Cyclohexenes 1,2,3-trisubstituted

The synthesis of the trisubstituted cyclohexane sector 160 commences with the preparation of optically active (/ )-2-cyclohexen-l-ol (199) (see Scheme 49). To accomplish this objective, the decision was made to utilize the powerful catalytic asymmetric reduction process developed by Corey and his colleagues at Harvard.83 Treatment of 2-bromocyclohexenone (196) with BH3 SMe2 in the presence of 5 mol % of oxazaborolidine 197 provides enantiomeri-cally enriched allylic alcohol 198 (99% yield, 96% ee). Reductive cleavage of the C-Br bond in 198 with lithium metal in terf-butyl alcohol and THF then provides optically active (/ )-2-cyclo-hexen-l-ol (199). When the latter substance is treated with wCPBA, a hydroxyl-directed Henbest epoxidation84 takes place to give an epoxy alcohol which can subsequently be protected in the form of a benzyl ether (see 175) under standard conditions. 

Dicyclohexyl ether [Brpnsted acid promoted ketone reduction, symmetrical ether], 123 Diels-Alder cycloaddition-cycloreversion pathway, alkene to alkane reductions, trisubstituted alkenes, 39-40 3,5-Dimethyl-1 -cyclohexen-1 -yl... 

Shi s method gives good results for disubstituted /f-alkenes compared to the Jacobsen epoxidation previously described, which is more specific for disubstituted Z-alkenes. Concerning the epoxidation of trisubstituted alkenes, the epoxidation of 1-phenyl-1-cyclohexene could not be validated because of... 

In addition, phenylsufonylallene (110), a,(3-unsaturated phosphonates (111), and alkenes with perfluorinated substituents (112) are all useful dipolarophiles. The yields observed with methyl 2-propenoate are significantly lower than those with the corresponding acrylate (entries 7 and 9), because of the additional substituent. On the other hand, the dipolar cycloadditions with either ethyl vinyl ether, 1-hexene, cyclohexene, or a trisubstituted dipolarophile provide the corresponding isoxazolidines in either low yields or not at all (18). 

Borane may react sequentially with 3 mol of alkene to form mono-, di-, and trialk-ylboranes. Both the alkene structure and reaction conditions affect product distribution. Trialkylboranes are usually formed from terminal olefins [Eq. (6.57)] and unhindered disubstituted alkenes such as cyclopentene irrespective of the reactant ratio.340 The reaction cannot be stopped at the mono- or dialkylborane stage. In contrast, hindered disubstituted olefins (e.g., cyclohexene) and trisubstituted alkenes are converted mainly to dialkylboranes [Eq. (6.58)]. Careful control of... 

The PTC method gives poor results with trisubstituted and 1,1-disub-stituted olefins. The oxyamination product may still form, but it is accompanied by a number of by-products. Fortunately, this class of olefins is successfully oxyaminated by the alternative procedure (B). Methyl-cyclohexene, a-methylstyrene, 2-methyl-2-hepten-6-one, and its ketal are examples of olqfins that give oxyamination products in good yield following procedure B. 

The fact that the residues R -R3 of the precursors A, B and C can be broadly varied demonstrates the high flexibility of our approach. R1 of component A can bear simple to demanding residues as well as valuable functional groups (Scheme 17). R2 is limited to aromatic and heteroaromatic substituents, due to the lower reactivity of the aliphatic ni-troalkenes. The residue R3 of component C allows the broadest diversity. Aliphatic as well as aromatic moieties are tolerated. Furthermore, acrolein (R3 = H) can be used, affording trisubstituted cyclohexene carbaldehydes. The best yields were obtained with aromatic substituents R2 and R3 (38%-60%). The replacement of R3 by aliphatic residues led to lower yields (25% and 29%), whereas sterically demanding aldehydes A had less influence on the yield. In contrast, the variation of the residues had only a small impact on the diastereoselectivity (68 32-... 

However, the utility of this Zweifel synthesis was limited in the past by the limited availability of dialkylboranes, because direct hydroboration leads cleanly to the formation of dialkylboranes only in the case of relatively hindered alkenes such as 2-methyl-2-butene and cyclohexene. More generally, the hydroboration fails to stop at the R2BH stages. Recent developments have provided a general preparation of a variety of dialkylboranes via the hydridation of dialkylhalo-boranes. Thus, dialkylvinylboranes prepared via the hydridation of dialkylhalo-boranes in the presence of an alkyne, react with iodine under basic conditions to produce disubstituted alkenes (Eq. 58) and trisubstituted alkenes (Eq. 59) of established stereochemistry. These results indicate a mechanism analogous to that... 

Z)-Disubstituted and trisubstituted alkenes were considerably less reactive. For example, cyclohexene does not react with the triimido complex and afforded only the hydroxy amine in poor yield with the diimido complex. 

The relative stabilities of olefinic bonds at various positions in the steroid nucleus have a direct bearing on reactions of several kinds, including elimination reactions Chapter 3), enolisation of ketones (Chapter 4) and the equilibration of olefinic structures (Chapter 5). Infrared absorption spectra in the region 1600-1700 cm""i, which for cyclohexene (1650 cm" ) and cyclopentene (1613 cm " ) reflect the greater strain (5-6 kcal/mole) present in cyclopentene [43], have been employed [44,45] to obtain some indication of the relative stabilities of cis-disubstituted and trisubstituted double bonds. The data are summarised in Table 2. 

The Lewis acid-promoted reaction of our oximinosulfonate with dienes and the conversion of the resulting cycloadducts to pyridines comprises a new annulation method for the synthesis of substituted pyridines from conjugated dienes. As illustrated in the Table, very good overall yields are obtained in reactions of 2-substituted dienes, providing 5-substituted pyridine-2-carboxylates. Reactions with 1-substituted dienes yield 3-substituted pyridines, and disubstituted dienes react smoothly to afford trisubstituted pyridines in good yield. Polycyclic systems are obtained when dienes such as 1-vinyl-1-cyclohexene are employed in the annulation. 

A 1,4-cyclohexadienic structure (46) was proposed for the octahydroparacyclophane formed in the hydrogenation (Pt02) of paracyclophane (47), whose unusual properties provided a degree of plausibility to the claim (equation 38).Actually, four isomeric dienes, none of which has the first postulated structure, are formed. The possible structures have one trisubstituted double bond in each six-carbon cycle, as in formula (48). Dienes are more reactive than the related arenes or cyclohexenes and apparently are more tightly bound to a catalytic site. - ... 

Bauld and coworkers, especially, developed the analogous Diels-Alder (4 + 2) cycloaddition reactions. These reactions are conveniently catalyzed by tris(4-bromophenyl)aminium hexachloroantimonate (78) or by photosensitization with aromatic nitriles. The radical cation-catalyzed Diels-Alder reaction is far faster than the uncatalyzed one, and leads to some selectivity for attack at the least substituted double bond for the monoene component (Scheme 18, 79 —> 80), but only modest endo selectivity (e- and x-80) [105]. Cross reactions with two dienes proved to be notably less sensitive to inhibition by steric hindrance of alkyl groups substituted on the double bonds than the uncatalyzed reactions, as cyclohexadiene adds detectably even to the trisubstituted double bond of 2-methylhexadiene (82), producing both 83 and 84. Dienes such as 85 react with donor-substituted olefins (86) to principally give the vinylcyclobutene products 87, but they may be thermally rearranged to the cyclohexene product 88 in good yield [105]. Schmittel and coworkers have studied the cation radical catalyzed Diels-Alder addition of both... 

The partial hydrogenation of 1,3,5-trisubstituted benzenes gives only a single cyclohexene product. When the substituents are large, as with 1,3,5-tri-tert-butylbenzene (6), selective formation of the cyclohexene, 7, occurs even over unmodified Pt/C and Rh/C catalysts when the reaction is run in heptane at room temperature and atmospheric pressure. With Pt/C, 45-50% selectivity toward the cyclohexene was found at 50% conversion while with Rh/C 60-65% selectivity was obtained at 60% conversion (Eqn. 17.5). ... 

Trisubstituted cyclohexen-2-ones produce fragments which are indicative of an alkyl (aryl) shift to the 3-position. The relative intensities of the peaks m/e = 69 and 131 in the case of (72) suggest a preference for phenyl migration22,24. ... 

Palladium-based catalysts also bring about cyclopropanations in high-yield. With palladium acetate/CHjNj, styrene , unactivated terminal olefins strained olefins , 1,3-dienesan enamine , as well as a,3-unsaturated carbonyl compounds have been cyclopropanated (Table 1). Contrary to an earlier report, the reaction also works well with cyclohexene if the conditions are chosen appropriately it seems that the notniyst is rapidly deactivated in the presence of this olefin >. Trisubstituted a,p-unsaturated carbonyl compounds were found to be unreactive, and the same is true for the double bonds in diethyl fumarate, maleic anhydride, coumarin and 1,3-dimethyluracil. Whereas the latter two were totally unreactive, [3-1-2] cycloaddition of diazomethane gave pyrazolines in the former two cases. The last entry of Table 1 shows that an allyl alcohol function can still be cyclopropanated, but methylene insertion into the O—H bond is a competing process. 

For trisubstituted olefins and certain hindered disubstituted olefins, e.g., cyclohexene and longifolene, hydroboration proceeds rapidly only to the dialkylborane stage. By careful control of conditions, the dialkylboranes can be obtained. In this way, certain important hydroborating agents, such as bis-3-niethyl-2-butylborane, dicyclohexylborane , dilongifolylborane " and diisopinocampheylborane , are synthesized ... 

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