An investigation into the synthesis of azido-functionalised coumarins for application in 1,3-dipolar “click” cycloaddition reactions

Abstract

A range of reported methods have been assessed for the synthesis of two coumarin fluorophores containing azides, 1a and 2, for subsequent "click" modification. In the case of 1a reported methods were successfully applied, but the resulting azide proved to be rather unstable and appears more suited to in-situ generation and conversion to the "click" triazole. In the case of 2, reported methods for the synthesis of precursor 5 were ineffective in two cases and resulted in either no bromination -to the carbonyl or the formation of multiple unwanted side-products, some of which were isolated, 6-13. The use of CuBr 2 in excess or Br 2 in 50% HBr in acetic acid did result in the isolation of 5, which could be efficiently converted to 2 using excess NaN 3 in THF.

Coumarin: A Natural, Privileged and Versatile Scaffold for Bioactive Compounds

“…Many azidocoumarins have been prepared [ 80 , 81 ] as fluorescent reagents for the synthesis of substituted 1,2,3-triazoles through the 1,3-dipolar click cycloaddition. Evans and coll.…”

“…Evans and coll. [ 80 ] have reported the preparation of a series of 7- N -alkyl and N , N -dialkylamino coumarins 14 ( Scheme 7 ) bearing an azidoacyl group at position 3, starting from the corresponding 3-acylcoumarins.…”

3-(Bromoacetyl)coumarins: unraveling their synthesis, chemistry, and applications

“…Evans and coworkers 58 reported the synthesis of coumarin fluorophore bearing an azidoacyl group 19 via the treatment of 3-(bromoacetyl)coumarin 1 with sodium azide (NaN 3 ) 18 at tetrahydrofuran ( Scheme 10 ).…”