Pyridinium salts regioselectivity

Regioselective Reactions of JV-Pyridinium Salts with Organometallic Reagents... 

Attack by phosphorus nucleophiles on pyridinium salts is well established, and is the basis for a method for the regioselective synthesis of 4-alkylpyridines,212 and of 1-alkylisoquinolines.213 Although the phosphonate adducts (67) were obtained in high yields in all cases examined (R = Me, Et, CH2=CHCH2, Bu, PI1CH2), the final step gave satisfactory yields only in the case R = Bu (Scheme 25). 

Alkyl-substituted pyridinium salts also exchange benzylic hydrogens with deu-terated solvents with reversed regioselectivity in comparison with pyrylium salts because their y-anhydrobases are less stable than a-anhydrobases [57],... 

Sodium dithionite reduction of pyridinium salts, usually substituted with electron-withdrawing groups in the 3- or 3,5-positions, chiefly affords the corresponding 1,4-dihydropyridines. The regioselectivity of formation of the dithionite adducts and mechanisms of decomposition have been studied <2005T10331, 2000TL1235>. The sodium... 

Heterocyclic cations will not easily react with electrophiles unless substituted by strongly electron-releasing groups. Alternatively, the reaction conditions are chosen in such a way that a reactive anhydro base or pseudobase intermediate is formed. Thus the thiazolo cation (336) can be nitrated at C-3 (78ZOR216) possibly via the ylide (337). The 6(8)-nitro-2,3-dihydrothiazolo[3,2-a]pyridinium salts (338) and (340) are readily brominated in hydroxylic solvents the regioselectivity and the ease of reaction are consistent with pseudobase intermediates (339) and (341) <81H(15)1349). 

The regioselectivity of Grignard addition to (V-alkoxycarbon y I pyridinium salts can often be controlled by changing the conditions. For example, C(4) addition can be enhanced by the presence of catalytic amounts of copper salts reaction of salt 288 (R = Me) with lithium dimethylcuprate gives also almost exclusively the 1,4-dihydro product 290 (R = Me, R Me). 

In the case of the pyridinium salt of the palladium(II) corrole derivative 2.161, methylation gave a mixture of two products, namely A (21)-methyl corrole 2.221 and 3,3-dimethyl corrole 2.222 (Scheme 2.1.75). As above, the regioselectivity of the C-methylation was elucidated by examining the methylation products of the 3,17-diethylcorrole derivative 2.160. Further, in this specific instance, it was determined that under the methylating conditions, compound 2.223 could not be obtained from 2.224, nor could this latter be made from 2.223. This was taken as an indication that these methylation reactions were under kinetic control. Interestingly, however, both of the methylated products were found to undergo reversible protonation in the presence of TFA, in both cases, the site of protonation was determined (by NMR spectroscopic analysis) to be at the C(5) mejo-position. 

Derivatives of 1,4-dihydronicotinamide (2) and l,4-dihydropyridine-3,5-dicarboxylic acid (8) are obtained from the corresponding pyridines by alkylation followed by reduction with sodium dithionite, as illustrated for (76) in equation (33). The absolutely regioselective reduction by dithionite of pyridinium salts to 1,4-dihydropyridines is true synthetic good fortune most other reducing agents reduce pyridinium salts nonregioselectively and often with reduction beyond the dihydro stage. 

Few truly catalytic systems have been reported. An V-alkylated 1,4-dihydropyridine forms a pyridin-ium salt on hydride loss. In principle the pyridinium salt may be recovered and reduced regioselectively with sodium dithionite (equation 33). This reaction is veiy general and fails only when the 1,4-dihydro-pyridines are excessively strained or too reactive to be isolated. 

Same methodology is applicable for the synthesis of heteroarenes containing (CF3)2CF substituent. Since hexafluoropropene readily forms (CF3)2CF under action of dry KF or CsF, the hrst step involves the reaction of HFP and the corresponding pyridinium salt in presence of KF, leading to the corresponding dihydropyridines 96 in 72-83% yield (Fig. 7.33). The solvent has a pronounced effect on the regioselectivity of this reaction and high selectivity in favor of 2 isomer (up to 11 1 ratio for — 2 and — 4 isomers at 72% yield) can be achieved in solvents with... 

Donohoe TJ, Connolly MJ, Walton L. Regioselective nucleophilic addition to pyridinium salts a new route to substituted dihydropyridones. Oro Lett. 2009 1 5562-5565. 

It is difficult to obtain pure isomers containing fluoro (or perfluorinated group) at 6- or 8-position. Since the substituents cannot be inserted directly into the pyridine fragment of indolizine ring, they should already exist in the precursors of the corresponding indolizines. However, this caused loss of regioselectivity (if )-substituted pyridinium salts were used) or necessity to use poorly available )-substituted a-picolines. 

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