Aryl-substituted 1,4-dihydropyridines

Dihydropyridines not only are intermediates for the synthesis of pyridines, but also are themselves an important class of N-heterocycles an example is the coenzyme NADH. Studies on the function of NADH led to increased interest in the synthesis of dihydropyridines as model compounds. Aryl-substituted dihy-dropyridines have been shown to be physiologically active as calcium antagonists. Some derivatives have found application in the therapy of high blood pressure and angina pectoris. For that reason the synthesis of 1,4-dihydropyridines has been the subject of intensive research and industrial use. The Hantzsch synthesis has thus become an important reaction. 

The oxidation of 167 with Mn02/bentonite was performed without a solvent to give a mixture of 155 and 156, depending on the alkyl substituent in 9 100% yields after irradiation for 2 10 min (Scheme 34). The ease of oxidation of the 4-substituted dihydropyridines was found to be in the order R = H> alkyl > aryl (91SC2137). 

An important extension of this work deals with the preparation of N-substituted l,4-dihydropyridine-3,5-diearboxylates. Tliirty examples have been deseribed (92SC3291). In most eases the reported yields (10-95%) are higher than those mentioned in the literature. Tire most signifieant results eoneern the synthesis of 1-aryl derivatives, whieh are hardly aeeessible by elassie methods. One should mention that the aminoeyelohexadiene 84 has been isolated as a by-produet when starting from ethyl A-benzylaminobut-3-enoate (Seheme 26). 

A one-pot synthesis of N-substituted 4-aryl-l,4-dihydropyridines (Scheme 8.34) was recently [52] mentioned at the Fifth International Electronic Conference on Syn-... 

A fairly general route to 1,2-dihydroazocines (64) is provided by the [2+2] cycloaddition of DMAD to 1,2-dihydropyridines (62) (74JCS(Pi)2496,77JOC2903). The reaction gives good yields of the dihydroazocine-6,7-dicarboxylates with N- alkyl, -aryl or functionally substituted removable protective groups. Other substituents can be present at C-3 or -4 in the pyridine, but carboxyl substituents at N-l or C-5 of the pyridine reduce the enamine character, and Diels-Alder addition of the acetylene occurs at the diene system. The [4.2.0] bicyclic intermediates (63) can be detected at -10 to 0°C by NMR warming to 20 °C causes complete conversion to (64). 

Balalaie, S. and Kowsari, E., One-pot synthesis of N-substituted 4-aryl-1,4-dihydropyridines under solvent-free conditions and microwave irradiation, Monatsh. Chem., 2001, 132, 1551-1555. 

The Hantzsch synthesis of dihydropyridines represents a classical example of MCR, generating an array of diversely substituted heterocycles in a one-pot reaction procedure. Given that the reaction requires elevated temperatures and extended reaction times to proceed, acceleration of the process by microwave irradiation could be envisioned. Indeed, dielectric heating of aldehyde (aliphatic or aromatic) and 5 equivalents of /i-keloesler in aqueous 25% NH4OH (used both as reagent and solvent) at 140-150 °C for merely 10-15 min furnished 4-aryl-l,4-dihydropyridines in 51-92% yield after purification on a silica gel column [100]. The Hantzsch synthesis under reflux conditions ( 100 °C) featured a remarkably longer time (12 hours) and lower yields (15- 72%). To demonstrate the suitability of the procedure for the needs of combinatorial chemistry, a 24-membered library of 1,4-dihydropyridines (DHP) was prepared (Scheme 36). 

An aryl substituent (R ), preferably substituted phenyl, appears optimum in the 4-position of the 1,4-dihydropyridine ring. The position of the substituent in the phenyl ring is quite critical 4 -substitution is invariably highly detrimental, whereas 2 - and 3 -substitutions increase activity. 

Organometallic reagents add very readily to A-alkyl-, A-aryl- and, with important synthetic significance, A-alkoxy- or iV-aryloxycarbonyl-pyridinium salts. In A-aUcyl- or iV-aryl-pyridininm cations, addition is to an a-carbon the resnlting 2-substituted-l,2-dihydropyridines are nnstable, bnt can be handled and spectroscopically identified, with care, and more importantly can be easily oxidised to a 2-snbstitnted pyridininm salt." ... 

A one-pot synthesis of N-substituted 4-aryl-l, 4-dihydropyridines using a microwave-assisted procedure was described in 2001 (Scheme 10.97) [187]. Among a variety of solid supports (Kio, acidic alumina, zeolite HY, silica gel), silica gel was proved to be the most efficient. After irradiation for 4 min, the reactions led to yields ranging from 62 to 94%. 

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