Oxyfunctionalization of Non-Natural Targets by Dioxiranes. 5. Selective Oxidation of Hydrocarbons Bearing Cyclopropyl Moieties¹

Abstract

The powerful methyl(trifluoromethyl)dioxirane (1b) was employed to achieve the direct oxyfunctionalization of 2,4-didehydroadamantane (5), spiro[cyclopropane-1,2'-adamantane] (9), spiro[2.5]octane (17), and bicyclo[6.1.0]nonane (19). The results are compared with those attained in the analogous oxidation of two alkylcyclopropanes, i.e., n-butylcyclopropane (11) and (3-methyl-butyl)-cyclopropane (14). The product distributions observed for 11 and 14 show that cyclopropyl activation of alpha-C-H bonds largely prevails when no tertiary C-H are present in the open chain in the tether; however, in the oxyfunctionalixation of 14 cyclopropyl activation competes only mildly with hydroxylation at the tertiary C-H. The application of dioxirane 1b to polycyclic alkanes possessing a sufficiently rigid framework (such as 5 and 9) demonstrates the relevance of relative orientation of the cyclopropane moiety with respect to the proximal C-H undergoing oxidation. At one extreme, as observed in the oxidation of rigid spiro compound 9, even bridgehead tertiary C-H's become deactivated by the proximal cyclopropyl moiety laying in the unfavorable "eclipsed" (perpendicular) orientation; at the other end, a cyclopropane moiety constrained in a favorable "bisected" orientation (as for didehydroadamantane 5) can activate an "alpha" methylene CH2 to compete effectively with dioxirane O-insertion into tertiary C-H bonds. Comparison with literature reports describing similar oxidations by dimethyldioxirane (1a) demonstrate that methyl(trifluoromethyl)dioxirane (1b) presents similar selectivity and remarkably superior reactivity.

Continued Progress towards Efficient Functionalization of Natural and Non‐natural Targets under Mild Conditions: Oxygenation by C−H Bond Activation with Dioxirane

“…The cyclopropyl moiety,i fsuitably oriented, can have am arked influencei na ctivating proximal a-CÀHb onds in polycyclic alkanes possessingas ufficiently rigid framework towards oxyfunctionalization by dioxirane 1b.F or example, we demonstrated that hydrocarbon CÀHb onds positioned a to ac yclopropaner ing might become activated towardd ioxirane O-insertion. [9,37] Treatmento fB inor S( 5) [38] with TFDO provided the ketone product deriving from C 6 ÀHm ethylene oxidation in 39 %y ield, [38a] along with productse xpected from preferential hydroxylation at bridgehead CÀHb onds (Scheme 6). [9, 38a] In the oxidation of 5,t he regioselectivity observed was rationalized on the basis of frontier molecular orbital (FMO) theory, according to Bach's model for oxygen insertion into hydrocarbon CÀHb onds by electrophiles and dioxirane.…”

“…Indeed, the rich-in-p character of the cyclopropaner ing orbitals are constrained by the rigid structure to lay in the favorable bisected orientation with respect to the pc omponent of the a methylene CÀH bonds;t he latter po rbitals interact with the dioxirane empty s* O-O orbitali no xenoid oxygen insertion by dioxirane ( Figure 2). [25,37] Such cyclopropyla ctivation can be cited to rationalize the preferential oxidation at the vicinal position of the spirooctane (8)a nd 2,4-didehydroadamantane (9), leaving the cyclopropane CÀCbonds intact (Scheme 7). [37] In the case of spiro adamantanylcyclopropane (10), the hydroxylation occurs at C 5 ÀHe xclusively,b ecause the p-orbital component of the C 3 ÀHa nd C 1 ÀHb onds is constrained in the unfavorable eclipsed arrangementw ith respectt ot he cyclopropaner ing ( Figure 2).…”

“…[25,37] Such cyclopropyla ctivation can be cited to rationalize the preferential oxidation at the vicinal position of the spirooctane (8)a nd 2,4-didehydroadamantane (9), leaving the cyclopropane CÀCbonds intact (Scheme 7). [37] In the case of spiro adamantanylcyclopropane (10), the hydroxylation occurs at C 5 ÀHe xclusively,b ecause the p-orbital component of the C 3 ÀHa nd C 1 ÀHb onds is constrained in the unfavorable eclipsed arrangementw ith respectt ot he cyclopropaner ing ( Figure 2). [37,38] Scheme5.O-insertion into the CÀHb ond with dioxirane.…”

Three‐Membered Heterocycles. Structure and Reactivity

“…In general, tertiary sites are preferred to secondary, a phenomenon underscored by the oxidation of adamantane (843) with excess TFD, in which only tertiary sites are affected [817]. In a selectivity study, Curci and coworkers [818] found that these bridgehead sites were also preferred to cyclopropane methylene positions, as demonstrated by the smooth conversion of the spiro cyclopropyladamantane 846 into the monohydroxy derivative 847.…”

Methy(trifluoromethyl)dioxirane (TFD): A Powerful and Versatile Oxidant in Organic Synthesis

“…Exemplary transformations are the monohydroxylation of alkanes, 2 chemoselective oxidation of allylic alcohols, 3 optically active sec,sec-1,2-diols 4 and simple sulfides, 5 oxyfunctionalization of unactivated tertiary and secondary C-H bonds of alkylamines 6 and aliphatic esters, 7 epoxidation of primary and secondary alkenylammonium salts 8 and chiral camphor Nenoylpyrazolidinones, 9 oxidative cleavage of acetals, ketals 10 and aryl oxazolines, 11 and conversion of cyclic ethers into lactones. 10 It is also found to be a useful reagent for the oxyfunctionalization of natural [12][13][14] and nonnatural [15][16][17][18][19] targets, which include the direct hydroxylation at the side-chain C-25 of cholestane derivatives and vitamin D 3 Windaus-Grundmann ketone, 12 high stereo-and regioselective conversion of vitamin D 2 into its (all-R) tetraepoxide and C-25 hydroxy derivative, 13 stereoselective synthesis of (all-R)-vitamin D 3 triepoxide and its 25-hydroxy derivative, 14 oxidation of centropolyindans, 15 buckminsterfullerene C 60 , 16 Binor S, 17 hydrocarbons bearing cyclopropyl moieties, 18 and selective bridgehead dihydroxylation of fenestrindane. A convenient application of TFD in organic synthesis is the direct oxyfunctionalization of saturated hydrocarbons.…”