Synthesis 2019; 51(14): 2792-2808
DOI: 10.1055/s-0037-1611549
short review
© Georg Thieme Verlag Stuttgart · New York

Weinreb Amides as Privileged Acylating Agents for Accessing α-Substituted Ketones

Raffaele Senatore
,
Laura Ielo
,
Serena Monticelli
,
Laura Castoldi
,
Vittorio Pace  *
University of Vienna, Department of Pharmaceutical Chemistry, Althanstrasse 14, 1090 Vienna, Austria   Email: vittorio.pace@univie.ac.at
› Author AffiliationsThe authors thank Universität Wien (University of Vienna) for generous support.
Further Information

Publication History

Received: 18 March 2019

Accepted after revision: 17 April 2019

Publication Date:
22 May 2019 (online)

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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