Silver Tetrafluoroborate intermediates

Cyclizations with nitrogen nucleophiles involving alkynes and allenes have received little attention until recently. The cyclizations of several a-aminoallenes to 3-pyrrolines with silver tetrafluoroborate was reported by Claesson and coworkers (equation 133).264 A similar cyclization to form A -carba-penems has been reported (equation 134).265 Diastereomeric allenes (R1 R2) were shown to cyclize with complete stereocontrol. Cyclization with palladium chloride in the presence of allyl bromide or electrophilic alkenes allowed for the intermediate vinylpalladium species to be trapped by the electrophile.2651 A related product was obtained by cyclization of an alkynic substrate (equation 13S).265 Other examples of 5-endo cyclization of p-aminoalkynes50 include the formation of indoles by cyclization of 2-alkynylanilines with mercury salts200 or palladium chloride,266a,266b,266c formation of 1-pyrrolines with catalytic palladium chloride (equation 136)198 and formation of pyrroles by cyclization of hydroxy-substituted p-aminoalkynes.198,2666... 

This reactivity proved to be a general process, providing the unique products in moderate yields following cyclopropanation and immediate treatment with silver tetrafluoroborate. These structures revealed that a cascade sequence was proceeding stereoselectively in every case to furnish a single product as the result of conrotatory 4jt electrocyclization, electrophilic aromatic substitution at the least hindered position on the arene moiety (para to the MeO) in favor of six-membered ring formation, and desilylation with protonation from the exo face of the bicyclic product. Dehydrochlorination to form a second cationic intermediate did not occur in this case, due to structural restrictions imposed by the bridged architecture of 81. 

This rearrangement must occur by heterolytic cleavage of the carbon-chlorine bond in 19 to yield the intermediate cation 6+, which is then attacked by the nucleophilic chloride at one of the partially positively charged cyclopropyl groups. With the less nudeophilic tetrafluoroborate counterion, generated by treating 19 with silver tetrafluoroborate under sol-... 

These compounds have been obtained by the addition of cyclooctadiene to an equimolar mixture of /i3-allyl or /d -crotyl-(2,4-pentanedionato)palladiuni(II) and tetrafluoroboric acid in methylene chloride-ether solution.1 If silver tetrafluoroborate is on hand, the slight modification described below obviates the need to prepare the /3-diketonate complex as an intermediate. 

The case of p-hydroxy-y-alkenyl selenides merits further comments. The rearrangement efficiently takes place using the thallium(I) ethoxide method and the presence of an additional double bond in the reactant does not introduce a serious problem associated with unwanted reaction with the dichlorocarbene intermediate. This is not the case when silver tetrafluoroborate is used. 

Syntheses of Alkylidene cyclopropanes Via the Selenonium route The selenonium route proved to be more valuable. It has been specifically designed by us to replace the deficient selenoxide route (Scheme 38). It was expected to produce alkylidene cyclopropanes by a mechanism which mimics the selenoxide elimination step but which involves a selenonium ylide in which a carbanion has replaced the oxide. Cyclopropyl selenides are readily transformed to the corresponding selenonium salts on reaction with methyl fluorosulfonate or methyl iodide in the presence of silver tetrafluoroborate in dichloromethane at 20 °C and, as expected, methylseleno derivatives are more reactive than phenyl-seleno analogs. Alkylidene cyclopropanes are, in turn, smoothly prepared on reaction of the selenium salts at 20 °C with potassium tert-butoxide in THF (Scheme 38). Mainly alkyl cyclopropenes form at the beginning of the reaction. They then slowly rearranges, in the basic medium, to the more stable alkylidene cyclopropanes( 6 kcal/mol). In some cases the complete isomerisation requires treatment of the mixture formed in the above reaction with potassium fcrt-butoxide in THF. The reaction seems to occur via a selenonium ylide rather than via a P-elimina-tion reaction promoted by the direct attack of the /crt-butoxide anion on the P-hydrogen of the selenonium salt, since it has been shown in a separate experiment that the reaction does not occur when a diphenylselenonium salt (imable to produce the expected intermediate) is used instead of the phenyl-methyl or dimethyl selenonium analogs. It has also been found that the elimination reaction is the slow step in the process, since styrene oxide is formed if the reaction is performed in the presence of benzaldehyde which traps the ylide intermediately formed... 

A semi-synthetic approach by the Merck group (775) makes use of the 4-chloro-azetidinone (153) which can be obtained from 6-aminopenicillanic acid. Reaction with the silylated diazo-intermediate (154) in the presence of silver tetrafluoroborate followed by desilylation provides a one-step process to (148) from (153). A similar displacement with a 4-acetoxy substituted azetidinone derived from aspartic acid provides another route (776) to (148). The amidine derivative (155) of thienamycin is chemically more stable than the amine and a direct introduction of this side-chain by way of the keto-ester has also been achieved (777). It is this amidine (MK 0787) that is undergoing clinical investigation rather than thienamycin itself... 

In addition to these deacylation or transacylation methods, much effort has been directed towards the introduction of a 7a-methoxy substituent into the cephalosporin nucleus. Such methods have also usually been applicable to penicillins. One of the first methods developed made use of the diazo intermediate (211) derived from 7-aminocephalosporanic acid (183). Treatment with bromo-azide yielded a mixture of isomers (212), which with silver tetrafluoroborate and methanol formed (213). Reduction and acylation readily followed. The stereoselective addition of methoxide to... 

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