Nickel-catalyzed coupling reaction of alkyl halides with aryl Grignard reagents in the presence of 1,3-butadiene: mechanistic studies of four-component coupling and competing cross-coupling reactions

Abstract

We describe the mechanism, substituent effects, and origins of the selectivity of the nickel-catalyzed four-component coupling reactions of alkyl fluorides, aryl Grignard reagents, and two molecules of 1,3-butadiene that affords a 1,6-octadiene carbon framework bearing alkyl and aryl groups at the 3- and 8-positions, respectively, and the competing cross-coupling reaction. Both the four-component coupling reaction and the cross-coupling reaction are triggered by the formation of anionic nickel complexes, which are generated by the oxidative dimerization of two molecules of 1,3-butadiene on Ni(0) and the subsequent complexation with the aryl Grignard reagents. The C-C bond formation of the alkyl fluorides with the γ-carbon of the anionic nickel complexes leads to the four-component coupling product, whereas the cross-coupling product is yielded via nucleophilic attack of the Ni center toward the alkyl fluorides. These steps are found to be the rate-determining and selectivity-determining steps of the whole catalytic cycle, in which the C-F bond of the alkyl fluorides is activated by the Mg cation rather than a Li or Zn cation. ortho-Substituents of the aryl Grignard reagents suppressed the cross-coupling reaction leading to the selective formation of the four-component products. Such steric effects of the ortho-substituents were clearly demonstrated by crystal structure characterizations of ate complexes and DFT calculations. The electronic effects of the para-substituent of the aryl Grignard reagents on both the selectivity and reaction rates are thoroughly discussed. The present mechanistic study offers new insight into anionic complexes, which are proposed as the key intermediates in catalytic transformations even though detailed mechanisms are not established in many cases, and demonstrates their synthetic utility as promising intermediates for C-C bond forming reactions, providing useful information for developing efficient and straightforward multicomponent reactions.

Scheme 1. Ni-catalyzed dimerization and alkylarylation of 1,3-dienes.

Scheme 2. The Ni-catalyzed four-component coupling reaction of alkyl fluorides, aryl Grignard reagents, and 1,3-butadiene. Isolated yields. The yields of cross-coupling products 4 are shown in parentheses. ^aca. 20% of 1g was recovered. ^bThe reaction time was 42 h. ^cn.i. = not isolated. ^d44% of 1g was recovered.

Scheme 3. The scope and limitations of the four-component coupling reaction. ^aThe reaction was conducted in a 0.1 M concentration of 1 for 20 h.

Scheme 4. Proposed catalytic cycles of the Ni-catalyzed four-component coupling and cross-coupling reactions.

Fig. 1. ¹H NMR spectra for the reaction of Ni(0) with 1,3-butadiene and 2m in THF-d₈ at 20 °C. (a) Ni(cod)₂, (b) Ni(cod)₂ and 5 equiv. of 1,3-butadiene, and (c) Ni(cod)₂, 1,3-butadiene (5 equiv.), and 2m (2 equiv.).

Scheme 5. Isolation of anionic Ni complexes.

Fig. 2. An ORTEP drawing of one of the four asymmetric units of [Ni(C₈H₉)(C₈H₁₂)·Li(12-crown-4)₂]₄(thf)(C₅H₁₂)₂ (8) with thermal ellipsoids at the 50% probability level. All hydrogen atoms and solvent molecules are omitted for clarity.

Scheme 6. The stoichiometric reaction of nickelate complex 7 with 1a: effect of the Mg ion.

Scheme 7. The reaction of arylzinc, aryllithium, and aryl Grignard reagents. Conversion and yields were determined by GC.

Fig. 3. Double logarithm plots of the initial reaction rates against initial concentrations of each substrate. (a) [1a]₀ = 0.21 to 0.45 M, (b) [2j]₀ = 0.33 to 0.66 M, (c) [NiBr₂(dme)]₀ = 0.010 to 0.023 M, and (d) [1,3-butadiene]₀ = 0.67 to 1.34 M.

Fig. 4. (a) Time-course of the reaction of 1a with 2j at 30 °C (), 35 °C (), 40 °C (), 45 °C (), and 50 °C (). (b) Time-course of the reaction of 1a with 2m at 30 °C (), 35 °C (), 40 °C (), 45 °C (), and 50 °C (). (c) Eyring plot of the reaction using 2j () and 2m ().

Fig. 5. Hammett plot of the relative reaction rates against Yukawa–Tsuno’s σ⁰.

Fig. 6. The relationship between the product ratio 3/4 of substituted Grignard reagents against σ⁰.

Fig. 7. The molecular structures of nickelate complexes 11 (left) and 8 (right). Bottom: the dihedral angle between the square planar Ni plane and the aryl ring.

Fig. 8. Space-filling models of the nickelate complexes (top view) in Fig. 7. The reacting carbon of the σ-allyl group and Ni atom are shown in orange and green, respectively.

Fig. 9. Hammett plot of the relative reaction rates obtained in the competitive reaction against σ+p.

Fig. 10. Reaction pathways of nickel-catalyzed four-component coupling (blue) and cross-coupling (red) reactions of methyl fluoride, phenyl Grignard reagent, and 1,3-butadiene.

Fig. 11. The molecular structures of important transition states in Fig. 10 with selected bond distances.

Fig. 12. Optimized structures and the corresponding energy barriers for the transition states of γ-carbon attack (TS3) and Ni-attack (TS10) toward MeF for 2-methylphenyl and 2,6-dimethylphenyl Grignard reagents. Bond distances between key atoms are given.

Fig. 13. Optimized structures and the corresponding energy barriers for the transition states of γ-carbon attack (TS3) and Ni-attack (TS10) toward n-OctF for phenyl and 2,6-dimethylphenyl Grignard reagents. Bond distances between key atoms and representative short H–H distances are given.