Borate-catalysed direct amidation reactions of coordinating substrates

Abstract

The catalytic activity of different classes of boron catalysts was studied in amidation reactions with 4-phenylbutylamine/benzoic acid, and with 2-aminopyridine/phenylacetic acid. Whilst a simple boronic acid catalyst showed high catalytic activity with the former substrates, it was completely inactive in the latter reaction. In contrast, a borate ester catalyst was able to mediate the amidation of both substrate pairs with moderate activity. By screening a range of borate esters we were able to identify a novel borate catalyst that shows high reactivity with a range of challenging carboxylic acids/amine pairs, enabling catalystic amidation reactions to be achieved effectively with these industrially relevant compounds. The reactions can be performed on multigram scale with high levels of efficiency, and in situ catalyst generation from commercially available reagents renders the process readily accessible for everyday laboratory use. Further experiments showed that the deactivating effect of 2-aminopyridine on boronic acid catalysts was due to its ability to stabilise catalytically inactive boroxines.

Scheme 1. Time course experiments of boron catalysts in the reaction of 4-phenylbutylamine and benzoic acid.

Scheme 2. Time course experiments of boron catalysts in the reaction of 2-aminopyridine and phenylacetic acid.

Fig. 1. Additional structures of catalysts examined in Tables 1 and 2.

Scheme 3. Reaction scope of B(OAr^F)₃-catalysed amidation reactions with challenging substrates ^a 5% catalyst; ^b 2% catalyst; ^c catalyst generated in situ from 10 mol% BH₃·SMe₂ and 30 mol% Ar^FOH; ^d catalyst generated in situ from 10 mol% BH₃·SMe₂ and 20 mol% Ar^FOH; ^e reaction time 40–45 h; ^f using 10% A as catalyst; ^g purified by recrystallisation; ^h reaction time 24 h; ⁱ toluene used as reaction solvent; ^j no epimerisation observed; ^k catalyst generated in situ from 15 mol% BH₃·SMe₂ and 30 mol% Ar^FOH, 90 : 10 enantiomeric ratio; ^l reaction time 72 h.

Scheme 4. Multigram scale amidation reactions and in situ catalyst generation.

Scheme 5. (A) Complexation of boroxines with 2-aminopyridine and other amines; (B) X-ray crystal structure of the complex between phenylboroxine and 2-aminopyridine showing the key hydrogen bonding interaction (yellow).