A Fast and General Route to Ketones from Amides and Organolithium Compounds under Aerobic Conditions: Synthetic and Mechanistic Aspects

Abstract

We report that the nucleophilic acyl substitution reaction of aliphatic and (hetero)aromatic amides by organolithium reagents proceeds quickly (20 s reaction time), efficiently, and chemoselectively with a broad substrate scope in the environmentally responsible cyclopentyl methyl ether, at ambient temperature and under air, to provide ketones in up to 93 % yield with an effective suppression of the notorious over‐addition reaction. Detailed DFT calculations and NMR investigations support the experimental results. The described methodology was proven to be amenable to scale‐up and recyclability protocols. Contrasting classical procedures carried out under inert atmospheres, this work lays the foundation for a profound paradigm shift of the reactivity of carboxylic acid amides with organolithiums, with ketones being straightforwardly obtained by simply combining the reagents under aerobic conditions and with no need of using previously modified or pre‐activated amides, as recommended.

Crystallographic Characterisation of Organolithium and Organomagnesium Intermediates in Reactions of Aldehydes and Ketones

“…It is proposed that compound 3 is the product of two distinct reactions (see Scheme 4). One is the insertion of a single unit of benzaldehyde into the γ‐carbon position of the NacNac ligand, analogous to the insertion of other small unsaturated molecules at this position seen previously by the Mulvey group and other groups involving, for example, alkenes, alkynes, isocyanates, isothiocyanates, carbodiimides, CO 2 or diphenylketene [4–54] . The second is the initiation of a Tishchenko reaction, which describes the dimerization of aldehydes to the corresponding carboxylic ester, in this case two units of benzaldehyde converting to benzyl benzoate.…”

“…As beautifully highlighted by Williard in 1993, the range of intermediate structures which may be obtained from similarly long established organolithium reactions is significant, presenting a far more complex picture of organolithium reactions than is typically given in organic textbooks [20] . Exciting steps forward have been trodden in the development of new mechanistic insights and enhanced stability of commonly used organometallic reagents by the Capriati , Garcia‐Alvarez and Hevia groups, primarily in the deployment of such reagents in air, potentially revolutionising the safety and accessibility of such reactions [21–29] . These ongoing developments clearly show that we have not yet had the final word on the mechanisms, structures and behaviours of organolithium and organomagnesium reagents, and that this field remains a thriving and heavily utilised area of research.…”

Design of a New Chiral Deep Eutectic Solvent Based on 3-Amino-1,2-propanediol and Its Application in Organolithium Chemistry

“…In the context of organic synthesis, desirable features of DESs include (i) low vapor-pressure [ 21 ], (ii) chemical stability, (iii) ease of design and preparation in the absence of any VOC, and (iv) handy separation of the reaction crude by simple precipitation or aqueous work-up [ 22 ]. Last but not least, the handiness of organic compounds and even their reactivity in DESs have often been found to be surprising, offering food for thought from a mechanistic point of view [ 23 , 24 , 25 , 26 ].…”

“…Consequently, DESs are commonly prepared by mixing and/or heating a proper hydrogen bond donor (HBD) and a suitable hydrogen bond acceptor (HBA) [ 6 ]. However, the unambiguous classification of such kind of mixture as a true DES is anything but obvious [ 26 ], unless two room-temperature solid components lead to a room-temperature liquid mixture. Following on from our previous studies, we managed to design, prepare and characterize a new DES by introducing an unexplored HBD, namely 3-amino-1,2-propanediol ( Figure 1 ), herein referred to as aminoglycerol (AGly).…”

How do arenediazonium salts behave in deep eutectic solvents? A combined experimental and computational approach

“…[26] Despite the increasing use of DESs in organic synthesis has already brought to their employment within the framework of important processes (e.g. aldol condensation, [28] Diels-Alder cycloaddition, [29] electrocyclization reactions, [30] nucleophilic acyl substitution [31] among others), they have never been used as solvents in the reactions of diazonium salts, excluding two very recent examples. The first describes one-pot diazotization/coupling reactions in choline chloride/tartaric acid DES; [32] the second describes the electro-grafting of arenediazonium salts on carbon surfaces in the presence of ethaline.…”