i-Pr₂NMgCl·LiCl Enables the Synthesis of Ketones by Direct Addition of Grignard Reagents to Carboxylate Anions

Abstract

The direct preparation of ketones from carboxylate anions is greatly limited by the required use of organolithium reagents or activated acyl sources that need to be independently prepared. Herein, a specific magnesium amide additive is used to activate and control the addition of more tolerant Grignard reagents to carboxylate anions. This strategy enables the modular synthesis of ketones from CO2 and the preparation of isotopically-labelled pharmaceutical building blocks in a single operation. Ketones (1) are one of the cornerstones of organic chemistry, being a fundamental class of products and essential synthetic intermediates. Aromatic ketones are particularly relevant drugs and fragrances, and they are key to the synthesis of heterocyclic cores in valuable products. 1 As a result, extensive research has been dedicated to obtain ketones from raw carboxylic acids (2) and CO2 (3). However, the addition of localized carbon nucleophiles to carboxylic acids is a key transformation that remains challenging after decades of research (Scheme 1A). Most approaches elaborate carboxylic acids 2 into more electrophilic derivatives 4, such as acyl chlorides, 2 anhydrides, 3 thioesters, 2f,4 cyanides, 5 ketimines, 6 imides, 7 amides 8 and Weinreb amides. 9 Special carbon nucleophiles 5 with lower reactivity like cuprates, 10 organozincs, 4,11 and boronates, 2g,3b,7,12 are often used to avoid the rapid over-addition to the resulting ketone products 1. Alternatively, the direct coupling of carbon nucleophiles with unactivated carboxylic acids requires unstable organolithium reagents, often in excess. 13,14 These addition reactions to lithium carboxylate anions Li-6 benefit from the stability of the addition complex Li-7, but are limited by competing metalation reactions, carbonyl reduction, and the narrow functional scope of the lithium organometallics. 14 Grignard reagents (8) are preferred nucleophiles for their enhanced stability and functionalgroup tolerance, particularly in large-scale processes. 15,16 Unlike organolithiums, Grignard reagents (8) are poorly reactive towards carboxylate anions (6), and the resulting addition intermediates are unstable, giving rise to tertiary alcohol over-addition by-products. 13d,14

Computational and Experimental Study of Turbo‐Organomagnesium Amide Reagents: Cubane Aggregates as Reactive Intermediates in Pummerer Coupling

“…Moreover,i tw as recently found that the same Grignard-DIPAMgCl•LiCl combinationi su niquely more reactive and more selectivei na ddition reactions to chal-lenging carboxylate anions. [18] This further suggests that an ew speciesi sf ormed in solution upon mixing Grignardr eagents 1 and DIPAMgCl•LiCl (4a), and this is relevant for the new reactivity observed.…”

“…It was also found that LiCl (entry 4), and in particular the 1:1:1 stoichiometry between the Grignard, the base and LiCl, are critical for the success of this reaction (entries 5 and 6). Moreover, it was recently found that the same Grignard‐DIPAMgCl⋅LiCl combination is uniquely more reactive and more selective in addition reactions to challenging carboxylate anions [18] . This further suggests that a new species is formed in solution upon mixing Grignard reagents 1 and DIPAMgCl⋅LiCl ( 4 a ), and this is relevant for the new reactivity observed.…”

Deoxygenative Functionalizations of Aldehydes, Ketones and Carboxylic Acids

“…Unlike the prosperous development of carbon–heteroatom bond formation mentioned above, carbon–carbon bond‐forming reactions involving exhaustive carboxylic deoxygenation have remained elusive. On the contrary, the mono‐deoxygenative version, wherein the carboxylic acid behaves as an acyl equivalent, has seen prominent advancement in recent years [2, 4, 159–160] …”

Decarboxylative Alkyl Coupling Promoted by NADH and Blue Light

“…Decarboxylative radical addition reactions (Scheme A) have recently emerged as prime tools to create aliphatic ligations in biomolecules. , These methods take advantage of the abundance of carboxylic acids , and the various technologies developed with Michael acceptors. , Despite their success, radical addition reactions are slow (6–12 h) and require additional catalysts, inorganic reducing suspensions, and/or additives that are not native to biological systems . The abundance of endogenous carboxylic acids in biomolecules or biomatrices poses a selectivity challenge for carboxylic acid substrates ( 1 ), due to their similar oxidation potentials. − In contrast, the N -hydroxyphthalimide (NHPI) esters ( 2 ) can be orthogonally activated in the presence of other carboxylates via single-electron reduction. ,,− Recent methods based on desymmetrization and late-stage carbene transfer illustrate the potential of redox-active esters to be introduced through strategies unavailable to the parent carboxylic acids.…”