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. 2021 Oct 19;13(1):44-49.
doi: 10.1039/d1sc05315a. eCollection 2021 Dec 22.

General stereoretentive preparation of chiral secondary mixed alkylmagnesium reagents and their use for enantioselective electrophilic aminations

Alexander Kremsmair  1 , Henrik R Wilke  1 , Matthias M Simon  1 , Quirin Schmidt  1 , Konstantin Karaghiosoff  1 , Paul Knochel  1
Affiliations

General stereoretentive preparation of chiral secondary mixed alkylmagnesium reagents and their use for enantioselective electrophilic aminations

Alexander Kremsmair et al. Chem Sci. .

Abstract

A general preparation of enantiomerically and diastereomerically enriched secondary alkylmagnesium reagents was reported as well as their use for performing highly stereoselective transition-metal free electrophilic aminations leading to α-chiral amines in up to 97% ee. Thus, the reaction of t-BuLi (2.2 equiv.) with a mixture of chiral secondary alkyl iodides and the commercially available magnesium reagent Me3SiCH2MgCl in a 2 : 1 mixture of pentane and diethyl ether at up to -50 °C provided optically enriched secondary mixed alkylmagnesium species of the type alkyl(Me)CHMgCH2SiMe3 with high retention of configuration (up to 99% ee). The resulting enantiomerically enriched dialkylmagnesium reagents were trapped with electrophiles such as non-enolizable ketones, aldehydes, acid chlorides, isocyanates, chlorophosphines and O-benzoyl hydroxylamines providing α-chiral tertiary alcohols, ketones, amides, phosphines and tertiary amines in up to 89% yield (over three reaction steps) and up to 99% ee.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Scheme 1
Scheme 1. (a) Previous preparation of chiral secondary alkyl organometallics of type 3via I/Li-exchange and subsequent transmetalation at −100 °C; (b) Barbier-type preparation of chiral secondary alkylmagnesium reagents (5) via I/Li-exchange and in situ transmetalation with Me3SiCH2MgCl at −50 °C or −78 °C.
Scheme 2
Scheme 2. Scope of optically enriched secondary alkylmagnesium reagents 5a-i and subsequent reactions with electrophiles (6a–l). Enantiomerically and diastereomerically enriched secondary alkylmagnesium reagents 5a–i prepared by an I/Li-exchange in the presence of Me3SiCH2MgCl and their reactions with electrophiles (6a–l) leading to the corresponding optically and diastereomerically enriched products 4a–r. aThe enantiomeric excess (% ee) was determined by chiral HPLC-analysis. The diastereomeric ratio (dr; syn/anti ratio) was determined by 1H-NMR spectroscopy and GC-analysis. bYield refers to isolated analytically pure compounds.
Scheme 3
Scheme 3. Scope of prepared enantiomerically and diastereomerically enriched α-chiral tertiary amines. Enantiomerically and diastereomerically enriched tertiary amines 8a–j obtained by electrophilic amination of secondary alkylmagnesium reagents 5a–i with O-benzoyl hydroxylamines (7a–g). The enantiomeric excess (% ee) was determined by chiral HPLC-analysis. The diastereomeric ratio (dr; syn/anti ratio) was determined by 1H-NMR spectroscopy and GC-analysis.
Fig. 1
Fig. 1. X-ray structure of (S)-8g crystallized as the corresponding amine hydrochloride as a representative example of the overall stereoretention of the electrophilic amination.
See this image and copyright information in PMC

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