3-Oxidopyridinium, dipolar cycloaddition

Synthesis of Hesitine Diterpenoid Alkaloids. An efficient enantioselec-tive approach to the hesitine class of the C2o-diterpenoid alkaloids involves an intramolecular oxidopyridinium dipolar cycloaddition with a vinylic sulfone as the key transformation as depicted in Eq. 156.266 Once the sulfonyl group has played its role in the C-C bond formation, it is removed by a Na/Hg-promoted reductive desulfonylafion. 

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

Each of the 3-oxidopyridinium betaine substrates 83, 91, and 98 were extensively investigated for their potential to engage in intramolecular dipolar cycloaddition (Scheme 1.10). Heating a solution of ene-nitrile 83 in variety of solvents failed to effect the desired intramolecular [3+2] dipolar cycloaddition to form the bridged pyrrolidine 100, as tricyclic oxidopyridinium betaine 103 was the only... 

A review on die inter- and intra-molecular cycloaddition of oxidopyridiniums and pyridinium ylides has appealed.117 The known 1,3-dipolar cycloaddition of 1 -methyl-4-phenyl-3-oxidopyridinium with electron-deficient dipolarophiles has been used to produce tropenones which can be transformed into 6- and 7-substituted 3-phenyltropanes, analogues of cocaine.118... 

Smith, M.P., George, C. and Kozikowski, A.P. (1998) The synthesis of tricyclic cocaine analogs via the 1,3 dipolar cycloaddition of oxidopyridinium. Tetrahedron Lett. 39 197-200. 

The quaternary salts of 3-hydroxypyridines are converted by mild base into zwitterionic, organic-solvent-soluble species for which no neutral canonical form can be drawn. These 3-oxidopyridiniums undergo a number of dipolar cycloaddition reactions, especially across the 2,6-positions. 

There has been strong interest in dipolar cycloaddition reactions of 3-oxidopyr-yliums, formally, 3-hydroxypyryliums rendered overall neutral by loss of the phenolic proton, though this is not always the method for their formation. These species undergo cycloadditions across the 2,6-positions and in so doing parallel the reactivity of 3-oxidopyridiniums (section 5.8). 

The oxidopyridinium betaine 27 undergoes 1,3-dipolar cycloadditions with the chiral vinyl sulfoxide to afford an enantioselective synthesis of the phenyltropane 28 <97CC1875, 97JOC503>. 

Koizumi and coworkers have recently reported an asymmetric 1,3-dipolar cycloaddition between (i )-(+)-p-tolyl vinyl sulfoxide and cyclic dipoles such as 1-methyl-3-oxidopyridinium salt (263) to give the cycloadducts (264a), (264b), and (265) in the ratios shown (Scheme 5.86) [197]. The major cycloadduct results from addition of the dipolar species from the face of the sulfoxide containing the lone pair, assuming that the dipolarophile reacts from an s-frans conformation. 

The cationic, goid(I)-catalysed tandem heterocyclization/3 + 2-cycloaddition of 2-(l-alkynyl)-2-alken-l-ones (1) with 3-styrylindoles (2) yielded highly substituted cyclopenta[c]furans (3) in a one-pot reaction under mild conditions. The expected cyclohepta[c]furans (4) were not isolated (Scheme 1). The 1,3-dipolar cycloaddition of 3-oxidopyridinium betaines with pentafulvenes produced a variety of bicyclo[6.3.0]undecanes and bicyclo[5.3.0]decanes via 3 + 2- and 6 + 3-cycloadditions. ... 

Katritzky and co-workers have demonstrated the 1,3-dipolar character of 3-oxidopyridinium betaines by cycloaddition of olefinic and acetylenic dipo-larophiles, including in some cases benzyne, across the 2- and 6-positions of the pyridine ring. Thus, 1 -phenylpyridinium 3-oxide (194) and benzyne afford the 1 1 adduct 196 (35%) 1-methylpyridinium 3-oxide (195) and benzyne give a 1 2 adduct (21%), which is formulated as 198 and its formation explained in terms of the mechanism outlined in Scheme 18 (cf. Scheme 12).103 Attempts to substantiate this mechanism were unsuccessful, since compounds 199 (R = CN, C02Me) analogous to the intermediate 1 1 adduct 197 failed to react with benzyne under similar conditions. 1,6-Dimethylpyridinium 3-oxide with benzyne gave a 1 2 adduct of the same type as 198.103... 

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