Nickel- and palladium-catalyzed cross-coupling reaction of polyfluorinated arenes and alkenes with grignard reagents

Article abstract of DOI:10.1055/s-2005-871571

The cross-coupling reaction of fluorobenzene with an aryl Grignard reagent has been reinvestigated which revealed that the reaction readily proceeds under ordinary conditions using a catalytic amount of NiCl₂(dppp) even at room temperature. The use of nickel catalysts and Grignard reagent is essential for the activation of the carbon-fluorine bond. The palladium catalyst is also effective for the 1,2-difluorobenzene and trifluorobenzenes to selectively produce the corresponding mono-coupled products while the nickel-based catalyst system affords a mixture of the mono-coupled product and di- or tri-coupled product. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871571

CLUSTER
1771
Nickel- and Palladium-Catalyzed Cross-Coupling Reaction of Polyfluorinated
Arenes and Alkenes with Grignard Reagents
C
T
ross-Coupling
o
Reaction of
m
Polyfluorinated Ar
o
o
m
atic Comp
y
ounds uki Saeki,* Yohei Takashima, Kohei Tamao*1
International Research Center for Elements Science, Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
Fax +81(774)383186; E-mail: tamao@scl.kyoto-u.ac.jp
Received 30 March 2005
utilizing a number of activated aryl fluorides such as o-
Abstract: The cross-coupling reaction of fluorobenzene with an
fluorobenzaldimine,10 fluoroarene–chromium complex,
11
aryl Grignard reagent has been reinvestigated which revealed that
the reaction readily proceeds under ordinary conditions using a cat-
12
13
fluoroazine and diazine, o-fluoronitro-benzene, and o-
alytic amount of NiCl (dppp) even at room temperature. The use of fluorobenzoates14 have appeared. Very recently, the
2
nickel catalysts and Grignard reagent is essential for the activation cross-coupling reaction of unactivated aryl fluorides was
of the carbon–fluorine bond. The palladium catalyst is also effective
also reported using a nickel catalyst with a bulky and
highly electron-donating carbene ligand by Herrmann or
for the 1,2-difluorobenzene and trifluorobenzenes to selectively
produce the corresponding mono-coupled products while the nick-
el-based catalyst system affords a mixture of the mono-coupled
product and di- or tri-coupled product.
15
a palladium catalyst with a microwave apparatus by
Dankwardt.16 These publications prompted us to report
our recent results on the nickel- and palladium-catalyzed
cross-coupling reaction of fluoroarenes and fluoroalkenes
with Grignard or organozinc reagents.17
Key words: cross-coupling, nickel, palladium, Grignard reagent,
fluoroarene
Monofluorobenzene Based on a previous observation
we first reexamined the reaction conditions for the cross-
coupling reaction of fluorobenzene (1) with 4-methyl-
phenylmagnesium bromide (2) as a model reaction to
reveal that the reaction readily proceeds under ordinary
Since the early study of the reaction of aryl and alkenyl
halides with Grignard reagents in the presence of an iron
or nickel catalyst was independently reported by the re-
search groups of Kochi, Corriu, and Kumada in the early
1
8
2
conditions using 0.05 equivalents of NiCl (dppp) as a
1
970s, the transition metal-catalyzed cross-coupling re-
2
catalyst even at room temperature to afford 4-methyl-
biphenyl (3) in 92% GC yield after 24 hours (Scheme 1).
action has become the most powerful and promising syn-
thetic tool for the construction of carbon–carbon and
3
carbon–heteroatom bonds. A variety of organometallic
reagents have already been successfully utilized for the
catalytic system, as represented by the Suzuki–Miyaura
(
(
B), Hiyama (Si), Negishi (Zn), and Kosugi–Migita–Stille
Sn) reactions. On the other hand, recent interests in the
cross-coupling reaction seems to be concentrated on the Scheme 1 Cross-coupling reaction of fluorobenzene with
development of reaction systems involving less reactive
substrates such as aryl chlorides, aryl cyanides, and
aryl ethers.
4
-MeC H MgBr
6
4
4
,5
6
7
Other phosphine ligands examined in the screening of the
catalyst system were less effective: NiCl (PEt ) , 34%;
NiCl (PCy ) , 64%; NiCl (PPh ) , 53%; NiCl (dppb),
2
3 2
Until recently, aryl fluorides were regarded as an uncom-
mon coupling partner for the transition metal-catalyzed
cross-coupling reaction due to the strong carbon–fluorine
bond (154 kcal/mol for C F ), and the resulting lack of re-
activity for oxidative addition. Although the reaction
conditions were not optimized at that time, however, one
of us, together with Kumada, had already found in 1973
that the nickel-catalyzed cross-coupling reaction was also
applicable to aryl fluorides. This was the first demon-
stration of the catalytic cleavage of the sp -carbon–fluo-
rine bond. Twenty years later, the rhodium-catalyzed
hydrogenation of aryl fluorides was reported by Aizen-
berg and Milstein in 1994. Since then, several reports on
2
3 2
2
3 2
2
2
6%; NiCl (dppf), 65%. The catalyst loading can be re-
2
duced to 0.01 equivalents without any loss in the product
yield, as optimized in another experiment. It should be
noted that the palladium catalysts, such as PdCl (PPh ) ,
PdCl (dppb), and PdCl (dppf), were totally ineffective
and the other organometallic reagents such as organo-
6
6
8
2
3 2
2
2
2
d,e
boron, silicon, zinc, zirconium, and tin compounds pro-
19
2
duced only a trace amount of the product. The reason for
the specificity to the organomagnesium compounds re-
mains to be clarified, but the interaction between the mag-
nesium atom and the fluorine atom might play an essential
role in the oxidative addition process. The reaction condi-
tions for the cross-coupling reaction of fluorobenzene (1)
with n-butylmagnesium bromide were also screened in a
9
the transition metal-catalyzed cross-coupling reactions
SYNLETT 2005, No. 11, pp 1771–1774
Advanced online publication: 27.06.2005
0
7
.0
7
.2
0
0
5
similar manner to reveal that NiCl (dppp) is still the most
2
DOI: 10.1055/s-2005-871571; Art ID: Y00605ST
©
Georg Thieme Verlag Stuttgart · New York

1
772
T. Saeki et al.
CLUSTER
Table 1 Cross-Coupling Reaction of Difluorobenzenes with
oxidative addition of the carbon–fluorine bond, but all
attempted reactions with 2-methoxy-, 2-chloro-, and 2-
hydroxyfluorobenzenes resulted only in the formation of
undesired products.
a
4
-MeC H MgBr
6 4
Trifluorobenzene The coupling reaction was extended to
the reaction of 1,2,3- and 1,3,5-trifluorobenzenes (7a,b)
with the aryl Grignard reagent 2 as summarized in
Table 2. In the reaction of 1,2,3-trifluorobenzene (7a) us-
ing the nickel catalyst, the corresponding di-coupled prod-
2
1
uct 9a was exclusively obtained in 41% yield (entry 1),
while the reaction of 1,3,5-trifluorobenzene (7b) afforded
the tri-coupled product 10b in 60% yield along with the
di-coupled product 9b22 in 7% yield (entry 3): in the di-
coupled product 9a, the steric hindrance around the re-
maining ortho-fluorine atom could be responsible for pre-
venting any further reaction. On the other hand, the
Entry
Substrate
Catalyst
Yield (%)b
5
6
1
2
3
NiCl (dppp)
38
24
91
40
40
0
2
c
c
c
NiCl (dppp)
2
PdCl (dppf)
2
reactions with palladium catalysts, such as PdCl (dppf)
2
and PdCl (PPh ) , almost exclusively afforded the corre-
2
3 2
4
5
6
NiCl (dppp)
37
11
15
36
78
0
23
2
sponding mono-coupled products 8a and 8b in 69% and
0% yields, respectively (entries 2 and 4).
NiCl (dppp)
2
6
PdCl (dppf)
2
The higher reactivity of the trifluorobenzenes than the di-
fluorobenzenes (entry 4, Table 2 vs. entry 6, Table 1) is
obviously attributable to the successive introduction of
the electronegative fluorine atom.
7
8
9
NiCl (dppp)
23
10
6
45
87
0
2
NiCl (dppp)
2
PdCl (dppf)
2
gem-Difluoroalkene Finally, we applied the catalyst sys-
tem to the cross-coupling reaction of gem-difluoroalkene
a
Reaction conditions: difluorobenzene 4 (1.0 mmol),
-MeC H MgBr (2, 1.5 mmol), and catalyst (0.01 mmol), THF
5.0 mL), reflux, 48 h.
4
6
4
1
1 (Scheme 2).
(
b
Determined by GC and NMR analysis with eicosane and 1,3,5-tri-
methoxybenzene as an internal standard, respectively.
c
Larger amounts of catalyst (0.05 mmol) and the Grignard reagent
(
5.0 mmol) were employed.
effective to afford n-butylbenzene in 93% yield after 24
hours of stirring under reflux.
Difluorobenzene We next examined the cross-coupling
reaction of 1,2-, 1,3-, and 1,4-difluorobenzenes (4a–c)
with the aryl Grignard reagent 2 as shown in Table 1. Un-
der the optimized conditions using 0.01 equivalents of
NiCl (dppp) and 1.5 equivalents of the Grignard reagent
2
2
5
, a mixture of the corresponding mono-coupled product
and di-coupled product 6 was obtained in the total yields Scheme 2 Cross-coupling reaction of gem-difluoroalkene with an
2
0
arylzinc reagent
ranging from 68% to 78% (entries 1, 4, and 7). When the
amounts of the nickel catalyst and the Grignard reagent
were increased to 0.05 and 5 equivalents, respectively, the The palladium-based catalyst system with PdCl (dppp)
2
di-coupled product 6 dominated over the mono-coupled was most effective for the selective formation of mono-
24
product 5 (entries 5 and 8), except for 1,2-difluorobenzene coupled product (Z)-13 and, in sharp contrast to the re-
4a) probably due to the steric hindrance between the actions of fluroarenes, arylzinc reagent 12 was found to be
(
ortho substituents (entry 2). In our efforts to determine the more effective than the Grignard reagent to produce the
catalyst system suitable for the selective formation of the mono-coupled product (Z)-13 in 70% yield after 48 hours
mono-coupled product 5, PdCl (dppf) was found to be of stirring under reflux, along with di-coupled product
2
25
exceptionally effective for the coupling reaction of 1,2-di- 14 in 23% yield; the formation of an isomer (E)-13 was
fluorobenzene (4a) to exclusively afford the corres- not observed. In a similar reaction using NiCl (dppp) and
2
ponding mono-coupled product 5a in 91% yield (entry 3). an excess amount of the aryl Grignard reagent 2, the di-
Based on the observation that the other difluorobenzenes coupled product 14 was obtained in 58% yield as a major
were ineffective in the palladium-based catalyst system product. It is noted that the coupling reaction of the di-
(
entries 6 and 9), a chelating effect of the adjacent fluorine fluoroalkene 11 with the aryl Grignard reagent 2 proceed-
atom was expected to play a crucial role in promoting the ed even in the absence of the transition metal catalysts
Synlett 2005, No. 11, 1771–1774 © Thieme Stuttgart · New York

CLUSTER
Cross-Coupling Reaction of Polyfluorinated Aromatic Compounds
1773
a
Table 2 Cross-Coupling Reaction of Trifluorobenzenes with 4-MeC H MgBr
6
4
Entry
Substrate
Catalyst
Catalyst (equiv)
2 (equiv)
Yield (%)b
8
9
10
1
2
NiCl (dppp)
0.05
0.01
6.0
1.5
0
69
41
9
0
0
2
PdCl (dppf)
2
3
4
NiCl (dppp)
0.05
0.01
6.0
1.5
0
60
7
9
60
0
2
PdCl (PPh )
2
3 2
a
Reaction conditions: trifluorobenzene 7 (1.0 mmol), 4-MeC H MgBr (2, 6.0 or 1.5 mmol), catalyst (0.05 mmol or 0.01 mmol), THF (5.0 mL),
6
4
reflux, 48 h.
b
Determined by GC and NMR analysis with eicosane and 1,3,5-trimethoxybenzene as an internal standard, respectively.
probably due to the addition–elimination mechanism, but
(3) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich,
F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
(b) Cross-Coupling Reactions: A Practical Guide, In Top.
Curr. Chem., Vol. 219; Miyaura, N., Ed.; Springer-Verlag:
Berlin, Heidelberg, 2002. (c) 30 Years of Cross-Coupling
Reaction, In J. Organomet. Chem. (Special Issue), Vol. 653;
Tamao, K.; Negishi, E.-i.; Hiyama, T., Eds.; 2002.
the geometry of the double bond was confused thereby
producing a mixture of the isomers, (Z)-13 and (E)-13,26
in the ratio of 1:4 in 50% total yield (68% conversion after
4
8 h of stirring under reflux).
In summary, the cross-coupling reaction of fluoro-arenes
with Grignard reagents was reexamined and revealed that
the use of nickel catalysts and the Grignard reagent is
essential for the activation of the carbon–fluorine bond.
The palladium catalyst was also effective for the poly-
fluorinated arenes and alkenes to selectively afford the
corresponding mono-coupled products.
(
4) (a) Stürmer, R. Angew. Chem. Int. Ed. 1999, 38, 3307.
(
4
b) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41,
176; and references cited therein.
(
5) Aryl chlorides are generally known to be most suitable
compared to the corresponding bromides and iodides in the
2
e
nickel-catalyzed reaction with Grignard reagents.
(6) (a) Miller, J. A. Tetrahedron Lett. 2001, 42, 6991.
b) Miller, J. A.; Dankwardt, J. W. Tetrahedron Lett. 2003,
4, 1907. (c) Miller, J. A.; Dankwardt, J. W.; Penney, J. M.
(
4
Acknowledgment
Synthesis 2003, 643. (d) Penney, J. M.; Miller, J. A.
Tetrahedron Lett. 2004, 45, 4989.
7) (a) Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am.
Chem. Soc. 1979, 101, 2246. (b) Wenkert, E.; Michelotti, E.
L.; Swindell, C. S.; Tingoli, M. J. Org. Chem. 1984, 49,
We thank the Ministry of Education, Culture, Sports, Science and
Technology, Japan, for the Grant-in-Aid for COE Research on
Elements Science, No. 12CE2005.
(
4894. (c) Dankwardt, J. W. Angew. Chem. Int. Ed. 2004, 43,
2428.
References
(
8) (a) Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Chem.
Rev. 1994, 94, 373. (b) Activation of Unreactive Bonds and
Organic Synthesis; Murai, S., Ed.; Springer-Verlag: Berlin,
Heidelberg, 1999.
(
1) Present address: RIKEN Frontier Research System, 2-1
Hirosawa, Wako, Saitama 351-0198, Japan. Email:
tamao@riken.jp.
(
2) (a) Tamura, M.; Kochi, J. K. J. Am. Chem. Soc. 1971, 93,
(9) (a) Aizenberg, M.; Milstein, D. Science 1994, 265, 359.
(b) Aizenberg, M.; Milstein, D. J. Am. Chem. Soc. 1995,
117, 8674.
(10) Cahiez, G.; Lepifre, F.; Ramiandrasoa, P. Synthesis 1999,
2138.
1487. (b) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem.
Commun. 1972, 144. (c) Tamao, K.; Sumitani, K.; Kumada,
M. J. Am. Chem. Soc. 1972, 94, 4374. (d) Kiso, Y.; Tamao,
K.; Kumada, M. J. Organomet. Chem. 1973, 50, C12.
(
e) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.;
(11) (a) Widdowson, D. A.; Wilhelm, R. Chem. Commun. 1999,
2211. (b) Wilhelm, R.; Widdowson, D. A. J. Chem. Soc.,
Perkin Trans. 1 2000, 3808.
Fujioka, A.; Kodama, S.-i.; Nakajima, I.; Minato, A.;
Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958.
Synlett 2005, No. 11, 1771–1774 © Thieme Stuttgart · New York

1
774
T. Saeki et al.
CLUSTER
biphenyl (5a) was formed in 91% yield. The further
(
12) (a) Mongin, F.; Mojovic, L.; Guillament, B.; Trécourt, F.;
Quéguiner, G. J. Org. Chem. 2002, 67, 8991. (b) Braun, T.;
Perutz, R. N. Chem. Commun. 2002, 2749; and references
cited therein.
purification was performed with column chromatography on
silica gel and high performance liquid chromatography
(HPLC).
1
(
13) (a) Jakt, M.; Johannissen, L.; Rzepa, H. S.; Widdowson, D.
A.; Wilhelm, R. J. Chem. Soc., Perkin Trans. 2 2002, 576.
(21) 2-Fluoro-1,3-bis(4-methylphenyl)benzene (9a): H NMR
(C D ): d = 2.16 (s, 6 H), 7.00 (t, J = 7.5 Hz, 1 H), 7.08 (d,
6
6
(
(
5
b) Kim, Y. M.; Yu, S. J. Am. Chem. Soc. 2003, 125, 1696.
c) Widdowson, D. A.; Wilhelm, R. Chem. Commun. 2003,
78. (d) Mikami, K.; Miyamoto, T.; Hatano, M. Chem.
J = 8.1 Hz, 4 H), 7.27 (dd, J = 7.5, 7.2 Hz, 2 H), 7.52 (d,
J = 8.1 Hz, 4 H).
(22) 1-Fluoro-3,5-bis(4-methylphenyl)benzene (9b): H NMR
1
Commun. 2004, 2082.
(C D ): d = 2.18 (s, 6 H), 7.06 (d, J = 7.8 Hz, 4 H), 7.26 (dd,
6
6
(
(
14) Bahmayar, S.; Borer, B. C.; Kim, Y. M.; Kurtz, D. M.; Yu,
S. Org. Lett. 2005, 7, 1011.
J = 9.6, 1.5 Hz, 2 H), 7.37 (d, J = 7.8 Hz, 4 H), 7.64 (t,
J = 1.5 Hz, 1 H).
(23) 1,2-Difluoro-3-(4-methylphenyl)benzene (8a): H NMR
1
15) Böhm, V. P. W.; Gstöttmayr, C. W. K.; Weskamp, T.;
Herrmann, W. A. Angew. Chem. Int. Ed. 2001, 40, 3387.
16) Dankwardt, J. W. J. Organomet. Chem. 2005, 690, 932.
17) The nickel- and copper-catalyzed cross-coupling reaction of
alkyl fluorides has been reported: (a) Terao, J.; Ikumi, A.;
Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125,
(C D ): d = 2.13 (s, 3 H), 6.61 (tdd, J = 8.1, 4.8, 1.5 Hz, 1 H),
6
6
(
(
6.73 (dddd, J = 9.9, 8.1, 7.2, 1.5 Hz, 1 H), 6.89 (ddt, J = 8.1,
6.3, 1.5 Hz, 1 H), 7.02 (d, J = 7.8 Hz, 2 H), 7.35 (dd, J = 8.1,
1.8 Hz, 2 H).
(24) (Z)-1-Fluoro-1-(4-methylphenyl)-2-(1-naphthyl)ethene
1
5646. (b) Terao, J.; Todo, H.; Watanabe, H.; Ikumi, A.;
[13-(Z)]: H NMR (C D ): d = 2.12 (s, 3 H), 6.89 (d, J = 37.2
6
6
Kambe, N. Angew. Chem. Int. Ed. 2004, 43, 6180.
18) Ligand abbreviation:
Hz, 1 H), 7.01 (d, J = 8.7 Hz, 2 H), 7.33–7.38 (m, 3 H), 7.56
(d, J = 8.7 Hz, 2 H), 7.62 (d, J = 8.4 Hz, 1 H), 7.69–7.72 (m,
1 H), 8.02–8.05 (m, 1 H), 8.08 (d, J = 7.2 Hz, 1 H).
(
dppp = 1,3-bis(diphenylphosphino)propane,
dppb = 1,4-bis(diphenylphosphino)butane, and
dppf = 1,1¢-bis(di-phenylphosphino)ferrocene.
19) n-BuB(OH) , 4%; 4-MeC H SiF , trace; n-BuZnCl, 7%;
1
(25) 1,1-Bis(4-methylphenyl)-2-(1-naphthyl)ethene (14): H
NMR (C D ): d = 2.01 (s, 3 H), 2.20 (s, 3 H), 6.80 (d, J = 8.0
6
6
(
(
Hz, 2 H), 7.05 (dd, J = 8.4, 8.1 Hz, 1 H), 7.08 (d, J = 8.1 Hz,
2 H), 7.16 (d, J = 8.0 Hz, 2 H), 7.30–7.34 (m, 3 H), 7.46 (d,
J = 8.1 Hz, 2 H), 7.45–7.49 (m, 1 H), 7.51 (s, 1 H), 7.65–7.69
(m, 1 H), 8.10–8.13 (m, 1 H).
2
6
4
3
n-C H CH=CHZrCp Cl, 0%; n-Bu Sn, trace.
6
13
2
4
20) A Typical Procedure for the Cross-Coupling Reactions.
To a suspension of PdCl dppp) (7.8 mg, 0.01 mmol) and
2
(
1
,2-difluorobenzene (4a, 115 mg, 1.0 mmol) in THF (3.0
(26) (E)-1-Fluoro-1-(4-methylphenyl)-2-(1-naphthyl)ethene
1
mL) was added 4-MeC H MgBr (2, 1.0 M THF solution; 1.5
[13-(E)]: H NMR (C D ): d = 1.88 (s, 3 H), 6.64 (d, J = 8.1
6
4
6
6
mL, 1.5 mmol) at r.t. and the mixture was heated under
reflux for 48 h. The reaction was monitored by GC analysis
with eicosane (54 mg) as an internal standard to reveal that
the reaction completed within 48 h and 2-fluoro-4¢-methyl-
Hz, 2 H), 6.86 (d, J = 21.0 Hz, 1 H), 7.09 (dd, J = 8.1, 7.5
Hz, 1 H), 7.28–7.32 (m, 3 H), 7.31 (d, J = 8.1 Hz, 2 H), 7.56
(d, J = 7.5 Hz, 1 H), 7.63–7.69 (m, 1 H), 7.98–8.03 (m, 1 H).
Synlett 2005, No. 11, 1771–1774 © Thieme Stuttgart · New York