Reductive Fragmentation of Tetrazoles: Mechanistic Insights and Applications toward the Stereocontrolled Synthesis of 2,6-Polysubstituted Morpholines

Abstract

A new methodology to synthesize 2,6-di-, and 2,2′,6-trisubstituted morpholines via the reduction of oxabicyclic tetrazoles under mild conditions is described. The reaction proved successful for a wide range of tetrazoles, including sterically encumbered ones harboring gem-substituents on tertiary carbon centers. The mechanism for the decades-old reduction of tetrazoles to secondary amines is elucidated.

Design and Synthesis of Backbone-Fused, Conformationally Constrained Morpholine-Proline Chimeras

“…These features may be useful in the context of the peripheral attachment of chimeras 4 and 5 to bioactive compounds as bulky amides possessing localized sites of electron density. We note that there are only a few reported examples of morpholines fused to other cyclic entities 22 and of bicyclic morpholino carboxylic acids 23 but none involving backbonefused bridged morpholine-proline chimeras. 24,25…”

Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

“… Reductive fragmentation of tetrazoles toward stereochemically defined 2,6‐di‐ and 2,2’,6‐trisubstituted morpholines. Reagents and conditions : a) TMSCN, BF 3 ⋅ OEt 2 , CH 3 NO 2 , 0 °C to rt; b) LiEt 3 BH, Et 2 O, rt (overall yield: 59–94 %) . (TMSCN: trimethylsilyl cyanide, PG: protecting group).…”

“…Reagents and conditions: a) TMSCN, BF 3 · OEt 2 , CH 3 NO 2 , 0°C to rt; b) LiEt 3 BH, Et 2 O, rt (overall yield: 59-94 %). [66] (TMSCN: trimethylsilyl cyanide, PG: protecting group). [69] as well as diastereoselectivity (up to 21 : 1) between the major and minor annulation products, while it was applicable for gram scale-up.…”

“…A mechanistic analysis of reductive fragmentation of tetrazoles led Duchamp and co‐workers to the development of a new synthetic route toward stereochemically defined 2,6‐di‐ and 2,2’,6‐trisubstituted morpholines . The reaction between commercially available enantioenriched 3‐chloro‐ and 3‐azidopropane‐1,2‐diols and various readily accessible oxabicyclic tetrazoles (even sterically hindered ones) led to trans di‐ or tri‐ gem ‐substituted morpholine analogues (Scheme A and B, respectively).…”

Cyanide-Free Synthesis of Air Stable N-Substituted Li and K Cyanamide Salts from Tetrazoles. Applications toward the Synthesis of Primary and Secondary Cyanamides as Precursors to Amidines

“…Further to our interest in the reductive fragmentation reactions of tetrazoles, 20 we became intrigued by the equally remarkable [3+2] cycloreversion reaction of N-substituted tetrazoles induced by strong bases leading to the corresponding N-substituted metalo cyanamides that have not been hitherto isolated as such. Herein, we report our results on the isolation of air stable N-substituted metalo cyanamides, their reactivities, and their conversion into diverse N-substituted cyanamides.…”