Dihydropyridine derivatives, formation

The formation of a double bond during anodic oxidations can result from eliminations of protons, carbon dioxide or acylium cations. The electrooxi dative aromatization of dihydropyridine derivatives and heterocycles containing nitrogen atom (di-hydroquinoxalines, tetrahydrocinnolines) involves an ECE mechanism as previously... 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

The basis of the chemistry was the photo-oxidation of dihydropyridines (DHP) and similar materials. It was believed that the oxidation resulted in formation of an aromatic pyridine derivative, which added adhesiveness to the coating surface. A number of dihydropyridine derivatives were prepared from readily available aldehydes and acetoacetic esters. Typical of these was derivative I. 

Details have been published of Sundberg s synthesis of desethylcatharanthine,121 and an independent new synthesis has also been reported.122" This new approach relies, for the formation of the complete skeleton, on a biogenetically patterned cycloaddition of an indole-2-acrylate to a 1,2-dihydropyridine derivative, and has immediately been applied to the synthesis of ( )-catharanthine (263) itself (Scheme 37).122 For this purpose, an iV-substituted 3-ethyl-1,2-dihydropyridine (264) was required, and since no reliable method for the synthesis of this compound was available, the route shown was devised. Addition of the indole-2-acrylate (265) to (264) gave (266) (major product) and the desired tetracyclic base (267) formation of the bond between Nb and C-5 then gave the quaternary bromide (268), and the... 

Miscellaneous Processes - The formation of cw-dimers is reported to occur when 1,4-dihydropyridine derivatives are irradiated in solution. ... 

Irradiation of some 1,4-dihydropyridine derivatives leads in some cases to the formation of cw-dimers and in others to oxidation products, and an enhanced regioselectivity has been observed for the [4 + 4] photodimerisation of 9-aminoacridizinium perchlorate (171 R = NH2, X = C104 ) as compared with (171 R = H, X = Br ). The head-to-tail products syn (172) and anti (173) are produced exclusively. Styryldicyanopyrazines undergo a selective topo-chemical photodimerisation in the solid state by a process whose reactivity and stereochemistry are controlled by differences in their molecular stacking. 

The method of Fan and Dasgupta (1994) relics on tlie reaction of formaldehyde with 1,3-cyclohexane-dione in acidified ammonium acetate to form the fluorescent dihydropyridine derivative in a flow injection analysis system. Formaldehyde trapped in water can be reacted with pararosaniline and sodium sulfite under mild conditions (neutral pH, room temperature equilibration) to produce a colored product that is measured at 570 nm (Petreas et al. 1986). The presence of bisulfite is an interference in this reaction so the method cannot be used to sample atmospheres that contain sulfur dioxide. In addition, the method is reported to suffer from interferences resulting from the presence of other aldehydes and phenol (Hoogenboom et al. 1987). The indirect method of Hoogenboom et al. (1987) relies on the reaction of excess bisulfite in an aqueous solution of formaldehyde with 5,5 -dithiobis(2-nitrobenzoic acid) to form a colored product, the absorbance of which is measured at 412 nm. The method reported by Naruse et al. (1995) relies on the formation of a colored product obtained by reacting the aqueous formaldehyde with acetylacetone and ammonium acetate in acetic acid. Absorbance is measured at 414 nm. 

Dehalogenation of a-halo ketones. a-Halo ketones can be dehalogenated by treatment with pyridine in acetone followed by addition of sodium hydrosulfite yield 50-75%. The method involves formation of a pyridinium salt, which is then reduced in acetic acid to a 1,4-dihydropyridine derivative this fragments spontaneously to the ketone and pyridine. ... 

Photoreactions of Pyridones - Irradiation of 1-benzyl-1,4-dihydronicotina-mide (161) with the malonate derivative (162) affords a variety of products resulting from debromination and dimerisation. The dihydropyridine derivatives (163) are photochemically reactive in the solid phase. The formation of the products by irradiation has been shown to be a two step process affording the (2+2)-cycloaddition product (164) in the first step. Secondary irradiation of (164) then gives the cage compounds (165) in yields greater than 90%. 

Whereas 4-methoxypyridinium salts react with cyclopentadienide anions to give cyclopentadienylidene-dihydropyridine derivatives, an attempted analogous reaction using 4-methoxypyrylium salts led to the formation of an azulene instead [185] ... 

Taking into account these considerations and the appearance of the second wave at a potential where the dimer is not reduced (see following text), in addition to the high dimeri2ation rate (reaction 12 and Sch. 1), and cychc voltammetric patterns, Elving and coworkers concluded that the second electron transfer has to be faster than the dimerization and thus, NAD+ is directly reduced to the dihydropyridine at the second wave in an overall 2e process. The rationale for involvement of a proton in the overall NAD+-reduction process derives from the formation of enzymatically active NADH. Two different sequences were thus postulated by these authors (1) e , e , H+ or (2) e , H+, e . If protonation of the free radical formed on addition of the first electron is very rapid, as compared with its dimerization rate constant, either sequence could be competitive with the dimerization reaction in producing the dihydropyridine derivative otherwise, the first sequence would be more likely [75]. This uncertainty was clearly solved by the fact that the neutral radical NAD is not further reduced in aprotic media and thus, protonation... 

The latter profile was interpreted in terms of the formation of two different types of complexes (Ohno et al. 1980a). In the presence of metal ions in excess, both the substrate and the 1,4-di-hydropyridine derivative are complexed by the metal ion. Under such circumstances, the 1,4-dihydropyridine derivative and the substrate cannot come close together because of the repulsive force between two positive charges on the magnesium ions. Consequently, the formation of the ternary complex that is indispensable for the reduction is suppressed. It should be emphasized that the formation of a ternary complex by the chelation with the metal ion is the most important factor for the metal ion-catalyzed model system. 

When methyl 2-(indol-2-yl)acrylate derivative (22a) reacted with A-methoxy-carbonyl-l,2-dihydropyridine (8a) in refluxing toluene, in addition to the dimer of 22a (25%), a mixture of the expected isoquinculidine 23a and the product 24a (two isomers) was obtained in 7% and 45% yields, respectively (81CC37). The formation of 24a indicates the involvement of the 3,4-double bond of dihydropyridine. Similarly, Diels-Alder reaction of methyl l-methyl-2-(indol-2-yl)acrylate (22b) with 8a gave, in addition to dimer of 22b, a mixture of adducts 23b and 24b. However, in this case, product 23b was obtained as a major product in a 3 2 mixture of two isomers (with a- and (3-COOMe). The major isomer shows an a-conhguration. The yields of the dimer, 23b, and 24b were 25%, 30%, and 6%, respectively. Thus, a substituent on the nitrogen atom or at the 3-position of indole favors the formation of the isoquinuclidine adduct 23. 

Alkyl-1,4-dihydropyridines on reaction with peracids undergo either extensive decomposition or biomimetic oxidation to A-alkylpyridinum salts (98JOC10001). However, A-methoxycarbonyl derivatives of 1,4- and 1,2-dihydro-pyridines (74) and (8a) react with m-CPBA to give the methyl tmns-2- 2>-chlorobenzoyloxy)-3-hydroxy-1,2,3,4-tetrahydropyridine-l-carboxylate (75) and methyl rran.s-2-(3-chlorobenzoyloxy)-3-hydroxy-l,2,3,6-tetrahydropyridine-l-carboxylate (76) in 65% and 66% yield, respectively (nonbiomimetic oxidation). The reaction is related to the interaction of peracids with enol ethers and involves the initial formation of an aminoepoxide, which is opened in situ by m-chlorobenzoic acid regio- and stereoselectively (57JA3234, 93JA7593). 

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... 

Step, aldol condensation to form the benzylidene derivative (12-3). Conjugate addition of a second mole of acetoacetate would then afford the 1,5-diketone (12-4). Reaction of the carbonyl groups with ammonia will lead to the formation of the dihydropyridine ring. Alternatively, acetoacetate may go on to form the imine (12-5) reaction of this with the aldol product (13-3) will give the same dihydropyridine. The product, nifedipine (12-6) [13], has been used extensively for the treatment of angina and hypertension. 

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. 

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