S y n t h e s i s o f S u b s t i t u t e d 2 -H y d r o x y m e t h y l -2 -m e t h y l -2 H -c h r o m e n e sAbstract: A new and efficient three step procedure for the synthesis of functionalized 2H-chromenes 1 is described, starting from commercially available salicylaldehydes 2 and 2-methylpropenylmagnesium chloride 3, which involves catalytic acid-mediated intramolecular cyclization of phenolic epoxide 5 as the key step.Synthesis of Substituted 2-Hydroxymethyl-2-methyl-2H-chromenes 2H-Chromenes are key heterocyclic units in many natural and biologically polyoxygenated active compounds. 1 Moreover, they are widely employed as useful intermediates in the synthesis of medicinal agents such as cordiachromene, 2 potassium channel activating drugs 3 and a range of tannins. 4 A common building block for the synthesis of such structures is 2-hydroxymethyl-2-methylchromene 1 (Scheme 1).
Scheme 1Although several methods have been reported in literature 5 for the construction of such various 2,2-dialkylchromene skeletons, only few direct preparations of 2-functionalized chromenes have been described. 2,6 We herein report a new and facile route to diverse 2-hydroxymethyl-2-methylchromenes 1, starting from commercially available salicylaldehydes 2, which involves the cyclization of 5, a nucleophilic epoxide opening reaction as the key step. The synthetic strategy requires the preparation of epoxides 5, whose aryl ether-forming reaction provides chromenemethanols 1 via a (6-exo) mode of cyclization, followed by an intramolecular dehydratation reaction (Scheme 2).Preparation of epoxide 5 is outlined in Scheme 3. The treatment of salicylaldehydes 2 with an excess of 2-methylpropenylmagnesium chloride 3 in THF afforded the corresponding homoallylic alcohols 4 in good to excellent yields (Table 1). For the preparation of key epoxides 5, homoallylic alcohols 4 were subjected to standard epoxidation with m-CPBA in CH 2 Cl 2 . The reaction was carried out at 0 °C for 4 hours. Purified by column chromatography on silica, the corresponding epoxides 5a-d were obtained in a 70-75% yield. It will be noteworthy that in the case of compounds 4e,f, m-CPBA epoxidation leads to epoxides 5e,f in only 20-30% yields. These low yields are due to the instability of compounds 5e,f on silica. To improve these yields, phenolic groups of compounds 2e,f were protected by the TBS group, 7 then allylmetallation and epoxidation reactions were successful (Table 1, entries 7 and 8). Subsequent O-silyldeprotection of 5g,h with TBAF 7 gave corresponding phenolic epoxides 5e,f in quantitative yields. These epoxides were, then, immediately used in the next step without further purification. (3), THF, -20°C. ii) m-CPBA, CH 2 Cl 2 , 0 °C.
Scheme 3 Reagents and conditions i) CH 2 =C(CH 3 )CH 2 MgClIn the last step (Scheme 4), the crucial cyclization of epoxides 5a-e with AlCl 3 (2 equiv) in THF at 0 °C did not give the expected chromanemethanols 1a-e but instead bicyclic compounds 7a-e. The naphthalene derivative 5f leads, under these conditions, to the expec...
