Dihydropyridine system

The reaction is of wide scope. Instead of ester groups as substituents at C-3 and C-5, other acceptor substituents—e.g. oxo, cyano, sulfonyl or nitro groups—can be employed in order to stabilize the 1,4-dihydropyridine system. 

Most of the data in Table 12 come from the work of Shvo et al. (78). Careful band-shape analysis and solvent-effect studies permitted evaluation of the rate constants and AG values at 298 K, which renders the discussion of substituent effects more meaningful than usual. The authors obtained reasonably linear Hammett plots when correlating log km with Or (79) for X and Y, holding one of these substituents constant. They also found that the dihydropyridine system may act as an unusually efficient donor, giving a AG of 17.6 kcal/mol with X, Y = H, CN, the only barrier below 25 kcal/mol reported for any donor-substituted cyanoethylene. However, with other acceptor combinations the dihydropyridine moiety is not so outstanding, and this illustrates the difficulty of measuring donor and/or acceptor effects by rotational barriers alone (vide infra). 

Cyclization of 1,5-diketones The reaction between 1,5-diketones and NH3 produces dihydropyridine systems, which can easily be oxidized to pyridmes. 

Dihydropyridines may be prevented from undergoing further reduction by carrying out reductions in aprotic solvents or in protic systems at high pH. Phase transfer methods have also been used to remove the dihydro adducts from the reactive medium prior to further reduction. An elegant solution to the problem of overreduction was developed by Fry reduction is carried out in the presence of cyanide ion, which traps the dihydropyridine system as 2-cyano-l,2,3,6-tetrahydropyridine (57 Scheme 13). The addition of alkoxide re-forms the dihydropyridine (58). Separation of 1,4-dihydropyridines from mix-... 

Heteroaromatic cations undergo reduction when treated with 1,4-dihydronicotinamide. An early study showed that the 10-methylacridinium ion (87) was rapidly reduced in a redox reaction to the 9,10-dihydro adduct by 1,4-dihydronicotinamides (M Scheme 18). A variety of systems including py-ridines, isoquinolines, quinolines and phenanthridines have been studied using this and related procedures. The selective reduction of pyridinium and quinolinium salts with 1-benzyl-1,2-dihydro-isonicotinamide (89) has been achieved. The selective conversion to the thermodynamically more stable 1,4-dihydro species (90 Scheme 18) is rationalized by the reversibility in the formation of the kinetic products (i.e. the 1,2-adducts) in the presence of pyridinium ions. In the pyridinium case 1,6-di-hydro adducts were also observed in some cases. Reactivity in such systems is sometimes hindered due to hydration of the dihydropyridine system. This is particularly so in aqueous systems designed to replicate biological activity. Dihydroazines derived from isoquinolines and 3,5-disubstituted pyridines have been reported to overcome some of these difficulties. ... 

When bicyclopropylidene was treated in the same way only trimers of the initially formed 8,9-diazadispiro[2.0.2.4]deca-7,9-diene were isolated.The cycloaddition reaction of the unsym-metrical dimethyl 3-cyano-l, 2,4-triazine-5,6-dicarboxylate with methylenecyclopropane was re-gioselective. The primary product was the 2-cyanospiro-3,4-dihydropyridine system (with C3 as spirocenter) which hydrolyzed readily upon chromatography. Dimethyl 4-oxo-5-aza-spiro[2.5]oct-5-ene-6,7-dicarboxylate was isolated as a stable product in 8%> yield. ... 

Reactions that proceed by transfer of hydride ions are widespread in organic chemistry, and they are important also in biological systems. Reductions involving the reduced forms of coenzymes I and II, for example, are known to proceed by transfer of hydride ion from a 1,4-dihydropyridine system to the substrate. In the laboratory, the most useful reagents of this type in synthesis are aluminium isopropoxide and various metal hydride reducing agents. 

Slama JT, Radziejewski C, Oruganti SR, Kaiser ET (1984) Semisynthetic enzymes Characterization of isomeric flavopapains with widely different catalytic efficiencies. J Am Chem Soc 106 6778-6785 Srinivasan R, Medary RT, Fisher HF, Norris DJ, Stewart R (1982) The pyridinium-dihydropyridine system. Reduction potentials and the mechanism of oxidation of 1,4-dihydropyridines by a Schiff base. J Am Chem Soc 104 807-812... 

A method for the synthesis of dialkyl carbonates makes use of l,l -carbonyl-bis(4-benzylidene-l,4-dihydropyridine) 993 as a reagent. The required activation energy for this reaction is provided by the aromatization energy of the 1,4-dihydropyridine system forming the 4-substituted pyridine 995. Di-tert-butyl carbonate 994 can be obtained in 66% yield [715]. 

Obviously, the aromatic nature of the pyridine ring is lost, too. This changes the light absorption very characteristically. The dihydropyridine system has a broad absorption maximum at 340 xn l, whereas the pyridine system does not absorb at that wavelength (cf. Fig. 22). If NADH is produced during a reaction, the absorption at 340 mu rises gradually. This rise in light absorption can be measured quite easily and thus the transition NAD+ <= NADH can be followed optically. The increase of absorption per unit time is proportional to the enzyme concentration (cf. Fig. 23). This optical test for enzyme activity, or enzyme assay, is of extreme practical importance in the laboratory. 

The basic metal salts and soaps tend to be less cosdy than the alkyl tin stabilizers for example, in the United States, the market price in 1993 for calcium stearate was about 1.30— 1.60, zinc stearate was 1.70— 2.00, and barium stearate was 2.40— 2.80/kg. Not all of the coadditives are necessary in every PVC compound. Typically, commercial mixed metal stabilizers contain most of the necessary coadditives and usually an epoxy compound and a phosphite are the only additional products that may be added by the processor. The requited costabilizers, however, significantly add to the stabilization costs. Typical phosphites, used in most flexible PVC formulations, are sold for 4.00— 7.50/kg. Typical antioxidants are bisphenol A, selling at 2.00/kg Nnonylphenol at 1.25/kg and BHT at 3.50/kg, respectively. Pricing for ESO is about 2.00— 2.50/kg. Polyols, such as pentaerythritol, used with the barium—cadmium systems, sells at 2.00, whereas the derivative dipentaerythritol costs over three times as much. The P-diketones and specialized dihydropyridines, which are powerful costabilizers for calcium—zinc and barium—zinc systems, are very cosdy. These additives are 10.00 and 20.00/kg, respectively, contributing significantly to the overall stabilizer costs. Hydrotalcites are sold for about 5.00— 7.00/kg. 

Another dideoxypyrimidine nucleoside active against human immunodeficiency vims is 3 -azido-2/3 -dideoxyuridine [84472-85-5] (AZDU or CS-87, 64) C H N O. Since its synthesis, (167) CS-87 has been identified as a promising antiHIV agent (168) and is currentiy undergoing phase I clinical trials in patients with AIDS and AIDS-related complex. It appears to be less potent than AZT against HIV in a peripheral blood mononuclear (PBM) cell screening system and in MT-4 cell lines. This lower activity in PBM cells appears to be related to a lower affinity of CS-87 for the enzyme responsible for its initial phosphorylation (169). However, CS-87 has significantly lower toxicity on bone marrow cells than AZT (170) and penetration of the CNS as a 5 -dihydropyridine derivative. 

Hansa Yellows, 1, 334 5, 299 Hantzsch synthesis, 2, 87-88 1,4-dihydropyridine, 2, 482 thiazoles, 6, 294-299 A -thiazolines, 6, 314 Hantzsch-Widman names parent names, 1, 35 stem suffixes, 1, 12 Hantzsch-Widman system nomenclature, 1, 11-12 Hardeners in photography... 

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). 

Azepines are much less common than the 1H- and 3//-isomers, and one of the few general synthetic approaches to this system is by base-catalyzed ring expansion of 4-(chloromethyl)-l, 4-dihydropyridines. e. g. I.29 Curiously, the ring expansion is also effected by potassium cyanate in refluxing ethanol. 

One problem with both these theories is that disruption of noradrenergic transmission by selective adrenoceptor antagonists has little impact on the development of escape deficits. However, such antagonists do prevent the reversal of learned helplessness by antidepressants (reviewed by Stanford 1995). Also, it would be most unlikely that a deficit in only one neurotransmitter system fully accounts for learned helplessness. Indeed, there is plenty of evidence for a role for 5-HT in learned helplessness for instance, this behaviour is reversed by microinjection of 5-HT into the prefrontal cortex (Davis et al. 1999). Finally, it is clear that opioid, GABAergic and cholinergic systems (among others) are all linked with this behavioural deficit and even dihydropyridine antagonists of Ca + channels prevent its development. 

Fig. 8 Schematic representation of dihydropyridine-pyridinium redox delivery system. (From Ref. 66)...

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