Asymmetric Azidation under Hydrogen Bonding Phase-Transfer Catalysis: A Combined Experimental and Computational Study

Area of Science:

• Organic Chemistry
• Asymmetric Catalysis
• Synthetic Methodology

Background:

• Enantioenriched nitrogen-containing molecules are crucial building blocks in pharmaceuticals and agrochemicals.
• Existing asymmetric catalytic azidation methods often rely on expensive or hazardous azide sources.
• Sodium azide, an inexpensive and readily available reagent, has been underexplored in enantioselective azidation reactions.

Purpose of the Study:

• To develop a novel asymmetric catalytic azidation method utilizing inexpensive sodium azide.
• To investigate the application of hydrogen bonding phase-transfer catalysis (HB-PTC) for enantioselective azidation.
• To explore the activation of sodium azide through HB-PTC for the synthesis of chiral nitrogen-containing compounds.

Main Methods:

• Asymmetric ring opening of meso-aziridinium electrophiles derived from beta-chloroamines using sodium azide.
• Employing a chiral bisurea catalyst to facilitate hydrogen bonding phase-transfer catalysis.
• Structural and mechanistic investigations using computational analysis, X-ray diffraction, and NMR spectroscopy (1H and 14N/15N).

Main Results:

• Successful enantioselective azidation of meso-aziridinium electrophiles with sodium azide was achieved.
• A chiral bisurea catalyst, specifically N-isopropylated BINAM-derived bisurea, was found to be effective.
• Structural studies revealed favorable end-on binding of the azide anion to the catalyst, with computational analysis supporting attack from the hydrogen-bonded end in the transition state.
• Kinetic studies indicated that the turnover rate is limited by the formation of a chiral ion pair and is inhibited by NaCl accumulation.

Conclusions:

• Hydrogen bonding phase-transfer catalysis (HB-PTC) is a viable activation mode for inorganic salts beyond metal alkali fluorides in asymmetric synthesis.
• This work expands the utility of inexpensive sodium azide in enantioselective azidation reactions.
• The developed methodology provides a new route to enantioenriched nitrogen-containing molecules.