Pyridinium salts dithionite reduction

The key intermediate 124 was prepared starting with tryptophyl bromide alkylation of 3-acetylpyridine, to give 128 in 95% yield (Fig. 37) [87]. Reduction of 128 with sodium dithionite under buffered (sodium bicarbonate) conditions lead to dihydropyridine 129, which could be cyclized to 130 upon treatment with methanolic HC1. Alternatively, 128 could be converted directly to 130 by sodium dithionite if the sodium bicarbonate was omitted. Oxidation with palladium on carbon produced pyridinium salt 131, which could then be reduced to 124 (as a mixture of isomers) upon reaction with sodium boro-hydride. Alternatively, direct reduction of 128 with sodium borohydride gave a mixture of compounds, from which cyclized derivative 132 could be isolated in 30% yield after column chromatography [88]. Reduction of 132 with lithium tri-f-butoxyaluminum hydride then gave 124 (once again as a mixture of isomers) in 90% yield. 

After its isolation, the structure of alkaloid deplancheine (7) was unambiguously proved by several total syntheses. In one of the first approaches (14), 1,4-dihydropyridine derivative 161, obtained by sodium dithionite reduction of A-[2-(indol-3-yl)ethyl]pyridinium salt 160, was cyclized in acidic medium to yield quinolizidine derivative 162. Upon refluxing 162 with hydrochloric acid, hydrolysis and decarboxylation took place. In the final step of the synthesis, the conjugated iminium salt 163 was selectively reduced to racemic deplancheine. 

A series of papers have been published by Lounasmaa et al. (122-128) on the synthesis of different alkaloid-like indolo[2,3-a]quinolizidine derivatives by means of reduction and subsequent cyclization of A-[2-(indol-3-yl)ethyl]piridi-nium salts, developed as a general method for indole alkaloid synthesis by Wenkert and co-workers (129, 130). Aimed at the total synthesis of vallesiachotamine (9), valuable model studies were reported (131-133). Reduction of pyridinium salts 183 and 184 with sodium dithionite and subsequent acid-induced cyclization represents a convenient method for preparing val-lesiachotamine-type derivatives 185 and 186, respectively. 

An intriguing use of a quaternary ammonium salt in a two-phase reaction is to be found with the regeneration of 1 -benzyl-1,4-dihydronicotinamide by sodium dithionite in a biomimetic reduction of thiones to thiols [12], The use of sodium dithionite in the presence of sodium carbonate for the 1,4-reduction of the pyri-dinium salts to 1,4-dihydropyridines is well established but, as both the dithionite and the pyridinium salts are soluble in water and the dihydropyridine and the thione are insoluble in the aqueous phase and totally soluble in the organic phase, it is difficult to identify the role of the quaternary ammonium salt in the reduction cycle. It is clear, however, that in the presence of benzyltriethylammonium chloride, the pyridine system is involved in as many as ten reduction cycles during the complete conversion of the thione into the thiol. In the absence of the catalyst, the thione is recovered quantitatively from the reaction mixture. As yet, the procedure does not appear to have any synthetic utility. 

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... 

The reduction of N-(fi-indolylethyl)-pyridinium salts [e.g. (117)] by means of sodium dithionite is accompanied by cyclization in the acidic reaction medium of the 1,4-dihydropyridine so generated, with the formation of tetracyclic bases [e.g. (118)] that are useful as models for the synthesis of vallesiachotamine. If, however, the reaction medium is buffered, the intermediate 1,4-dihydropyridine can be isolated subsequent acid-induced cyclization of this gives the thermodynamically more stable tetracyclic base (119), containing an equatorial substituent at C-15 a high degree of stereoselectivity at positions 3 and 15 is therefore possible in this synthetic approach.77"... 

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. 

Pyridinium salts can be reduced with the mildly nucleophilic dithionite ion to produce mixtures of di-hydropyridines. Much work has been carried out since the early observation that NADPH could be obtained from NADP with this reagent. Reduction produces mainly the 1,4-dihydro isomer with minor amounts of the 1,2- or 1,6-dihydro adducts. The reduction is believed to proceed via a stable and sometimes isolable sulfinate intermediate (91). In acid solution this decomposes with loss of sulfur dioxide to form the dihydropyridine (92 Scheme 19). Various substituted pyridinium species undergo this reaction and the Isomer ratio obtained is dependent upon the nature of the solvent, temperature and pH. With l-methyl-4-carbamoylpyridinium bromide (93) and dithionite in aqueous sodium carbonate at 0-5 C for 10 min the only isolated product was the 1,2,5,6-tetrahydropyridine (94) obtained in 16% yield, but the 3-carbamoyl salt gave the 1,4-dihydronicotinamlde (95) in 90% yield, free of the 1,6-isomer. The 3-chloropyridlnium ion (96) gave a moderate yield of the 1,4-dlhydropyridlne (97). 

Pyridinium salts may also be reduced to dihydropyridines with sodium dithionite although not clearly understood, the 1,4 isomer is very often the sole product obtained when electron-withdrawing groups in the 3 position are present. Reductions with NAD(P) models have indicated that these... 

The easy specific reduction of 3-acylpyridinium salts giving stable 3-acyl-1,4-dihydropyridines using sodium dithionite is often quoted, because of its perceived relevance to nicotinamide coenzyme activity the mechanism involves addition of sulfur at C-4 as its first step, as shown below.1,4-Dihydropyridines are normally air-sensitive, easily rearomatised molecules the stability of 3-acyl-1,4-dihydropyr-idines is related to the conjugation between ring nitrogen and side-chain carbonyl group (see also Hantzsch synthesis, section 5.15.1.2). However, even simple pyridinium salts, provided the A-substituent is larger than propyl, or for example benzyl, can be reduced to 1,4-dihydropyridines with sodium dithionite. ... 

Lounasmaa et al. ° have continued their investigations into the synthesis of indoloquinolizidine derivatives, with particular reference to vallesiachotamine models. The most advanced work in this area to date involves synthesis (Scheme 9) of the closely related vallesiachotamine derivative (75). The critical stage in this synthesis was the reduction of the pyridinium salt (76) by means of sodium dithionite, which, in buffered (NaHC03) solution, allowed the isolation of the dihydropyridine derivative (77). Cyclization of (77) in the presence of acid gave, preferentially, the desired 3H,15H-trans-isomer (75), as had previously been established " in model systems. Alternatively, alkylation of the unsaturated ester (78) with tryptophyl bromide gave the pyridinium salt (79), which, on reduction with sodium dithionite in aqueous methanol, gave a mixture of (75) and the uncyclized tetrahydropyridine derivative (80). >yhen the sodium dithionite reduction medium was buffered (with NaHCOa), and the dihydropyridines so obtained were cyclized in acid, the products were the tetracyclic geometrical isomers of structure (81) (Scheme 9). 

A redox system (50/51) to affect brain delivery of y-aminobutyric acid (GABA) derivatives and analogues was also developed. Zincke reaction of 41 with acetal 49 followed by dithionite reduction afforded the 1,4-dihydropyridine prodrug 50, which was hydrolyzed and oxidized in vivo to the active GABA analogue 51. The neutral and lipophilic 1,4-dihydropyridine 50 can penetrate the blood-brain barrier (BBB), whereas the oxidized pyridinium salt 51 is retained in the brain for an extended period and then eliminated. 

Intermediates in the sodium dithionite reduction of pyridinium salts have been isolated. Thus l-(p-chlorobenzyl)nicotinamide (X-129) yielded the dihydrosulfmate X-130, which is desulfmated in alkaline media to l-(p-chlorobenzyl)-l,4-dihydronicotinaniide (X-131). The desulHnation of X-130 was confirmed by deuterium exchange experiments. 

Diphosphopyridine nucleotide and analogous quaternary pyridinium salts form complexes with bisulphite and with thiols 2-5, xhe orientation of these additions is usually uncertain and may vary with the reaction solvent used " 4, The dithionite addition products formed by quaternary pyridinium salts have attracted interest because of their connection with the dithionite reduction of diphosphopyridine nucleotide (p. 259). Thus, the formation of a 1,4-dihydropyridine (122) by reduction of (120) has been represented 6 as proceeding through a 1,2-addition product (121). Regardless of the correctness or otherwise of structure (121), the relevance of the intermediate for diphosphopyridine nucleotide reduction by dithionite has been questioned, and the yellow intermediate formed in this reaction has been formulated 8 as a charge-transfer complex between the pyridinium nucleus and 820 (see p. 261). 

Before truly reliable criteria for distinguishing between 1,2- and 1,4-dihydropyridines were available, the products of dithionite reduction of many quaternary salts, mainly nicotinamide derivatives, had been examined, notably by Karrer and his co-workers and wrongly formulated as 1,2-dihydropyridines. Whilst each example requires careful examination, it seems to be almost generally true that dithionite reduction of pyridinium salts gives l,4-dihydropyridinesi 1077, 1090-2, 1101 An exception is the... 

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