Direct conjugate alkylation of α,β-unsaturated carbonyls by Ti^III-catalysed reductive umpolung of simple activated alkenes

Abstract

The titanium(iii)-catalysed cross-selective reductive umpolung of Michael-acceptors represents a unique direct conjugate β-alkylation reaction. It allows the cross-selective preparation of 1,6- and 1,4-difunctionalised building blocks without the requirement of stoichiometric organometallic reagents. In this full paper, the development and scope of the titanium(iii)-catalysed cross-selective reductive umpolung of Michael-acceptors is described. Based on the observed selectivities and additional mechanistic experiments a refined mechanistic proposal is presented.

Shining Light on TiIV Complexes: Exceptional Tools for Metallaphotoredox Catalysis

“…This reaction was further investigated in useful intramolecular versions. [42][43][44] Scheme 2. Reductive cross-coupling of enones with acrylonitriles.…”

Cp2Ti(III)Cl and Analogues as Sustainable Templates in Organic Synthesis

“…2,12,13 The development of catalytic methodologies that use stoichiometric amounts of a metal in combination with 2,4,6-collidine/TMSCl 14 to regenerate the Cp 2 TiCl 2 has increased its application in the synthesis of terpenoids and bioactive natural products. 15 Cp 2 Ti(III)Cl has a characteristic lime green solution in THF, although it can also be formed in other solvents such as THP, 16 1,4-dioxane, 17 toluene, 18 CH 2 Cl 2 , 15 Et 2 O, 19 or hexane. 16 In THF solutions, the Ti(III) species is in equilibrium between the monomer 8 and the half-open dimer 10, where the free coordination site is occupied by a molecule of solvent.…”

“…Initially the nitrile and ketone groups are coordinated to two monomeric Ti(III) species, which are stabilised with Et 3 N•HCl. 19,23,45 The two Ti(III)-coordinated species can behave as a template for the formation of the C-C bond by SET from the ketyl radical to the Ti(III) complex coordinated nitrile group 34. This addition was identified as the rate-determining key step.…”

“…37b In a series of papers the Streuff group reported a high regio-and stereoselective Ti(III)-catalysed reductive β-alkylation of enones with acrylic derivatives in a redox umpolung process. 19,41,43,49 The cross-coupling between linear enones with acrylonitrile proceeded in moderate yields whereas better yields and diastereoselectivities were achieved with cyclic enones (Scheme 23). These latter, also tolerated Michael acceptors such as acrylonitriles, methacrylonitriles, and acrylamides.…”

“…19,49 The scope of the reaction was extended by the Streuff group to N-substituted quinolones, 19,43 chromones, 19,43 and coumarins. 19 Unsubstituted and 3-substituted quinolones worked well with acrylonitrile, whereas the presence of other substituents on the aromatic ring led to lower yields. 3-Substituted quinolones were also coupled with both acrylonitrile derivatives and acrylates leading exclusively to the syn-diastereomer in good yields (Scheme 24).…”