Lithium Halomethylcarbenoids: Preparation and Use in the Homologation of Carbon Electrophiles

• Published in: Chemical record Vol. 16; no. 4; pp. 2061 - 2076
• Main Authors: Pace, Vittorio, Holzer, Wolfgang, De Kimpe, Norbert
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.08.2016; Wiley Subscription Services, Inc
• Subjects: carbenoids; carbonyl compounds; homologation reactions; lithium; synthetic methods; homologation reactions; lithium; carbenoids; carbonyl compounds; synthetic methods
• ISSN: 1527-8999; 1528-0691
• DOI: 10.1002/tcr.201600011

α‐Halomethyllithium carbenoids are useful homologating reagents which – reacting under proper reaction conditions as carbanions – enable the installation via nucleophilic addition of a reactive halomethyl fragment onto a preformed carbon–heteroatom bond. The pronounced thermolability represented – since seminal studies by Köbrich – the Achilles' heel of these reagents: the use of Barbier‐type methodologies (i.e., the electrophile should be present in the reaction mixture prior to the formation of the carbenoid) was pivotal in order to suppress decomposition through α‐elimination processes. Nowadays, the use of low temperatures (−78 °C) guarantees reliable procedures and, significantly, the employment of microreactor technologies allows external trapping to be performed even at higher temperatures as reported by Luisi. We will discuss the α‐halomethyllithium‐mediated homologations of a series of carbon electrophiles such as carbonyl compounds, imines, esters, Weinreb amides, and isocyanates. Lithium halomethylcarbenoids generated through different methods react as versatile homologating agents for a plethora of carbon electrophiles, including carbonyls, esters, Weinreb amides, and isocyanates. They constitute excellent delivery agents for useful halomethyl groups susceptible to further reactions. Recently, the configurational stability of these species has been noticed, thus setting the basis for developing synthetic strategies dealing with the use of chiral halomethyllithiums.