Tandem Addition β-Lithiation−Alkylation Sequence on α,β-Unsaturated Aldehydes

Abstract

A tandem reaction between (E)-cinnamaldehyde, 1a, and phenyllithium affording beta-substituted dihydrochalcones was recently reported. NMR spectroscopic studies on the reaction mixture, as well as isotopic exchange reactions and trapping of two intermediates, provide clues on the several mechanistic steps of this new reaction. Extended studies revealed that beta-alkyl-substituted alpha,beta-unsaturated aldehydes and aliphatic lithium reagents did not afford good yields of the tandem reaction products, while aromatic lithium reagents gave good results. The aggregation features of the aryllithium reagents and the extended charged delocalization effects are considered to promote beta-selectivity. This approach provides a convenient route for the synthesis of a wide variety of beta-alkyl-substituted dihydrochalcones.

Solvent and Ligand Effects on the Tandem Addition-Lithiation-Electrophilic Substitution of Phenyllithium on α,β-Unsaturated Carbonyl Compounds

“…It was observed that by increasing the [PhLi]: [1] ratio up to three, an almost quantitatively conversion of 1 into the 1,2-dihydrochalcone 5 is observed after 6 h reaction [3]. This result, together with the high sensitivity of the reaction to the medium effects, could be interpreted as a consequence of the dimeric phenyllithium attacking 1 without previous de-aggregation as shown in the Scheme 2.…”

“…By-side products were E-cinnamyl alcohol (3), E-chalcone (4), and E-1,2-dihydrochalcone (5), as shown in Scheme 1. [3,7] and it shows the yields of the several reaction products determined when carrying out the reaction in three solvents, namely: ethyl ether, toluene and THF. In all cases, the time of reaction was 3h, and it can be observed that the results are quite dependable of the reaction conditions.…”

“…If the mechanism proposed in the Scheme 2 is correct, intermediate II is also an organo-lithium reagent that could react with an electrophile. Indeed, by carrying out the reaction in the presence of propylbromide the 3-propyl-1,3-diphenylpropanone is produced in high yield (up to 91%) [3]. To confirm that the real reagent is dimeric phenyllithium, reactions were then run in the presence of certain additives that are known to form mixed aggregates.…”

“…Then the same solvent (14 mL) and of E-cinnamaldehyde (132 mg, 1 mmol) were added to the stirred solution all at once; by this procedure, both reagents have a final concentration of 0.07 M. Reactions were carried out protected from light. The reaction mixtures were worked up by treating with saturated NH 4 Cl solution (0.5 mL), extracted with ethyl ether and the % yields determined by GC following procedures already described [3].…”

“…The seminal work by Seebach in 1984 and a second paper in 1998, alerted synthetic organic chemists to the possible consequences of aggregation in organolithium chemistry [2]. We have recently reported a marked effect of the reaction conditions on the reactivity of phenyllithium with α,β-unsaturated aldehydes, that results in a complete change of the reaction products leading to a new tandem addition-lithiation-electrophilic substitution [3].…”