Synthesis and SAR of 2,3-Dihydro-1-benzofuran-4-carboxylates: Potent Salicylic Acid-Based Lead Structures against Plant Stress

New 2,3-dihydro-1-benzofuran-4-carboxylic acid derivatives have been identified as potent lead structures against drought and cold stress in crops starting from the synthetic exploration of stabilized analogs of the natural product lunularic acid. An optimized Lewis-acid mediated cyclization gave a short and efficient access to the envisaged 2,3-dihydro-1-benzofuran-4-carboxylates. Enantioselective approaches were investigated to assess the potential impact of the chiral center on in vivo activity. Whilst 2,3-dihydro-1-benzofuran-4-carboxamides and 2,3-dihydro-1-benzofuran-4-carboxylates carrying phenyl substituents with electron-withdrawing groups exhibited only low to moderate in vivo activity, the corresponding 2,3-dihydro-1-benzofuran-4-carboxylates carrying optimized electron-donating substituents in the phenyl moiety revealed strong in vivo activity, both against drought stress in several broad-acre crops, as well as against cold stress in corn. Remarkably, several 2,3-dihydro-1-benzofuran-4-carboxylates showed stronger efficacy than the internal standards used in our in vivo SAR study.