Intermolecular reductive coupling

For a review encompassing the intermolecular reductive coupling of acetylenic aldehydes, see Miller, K. M. Molinaro, C. Jamison, T. F. Tetrahedron Asymmetry 2003, 14, 3619-3625. 

For use of conjugated enones as nucleophilic partners in catalytic intermolecular reductive couplings to aldehydes, see ... 

Procter reported a solid-phase variant of Fukuzawa s asymmetric y-butyr-olactone synthesis (see Chapter 5, Section 5.2) that involves the intermolecular reductive coupling of aldehydes and ketones with a,p-unsaturated esters, immobilised using an ephedrine chiral resin 12.44 For example, treatment of acrylate 13 and crotonate 14 with cyclohexanecarboxaldehyde, employing Sml2 in THF, with tert-butanol as a proton source, gave lactones 15 and 16, respectively, in moderate yield and good to high enantiomeric excess (Scheme 7.11).44 The ephedrine resin 12 can be conveniently recovered and recycled.45... 

A. Intermolecular reductive coupling of alkenes with other types of substrates... 

A. Intermolecular Reductive Coupling of Alkenes with Other Types of Substrates... 

Intermolecular reductive couplings between aromatic rings mostly involve either reactive aryl cr-radicals, for example, derived from aromatic halides by cleavage of the radical anions, or relatively stable 7r-radical anions derived from aromatic compounds activated by electron-withdrawing substituents. 

Ni-catalyzed multi-component coupling reactions are an efficient protocol for carbon-carbon bond formation [97]. The Ni-catalyzed asymmetric intermolecular reductive coupling of 1,3-dienes and aldehydes with Et Zn as a reducing reagent was realized... 

Several contributions have appeared in which intermolecular reductive couplings between ketones or aldehydes and electron-deficient alkenes have been described [30h, 53]. Reactions of aldehydes and ketones with unsaturated esters result in the formation of lactones. Diastereoselectivities are normally modest in these cases, but can be quite high for certain substitution patterns (Eq. 45). 

Reaction conditions amenable to nickel-catalyzed reductive cyclization of alkynyl enones were ineffective in the intermolecular variant In the course of developing catalytic [3 -l- 2] cycloadditions of alkynes and enals [24], it was discovered that by simply using an enone instead of an enal electrophile, catalytic intermolecular reductive coupling could be achieved in a Ni(COD)2/Bu3P catalyst system using EtsB as a reducing agent in a MeOH/THF (8 1) solvent system (Scheme 8.5) [25). 

Intermolecular reductive couplings of alkynes and enoates are not yet achievable. 

The dearest empirical evidence for the productive involvement of an 1] , O-bound nickel enolate comes from the intermolecular reductive coupling of alkynes and enals (Scheme 8.9) [27]. The extremely high levels of Z-isomer stereoselectivity (>98 2) can best be rationalized via the metallacycle intermediate 5 which undergoes o-bond metathesis to afford nickel hydride 6, followed by reductive eUmina-tion to yield the Z-selective enol silane product 7. A mechanism consisting of a nickel Jt-allyl species would not be expected to lead to high selectivities of Z-enol silanes, and has been imphcated in reactions leading to the selective production of T-enol silanes [28],... 

The first nickel-catalyzed intermolecular reductive coupling utilized the combination of COD-stabilized zero-valent nickel, monodentate phosphine ligands, and... 

Another effective catalyst system for intermolecular reductive coupling is the combination of Ni(COD)2/NHC with EtsSiH as a stoichiometric reducing agent (Scheme 8.21) [40]. The NHC catalyst is more reactive than analogous phosphine-based catalysts and a broad range of alkynes and aldehydes undergo reductive coupling under these conditions. 

Examination of various enynes in intermolecular reductive couplings of aldehydes and alkynes illustrated that alkene direction is an effective strategy for controlling regioselectivity. Using conjugated enynes, both NHC/EtaSiH [21] and PRa/EtsB [30] variants proceed with excellent diastereoselectivity favoring addition of the alkyne terminus that is distal to the alkene substituent (Scheme 13). This effect may be derived from predisposition of the alkyne in the orientation 17 that leads to the distal substitution, and increased stability of the jj -stabiUzed metallacycle 18 may also be a factor. 

Alkenes may be generated via the intra- or intermolecular reductive coupling of carbonyl compounds in a titanium-mediated process known as the McMurry coupling. ... 

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