Beyond Monoaddition: Stereodivergent Ethyl Acetate Enolate Additions to N-tert-Butanesulfinyl Imines toward Chiral 1,3-Bis-sulfinamide Ligands and Diamines

Introduction

The addition of ester enolates to N-tert-butanesulfinyl imines is a powerful entry to β-aminoester scaffolds. Beyond monoaddition, ethyl acetate enolate provides access to 2-ethoxycarbonyl-1,3-bis-sulfinamides, valuable as chiral ligand scaffolds for asymmetric catalysis and as precursors of chiral 1,3-diamines. This work analyses the stereochemical variables governing this sequential monoaddition/double-addition manifold.

Methods

The reaction of a 2-naphthyl-N-tert-butanesulfinylimine with ethyl acetate/LHMDS in THF at −78°C was used as a model. The influence of base loading, imine/ester stoichiometry and order of addition were assessed. The second addition was examined through one-pot and stepwise protocols using isolated mono-sulfinamide diastereomers. Configurations were assigned by NMR and X-ray diffraction. Selected bis-sulfinamides were desulfinylated with HCl/dioxane to afford diamine hydrochlorides.

Results

Monoaddition displayed a protocol-dependent stereochemical switch. In situ enolate generation favored the (R_S,S_C)-mono-adduct, whereas preformed-enolate or excess LHMDS favored the epimeric (R_S,R_C)-product. In double-addition manifold, excess sulfinylimine enabled formation of configurationally defined 2-ethoxycarbonyl-1,3-bis-sulfinamides. The optimized one-pot protocol afforded a non-C₂-symmetric bis-sulfinamide, while stepwise experiments showed access to both C₁- and C₂-symmetric derivatives depending on the configuration of the mono-adduct and sulfinylimine. Acidic desulfinylation furnished chiral 1,3-diamine-hydrochlorides.

Conclusions

Ethyl acetate enolate addition to N-tert-butanesulfinylimines is a stereodivergent platform for accessing configurationally defined 1,3-bis-sulfinamide ligand scaffolds and their corresponding chiral 1,3-diamines.

Acknowledgment

This work was supported by Ministerio de Ciencia,Innovación y Universidades (grant number PID2019-104767RB-I00/AEI/10.13039/501100011033), and Consejería de Economía, Conocimiento,Empresas y Universidad, Junta de Andalucía (grant number:US-1381590).