Synthesis of Benzodioxepinone Analogues via a Novel Synthetic Route with Qualitative Olfactory Evaluation

Marine odorants represent a minor yet diverse class of substances within the fragrance industry, of which 7‐methyl‐2 H ‐1,5‐benzodioxepin‐3(4 H )‐one ( 1 ) is commercially known as Calone 1951 ® , a synthetic first in the area of marine‐fragrance chemistry. To determine the extent to which the characteristic marine odor of Calone 1951 ® corresponds to the substitution at the benzo portion of the molecule, a variety of aromatic substituents were incorporated into the benzodioxepinone structure ( Scheme 1, Table 3 ). In light of the difficulty experienced in applying patented literature to deriving the analogues 12 – 18 , particularly those with electron‐withdrawing substituents, an alternative synthetic scheme was implemented for the construction of all analogues in favorable yields ( Scheme 4, Table 3 ). Formation of the hydroxy‐protected dihalo alkylating agent 24 via epoxide cleavage of epichlorohydrin ( Scheme 3 ) allowed etherification favoring dihalo displacement and subsequent intramolecular ring closure (→ 26a – g ). THP Deprotection followed by oxidation of the alcohols 27a – g to the ketones 12 – 18 provided a general pathway to the benzodioxepinone products. The influence of the substituent nature on odor activity revealed a diverse scope of olfactory character ( Table 4 ).