1.2- Dihydropyridine, formation

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. 

The methyl ester of nicotinic acid is selectively reduced to the 1,2-dihydropyridine 166 in a vast improvement over previous methods (Equation 87) <20010L201>. Low temperatures and choice of pyridinium-activating agent are crucial to avoid 1,4-dihydropyridine formation. A modification of Fowler s dihydropyridine synthesis was used to prepare the iV-acyldihydropyridine 167 (Equation 88) <20060L2961>. 

Dlcyanopyrldine produces mixtures of 1,2-dihydropyridines (35) and 1,4-dihydropyridines (36 Scheme 8)) with LAH. The more hindered alkoxyalumlnates favor 1,4-dihydropyridine formation. 1-Alkyl-2-pyridones (37) are reduced when aluminum chloride is used in conjunction with LAH. Tetra-hydropyrldlnes (38) are the major products produced, minor amounts of the piperidines (39) are also formed. ... 

If the substituent R contains an a-CH2 group, an intramolecular aldol condensation to give cyclohexanone derivatives 158 competes with 1,4-dihydropyridine formation. This can be avoided by using hydroxylamine for the cyclocondensation moreover, the dehydrogenation becomes superfluous, because the A -hydroxy intermediate 159 allows H2O elimination, yielding the pyridine derivative 157 directly. The synthesis of the dihydrocyclopenta[b]pyridine 160 provides an example ... 

As shown in Scheme 29, the dihydropyridine formation does not go to completion in the absence of p-toluenesulfonic acid, and the desired 1,2-dihydropyridine 85a was isolated in 65% yield together with 28% of the noncyclized enamine 86a. It is assumed that the p-toluenesulfonic acid additive facilitates isomerization to the corresponding azatriene, which then undergoes 6jt-electrocyclization to afford the 1,2-dihydropyridine 85. 

Imidazole efficiently catalyzed the 1,4-dihydropyridine formation between 2-cyanoacetamide, aromatic aldehydes, and 1,3-dicarbonyl compounds [70]. 

The preceding reactions represent 1,4-dihydropyridine formations utilizing two dissimilar CH acids that readily contain a nitrogen atom. Other methods have been described where the CH acids do not bear any nitrogen. Instead, this is provided by nitrogen sources like ammonium acetate [71]. 

For example, a bioinspired oxidation with hydroperoxy-flavins 590 combined with a catalyst-free 1,4-dihydropyri-dine synthesis effectively produces C4-unsubstituted pyridines 591 (Scheme 13.147) [267], whereas a palladium on carbon oxidation combined with an MK-10 catalyzed 1,4-dihydropyridine formation under microwave assistance reduces the reaction time (Scheme 13.148) [268]. A one-pot performance of the pyridine synthesis is also possible in water with stoichiometric soluble oxidants like iron chloride or potassium permanganate (Scheme 13.148) [266]. Nevertheless, both examples (Scheme 13.148) cleave off... 

Jochmann P, Dols TS, Spaniol TP, Perrin L, Maron L, OkudaJ. Insertion of pyridine into the calcium aUyl bond regioselective 1,4-dihydropyridine formation and C—H bond activation. Angew Chem Int Ed. 2010 49 7795-7798. 

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 Zincke reaction has also been adapted for the solid phase. Dupas et al. prepared NADH-model precursors 58, immobilized on silica, by reaction of bound amino functions 57 with Zincke salt 8 (Scheme 8.4.19) for subsequent reduction to the 1,4-dihydropyridines with sodium dithionite. Earlier, Ise and co-workers utilized the Zincke reaction to prepare catalytic polyelectrolytes, starting from poly(4-vinylpyridine). Formation of Zincke salts at pyridine positions within the polymer was achieved by reaction with 2,4-dinitrochlorobenzene, and these sites were then functionalized with various amines. The resulting polymers showed catalytic activity in ester hydrolysis. ... 

Methyl propiolate and pyridine give a rather unstable 2 1 molar adduct which is the 1,2-dihydropyridine (112). The reaction sequence proposed to account for its formation is identical in principle to a similar scheme proposed earlier in the acridine series (Section II,A,2) and is also supported by the observation that the 1-benzoyl-pyridinium cation with the phenylacetylide anion yields (113). ... 

When methyl 2-(indol-2-yl)acrylate derivative (22a) reacted with A-methoxy-carbonyl-l,2-dihydropyridine (8a) in refluxing toluene, in addition to the dimer of 22a (25%), a mixture of the expected isoquinculidine 23a and the product 24a (two isomers) was obtained in 7% and 45% yields, respectively (81CC37). The formation of 24a indicates the involvement of the 3,4-double bond of dihydropyridine. Similarly, Diels-Alder reaction of methyl l-methyl-2-(indol-2-yl)acrylate (22b) with 8a gave, in addition to dimer of 22b, a mixture of adducts 23b and 24b. However, in this case, product 23b was obtained as a major product in a 3 2 mixture of two isomers (with a- and (3-COOMe). The major isomer shows an a-conhguration. The yields of the dimer, 23b, and 24b were 25%, 30%, and 6%, respectively. Thus, a substituent on the nitrogen atom or at the 3-position of indole favors the formation of the isoquinuclidine adduct 23. 

Alkyl-1,4-dihydropyridines on reaction with peracids undergo either extensive decomposition or biomimetic oxidation to A-alkylpyridinum salts (98JOC10001). However, A-methoxycarbonyl derivatives of 1,4- and 1,2-dihydro-pyridines (74) and (8a) react with m-CPBA to give the methyl tmns-2- 2>-chlorobenzoyloxy)-3-hydroxy-1,2,3,4-tetrahydropyridine-l-carboxylate (75) and methyl rran.s-2-(3-chlorobenzoyloxy)-3-hydroxy-l,2,3,6-tetrahydropyridine-l-carboxylate (76) in 65% and 66% yield, respectively (nonbiomimetic oxidation). The reaction is related to the interaction of peracids with enol ethers and involves the initial formation of an aminoepoxide, which is opened in situ by m-chlorobenzoic acid regio- and stereoselectively (57JA3234, 93JA7593). 

Apparently, aminobutenyne A, the intermediate of the pyrrole synthesis, is fixed in an advantageous eonfiguration by eoordination to the Cu eation, whereas the absenee of eatalyst may result in the formation of imine B having an aetive methylene group whieh attaeks the aeetylene bond to form dihydropyridine C and then pyridine 2 (by dehydrogenation). 

The formation of pyridine 210 appears to start with dimerization of aminobutenone 207 due to carbonyl-amino group interaction. Then the intermediate 208 undergoes [3,3]-sigmatropic rearrangement, whereupon dihydropyridine 209 eliminates ammonia. 

Evidently, the reaction proceeds via the formation of bis-adduct 289 which undergoes cyclization to dihydropyridine 290. A similar reaction with methoxybutenone, but in the presence of ammonia, which is likely to involve replacement of methoxy group, has been described (80MI2). 

A pair of reactions of 1,4-dihydropyridines with electron-accepting alkenes (Scheme 31) shows experimental evidence for the mechanistic spectrum between the pseudoexcitation and transfer bands. Acrylonitrile undergoes an ene reaction [143] (Scheme 31a). This is a reaction in the pseudoexcitation band. A stronger acceptor, alkylidene- and arylmethylydenemalonitriles are reduced [144] (Scheme 31b). This is a reaction in the transfer band, where a hydride equivalent shifts without bond formation between the ti bonds of the donors and acceptors. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

Formation of the ammonium salt of the bistetronate 118 followed by heating results in cyclization to the 1,4-dihydropyridine, which can be aromatized to give 119 by treatment with nitric/sulfuric acids (Equation 27)... 

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... 

Cycloadditions to a cyano group are comparatively rare. The high-temperature reactions of 1,3-dienes, e.g. butadiene, isoprene and 2-chloro-l,3-butadiene, with dicyanogen, propionitrile or benzonitrile result in formation of pyridines (equation 80)70. Sulfonyl cyanides 147, obtained by the action of cyanogen chloride on sodium salts of sulfinic acids, add to dienes to give dihydropyridines 148, which are transformed into pyridines 149 by oxidation (equation 81)71. 

Acylnitroso compounds 197 (R = Me, Ph or Bn) react in situ with 1-methoxycarbonyl-1,2-dihydropyridine to yield solely the bridged adducts 198 quantitatively. On the other hand, 1 1 mixtures of the regioisomers 199 and 200 were formed from the nitroso-formates 187 (R = Me or Bn) (equation 110)103. The chiral acylnitroso compounds 201 and 202, which are of opposite helicity, add to cyclohexadiene to give optically active dihydrooxazines in greater than 98% diastereomeric excess (equations 111 and 112)104. Similarly, periodate oxidation of the optically active hydroxamic acid 203 in the presence of cyclopentadiene, cyclohexa-1,3-diene and cyclohepta-1,3-diene affords chiral products 204 (n = 1, 2 and 3, respectively) in 70-88% yields and 87-98% de (equation 113)105. 

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... 

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