Direct palladium-catalyzed intermolecular allylation of highly electron-deficient polyfluoroarenes

Article abstract of DOI:10.1002/anie.201008174

A simple operation: The use of readily available PPh₃, high reaction efficiency, and good stereo- and regioselectivity provided useful and operationally simple access to polyfluoroarylated derivatives through the title transformation (see schem

Full text of DOI:10.1002/anie.201008174

Communications
DOI: 10.1002/anie.201008174
À
C H Activation
Direct Palladium-Catalyzed Intermolecular Allylation of Highly
Electron-Deficient Polyfluoroarenes**
Shilu Fan, Fei Chen, and Xingang Zhang*
Allylated arenes are an important class of substituted
aromatic compounds owing to the presence of allylic arene
moieties in many biologically active compounds.[1] Moreover,
the allylic substituent is synthetically useful, because the
carbon–carbon double bond can lead to a variety of structures
after simple manipulations.[2] The most common synthetic
method used to prepare this functional group is the cross-
couplings of allylic electrophiles with stoichiometric amounts
of aryl metals, such as aryl copper,[3] aryl magnesium halide,[4]
and aryl boron reagents.[5] However, these strategies have
drawbacks in terms of the stability and availability of aryl
metal reagents. Furthermore, additional transformations are
required for preparation of these reagents. Therefore, for
À
synthetic simplicity, the direct C H allylation of aromatic
rings represents an attractive alternative.[6] Although in some
Scheme 1. Intermolecular allylation of aromatic rings.
À
cases, the direct C H allylation of electron-rich arenes
catalyzed by Lewis acids[7] or transition metals[8] has been
devices.[12] Hence, it is of great synthetic interest to develop an
efficient reaction for installing various fluoroaryl groups.
Despite impressive progress in direct arylation of polyfluor-
oarenes,[13] there are few coupling methods for introducing
alkyl (Csp3) substituents.[14] Herein, we report our preliminary
results on direct palladium-catalyzed intermolecular allyla-
tion of highly electron-deficient polyfluoroarenes. This
approach provides a highly efficient protocol for the prepa-
ration of a wide range of allyllated polyfluoroarene com-
pounds.[15]
Initially, the reaction of pentafluorobenzene 1 with
cinnamyl methyl carbonate 2 was investigated in the presence
of Pd(OAc)2 (10 mol%) and PPh3 (20 mol%) in toluene at
1208C. This reaction provided only a trace amount of
allylated pentafluorobenzene (Table 1, entry 1). However,
when the 2 was switched to tert-butyl cinnamyl carbonate (E)-
3a, 60% yield of linear allylated product 5a was isolated
along with a trace amount of isomer 4a (5a/4a = 68:1), thus
suggesting that more-basic alkoxide is essential for the
reaction to proceed efficiently (Table 1, entry 2). Notably,
no branched product was observed under this catalytic
system. Encouraged by this result, a variety of palladium
catalysts, ligands, and solvents were examined. Other PdII
catalysts, such as [Pd(TFA)2], PdCl2, [PdCl2(CH3CN)2], and
[PdCl2(PhCN)2], were ineffective, and only Pd0 catalysts
[Pd(PPh3)4] and [Pd(dba)2] afforded 18% to 33% yield based
on NMR spectroscopy (see Table S1 in the Supporting
Information). The reaction was also found to be sensitive to
the phosphine ligands and solvents, and the readily available
PPh3 and toluene were the best choice (see Table S1).
Considering that copper complexes can function as
copromoters in the palladium-catalyzed processes,[16] and
1,10-phenanthroline (phen) may stabilize the soluble copper
À
developed, the direct C H allylation of electron-deficient
arenes is an ongoing challenge owing to their poor reactiv-
ities.[9] Inspired by our recent study on the palladium-
catalyzed direct olefination of polyfluoroarenes, which rep-
resents one of the rare examples of catalytic direct olefination
of electron-deficient arenes,[10] we hypothesized that the
À
direct palladium-catalyzed C H allylation of highly elec-
tron-deficient polyfluoroarenes with allylic electrophiles may
be possible, and would benefit the preparation of allylated
electron-deficient arenes (Scheme 1). Although Tsuji–Trost
reaction involving addition of a nucleophile to (p-allyl)palla-
dium intermediate offers a powerful tool for preparation of
allyl-substituted compounds,[11] the reaction of highly elec-
tron-deficient polyfluoroarenes through the present strategy
has never been studied. Consequently, developing new direct
transition-metal-catalyzed allylative cross-coupling reactions
for widespread applications is still highly desirable.
It is well established that polyfluoroarenes are a key
structural unit for various functional molecules, such as
pharmaceuticals, agrochemicals, liquid crystals, and electronic
[*] S. Fan, F. 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)
Fax: (+86)21-6416-6128
E-mail: xgzhang@mail.sioc.ac.cn
[**] This work was financially supported by the NSFC (20902100,
20832008), the Shanghai Rising-Star Program (09QA1406900), and
the SIOC. We thank Prof. Wei-Liang Duan and Prof. Shu-Li You for
helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201008174.
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Table 1: Representative results for optimization of direct palladium-
catalyzed intermolecular allylation of pentafluorobenzene 1.[a]
Table 2: Direct palladium-catalyzed allylation of pentafluorobenzene 1
with various allyl carbonates (E)-3.[a]
Entry Product
Entry Product
Entry x/y [mol%] Additive (mol%)
Base (equiv)
Yield of
5a [%][b]
1[c]
2
3
10/20
10/20
10/20
10/20
10/20
10/20
10/20
10/20
10/20
10/20
10/20
10/20
10/–
–
–
–
–
–
trace
(60)
67
1
6
CuI (10)/phen (10)
CuI (10)/phen (10)
CuI (10)/phen (10)
CuI (10)/phen (10)
CuI (10)/phen (10)
CuI (10)/phen (10)
CuCl(10)/phen(10)
CuBr(10)/phen(10)
CuBr2(10)/phen(10) Cs2CO3 (1.2) 85
–/phen (10)
–/phen (10)
CuI (10)/phen (10)
CuI (5)/phen (5)
4
Cs2CO3 (1.2) 100 (87)
Cs2CO3 (1.2) 100 (86)
K2CO3 (1.2)
K3PO4 (1.2)
tBuOLi (1.2)
5[d]
6[d]
7[d]
8[d]
9[d]
10[d]
11[d]
12
13
14
15
60
35
35
2
3
4
7
8
Cs2CO3 (1.2) 66
Cs2CO3 (1.2) 80
–
–
63
NR
–/–
5/10
Cs2CO3 (1.2) NR
Cs2CO3 (1.2) (96)
[a] Reaction conditions (unless otherwise specified): 1 (2.0 equiv), (E)-
3a (0.4 mmol), toluene (2.0 mL), 12 h, 1208C. 5a/4a=68:1, determined
by HPLC methods. [b] Yield determined by 19F NMR spectroscopy using
fluorobenzene as the internal standard and the yield of the isolated
product is in parentheses. [c] Cinnamyl methyl carbonate 2 was used
instead of (E)-3a. [d] Reaction run at 1008C. NR=no reaction.
9[b]
complexes by chelation and increase electron density at the
copper center,[17] we assumed that the presence of a catalytic
amount of CuI/phen in this Pd(OAc)2/PPh3 catalytic system
may assist the reaction of 1 with the (p-allyl)palladium
intermediate and improve the yield of the reaction. However,
the use of CuI/phen (10 mol%) only resulted in a comparable
yield (Table 1, entry 3). Introduction of Cs2CO3 (1.2 equiv) to
this catalytic system significantly improved the reaction
efficiency and gave 87% yield (Table 1, entry 4), while
other bases and copper salts were less effective (Table 1,
entries 6–11). In addition, Pd(OAc)2/PPh3 are essential for the
reaction, because the absence of either of them failed to give
any desired product, and therefore ruled out the possibility
that copper catalyzes this reaction under our present reaction
conditions[15] (Table 1, entries 13 and 14). Further optimiza-
tion showed that the best yield of isolated product (96%) was
afforded by decreasing the Pd(OAc)2 loading to 5 mol% with
use of Ph3P (10 mol%) and CuI/phen (5 mol%; Table 1,
entry 15).
A variety of allylated pentafluorobenzene compounds
were generated by the present method and good to high yields
and regioselectivities were obtained (Table 2). For the
aromatic allyl carbonate, the reaction efficiency and the
regioselectivity depended on the nature of the substituents on
the aromatic ring (Table 2, entries 1–6). Substrates bearing an
electron-donating group furnished the product smoothly in
excellent yields (up to 96%) with high regioselectivity
(Table 2, entries 1–4), while for electron-withdrawing substi-
tuted aromatic allyl carbonates, slightly lower yields (78–
5
[a] Reaction conditions (unless otherwise specified): 1 (2.0 equiv), (E)-3
(0.6 mmol), toluene (2.0 mL), 12 h, 1208C. Yields are of the isolated
product. [b] 1 (0.6 mmol), (E)-3i (2.0 equiv).
85%) and regioselectivities were observed (Table 2, entries 5
and 6). The increasing formation of isomers 4 with use of
electron-deficient allyl carbonates is probably a result of the
relatively easier 1,3-hydrogen shift taking place under basic
conditions. Chloride is compatible with the catalytic system,
and provided a good opportunity for further transformations
utilizing traditional techniques (Table 2, entry 5). A pyridyl
group did not interfere with the coupling reaction (Table 2,
entry 7). Less-reactive aliphatic allyl carbonates are also
suitable substrates, and reasonable yields with moderate
regioselectivities were still afforded (Table 2, entries 8 and 9).
But for linear (E)-tert-butyl dec-2-enyl carbonate (E)-3i, a
small amount of branched product 5i’ was obtained (Table 2,
entry 9), thus suggesting that the steric effect plays an
important role in the regioselectivity.
The reactions of Z-allyl carbonates (Z)-3 and branched
allyl carbonates 6 were also tested. As shown in Equations (1)
and (2) of Scheme 2, the linear E-allylated products 5 were
obtained in high stereo- and regioselectivities with no
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Communications
Table 3: Direct palladium-catalyzed allylation of fluoroarenes 7 with allyl
carbonates (E)-3.[a]
observation of Z-allylated or branched isomers, thus indicat-
ing that a (p-allyl)palladium intermediate is involved in the
catalytic process.
In addition to the demonstrated broad range of poly-
fluoroarenes, various fluoroarenes 7 containing 3 or 4
fluorines were also competent coupling partners (Table 3).
For substrates bearing 3 or 4 fluorine atoms, thus containing
Entry Product
Entry Product
1
5[b]
2
6[b]
7[e]
8[c]
3[c]
Scheme 2. Direct palladium-catalyzed allylation of pentafluorobenzene
1 with linear allyl carbonates (Z)-3 and branched allyl carbonates 6.
4[d]
more than one reaction site, good yields of monoallylated
products were still observed with using 3.0 equivalents of
fluoroarenes[18] (Table 3, entries 1–3 and 8). The low yield
(43%) of 8 f is probably a result of the highly electron-
withdrawing effect of 1,2,4,5-tetrafluoro-3-(trifluoromethyl)-
benzene 7 f, which could influence the catalytic cycle[19]
(Table 3, entry 6). Benzylated fluoroarene 7g was also a
suitable substrate and provided allylated product in a
reasonable yield with high regioselectivity (Table 3, entry 7).
The X-ray crystallographic analysis of 8g further confirmed
its structure.[20] However, for 1,2,3,5-tetrafluorobenzene (7c),
1,2,4,5-tetrafluoro-3-methoxybenzene (7d), and 1,3,5-trifluo-
robenzene (7h), unsatisfactory yields were afforded under the
standard conditions. The addition of PivOH[10,21] benefited the
reaction (see Table S2). Further optimization revealed that
the use of PivOH instead of CuI/Phen afforded the desired
products in moderate to good yields (Table 3, entries 3, 4, and
[a] Reaction conditions (unless otherwise specified): 7 (3.0 equiv), (E)-3
(0.6 mmol), toluene (2.0 mL), 12 h, 1208C. Yields are of the isolated
product. [b] 7 (2.0 equiv), (E)-3 (0.6 mmol), toluene (2.0 mL), 12 h, 1208C.
[c] 7 (3.0 equiv), (E)-3 (0.6 mmol), PivOH (1.2 equiv), Cs2CO3 (2.4 equiv),
toluene (2.5 mL), 12 h, 1408C. [d] 7 (2.0 equiv), (E)-3 (0.6 mmol), PivOH
(1.2 equiv), Cs2CO3 (2.4 equiv), toluene (2.5 mL), 12 h, 1408C. [e] Fluo-
roarene (1.2 equiv), (E)-3 (1.8 mmol, 1.0 equiv).
8). But 1,3-difluorobenzene did not react owing to the low
[22]
À
acidity of the C H bond that was to be activated.
It was also possible to prepare highly functionalized
polyfluoroarenes from simple fluoroarenes by using the
present strategy. As depicted in Scheme 3, after iterative
À
palladium-catalyzed C H bond functionalization of 1,2,4,5-
tetrafluorobenzene, namely palladium-catalyzed oxidative
olefination,[10] and direct allylation, compound 8i was
obtained in a highly efficient manner. This approach features
the present method and was used to synthesize the target in
fewer steps compared to traditional techniques.
À
Scheme 3. Iterative palladium-catalyzed C H bond functionalization.
DMF=N,N-dimethylformamide, Piv=pivaloyl.
To investigate the working mode of the present catalytic
systems, we looked at the kinetic isotope effect (KIE;
Scheme 4). The intermolecular competition reactions
between pentafluorobenzene and its deuterated derivative
do not exhibit a kinetic isotope effect (kH/kD = 1.2; Scheme 4).
polyfluoroarenes is not involved in the rate-determining step
in the overall catalytic process. This finding is different from
À
This observation implies that cleavage of the C H bond in
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Scheme 4. Kinetic isotope effect study.
the well-known concerted metalation/deprotonation (CMD)
process,[13a,23] in which C H bond activation is a rate-
determining step.
À
In an attempt to understand the mechanism of the present
palladium-catalyzed direct allylation of polyfluoroarenes, a
proposal is shown in Scheme 5 on the basis of preliminarily
Scheme 6. Experiments for mechanistic studies. THF=tetrahydro-
furan.
the literature (Equations 1 and 2 of Scheme 6), in which the
successful generation of V-1 through the reaction of penta-
fluorobenzene with tBuOLi and CuCl/phen (Equation 2 of
Scheme 6) convinced us that the copper complex V is
À
Scheme 5. Mechanistic proposal for direct palladium-catalyzed allyla-
tion of polyfluoroarenes with allyl carbonates. Arf =polyfluoroaryl,
Boc=tert-butoxycarbonyl.
involved in the catalytic cycle when the C H allylation
reaction was carried out in the presence of CuI/phen. With
these two intermediates in hand, we then investigated the
formation of the Pd(polyfluoroaryl)(allyl) complex III by the
reaction of I-1 with V-1 (Equation 3 of Scheme 6). The
reaction was monitored by NMR spectroscopy, which showed
kinetic data and the fact that copper does not catalyze the
reaction under our present conditions (Table 1, entry 14) and
a (p-allyl)palladium intermediate is involved in the catalytic
cycle (equation (2) in Scheme 2). The sequence begins with
the formation of p-allylpalladium complexes I by decarbox-
ylation of allylic carbonates 3 with Pd0. Subsequently, base
that
two
regioisomers
(III-1
and
III-2)
of
Pd(pentafluorophenyl)(allyl) complex III was formed.
These regioisomers are air stable and can be isolated by
flash column chromatography, and their formation indicates
the attack of copper complex V-1 at the palladium center.
Assignments of the spectra of III-1 and III-2 were mainly
based on the preferential coupling of 31P with allylic protons
trans to the phosphorus atom, thus leading to the location of
the phenyl in III-2 trans to the phosphine group.[26] The X-ray
crystallographic analysis of III-2 further confirmed its struc-
ture (Figure 1).[20] Because III-1 and III-2 can easily isomerize
into each other,[27] a mixture of III-1 and III-2 was used to
investigate the final step, reductive elimination. Subjection of
a solution of III-1 and III-2 in toluene to heating at 1008C
indeed afforded allylated product 5a (Equation 4 of
Scheme 6),[28] thus demonstrating that the generation of the
final product via path B is involved in the catalytic cycle. In
addition, the possibility of formation of III via path Awas also
examined. As shown in Equation 5 of Scheme 6, 31% yield of
III was afforded when the (p-allyl)palladium complexes I-1
À
abstracts a proton from the acidified C H bonds on the
polyfluoro aromatic rings[13c,d] to generate intermediate II,
followed by the reaction of Pd species I with II, thus providing
the Pd(polyfluoroaryl)(allyl) complex III, which may lead to
two regioisomers (path A). Finally, the reductive elimination
would lead to the expected allylated compound 5 or 8, and
regenerate the Pd0 species.[24] Alternatively, the presence of
copper complex IV may easily produce polyfluoroarylcopper
complex V,[13c,d] which would make the generation of key Pd
species III relatively easier by transmetalation (path B), thus
resulting in higher reaction yields in most cases.
To further probe the reaction mechanism illustrated in
Scheme 5, several experiments were conducted (Scheme 6).
Firstly, the (p-allyl)palladium complexe I-1[25] and pentafluor-
ophenylcopper complex V-1[13d] were prepared according to
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À
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In conclusion, we have developed an efficient and
straightforward Pd(OAc)2/PPh3-catalyzed method for direct
allylation of highly electron-deficient polyfluoroarenes, which
represents a concise, operationally simple, and useful method
to the preparation of polyfluoroarylated derivatives of
interest in both life and materials science. Further studies to
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Experimental Section
Representative general procedure for direct palladium-catalyzed
intermolecular allylation of highly electron-deficient polyfluoroar-
enes: Pd(OAc)2 (5 mol%), PPh3 (10 mol%), Cs2CO3 (1.2 equiv), CuI
(5 mol%), phen (5 mol%), and toluene (2 mL) were added to a
sealed tube (25 mL) fitted with a septum cap under N2, and then
stirred. Polyfluoroarene (1.2 mmol, 2.0 equiv) and allyl carbonate
(0.6 mmol, 1 equiv) were then added subsequently. The sealed tube
was screw capped and heated to 1208C (oil bath). After stirring for
12 h, the reaction mixture was cooled to RT, diluted with ethyl
acetate, washed with brine, dried over Na2SO4, filtered, and
concentrated. The residue was purified with column chromatography
on silica gel to provide the pure product.
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À
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Received: December 24, 2010
Revised: April 4, 2011
Published online: May 17, 2011
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À
Keywords: allylation · C H activation · cross-coupling ·
palladium · polyfluoroarenes
.
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À
[15] After we submitted this manuscript, a copper-catalyzed C H
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[20] CCDC 805239 (8g) and 816308 (III-2) contains the supplemen-
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[27] Complexes III-1 and III-2 can easily isomerize into each other in
CH2Cl2 or CHCl3.
[28] As determined by monitoring the reaction by NMR spectrosco-
py; the reductive elimination of III showed that the formation of
allylated product 5a did not occur until the reaction temperature
increased to 808C, thus indicating that the reductive elimination
is the rate-determining step in the overall catalytic process. For
details see Figure S1.
Angew. Chem. Int. Ed. 2011, 50, 5918 –5923
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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