A Convenient and Improved Baylis-Hillman Synthesis of 3-Substituted 2H-1-benzopyran-2-ones

Abstract

Halogen acid-catalysed deprotection and cyclisation of Baylis-Hillman products obtained using O-benzylated salicylaldehyde precursors has been shown to afford 3-(halomethyl)coumarins (3-halomethyl-2H-1-benzopyran-2-ones) chemoselectively and in good yield.

Efficient and Chemoselective Access to 3-(Chloromethyl)coumarins via Direct Cyclisation of Unprotected Baylis-Hillman Adducts

“…7 Concd HCl (4 mL) was added to a solution of 12a (0.51 g, 2.0 mmol) in HOAc (2 mL). The mixture was boiled under reflux for 2 h, allowed to cool to r.t. and then poured into ice-cooled H 2 O (10mL).…”

“…1 Recently reported examples include: coumarin-7-xylosides, as oral anti-thrombotic agents; 2 synthetic analogues of the naturally-occuring anti-bacterials, novobiocin and clorobiocin; 3 and khellactone derivatives as potential HIV-1 inhibitors. 4 Various syntheses of coumarin derivatives have been developed 5 and, in recent communications, 6,7 we have reported the application of Baylis-Hillman methodology in the preparation of 3-substituted coumarins.…”

“…Cyclisation to the chromenes via conjugate addition (Path I; Scheme 1) was prevented by nucleophilic interception of the electrophilic vinylic centre through the addition of either an amine (benzylamine or piperidine) 6 or a halogeno acid. 7 Subsequent removal of the O-benzyl protecting group and cyclisation via acyl substitution then afforded the 3-substituted coumarins 7, 8, 9 or 10 (Scheme 2). We now report an application of Baylis-Hillman methodology in which 3-(chloromethyl)coumarins are produced chemoselectively without any recourse to the use of protecting groups.…”

“…Full characterisation of the 3-(halomethyl)coumarins 9 and 10, prepared in this study, has been reported previously. 6,7 The general synthetic procedures are illustrated by the following examples.…”

The Skeleton Construction and Pharmaceutical Activity of Coumarins

“…1, type 2) Cyclic condensation reaction of carbonyl compounds with phenol derivatives is a general method in organic synthesis. To obtain various types of coumarins, Knoevenagel [16], Perkin [17], Wittig and Horner-Wittig [18], Pechmann [19], Ponndorf [20], Houben-Hoesch [21], Baylis-Hillman [22], Wittig and Reformatsky methodology [23] have been used [24]. Also cylic condensation reactions include the condensation of ohydroxyacetophenones with diethyl carbonate.…”