Seven-membered ring annulation and spiro-annulation processes via preparation and thermal rearrangement of β-(2-vinylcyclopropyl) α,β-unsaturated ketones

Abstract

Treatment of the β-iodo enones 4 and 26–28 with lithium (phenylthio)(2-vinylcyclopropyl)cuprate (21, mixture of epimers), followed by thermolysis (180 °C, 30–45 min) of the initially formed β-(2-vinylcyclopropyl) enones, provided excellent yields of the seven-membered ring annulation products 25 and 30–32, respectively. In similar fashion, the (E)-2-(iodomethylene)cycloalkanones 8 and 29 were transformed efficiently into the spiro-annulation products 34 and 35 respectively. When compound 36 was treated with bromoform – sodium hydroxide in the presence of a phase-transfer catalyst, the dibromocyclopropane 37 was produced. The latter substance served as the starting material for a sequence of reactions (hydrolysis with hydrochloric acid in methanol, 37 → 38; oxidation with pyridinium chlorochromate, 38 → 39; Wittig reaction with methylenetriphenylphosphorane, 39 → 40; reduction with zinc in acetic acid, 40 → 41) culminating in the stereoselective formation of cis-1-bromo-2,2-dimethyl-3-vinylcyclopropane (41). On the other hand, treatment of compound 37 with n-butyllithium (ether, −90 °C), followed by protonation of the presumed intermediate 43 and hydrolysis of the resultant product 44, provided the bromo alcohol 45 in 70% yield. The latter substance was converted into trans-1-bromo-2,2-dimethyl-3-vinylcyclopropane (47). When the cuprate reagents 42 and 48 (prepared from the bromocyclopropanes 41 and 47, respectively) were allowed to react with the iodo enones 4 and 26, the β-(2-vinylcyclopropyl) α,β-unsaturated ketones 49, 52, 54, and 56 were produced in high yields. The enone 49, upon thermolysis in refluxing n-hexane, underwent facile Cope rearrangement to produce the annulation product 50 quantitatively. In contrast, the homolog 54 was notably resistant to [3,3]-sigmatropic rearrangement and, upon thermolysis in o-xylene, o-dichlorobenzene, or collidine at elevated temperatures produced, in varying ratios, the Cope rearrangement product 55 and the isomerization product 56. Thermal rearrangement (o-dichlorobenzene, 220 °C, sealed tube) of trans-3-(2,2-dimethyl-3-vinylcyclopropyl)-2-cyclohexen-1-one (52) provided the annulation product 51 (59% yield). In contrast, the corresponding homolog 56, under very similar conditions, produced only a minor amount of the annulation product 55. In this case, the major product (trienone 57) was that resulting from a [1,5]-sigmatropic hydrogen migration (ratio of 55/57 ≈ 1:4).

Preparation and thermal rearrangement of trans-3-[1-methyl-2-(2-methyl-1-propenyl)cyclopropyl]-2-cyclohexen-1-one. A synthesis of (±)-[β-himachalene

“…In principle, based on the work reported in the accompanying paper (5), the key step of the projected synthesis of (? )-P-himachalene (2) could involve thermal rearrangement of either of two possible substrates, cis-3-[l-methyl-2-(2-methyl-1 -propenyl)cyclopropyl]-2-cyclohexen-1 -one (1 1) or the corresponding tratzs isomer 18 (see Scheme I).…”

“…Thus, for example, treatement of 3-iodo-2-cyclohexen-I-one (4) with the substituted cyclopropylcuprate reagent 10 (presumably derived from the requisite bromide 9) should afford the intermediate 11. The latter substance would be expected (5) to undergo Cope rearrangement at, or slightly above, ambient temperatures to afford the required bicyclic dienone 12. Reductive removal of the "extra" double bond in 12, and use of the carbonyl group as a "handle" for introduction of the necessary methyl group and the alkene function would provide (2)-P-himachalene (2).…”

“…Under these conditions, a photo-induced equilibration between 20 and the isomeric material 22 occurs and, although compound 20 is thermally stable at 98"C, the isomer 22 readily undergoes Cope rearrangement at this temperature. This elegant procedure niight also be applicable to the conversion of 18 into 12, if high temperature thermolysis of 18 were to produce significant amounts of product 19, resulting from a [1,5]-sigmatropic hydrogen migration.…”

“…ally smooth and efficient (5). We report herein the application of this new annulation procedure to a total synthesis of racemic P-himachalene (2).…”

“…J. Chem. 61, 1239( 1983.A total synthesis of the scsquiterpenoid (2)-P-himachalene (2) is described. Treatment of 5.5-dimethyl-2-vinyl-1.3-dioxane (24) with brornoform and aqueous sodium hydroxide in the prcscncc of a phase-transfcr catalyst afforded the dibromocyclopropane 25.…”