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

Abstract

Marine odorants represent a minor yet diverse class of substances within the fragrance industry, of which 7‐methyl‐2H‐1,5‐benzodioxepin‐3(4H)‐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).

Synthesis and Qualitative Olfactory Evaluation of Benzodioxepine Analogues

“…The yields and purities of 3 -11 are given in Table 1. The 1 H-and 13 C-NMR resonances of CH 2 (2) and CH 2 (4) and the fusion atoms C(5a) and C(9a) for all analogues 3 -11 were verified with HMQC and HMBC data. Scheme a) NH 2 OH · HCl, AcONa, H 2 O/MeCN, 508, 24 h; 94% of 3. b) NaBH 4 , H 2 O/MeOH, r.t., 4 h; 89% of 4. c) CH(OMe) 3 , MeOH, cat.…”

Heiße Luft oder cooler Duft? Die Trends der letzten 20 Jahre in der Riechstoffchemie

“…[55] Füre inige strukturell verwandte Inhaltsstoffe siehe Abschnitt 7.2. Die Anfänge des marinen Trends haben wir bereits in unserem letzten Aufsatz behandelt, [1] und Calon 1951 (58) wurde tatsächlich zum Inbegriff der 1990er und frühen 2000er Jahre -p rominent herausgearbeitet in "Hugo Element" (Hugo Boss,2 009) und in "fluo_ral" (Nomenclature,2 019). Es gibt sogar einen Raumduft namens "Calone 17" (Le Labo, 2015), so dass 58 von vielen Menschen mit funktionalen und synthetischen Attributen assoziiert wird.…”

“…Interessanterweise besitzen einige marine Riechstoffe unerwartete süß-würzige Va nille-Nebennoten. Diese sind sogar der Hauptcharakter des Aldehyds 63 (Abbildung 7), [58] der eine offensichtliche strukturelle ¾hnlichkeit mit Va nillin aufweist ( [59] Um diese Doppelbindungseffekte zu berücksichtigen, musste das Olfaktophor-Modell in Abbildung 9 überarbeitet werden, was zu einer beeindruckend guten Korrelation zwischen gemessenen und berechneten Schwellenwert-Daten führte (Abbildung 7).…”

Structure–Activity Relationships in the Domain of Odorants Having Marine Notes

“…This domain was later revisited, [2][3][4][5][6][7][8][9][10][11] and now compounds such as Transluzone (1b), Aldolone ® (1c), and Azurone ® (1d) are produced on a ton scale by Firmenich and Givaudan, and used in fine fragrance as well as in body-and home-care products (e.g., shower products, air fresheners, and powder detergents).…”