A Facile Synthesis of 4-Hydroxycoumarin and 4-Hydroxy-2-quinolone Derivatives

Coumarin derivatives possessing diverse biological activities play important roles as versatile building blocks for the synthesis of natural products and biologically active compounds. In particular, 4-hydroxycoumarin derivatives, such as 4-hydroxycoumarin and 4-hydroxythiocoumarin, have been used as useful intermediates for the synthesis of anticoagulants, herbicides, and anticancer agents. Recent reports show 4-hydroxy-2-quinolone derivatives are selective glycine site antagonists related to several central nervous system disorders including stroke, epilepsy, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Furthermore, coumarin derivatives, possessing a hetrocyclic skeleton with a ring oxygen on a carbonyl group, are well-known fluorescence dyes for their high photoluminescence quantum efficiencies. A number of coumarins have been synthesized and explored the possibility of their application to electrooptic materials, such as laser dyes, organic scintillators, and photoelectonic sensitizers. The Pechman reaction is the method widely applied, in a practical sense, for synthesizing coumarins as it involves the condensation of phenols with β-ketoesters in the presence of a variety of Lewis acid catalysts and gives good yields of 4substituted coumarins. In variation, 4-hydroxythiocoumarins were prepared by heating excess thiophenol and malonic acid with POCl3 at 110-115 C and cyclizing the resulting dithiophenylmalonic esters in the presence of AlCl3 at 180190 C. Also, 4-hydroxycoumarins and 4-hydroxy-2-quinolones were similarly prepared from diarylmaonates (ZnCl2 and POCl3, 30 h, 202-204 C) and dianilides (AlCl3 and NaCl, 250 C; polyphosphoric acid, 158-160 C), respectively. This method suffers from several disadvantages such as harsh reaction conditions; use of excess substrate like thiophenol, a large amount of promoters, elevated reaction temperature and long reaction time. Recently, 2-mercaptobenzoic acid or 2'-mercaptoacetophenone has been used for the synthesis of 4-hydroxythiocoumarin derivatives utilizing multi-steps or expensive reagents, respectively. We envisioned that preparation of half malonic acid 3a-c would offer most concise synthetic route to 4-hydroxycoumarin derivatives 4a-c, as shown in Scheme 1. Aminolysis of Meldrum’s acid 2 with aniline would give the half acid 3a, which cyclize in the presence of Lewis acid to afford 4-hydroxy-2-quinolone 4a. Herein, we report a facile synthesis of 4-hydroxycoumarin derivatives starting from cheap materials, such as phenol and malonic acid. Ring opening of Meldrum’s acid 2 with aniline and phenol gave the monoanilide 3a in 86% and the monoester 3b in 92% isolated yield, respectively, under solvent-free conditions at 85-90 C. However, the yield of 3c was quite low due to the rapid formation of dithiophenyl ester in the initial conditions, while the rate was very sluggish in the lower temperatures. Hence the influence of bases or additives on the hydrolysis of 2 in varying solvents was investigated. The addition of bases/additives (K2CO3 or Cs2CO3; DMAP or CsF) was proven to be useless, while facilitated the formation of dithioester. As shown in Table 1, aprotic polar solvents such as THF or 1,4-dioxane were found to be efficient to suppress the formation of dithioester. However, DMF exclusively facilitated the formation of dithioester. The best choice was found to be 1,4-dioxane in term of yield of 3c (entry 6). Previously, 4-hydroxythiocoumarins were prepared by Scheme 1