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 Introduction1.1 Alkyne-Carbonyl Coupling Pathways1.2 Coupling/Cyclization Cascades Using the Alkynyl Prins Reaction2 Alkynyl Prins Annulation (Oxocarbenium Electrophiles)2.1 Early Work2.2 Halide as Terminal Nucleophile2.3 Oxygen as Terminal Nucleophile2.4 Arene as Terminal Nucleophile (Intermolecular)2.5 Arene Terminal Nucleophile (Intramolecular)2.6 Cyclizations Terminated by Elimination3 Synthetic Utility of Alkynyl Prins Annulation3.1 Alkynyl Prins-Mediated Synthesis of Dienes for a [4+2] Cyclo- addition-Oxidation Sequence3.2 Alkynyl Prins Cyclization Adducts as Nazarov Cyclization Precursors3.3 Alkynyl Prins Cyclization in Natural Product Synthesis4 Alkynyl Aza-Prins Annulation4.1 Iminium Electrophiles4.2 Activated Iminium Electrophiles5 Alkynyl Aza-Prins Cyclizations in Natural Product Synthesis6 Summary and Outlook
A novel metal-free
double-annulation cascade for the construction
of unusual fused heterocyclic systems is described. This simple protocol
enables the sequential assembly of two rings in one pot from two simple
precursors. Acidic conditions promote the condensation and the intramolecular
alkynyl Prins reaction of an enyne or arenyne alcohol with a cyclic
hemiaminal to form a five-, six-, or seven-membered oxacycle followed
by a seven- or eight-membered azacycle. In this transformation, chemical
complexity is rapidly generated with the formation of three new bonds
(one C–O, one C–C, and one C–N) in one synthetic
operation. The strategy is modular and relatively general, providing
access to a series of unique fused bicyclic scaffolds.
Metrics & MoreArticle Recommendations * sı Supporting Information H igh-resolution mass spectrometry (HRMS) data and a description of a reaction on a 1 mmol scale were left out of the original manuscript because we could not collect this data in a timely manner due to the COVID-19 pandemic lockdown. The appropriate HRMS data and experimental details of the 1 mmol scale reaction are provided in the Supporting Information here as an addition.
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