Oxidative Umpolung α-Alkylation of Ketones

Abstract

We disclose a hypervalent iodine mediated α-alkylative umpolung reaction of carbonyl compounds with dialkylzinc as the alkyl source. The reaction is applicable to all common classes of ketones including 1,3-dicarbonyl compounds and regular ketones via their lithium enolates. The α-alkylated carbonyl products are formed in up to 93% yield. An ionic mechanism is inferred based on meticulous analysis, NMR studies, trapping and crossover experiments, and computational studies.

Electrophilic Activation of Iodonium Ylides by Halogen‐Bond‐Donor Catalysis for Cross‐Enolate Coupling

“…[14,18] Notably, the resonance of the ylide carbon atom of the iodonium ylide was shifted significantly downfield (ca. Our present understanding of the mechanism involves attack of silyl enol ether 1 at the iodine atom of XB-activated ylide 2 to form an enolonium species, [27] with the subsequent rearrangement [4,28] furnishing 1,4-dicarbonyl compounds 3.H owever, further mechanistic studies are in progress to distinguish between this and other possible mechanistic scenarios. Starting from various initial structures,two possible XB interaction modes were found, namely an interaction between the s-hole of the XB donor and the carbonyl oxygen atom of 2a (mode A) and an XB interaction between the donor and the ylide carbon atom (mode B).…”

“…

The umpolung alkylation of silyl enol ethers with an iodonium(III) ylide proceeds under mild conditions to afford various 1,4-dicarbonyl compounds in high yields in the presence of ah alogen-bonding catalyst. Compared with a-arylation and a-alkynylation, C(sp 3 )ÀC(sp 3 )b ondforming reactions [4] are less well developed, despite the utility of the resulting products. The identification of ac ompatible Bronsted base catalyst enabled the extension of this method to enols generated in situ to give the corresponding adducts in good yields.

Hypervalent iodine compounds have become essential in organic synthesis because avariety of oxidation and oxidative bond-forming reactions can be achieved with these reagents.

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“…[1] In particular, recent advances in the use of iodonium(III) salts have enabled the a-functionalization of various carbonyl compounds under mild conditions.I nt hese reactions, ac opper(I) catalyst [2] or as toichiometric amount of acid [3] is used to activate the iodonium salt (Scheme 1a). Compared with a-arylation and a-alkynylation, C(sp 3 )ÀC(sp 3 )b ondforming reactions [4] are less well developed, despite the utility of the resulting products. [1][2][3] We envisioned that the crosscoupling of an iodonium(III) ylide [1,5] with carbonyl compounds would enable C(sp 3 ) À C(sp 3 )b ond formation and provide 1,4-dicarbonyl compounds (Scheme 1c), which are found in av ariety of important natural product scaffolds or used for their preparation.…”

“…It is worth noting that other potential catalysts,i ncluding Schreinerst hiourea 7, [22] phosphoric acid 8, [23] Lewis acidic metals, [3] and transition-metal complexes, [1,5] did not accelerate the reaction efficiently (entries 4-10), because of either catalyst decomposition (entries 5and 6) or degradation of the iodonium ylide [11] (entries 6-10). When Rh 2 (OAc) 4 ,w hich is known to form metal carbenoid species [1,5] with iodonium ylides,w as employed, neither 2a nor the corresponding cyclopropane intermediate were observed (entry 10). From these results,formation of 3a through cyclopropanation of 1a followed by ring opening is highly unlikely as the operative mechanistic pathway.S olvent effects were found to be important;d ichloromethane and toluene gave lower yields than THF (entries 11 and 12).…”

“…[26] According to the calculated interaction energies,t he intermediate interacting through the Oatom (mode A) is more favorable than that interacting through the Catom (mode B). Our present understanding of the mechanism involves attack of silyl enol ether 1 at the iodine atom of XB-activated ylide 2 to form an enolonium species, [27] with the subsequent rearrangement [4,28] furnishing 1,4-dicarbonyl compounds 3.H owever, further mechanistic studies are in progress to distinguish between this and other possible mechanistic scenarios. [25] [a] Unless otherwise noted, the yields were determined by 1 HNMR analysis with dimethyl sulfone as an internal standard.…”