Unexpected Direct Synthesis of N‐Vinyl Amides through Vinyl Azide–Enolate [3+2] Cycloaddition

Abstract

The unexpected synthesis of industrially important N-vinyl amides directly from aldehydes and a,b-unsaturated N-vinyl amides from esters is reported. This reaction probably proceeds through an initial [3+ +2] azide-enolate cycloaddition involving av inyl azide generated in situ. As urvey of the reaction scope and preliminary mechanistic findings supported by quantum computational analysis are reported, with implications for the future development of atom-efficient amide synthesis.I ntriguingly,t his study suggests that (cautious) reevaluation of azidoethene as as ynthetic reagent may be warranted. Scheme 2. Azide-enolate [3+ +2] cycloaddition reactions implicated in amide and triazoline synthesis. LDA = lithium diisopropylamide, LHMDS = lithium hexamethyldisilazide. Scheme 1. Industrially important N-vinyl amides 1 and 2. [3a]

N-Vinyl Acrylamides: Versatile Heterobifunctional Electrophiles for Thiol–Thiol Bioconjugations

“…We began our investigation with the preparation of heterobifunctional N -vinyl acrylamide linker 1 via a base-catalyzed cycloaddition/rearrangement strategy following the previously published protocol by our group (Scheme ). Briefly, nucleophilic substitution of azide on 2-bromoethan-1-ol 2 followed by tosylation of 3 and iodination of 4 afforded azidoiodide 5 . Vinyl azide was then formed in situ , which participated in 1,3-dipolar cycloaddition with enolate anion 6 – (formed from methyl isobutyrate 6 under basic conditions), resulting in triazoline 7 , which then rearranges to give N -vinyl acrylamide 1 in 52% yield accompanied by extrusion of N 2 .…”

“…N-Vinyl acrylamides possess both an α,β-unsaturated Michael acceptor that is amenable to thia-Michael addition and a vinyl amide functionality that can be exploited for participation in a radical thiol−ene "click" reaction (Scheme 1A). 29 Importantly, linkers possessing minimal functionality such as amide bonds are expected to minimally perturb target binding relative to large, unnatural moieties.…”

Carborane‐Containing Matrix Metalloprotease (MMP) Ligands as Candidates for Boron Neutron‐Capture Therapy (BNCT)

“…[13,33] The preparation of the requisite carboranyl propyl azide is shown below in Scheme 2. Formation of 1-azido-iodopropane was accomplished based on literature precedent, [34] which entailed S N 2 reaction of sodium azide and 1-bromo-3-chloropropane in DMF providing a 95 % mass balance of 1-azido-3-chloropropane as the major product along with 1 H NMR showing a 85 : 15 mixture of chloro/bromo which was taken forward without further purification. The crude 1-azido-3-halopropane was subjected to Finkelstein conditions using sodium iodide in acetone that generated pure 1-azido-3iodopropane in 81 % isolated yield after filtration through a plug of silica gel.…”

“…1‐Azido‐3‐iodopropane (13) : According to the general precedent, to a 1000 mL 3‐necked round bottomed flask was added 19.35 g of sodium iodide, 7.5 g of crude 1‐azido‐3‐chloropropane and 190 mL of acetone. The vessel was purged with dry nitrogen, covered with aluminum foil, and heated to 52 °C.…”

“…TBDMS propyl azido carborane 15 : According to a general precedent, to a dry 100 mL round bottomed flask under a nitrogen atmosphere was added anhydrous THF (18 mL) and 1 M LiHMDS (9.7 mL). The mixture was cooled to −78 °C.…”