A Hofmann Rearrangement–Ring Expansion Cascade for the Synthesis of 1‐Pyrrolines: Application to the Synthesis of 2,3‐Dihydro‐1H‐pyrrolo[2,1‐a]isoquinolinium Salts

Abstract

Tr eatmento fc yclobutanecarboxamide with bis(trifluoroacetoxy)iodobenzene,P hI(O-COCF 3 ) 2 ,r esulted in the formationo f1 -pyrroline via Hofmann rearrangement of the former followed by in situ ring expansion reaction of the cyclobutylamine intermediate.F urther elaboration of this meth-odology to the synthesiso f2 ,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinium salts has also been described.

Oxidative Rearrangement of Primary Amines Using PhI(OAc)2 and Cs2CO3

“…During our ongoing study of the hypervalent iodine­(III) reagent-mediated oxidative rearrangement of amines, we noticed that secondary and primary amines showed a quite different reactivity: Although tritylamine was applicable in our previously reported reaction, the conditions used for secondary amines were not very effective for rearrangement of other primary amines (Table , entry 1). Taking note of this, we then re-investigated the reaction of primary amines . Herein, we report our recent success in finding that the combined use of PhI­(OAc) 2 with Cs 2 CO 3 efficiently induces the rearrangement of primary amines (Scheme c).…”

Synthesis of 1‐Pyrroline by Denitrogenative Ring Expansion of Cyclobutyl Azides under Thermal Conditions

“…1‐Pyrrolines could also be synthesized by the Hofmann rearrangement and subsequent ring expansion of cyclobutane carboxylamides with more than 2 equiv. of phenyliodine(III) bis(trifluoroacetate) [3d] . On the other hand, cyclopropyl azides underwent denitrogenative ring expansion under thermal conditions to produce 1‐azetines, while the reactivity of cyclobutyl azides was relatively lower (Scheme 1a) [4] .…”

“…[1] They are also used as precursors [2] for the synthesis of pyrroles by oxidation [2a] and pyrrolidines via reduction. [2d] Although some synthetic methods have been reported, [3] the applicable substrates are limited, and there seems to be no systematic method for the synthesis of 1-pyrrolines. The reaction of 4-chlorobutyronitrile with Grignard reagents gave imine intermediates, which underwent intramolecular nucleophilic substitution to the chlorine substituent to produce 1pyrrolines.…”

Hypervalent iodine-mediated synthesis and late-stage functionalization of heterocycles

“…Chang and co-workers prepared 2-aryl-1-pyrrolines 127 by treating 1-arylcyclobutanecarboxamides 126 with (PhI(OCOCF3)2) 120 via Hofmann rearrangement-ring expansion cascade reaction (Scheme 30). 68 Substrates 126 with aromatic ring bearing ortho-, meta-and para substituents reacted cleanly under mild conditions to deliver products in 35-95% yields. However, substrates with electron withdrawing groups delivered products in lower yields.…”