Application of the Brook Rearrangement in Tandem with Single Electron Transfer Oxidative and Radical Processes

Abstract

Merging rearrangement with radical reactions is a largely unexplored field but may hold promise for approaching scaffolds that are inaccessible by other methodology. Here a tandem nucleophilic substitution/Brook rearrangement/singleelectron transfer oxidation/radical oxygenation strategy is presented, through which α,γ-dioxygenated ε, -unsaturated amides are efficiently prepared in a single step from enantiomerically enriched allylepoxides and 2-silylacetamides. The resulting compounds can be easily transformed by persistent [a] 2854 radical effect-based 5-exo-trig or 6-endo-trig radical cyclization reactions to functionalized carbocycles bearing three or four stereocenters. The stereochemical outcome of the cyclization reactions can predicted by the Beckwith-Houk model. The cyclic compounds can be easily diversified by post-cyclization modifications. The tandem process can be further extended by an acylation step leading to -dicarbonyl enolates, which were also transformed to cyclopentane and cyclohexane derivatives under oxidative conditions. Scheme 1. (A) Connectivity change and chirality transfer in a sigmatropic rearrangement. (B) Anionic rearrangement types. (C) Known rearrangementradical reaction sequences and the proposed strategy.atom has been recently frequently used to trigger further nucleophilic transformations with alkyl halides, [13] epoxides, [14] al-Full Paper

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

“…Amides with a terminal alkene unit furnished dioxygenated pyrrolidones 12a–f , h – j as products, amides 9g , k with trisubstituted alkene units exclusively lead to isopropenylpyrrolidones 12g , k . A similar reactivity was observed before in thermal radical cyclizations leading to cyclopentane derivatives [ 74 – 75 ]. All γ-silyloxy amides 9a – k cyclize in the 5- exo mode via envelope transition states 21a – k in which both the amide resonance and the resonance of the radical with the carbonyl group are disturbed [ 83 – 84 ].…”

“…In a similar manner as described in [ 74 ]: LiCl (252 mg, 6 mmol) was added to a round-bottomed flask containing a stirring bar, which was sealed with a septum, and dried under vacuum by a heat gun. Dry THF (8 mL) and amide 8 (1.0 mmol) were added under argon.…”

“…Recently, we became interested in merging sigmatropic rearrangements with radical oxygenation reactions since profound changes in the connectivity patterns during both reaction modes will potentially significantly simplify the access to complex target molecules [ 74 – 75 ]. The principle is illustrated for a merger of nucleophilic opening of allylepoxides 1 with silylacetamides 2 /Brook rearrangement [ 76 – 78 ] and oxygenation with TEMPO ( 3 ) leading to γ-(silyloxy)-α-(aminoxy)amides 5 , which can be subsequently subjected to thermal radical cyclization reactions according to the persistent radical effect [ 79 – 80 ] forming functionalized cyclopentanes 6 ( Scheme 1B ).…”

Organic Synthesis Using Nitroxides

“…Instead of Li amides, ester enolates were also implemented as nucleophiles in the initial Michael addition, and after oxidative radical cyclization, cyclopentanes 1212,1213 were obtained. In addition, precursors for cyclopentanes were constructed by nucleophilic addition to epoxides and subsequent Brook rearrangement 1214 or through nucleophilic 1,2-addition to α,β-unsaturated aldehydes followed by ruthenium-catalyzed olefin isomerization. 1215 The applicability and relevance of such oxidative sequences were proven by imbedding such a cascade into the total synthesis of 15-F 2t -isoprostane.…”

Chemoselective γ‐Oxidation of β,γ‐Unsaturated Amides with TEMPO

“…Intriguingly, when a monosubstituted olefin ( 2 v ) was utilised as an acceptor, an OTMP‐transfer cyclisation product ( 4 d ) was obtained in 62 % yield rather than the previously observed alkene (Scheme 4 b‐ 4 ). [ 25a , 26 ]…”