Fused bicyclic compounds

Like LiAlH4 reduction, addition of a Grignard reagent to camphor occurs almost entirely from the endo face, but almost entirely from the exo face with norbornanone. 

In a similar style, epoxidation of the two alkenes is totally stereoselective, occurring exo in nor-born ene and endo when methyl groups are present on the bridge. These stereoselectivities would be remarkable in a simple monocyclic compound, but in a rigid bridged bicyclic structure they are almost to be expected. 

Reactions that break open bridged molecules preserve stereochemistry 

Some powerful oxidizing agents are able to cleave C-C bonds, as you will see in Chapter 35. Oxidation of camphor in this way produces a diacid known as camphoric acid. The usual reagent is nitric acid (HN03) and oxidation goes via camphor s enol. 

Note that only one enol can form enolization the other way would lead to an impossible planar carbon at the bridgehead position. See p. 717. 

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Double Michael addiQoas of rutro compounds beanng tethered acidic carbons to 3-butyn-3-one under NaH catalysis give nitrocyclohexanes v/ith high stereoselectivity The products are transformed into rrruii -fused bicyclic compounds via the Dickmarm reaction on treatment with base fEq 4 139 ... 

Analogous to the allylsilane cyclizations, alkynylsilanes can also be used to synthesize 1,2-fused bicyclic compounds. The intramolecular addition of 4-[5-(trimethylsilyl)-3-pentynyl]-2-cyclo-hexenone proceeded smoothly in the presence of various Lewis acids, yielding functionalized cw-fused octahydro-5/f-inden-5-ones containing the synthetically useful terminal allene unit45. 

The cyclobutene (310) opened at 100 °C to facilitate the intramolecular Diels-Alder reaction, from which the m-fused bicyclic compound (311) was isolated 108). 

Later Grubbs discovered ruthenium carbene complex and used it for a metathesis reaction to synthesize cyclic compounds 5a-d [Eqs. (6.4) and (6.5)]. In 1995, Grubbs found that ruthenium benzylidene carbene complex Ic," which is now commercially available, has the same reactivity as that of lb. Many researchers have therefore used this complex for olefin metathesis, and this reaction has been useful for the synthesis of carbo- and heterocyclic compounds and fused bicyclic compounds [Eq. [6.6)] °... 

The structures of bicyclic and polycyclic small-ring compounds have attracted some interest. The relationship between the C-C-H bond angles at the bridgehead of bicyclo[1.1.0]butane (2) and the angle between its cyclopropane rings has been studied.31 Bicyclobutane and most other cyclopropane derivatives have bonds that are formed from orbitals that are bent in the same direction. However, with some mm -fused bicyclic compounds containing a cyclopropane... 

Oxidations of alkylated fluoroaromatic compounds arc mostly applied in the syntheses of the corresponding aromatic mono-, di- and tricarboxylic acids. The reactions in this section also include aromatization (i.e., dehydrogenation) of polyhydroaromatic compounds and epoxi-dation of unsaturated benzo-fused bicyclic compounds. 

The reaction of SiF-coupled six-membered rings with lithium organyls first produces ring contraction and subsequently eliminates LiF. As discussed in Section II, we have now obtained an intermediate ylide that contains silicon atoms with the coordination numbers three and five. This gives rise to a nucleophilic migration of a methanide ion. A fused bicyclic compound is formed (Scheme 24). This compound has also been characterized by an X-ray analysis and the structure is shown in Fig. 13. Both the four-membered rings are planar.42,46,50... 

Mn(OAc)3-mediated reaction of acetylacetone with 1,5-cyclooctadiene (137) leads to the formation of a cis-fused bicyclic compound (138), through the addition of a acetylacetonyl radical to 1,5-cyclooctadiene and subsequent intramolecular radical cyclization (eq. 4.48). 

There are two series of fused bicyclic compounds incorporating both an isothiazole and a benzene ring. These two ring systems are now generally known as 1,2-benzisothiazole (1) and 2,1-benzisothia-zole (2). 

Eilbracht et al. by means of rhodium-catalyzed tandem hydroformylation/acetalization of cccw-alkenediols [20]. It had been previously reported that hydroformylation of alkenol resulted in cyclic hemiacetal [21]. Starting from enediols, the authors paved the way for subsequent acetalization, leading to fused bicyclic compounds in a one-pot cascade. As expected, exclusive formation of czs-fused perhydrofuro[2,3fr]furan 6 occurred when applying 60 bar of syngas (CO H2 = 3 1) at 120 °C in dichloromethane to diol 5 in the presence of a [Rh(cod)Cl]2/PPh3 catalytic system (Scheme 4). 

Briggs et al. proposed a new strategy for the synthesis of tricyclic structures using acyl xanthates as precursor for acyl radicals [121]. Irradiation with visible light of a solution of acyl xanthate in presence of 1,6-diene 126 afforded czs-fused bicyclic compound 127 in a good yield (Scheme 38). Radical reduction of xanthate and subsequent aldol condensation leads to the formation of [5.5.5]-fused ring systems similar to those of the triquinane terpene family. 

On the other hand, when the opposite Markovnikov bias occurs, due to tertiary carbocation formation, five-membered ring formation is favored and both the 6,5- and 6,6-fused bicyclic compounds are obtained, in an 82 18 ratio, in 70% overall yield13. 

The diastereoselectivity of the cycloadditions of 4-substituted 3//-l,2,4-triazole-3,5(4//)-diones to cis-fused bicyclic compounds A-I has been examined. 

In a study related to the conformational properties of the cyclohexane-fused six-membered heterocycles, new bicyclic dithiolanes, 285-/ra r (Scheme 52) and 285-crr (not shown), were prepared along the reaction pathway, as precursors used further for the syntheses of 2-methyl substituted and unsubstituted /ra r-fused 4a,5,6,7,8,8a-hexahydro-2//,4//-1,3-benzodithiines, exemplified by structure 288-/ra ir (R=R = H) <2002JOC1910>. Thus, ditosylation of cis-Z-hydroxymethyl cyclohexanol 284, and subsequent reaction with sodium sulfide and sulfur, provided a mixture of new bicyclic products 285 and 286, albeit in very low yields, with configurational inversion at C-1. These were reduced by LiAlH4 to provide /ra r-2-mercaptomethyl cyclohexanethiol 2 l-trans. Upon acetalization or transacetalization, the desired 2SS-trans derivative was obtained. The same methodology with the precursor 2E4-trans was extended to the preparation of the r-fused bicyclic compounds 285-288. 

Regioselectivity is markedly enhanced in conformationally more biased systems such as carbohydrates and fused bicyclic compounds. Some examples are shown in Scheme 17. - ... 

The cyclization of unsaturated mixed bromoacetals, formed in one step from the corresponding homoallylic alcohol, is used to construct cw-fused bicyclic compounds. 

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