1.2- Dihydropyridine protonation

An interesting result has been observed when 4-formylantipyrine 89 was converted into the corresponding pyridinium salt 90 and reacted with alkyl 3-aminobut-2-enoates. Tire expected 1,4-dihydropyridines 91 are transient species in these syntheses and readily lose the 4-substituent (antipyrine, 93) so that dialkyl 2,6-dimethylpyridine-3,5-dicarboxylates 92 are obtained (85-95%) (94H815). Protonation of the pyrazole ring by the evolved hydrochloric acid accounts for this particular behavior (Scheme 29). 

Another approach to the generation of an iminium cation suitable for cyclization is the protonation of dihydropyridine derivatives. One example can be found in Scheme 48, where treatment of compound 243 with acid induced its cyclization to indoloquinolizine 244, a precursor in the first total synthesis of (i)-tangutorine 245, an alkaloid isolated from a traditional Chinese medicinal plant <2001TL6593>. 

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... 

One very unusual case of prototropic isomerization was revealed for anion-radicals of 1,4-dihydropyridine derivatives (Gavars et al. 1999). These anion-radicals transform into 4,5-dihydro-pyridine analogs through proton detachment and addition. 

Electron transfer reduction of pyridines in both acid and alkaline solution generates the protonated radical-anion. This rapidly accepts a further electron and a proton to give a mixture of dihydropyridines. Enamine structures in these dihydro-pyridines can tautomerise to the imine, which is more readily reduced than the original pyridine molecule. Further reaction of the 1,4-dihydropyridine leads to piperidine while reduction of the t, 2-dihydropyridine leads to a tetrahydropyridine in which the alkene group cannot tautomerise to the imine and which is not therefore reduced to the piperidine stage. The reaction sequence is illustrated for 2,6-dimethyl-pyridine 18 which yields the thermodynamically favoured cis-2,6-dimethylpiperidine in which the two alkyl substituents occupy equatorial conformations. 

The mechanism of 1,4-dihydropyridine reductions is actively being pursued (B-78MI20702). A mechanism involving hydride transfer is attractive because of its simplicity (80JA4198). However, many workers in the area prefer an electron transfer as the first step (79JA7402). The hydride mechanism can be completed by the transfer of a proton followed by an electron or by the transfer of a hydrogen atom (Scheme 29). It is unlikely that the mechanistic question will be resolved in the near future. It may be that the mechanistic pathway that these reactions follow is very sensitive to both the structure of the dihydropyridine and the compound being reduced. 

Lehn and coworkers have profitably employed tartaric acid-containing crown ethers as enzyme models. The rate of proton transfer to an ammonium-substituted pyridinium substrate from a tetra-l,4-dihydropyridine-substituted crown ether was considerably enhanced compared to that for a simple 1,4-dihydropyridine. The reaction showed first order kinetic data and was inhibited by potassium ions. Intramolecular proton transfer from receptor to substrate was thus inferred via the hydrogen bonded receptor-substrate complex shown in Figure 16a (78CC143). 

Recently, we established that several proton acids catalyze the metal-free reduction of ketimines under hydrogen-transfer conditions with Hantzsch dihydropyridine as the hydrogen source.Additionally, we were able to demonstrate a catalytic enantioselective procedure of this new transformation by employing a chiral Br0nsted acid as catalyst.(see Chapter 4.1). 

A proton is also transferred easily to C-5. Thus by the action of methanol on 1 -lithio-2-tcr/-butyl-1,2-dihydropyridine at -70°C, a mixture of 2-tert-butylpyridine and 2-/ert-butyl-1,2,5,6-tetrahydropyridine was formed through the intermediacy of 2-tert-butyl- 1,2-dihydro- and 2-tert-butyl-2,5-dihydropyridines.137 The latter types of intermediates have been actually isolated in a number of instances to provide some general validity to the sequence shown in Eq. (17).143... 

Treatment of 2-fluoro or 2-chloropyridine (8 or 9) with /i-BuLi or its TMEDA complex leads, by nucleophilic C-6 addition, to species 10 which, if protonated or alkylated, provides as the only isolable products the surprisingly stable 2,5-dihydropyridines 11 (Scheme 3) (81JOC4494). 

The importance of 1,4-dihydropyridine nucleotides in biological systems prompted the increasing interest in their electrochemical oxidation.238-243 The mechanistic aspects of the electrochemical oxidation of NADH involving removal of two electrons and one proton to form NAD4 has been examined in aqueous and DMSO media at a glassy carbon electrode.242 The reaction occurs according to an ECE mechanism ... 

Cationic rings are readily reduced under relatively mild conditions. 1-Methylpyridinium ion with sodium borohydride (in H20, 15°C) gives the 1,2-dihydro derivative (330) at pH > 7 and the 1,2,3,6-tetrahydro derivative (331) at pH 2-5. The tetrahydro compound is probably formed via (332) which results from proton addition to (330). Pyridine cations are also reduced to 1,2-dihydropyridines by dissolving metals, e.g. Na/Hg. 

Similar studies have been carried out in the 1,4-dihydropyridine series. Nevertheless, the detailed mechanism remains questionable and evidence in support of both possible reaction pathways, direct hydride transfer and electron-proton-electron transfer, were presented. 

Very strong bases can extract a proton from the 1,2- or 1,4-dihydropyridine ring giving a fully conjugated eight-7T-electron antiaromatic system, which can be trapped by electrophiles. 

Dihydropyridines (510) are susceptible to electrophilic attack. The 5-position is the kinetic site of protonation giving a 2,5-dihydropyridinium cation (511) which slowly rearranges to the thermodynamically more stable 2,3-dihydropyridinium ion (512). Alkylation of a 1,2-dihydropyridine at the 5-position can be carried out under phase-transfer conditions (513 — 514). 

The chemistry of flavins is complex, a fact that is reflected in the uncertainity that has accompanied efforts to understand mechanisms. For flavoproteins at least four mechanistic possibilities must be considered.1533 233 (a) A reasonable hydride-transfer mechanism can be written for flavoprotein dehydrogenases (Eq. 15-23). The hydride ion is donated at N-5 and a proton is accepted at N-l. The oxidation of alcohols, amines, ketones, and reduced pyridine nucleotides can all be visualized in this way. Support for such a mechanism came from study of the nonenzymatic oxidation of NADH by flavins, a reaction that occurs at moderate speed in water at room temperature. A variety of flavins and dihydropyridine derivatives have been studied, and the electronic effects observed for the reaction are compatible with the hydride ion mecha-nism.234 236... 

We illustrate this by two examples. Reaction of the 6-phenyl-1,2,4-triazine (407) with the enamine (406) follows orientation A since secondary orbital interactions between the n-electrons of the amino group and the 77-electrons of the phenyl ring are possible. The dihydropyridine (408) can eliminate the amine to form the cyclopenta[c]pyridine (409) since the cis orientated proton at C-3 can shift to the nitrogen to form the 1,4-dihy-dropyridine (410) from which the amine is eliminated. 

When 3-phenyl-l,2,4-triazine (411) reacts with the enamine (406), orientation B is followed. In this case the 3,4-dihydropyridine (412) is formed and is isolated. Elimination of the amine directly is unfavourable, because of the cis orientation, and transfer of the proton to the pyridine nitrogen is impossible. Oxidation to the (V-oxide (413) and Cope elimination affords the condensed pyridine (414) (78UP21900). 

Methyl groups attached to the pyridine ring are not usually involved in reactions with MP, but a minor product from 4-methylpyridine is the dihydropyridine 102.291 It could be formed via a zwitterion corresponding to 95, proton transfer giving 101, addition to another molecule of MP, and a further proton shift. 

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