88 / 2023-09-26 09:52:09

Palladium-catalyzed Asymmetric [4+3] Cycloadditions of Indene-2-carbaldehydes with 4-Vinylbenzoxazinanones Toward Polycyclic 5H-Benzo[b]azepines

Cycloaddition; Enantioselectivity; Axially chiral bisphosphorous ligands

Phosphorus in Synthetic Chemistry > 1) Phosphorus compounds as catalysts

Palladium-catalyzed Asymmetric [4+3] Cycloadditions of Indene-2-carbaldehydes with 4-Vinylbenzoxazinanones Toward Polycyclic 5H-Benzo[b]azepines

Xiyuan Zhang¹, Zhiwei Miao<sup>1, *

1</sup>State Key Laboratory and Institute of Elemento-Organic Chemistry, University of Nankai, Weijin Road 94, Tianjin, 300071

^*E-mail: miaozhiwei@nankai.edu.cn



Benzazepines as aza-heterocyclic fused aromatic ring have long been considered privileged scaffolds in numerous natural products and pharmacologically active substances. Specifically, 1-benzazepine is featured in the angiotensin-converting enzyme (ACE) inhibitor benazepril and the cholestery ester transfer protein (CETP) inhibitor drug candidate evacetrapid. However, general, highly efficient synthetic approaches to these complex, structurally diverse 7-membered aza-heterocyclic fused aromatic scaffolds are quite limited. Catalytic asymmetric decarboxylative cycloaddition reactions of vinyl benzoxazinanones have been employed to synthesize enantiopure nitrogen-containing heterocyclic compounds. Recently, we have developed asymmetric [4+3] cycloaddition reactions between 4-vinyl benzoxazinanones and azomethine imines to generate 1,2,4-benzotriazepine skeletons in the combination of spiro-phosphoramidite ligands and Pd⁰. On the basis of our previous works, we described herein a palladium-catalyzed enantioselective decarboxylative [4+3] cycloaddition reactions in the presence of axially chiral bisphosphorous ligands, in which indene-2-carbaldehydes were first used as a 3-atom synthon for dipolar Pd-catalyzed cycloadditions and vinyl benzoxazinanones were used as the 1,4-dipoles. This protocol allows for convenient synthesis of chiral polycyclic 5H-benzo[b]azepines in moderate to good yields (up to 89%) with good enantioselectivities (up to 95.5:4.5 er). These reactions proceeded smoothly under mild conditions, providing a broad range of fused polyheterocycle compounds.



Fig. 1 Cycloadditions of Indene-2-carbaldehydes with 4-Vinylbenzoxazinanones

Keywords: Cycloaddition; Enantioselectivity; Axially chiral bisphosphorous ligands

References

1. Gao, Y. F.; Zhang, X. G.; Zhang, X. Y.; Miao, Z. W. Org. Lett. 2021, 23, 2415−2420.


2. Zhang, X. Y.; Gao, Y. F.; Miao, Z. W. Adv. Synth. Catal. 2023, 365, 381–387.