Pd(OAc)2-catalyzed cross-coupling of polyfluoroarenes with simple aromatics in imidazolium ionic liquids (ILs) without oxidant and additive and with recycling/reuse of the IL

Article abstract of DOI:10.1016/j.tetlet.2011.08.077

Polyfluoroarenes can be cross-coupled with simple aromatics (benzene, toluene, and anisole), in good isolated yields, by using Pd(OAc)₂ dissolved in imidazolium ILs [(bmim)PF₆ and (bmim)BF₄] as solvent, without the need fo

Full text of DOI:10.1016/j.tetlet.2011.08.077

Tetrahedron Letters 52 (2011) 5525–5529
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Pd(OAc)2-catalyzed cross-coupling of polyfluoroarenes with simple aromatics
in imidazolium ionic liquids (ILs) without oxidant and additive
and with recycling/reuse of the IL
⇑
Rajesh G. Kalkhambkar, Kenneth K. Laali
Department of Chemistry, University of North Florida, 1, UNF Drive, Jacksonville, FL 32224, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Polyfluoroarenes can be cross-coupled with simple aromatics (benzene, toluene, and anisole), in good iso-
lated yields, by using Pd(OAc)2 dissolved in imidazolium ILs [(bmim)PF6 and (bmim)BF4] as solvent, with-
out the need for an oxidant and an additive. The reaction is catalyzed by HOAc and it is subject to a
primary isotope effect (KH/KD = 4.87). Competitive cross-coupling reactions of 1,2,4,5-tetrafluorobenzene
with benzene/toluene, benzene/anisole, and anisole/toluene gave KB/KT = 5.1, KB/KA = 5.7, and KA/KT = 5.0,
respectively, indicative of a remote substituent effect on Pd insertion into the phenyl C–H bond. Mild
reaction conditions, simple product isolation and recycling/reuse of the IL are additional advantages of
this method.
Received 22 July 2011
Revised 11 August 2011
Accepted 15 August 2011
Available online 22 August 2011
Keywords:
Polyfluoroarenes
Pd(OAc)2 in imidazolium IL
Cross-coupling
Ó 2011 Elsevier Ltd. All rights reserved.
Polyfluorinated biaryl synthesis
Primary isotope effect
Competitive cross-coupling
There are notable earlier studies in the literature on fluorinated
biaryl synthesis via the transition metal catalyzed cross-coupling
reactions, whereby electron-deficient polyfluorobenzenes are cou-
pled to arylboronic acids,1 or pentafluorophenylboronic acid is
coupled to aryl halides (iodide and bromide) via a Suzuki–Miyaura
reaction.2 The Pd-catalyzed decarboxylative cross-coupling in
which polyfluorobenzoate salts are coupled to aryl halides (bro-
mide, chloride, or triflate) constitutes another approach to unsym-
metrical biaryl synthesis.3,4 A further development in this area was
the finding that perfluoroarenes can be directly coupled to aryl
halides by using an in situ generated Pd-catalyst in conjunction
with K2CO3 in dimethyl acetamide (DMA) as solvent.5
report here on the facile cross-coupling of polyfluoroarenes with
simple arenes (benzene, toluene, and anisole) under Pd(OAc)2
catalysis in (bmim)BF4 or (bmim)PF6 in the presence of catalytic
amounts of HOAc, without an oxidant or an additive, under mild
reaction conditions with recycling/reuse of the IL. Other studies
are also presented in an effort to define the scope and to gather
mechanistic insights.
As summarized in Scheme 1, pentafluorobenzene, 1,2,4,5-tetra-
fluorobenzene, tetrafluoropyridine, and 2,3,5,6-tetrafluorobenzo-
trifluoride reacted smoothly with benzene, toluene, and with
anisole in the presence of 10 mol % Pd(OAc)2 in imidazolium ILs
as solvent and with catalytic amounts of HOAc, to furnish the cor-
responding unsymmetrical biaryls in isolated yields ranging from
56% to 72%.10 The results are gathered in Table 1.
It is instructive to compare and contrast chemo- and regiose-
lectivities observed in the present study in ILs with those re-
ported in Ref. 7 under a very different set of conditions. In
cross-coupling of tetrafluorobenzene with benzene a mixture of
mono- and bis-coupling products were obtained by Shi et al.7
whereas no bis-coupling product was detected in the present
study. The isomer distribution observed in cross-coupling of pen-
tafluorobenzene with toluene (meta:para 1 to 1) is close to that
reported by Shi et al.7 (meta:para 1.2 to 1), but that for coupling
to anisole (meta:para 1 to 0.15) is substantially different (meta:-
para 2.1 to 1).
Recent studies reported by Wei and Su,6 and by Shi and associ-
ates,7 in which polyfluoroarens are coupled with nonactivated ‘sim-
ple’ arenes under Pd(OAc)2 catalysis to form fluorinated biaryls
constitute a noteworthy new development. In the Wei and Su meth-
od,6 an oxidant and a base are required and the reactions are carried
out in DMA as solvent. In the method developed by Shi et al.7 an oxi-
dant (typically AgCO3) and an acid (HOAc, TFA, TFE, or tBuCOOH)
along with an additive are required. Among various such additives
that were surveyed, di-isopropyl sulfide was quite effective. In both
methods high temperatures must be employed (110–120 °C).
In continuation of our studies on electrophilic and onium ion
chemistry in ionic liquids (ILs),8 and as a follow up to our recent
work on Pd(OAc)2-catalyzed Matsuda–Heck reaction in ILs,9 we
Focusing on the catalytic role of the acid, in their yield optimi-
zation studies Shi et al.7 found several acids (HOAc, TFA, TFE, and
tBuCOOH) to be effective along with an oxidant (typically Ag2CO3)
⇑
Corresponding author. Tel: +1 904 620 1503; fax: +1 904 620 3535.
E-mail address: kenneth.laali@UNF.edu (K.K. Laali).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.077

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R. G. Kalkhambkar, K. K. Laali / Tetrahedron Letters 52 (2011) 5525–5529
F
N
F
F
F
R
F
F
a)
N
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
a)
F3C
R
F
R
H
R
a)
F
F
F
F
F3C
For R = Me a 1:1 mixture of
meta and para isomers; For
R = OMe a 1: 0.15 mixture of
meta and para isomers
F
F
F
F
a)
F
F
R
F
F
[For R = Me and OMe only para isomer]
R = H, CH3, OCH3
a) = Pd(OAc)2 10 mol%, AcOH 1 mol%, (bmim)BF4 or (bmim)PF6, 60-70ºC, 4-12h
Scheme 1. Pd(OAc)2-catalyzed cross coupling of polyfluoroarenes with simple arenes in ILs.
Table 1
Pd(OAc)2-catalyzed cross-coupling of polyfluoroarenes with simple arenes
Entry
Arenes
Polyfluoroarenes
Product
Time (h)
4.5
Ionic liquida,b
(bmim)BF4
Isolated yieldc(%)
72
F
F
F
F
F
F
F
F
1
F
F
F
F
F
F
F
F
F
2
3
12d
(bmim)PF6
(bmim)BF4
68
70
F
F
F
F
F
meta to para isomer ratio 1:1
F
F
O
F
F
F
6e
O
F
F
F
F
meta to para isomer ratio 1:0.15
F
F
F
4
5
6
4
(bmim)BF4
(bmim)PF6
(bmim)BF4
64
56
62
F
F
F
F
F
F
F
F
12
8
F
F
F
F
F
F
F
F
O
O
F
F
F
F

R. G. Kalkhambkar, K. K. Laali / Tetrahedron Letters 52 (2011) 5525–5529
5527
Table 1 (continued)
Entry
Arenes
Polyfluoroarenes
Product
Time (h)
8
Ionic liquida,b
(bmim)PF6
Isolated yieldc(%)
F
N
F
F
N
F
F
N
F
F
F
F
N
7
8
62
58
F
F
F
F
F
F
N
F
6
(bmim)PF6
(bmim)BF4
(bmim)BF4
(bmim)BF4
F
F
F
F
N
F
F
F
O
O
9
10
11
6.5
12
12
66
64
58
F
F
no other isomer detected
F
F
F
F3C
F3C
F3C
F3C
F
F
F
F
F
F
F
F
F
F
F
F
F
F
no other isomer detected
F
F
O
F3C
O
F3C
12
12
(bmim)PF6
70
F
F
F
F
no other isomer detected
a
Fresh IL was used in runs 1, 2, 6, 9, and 11, whereas recycled IL was used in others.
b
c
The IL could be reused without purification for up to three runs, after which it was purified and reused (see Ref. 10)
Isolated yield based on quantity of polyfluorinated arenes used.
Isomer ratios determined by 1H and 19F NMR.
d
e
Isomer ratios determined by GC and 19F NMR.
F
F
F
F
F
Benzene
X
TFA
Pd(OAc)2
N
N
Bu
F
F
OTf
Benzene
Pd(OAc)2
F
F
F
F
F
F
F
SO3H
X
X
F
(bmim)BF4
Benzene
Pd(OAc)2
F
F
F
F
F
Benzene
NH3 NO3
Pd(OAc)2
X
F
F
F
F
F
Scheme 2. Control experiments to examine the role of acid catalyst.

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R. G. Kalkhambkar, K. K. Laali / Tetrahedron Letters 52 (2011) 5525–5529
O
O
F
F
F
F
NH3
O
X
NH3
O
F
F
F
F
TfOH
Pd(OAc)2
F
F
F
F
F
X
Benzene
Pd(OAc)2
Benzene
F
F
O
NH3
Benzene
Pd(OAc)2
O
X
N
N
OTf
SO3H
F
Bu
F
F
F
F
Scheme 3. Additional control experiments to shed light on the role of acid.
F
F
F
F
F
F
F
F
F
F
F
F
a)
1:1 mixture of
Benzene + Benzene-d6
d5
KH / KD = 4.87
a) = Pd(OAc)2 20 mol%, AcOH 1-2 mol%, (bmim)BF4, 75ºC, 12h
Scheme 4. Determination of kinetic isotopic effect (KIE).
and an additive (various sulfides, sulfoxides, or DMSO). Presence of
catalytic amounts of HOAc was found to be crucial in the present
study in IL. Using the cross-coupling reaction of pentafluoroben-
zene with benzene as a benchmark, Brønsted acidic ILs [EtNH3][-
NO3] and [BBIM(SO3H)][OTf] were tested and found to be
ineffective, and TFA similarly did not work (see Scheme 2). To
check on the possible role of acetate anion in this process, [EtN-
H3][OAc] was tested alone and in combination with a Brønsted
acidic IL [BBIM(SO3H)][OTf] or TfOH. However, none of these com-
binations proved successful (see Scheme 3). These findings imply
that cross-coupling in IL is governed by specific acid catalysis
and the mechanistic details of the process are yet to be understood.
In an effort to extend the synthetic scope of this cross-coupling
reaction, a number of other substituted arenes were studied for
coupling to pentafluorobenzene. Halobenzenes (X = F, Cl, Br), PhCN,
and PhNO2 did not undergo cross coupling. Similarly no coupling
occurred with the electron rich systems namely ethyl benzene,
mesitylene, cumene, and 2,3-dimethoxybenzene.
present study, using tetrafluorobenzene, three types of competi-
tive cross-coupling experiments were performed with benzene/
toluene (1:1), benzene/anisole (1:1), and toluene/anisole (1:1)
and this gave the following substrate selectivities: KB/KT = 5.1,
KB/KA = 5.7, and KA/KT = 5.0, respectively. The data indicate that
the p-Me and p-OMe groups lower the cross-coupling reactivity
relative to p-H by five- to sixfold, and that p-Me lowers the reac-
tivity by fivefold relative to p-OMe.
In summary, cross-coupling reactions of various polyfluorinat-
ed aromatic/heteroaromatic compounds to benzene, toluene, and
anisole using Pd(OAc)2 dissolved in imidazolium ILs as catalyst
have been demonstrated. Whereas catalytic amounts of HOAc
are essential for the reaction to proceed, no oxidant or additives
are required. The mild reaction conditions employed, facile prod-
uct isolation, and recycling and reuse of the IL are additional
advantages of this method. Whereas the IL version of this chem-
istry can be applied to a variety of polyfluorinated arenes, its
scope relative to the coupling partner seems limited. The chemo-
and regioselectivities observed in this study were compared and
contrasted with those reported previously under a very different
set of reaction conditions. In concert with earlier studies, the
reaction is subject to a primary kinetic isotope effect. Competi-
tive cross-coupling reactions imply a relative reactivity sequence
p-H > p-OMe > p-Me, but further studies are needed to better
understand these remote substituent effects.
Focusing on the question whether the C–H cleavage of the non-
fluorinated arene is part of the rate determining step in the IL ver-
sion of this chemistry, coupling of tetrafluorobenzene with a 1:1
mixture of C6H6 and C6D6 was studied (Scheme 4).
A primary isotope effect was measured (by 1H and 19F NMR; see
Supplementary data) with KH/KD = 4.87. For comparison,
a
KH/KD = 6.81 was reported in Ref. 7 for cross-coupling to 2,3,5,
6-tetrafluoroanisole.
Whereas competitive experiments to establish relative reactiv-
ity of different polyfluorobenzenes have been reported,5 to our
knowledge competitive cross-coupling of a given polyfluorinated
arene with two aromatics has not been investigated in an effort
to shed light on the electronic effect of the substituent. In the
Acknowledgments
Support of this work via research support provided to K.L. by
UNF is gratefully acknowledged. We also thank Dr. Nelson Zhao
of this department for NMR assistance.

R. G. Kalkhambkar, K. K. Laali / Tetrahedron Letters 52 (2011) 5525–5529
5529
2007, 72, 6758; (l) Hubbard, A.; Okazaki, T.; Laali, K. K. J. Org. Chem. 2008, 73,
316; (m) Kalkhambkar, R. G.; Waters, S. N.; Laali, K. K. Tetrahedron Lett. 2011,
52, 867; (n) Aridoss, G.; Sarca, V. D.; Ponder, J. F., Jr.; Crowe, J.; Laali, K. K. Org.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.077.
9. Kalkhambkar, R. G.; Laali, K. K. Tetrahedron Lett. 2011, 52, 1733.
10. General procedure: The desired polyfluoroarenes (1 mmol) were introduced at
rt into an oven-dried Schlenk tube charged with (bmim)PF6 or (bmim)BF4 ionic
liquid (ꢀ4 mL) under a nitrogen atmosphere. After efficient magnetic stirring
(for 10–20 min) Pd(OAc)2 (10–20 mol %) was introduced and was dissolved in
the IL by efficient magnetic stirring (for 10–20 min). The reaction mixture was
then charged with the arene partner (benzene, toluene, or anisole) (3 mmol).
After addition of AcOH (1–2 mol %), the reaction mixture was stirred at 60–
75 °C under nitrogen while monitoring the progress of the reaction by TLC and
by GC–MS. Upon completion, the brown-colored reaction mass was cooled to rt
and the products were extracted with dry diethyl ether (4–5 times). Removal of
solvent under vacuum furnished the crude products which were
chromatographed with hexane-ethyl acetate mixture (75:25) to afford the
pure cross-coupling products which were characterized by GC–MS, 1H, 13C and
19F NMR. The brown-colored IL was dried overnight under vacuum at 50 °C and
reused for up to three runs, after which it was set aside for recovery and
recycling as outlined below.
References and notes
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8. (a) Laali, K. K.; Gettwert, V. J. J. Fluorine Chem. 2001, 107, 31; (b) Laali, K. K.;
Gettwert, V. J. J. Org. Chem. 2001, 66, 35; (c) Laali, K. K.; Borodkin, G. I. J. Chem.
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2005, 3, 1034; (f) Sarca, V. D.; Laali, K. K. Green Chem. 2006, 8, 615; (g) Laali, K.
K. In Ionic Liquids in Organic Synthesis, ACS Symp. Ser. 950; Malhotra, S. V., Ed.;
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Procedure for recycling of the ionic liquid: The combined brown-colored ionic
liquids recovered from several set of experiments were dissolved in MeCN and
filtered through Celite to remove insoluble black particles. After removal of
solvent from the filtrate under vacuum, the recycled IL was dried overnight
under vacuum at 50 °C and reused in subsequent runs.