Nucleophilic acylation, enone

Sulfur compounds have also proven to be useful as nucleophilic acyl equivalents. The first reagent of this type to find general use was 1,3-dithiane, which on lithiation provides a nucleophilic acyl equivalent. The lithio derivative is a reactive nucleophile toward alkyl halides, carbonyl compounds and enones.116 117 118... 

Nucleophilic Acylation of Enones and Enoates (Stetter Reaction).. 6... 

The palladium-catalyzed coupling reactions with organic halides [32], nucleophilic acylation of aji-enones [33], enantioselective 1,2-addition to enone [34] and 1,4-addition to ynone [35] were therefore successfully developed (Scheme 12.28). 

Reaction of the ambidentate complex 1 with carbon nucleophiles results in exclusive 1,4-addition (Michael addition) to the enone-like acyl ligand no products of 1,2-addition of the nucleophile are observed (see also Houben-Weyl, Volume 13/9 a, p 416)38 39. 

This mechanistic sequence (Sch. 4) wherein the triplet excited enone adds to the alkene, either via an exciplex intermediate or directly, to afford triplet 1,4-biradicals, which (after undergoing intersystem crossing) either cyclize to product(s) or revert to ground state reactants, is confirmed by both semi-empirical and ab-initio calculations [21-24], The origin of regioselectivity is supposed to stem from the primary binding step, the enone triplet being considered as a (nucleophilic) alkyl radical at C(3) linked to an (electrophilic) ot-acyl radical at C(2) [25], Thus additions of C(2) to the less substituted terminus of electron rich alkenes and of C(3) to the least substituted terminus of electron deficient alkenes should occur preferentially [26],... 

Ethynyl carbinols (propargylic alcohols) such as 134 (Scheme 2.58) represent another important group of oxidation level 3 compounds. Their preparation involves nucleophilic addition of acetylides to the carbonyl group, a reaction that is nearly universal in its scope. Elimination of water from 134 followed by hydration of the triple bond is used as a convenient protocol for the preparation of various conjugated enones 135. Easily prepared O-acylated derivatives are extremely useful electrophiles in reactions with organocuprates, which proceed with propargyl-allenyl rearrangements to furnish allene derivatives 136. 

The tin enolates are useful in organic synthesis as a mild source of the nucleophilic enolate group in its reaction with alkyl or acyl halides, aldehydes or enones. The tin enolates are less basic than the lithium enolates, and more reactive though rather less easy to handle than the silicon enolates.105-113... 

Disconnection 4a to an enone 5 is still possible, but we should have to add a d1 reagent, or acyl anion equivalent 6 instead of an enolate. At the time of Stork s work, there were no d1 reagents which reliably added Michael fashion, so he invented one. It would obviously be convenient if the d1 reagent would also act as an alkylating agent in the synthesis of 6, that is if it would act as the doubly nucleophilic synthon 7. 

By dehydrohalogenation of /-butyl chloride, the nucleophilic isobutene, and by its reaction with carbon monoxide the electrophilic pivalyl chloride, are produced. These two reagents afford the monoacylation products 141 and 142 the unconjugated enone 142 is able to undergo a second acylation (reaction of the type in Section II, C, 1, a) leading to the pyrylium salt 142. 

The reaction in Entry 12 is related and uses thioglycolate esters as a chain transfer agent. In this particular reaction involving an electron-rich alkene, the yield is only 8% in the absence of the thioglycolate. Entry 13 is another example of the addition of an acyl radical to relatively electrophilic alkene. Entry 14, involving the addition of formamide was done with acetone photosensitization. The 2-dioxolanyl radical involved in Entry 15 would be expected to be nucleophilic in character and higher yields were obtained with diethyl maleate than with typical terminal alkenes. The addition of 1,3-dioxolane to various enones has been done using benzophenone sensitization.The radicals in Entries 17 and 18 are electrophilic in character. Entries 19 and 20 are examples of thiol additions. 

One of the first eye-catching synthetic applications of arene-chromium chemistry was the synthesis of the sp/ro-sesquiterpenes ( )-acorenone and ( )-acorenone B (rac-7) disclosed by Semmelhack and Yamashita in 1980 [14]. These authors twice exploited the meta-selective nucleophile addition to anisole-Cr(CO)3 derivatives (Scheme 1). Starting from complex rac-1, such a reaction is first used for the regioselective introduction of an acyl sidechain to give 2 after oxidative workup. A few steps later, the nitrile rac-4 (obtained from rac-3 by complexation and separation of the diastereomeric products by preparative HPLC) is deprotonated to form the spiro addition product rac-5, from which the enone rac-6 is obtained after protonation and hydrolysis of the initially formed dienol ether. The final conversion of rac-6 into acorenone B (rac-7) efficiently proceeds over five steps and involves a diastereoselective hydrogenation of an exo-methylene group. 

Can we use any of the acyl anion equivalents that we met in Section 20.2.2 to make 1,4-difunc-tionalized compounds This should work if, instead of adding them directly to a carbonyl compound, we add them to an a,p-unsaturated species. Thus, we can add cyanide to an enone (Figure 20.30), and the product can be hydrolyzed to a carboxylic acid, reduced to an amine, or otherwise elaborated. Remember that simple nucleophiles such as cyanide undergo conjugate addition to enones under conditions of thermodynamic control. 

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