Lewis Acid Mediated Nucleophilic Substitution Reactions of 2-Alkoxy-3,4-dihydro-2H-1-benzopyrans: Regiochemistry and Utility in the Synthesis of 3,4-Dihydro-2H-1-benzopyran-2-carboxylic Acids

Article abstract of DOI:10.1021/jo00275a010

The Lewis acid mediated nucleophilic substitution reactions of a variety of 2-alkoxy-, 2-hydroxy-, and 2-(acyloxy)-3,4-dihydro-2H-1-benzopyrans (chromans) have been studied within the context of developing new synthetic routes to chroman-2-carboxylic acids, certain of which have utility as antioxidants and drug intermediates.The scope and limitations of these transformations have been determined.Treatment of 2-methoxychromans in the α-tocopherol structural class (9, 25) with cyanotrimethylsilane in the presence of TiCl4 or BF3 etherate generally leads in good yield to the desired 2-cyanochromans 10 and 26.On the other hand, ketals of the type 19 react less efficiently, giving poor to moderate yields of the cyanochromans 36 along with regioisomeric products (37, 38).Spiro-fused ketals such as 28 exhibit dichotomous behavior dependent on the Lewis acid employed, while the pyranochroman 34b affords 35 in good yield.Thus the regioselectivity of these processes appears to be highly dependent on substrate structure and the nature of the Lewis acid.