The aim of this thesis is the development of nickel-catalyzed cross-coupling reactions between alkyl Grignard reagents and alkenyl bromides. In the Chapter 2, a Ni-catalyzed enantioconvergent cross-coupling reaction of racemic secondary benzyl Grignard reagents with b-bromostyrenes was developed. In the second section, the scope of the electrophiles was extended to include tertiary Grignard reagents for the construction of sterically hindered quaternary carbons.
Transition-metal-catalyzed cross-coupling reactions have revolutionized the way chemists design and synthesize molecules. The convergence of cross-coupling reactions and asymmetric transformations has driven the development of asymmetric transition-metal-catalyzed cross-coupling reactions. The rapid racemization of secondary alkyl Grignard reagents opens the possibility to exploit dynamic kinetic resolution for the development of an enantioselective Ni-catalyzed Kumada-Corriu reaction. In this context, we developed a nickel-catalyzed enantioconvergent cross-coupling reaction of various racemic secondary benzyl Grignard reagents with b-bromostyrenes (Figure 1).
The cross-coupling was achieved using nickel and a specially designed (P,N) ligand, yielding a series of a-chiral olefins with moderate to high enantioselectivity. The reaction exhibited excellent tolerance to b-bromostyrenes bearing different functional groups. Substrates with polyene motifs were constructed without any isomerization on double bonds and maintained an appreciable enantiomeric ratio (er). However, variations in the Grignard reagents showed to be more challenging, leading to lower enantioselectivity. Consistent with our interest in mechanistic studies of transition-metal-catalyzed cross-coupling reactions, supporting organometallic experiments, radical clock experiments, and VTNA analysis revealed that bis-ligated nickel serves as the active catalyst. After a careful evaluation of experimental data and DFT analysis, we prosed a radical-based Ni(I)/Ni(II) mechanism with an off-cycle dimeric nickel species.
Due to the importance of quaternary carbons in enhancing potency, selectivity, and metabolic stability in bioactive molecules, strategies to construct congested quaternary carbons are highly sought after. To contribute in this important field, we focused on developing the challenging Ni-catalyzed cross-coupling of tertiary (Csp3) Grignard reagents with bromostyrenes (Figure 2).
A readily available catalytic system, [(dme)NiCl2]/PPh3, enabled the cross-coupling of tertiary (Csp3) Grignard reagents with bromostyrenes, delivering a series of products in practical yields. Furthermore, another catalytic system, [(dme)NiCl2]/IMes, demonstrated excellent performance in cross-coupling reactions involving a-magnesiated nitriles as nucleophile. However, unexpected isomerization was observed when a-bromostyrene was used, resulting in either a- or b-coupling products, depending on the nature of the electrophiles.
