Palladium-catalyzed C-F activation of polyfluoronitrobenzene derivatives in suzuki-miyaura coupling reactions

Article abstract of DOI:10.1021/jo100877j

Highly fluorinated nitrobenzene derivatives are suitable substrates for palladium-catalyzed C-F bond arylation using readily available palladium catalysts under both conventional heating and microwave conditions. Arylation occurs ortho to the nitro group offering a synthetic route to polyfluorinated 2-arylnitrobenzene systems. The regiochemistry of the arylation reactions suggests that there is a significant directing interaction between the nitro group and the incoming nucleophilic palladium catalyst which is facilitated by the presence of several fluorine atoms attached the ring. Investigations into the regioselectivity and reactivity of several tetrafluoro- and trifluoronitrobenzene derivatives provides further evidence for the highly nucleophilic character of the oxidative addition step in contrast to the concerted mechanism of more conventional Suzuki-Miyaura coupling reactions involving aryl iodides and bromides.

Full text of DOI:10.1021/jo100877j

pubs.acs.org/joc
Palladium-Catalyzed C-F Activation of Polyfluoronitrobenzene
Derivatives in Suzuki-Miyaura Coupling Reactions
Matthew R. Cargill,† Graham Sandford,*,† Andrezj J. Tadeusiak,† Dmitrii S. Yufit,‡
Judith A. K. Howard,‡ Pinar Kilickiran,§ and Gabrielle Nelles§
†Department of Chemistry, and ‡Chemical Crystallography Group, Department of Chemistry,
Durham University, South Road, Durham DH1 3LE, U.K., and Sony Deutschland GmbH,
Stuttgart Technology Center, Hedelfinger Strasse 61, 70327 Stuttgart, Germany
§
graham.sandford@durham.ac.uk
Received May 5, 2010
Highly fluorinated nitrobenzene derivatives are suitable substrates for palladium-catalyzed C-F bond
arylation using readily available palladium catalysts under both conventional heating and microwave
conditions. Arylation occurs ortho to the nitro group offering a synthetic route to polyfluorinated
2-arylnitrobenzene systems. The regiochemistry of the arylation reactions suggests that there is a significant
directing interaction between the nitro group and the incoming nucleophilic palladium catalyst which is
facilitated by the presence of several fluorine atoms attached the ring. Investigations into the regioselectivity
and reactivity of several tetrafluoro- and trifluoronitrobenzene derivatives provides further evidence for the
highly nucleophilic character of the oxidative addition step in contrast to the concerted mechanism of more
conventional Suzuki-Miyaura coupling reactions involving aryl iodides and bromides.
Introduction
as the electrophilic coupling partners4 due to the higher
carbon-chlorine bond strength and, consequently, are much
less reactive. For similar reasons, analogous reactions involv-
ing metal-catalyzed C-F activation are rarer still due to the
very strong carbon-fluorine bond. However, various nickel-
catalyzed functionalizations in Kumada5-12 and Suzuki13
couplings and hydrodefluorination14 processes and some
Palladium-catalyzed cross-coupling reactions have been the
subject of extensive research in recent years because of the wide
variety of synthetically useful carbon-carbon bond-forming
reactions that may be achieved in high yield and regioselectivity
under mild conditions. The application of palladium-catalyzed
processes, such as Suzuki-Miyaura, Sonogashira, Heck, and
Stille reactions, to natural product target synthesis, heterocyclic
chemistry, and parallel syntheses in drug discovery programs
are well documented and continue to increase.1-3
In general, the haloaromatic electrophilic species in many
metal-catalyzed processes are most frequently aryl iodides or
bromides because of the relative ease of oxidative addition of
the catalyst into relatively weak carbon-iodine or carbon-
bromine bonds. In contrast, aryl chlorides are used less often
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Published on Web 08/12/2010
DOI: 10.1021/jo100877j
r
2010 American Chemical Society

Cargill et al.
JOCArticle
successful reactions involving cobalt,15 platinum,16,17 and
titanium18 species have been described and comprehensively
summarized in a recent review article.19 There remain
only a few other examples of analogous palladium-catalyzed
processes.20-27
unusual reactivity profile for the synthesis of, for example,
macrocycles,29-31 ring fused systems32-34 and polyfunctional
heterocyclic derivatives.35-38 Consequently, we reasoned that
carbon-fluorine bonds in highly fluorinated nitrobenzene
derivatives such as pentafluoronitrobenzene should be suffi-
ciently activated toward nucleophilic oxidative addition by
palladium catalysts and that the presence of the nitro group
on the aromatic ring would aid this process to provide efficient
palladium-catalyzed C-F activation in perfluorinated systems.
Indeed, it is established that pentafluoronitrobenzene reacts
with nucleophiles to give products arising from substitution of
fluorine principally at the 4-position, although some substitu-
tions occur at the 2-position depending upon the nucleophile
and reaction conditions.28 The only direct arylation reactions of
pentafluoronitrobenzene described in the literature involve
reactions of pentafluorophenylmagnesium bromide39 and
pentafluorophenyllithium40 with products arising from nucleo-
philic aromatic substitution of fluorine located para to the nitro
group. In our hands, we have found that reaction of phenyl-
lithium and phenylmagnesium bromide with pentafluoronitro-
benzene does not give any useful product.
The first examples of catalytic C-F bond activation of
highly and perfluorinated heterocyclic systems were reported
by Braun where vinylation of 2,3,5,6-tetrafluoropyridine by
a Stille coupling reaction21 and Suzuki-Miyaura arylation
of 5-chloro-2,4,6-trifluoropyrimidine22 were achieved by
nickel catalysis. Subsequently, Radius reported the first
example of catalytic C-F activation of a perfluoroaromatic
system by employing an N-heterocyclic carbene stabilized
nickel(0) complex as the catalyst for a Suzuki-Miyaura
arylation of perfluorotoluene and perfluorobiphenyl.26 How-
ever, catalysts based on nickel(0) systems are very air sensi-
tive and are difficult to use in general organic synthesis.
Consequently, the development of reaction conditions that
allow the activation of C-F bonds in highly and perfluori-
nated aromatic systems by standard, commercially available
palladium catalysts that may be used in typical laboratory
processes are required to enable further development of C-F
activation chemistry.
More recently, palladium-catalyzed C-F activation and
functionalization of several monofluorinated nitrobenzene
derivatives under standard Suzuki-Miyaura conditions
using conventional palladium catalysts were reported by
the groups of Kim and Yu27 and Widdowson.20 It was
suggested that the nitro group, in addition to its activating
electron-withdrawing properties, directs the palladium cata-
lyst into the adjacent ortho C-F bond, thereby lowering the
activation energy for the oxidative addition step. It was
postulated that oxidative addition of the palladium catalyst
into the carbon-fluorine bond occurs via a nucleophilic
aromatic substitution-type process. Indeed, the nitrofluoro-
aromatic derivatives required the presence of a further
electron-withdrawing group (CN, CHO) attached to the
aromatic ring to sufficiently activate the aromatic system
toward nucleophilic oxidative addition of the catalyst into
the C-F bond, consistent with the suggested process.
In contrast to hydrocarbon aromatic systems which react
with electrophilic species, highly and perfluorinated aromatic
systems are very susceptible toward nucleophilic attack, and
indeed, significant work28 has been performed to exploit this
In this paper, we report the first examples of palladium-
catalyzed Suzuki-Miyaura coupling reactions of perfluoro-
aromatic systems using standard conditions and readily
available palladium catalysts for the synthesis of various
highly fluorinated biphenyl systems.
Results and Discussion
In our initial studies, we chose to carry out reactions of
pentafluoronitrobenzene in palladium-catalyzed Suzuki coupl-
ing reactions using the conditions analogous to those reported
by Kim and Yu41 and, in this case, reaction between penta-
fluoronitrobenzene 1 and phenylboronic acid with Pd(PPh3)4
as the catalyst furnished the desired biphenyl derivative 2
(Scheme 1). Microwave irradiation was employed to ensure
that a rapid and reproducible heating profile was maintained.
GC-MS and 19F NMR analysis of the crude reaction
mixture identified the presence of a small quantity of terphenyl
derivative 3, due to reaction with the slight excess of phenyl-
boronic acid present, and a trace amount of 5 (m/z 315) arising
from nucleophilic attack of the phenylboronate anion on
pentafluoronitrobenzene. 2,3,5,6-Tetrafluoro-4-nitrophenol 4
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A. S.; Howard, J. A. K. J. Fluorine Chem. 2005, 126, 1002–1008.
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66, 519–529.
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J. A. K.; Vong, A. Tetrahedron 2007, 63, 5204–5211.
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J. A.; Miller, D. D. Tetrahedron 2009, 65, 8844–8850.
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SCHEME 1. Palladium-Catalyzed Suzuki-Miyaura Reactions
of Pentafluoronitrobenzene 1
FIGURE 1. ORTEP diagram of the molecular structure of [Pd-
(PPh3)2(F)(C6F4NO2)] 1b in the solid state (ellipsoids set at 40%
probability level). Hydrogen atoms have been omitted for clarity.
The nitro group is disordered 1:1 over two positions.
SCHEME 2. Mechanism of Pd-Catalyzed C-F Activation of
Pentafluoronitrobenzene
was isolated and characterized by 19F NMR spectroscopy and
consistent with literature data,42 and we suggest that this is
formed from either the nucleophilic attack of water, which is
present in small quantities due to the hygroscopic properties of
the base, or the attack of cesium carbonate and its subsequent
decarboxylation. In a control experiment, we found that no
biaryl coupled product 2 was obtained in the absence of the
palladium catalyst.
The reactions described above (Scheme 1) indicate that a
base is required that would not lead to any apparent reaction
of the perfluorinated aromatic substrate. Fluoride ion, most
conveniently as either potassium fluoride or potassium fluo-
ride adsorbed on the surface of alumina, seemed ideal for
this purpose since reaction of fluoride with the perfluoro-
aromatic substrate would not affect the outcome of the
coupling process. Of course, alumina-supported fluoride
ion systems have been used as the base in many organic
transformations and in various palladium-catalyzed cou-
pling reactions.43 Consequently, the coupling reaction of
pentafluoronitrobenzene 1 with the neopentylglycol ester
of phenylboronic acid using 40% KF/alumina as the base
and Pd(PPh3)4 as the catalyst allowed complete consumption
of 1, as indicated by 19F NMR analysis of the reaction
mixture, and desired biphenyl 2 was successfully isolated in
good yield (Scheme 1). 2,3,5,6-Tetrafluoro-4-nitrophenol 4
was not observed, and X-ray analysis of the purified product
(Supporting Information) confirms the regiochemistry of the
arylation process as being ortho to the nitro group.
addition intermediate was synthesized in a separate experi-
ment by reaction of a stoichiometric quantity of Pd(PPh3)4
with pentafluoronitrobenzene in dry, degassed DMF heated
at 80 °C for 8 h using standard Schlenk-line techniques.
Subsequent recrystallization of the crude reaction mixture
from dry, degassed THF afforded the pure product, which
was dissolved in toluene-d8 and analyzed by 19F NMR
spectroscopy. The resulting spectrum shows four resonances
(δ -110, -145, -150, -162 ppm) corresponding to the
2-nitrotetrafluoryl group and a fifth resonance (δ -311 ppm)
corresponding to the metal-bound fluorine. Single crystals
suitable for X-ray diffraction were obtained via the slow
evaporation of diethyl ether from the recrystallized solid,
and the structure clearly shows the presence of the C-Pd-F
moiety (Figure 1).
In order to provide evidence that carbon-fluorine bond
activation proceeds via the insertion of the palladium cata-
lyst into the C-F bond ortho to the nitro group, the oxidative
A catalytic cycle for the C-F activation reaction can be
postulated (Scheme 2) in which the nitro group directs the
nucleophilic palladium center toward the adjacent C-F
bond to give 1a, which leads directly to the oxidative addi-
tion intermediate 1b, consistent with earlier discussion.41
(42) Birchall, J. M.; Haszeldine, R. N.; Nikokavouras, J.; Wilks, E. S.
J. Chem. Soc. C. 1971, 562–566.
(43) Basudeb, B.; Pralay, D.; Sajal, D. Curr. Org. Chem. 2008, 12,
141–158.
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TABLE 1. Effect of Metal Catalyst
TABLE 2. Palladium-Catalyzed Suzuki-Miyaura Reactions of
Pentafluoronitrobenzene
catalyst
yield of 2,a %
Pd0
[Pd(PPh3)4]
96
78
0
9
4
[Pd2(dba)3], 4 PhPCy2
[Pd2(dba)3], 4 PtBu3
[Pd(OAc)2]
PdII
NiII
[Pd(dppf)Cl2]
[Ni(acac)2]
0
2
[Ni(acac)2], PtBu3
aNMR yield.
Transmetalation and reductive elimination proceed follow-
ing established literature pathways to give the biphenyl
product 2.
Several catalyst and ligand combinations have been screened
in order to establish the most active catalytic system for the
palladium-catalyzed cross-coupling procedure (Table 1). In
general, palladium(0) catalysts are observed to be much more
effective than palladium(II) systems, whereas nickel(II) deriva-
tives are very inefficient. In a typical reaction procedure, all
solids were charged into the reaction vessel, which was repeat-
edly purged under vacuum and backfilled with argon, before
the solvent and liquid reagents were added and heated under
microwave irradiation. Quantitative data was obtained via
19F NMR analysis of the crude reaction mixtures relative to a
known quantity of 1,4-difluorobenzene, which was added after
the reactions had been cooled to room temperature.
The results in Table 1 show that palladium(0) catalysts are
highly effective species for initiating the coupling procedure.
Subsequently, a second reaction optimization process was
carried out by varying the phosphine ligand system, and
these results are contained in the Supporting Information
(Table S1). While PPh2Cy is observed to offer the highest
conversion of pentafluoronitrobenzene to 2, there is no signifi-
cant difference in the performance of either PPh3 or PPhCy2 as
ligands, and so, because of its commercial availability and rela-
tive stability toward atmospheric decomposition, Pd(PPh3)4
remains our catalyst of choice.
In addition, several aprotic solvents of differing polarity
were screened in an attempt to further improve the efficiency
of the cross-coupling reaction (Table S2, Supporting Infor-
mation), and we found that the more polar solvents are
generally the most effective reaction media for the arylation
of pentafluoronitrobenzene and that both DMF and DMSO
offer the highest conversions of starting material to product.
As DMF is marginally easier to remove during the purifica-
tion procedure, it was selected as solvent for further coupling
reactions in the first instance.
Regiospecific arylation ortho to the nitro group is observed
in all cases, and the structures of biphenyl derivatives 2 and 9
were confirmed by X-ray crystallography. The presence of
four signals in the 19F NMR spectrum of each product, all of
which have chemical shifts similar to those of 2 and 9 and
3
show the appropriate JFF coupling constants (∼20 Hz),
confirm the structures of the remaining biphenyl derivatives
6-8, 10, and 11.
In order to probe the factors that affect the mechanism of
this C-F activation process, we studied arylation reactions
of the three tetrafluoronitrobenzenes (Table 3) under similar
reaction conditions, although extended heating was required
to achieve complete conversion of the starting materials.
Arylation ortho to the nitro group is observed in all cases,
and the structures of 15 and 17 were confirmed by X-ray
crystallography (see the Supporting Information).
The tetrafluoronitrobenzene derivatives are significantly
less reactive toward Pd-catalyzed arylation than penta-
fluoronitrobenzene, reflecting the one less activating fluorine
substituent present in these substrates. While the reaction
Using our preferred conditions, several boronic acids and
esters bearing electron-releasing and -withdrawing groups
were successfully coupled to pentafluoronitrobenzene in
moderate to good yield (Table 2), demonstrating the applic-
ability of this carbon-fluorine bond activation process to
some functionalized aromatic substrates.
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TABLE 3. Palladium-Catalyzed Suzuki-Miyaura Reactions of Tetrafluoronitrobenzene Derivatives
mixtures of all three reactions predominantly consist of the
desired arylated material, significant quantities of byproduct
13a, 15a, and 17a were observed. In each case, the major
byproduct was isolated and characterized as the correspond-
ing dimethylamino-substituted trifluoronitrobenzene deriva-
tive. In order to verify the identity of several of the byproduct
arising from the decomposition of DMF during the arylation
of tetrafluoronitrobenzene systems (Table 3), we carried out
separate amination reactions of 12, 14, and 16 by reacting
excess dimethylamine with each of the tetrafluoronitro-
benzene starting materials, and these results are collated in the
Supporting Information (Scheme S1).
the decomposition of solvent DMF under the relatively
harsh reaction conditions required.
Consequently, to avoid the problems associated with using
DMF as the arylation reaction medium, we carried out the
Suzuki-Miyaura reactions in DMSO (Table 3), which is
stable under the reaction conditions and, from solvent
screening studies (Table S2, Supporting Information), offers
conversions of starting materials similar to those using DMF.
Gratifyingly, complete conversion of starting materials was
achieved in each case, and overall competing processes were
significantly reduced, as reflected by the increased isolated
yields of 13, 15, and 17.
It is evident, therefore, that DMF is not stable under the
relatively forcing reaction conditions employed in these
arylation procedures and that decomposition to dimethyl-
amine becomes problematic. Indeed, repeating the reactions
in the absence of boronic acid and catalyst results in a
complex mixture of products, from which a small quantity
of dimethylamino-substituted derivatives are readily identi-
fiable by GC-MS and 19F NMR analysis. For less activated
systems such as the tetrafluoronitrobenzene substrates, be-
cause higher reaction temperatures are required to achieve
significant yields of arylated product, there is a competing
nucleophilic aromatic substitution amination process due to
These experiments allow us to assess the relative effects of
the fluorine atoms that are ortho, meta, and para to the site of
arylation and provide insight into whether the oxidative
addition of palladium to the C-F bond is a nucleophilic-
type process. It is well-known, for nucleophilic aromatic
substitution reactions of perfluorinated aromatic systems,
that fluorine located at positions ortho to the site of nucleo-
philic attack is strongly activating, meta fluorine is activat-
ing, and para fluorine is slightly deactivating with respect to
hydrogen, as determined by a series of competitive kinetics
experiments.28 Consequently, it was established that, for
the majority of cases, nucleophilic aromatic substitution
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TABLE 4. Competition Experiment
FIGURE 2. C-F bonds activated in tetrafluoronitrobenzene 12.
reactions of perfluoroaromatic systems occur to give pro-
ducts arising from maximizing the number of fluorine atoms
ortho and meta to the site of nucleophilic attack.
Thus, for 12 there are two sites at which arylation may occur,
but the reaction is completely regioselective. If the oxidative
addition of palladium into the C-F bond is assumed to be the
overall rate-determining step and the palladium catalyst can be
considered to have significant nucleophilic character, as des-
cribed above and suggested elsewhere,41,44 then it is possible to
consider the regiochemistry of this C-F activation process in a
manner similar to that for nucleophilic aromatic substitution
processes in perfluoroaromatic systems (Figure 2). For tetra-
fluoronitrobenzene 12, there are two sites (FA and FB) which
are ortho to the nitro group and, therefore, sites of possible
arylation. Both FA and FB are activated by two meta fluorine
atoms, but FB is further activated by an ortho fluorine. Con-
sequently, FB is postulated to be more activated toward nucleo-
philic attack by the palladium catalyst, and this is confirmed by
experiment.
aAs measured by 19F NMR analysis. bCalibrated literature values for
methoxydefluorination processes.45
TABLE 5. Palladium-Catalyzed Suzuki-Miyaura Reactions of Trifluoro-
nitrobenzene Derivatives
Of course, for tetrafluoronitrobenzenes 14 and 16 there is
only one possible site that is ortho to the nitro group at which
arylation may occur. However, as both 14 and 16 are only
activated by one, rather than two, meta fluorine atoms they
are noticeably less reactive than 12, and this is reflected in the
longer reaction times required to effect complete conversions
of 14 and 16 relative to 12.
In order to establish the relative reactivities of each of the
tetrafluoronitrobenzene systems toward arylation, a com-
petition reaction was performed in which 10 mol % of 12, 14,
and 16 and 5 mol % of Pd(PPh3)4 were dissolved in degassed
DMSO (2 mL) and heated to 100 °C, under microwave
irradiation, for 30 min. Quantitative reactivity data was
obtained by 19F NMR signal intensities, with reference to a
known quantity of 1,4-difluorobenzene (Table 4).
There appears to be a reasonable correlation between the
relative rates of palladium-catalyzed C-F activated aryla-
tion and those concerning analogous methoxydefluorination
processes of 12, 14, and 16,45 offering further evidence for the
nucleophilic character and rate-determining nature of the
oxidative addition step.
Subsequently, palladium-catalyzed coupling reactions of
several trifluoronitrobenzene derivatives were investigated
(Table 5). These processes require a higher catalyst loading
(10 mol %) and extended heating in order to effect complete
conversion of starting material to products, and DMSO is
preferred as the solvent for these transformations due to the
aforementioned instability of DMF.
Ortho arylation is observed in each case, but it was not
possible to gather reliable kinetic data on the relative reac-
tivities of 18, 20 ,and 22 because a number of side products
are formed in the coupling process due to the harsh reaction
conditions, and consequentially, 19F NMR analysis of the
product mixture is not particularly reliable in this case.
However, the low conversion and poor isolated yield of 23
indicates that 22 is the least activated of the trifluoronitro-
benzene derivatives screened, and this can be attributed to
the fact that the site of arylation is only significantly acti-
vated by a single meta fluorine atom.
(45) Bolton, R.; Sandall, J. P. B. J. Chem. Soc., Perkin Trans. 2 1978,
(44) Widdowson, D. A.; Wilhelm, R. Chem. Commun. 2003, 578–579.
141–144.
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Conclusions
5JFF = 10.7 Hz), -147.82 (1F, ddd, 3JFF = 21.2 Hz, 4JFF = 5.1
Hz, 5JFF = 10.7 Hz), -149.95 (1F, ddd, 3JFF = 22.4 Hz, 3JFF
= 20.7 Hz, 4JFF = 5.1 Hz), -152.87 (1F, ddd, 3JFF = 21.2 Hz,
3JFF = 20.7 Hz, 4JFF = 3.5 Hz); FT-IR (cm-1) 1365, 1546; m/z
(EIþ) 272 (Mþ, 1), 271 (Mþ, 8), 243 (65), 224 (73), 187 (100), 175
(30), 51 (14), 30 (13). Anal. Calcd for C12H5F4NO2: C, 53.15;
H, 1.86; N, 5.17. Found: C, 53.20; H, 1.89; N, 5.17.
2,3,4-Trifluoro-6-nitrobiphenyl. Reaction of 2,3,4,5-tetra-
fluoronitrobenzene (0.243 g, 1.25 mmol) with 4,4,5,5-tetramethyl-
2-phenyl-1,3,2-dioxaborolane (0.283 g, 1.41 mmol) afforded
2,3,4-trifluoro-6-nitrobiphenyl as a yellow solid (0.085 g,
Highly fluorinated nitrobenzene derivatives undergo regio-
selective Suzuki-Miyaura cross-coupling reactions via the
insertion of palladium(0) catalysts into a C-F bond located
ortho to the nitro group. The arylation of pentafluoronitro-
benzene offers a synthetic route to previously unreported
2,3,4,5-tetrafluoro-6-nitrobiphenyl derivatives, and these pro-
cesses represent the first examples of palladium-catalyzed
Suzuki-Miyaura cross-coupling reactions of a perfluorinated
aromatic system. Tetrafluoronitrobenzene and trifluoronitro-
benzene systems are less reactive than pentafluoronitro-
benzene, as expected due to the corresponding reduction in
electrophilicity of the aromatic ring. A reactivity study of the
arylation of the three tetrafluoronitrobenzenes parallels that
of typical nucleophilic aromatic substitution processes and
provides evidence for the nucleophilic character and rate-
limiting nature of the oxidative addition step.
1
27%): mp 104-106 °C; H NMR (400 MHz, CDCl3) δ 7.27
(2H, m), 7.48 (3H, m), 7.68 (1H, ddd, 3JHF=9.0 Hz, 4JHF=6.6
Hz, 5JHF=2.3 Hz); 13C NMR (176 MHz, CDCl3) δ 109.5 (dd,
=
2JCF=22.0 Hz, 3JCF=3.9 Hz), 123.9 (dd, 2JCF=17.7 Hz, 3JCF
4.3 Hz), 128.8 (s), 129.1 (s), 129.1 (s), 129.6 (s), 143.2 (ddd,
1JCF=262 Hz, 2JCF=16.5 Hz, 2JCF=14.9 Hz), 144.1 (m), 149.2
(ddd, 1JCF=253 Hz, 2JCF=10.8 Hz, 3JCF=3.7 Hz), 149.7 (ddd,
1JCF=255 Hz, 2JCF=10.9 Hz, 3JCF=4.2 Hz); 19F NMR (658
MHz, CDCl3, CFCl3) δ -130.06 (1F, dd, 3JFF=21.4 Hz, 4JFF
7.7 Hz), -131.08 (1F, ddd, 3JFF=20.9 Hz, 3JFH=9.0 Hz, 4JFF
=
=
Experimental Section
3
3
7.7 Hz), -150.14 (1F, ddd, JFF = 21.5 Hz, JFF =21.3 Hz,
4JFH=6.6 Hz); FT-IR (cm-1) 1359, 1530; m/z (EIþ) 253 (Mþ,
3), 225 (22), 169 (44), 51 (31), 30 (100). Anal. Calcd for
General Method for Suzuki-Miyaura Reactions of Highly
Fluorinated Nitrobenzene Substrates. The boronic acid or boro-
nic ester (1.1 equiv), 40% KF/alumina (1.2 equiv), and Pd(PPh3)4
(0.05 equiv) were charged to a microwave vial (0.5-2.0 mL) and
sealed. The microwave vial was evacuated under high vacuum
and backfilled with argon three times to create an inert atmo-
sphere. Dry, degassed DMF or DMSO (2 mL) and the relevant
polyfluoronitrobenzene (1.0 equiv) were added to the vial and
heated (150 °C, 20-120 min) with stirring. The vial and its
contents were cooled and filtered through silica gel and volatile
material was evaporated. Purification by column chromatog-
raphy on silica gel using hexanes and DCM (4:1) as the eluent
and recrystallization from hexanes afforded the pure product.
2,3,4,5-Tetrafluoro-6-nitrobiphenyl. Reaction of pentafluor-
onitrobenzene (0.248 g, 1.16 mmol) with 5,5-dimethyl-2-phenyl-
1,3,2-dioxaborinane (0.263 g, 1.39 mmol) afforded 2,3,4,5-tetra-
fluoro-6-nitrobiphenyl as an off-white solid (0.251 g, 80%): mp
70-71 °C; 1H NMR (700 MHz, CDCl3) δ 7.34 (2H, m),
7.46-7.52 (3H, m); 13C NMR (126 MHz, CDCl3) δ 121.2
(ddd, 2JCF = 18.9 Hz, 3JCF = 4.3 Hz, 3/4JCF = 1.1 Hz), 127.0
C
2.43; N, 5.58.
12H6F3NO2: C, 56.93; H, 2.39; N, 5.53. Found: C, 56.67; H,
3,5-Difluoro-6-nitrobiphenyl. Reaction of 2,4,6-trifluoroni-
trobenzene (0.262 g, 1.50 mmol) with 4,4,5,5-tetramethyl-2-
phenyl-1,3,2-dioxaborolane (0.323 g, 1.58 mmol) afforded 3,5-
difluoro-6-nitrobiphenyl as a yellow solid (0.188 g, 54%): mp
1
52-53 °C; H NMR (700 MHz, CDCl3) δ 7.00 (2H, m), 7.35
(3H, m), 7.45 (2H, m); 13C NMR (176 MHz, CDCl3) δ 105.5 (dd,
=
2JCF=23.1 Hz, 2JCF=26.8 Hz), 113.9 (dd, 2JCF=23.4 Hz, 4JCF
3.6 Hz), 127.92 (s), 129.37 (s), 129.8 (s), 134.7 (s), 136.0 (m),
2/3
1
3
139.0 (d,
J
CF
=10.1 Hz), 154.9 (dd, JCF =260 Hz, JCF =
13.5 Hz), 162.8 (dd, 1JCF=256 Hz, 3JCF=12.1 Hz); 19F NMR
(658 MHz, CDCl3, CFCl3) δ -103.75 (1F, m), -118.96 (1F, m);
FT-IR (cm-1) 1350, 1530; m/z (EIþ) 235 (Mþ, 18), 207 (76), 188
(99), 151 (100), 51 (16). Anal. Calcd for C12H7F2NO2: C, 61.28;
H, 3.00; N, 5.96. Found: C, 61.27; H, 3.01; N, 5.90.
Acknowledgment. We thank EPSRC and the SONY Corp.
for funding (studentships to A.J.T. and M.R.C.).
(s), 129.3 (s), 129.5 (s), 130.5 (s), 135.8 (m), 141.2 (dddd, 1JCF
=
259 Hz, 2JCF = 14.7 Hz, 2JCF = 13.5 Hz, 3JCF = 3.4 Hz), 141.1
(dddd, 1JCF = 260 Hz, 2JCF = 11.6 Hz, 3JCF = 4.8 Hz, 4JCF
2.7 Hz), 142.8 (dddd, 1JCF = 261 Hz, 2JCF = 17.5 Hz, 2JCF
12.3 Hz, 3JCF = 3.2 Hz), 143.9 (dddd, 1JCF = 253 Hz, 2JCF
=
=
=
Supporting Information Available: Tables S1 and S2,
Scheme S1, representative NMR spectra of all new compounds,
and X-ray files for 1b, 2, 9, 13a, 15, and 17 (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
11.0 Hz, 3JCF = 3.8 Hz, 4JCF = 1.8 Hz); 19F NMR (658 MHz,
CDCl3, CFCl3) δ-138.17 (1F, ddd, 3JFF = 22.4 Hz, 4JFF =3.5Hz,
5866 J. Org. Chem. Vol. 75, No. 17, 2010