Tandem β-Alkylation−α-Arylation of Amines by Carbolithiation and Rearrangement of N-Carbamoyl Enamines (Vinyl Ureas)

Abstract

Organolithiums add in an umpolung fashion to the beta-carbon of N-carbamoyl enamines (N-vinyl ureas). The reaction proceeds with syn diastereospecificity and provides urea-stabilized, configurationally defined organolithiums. Facilitated by coordinating solvents (THF or DMPU), these undergo intramolecular attack on an N'-aryl group, resulting in retentive arylation of the organolithium and hence overall addition of an alkyl or aryl group to both carbon atoms of the urea-substituted alkene. Facile deprotection in hot butanol permits the rapid, multicomponent construction of heavily substituted amines.

Advances in Carbolithiation

“…The intermolecular carbolithiation of a carbon-carbon double bond controlled by a coordinating functional group followed by an N → C aryl transfer of N-carbamoyl enamines (vinyl ureas) 28 and O-vinylcarbamates 33 was recently reported by Clayden and coworkers [19,20] (Scheme 11.10).…”

“…The reaction occurs with retention of configuration, leading to the formation of the lithiated intermediate 32, and therefore products 29 or 34 upon the addition of a protic source. As the rearranged products can be easily converted to diastereomerically pure secondary amines 30 [19] or tertiary diaryl alcohols 35 [20], this synthetic strategy can be considered as a valuable new method for the construction of highly functionalized products. In a similar manner, α-(2-pyridyloxy)styrene 36 was reported to undergo rearrangement in the carbolithiation reaction, resulting in O → C displacement of the 2-pyridyl moiety (Scheme 11.11) [21].…”

The Urea Renaissance

“…Using alkyllithium bases instead of LDA results in stereospecific carbolithiation of the vinyl urea 46 instead of deprotonation. [60] The addition to the alkene (see 48 and 49) is stereospecific and regioselective with the normally nucleophilic b-carbon atom of the N-carbamoyl enamine acting as the electrophilic center. Carbolithiation is followed by stereospecific rearrangement of the resulting benzyllithium in a sequence involving two nucleophilic attacks of an organolithium on an electron-rich p system (see 50 and 51).…”

The Mechanism of the Stereospecific Intramolecular Arylation of Lithiated Ureas: The Role of Li+ Probed by Electronic Structure Calculations, and by NMR and IR Spectroscopy

“…Furthermore, related reactions occur with allylic ureas, [19] cyclic ureas, [20] lithiated ureas generated by carbolithiation, [21] and benzylic thiocarbamates. [22] Conversion of the rearranged ureas 7 or carbamates 8 into the amines 9 or alcohols 10 results in an overall stereospecific arylation of an α-methylbenzylamine or α-methylbenzyl alcohol derivative.…”