Face Selectivity in the 1,3-Dipolar Cycloaddition Reactions of Benzonitrile Oxide with 5-Substituted Adamantane-2-thiones and 2-Methyleneadamantanes

Abstract

The 1,3-dipolar cycloaddition reactions of benzonitrile oxide with 5-substituted adamantane-2thiones (2-X) and 2-methyleneadamantanes (3-X) produced two geometrically isomeric ∆ 2 -1,4,2oxathiazolines (5-Xs) and two ∆ 2 -isoxazolines (6-Xs), respectively. The substituent was varied from fluoro, chloro, bromo, to phenyl. X-ray single-crystal analysis confirmed the configuration of (Z)-5-F. The product formation bias resulting from the favored attack of nitrile oxide on the zu-face is discussed in terms of transition-state hyperconjugation and frontier molecular orbital theory.1,3-Dipolar cycloadditions offer a convenient one-step route for the construction of a variety of complex fivemembered heterocycles that are synthetically useful compounds. 1 Nitrile oxide cycloadditions to terminal alkenes proceeded regioselectively to give 5-substituted ∆ 2 -isoxazolines as single products. 1b The cycloaddition of nitrones and nitrile oxides to thiones leading to ∆ 2 -1,4,2-oxathiazolidines and ∆ 2 -1,4,2-oxathiazolines, respectively, have also drawn much attention recently. 2 Because of their extremely high reactivity toward 1,3dipoles, thiones have been called superdipolarophiles by Huisgen. 2a,b 5-Substituted adamantan-2-ones 1-X and their derivatives have proven to be useful probes in research aimed at understanding the electronic factors in face selection. 3 Studies by le Noble et al. 3a of a variety of reactions indicate that the reagent prefers to attack the face that is antiperiplanar to the more electron-rich vicinal bonds (zu and en face preference in 1 when X equals an electronwithdrawing and electron-donating group, respectively). Their results have been reconciled with Cieplak's transition-state hyperconjugation model. 4 The Diels-Alder reaction of 2,3-dimethylbuta-1,3-diene with 5-fluoroadamantane-2-thione (2-F) has been re-ported to follow Cieplak's prediction. 5 When frontier molecular orbital (FMO) theory is applied to this Diels-Alder reaction, the diene functions as the donor, and the reaction is controlled by the HOMO (diene)-LUMO (dienophile) interaction. In other words, this is a normal Diels-Alder-type reaction. 1a,2d,6 On the other hand, 1,3dipolar cycloadditions of benzonitrile oxide with thiones 2, or terminal alkenes 3, are controlled mainly by the LUMO (dipole)-HOMO (dipolarophile) interaction (an inverse electron-demand type of reaction). Thus, 1,3dipolar cycloaddition reactions to 2 and 3 provide an important test of the transition-state hyperconjugation model because Cieplak's model stresses that, regardless of the type of reaction (nucleophilic, electrophilic, radical addition, etc.), the newly developing σ * orbital should attract electron density with the same directional preference provided the transition states are electron deficient. 3a,4c We report here our study of the 1,3-dipolar cycloaddition reactions of benzonitrile oxide with 5-substituted adamantane-2-thiones (2-X) and 2-methyleneadamantanes (3-X). We find that the favored approach is indeed syn as predicted, in all in...

Inductive and Resonance Effects of Substituents on π-Face Selection

“…Stereochemical Evidence. The γ-substituted probes include 5-X-2-methyleneadamantanes, ,,, adamantan-2-ones, ,,,, 4-X- pentacyclo(4.3.0.0 2,4 .0 3,8 .0 5,7 )decan-9-ones, , and 4-X-pentacyclo(4.4.0.0 2,4 .0 3,8 .0 5,7 )undecan-9-ones (norsnoutan-9-ones and snoutan-9-ones, see section 2.3.2.2.) …”

The Exterior Frontier Orbital Extension Model

“…Extensive studies on π-facial stereoselection of adamantan-2-ones − may offer a unique opportunity to test the utility of the EFOE model. le Noble adopted the adamantanone system as an ideal probe to delineate electronic effects on π-facial stereoselection in the absence of steric effects and conformational uncertainties.…”

“…Only electronic effects arising from a remote substituent at C-5 would be expected to be of importance in the conformationally rigid and sterically unbiased carbon framework. The 2-adamantanone derivatives studied thus far are 5-substituted adamantan-2-ones ( 20a ; X = C), 5-azaadamantan-2-ones ( 20b − d ; X = N), adamantan-2-thiones ( 21 ), 4,9-substituted adamantan-2-ones ( 22 ),43a perfluoroadamantan-2-ones ( 23 ),43b noradamantanones ( 24 ), and homoadamantan-9-ones ( 25 ) . They tentatively rationalized the observed stereoselectivity in terms of the Cieplak hyperconjugation model .…”

“…This strongly indicates that in the 2-adamantanone system, where π-facial difference in frontier orbital extension is marginal, the subtle steric effect may be more important for facial stereoselection in agreement with Gung's recent analysis of adamantan-2one-5-N-oxide (20b). 45 The EFOE analysis of three 5-substituted adamantan-2-thiones ( 21) 42 was performed. Both the EFOE density and the steric parameters are consistent with the observed stereoselectivity without exception.…”

Intramolecular 1,3-Dipolar Cycloadditions of Norbornadiene-Tethered Nitrile Oxides

“…8, 143.2, 142.4, 139.7,75.1, 73.7, 69.5, 64.8, 51 -2 , 50.1. Anal-Caicd-for CloHi3N03: C, 61.53; H, 6.71; N, [7][8][9][10][11][12][13][14][15][16][17]61.44;H,6.70;N,7.31. MHz) 6 164.6, 138.2, 136.7, 92.9, 76.7, 73.2, 61.0, 50.6, 47.1, 44.7.…”