Traceless Redox-Annulations of Alicyclic Amines

Abstract

Amines such as 1,2,3,4-tetrahydroisoquinoline undergo redox­-neutral annulations with ortho-(nitromethyl)benzaldehyde. Benzoic­ acid acts as a promoter in these reactions, which involve concurrent amine α-C–H bond and N–H bond functionalization. Subsequent removal of the nitro group provides access to tetrahydroprotoberberines not accessible via typical redox-annulations. Also reported are decarboxylative annulations of ortho-(nitromethyl)benzaldehyde with proline and pipecolic acid.

Synthesis of Polycyclic Isoindolines via α-C–H/N–H Annulation of Alicyclic Amines

“…Given the prevalence of saturated azacycles as core structures of numerous bioactive materials, the development of methods for the synthesis of more complex amines via the C–H bond functionalization of their parent heterocycles continues to inspire the development of diverse synthetic strategies. , Despite the tremendous progress that has been achieved in this area, there is a lack of available methods that enable direct amine annulation via concurrent N–H and α-C–H bond functionalization as an attractive entry to polycyclic amines (Scheme ). While redox-annulations (Scheme a) are highly appealing in this regard, these transformations remain limited to aldehydes containing activated pronucleophiles . For instance, direct access to polycyclic isoindolines via redox-annulation of alicyclic amines and aryl aldehydes would be highly desirable (Scheme b), given the privileged nature of such compounds in drug discovery and the need for multiple-step sequences when these materials are accessed via traditional approaches. , However, due to other, more facile reaction pathways, this transformation has remained elusive .…”

The Last Fortress of Tin's Tyranny – Protodenitration of Nitroalkanes

“…Thus, the replacement of Bu 3 SnH became an important goal in the field, and multiple options emerged over the past four decades. Traditional reducing 2019), [213] Yuan (2019), [214] Yuan (2019), [215] Valeev (2020), [216] Seidel (2020), [217] Cobb (2020), [218] Wang and Guo (2020), [219] Zhang (2020), [220] Pan (2021), [221] Norrby and Wärnmark (2021), [222] Matsuo (2021), [223] and Corey (2021). [224] Scheme 11.…”

“…Since Carreira's persuasive report, more research groups employed transition metal-promoted protodenitrations in both novel method development and a total synthesis (products 329-338 Figure 12). [258][259][260][261][262][263][264][265][266]217] Unfortunately, despite the relatively high number of all reported cases, transition metal-promoted protodenitrations remain limited primarily to substrates having the nitro group in allylic or benzylic position. Only a few tertiary or secondary nitroalkanes underwent protodenitration with the assistance of a transition metal.…”

Condensation-Based Methods for the C–H Bond Functionalization of Amines

“…In related work, we reported redox-annulations with ortho-(nitromethyl)benzaldehydes (Scheme 66). 119 While no diastereoselectivity is observed for product 128d (thermodynamic equilibrium ratio is 1:1), products such as 128a are obtained essentially as single diastereomers. The nitro group in the products can be removed, effectively rendering the annulation process traceless.…”