Electrophiles carbonyl compounds reduction

Dihydro-2-fluoromethyl-4,4,6-trimethyl-4/f-l,3-oxazine (86) can be deprotonated by treatment with butyllithium, and the anion then reacted with electrophiles such as alkyl halides and carbonyl compounds. Reduction and hydrolysis of the products destroy the heterocycle and releases the corresponding a-fluoroaldehydes. For example, reaction of the anion with 3-chloropropene yields the fluorobutenyl-l,3-oxazine (87), which on reduction and hydrolysis yields 2-fluoropent-4-enal (88) (Scheme 19) <90TL179>. 

On the other hand, trialkylhydrosilanes are capable of reducing carbonyl compounds and some activated olefins in the presence of Brc nsted or Lewis acids. Apparently, coordination of carbonyl oxygen to acid is important to activate electrophilic carbons. We thought that pentacoordinate hydridosilicates should be a good hydride transfer reagent because of the intrinsic nucleophilicity, while the significant Lewis acid character of the silicon center should activate the substrate carbonyl compounds. Reduction of carbonyl compounds with pentacoordinate hydridosilicates are expected to proceed without any additives and thus very interesting from both mechanistic and practical point of view. 

Reduction to Alcohols. The organosilane-mediated reduction of ketones to secondary alcohols has been shown to occur under a wide variety of conditions. Only those reactions that are of high yield and of a more practical nature are mentioned here. As with aldehydes, ketones do not normally react spontaneously with organosilicon hydrides to form alcohols. The exceptional behavior of some organocobalt cluster complex carbonyl compounds was noted previously. Introduction of acids or other electrophilic species that are capable of coordination with the carbonyl oxygen enables reduction to occur by transfer of silyl hydride to the polarized carbonyl carbon (Eq. 2). This permits facile, chemoselective reduction of many ketones to alcohols. 

The prime functional group for constructing C-C bonds may be the carbonyl group, functioning as either an electrophile (Eq. 1) or via its enolate derivative as a nucleophile (Eqs. 2 and 3). The objective of this chapter is to survey the issue of asymmetric inductions involving the reaction between enolates derived from carbonyl compounds and alkyl halide electrophiles. The addition of a nucleophile toward a carbonyl group, especially in the catalytic manner, is presented as well. Asymmetric aldol reactions and the related allylation reactions (Eq. 3) are the topics of Chapter 3. Reduction of carbonyl groups is discussed in Chapter 4. 

A number of electrocatalytic reactions have been reported in which the EGB is derived by initial reduction of an aldehyde or a ketone that at the same time functions as the electrophile in a coupling reaction [136-139]. It is Kkely that the actual EGB is a dimer dianion of the carbonyl compound or a dianion of the carbonyl compound formed by disproportionation. The general principle is outlined in Scheme 38. The reactions become catalytic when the product anion, P , is protonated by the weak acid, NuH, whereby the nucleophile, Nu , is regenerated. 

The Pd(0)-catalyzed displacement of allylic acetates (297) with various nucleophiles via the allylic Pd(II) complex (298) is a well-established procedure (Scheme 114). Through attack of electrons (+2e ) in place of nucleophiles, (298) is expected to undergo a reductive cleavage providing allylic carbanions (299) and the acetate anion along with Pd(0) complexes. The latter can then be captured by various electrophiles (polarity inversion. Scheme 114) leading to (300) [434]. This procedure is useful for the deprotection of allyl esters under neutral conditions. Recently, a mechanistic study of the Pd-catalyzed reaction of allylic acetate (297), using carbonyl compounds as an electrophile, has been reported [435]. 

Maruoka reported the use of the didentate catalyst 8 for double electrophilic activation of carbonyl compounds [70], but since no comparison with monofunctional phenolates was given it is not clear whether having two aluminium centres in the same catalyst offers any special advantages. They used this catalyst to effect transfer hydrogenation between remote aldehyde and alcohol groups in the same molecule [71], but again it is not clear whether the transfer is truly intramolecular or in any way different from that of reduction by an external alcohol using 8 or a monuclear aluminium catalyst. 

There are very few reactions of real synthetic significance which proceed via condensation of two 1,3-electrophile-nucleophile species. Probably the most important of this latter type of reaction is the synthesis of pyrazines by self-condensation of an a-acylamino compound to the dihydropyrazine followed by aromatization (equation 132). The a-acylamino compounds, which dimerize spontaneously, are normally generated in situ, for example by treatment of a- hydroxy carbonyl compounds with ammonium acetate or by reduction of a-azido, -nitro or -oximino carbonyl compounds. Cyclodimerization of a-amino acids gives 2,5-dioxopiperazines (equation 133), many derivatives of which occur as natural products. Two further reactions which illustrate the 1,3-electrophile-nucleophile approach are outlined in equations (134) and (135), but su i processes are of little general utility. 

A problem inherent in metallation reactions with Grignard reagents is the poor chemos-electivity of the reactions. The most common side-reactions are the competing nucleophile addition and the reduction of the carbonyl compounds. An interesting alternative would be to use the high electrophilicity of the Mg + cation and its tendency to form a multicoordinate complex. The preformation of a Mg(II) complex with a carbonyl compound or a carboxylic acid derivative enhances the acidity of the substrate to the point where a relatively mild base can be used. 

Carbonyl compounds, particularly aromatic aldehydes, when activated with electrophilic catalysts, can also react with aromatics.241 The process is often called condensation or reductive alkylation, but it is actually a multistep Friedel-Crafts alkylation reaction. 

In the lithiation step (Equation 13), a reductive opening of the dihydrothiepine took place giving possible intermediate 121, which by reaction with the carbonyl compound R R2CO used as electrophile gave the second intermediate 122, precursor of products 120 by acidic hydrolysis. A variant of the lithiation of the starting material 119 resulted when a second electrophile was introduced in the molecule. After the generation of the intermediate 122, instead of hydrolysis, a second lithiation took place at temperatures ranging between —78 and... 

Cathodic coupling proceeds via radicals or radical anions, which are reductively generated from suitable substrates, in general electrophiles, e.g., carbonyl compounds and activated olefins. These intermediates either dimerize (Eq. (182)) or add to activated double bonds to yield 1,4-radical anions, which are subsequently reduced to hydrodimers (Eq. (183) ). 

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