Copper-catalysed addition reactions

In attempted hydroalkoxylations of methylacrylate with ethanol catalysed by the copper ethoxides 100 or 102, copper-catalysed transesterification to the ethylacrylate was observed instead of the addition reaction [81]. 

S)-phenylglycine have been used in the copper-catalysed conjugate addition of MeLi to enones. Trialkylaluminum reagents were also involved in only a few reactions, but these represent an interesting alternative. 

Another class of new ligands was prepared in quantitative yields by Feringa et al., in 1997, by reaction between a-mercapto acids, aniline and 2-pyridine-carboxaldehyde." These pyridyl-substituted thiazolin-4-one ligands were further involved in the copper-catalysed conjugate addition of ZnEt2 to 2-cyclohexenone,... 

In order to prepare a new range of ligands incorporating both sulfoximine and phosphine moieties, Tye et al. reported, in 2001, the synthesis of a novel chiral phosphine-sulfoximine, which was tested as a ligand in the copper-catalysed 1,4-addition of ZnEt2 to enones. Whilst the reaction of acyclic enones gave the corresponding racemic 1,4-products, the best result was obtained upon... 

Carbon-carbon bond-forming reactions are one of the most basic, but important, transformations in organic chemistry. In addition to conventional organic reactions, the use of transition metal-catalyzed reactions to construct new carbon-carbon bonds has also been a topic of great interest. Such transformations to create chiral molecules enantioselectively is therefore very valuable. While various carbon-carbon bond-forming asymmetric catalyses have been described in the literature, this chapter focuses mainly on the asymmetric 1,4-addition reactions under copper or rhodium catalysis and on the asymmetric cross-coupling reactions catalyzed by nickel or palladium complexes. 

A copper-catalysed, enantioselective, conjugate addition of a terminal alkyne, which undergoes an in situ metallation, has been reported. The addition of phenylacetylene to Meldrum s acid-derived acceptors (196) takes place in aqueous medium, without recourse to an inert atmosphere. The success of the enantioselective reaction was made possible by the use of PINAP (198), a new class of P,IV-ligands (cf. QUINAP), which have the advantage of easier resolution. Furthermore, these modular ligands are responsive to numerous electronic and steric modifications that permit optimization of the reaction. The products (197) were obtained in good yields and with 82-97% ee.235... 

Corey chose a Wittig-style (HWE) reaction to control the aldol process and copper-catalysed addition of vinyl Grignard for the conjugate addition. Oxidation with NaI04 and catalytic OSO4 gave the keto-aldehyde 35 which cyclised cleanly under equilibrating conditions. 

Copper catalysed substitution reactions require high reaction temperatures and polar solvents like NMP.9 With activated alkenyl iodides bearing electron-withdrawing groups, copper-zinc reagents react readily leading to addition-elimination products.10-11 This method can be used to prepare a range of polyfunctional unsaturated molecules (Scheme 10.3).10-12... 

Two procedures have been devised for the synthesis of a novel class of cyclosteroids, the 4a,6a-cyclo-5/8-derivatives (190). Carbenoid decomposition (NaOMe 160 °C) of the tosylhydrazone (187) gave the unsaturated acid (188). Copper-catalysed decomposition of the derived diazo-ketone (189) gave the desired 4a,6a-cyclo-ketone (190) by a keto-carbene addition to the 5,6-double bond. A more satisfactory synthesis proceeded from the 6/3-tosylate (191), which gave the 4a,6a-cyclosteroid in high yield on reaction with base (KO Bu-HO Bu). Several hormone analogues with the 4a,6a-cyclo modification were devoid of biological activity. ... 

The mono-O-phenylation reaction of glycols discovered by David and Thieffry presents some characteristic features which are not compatible with the postulated covalent bismuth intermediate. (see section 6.3.2) The reaction is solvent-selective (methylene dichloride under reflux), light-catalysed (no reaction in the dark), and presents an induction period (2 hours in the case of the phenylation of 2,2-dimethylpropan-l,3-diol). Addition of small amounts of copper diacetate had a marked effect on the reaction. The reaction became fast reaction times can be as short as 15 minutes. Moreover, the copper-catalysed reaction is no more solvent selective nor light-catalysed. ... 

Copper-catalysed Michael addition followed by an aldol reaction with formaldehyde, gives a 1 1 mixture of diastereoisomers of the aldol 86 that can be eliminated to the enone 83. The resulting efficient photochemical cycloaddition gives ketone 82 with total regioselectivity probably because it is intramolecular. 

Perhaps the major disadvantage of the copper-catalysed Michael reaction is the need to protect functional groups. Michael reactions with heteroatom nucleophiles or functionalised carbon nucleophiles are usually carried out without copper. Many such nucleophiles, particularly enol equivalents, are excellent at Michael reactions, and are often to be preferred for ease of working. Silyl enol ethers, enamines, and stabilised enolates all carry out Michael reactions. In the next chapter we shall look at specific enol equivalents in more detail and note which ones are good at Michael additions. 

---