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

Abstract

<jats:p>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.</jats:p><jats:p>1 Introduction</jats:p><jats:p>1.1 Alkyne-Carbonyl Coupling Pathways</jats:p><jats:p>1.2 Coupling/Cyclization Cascades Using the Alkynyl Prins Reaction</jats:p><jats:p>2 Alkynyl Prins Annulation (Oxocarbenium Electrophiles)</jats:p><jats:p>2.1 Early Work</jats:p><jats:p>2.2 Halide as Terminal Nucleophile</jats:p><jats:p>2.3 Oxygen as Terminal Nucleophile</jats:p><jats:p>2.4 Arene as Terminal Nucleophile (Intermolecular)</jats:p><jats:p>2.5 Arene Terminal Nucleophile (Intramolecular)</jats:p><jats:p>2.6 Cyclizations Terminated by Elimination</jats:p><jats:p>3 Synthetic Utility of Alkynyl Prins Annulation</jats:p><jats:p>3.1 Alkynyl Prins-Mediated Synthesis of Dienes for a [4+2] Cyclo­- addition­-Oxidation Sequence</jats:p><jats:p>3.2 Alkynyl Prins Cyclization Adducts as Nazarov Cyclization Precursors</jats:p><jats:p>3.3 Alkynyl Prins Cyclization in Natural Product Synthesis</jats:p><jats:p>4 Alkynyl Aza-Prins Annulation</jats:p><jats:p>4.1 Iminium Electrophiles</jats:p><jats:p>4.2 Activated Iminium Electrophiles</jats:p><jats:p>5 Alkynyl Aza-Prins Cyclizations in Natural Product Synthesis</jats:p><jats:p>6 Summary and Outlook</jats:p>

Alkynyl Halo-Aza-Prins Annulative Couplings

“…The stereochemical assignments for the vinyl halide moiety ( E vs Z ) were made according to X-ray crystallographic data when possible, and otherwise by analogy to the overwhelming literature trend, wherein the major isomer has E geometry and is often the only isomer observed in alkynyl halo-Prins reactions. ,, …”

Stereoselective synthesis of gem-dihalopiperidines via the halo-aza-Prins cyclization reaction: access to piperidin-4-ones and pyridines

“…Aza-Prins cyclization, which involves the in situ generation of an iminium ion followed by a nucleophilic attack of an alkene or an alkyne, is a well-known reaction for the synthesis of nitrogen heterocyclic compounds. 8 Although halo-Prins/halo-aza-Prins cyclization wherein a halide ion acts as a nucleophile to give mono-halogenated compounds is well established, 9 the halo-aza-Prins reaction which provides gem -dihalo compounds is not yet reported. In our previous work, we have demonstrated an efficient methodology for the synthesis of 2,6-disubstituted tetrahydropyranones via the Prins cyclization of 3-bromobut-3-en-1-ols and aldehydes mediated by borontrifluoride etherate (BF 3 ·OEt 2 ) in moderate to good yields.…”

Regio- and Chemoselective Synthesis of 3-(Dihydrofuran-3(2H)-ylidene)isobenzofuran-1(3H)-imines via Tandem Alkynyl Prins- and Intramolecular Oxycyclization Reactions

“…Prins cyclization reaction has been utilized for the synthesis of various tetrahydrofuran, tetrahydropyran, and their nitrogen and sulfur analogues . Tetrahydrofuran derivatives are found in many biologically active molecules and natural products, including macrolides, oxidized lipids or acetogenins, and polyether ionophores .…”