The ammonia-free partial reduction of substituted pyridinium salts

Abstract

This paper reports a study into the partial reduction of N-alkylpyridinium salts together with subsequent elaboration of the intermediates thus produced. Activation of a pyridinium salt by placing an ester group at C-2, allows the addition of two electrons to give a synthetically versatile enolate intermediate which can be trapped with a variety of electrophiles. Furthermore, the presence of a 4-methoxy substituent on the pyridine nucleus enhances the stability of the enolate reaction products, and hydrolysis in situ gives stable dihydropyridone derivatives in good yields. These versatile compounds are prepared in just three steps from picolinic acid and can be derivatised at any position on the ring, including nitrogen when a p-methoxybenzyl group is used as the N-activating group on the pyridinium salt. This publication describes our exploration of the optimum reducing conditions, the most appropriate N-alkyl protecting group, as well as the best position on the ring for the methoxy group. Electrochemical techniques which mimic the synthetic reducing conditions are utilised and they give clear support for our proposed mechanism of reduction in which there is a stepwise addition of two electrons to the heterocycle, mediated by di-tert-butylbiphenyl (DBB). Moreover, there is a correlation between the viability of reduction of a given heterocycle under synthetic conditions and its electrochemical response; this offers the potential for use of electrochemistry in predicting the outcome of such reactions.

Synthesis, Reactivity and Stability of Aryl Halide Protecting Groups towards Di-Substituted Pyridines

“…After learning that aryl halides such as benzyl Iodide and 4-methoxybenzyl iodide react with disubstituted pyridines to give pyridinium salts our investigations started with formation of pyridinium salt from 4-methoxybenzyl bromide 16 rather than the iodide 11 earlier prepared by Donohoe [5,7]. Preparation of the 4-methoxybenzyl bromide 16 followed the procedure used by Donohoe.…”

“…For this reason, it was decide that other electron-rich benzyl rings be investigated. 3,4,5-Trimethoxybenzyl bromide 15 was therefore prepared from cheaply commercially available 3,4,5-trimethoxybenzaldehyde via the alcohol 14 before converting it to the bromide using procedure followed by Donohoe [7,[15][16][17][18]. Reduction of the benzaldehyde to the alcohol 14 was successfully achieved by use of NaBH4 in a solution of THF : H2O in a ratio of 97:3, respectively.…”

“…Initial studies involved benzyl iodide and homoallyl triflate since removal of the protecting groups would be easy by use of palladium-catalyzed hydrogenolysis or palladium-catalyzed deallylation [6,14], respectively. The synthesis of the pyridinium salts again started from the di-substituted pyridine 6 (Scheme III) [7][8].…”

“…Other electron-rich aryl protecting groups such as 4-methoxybenzyl and 3,4-dimethoxybenzyl protecting groups were also investigate by Donohoe during preparation of pyridinium salts 9 and 10, respectively (Scheme IV) [7][8][9][15][16]. The synthesis of paramethoxybenzyl iodide (PMB-I) started from commercially available 4-methoxybenzyl alcohol while the synthesis of 3,4-dimethoxybenzyl bromide (DMB-Br) started from commercially available 3,4-dimethoxybenzaldehye [10][11][12][13].…”

Reductive Lithiation and Multilithiated Compounds in Synthesis

“…Preliminary results showed that Birch reduction of salts of 2-carboxyisopropyl pyridine afforded the desired reaction products in very low yields, most probably because of the instability of the resulting 1,2-dihydropyridine, an inconvenience overcome by the introduction of a methoxy group at C-4, as in compounds 107 [49]. Indeed, upon acidic hydrolysis of the reduction mixture, which is incompatible with liquid ammonia as a solvent, the expected 1,2-dihydropyridines 109 were supposed to transform into the corresponding stable dihydropyridones 110 [50].…”