Alkynyl Prins and Alkynyl Aza-Prins Annulations: Scope and Synthetic Applications

Abstract

This review focuses on alkynyl Prins and alkynyl aza-Prins cyclization­ processes, which involve intramolecular coupling of an alkyne with either an oxocarbenium or iminium electrophile. The oxocarbenium or iminium species can be generated through condensation- or elimination-type processes, to achieve an overall bimolecular annulation that enables the synthesis of both oxygen- and nitrogen-containing­ saturated heterocycles with different ring sizes and substitution patterns. Also discussed are cascade processes in which alkynyl Prins heterocyclic adducts react to trigger subsequent pericyclic reactions, including [4+2] cycloadditions and Nazarov electrocyclizations, to rapidly construct complex small molecules. Finally, examples of the use of alkynyl Prins and alkynyl aza-Prins reactions in the synthesis of natural products are described. The review covers the literature through the end of 2019.

1 Introduction

1.1 Alkyne-Carbonyl Coupling Pathways

1.2 Coupling/Cyclization Cascades Using the Alkynyl Prins Reaction

2 Alkynyl Prins Annulation (Oxocarbenium Electrophiles)

2.1 Early Work

2.2 Halide as Terminal Nucleophile

2.3 Oxygen as Terminal Nucleophile

2.4 Arene as Terminal Nucleophile (Intermolecular)

2.5 Arene Terminal Nucleophile (Intramolecular)

2.6 Cyclizations Terminated by Elimination

3 Synthetic Utility of Alkynyl Prins Annulation

3.1 Alkynyl Prins-Mediated Synthesis of Dienes for a [4+2] Cyclo­- addition­-Oxidation Sequence

3.2 Alkynyl Prins Cyclization Adducts as Nazarov Cyclization Precursors

3.3 Alkynyl Prins Cyclization in Natural Product Synthesis

4 Alkynyl Aza-Prins Annulation

4.1 Iminium Electrophiles

4.2 Activated Iminium Electrophiles

5 Alkynyl Aza-Prins Cyclizations in Natural Product Synthesis

6 Summary and Outlook

Key words

Prins - annulations - cyclizations - natural products - oxa­cycles - azacycles - alkynes

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