring the utility of this method compared to traditional
techniques, thus allowing to access highly functionalized per-
fluorinated unsymmetrical diarylmethanes by a catalytic method.
Although the exact mechanism of the reaction is still not
clear, on the basis of the results reported by others,8b,13
a
The substrate scope of fluoroarene is not restricted to
pentafluoroarene 1, variations of fluoroarenes 4 containing
2–4 fluorines were also tested (Table 3). Generally, moderate
to high yields with high regioselectivities of desired products 5
were afforded under the standard conditions with 1.2 equiv. of
PivOH as additive. In particular, when 1,2,4,5-tetrafluoro-3-
methoxybenzene was examined, both electron-withdrawing
and electron-donating substituents on the aromatic ring of
the benzyl chlorides provided 5e and 5f in excellent yields
(94%–98%). Substrates bearing functional groups, such as
ester, nitrile and pyridine, all showed good tolerance to the
reaction conditions. It should be pointed out that although
substrates bearing 2–3 fluorines contain more than one reaction
site, moderate to good yields of mono-benzylated products
with high regioselectivities were still observed and the most
plausible mechanism is proposed and shown in Scheme 2. An
oxidative addition of benzylchlorides 2 to a zero valent Pd
species is envisioned to take place as an initial step leading to a
Pd-benzyl intermediate I. I subsequently goes through the
concerted metalation-deprotonation (CMD) process to form
II.8b,13 As the final step of the catalytic cycle, reductive
elimination of II produces perfluorinated unsymmetrical
diarylmethanes upon the regeneration of Pd(0) species.
In conclusion, we developed an efficient and practical,
Pd(OAc)2/PPh3 catalyzed system for direct benzylation of
highly-electron deficient perfluoroarenes. The reaction affords
high yields, good chemo- and regio-selectivity, and excellent
functional group compatibility. Hence, it is a concise and
operationally simple method to perfluorinated unsymmetrical
diarylmethanes of interest in both life and materials science.
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Table 3 Pd-catalyzed direct benzylation of fluoroarenes 4 with
various benzylchlorides 2a
Scheme 2 Plausible mechanism of the Pd-catalyzed direct benzyla-
tion of perfluoroarenes.
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a
Conditions: 4 (1.8 mmol, 3.0 equiv.), 2 (0.6 mmol, 1.0 equiv.),
Pd(OAc)2 (10 mol%), PPh3 (20 mol%), Cs2CO3 (2.4 equiv.), PivOH
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Scheme 1 Direct benzylation of alkenylated fluoroarene 4l with
benzylchloride 2b.
The NSF of China (20852003, 20902100, 20832008), the
Shanghai Rising-Star Program (09QA1406900) and SIOC are
greatly acknowledged for funding this work.
Notes and references
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This journal is The Royal Society of Chemistry 2010
4928 | Chem. Commun., 2010, 46, 4926–4928