Single‐Step Modular Synthesis of Unsaturated Morpholine N‐Oxides and Their Cycloaddition Reactions

Abstract

A single‐flask procedure for the generation of α‐keto‐N‐alkenylnitrones through a Chan–Lam coupling and subsequent spontaneous 6π electrocyclization of these intermediates for the synthesis of 2H‐1,4‐oxazine N‐oxides has been developed for a variety of α‐ketooximes and alkenylboronic acids. This transformation provides a new approach to C‐substituted unsaturated morpholine derivatives that are poised to undergo further functionalization for the preparation of a diverse array of novel heterocyclic structures. The scope of the new method for the synthesis of 2H‐1,4‐oxazine N‐oxides is discussed, in addition to initial studies describing the cycloaddition reactivity of these new heterocyclic intermediates.

Synthesis of Spirocyclic 1‐Pyrrolines from Nitrones and Arynes through a Dearomative [3,3′]‐Sigmatropic Rearrangement

“…The scope of the formation of spirocyclic pyrrolines 4 from N-alkenylnitrones 1 and benzyne was tested using nitrones prepared from a variety of oximes and alkenyl boronic acids (Scheme 3). [9] As shown for 4 a-4 d, malonatederived nitrones with N-styrenyl groups are well-tolerated for the pyrroline synthesis with both primary and secondary alkyl groups at the b-position. While the diastereoselectivity of C À C bond formation is high for all N-styrenyl substrates lacking chiral substituents, the defined stereochemistry of a 1phenethyl group at the b-position was shown to have little influence over the formation of 4 d. Nitrones with linear alkyl N-alkenyl substituents smoothly undergo the cascade transformation to form pyrrolines 4 e-4 f. While isomerically pure N-alkenyl nitrones give pyrrolines such as 4 e in high diastereoselectivity, nitrones that are isolated as mixtures of isomers or are prone to isomerization under reaction conditions give mixtures of products such as 4 f. Both carbocyclic and heterocyclic N-alkenyl groups are tolerated and diastereoselectively give 4 g-4 l in good yields.…”

Facile Synthesis of Azetidine Nitrones and Diastereoselective Conversion into Densely Substituted Azetidines

“…Recently,w er eported an ew method for the synthesis of unsaturated morpholines from alkenylboronic acids and a-keto oximes through a6 p-electrocyclization of at ransient N-alkenylnitrone (Scheme 1B). [13] Upon switching to malonate-derived oximes such as 1,w ed iscovered that the corresponding N-alkenylnitrones 3 undergo 4p-electrocycli-zation to give azetidine nitrones 4 (Scheme 1C). Thep reparation of related exomethylene azetidine nitrones from N-allenylnitrone intermediates has been reported by Nakamura and co-workers.These compounds are prone to thermal isomerization reactions through C À Nb ond cleavage and rearrangement (Scheme 1B).…”

Synthesis of Spirocyclic 1‐Pyrrolines from Nitrones and Arynes through a Dearomative [3,3′]‐Sigmatropic Rearrangement

“…[6] While isoxazolines such as 3 are difficult to prepare through heterocyclic N-functionalization, [7] we surmised that N-alkenylnitrones 1 could provide a versatile and facile route to these key intermediates through dipolar cycloadditions with arynes. [8,9] Herein, we disclose that when arynes are generated in the presence of nitrones 1, cycloaddition occurs to transiently form isoxazoline 3, which triggers a dearomative rearrangement to form spirocyclic pyrroline cyclohexadienones 4. This new method provides access to spirocyclic pyrrolines that are inaccessible through nitrile ylide dipolar cycloadditions due to regiochemical preferences (Scheme 1 C).…”