Oxidopyridiniums

Dipoles can be embedded in heterocyclic structures, just as dieneunits are present in pyrones and other ring structures (see p. 491). N-Substituted pyridinium-3-ols can be deprotonated to give 3-oxidopyridinium betaines that have 1,3-dipolar character.142... 

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. 

The third cycloaddition substrate explored the feasibility of a vinyl nitro functionality as an activated dipolarophile (98, Scheme 1.9c). Preparation of nitroalkene oxidopyridinium betaine 98 began with silylenol ether 92, which was treated with methoxydioxolane in the presence of Lewis acid catalyst, TrC104, to afford keto dioxolane 93 in 58 % yield [47]. Ketone 93 then underwent a-nitration by treatment with /-BuONCL and KOt-Bu to provide nitro ketone 84 (91 %), which was then converted to the nitroalkene functionality via reduction under Luche conditions to... 

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... 

Treatment of the iV-methylated product (115) of 3-hydroxypyridine with an ion exchange resin generates the betaine (116 Scheme 97) (71JCS(C)874). Reduction of 1-substituted 3-oxidopyridinium betaines with sodium borohydride gives hexahydro derivatives in good yields <8lH(l6)l883). 

Oxidopyridiniums (26 Z = NR, Y = O) are converted photochemically into the bicycle (27) corresponding 3-oxidopyryliums and especially 4-oxidoisochromyliums isomerize more easily (cfi 44 — 45). 5-Oxidopyridazinium betaines are isomerized photochemically into corresponding pyrimidin-4-ones by a similar path (Scheme 6). 

Cycloaddition reactions of 3-oxidopyridinium betaines involving addition at two of the ring atoms have been discussed in Section 3.2.1.10. However, with chloroketenes reaction occurs across the exocyclic oxygen atom and either the 4- or the 2-position giving compounds of type (782). 

Betaines analogous to the 3-oxidopyridinium species have been prepared, and found to dimerize rapidly on liberation from the perchloric acid salts. Two dimers are formed, (121) and (122), in the ratio ca. 12 1 when R = methyl, though only (121) is formed when R = H. When the betaine is benzannelated, however, the mode of dimerization is different, and affords (123) and (124) in the ratio 7 1 (75JCS(P1)1366,75JCS(Pl)2099>. 

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... 

Attempts to add one equivalent of hydrogen to the 3-oxidopyridinium salts 122 led to a mixture of products, the main component being the tetra-hydro derivative 123 (R = Ph, indolyl-3-ethyl) or the dimer 124 (R =... 

Solid-supported 3-oxidopyridinium betaine (260) [295], generated by alkylation of 3-hydroxypyridine with bromo-Wang resin and then treating the resulting polymer-bound pyridinium bromide (259) with NaOCHs in propanol, was reacted with vinyl sulfone (Scheme 58). 

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... 

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. 

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