Betaines, 3-oxidopyridinium

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. 

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). 

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). 

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... 

Hydroxypyridine is in equilibrium with a 3-oxidopyridinium betaine structure 3 depending on the solvent (see [81] regarding the pyridone-hydroxypyridine equilibrium). 

A further synthetic aspect is the reaction of some dimers of 3-oxidopyridinium betaines with dienamines to give bridged adducts (Scheme 6). 

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. ... 

Recent advances in microwave-assisted 2 + 2, 2 + 3, and 2+4-cycloaddition reactions under solvent or solvent-free conditions have been reviewed. A detailed investigation of the microwave-assisted 3 + 2- and 6 + 3-cycloadditions of 3-oxidopyridinium betaine with pentafulvenes has been presented. The effect of solvent polarity, temperature, and microwave irradiation on periselectivity has been discussed. ... 

Unlike the 3-oxidopyridinium betaines, about which much was reported last year, the analogous 3-imidopyridiniums, e.g. (55), do not give cyclo-adducts with electron-deficient or electron-rich alkenes. In addition, only resinous products are obtained with dimethyl acetylenedicarboxylate. The formation of pseudo-bases from quaternary pyridinium, quinolinium, and isoquinolinium cations has been reviewed. ... 

The chemistry of 3-oxidopyridinium betaines has been extensively studied notably by Katritzky and Dennis in the late 1970s and early 1980s, who have applied their cycloaddition to the synthesis of core fragments of tropone alkaloids and related natural products [2b]. A major advantage of these cycloaddition reactions results from the... 

In contrast to the abundant coverage of the intermolecular cycloaddition of 3-oxidopyridinium betaines [3, 87], relatively few intramolecular applications have been described. In this context, Peese and Gin have developed an efficient, asymmetric approach to the hetisine class of the C2o-diter-penoid alkaloids based on an intramolecular oxidopyridinium [5-1-2] cycloaddition in which simultaneous formation of the C5—C6 and CIO—C20 bonds in the 3-methyl-1-aza-tricyclo[5.2.1.0 ]decane core of these alkaloids was achieved [88]. As shown in Scheme 20.35, the heating of chiral oxidopyridinium betaine 81 in toluene at reflux produced the corresponding enantiopirre cycloadduct 82 in 77% yield. The latter constituted a potent intermediate for the asymmetric synthesis of the hetisine class of alkaloids, such... 

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