Nucleophilic enals

Homoenolate Protonation The p-protonation of homoenolates has been observed by Scheidt and co-workers, resulting in a redox transformation of enals to afford saturated esters 48. This process is catalysed by the NHC derived from imidazolium salt 46 and utilises phenol as a proton source [14]. A range of primary and secondary alcohols, and phenol itself, are competent nucleophiles with which to trap the acylazolium intermediate 47 generated by protonation (Scheme 12.8). 

Domino Michael/aldol processes, which are initiated by the addition of a halide to an enone or enal, have found wide attention. They are valuable building blocks, as they can be easily converted into a variety of extended aldols via subsequent SN2 reactions with nucleophiles or a halide/metal exchange. As an example, a-haloalkyl- 3-hy-droxy ketones such as 2-76 have been obtained in very good yields and selectivities by reaction of enones 2-71 with nBu4NX in the presence of an aldehyde 2-74 and TiCl4as described by the group of Shinokubo and Oshima (Scheme 2.16) [24]. 

Diastereoselective conjugate addition of nucleophiles to enones, enals, and enoates occurs with high stereocontrol and constitutes a powerful method in stereoselective synthesis.185... 

Ab initio calculations carried out by Tanaka and Kanemasa conclude that, under Lewis acid-catalyzed conditions, the formation of eudo-cycloadducts is preferred and that the attack of nucleophilic nitrone oxygen should become more favored to occur at the p-position of the enal rendering 3,4-cycloadducts [39]. In the iridium... 

Domino processes can also be performed on open-chain compounds. MacMillan and co-workers demonstrated this with their own imidazolidinone catalysts. Conjugate addition of a nucleophilic heterocycle 231 to the a,(i-unsaturated enal 230 followed by a-chlorination of the resulting enamine led to the syn products 234 in very high enantioselectivities and good sytv.anti diastereoselectivities (Scheme 38) [347]. Similar domino sequences, but with different nucleophile-electrophile partners, were also reported independently by Jprgensen [348]. 

Various aldehydes 184 and alcohols have been shown to be competent in the redox esterification of unsaturated aldehydes in the presence of the achiral mesityl triazo-lium pre-catalyst 186. Both aromatic and aliphatic enals participate in yields up to 99% (Table 13). Tri-substituted enals work well (entry 3), as do enals with additional olefins present in the substrate (entries 4 and 7). The nucleophile scope includes primary and secondary alcohols as well as phenols and allylic alcohols. Intramolecular esterification may also occur with the formation of a bicyclic lactone (entry 8). 

The direct nucleophilic acylation of enals by organocuprates is also successful.37-38 With either the lower order RCuCNLi/CO or higher order R2CuCNLi2/CO reagents, high yields of the 3-acylated pro duct were observed (equation 37). A wide variation in R was also reported to be tolerated. Unfortunately, only (3-monosubstituted enals were examined, so the extent to which substitution in the enal can be tolerated has yet to be determined. 

The first nan of -this reaction is technically called aidof addition but is sometimes referred in as aldol condensation, T e aldol to enal step is actually tlie condensation part of Ihe reaction and almost always accompanies aidol addition. Although complicated this reaction is easy to remember if yo-i keen in mind the acidity T the a-uydrogens am the planar configuration of the carbonyl, v hich makes it susceptible jo nucleophilic attack. You must know this reaction for i-.ii.AT... 

There remains the problem of choosing between the inside and outside positions. This is determined by the relative magnitude of the repulsion between the inside substituent and the enal fragment on the one hand, and the repulsion between the outside substituent and the incoming nucleophile on the other ... 

Several catalytic protocols have been developed for the 1,4-addition of silylcopper reagents to enones and other Michael acceptors. Lipshutz et al.183 treated phenyldimethylsilyllithium with dimethylzinc and used the silylzinc reagent PhMe2SiZnMe2Li thus formed as the nucleophile in copper-catalyzed 1,4-additions to various enones and enals, for instance, verbenone 248 which afforded the desired product 249 in almost quantitative yield (Equation (14)). Interestingly, the rather slow addition reaction is strongly accelerated by catalytic amounts of scandium triflate. 

The next example is particularly impressive. The enol partner is a symmetrical ketone that is very hindered—there is only one a hydrogen on either side. The electrophilic partner is a conjugated enal that is not enolizable but that might accept the nucleophile in a conjugate manner. In spite of these potential problems, the reaction goes in excellent yield. 

There is some interesting selectivity in this sequence. Only one of the three groups next to the alkene is oxidized and only one ( -) isomer of the enal is formed. No position next to the unsaturated ester is oxidized. All these decisions are taken in the initial cycloaddition step. The most nucleophilic double bond uses its more nucleophilic end to attack SeOi at selenium. The cycloaddition uses the HOMO (7t) of the alkene to attack the LUMO (rc of Se=0). Meanwhile the HOMO (Jt) of Se-0 attacks the LUMO (C-H a ) of the allylic system. 

An investigation of alkylation of 1,1-enediamines with a,/ -unsaturated aldehydes and ketones has been recently conducted by Jones and Hirst36. The reaction of 1,1-enediamine 93 and a,/ -enals affords the fused 1,4-dihydropyridines 133, via a nucleophilic addition and intramolecular dehydration sequence (equation 49). 93 reacts with propenal, however, to give the cyclohexene carboxaldehyde 134 in almost quantitative yield (equation 50). The formation of 134 is most probably due to addition of 93 to two... 

A polymeric binaphthyl zinc complex has been used for related epoxidation reactions <1999JOC8149>.A bimetallic samarium-based Lewis acid complex catalyzes the nucleophilic epoxidation of unsaturated carbonyl compounds very efficiently <2002JA14544>. The use of amino acids has organocatalysts for asymmetric epoxidations of enones and enals has been investigated <2005OL2579, 2005JA6964>. 

Lewis acid complexes of -substituted a, 3-unsaturated ketones and aldehydes are unreactive toward alkenes. Crotonaldehyde and 3-penten-2-one cannot be induced to undergo ene reactions like acrolein and methyl vinyl ketone. The presence of a substituent on the -carbon stabilizes the enal- or enone-Lewis acid complex and stericdly retards the approach of an alkene to the -carbon. However, Snider et al. have found that a complex of these ketones and aldehydes with 2 equiv. of EtAlCk reacts reversibly with alkenes to give a zwitterion (22). This zwitterion, which is formed in the absence of a nucleophile, reacts reversibly to give a cyclobutane (23) or undergoes two 1,2-hydride or alkyl shifts to generate irreversibly a p, -disubstituted-a,P-unsaturated carbon compound (24). 

Nucleophilic reactions of unmodified aldehydes are usually diiScult to control, affording complex mixture of products, often due to the high reactivity of the formyl group under either basic or acidic reaction conditions. The activity order of the supported amines was secondary > primary > tertiary, which may suggest the intervention of an enamine pathway the enals were exclusively obtained as ( ) isomers. Notably, FSM-16-(CH2)3-NHMe exhibited higher activity than conventional solid bases such as MgO and Mg-Al-hydrotalcite [hexanal self-aldol condensation FSM-16-(CH2)3-NHMe 97% conversion and 85% yield in 2h, MgO 56% conversion and 26% yield in 20 h, Mg-Al-hydrotalcite 22% conversion and 11% yield in 24 h]. 

In the last chapter we introduced the Heck reaction as a way to add nucleophiles to electrophilic alkenes. The details of the mechanism are discussed there. The reaction also occurs with allylic alcohols 218 and is a good way to make carbonyl compounds, particularly aldehydes, 219 as the alternative conjugate addition of an organometallic compound to an enal often shows poor regioselectivity (chapter 9). 

Deprotection of the dienes and oxidation of the resulting alcohols gave CE.Zj-b.S-decadi-enal and (is,Z)-6,8-decadienal13. These were converted to ( , .fc )-l-(phenylsulfonylj-1,7,9-un-decatriene and the corresponding (E,Z.E)-isomer by a nucleophilic addition-elimination sequence. 

The chemical reactivity of propenal is representative of a, -unsaturated carbonyl compounds. The conjugation between a carbon-carbon double bond and a carbonyl group leads to characteristic reactivity, which includes reduced reactivity of the carbon-carbon double bond toward electrophiles and enhanced susceptibility to the addition of nucleophilic reagents at the (3 carbon. The anion formed by addition is a delocalized enolate, with the negative charge shared by oxygen and carbon. The topic of nucleophilic addition to enals and enones is considered further in Section 2.6, Part B. 

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