Abstract
The application of an iridium-catalyzed hydrogen borrowing process to enable the formation of α-branched ketones with higher alcohols is described. In order to facilitate this reaction, ortho-disubstituted phenyl and cyclopropyl ketones were recognized as crucial structural motifs for C-C bond formation. Having optimized the key catalysis step, the ortho-disubstituted phenyl products could be further manipulated by a retro-Friedel-Crafts acylation reaction to produce synthetically useful carboxylic acid derivatives. In contrast, the cyclopropyl ketones underwent homoconjugate addition with several nucleophiles to provide further functionalized branched ketone products.
Highlights
The use of hydrogen borrowing catalysis to allow the alkylation of functional groups such as amines or ketones using alcohols has become a valuable method for organic synthesis.[1]
This concept relies on the use of a transitionmetal catalyst to reversibly abstract hydrogen from an alcohol to generate an aldehyde in situ
Our recent mechanistic studies showed that the intermediate aldol adducts formed from reactions with substituted aldehydes were not stable under the reaction conditions and reverted back to the methylene ketones rather than alkylated products
Summary
Optimization studies were performed using ortho-tolyl ketone 1, KOH, BnOH, and commercially available iridium catalysts at 85 °C We selected two ortho-disubstituted aryl ketones that held great potential for elaboration (2,4,6-trimethyl- and pentamethylphenyl) and synthesized a variety of substrates bearing different aliphatic side chains These were subjected to the hydrogen borrowing alkylation conditions with different alcohols (Scheme 3). Investigation of other ketones that might allow the formation of branched products revealed that the cyclopropyl group was suitable (Scheme 5) In this case slightly different conditions involving [Cp*IrCl2]2 (2 mol %) at 105 °C proved optimal, providing the desired alkylated products in good yields. The catalyst free alkylation of substrates (Ar = Me3C6H2), (Ar = Ph*), and is not general, and when nonbenzylic alcohols such as butanol and cyclopropylmethanol were used, the reactions gave no alkylated product In these cases the reaction mixture consisted of mostly unreacted (Ar ketones) or reduced starting material (cyclopropyl ketones).
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