Pyridinium salts dihydropyridine

Thus the critical synthetic 1,6-dihydropyridine precursor for the unique isoquinuclidine system of the iboga alkaloids, was generated by reduction of a pyridinium salt with sodium borohydride in base (137-140). Lithium aluminum hydride reduction of phenylisoquinolinium and indole-3-ethylisoquinolinium salts gave enamines, which could be cyclized to the skeletons found in norcoralydine (141) and the yohimbane-type alkaloids (142,143). 

Chiral dihydropyridines such as 103 were also accessible from Zincke-derived N-alkyl pyridinium salt 102 (Scheme 8.4.34). The dihydropyridine underwent cycloaddition with methylacrylate, providing chiral isoquinuclidine derivative 104 as the major diastereomeric product. ... 

Marazano and co-workers have also applied the reactions of tryptamine with various Zincke salts, including 115 (Scheme 8.4.39), in the synthesis of pyridinium salts such as 116. This type of product is useful for further conversion to dihydropyridine or 2-pyridone derivatives. For example, in a different study, Zincke-derived chiral pyridinium salts could be oxidized site-selectively with potassium ferricyanide under basic conditions as a means of chiral 2-pyridone synthesis (117 —> 118, Scheme 8.4.40). 

An interesting result has been observed when 4-formylantipyrine 89 was converted into the corresponding pyridinium salt 90 and reacted with alkyl 3-aminobut-2-enoates. Tire expected 1,4-dihydropyridines 91 are transient species in these syntheses and readily lose the 4-substituent (antipyrine, 93) so that dialkyl 2,6-dimethylpyridine-3,5-dicarboxylates 92 are obtained (85-95%) (94H815). Protonation of the pyrazole ring by the evolved hydrochloric acid accounts for this particular behavior (Scheme 29). 

Further elaboration of 152 resulted in the synthesis of (derived from the reduction of pyridinium salt 150b with excess of LiAlFt4 in THE Acid-catalyzed cyclization of 154 led to indoloquino-lizidine 155 (25% yield from 150b), a precursor of deplancheine (80TL2341) (Scheme 5). 

Omission of the phenolic group from cyclazocine results in a molecule which retains analgesic activity. In a classical application of the Grewe synthesis,15 the methylated pyridinium salt 54 is condensed with benzylmagnesium bromide. There is thus obtained the dihydropyridine 55. Treatment of that intermediate with sodium borohydride results in reduction of the iminium function to afford the tetrahydro derivative 56. Cyclization of 56 on treatment with acid leads to the desired benzomorphan nucleus. The cis compound (57) is separated from the mixture of isomers and demethylated by the cyanogen bromide procedure (58,... 

N Bodor, E Shek, T Higuchi. Delivery of a quaternary pyridinium salt across the blood-brain barrier by its dihydropyridine derivative. Science 190 155-156, 1975. 

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. 

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. 

A. El-Koussi, N. Bodor, Improved Delivery through Biological Membranes. XXV. Enhanced and Sustained Delivery of Trifluorothymidine to the Brain Using a Dihydropyridine <-> Pyridinium Salt Type Redox Delivery System , Drug Design Delivery 1987,... 

The electroreduction of deactivated pyridines or pyridinium salts affords selectively the corresponding 1,2- or 1,4-dihydropyridine derivatives according to the position of the substituents (Schemes 133 and 134) [243]. In the same experimental conditions a monoactivated pyridine is not reducible. 

Prokai, L. Hsu, B.-H. Farag, H. Bodor, N. Desorption Chemical Ionization, Thermospray, and FAB-MS of Dihydropyridine - Pyridinium Salt-Type Redox Systems. Anal. Chem. 1989, 61, 1723-1728. 

Silylcuprates have been reported to undergo reactions with a number of miscellaneous Michael acceptors [65]. Conjugate addition to 3-carbomethoxy acyl pyri-dinium salts [65a] affords 4-silyl-l,4-dihydropyridines. Oxidation with p-chlorand generates a 4-acyl pyridinium salt that gives the 4-silylnicotinate upon quenching with water, and methyl 4-silyl-2-substituted dihydronicotinates upon quenching with nucleophiles (nucleophilic addition at the 6-position). The stabilized anion formed by conjugate addition to an a, j8-unsaturated sulfone could be trapped intramolecularly by an alkyl chloride [65b]. 

The reaction of nucleophiles with pyridinium salts leads to addition, giving dihydropyridines. Attack... 

Nucleophilic addition readily takes place with pyridinium salts attack is normally easier at the C-2(6) position, since the inductive effect of the positively charged nitrogen atom is greatest here (Scheme 2.28). When the sites adjacent to the nitrogen are blocked, however, attack occurs at C-4. The products are dihydropyridines. 

Similar results are obtained from reaction of pyridine A-oxide derivatives with 146 and several transformations, including ring opening, have been described. Reaction of pyridinium salts and 146 gives the corresponding 4-substituted-1,4-dihydropyridine derivatives 212 (Scheme 7.65). 

Other carbonyl derivatives used in cyclization are mono- or di-anils pyridines are obtained, although dihydropyridines might have been expected. Dianils are generally made from pyridinium salts (see Section 2.08.3.4.4) but can be obtained from furfural (equation 7) (05CB3824). The products from dianils are Af-arylpyridinium salts (equation 7 and compound 9). The latter example shows the full sequence for conversion of one pyridinium salt to another, included here because the intermediate dianil can be isolated (05LA(34l)365). 

The Lewis acid-catalyzed three-component reaction of dihydropyridines, aldehydes, and />-substituted anilines efficiently yields highly substituted tetrahydroquinolines in a stereoselective manner, through a mechanism believed to be imine formation followed by formal [4-1-2] cycloaddition (Scheme 41). The 1,4-dihydropyridine starting materials were also prepared in situ by the nucleophilic addition of cyanide to pyridinium salts, creating in effect a one-pot four-component reaction <20030L717>. 

Bodor and Brewster (1983) first used the term CDS, in describing the use of dihydropyridine ester- (or amide)-linked prodrugs such as 27 (X-OH is the parent) which can partition readily into the CNS, there to be oxidized to pyridinium salts (28), which are effectively trapped in the biophase because of their extreme polarity, and which then undergo enzymic or chemical hydrolysis of the now very labile ester link to release active drug. 

An asymmetric synthesis of 1,2-dihydropyridines has been achieved by the addition of Grignard reagents to the pyridinium salt generated from 3-(triisopropylstannyl)pyridine and the chloroformate of 8-arylmenthyl based chiral auxiliaries (Scheme 22) (91JOC7167). 

Dihydropyridines can be prepared on cross-linked polystyrene by the addition of organometallic reagents to pyridinium salts (Entry 6, Table 15.21). These reactions do not always give high yields because of several competing processes (e.g. cleavage of the linker, deacylation of the /V-acylpyridinium salt). 

Support-bound alkylating agents have been used to N-alkylate pyridines and dihydropyridines (Entries 7 and 8, Table 15.21). Similarly, resin-bound pyridines can be N-alkylated by treatment with a-halo ketones (DMF, 45 °C, 1 h [267]) or other alkylating agents [246]. Polystyrene-bound l-[(alkoxycarbonyl)methyl]pyridinium salts can be prepared by N-alkylating pyridine with immobilized haloacetates (Entry 8, Table 15.21). These pyridinium salts react with acceptor-substituted alkenes to yield cyclopropanes (Section 5.1.3.6). Pyridinium salts have also been prepared by reaction of resin-bound primary amines with /V-(2,4-dinitrophenyl)pyridinium salts [268,269]. 

Dihydropyridines, such as 103, obtained from the corresponding pyridinium salts with bases, usually give 1 2 molar adducts (e.g., 105) with MP, but-l-yn-3-one, and 3-phenylprop-l-yn-3-one. Occasionally 1 1-molar adducts such as 104 can be isolated, and it is noteworthy that the acetylenes appear to attack only the exocyclic double bond.295... 

M. E. Brewster, K. S. Estes, R. Perchalski, and N. Bodor, A dihydropyridine conjugate which generates high and sustained levels of the corresponding pyridinium salt in the brain does not exhibit neurotoxicity in cynomolgus monkeys, Neurosci. Lett. 87 211 (1988). 

N. Bodor, R. G. Roller, and S. J. Selk, Elimination of a quaternary pyridinium salt delivered as its dihydropyridine derivative from brain of mice, J. Pharm. Sci. 67 685 (1978). 

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