Dihydropyridines dehydrogenation

Zhu Y, Wang F, Li Q, Zhu M, Du A, Tang W, Chen W (2014) Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation. Drug Metab Dispos 42 245-249... 

Apparently, aminobutenyne A, the intermediate of the pyrrole synthesis, is fixed in an advantageous eonfiguration by eoordination to the Cu eation, whereas the absenee of eatalyst may result in the formation of imine B having an aetive methylene group whieh attaeks the aeetylene bond to form dihydropyridine C and then pyridine 2 (by dehydrogenation). 

The above examples show the ability of microsome reductases to oxidize substrates in the processes where the first step is a one-electron reduction, which may or may not be accompanied by superoxide formation. However, cytochrome P-450 can directly oxidize some substrates including amino derivatives. For example, mitochondrial oxidation (dehydrogenation) of 1,4-dihydropyridines apparently proceeds by two mechanisms via hydrogen atom abstraction or one-electron oxidation [48 50]. Guengerich and Bocker [49] have shown that... 

No further research was performed in this field until three decades later, when Arcadi et al. developed a one-pot entry into functionalized pyridines. Reaction required a catalyst to dehydrogenate a dihydropyridine intermediate to pyridine. At that time, the liberated hydrogen was believed to be a consequence of aromatization [189]. 

The interaction between pyridine and organolithium compounds in benzene was first reported by Ziegler and Zeiser129 and was attributed to the formation of 1 1 adducts. Indirect evidence for intermediates of this kind was based on the formation of dihydropyridines by treatment of the reaction mixture with water. More definite evidence was obtained with quinoline, isoquinoline, and acridine.130 Phenyllithium reacts quantitatively with quinoline in ether to yield an adduct as a yellow powder that can be recrystallized. In order to define the site of attachment, the adducts were hydrolyzed to dihydro derivatives and the latter dehydrogenated. Because this treatment leads mainly to 2-phenyIquinoIine and l-phenylisoquinoline from quinoline and isoquinoline, respectively, the related adducts can be assumed to have structures 80 and 81. Isolation and characterization of the dihydro derivatives have been carried out, as well as in the case of the reaction of acridine with phenyllithium. 

This allows an aldol-type reaction with the A-methylpyrrolinium cation, and finally dehydrogenation of the dihydropyridine ring back to a pyridine gives nicotine. Nornicotine is derived by oxidative demethylation of nicotine. Anaba-sine is produced from nicotinic acid and lysine via the A1 -piperidinium cation in an essentially analogous manner (Figure 6.32). A subtle anomaly has been exposed in that a further Nicotiana alkaloid anatabine appears to be derived by... 

This reaction allows the preparation of dihydropyridine derivatives by condensation of an aldehyde with two equivalents of a p-ketoester in the presence of ammonia. Subsequent oxidation (or dehydrogenation) gives pyridine-3,5-dicarboxylates, which may also be decarboxylated to yield the corresponding pyridines. 

Ritter reaction. A similar cyclization dehydrogenation reaction had previously been observed by Kohler and Souther,83 who obtained both 102 and 103 when 101 was treated with dry hydrogen chloride. They suggested that 102 and 103 arose by a disproportionation of the intermediate dihydropyridine. 

A series of 4-aryl-6-(l//-indol-3-yl)-2,2-bipyridine-5-carbonitriles 9 was synthesized by Perumal and co-workers [60] via a one-pot MCR of an aromatic aldehyde, a 3-(cyanoacetyl)indole, 2-acetyl pyridine and ammonium acetate by microwave irradiation under solvent-free conditions. The compounds were obtained in high yields and in a very short period of time as compared to conventional heating. Remarkably, when 2,4-dichlorobenzaldehyde was used in this reaction, only the Hantzsch 1,4-dihydropyridine was isolated which had to be separately dehydrogenated to get the targeted pyridine (Scheme 9). 

Dihydropyridine derivatives resulting from the Hantzsch synthesis are dehydrogenated to pyridines by heating with a dilute mixture of nitric acid and sulfuric acid (yields 58-65%) [ 5S] (see equation 41). 

Pyridines. Hantzsch 1,4-dihydropyridines undergo dehydrogenation on exposure to bismuth nitrate pentahydrate in HOAc at room temperature (7 examples, 50-90%). 

Aromatization. Dehydrogenation of Hantzsch 1,4-dihydropyridines occurs under an oxygen atmosphere in the presence of RuClj. 

A great variety of methods is available for the ring synthesis of pyridines the most obvious approach is to construct a 1,5-dicarbonyl compound, preferably also having further unsaturation, and allow it to react with ammonia, when loss of two mole equivalents of water produces the pyridine. 1,4-Dihydropyridines, which can easily be dehydrogenated to the fully aromatic system, result from the interaction of saturated... 

Ammonia reacts with 1,5-dicarbonyl compounds to give 1,4-dihydropyridines, which are easily dehydrogenated to pyridines. With unsaturated 1,5-dicarbonyl compounds, or their equivalents (e.g. pyrylium ions), ammonia reacts to give pyridines directly. 

From an Aldehyde, Two Equivalents of a 1,3-Dicarbonyl Compound and Ammonia Symmetrical 1,4-dihydropyridines, which can be easily dehydrogenated, are produced from the interaction of ammonia, an aldehyde and two equivalents of a 1,3-dicarbonyl compound, which must have a central methylene. 

The 1,4-dihydropyridines produced in this approach, carrying conjugating substituents at each P-position, are stable, and can be easily isolated before dehydrogenation classically the oxidation has been achieved with nitric acid, or nitrous acid, but other oxidants such as ceric ammonium nitrate, cupric nitrate... 

The main chemical aspect in which compounds with a nitrogen in a five- or six-membered ring differ from their acyclic counterparts is that they can be dehydrogenated to the corresponding aromatic system. Dihydro-aromatic systems naturally show Ihe greatest tendency to aromatise, indeed one of the important reducing coenzymes, NADPH (a 1,4-dihydropyridine), makes use of this tendency - it is a hydride donor ... 

Dihydro compounds are often useful synthetic intermediates showing different reactivity patterns to the parent, aromatic heterocycle. For example, indolines (2,3-dihydroindoles) can be used to prepare indoles with substituents in the carbocyclic ring, via electrophilic substitution then aromatisation (20.16.1.17), and similarly, electrophilic substitutions of dihydropyridines, very difficult in simple pyridines, followed by aromatisation, can give substituted pyridines. Dehydrogenation of tetra- and hexahydro-derivatives reqnires more vigorous conditions. 

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