Dihydropyridine intermediates

The synthesis of 4-substituted pyridines via 1,4-addition of Grignard reagents to pyridinecarboxamides has been studied. After addition of Grignard reagents to pyridinecarboxamides 32, oxidation of the dihydropyridine intermediates with NCS or oxygen provides the substituted pyridines 33 in good yields <95T(51)9531>. 

No further research was performed in this field until three decades later, when Arcadi et al. developed a one-pot entry into functionalized pyridines. Reaction required a catalyst to dehydrogenate a dihydropyridine intermediate to pyridine. At that time, the liberated hydrogen was believed to be a consequence of aromatization [189]. 

The reductive cleavage of the C—O bond in 2- and 4-substituted hydroxy-methylpyridines was mentioned in Part I. The optically active l-(4-pyridyl)-alkanols are reduced in good yield to the optically inactive alkylpyridine, whereas the 2-substituted derivatives were reduced in lower yield to the optically active alkylpyridine (and some tetrahydropyridine derivatives).384,385 The difference in behavior was explained by orientation of the adsorbed pro-tonated pyridine, allowing contact between the electrode and the 2-substituent, but not the 4-substituent. This model was used in later work however, not excluded was the possibility that the higher stability of the p-quinonoid dihydropyridine intermediate, compared to the o-quinonoid dihydropyridine, played a role in the relative ease of reduction of the 4- and 2-substi-tuted pyridines. 

Oxygen must be rigorously avoided, particularly in smaller scale reactions, to prevent oxidation of the dihydropyridine intermediate to the corresponding pyridine. 

Trichloromethylarenes are found to activate the pyridine ring via N-alkylation such that 4-chloropyridines are formed (Scheme 20) <1995TL5075>. In the case of nicotinamide, the dihydropyridine intermediate 121 undergoes an intermolecular redox reaction with hydride transferred to the benzylic position to give 122. Subsequent displacement of the C-4 chloride with nicotinamide affords the bispyridinium salts 123. 

The versatility of d,v-aminoindanol as chiral auxiliary has been considered in various Claisen9293 rearrangements and was found to be particularly efficient in the 6-azaelectrocyclization reaction.93 Indeed, the reaction of ( >3-carbonyl-2,4,6-trienal 98 with enantiopure m-aminoindanol 1 proceeded under remarkably mild conditions to produce pentacyclic piperidine 99 as a single isomer. The reaction was thought to proceed via isomerization of dihydropyridine intermediate 100 toward the thermodynamically more stable aminoacetal 99 (Scheme 24.22). 

Pyridinium salts have been shown to be effective starting materials for synthesis. In Bennasar s total synthesis of (+)-16-epivinoxine and (-)-vinoxine, the chiral enolate of 38 was added to pyridinium 39 with modest facial control to provide dihydropyridine intermediate 40. Cyclization afforded 41 in a single pot, albeit in modest yield (Scheme 6) <02TA95>. 

The Hantzsch pyridine synthesis is an old discovery (1882) which sprang into prominence in the 1980s with the discovery that the dihydropyridine intermediates prepared from aromatic aldehydes are calcium channel blocking agents and therefore valuable drugs for heart disease with useful effects on angina and hypertension. 

Formation of methylaminoalkadienes might be explained invoking a 1,2-dihydropyridine intermediate and its cleavage by aluminum hydride, by analogy with the cleavage of enamines.79... 

The l-lithio-2-t-butyl-l,2-dihydropyridine intermediate (similar to the l-lithio-2-phenyl-l,2-dlhydropyridlne intermediate shown previously) has been isolated (21), but though this material should lend itself to reaction with alkylhalides to form 2-t-buty.l-... 

C3-Substituted A -benzhydrylpyridiniums were utilized as sources for 3,5-disubstituted pyridines through 1,4-dihydropyridine intermediates <03TL4711>. 

A mechanism has been proposed which involves dihydropyridine intermediates. Pyridines (173) are also obtained from the reaction of butadiyne with f3-aminocrotonale esters in the presence of sodium . 

The ability of coenzyme NAD(P)+ (57, R = sugar) and its mimics to accept and deliver hydride ion stereoselectively via 1,4-dihydropyridine intermediates has spurred much interest. Much work involving NADIP)" " and its simpler derivatives (56 R = PhCH2, BNAH R = C12H25, DNAH) as chiral reducing agents has been reported. ... 

The normal mechanism for the transamination reaction is shown in Fig. 4.24 (R=H) and involves the condensation of alanine and pyridoxal phosphate to give an imine. A proton is lost from the imine to give a dihydropyridine intermediate. This reaction is catalysed by a basic amino acid provided by the enzyme as well as the electron withdrawing effects of the protonated pyridine ring. The dihydropyridine structure now formed is hydrolysed to give the products. 

Trifluoroalanine contains three fluorine atoms which are very similar in size to the hydrogen atoms in alanine. The molecule is therefore able to fit into the active site of the enzyme and take alanine s place. The reaction mechanism proceeds as before to give the dihydropyridine intermediate. However, at this stage, an alternative mechan-... 

The addition of nucleophiles to 1-acylpyridinium salts has surfaced as a powerful method for the synthesis of substituted pyridines. The 1-acylpyridinium salts are formed in situ by adding an acyl chloride to a pyridine in an aprotic solvent such as tetrahydrofuran. The formation of the 1-acylpyridinium salt is very rapid and will occur in the presence of various organometallics without significant competition from the reaction of the nucleophile and the acyl chloride. The addition of ethyl chloroformate to a mixture of pyridine and ethylmagnesium bromide gives 1,2- and 1-4-dihydropyridines 29 and 30 in a ratio of 64/36. Although these dihydropyridine intermediates can be aromatized with hot sulfur to 2- and 4-alkylpyridines, the poor regioselectivity makes this procedure unattractive. 

A synthesis of 4-alkyl-3-pyridinols (55) from 3-benzyloxypyridine (52) utilizes a copper-catalyzed Grignard reaction. The dihydropyridine intermediates 53 are aromatized to 4-alkyl-3-benzyloxypyridines (54), which on hydrogenolysis provide the pyridinols 55 (85JHC1419). Substitution at the 4-position of 3-pyridinecarboxaldehydes can be achieved via 1-acylpyri-dinium salt 56. The intermediate acetal 57 is hydrolyzed to give pyridine-carboxaldehyde 58 (84H339). 

The isoxazolyloxazoline anion 63 and l-methoxycarbonylpyridinium chloride (62) give a mixture of 1,2- and 1,4-addition products. Oxidation of the intermediate dihydropyridines with p-chloranil provides the substituted pyridines 64 and 65 (85JOC5660). IV-Ethoxycarbonylpyridinium chloride (67) reacts with 2-trimethylsilylthiazole (66) regioselectively to give a 1,2-dihydropyridine intermediate, which on oxidative deacylation affords 2-substituted pyridine 68. In a similar manner, 4-methyl-2-trimethylsilyloxazole and 67 provide the corresponding 2-heteroarylpyridine (84TL3637). 

One can indirectly substitute the pyridine ring with electrophiles by using an electron-rich dihydropyridine intermediate. Dihydropyridines 150 can be prepared by a one-pot synthesis utilizing a copper-catalyzed Grignard addition to l-(phenoxycarbonyl)pyridinium chloride (149). Dihydropyridines 150 undergo regiospecific Friedel-Crafts acylation in good yield with many... 

Substituted 3-pyridinecarboxaldehydes can be prepared by Vilsmeier for-mylation of dihydropyridine intermediates. Various 3-substituted pyridines (161) can be transformed into 3-substituted l-(phenoxycarbonyl)-1,2-dihydro-pyridines (162) using NaBH4 and phenyl chloroformate in methanol. Treatment of these 1,2-dihydropyridines with Vilsmeier reagent (POCIj/DMF) gives 3-substituted 5-formyI-1 -(phenoxycarbonyl)-1,2-dihydropyridines (163), which are aromatized with sulfur to provide 5-substituted 3-pyridinecarboxaldehydes (164). The formylation of 4-substituted 1-(phenoxycarbonyl)-1,4-dihydropyridines 165 and subsequent aromatization give 3-pyridinecarboxaldehydes 166(87H2159). 

In Baldwin and Whitehead s pathway (Scheme 18), the intramolecular Diels-Alder cyclization of the bis-dihydropyridine intermediate 105a via isomerization to 105b gives iminium salt 106a. Redox exchange and hydrolysis of the resultant 106b affords aldehyde 108. Isolations of 103 and keramaphidin B (107) from... 

An ingenious solution to this problem has been suggested which involves inversion at C-3, C-7, and C-15 via dihydropyridine intermediates (Scheme 8) and is similar to that proposed to account for the biosynthesis of antipodal pentacyclic Aspidosperma alkaloids. The feasibility of such a mechanism chemically has been demonstrated with the thermal transformation of (107 20a-H) into (108 20-aH). 

Two unusual Hantzsch ester syntheses have been reported. One involved elimination of a 4-antipyiyl group during spontaneous aromatization of the 1,4-dihydropyridine intermediate (94H(37)815). Other reported formation of an oxygen-bridged tetrahydropyridine (34) (Scheme 14) <94JCR(S)106). 

And 4-cyano-3-methoxypyridines (X-170) are prepared from the corresponding 3-nitropyridines (X-169) by the action of methanol and cyanide ion. The mechanism might involve a series of addition-elimination steps as indicated. The final dehydrogenation of the hypothetical dihydropyridine intermediate (X-171) must be accomphshed by the expelled nitrite ion. The reaction is general and yields are reported to exceed 50% of theory. 

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