Nickel- and Palladium-Catalyzed Cross-Coupling Reaction of Polyfluorinated Arenes and Alkenes with Grignard Reagents

Abstract

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.

Key words

cross-coupling - nickel - palladium - Grignard reagent - fluoroarene

References

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1

Present address: RIKEN Frontier Research System, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Email: [e-mail].

5

Aryl chlorides are generally known to be most suitable compared to the corresponding bromides and iodides in the nickel-catalyzed reaction with Grignard reagents. [2e]

18

Ligand abbreviation:
dppp = 1,3-bis(diphenylphosphino)propane,
dppb = 1,4-bis(diphenylphosphino)butane, and
dppf = 1,1′-bis(di-phenylphosphino)ferrocene.

19

n-BuB(OH)₂, 4%; 4-MeC₆H₄SiF₃, trace; n-BuZnCl, 7%; n-C₆H₁₃CH=CHZrCp₂Cl, 0%; n-Bu₄Sn, trace.

20

A Typical Procedure for the Cross-Coupling Reactions.
To a suspension of PdCl_{2 (}dppp) (7.8 mg, 0.01 mmol) and 1,2-difluorobenzene (4a, 115 mg, 1.0 mmol) in THF (3.0 mL) was added 4-MeC₆H₄MgBr (2, 1.0 M THF solution; 1.5 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-biphenyl (5a) was formed in 91% yield. The further purification was performed with column chromatography on silica gel and high performance liquid chromatography (HPLC).

21

2-Fluoro-1,3-bis(4-methylphenyl)benzene ( 9a): ¹H NMR (C₆D₆): δ = 2.16 (s, 6 H), 7.00 (t, J = 7.5 Hz, 1 H), 7.08 (d, 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): ¹H NMR (C₆D₆): δ = 2.18 (s, 6 H), 7.06 (d, J = 7.8 Hz, 4 H), 7.26 (dd, 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): ¹H NMR (C₆D₆): δ = 2.13 (s, 3 H), 6.61 (tdd, J = 8.1, 4.8, 1.5 Hz, 1 H), 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 [13-( Z )]: ¹H NMR (C₆D₆): δ = 2.12 (s, 3 H), 6.89 (d, J = 37.2 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).

25

1,1-Bis(4-methylphenyl)-2-(1-naphthyl)ethene ( 14): ¹H NMR (C₆D₆): δ = 2.01 (s, 3 H), 2.20 (s, 3 H), 6.80 (d, J = 8.0 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).

26

(E)-1-Fluoro-1-(4-methylphenyl)-2-(1-naphthyl)ethene [13-( E )]: ¹H NMR (C₆D₆): δ = 1.88 (s, 3 H), 6.64 (d, J = 8.1 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).