Substrate‐Controlled Michael Additions of Titanium Enolates from Chiral α‐Benzyloxy Ketones to Conjugated Nitroalkenes

Abstract

Lewis acid mediated substrate‐controlled reactions of the titanium(IV) enolates of chiral α‐benzyloxy ketones with conjugated nitroalkenes give 2,4‐anti‐4,5‐syn Michael adducts in good yields and diastereomeric ratios. The supplementary Lewis acid plays a key role in the outcome of these transformations, probably as a consequence of the formation of dimetallic enolates that increase the reactivity of the enolate and direct the approach of the nitroalkene. Importantly, the most appropriate Lewis acid depends on the electrophilic partner: TiCl4 is the most suitable Lewis acid for β‐aryl‐nitroalkenes, whereas the best results for β‐alkyl‐nitroalkenes are obtained with SnCl4. Finally, the nitro group of the resultant compounds can be converted into the corresponding amine, oxime, and nitrile groups under mild conditions, which permits the synthesis of a variety of enantiomerically pure derivatives in excellent yields.

Direct, Enantioselective, and Nickel(II) Catalyzed Reactions of N‐Azidoacetyl Thioimides with Trimethyl Orthoformate: A New Combined Methodology for the Rapid Synthesis of Lacosamide and Derivatives

“…This made us suspect that some of the product was not being liberatedi nt he workup, possibly due to the formation of titanium complexes,which led us to scrutinize the quenchofthe reaction mixture. [26] We found that the yield improved when the mixture was left stirring for 3.5 ha fter the quench( compare entry 1a nd 2i nT able 5). Moreover,t he use of NH 4 Fi nstead of NH 4 Cl provided a6 0% yield of product 12 b after 3.5 h( entry 4 in Ta ble5); no further improvement was observed at longer times (compare entry 4and 5i nT able 5).…”