Insertion reactions transannular

Mioskowski et al. have demonstrated a route to spirocyclopropanes. As an example, treatment of epoxide 100 with n-BuLi in pentane stereoselectively gave tricyclic alcohol 101, albeit in only 47% yield (Scheme 5.21) [29]. With a related substrate, epoxide 102 stereoselectively gave dicydopropane 103 on treatment with PhLi uniquely, the product was isolable after column chromatography in 74% yield [35]. As was also seen with attempts to perform C-H insertion reactions in a non-transannular sense, one should note that steps were taken to minimize the formation of olefin products, either by the use of a base with low nudeophilicity (LTM P) and/or by slow addition of the base to a dilute solution (10-3 m in the case of 102) of the epoxide. 

On the contrary, a-lithiated epoxides have found wide application in syntheses . The existence of this type of intermediate as well as its carbenoid character became obvious from a transannular reaction of cyclooctene oxide 89 observed by Cope and coworkers. Thus, deuterium-labeling studies revealed that the lithiated epoxide 90 is formed upon treatment of the oxirane 89 with bases like lithium diethylamide. Then, a transannular C—H insertion occurs and the bicyclic carbinol 92 forms after protonation (equation 51). This result can be interpreted as a C—H insertion reaction of the lithium carbenoid 90 itself. On the other hand, this transformation could proceed via the a-alkoxy carbene 91. In both cases, the release of strain due to the opening of the oxirane ring is a significant driving force of the reaction. 

Analogous transannular carbene insertion reactions have also been reported as illustrated in Eq. (37). Both 9-noradamantanone,23) and N-methyl-9-aza-noradamantane124 have been prepared in this manner. 

Intramolecular insertion reactions lead to rearranged structures and are equivalent to a 1,2-migration of hydrogen. Alkylcarbenes almost invariably react by intramolecular C-H insertion to give cycloalkanes, which is transannular in the case of cycloalkylidenes, or by rearrangement to give alkenes (Scheme 5.43). 

Whereas exo-norbornene oxide rearranges to nortricyclanol on treatment with strong base through transannular C-H insertion (Scheme 5.11), endo-norbornene oxide 64 gives norcamphor 65 as the major product (Scheme 5.14) [15, 22]. This product arises from 1,2-hydrogen migration very little transannular rearrangement is observed. These two reaction pathways are often found to be in competition with one another, and subtle differences in substrate structure, and even in the base employed, can have a profound influence on product distribution. 

Catalyst 70 is very effective for the reaction of terminal alkenes, however 1,1-disubstituted olefins provide hydrosilylation products presumably, this is due to steric hindrance [45]. When a catalyst with an open geometry (78 or 79) is employed, 1,1-disubstituted alkenes are inserted into C-Y bonds to give quaternary carbon centers with high diastereoselectivities (Scheme 18). As before, initial insertion into the less hindered alkene is followed by cyclic insertion into the more hindered alkene (entry 1) [45]. Catalyst 79 is more active than is 78, operating with shorter reaction times (entries 2 and 3) and reduced temperatures. Transannular cyclization was possible in moderate yield (entry 4), as was formation of spirocyclic or propellane products... 

Figure 4.61 Peroxide and hydroperoxide formation in photo-oxygenation reactions addition of molecular oxygen to anthracene to form the transannular peroxide, and insertion into an olefin...

Numerous instances have been described in the literature on the base-catalyzed isomerization of oxiranes with various structures. The product in the reaction of benzocycloalkene oxiranes with lithium diisopropylamide depends on the ring size it is either a transannular insertion product or a transannular product and some a-ketone or only a /3-ketone (Eq. 112). ... 

Our laboratory has also taken advantage of multiple insertion processes to access the scopadulan diterpenes (Scheme 6-24) [52]. An early example was the economical conversion of aryl iodide 136 to tetracycle 137, an intermediate which was subsequently converted to ( )-scopadulcic acid B (138). In this conversion, migratory insertion of the neighboring exocyclic alkene provided a tricyclic intermediate having no /5-hydrogens, which subsequently underwent a transannular 5-exo Heck reaction with the trisubstituted... 

Upon photolysis of azicyclooctane (40), cw-cyclooctene (44) is readily formed, but so too are products derived from intramolecular C-H insertions of carbene 41. Of special interest is bicyclo[3.3.0]octane (42). Created from a 1,5-CH insertion within carbene 41 (Scheme 8),124 r/.v-fused 42 needs space to form. Since the free volume (A V) of a CyD depends on the number of monomer units of which it is comprised, it is not surprising that these factors conspire to limit bicyclo[3.3.0]octane (42) formation when azicyclooctane (40) is photolyzed within ot-CyD (Table 4).42,125 The occurrence of transannular C-H insertion becomes less probable as the cavity within the molecular reaction vessel gets smaller. 

Another transannular reaction, which likewise proceeds via carbene insertion, is the base-catalyzed decomposition of the tosylhydrazone of cyclooctanone. In general these carbenes react with a- and -C—H bonds to give alkenes and cyclopropanes. However, when the carbene carbon can approach distant C —H bonds, such as in the cyclooctane conformation, then bicyclo[3.3.0]octane derivatives are also formed from transannular insertion.Thus, cyclooctanone- and 5-phenylcyclooctanone tosylhydrazones reacted with sodium methoxide to give a mixture of mono- and bicyclic products 4-6 and 7-10, respectively, in the stated proportions. 

Epoxide isomerization. The alcohol 3 (decahydro-2,4,7-metheno-l/T-cyclopenta[a]pentalene-3-ol) can be prepared by epoxidation of 1 (the Diels-Alder adduct of norbornene and cyclopentadiene) followed by isomerization of the resulting oxide (2) with LDA (0-35°, 48 hours). This reaction involves a transannular carbenoid insertion. 

The most recent developments in the above area mainly concern enantioselective variants of these reactions (vide infra). The asymmetric version of transannular C-H insertions from enantioenriched hthiated epoxides has been extensively studied in the Hodgson laboratory over the last six years. In these... 

Various thiolans have been prepared by ionic hydrogenation of thiophens with EtjSiH in the presence of acids. Addition of singlet oxygen to alkyl-substituted thiophens, followed by reduction with di-imine, gave the bicyclic compounds (42) these are examples of the hardly known thia-ozonides. 9-Thia-noradamantane (43) has been synthesized from cyclo-octa-2,7-dienone by a reaction sequence involving a transannular C—H carbene insertion. A bicyclic product (44) has been obtained by the reaction of (—)-carvone with... 

Thianoradamantane has been synthesized in moderate yield starting from cyclo-octa-2,7-dienone. The important reaction in the sequence (Scheme 31) is the transannular C—H insertion by a carbenic species. 

Enantioselective desymetrization by a-deprotonation/tran-sannular C—H insertion of cyclooctene oxide (i.e., 173) was reported by Hodgson and co-workers for synthesis of bicycle[3.3.0] octanes, intermediates that are useful for pol-yquinane synthesis. The best yields and enantioselec-tivities of 175 were obtained when 173 was treated with j-PrLi and (—)-a-isosparteine (Scheme 20.42). Application of this reaction in natural product synthesis is yet to be reported. The same research group also reported expanding the scope of the reaction to synthesis of indolizidine 177 by a similar transannular reaction of 176. ... 

Reaction of exo-9-oxabicyclo[4.2.1]non-7-ene oxide with n-BuLi to exo-S-hydroxybicyclo[3.3.0]octan-2-one has been suggested to occur by elimination to a transient allene oxide that rearranges to a trans-tpoxide enolate before undergoing epoxide a-lithiation and transannular C-H insertion. " ... 

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