Highly Regio- and Stereoselective Asymmetric Bromoazidation of Chiral α,β-Unsaturated Carboxylic Acid Derivatives:  Scope and Limitations

Abstract

Lewis acid catalyzed asymmetric bromoazidation of chiral alpha,beta-unsaturated carboxylic acid derivatives was performed using N-bromosuccinimide (NBS) and trimethylsilyl azide (TMSN3) as the bromine and azide sources. Among the Lewis acids, Yb(OTf)3 was found to be the best catalyst. Regio- and anti-selectivity of 100% and moderate to good diastereoselectivity (up to 89:11) with good yields were obtained when Oppolzer's bornane sultam chiral auxilairy was used. Diastereoselectivity of >95:05 was observed when (2S,5S)-2,5-diphenylpyrrolidine was used as the chiral auxiliary.

2,5‐Disubstituted Pyrrolidines as Chiral Auxiliaries in Radical Reactions: A Theoretical Approach

“…For instance, ethyl or isopropyl groups are not predicted to induce high selectivity as they behave as methyl groups with one hydrogen atom orientated towards the attacking acrylate, thus inducing weak steric interactions (Table 3). Even 2,5-diphenylpyrrolidine, [23] which has been used as a chiral auxiliary in several ionic [24,25] and radical reactions, [26] is predicted to induce selectivities (Entry 5) lower than those calculated for the smaller methyl group (Entry 1). This happens because the phenyl ring adopts an orientation that is perpendicular to the radical chain, thus reducing the steric contacts with the attacking alkene.…”

“…To the best of our knowledge, nobody has attempted such an approach with radical systems, but a paper from Hajra et al [25] shows that this approach indeed works in ionic processes, in Lewis acid catalyzed asymmetric bromoazidation reactions of chiral α,β-unsaturated carbonyl compounds with NBS and TMSN 3 . In this study, the use of (2S,5S)-2,5-diphenylpyrolidine as the chiral auxiliary yielded much better results than the Evans auxiliary or bornanesultam when using Yb(OTf) 3 as the Lewis acid.…”

“…The mechanism proposed above does not disclose a possible existence of chelated complexes in systems that can form them, but allows for a possible development of new systems based on simple molecules that can induce high stereoselectivities without the need of chelating conditions or chelating LAs. To the best of our knowledge, nobody has attempted such an approach with radical systems, but a paper from Hajra et al [25] shows that this approach indeed works in ionic processes, in Lewis acid catalyzed asymmetric bromoazidation reactions of chiral α,β-unsaturated carbonyl compounds with NBS and TMSN 3 . In this study, the use of (2S,5S)-2,5-diphenylpyrolidine as the chiral auxiliary yielded much better results than the Evans auxiliary or bornanesultam when using Yb(OTf) 3 as the Lewis acid.…”

Recent advances in stereoselective bromofunctionalization of alkenes using N-bromoamide reagents

“…The mechanism was proposed to proceed via a bromonium ion ring intermediate which was With Yb(OTf) 3 as the catalyst, Hajra and co-workers were able to achieve a highly diastereoselective bromoazidation of a,b-unsaturated carboxylic acid derivatives with the aid of chiral auxiliaries such as (2R)-bornane sultam and (2S,5S)-diphenyl pyrrolidine (Scheme 22). 44 Another interesting example was achieved via the use of Sm(OTf) 3 as the catalyst for a NBS promoted Friedel-Crafts alkylation of alkenes (Scheme 23). 45 With electron-rich aromatic rings including toluene, o-xylene, anisole, 1,2-dimethoxy benzene, and 1,2,3-trimethoxy benzene, they were able to achieve this transformation with a number of olefinic partners.…”

Trimethylsilyl Azide (TMSN3): A Versatile Reagent in Organic Synthesis

“…16 Also, bromoazidation of a,b-unsaturated carbonyl compounds has been performed with Yb(OTf) 3 as catalyst. 17 (C) Tetrabutylammonium fluoride (TBAF) has been utilized in the [3+2] cycloaddition of TMSN 3 to variously substituted 3nitrocoumarins 18 and nitroethenes 19 under solvent-free conditions in high yields. This approach is defined as an environmentally benign protocol for accessing a new class of fused triazoles.…”