Dihydropyridines, solution-phase

Marubayashi et al. <1997J(P2)1309> have also shown that solid-state dimerization is possible and propose that there is a buffer zone in the crystal structure of 1,4-dihydropyridines that governs the solid-state photodimerization process. This is exemplified by the fact that dimethyl l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicar-boxylate 83 cannot undergo solid-state photodimerization (Equation 21), whereas the structurally related (4/ 3, l / 3 )-methyl-l-phenyl-2-piperidinoethyl-l,4-dihydro-2,6-dimethyl-4-(2-thienyl)pyridine-3,5-dicarboxylate 84 affords a single product 5 (Scheme 2). Interestingly, when the photodimerization conditions are applied to the corresponding solution-phase reaction, the sole product is that of aromatization giving product 85. 

The isoquinuclidine ring system is readily accessible through various synthetic routes. The most widely used approach to the construction of the ISQ ring system is through Diels-Alder or 4+2 cycloaddition reactions. Dihydropyridines (DHPs) or 1,3-cyclohexadienes are most commonly employed as diene components and various dienophiles have been employed based on the substitution pattern of the final desired product. Intramolecular cyclizations, tandem-Michael addition/aldolizations or cyclization via tricyclic aziridines or perhydro / -aminobenzoic acid derivatives have also been reported. Several synthetic routes employing asymmetric or chiral synthetic approaches have also been reported. Most recently, solution-phase parallel synthesis of ISQ derivatives using several of these approaches has been reported [49,50,51]. 

Parallel solution-phase synthesis of 1,4-dihydropyridine derivatives... 

To a stirred solution of a,/ -unsaturated aldehyde (0.5 mmol) in dioxane (7 mL) at 13 °C was added catalyst (20.4 mg, 0.05 mmol, 10 mol%) and, after a further 5 min, crystalline dihydropyridine (Hantzsch ester, 129.2 mg, 0.51 mmol). After a reaction time of 48 h the mixture was poured into distilled water (20 mL) and extracted with DCM (2 x 125 mL). The combined organic layers were dried (MgSCh), filtered, and concentrated. The product was isolated by FC (Si02, ethyl acetate/hexane) to give the saturated aldehyde. Enantiomeric excess was measured by chiral stationary phase GC-analysis. 

Solid-phase syntheses of a wide variety of heterocycles have been published over the past year (Fig. 7). A number of these involve the relative straightforward application of known solution-based sequences to solid phase. This includes solid-phase versions of the Biginelli reaction to prepare pyrimidinones [36], dihydropyridines [37], pyrazoles [38], and phthalhydrazides [39]. 

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-... 

Solid state NMR spectroscopy has been used to analyse the dimerisation of the 1,4-dihydropyridine derivative (107) that yields the two dimers (108) and (109) on irradiation. This report complements an earlier account of the same dimerisation. The reaction is claimed as a useful synthetic entry into derivatives of 3,9-diazatetraasteranes. The photodimerisation of the thymine derivative (110) does not take place to any great extent on direct irradiation in solution but when acetone-sensitisation is used all four possible (2+2)-cycloadducts are obtained. Only one of these dimers is obtained from the irradiation in the crystalline phase and this was identified as the cis,anti,cis dimer (111). Interestingly, when the thymine (110) is crystallised from acetonitrile both needles and plates are obtained but only the needle form of the crystalline compound gives the dimer (111). ... 

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