1.4- Dihydropyridines. synthesis

Yadav JS, Reddy BVS, Basak AK, Baishya G, Narsaiah AV (2006) lodoxybenzoic acid (IBX) an efficient and novel oxidizing agent for the aromatization of 1,4-dihydropyridines. Synthesis 451 54... 

Shah A, Gaveriya H, Motohashi N, Kawase M, Saito S, Sakagami H, Satoh K, Tada Y, Solymosi A, Walfard K, Molnar J (2000) 3,5-diacetyl-1,4-dihydropyridines synthesis and MDR reversal in tumor cells. Anticancer Res 20 373-377... 

Alvarez-Builla and coworkers have used microwave irradiation to improve Hantzsch 1,4-dihydropyridine synthesis [80]. Reduced reaction times and improved yields are generally associated with this procedure as exemplified in Scheme 10.37. 

The Hantzsch 1,4-dihydropyridine synthesis was also scaled successfully to the 0.5-1 mol level in the MARS unit, requiring heating up to 1 L of reaction mixture (Schane 5.12).29 One batch provided 250 g of dihydropyridine product in less than 1 h. 

Our own approach to the combination of crown ether and dihydropyridine chemistry has involved constructing the dihydropyridine as an integral portion of the macrocyclic crown ether ring (see 24b, for example). The first synthetic approach involved ring-closure of an alicyclic precursor by means of the Hantzsch 1,4-dihydropyridine synthesis as illustrated for the preparation of (50, eq. 24). Such Hantzsch esters (general type 46) are attractive in that the acid functionalities at the 3,5-positions can be used as handles for attaching the (dihydro)pyridine... 

The original Hantzsch 1,4-dihydropyridine synthesis is a one-pot reaction between an aldehyde, 2 equiv of a P-ketoester, and ammonia or an ammonia derivative. This process, known as the 3CP Hantzsch 1,4-dihydropyridine synthesis, is still useful for the synthesis of symmetrical 1,4-dihydropyridines. However, it is less successful for the synthesis of asymmetrical derivatives due to the number of side products formed when using mixed p-ketoesters in the reaction. Like the Hantzsch pyrrole... 

Additional modifications to the Hantzsch 1,4-dihydropyridine synthesis generally involve the use of activated methylene compounds such as 1,3-diketones, co-cyanoacetophenone, co-phenylacetophenone, a, P-unsaturated ketones, and indane-l,3-diones. A number of efforts to improve reaction yields using eatalysts have also been reported, including the use of hydrotalcite materials, triphenylphosphine copper II triflate, and covalently anchored sulfonic acid on silica gel. Dihydropyridine synthesis has also recently been studied with high success using microwave and solvent-free" reaction conditions. 

Hantzsch s original 1,4-dihydropyridine synthesis involved the one-pot reaction between 2 equiv of ethyl acetoacetate 8 and acetaldehyde 178 in refluxing aqueous ammonia to give the corresponding 1,4-dihydropyridine 179. 

Although the Hantzsch 1,4-dihydropyridine synthesis was originally reported in the late 1800s, interest in this reaction developed only in the past 50 years with Bossert and co-workers synthesis of nifedipine, a potent calcium channel antagonist. The elucidation of the structure of NADH, which contains a dihydropyridine moiety, in the 1980s led to a second surge of research in this area. ... 

Bossert and co-workers original three-component Hantzsch synthesis of nifedipine used 1 equiv of 2-ntirobenzaldehyde 181, 2 equiv of methyl acetoacetate 180, and ammonia to give nifedipine in 72% yield. Since their report, a number of variations on the Hantzsch 1,4-dihydropyridine synthesis have been reported. Many of the initial reports on the synthesis of 1,4-dihydropyridine derivatives were aimed at studying the structure activity relationships of these compounds with the goal of developing more potent and specific analogs of nifedipine. 

One variation of the 1,4-dihydropyridine synthesis uses acetylene derivatives in place of P-ketoesters. Chennant and Eisner reported on the reaction between 2 equiv of methyl propionate 182 with aromatic aldehydes such as 183 and ammonium acetate in acetic acid to produce a series of dihydropyridine derivatives 184 in good yield. Unfortunately, differentially substituted acetylene derivatives and alkyl or nitrosubstituted aromatic aldehydes gave little to no yield of the desired 1,4-diydropyridine derivatives under the reported conditions. However, this method remains the best way to prepare of 2,6-unsubsitituted 1,4-dihydropyridines. 

Hermecz and co-workers used the Hantzsch 1,4-dihydropyridine synthesis in their preparation of naphthyridines. Reaction of ethyl acetoacetate 8 and hexamethylenetetramine 221 as a novel source of nitrogen... 

Gdrlitzer and Vogt employed the Hantzsch 1,4-dihydropyridine synthesis in their preparation of novel thiopyrone derivatives for use as potential leukotriene antagonists for the treatment of asthma.Reaction of aldehydes 224 and 226 with P-aminocrotonate 214 in glacial acetic acid at 50-60 °C for a period of 24 h gave the corresponding dihydropyridine derivatives 225 and 227 in 83 and 86% yield, respectively. 

Sagitullina and co-workers synthesized a number of nitropyridines and their quaternary salts using a two-component Hantzsch 1,4-dihydropyridine synthesis. Treatment of 2-nitro-l,3-diphenylpropenone 258 with p-aminocrotonate derivatives 259, 210, 217 and 263 in acetic acid at room temperature gave the corresponding 1,4-dihydropyridine derivatives in modest yields. The corresponding salts (not shown) were produced using dimethylsulfate and methyl fluorosulfonate. 

The experimental examples provided below are given for the Hantzsch pyrrole, thiazole, and 1,4-dihydropyridine synthesis. The traditional method for preparing each type of heterocycle is presented first, followed by a modified protocol. 

In the Hantzsch 1,4-dihydropyridine synthesis, the p-ketocar-bonyl compound II condenses on the one hand with a nitrogen source forming an enamine I and, on the other hand, with the appropriate aldehyde in a Knoevenagel condensation, forming an unsaturated p-ketocarbony 1 compound HI (Scheme 13.128). 

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). 

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