Published as part of the Bürgenstock Special Section 2018 Future Stars in Organic Chemistry
Abstract
The acylation of α-substituted carbanion-type reagents (MCR1R2X; X = halogen, OR, SR, NR3R4, SeR, etc.) with Weinreb amides constitutes a highly versatile and flexible approach
for accessing α-functionalized ketones. In this short review we will present a series
of transformations—from our own and the work of others—documenting the general applicability
of the methodology. Chemoselectivity is uniformly manifested including for critical
substrates featuring additional electrophilic functionalities or sterically demanding
elements. Importantly, the stereochemical information contained in the Weinreb amides
can be fully transferred to the targeted ketones without affecting the optical purity.
The protocol is also applicable to chiral carbanions generated through sparteine-mediated
asymmetric deprotonation: the careful design of the experimental procedure allows
recycling of the sparteine and the Weinreb ‘amine’ (N,O-dimethylhydroxylamine), thus improving the sustainability perspective of the processes.
1 Introduction
1.1 The Problem of the Synthesis of α-Substituted Ketones
1.2 Weinreb Amides: General Features and Preparation
2 Synthesis of α-Substituted Ketones
2.1 α-Haloketones
2.2 Synthesis of α-Cyanoketones
2.3 Synthesis of α-Oxyketones
2.4 Synthesis of β-Oxo Thioethers (α-Thioketones)
2.5 Synthesis of Chiral α-Oxy and α-Nitrogen Ketones via the Sparteine-Mediated Generation
of Optically Active Organolithiums
2.6 Synthesis of α-Selenomethyl Ketones
2.7 Reactivity of α-Phosphorus Carbanions with Weinreb Amides
2.8 Modification of the Weinreb Amide Core: The CLAmP Reagent
3 Competing Attack of Nucleophiles at More Reactive Electrophilic Sites than Weinreb
Amides
4 Conclusions
Key words
ketones - homologation - carbenoids - chemoselectivity - additions
