Advances in the synthesis of nitrogen-containing heterocyclic compounds by in situ benzyne cycloaddition

Abstract

Nitrogen-containing heterocyclic compounds are prevalent in various natural products, medicines, agrochemicals, and organic functional materials. Among strategies to prepare nitrogen-containing heterocyclic compounds, pathways involving benzyne intermediates are attractive given that they can readily assemble highly diverse heterocyclic compounds in a step-economical manner under transition-metal-free conditions. The synthesis of nitrogen-containing heterocyclic compounds from benzyne intermediates offers an alternative strategy to the conventional metal-catalyzed activation approaches. In the past years, chemists have witnessed the revival of benzyne chemistry, mainly attributed to the wide application of various novel benzyne precursors. The cycloaddition of benzynes is a powerful tool for the synthesis of nitrogen-containing heterocyclic compounds, which can be constructed by [n + 2] cyclization of benzyne intermediates in situ generated from benzyne precursors under mild reaction conditions. This review focuses on the application of cycloaddition reactions involving in situ benzynes in the construction of various nitrogen-containing heterocyclic compounds.

Scheme 1. (a) Some examples of functional aromatics, (b) general benzyne species, (c) preparation strategy of benzyne species.

Scheme 2. Some examples of the preparation of benzyl intermediate.

Scheme 3. Some examples of [2 + 2] cycloadditions.

Scheme 4. Tandem benzyne-enamide – [2 + 2]–[4 + 2].

Scheme 5. Tandem enamide-benzyne – [2 + 2]–[4 + 2].

Scheme 6. Benzynes [2 + 2] cycloaddition/ring-opening sequence of benzynes with N-arylimines.

Scheme 7. Palladium-catalyzed selective [2 + 2 + 2] annulation.

Scheme 8. Multi-functionalization of benzyne precursors by cyclization/ring-opening.

Scheme 9. Cycloadditions of benzyne with nitrones.

Scheme 10. Photoinduced benzyne [3 + 2] cycloaddition.

Scheme 11. Benzotriazoles via [3 + 2] cycloaddition of 1,3-dipolar compounds and benzynes.

Scheme 12. Intramolecular cycloadditions of aryne precursors bearing an azido.

Scheme 13. [3 + 2] Cycloaddition of arynes and 2-aminoquinones.

Scheme 14. Synthesis of benzo[e]indole from 2-vinylpyrroles and aryne precursors.

Scheme 15. Domino aryne annulation via a nucleophilic–ene.

Scheme 16. 1,3-Dipolar cycloaddition reactions with benzynes. (a) Synthesis of spiro[oxindole-3,2′-pyrrolidine] derivatives, (b) synthesis of N-substituted indazolo[3,2-a]isoquinolines skeleton.

Scheme 17. Synthesis of nitrogen-containing heterocycles by [3 + 2] cycloaddition.

Scheme 18. Construction of polycyclic compounds via [4 + 2] cycloadditions of benzyne with diene. (a) Synthesis of benzo barrelene compounds, (b) synthesis of naphthyl[2,3-b]benzofuran skeleton, (c) synthesis of 9,10-dihydrophenanthrenes containing substituted aromatics.

Scheme 19. Arene tri-functionalization with highly fused ring systems.

Scheme 20. Arene trifunctionalization with highly fused ring systems.

Scheme 21. DA reaction of benzyne with nitrogen-containing dienes. (a) Synthesis of isoquinolines via the oxidative aza-DA reaction, (b) synthesis of pyrrolo[2,3-c]isoquinolines scaffold via aza-DA reactions, (c) photolysis of a benzyne precursor, (d) synthesis of aryl-substituted 1,4-dihydroquinolines by [4 + 2] cycloaddition.

Scheme 22. Synthesis of N-contain compounds via [4 + 2] the cycloaddition reaction.

Scheme 23. The three-component diastereoselective [6 + 3] annulation reaction.

Scheme 24. The tandem reaction of [8 + 2]/aryl–olefins.

Scheme 25. 2-Vinylazetidines with benzyne of the [6 + 2] cycloaddition reaction.

Scheme 26. Intramolecular aryne–ene reaction.

Scheme 27. HDDA cycloaromatization reactions, TBS = tert-butyldimethylsilyl, Ts = para-toluenesulfony. (a) The general mode of HDDA reaction, (b) intramolecular trapping reactions of HDDA.

Scheme 28. Examples of the intramolecularly or intermolecularly trap HDDA reaction.

Scheme 29. Cyclization reactions involving different HDDA benzyne precursors. (a) Synthesis of fused isoindolines, (b) construction of saturated heterocycles from triyne, (c) synthesis of dihydrobenzothiazole from thioamides with benzynes, (d) construction of polyacene nitrogen-containing fused aromatics.