The electrochemical oxidation of 4-monoalkyl-substituted 1,4-dihydropyridines has been studied in an aprotic medium and in the presence of pyridine. In an aprotic medium the products of oxidation are both 4-alkyl-substituted and 4-unsubstituted pyridines or mixtures of them. On oxidation in acetonitrile of 4- 2,3, were obtained in addition to the oxidized forms. In the presence of base the products of preparative electrolysis of the studied compounds were 4-alkyl-substituted pyridines. The exception was the 4-i-Prsubstituted dihydropyridine which was dealkylated on oxidation even in the presence of base.Dihydropyridines are one of the most investigated classes of organic compounds. The synthesis and reactions of 1,4-dihydropyridines have been examined in detail in reviews [1][2][3][4]. Many compounds of this series possess pharmacological activity. A series of pharmaceuticals [5] has been developed based mainly on 4-arylsubstituted 1,4-dihydropyridines. Antioxidant properties have also been confirmed for the heterocycle itself in reactions with various radicals [6,7]. On the other hand study of the redox reaction of the dihydropyridine ring is also important for the reason that its oxidation is the main metabolism of dihydropyridines.The attention of electrochemists is mainly attracted [8][9][10][11][12][13] by the oxidation of 4-methyl-, 4-aryl-1,4-dihydropyridines or those unsubstituted in position 4. In all the mentioned cases proton is split off from the position 4 of the ring on oxidation. N Me H Me R H COOMe MeOOC 1-5 1 R = Me, 2 R = Et, 3 R = n-Pr, 4 R = i-Pr, 5 R = i-Bu
A series of 6-alkylsulfanyl-1,4-dihydropyridines (±)-2 bearing a methoxycarbonylethyl group as a mild easily removable protecting group at S atom have been prepared by alkylation of 6-thioxo-1,4-dihydropyridines 1 with methyl bromopropionate. Candida antarctica lipase B (Novozyme 435 ® , CAL-B) -and Amano Acylase (Aspergillus mellus)-catalyzed kinetic resolution has been investigated in water-saturated diisopropyl ether (IPE) at 25 and 45 C. After acrylic acid methyl ester as leaving group cleavage and alkylation of formed enantioenriched 1,4-dihydropyridine-6-thiolates (-)-4 and (+)-4, optically active 1,4-dihydropyridines (-)-2, (+)-2, (-)-5 and (+)-5 were obtained in 85-99% enantiomeric excess. The experiments present the 6-(methoxycarbonylethyl)sulfanyl group as an essentially new enzymatically labile (activating) group. The ester group being 6 bonds remote from the chiral center undergoes easy enzymatic hydrolysis and could be used for kinetic resolution of racemic 1,4-DHPs. This developed method offers access to mild optically active nucleophilic tiolates, which could be easily derivatized with electrophilic reagents. sodium, potassium or chloride channels and act as selective or multifunctional molecules for the various pharmacobiological activities such as bioprotective, 5 neurotropic, 6 membrane protecting, 7-9 radioprotecting, 10 antidiabetic, 11 gene-transfection, 12 and antibacterial. 13 6-Alkylsulfanyl-1,4-DHPs display cardiovascular, 14-15 hepatoprotective, 16 antioxidant, 17 and antiradical 18 activities (in addition to the above mentioned activities), however, these compounds are still insufficiently studied.Chirality plays an important role in the activity of 1,4-DHPs and both quantitative and qualitative differences between different stereoisomers (enantiomers) have been reported. 19,20 Pharmaceutical evaluations of chiral 1,4-DHPs revealed that their strereoisomers usually have different biological activities. Sometimes the undesired enantiomer caused serious side effects, while in other cases enantiomers were reported to have even the opposite action profile (calcium antagonist -calcium agonist;hypotensive activity -hypertensive activity). 21Chemoenzymatic methods for preparation of chiral drugs have a number of distinct advantages: they are simple, direct, efficient, mild, and cheap in case of multiple (repeated) use of the enzyme. The standard resolution technique, such as incorporation of an enzymatically labile group for the resolution of monocyclic 1,4-DHPs has been in use for the last decade. This approach has been pioneered by groups of Sih 22 and Achiwa, 23 applied to 6-derivatised 1,4-DHPs 24-26 and also used by our research group. [27][28][29][30][31][32] It is worth mentioning that many activating groups applicable to enantioselective lipase-catalyzed kinetic resolution of 1,4-dihydropyridine-3-carboxylates have been screened. An asymmetric 1,4-DHPs alkoxycarbonylmethoxycarbonyl (double esters), 27,28 alkylcarboxymethyloxycarbonyl (reverse esters) in position 5 25,30-33 and acetoxy...
Abstract6-Alkylsulfanyl-1,4-dihydropyridines
The hydrogenation of sodium and ethyl 2-oxo-4-(2-thienyl)butenoate at Raney nickel and pai~dium black was investigated. With Raney nickel the reaction products were the corresponding derivatives of 2-oxo-4-(2-thienyl)butyric acid and 2-hydroxy-4-(2-thienyl)butyric acid and the products from bimolecular condensation.If palladium black is used, the reaction can be directed toward the selective formation of the corresponding derivative of 2-oxo-4-(2-thienyl) The derivatives of 4-substituted 2-oxobutyric acids are important synthons for the production of antihypertensive products [1], homoamino acids, hydroxamic acids, and other compounds [2]. In order to obtain these synthons we investigated the hydrogenation of derivatives of the 2-oxo-4-phenylbutenoic acid series at nickel and palladium catalysts [2][3][4]. During the hydrogenation of sodium 2-oxo-4-phenylbutenoate at nickel catalysts the corresponding salt of 2-hydroxy-4-phenylbutyric acid is obtained with yields of up to 94% [3]. At palladium catalysts a mixture of the salts of 2-hydroxy-4-phenylbutyric and 2-oxo-4-phenylbutyric acids is formed [4, 5]. Under strictly defined conditions the process can be directed toward the selective formation of sodium 2-oxo-4-phenylbutyrate. The 2-oxo-4-phenylbutenoic esters are hydrogenated at a higher rate but less selectively with respect to the formation of the corresponding saturated oxo compound than the corresponding sodium salt.During the hydrogenation of sodium 2-oxo-4-phenyl-(2-furyl)butenoate at Raney nickel catalyst the corresponding salts of 2-oxo-4-(2-furyl)butyric and 2-hydroxy-4-(2-furyl)butyrie acids and aliphatic compounds from the hydrogenolysis of the initial compound are formed [5]. Sodium 2-hydroxy-4-(tetrahydrofuryl)butyrate and a condensation product [a derivative of 3-(2-furylmethyl)-4-(2-furyl)-2-oxo-3,4-didehydroglutaric acid] were also detected in the products.Comparison of the hydrogenation of the derivatives of 4-substituted furyl-and phenylbutenoic acids at Raney nickel catalysts indicates that the formation of sodium 2-oxo-4-(2-furyl)butyrate (yield 66%) is highly selective compared with the hydrogenation of the corresponding phenyl derivative, with which sodium 2-hydroxy-4-phenylbutyrate is mainly formed. The increased selectivity for the formation of the salt of the c~-keto acids of the furan series is probably due to complexation between the compound and the nickel.In the present communication we present data on the hydrogenation of sodium and ethyl 2-oxo-4-(2-thienyl)butenoate at Raney nickel and palladium black. There is no information in the literature on the hydrogenation of these compounds. The hydrogenation was carried out at 17-80~ with the compound at an initial concentration of 0.18-0.21 M in water-alcohol solution and a compound-Raney nickel (wet) ratio 1:1 and a compound--palladium black (wet) ratio 1:0.86 (Table I). The hydrogenation products contained sodium 2-oxo-4-(2-thienyl)butyrate and 2-hydroxy-4-(2-thienyl)butyrate and condensation products. In the esterification products b...
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