Brønsted Acid Catalyzed α‐Alkylation of Aldehydes with Diaryl Methyl Alcohols

Abstract

The catalytic a-alkylation of carbonyl compounds is a common approach in organic synthesis. In recent years, many efforts have been directed towards the activation of ketones and aldehydes by means of enamine catalysis to react with a broad range of electrophiles. In 2004, List reported an elegant intramolecular alkylation of aldehydes with alkyl halides using proline-based amine catalysts. While the long-sought intermolecular versions of such enamine-catalytic SN2-type a-alkylation of aldehydes [3] remain challenging, research by the groups of Melchiorre, Cozzi, Jacobsen and others have pioneered the amine-mediated SN1type intermolecular reactions between aldehydes and arylsulfonyl indoles, diaryl alcohols, or halides. In the approach used by Cozzi and others, amine catalysts were used to activate the aldehydes via enamine intermediates, and Bronsted acids were used to mediate the formation of diaryl methyl cations from the corresponding diaryl methanols. Despite the success of this amine/acid co-catalysis approach for diaryl methyl alcohols (e.g., 1a) that generate highly stabilized carbocations, the scope of the reactions still remains limited: diaryl methyl alcohols (such as 1b–f) that lead to “less stabilized” diaryl methyl carbocation electrophiles are ineffective substrates in these alkylation reactions. Instead of using enamine catalysis for aldehyde activation, here we disclose the use of Bronsted acids alone to catalyze these SN1 type aldehyde alkylations. The acid catalyst is believed to facilitate the formation of alcohol-derived carbocations and to accelerate the enolization of aldehydes. A much broader scope of substrates is thereby realized: diaryl methyl alcohols that lead to less stabilized carbocations can be used; aldehydes with a,a-disubstituents react efficiently as well to generate products containing quaternary carbon centers. Our work began by using diaryl methanol 1b as a model substrate to develop an acid-catalysis approach. According to the Mayr reactivity scales, such substrates lead to lessstabilized carbocations (e.g., compared to that from 1a) and were ineffective using the enamine/acid co-catalytic strategies. The results of our initial studies are summarized in Table 1. Weak acids, such as acetic acid, could not mediate