4-Aryl-l,4-dihydropyridine

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-... 

Correlations with Hantzsch esters) (70) (77BSB267). This latter type of compound is of interest as an effective model for the NAD/NADH coenzyme system, and this work provides detailed analysis of H and 13C NMR of such compounds. 

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). 

Aryl-l,4-dihydropyridines are of interest since related systems have application as calcium channel antagonists. The energy barrier to rotation about the aryl-dihydropyridine bond is small, with the coalescence temperatures observed by NMR spectroscopy to be well below room temperature <1996T9665>. When the aryl group at the 4-position is replaced with a biaryl group, the antiperiplanar form dominates <1997BML2519>. 

Hantzsch dihydropyridine synthesis. The original Hantzsch synthesis2 involves condensation of two equivalents of a keto ester with an aldehyde in the presence of ammonia. In an enantioselective version.5 the chirality is introduced by use of a chiral hydrazone (2) of an alkyl acetoacetate prepared from 1. The anion of 2 is then treated with Michael acceptors to form adducts (3), which cyclize to 4-aryl-l,4-dihydropyridines (4), in 64-72% overall yield and in 84-98% ee. 

Aryl-l,4-dihydropyridine-3,5-dicarboxylates are widely studied due to their use in the treatment of cardiovascular diseases. Most of these compounds are synthesized using the Hantzsch method (Section 4.2.3.4.2) but this is less suitable for the synthesis of unsymmetrical or chiral derivatives. Enzymatic desymmetrization of bis(ethoxycarbonyl-methyl)-l,4-dihydropyridine-3,5-dicarboxylates, using Candida antarctica lipase B, can generate enantiopure 1,4-dihy-dropyridines in reasonable to high yields with good enantiomeric selectivity <2000TA4559>. 

Aryl-l,4-dihydropyridines, which are easily convertible to 4-arylpyridines, are usually prepared according to the method of Hantzsch starting from arylaldehyde, 1,3-dicarbonyl compound and ammonia in a one-step reaction17-19. 

Aryl-l,4-dihydropyridines, which are easily convertible to 4-arylpyridines, are usually prepared accorchng to the method of Hantzsch starting from arylaldehyde, 1,3-dicarbonyl compound and ammonia in a one-step reaction A variation of the Hantzsch synthesis uses enaminones instead of -dicarbonyl derivatives (for another variant, see Section ILA.l.e). Here the method consists of a condensation of two enaminone molecules and one molecule of aromatic or aliphatic aldehyde to give 1,4-dihydropyridines (equation 14). Various dihydropyridines have been synthesized by this rnethod ". Enaminonitriles can be cyclocondensed in the same manner (equation 15). 

Extending the Hantzsch synthesis and in the course of producing new 4-aryl-l,4-dihydropyridines related to the powerful calcium antagonist Nifedipine (Adalat),16 arylalkylideneacetoacetates, ketones, and malonic esters (18 and 21) have been treated with ketenaminals (19) to give 2-amino-l,4-dihydropyridine-3-carboxylic esters 20 and 2217 (Scheme 7). This reaction was also applied to 4-arylalkylidene-2-methyl-l,3-oxazolinone-5.18... 

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%. 

A soln. of startg. 4-aryl-1,4-dihydropyridine in DMF treated with NaCN at 60°, and stirred for 20 min - 3-methyl 5-(isopropyl) 2-(fluoromethyl)-6-methylpyridine-3,5-dicarboxylate and l-chloro-4-fluoro-2-(trifluoromethyl)benzene (Y 72%). This is the first generally applicable fragmentation-type aromatization of a Hantzsch ester under mild, basic, non-oxidative conditions. F.e.s. T. Mclnally, A.C. Tinker, J. Chem. Soc. Perkin Trans. I 1988, 1837-44. 

Atwal,K.S.,Rovnyak,G.C., Kimball, S.D.,Floyd,D.M.,Moreland, S.,Swanson,B.N.,Gougoutas, J.Z., Schwarts, J., Smillie, K.M. and Malley, M.F. 1990. Dihydropyrimidine calcium channel blockers. 2. 3-Substituted-4-aryl-l,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters as potent mimics of dihydropyridines. J. Med. Chem. 33(9) 2629-2635. 

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). 

The oxidation of alkyl and aryl hydrazines or 4-alkyl-3,5-bis(carbethoxy)-2,6-dimethyl-l,4-dihydropyridines by cytochrome F-450 results in addition of the... 

Bocker RH, Guengerich FP (1986) Oxidation of 4-aryl- and 4-alkyl-substituted 2,6-dimethyl-3,5-bis(alkoxycarbonyl)-l,4-dihydropyridines by human liver microsomes and immunochemical evidence for the involvement of a form of cytochrome P-450. J Med Chem 29 1596-1603... 

The complex [Cp Ru(MeCN)3PFg] and Hantzsch l,4-dihydropyridine as a H2 surrogate catalyse the cyclization of 1,6-diyne with terminal aryl groups to exocyclic... 

Enantioselective reduction of 3-aryl-2//-l,4-benzothiazines using a dihydropyridine as the reducing agent has been reported (Equation 11) <2006AGE6751>. 

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