5.6- Dihydropyridin-2-ones, formation

Once formed, 7 and 8 undergo a Michael reaction that gives rise to ketoenamine 9. Ring closure, to form 10, and loss of water then afforded 1,4-dihydropyridine 11. The presence of 9 and 10 could not be detected thus ring closure and dehydration were deduced to proceed faster than the Michael addition. This has the result of making the Michael addition the rate-determining step in this sequence. Conversely, if the reaction is run in the presence of a small amount of diethylamine, compounds related to 10 could be isolated. Diol 20 has been isolated in an unique case (R = CFb). Attempts to dehydrate this compound under a variety of conditions were unsuccessful. Stereoelectronic effects related to the dehydration may be the cause. In related heterocyclic ring formations, it has been determined that dehydration (20 —> 10) is about 10 times slower than diol formation (19 —> 20). Therefore, one would expect 20 to... 

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... 

The Lewis acid-catalyzed three-component reaction of dihydropyridines, aldehydes, and />-substituted anilines efficiently yields highly substituted tetrahydroquinolines in a stereoselective manner, through a mechanism believed to be imine formation followed by formal [4-1-2] cycloaddition (Scheme 41). The 1,4-dihydropyridine starting materials were also prepared in situ by the nucleophilic addition of cyanide to pyridinium salts, creating in effect a one-pot four-component reaction <20030L717>. 

When toluene solutions of 2-azabicyclo[3.2.0]hepten-4-ones were heated between 120-200°C in sealed tubes, a [1,3] shift of Cl and an ensuing decarbonylation produced dihydropyridines 220,21,130,133 an(j 3 132 either ri or r2 were vinyl groups, other [1,3] or [3,3] shifts competed successfully with dihydropyridine formation (see Sections 2.4.3.1. and 2.4.4.). The proposed intermediates of this reaction, e.g. 2-azabicyclo[2.2.1]heptenes 4 and 5 were isolated in the thermolysis of the related 3-ethoxy-2-azabicyclo[3.2.0]heptenes20-130,131,133 in toluene between 140-180°C. 

On the other hand, one of the intermediate structures, namely structure VII, seems to be possibly converted to 1,4- dihydropyridine structure (XI), from the structural point of view. Besides, since A max of band III14 for XI is expected to be similar to that of the above side peak,15 the appearance of this peak would indicate the actual formation of XI. From the observation that the appearance of this peak was always temporary, and also from the structural relation between XI and the end structure IX — the expected... 

Perhaps one of the best known syntheses of a heterocyclic polymer via the modification method is the generation of nitrogen-containing ladder polymers by pyrolysis of polyacrylonitrile) (77MI11109). The thermolysis is known to take place in discrete steps. The first step in the sequence, which can take place with explosive violence if the heating rate is not sufficiently slow, occurs at about 150 °C and can be detected by the onset of intense color formation. The product of this reaction (Scheme 101) is the cyclic tetrahydropyridine ladder structure (209). The next step, which is conducted in the presence of air at ca. 250 °C, involves the thermooxidation of polymer (209) to form what is best described as terpolymer (210) containing dihydropyridine, pyridone and pyridine units. 

A one-step synthesis of furo[3,2-c]- and furo[3,2-6]-pyridines has been realized using a cycloaddition reaction of an alkynic compound with 3,5-dichloropyridine 1-oxide (Scheme 15) (75JA3227). Formation of (75) probably proceeds through a 1,2-dihydropyridine (73) with a subsequent 1,5-sigmatropic shift to (74) elimination of hydrogen chloride yields... 

Examination of the molecular dynamics (MD) simulation dehydrogenases with substrate and NAD(P)H at the active site shows that only one of the possible quasi-boat conformations exists (Bruice and Lightstone, 1998). The NAC structure in the lactate dehydrogenase active site is associated with the formation of the quasi-boat conformation. In this configuration the distance between the transferring hydride and pyruvate carbonyl is about 1 A shorter when the dihydropyridin ring is in the boat form than in the planar conformation. The closeness of the approach of the reactants in this pretransition state, and... 

The resulting achiral iminium cations, with chiral phosphate counteranion, were then enantioselectively reduced using an achiral Hantzsch ester (dihydropyridine) providing enantioenriched amines. During this imine reduction study, one example was shown in which acetophenone and p anisidine [16] were prestirred in the presence of toluene and 4 A molecular sieves [17] for 9h (imine formation), after which the temperature was raised to 35 °C, and the Hantzsch ester (1.4 equiv) and phosphoric acid (TRIP, 5 mol%) were added to give the amine product in 88% ee over an additional 45 h. This is an exciting observation and while not a reductive amination, it is an operational improvement over simple imine reduction which requires imine isolation. 

Formally, one can also propose the formation of the 2,5-dihydro isomer, but even if this isomer does form during the reaction, it is easily transformed to the thermodynamically more stable 1,2-dihydro compound. This reaction is nearly identical to the classical Hantzsch s synthesis of dihydropyridines, with only the molar ratio of starting materials being changed. However, in contrast to the widely investigated Hantzsch reaction, there are few examples in the literature, and it needs detailed study. 

In addition to natural products, a multitude of biologically active unnatural compounds have also been synthesized using the Knoevenagel condensation. A few recent examples are given here. In an attempt to obtain enantiomerically pure 1,4-dihydropyridines as calcium channel antagonists, (/ )-sulfmylpropan-one (320) was condensed with 2-chlorobenzaldehyde in acetonitrile with piperidine as catalyst to provide exclusively the ( )-benzylidene compound (321). Formation of the (5)-l,4-dihydropyridine (323) as a... 

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