Dihydropyridines tautomerism

However, no tautomeric interconversions between 1,2-dihydro- and 1,4-dihydropyridine analogs have been observed, probably because a high energy barrier is inherent to this transformation. 

V-Unsubstituted dihydropyridines can exist in at least five tautomeric forms (Section 2.2.5.2). At least for /V-substituted compounds 1,4-dihydropyridines (cf. 453) are generally more stable, by ca. 9 kJ mol than the 3,4-dihydro and the 1,2-dihydro isomers (cf 454). By contrast 2/f-pyrans appear to be thermodynamically more stable than 4//-pyrans. All three types of 1,3-oxazine are known. 

A high density of electrons associated with atoms C(3) and C(5) of 1,4-dihydropyridines and 1,4-dihydropyrimidines is also observed when these heterocycles undergo electrophilic substitutions such as Friedel-Crafts [315, 316, 317, 318, 319, 320] and Vilsmeier [297, 321] reactions (Scheme 3.99). In [315] it was shown that treatment of dihydropyridines 371 with aroyl or acyl chlorides 372 in the presence of SnCl4 leads to acylation of the heterocycle at position 3 (compounds 373). Dihydropyridines 374 and dihydroazolopyrimidines 376 undergo Vilsmeier reaction with the formation of the corresponding derivatives 375 and 377. It is interesting that imine heterocycle 376 after Vilsmeier reaction exists in the enamine tautomeric form. The tautomerism of dihydroazines and factors influencing it will be discussed in detail in Sect. 3.8. 

There are many possibilities for tautomerism in partially-saturated derivatives. Dihydropyridines can exist in several tautomeric forms, e.g., 37 and 38, of which the 1,4-dihydro isomers are usually the most stable. Similarly, dihydro-1,2,4,5-tetrazines have been formulated as the 1,2-, 1,4-, 1,6- and 3,6-dihydro structures but the 1,4-dihydro structure is probably the most stable. In contrast, 2/7-pyrans, e.g., 67, are more stable than 4/7-pyrans, e.g., 68. Of the five possible dihydropyrimidines most known derivatives have 1,2-, 1,4-, or 1,6-dihydro structures of which the 1,2-structure is calculated to be the most stable <1985AHC(38)1>. 

If the internal nucleophile is an alkenic group, then 5,6-dihydropyridine (Scheme 18) " or 1-pyrroline (Scheme 19) rings are produced. In a recent development of the latter process, the diol (44) follows the same sequence to yield the carbenium ion (45 R = Bn). However, this now cyclizes onto the aromatic group originating from the nitrile component and produces the tetrahydrobenz indole (46) in good yield, with the conventional pyrroline structure (47) now being only a minor product. Compound (46), present as a tautomeric mixture, was rapidly autoxidized to (48 Scheme 20). A further unusual variant of this process is the production of small quantities of the 3-azabicyclo[3.3.0]octanes (49) and (50) from Ritter reaction of l-vinylbicyclo(2.1.1]hexane (equation 32). ... 

Pyrazol-3-one 392 reacts with arylidene malononitriles 393a-c in basic ethanolic medium to yield the 6-(3-oxopyrazol-4-yl)-2-oxo-l,2,3,4-tetrahydropyridine/ 2-hydroxy-6-(3-oxopyrazol-4-yl)-3,4-dihydropyridine adducts 397 398a-c in a 1 1 ratio (87AP140) (Scheme 109). The mechanism is assumed to proceed via intermediate 396 formed from Michael adduct 394 or possible isomer 395. The pyran derivative 396 rearranges to the pyrid-2(l//)-one/2-hydroxypyridine tautomeric mixture 397/398. 

The stable enaminone 168 undergoes an aza-Cope reaction 170 at nearly 200 °C in nitrobenzene. It may seem odd that a linear alkyne should take part in such a reaction but in fact this is not unusual. The product is an allene 171 that undergoes tautomerism to the more stable enaminone 172 then a [1,5] sigmatropic H shift before cyclising to a dihydropyridine 174. The cyclisation is formally a six electron disrotatory electrocyclic reaction 173. The solvent PhN02 oxidises 174 to the pyridine 169. 

In the above reactions of enamine derivatives with oxazolidines and oxazinanes, pyridine systems did not constitute direct targets but were formed, in a few cases, by air oxidation of initially formed dihydropyridine derivatives. Oxazolidines 30, possessing electron-withdrawing groups in C-2 substituents, exist mainly as tautomeric acyclic enamines 28 (Section II.C.2), which in the presence of an acid would also generate iminium cations such as 54 that should react with nucleophiles. Thus, it has been found that such oxazolidines in presence of an acid, react with acyclic, cyclic, and heterocyclic enamine derivatives in 1 1 stoichiometry to provide a unique synthesis of pyridine, quinolinone, and pyridopyrimidine derivatives (98T935). 

Following the approach taken by Eisner and Kuthan in their review of dihydropyridines,1 this article will incorporate only isolable or spectroscopically identified monocyclic dihydrodiazines and dihydrotriazines. We specifically exclude compounds containing exocyclic double bonds, i.e., particularly azine methenes, as well as oxo-, thio- or iminodihydroazines (5a), which can be considered as tautomeric azines (5b), and hydroxy, mercapto, and amino DHA (6a), which can exist in the tautomeric tetrahydroazine form (6b). 

Coleman and Petcavich (1978) [192] used FTIR to propose a route (Scheme XIX) via the initial formation of the Grassie ladder, followed by a tautomeric change to the polycyclic dihydropyridine structure. Oxidation followed, producing carbonyl groups, a prerequisite for the subsequent condensation reaction between adjacent ladder formations to give a final structure proposed by Potter and Scott and more fully reported by... 

Both formed compounds react in a Michael-type reaction to give, after tautomerization and condensation, the 1,4-dihydropyridines IV (Scheme 13.129). 

At first, analogous to the 1,4-dihydropyridine synthesis, in the Hantzsch pyrrole synthesis, a p-ketocarbonyl compound reacts with ammonia or a secondary amine, forming an enamine II. This enamine II reacts with the a-haloketone I in a nucleophilic substitution and gives, after tautomerization and condensation, the pyrroles HI (Scheme 13.130). 

Davies and coworkers discovered that pyridines can be produced by rhodium-catalyzed cyclization of carbenoids and isoxazoles as well [74], Highly functionalized pyridines and 1,4-dihydropyridines could be produced by this procedure in good yields (Scheme 3.35). For the reaction mechanism, the reaction proceeds through an initial carbenoid induced ring expansion of isoxazoles and then followed by a rearrange-ment/tautomerization/oxidation sequence. 

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