Synthesis of Dihydropyridines

An efficient Rh-catalyzed C-H alkenylation and electrocyclization sequence that provides easy access to highly substituted dihydropyridines 91 from a,p unsaturated imines and alkynes was reported by Ellman (Eq. (5.88)) [47]. The alkyne scope was good nonsymmetric alkynes gave the dihydropyridine products as single regioisomers in most cases. The 1,2-dihydropyridines can be oxidized efficiently to pyridines. 

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Zincke salts have played an important role in the synthesis of NAD /NADH coenzyme analogs since a 1937 report on the Zincke synthesis of dihydropyridine 7 for use in a redox titration study.The widely utilized nicotinamide-derived Zincke salt 8, first synthesized by Lettre was also used by Shifrin in 1965 for the preparation and study of NAD /NADH analogs. In 1972, Secrist reported using 8 for synthesis of simplified NAD analogs such as 10 for use in spectroscopic studies (Scheme 8.4.4). Subsequent utilization of 8 is discussed later in this article. 

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. 

Scheme 3.27 Hantzsch reaction for the synthesis of dihydropyridine derivatives (189) [287],...

There are several significant ring syntheses for pyridines, of which the most important is the Hantzsch synthesis of dihydropyridines (Section 4.2.3.4.2). However, the majority of substituted pyridines are prepared from pyridine itself or from a simple alkyl derivative. 

Synthesis of dihydropyridines through preliminary transformation of unsaturated ketones into 1,5-dicarbonyl compounds (Scheme 3.1, reaction a— variant of Hantzch synthesis)... 

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). 

Scheme 37 Synthesis of dihydropyridines using task-specific ionic liquids as a soluble polymeric matrix...

Table 4 The reaction of vinyliminophosphoranes with aldehydes leading to the synthesis of dihydropyridines (Equation 150)...

The mechanism of this hydrogen migration needs further study. It would be interesting to compare the rates of and substituent influences on this migration with the similar processes in the last step of Hantzsch s synthesis of dihydropyridines (Scheme 3) and in hydrogen migration in the dihydropyri-dazine series (Section IV,C). 

Formally, one can also propose the formation of the 2,5-dihydro isomer, but even if this isomer does form during the reaction, it is easily transformed to the thermodynamically more stable 1,2-dihydro compound. This reaction is nearly identical to the classical Hantzsch s synthesis of dihydropyridines, with only the molar ratio of starting materials being changed. However, in contrast to the widely investigated Hantzsch reaction, there are few examples in the literature, and it needs detailed study. 

Preparation of intermediate products for the synthesis of dihydropyridines of the type shown in Scheme 10 (product 20), which are of interest clinically because of their antihypertensive activity, has been conducted with ion-exchanged zeolites... 

New approaches to nitrogen-containing heterocycles Enantioselective organocatalyzed synthesis of dihydropyridines, quinoHzidine derivatives, and dihydropyrimidines 12COC1754. 

The Hantzsch dihydropyridine synthesis was first reported by Arthur Rudolf Hantzsch in 1881. The Hantzsch pyrrole and thiazole reactions were reported in the years following Hantzsch s initial report on the synthesis of dihydropyridines. 

Synthesis of dihydropyridines by condensation of two moles of a p-dicarbonyl compound with one mole of an aldehyde in the presence of ammonia. Dehydrogenation to the corresponding pyridine is accomplished with an oxidizing agent ... 

Scheme 3.35 Pd-catatyzed synthesis of dihydropyridines and related derivatives.

SCHEME 13.80 A small insight into the synthesis of dihydropyridine derivatives by exchange of the heterocyclic component in the Yonemitsu reaction [138-143]. 

An efficient diketene ring-opening synthesis of dihydropyridine derivatives using SBA-15 sulfonic acid-modified mesoporous substrate as a green and reusable... 

Scheme 1.44 Phosphonic acid-catalysed synthesis of dihydropyridines.

Scheme 3.5 Sequential, multicomponent, diastereoselective synthesis of dihydropyridin-2-ones developed by Orru.

SCHEME 51 Synthesis of dihydropyridines in the presence of TMGT and ultrasound. 

Shaabani et al. [189] using ILs reported a modified method for synthesis of dihydropyridines 97 by a three-component condensation of aldehydes, j8-ketoesters, and ammonium acetate in the presence of TMGT (1,1,3 -N,N,N, N-tetramethylguanidinium trifluoroacetate) in a molar ratio of 1 0.5 (reactant/lL) and ultrasound irradiation at RT (Scheme 51). The IL was recovered and reused fom times with no appreciable decrease in yield. The methodology was foxmd to be advantageous over conventional methods in terms of yield, reduced reaction time, and feasibility at RT. It was also noted that ultrasound irradiation dramatically influences the yield of product 97 [189]. 

The formation of N-acylpyridinium ions from acyl chlorides and pyridines is effectively promoted by (la) and i-Pr3SiOTf. The N-acylpyridinium ions are usable for the synthesis of dihydropyridines and their derivatives by alkylation with Grignard reagents [128]. This reaction sequence has been applied to asymmetric alkylation of pyridines using a chiral acyl chloride [129]. 

Scheme 42.40 Enantioselective sequential Hantzsch-type synthesis of dihydropyridine 177 starting from p-nitrocinnamaldehyde (175), anisidine (119), and ethyl acetoacetate...

Dihydropyridines find important applications in medicine (mainly as calcium channel blockers) and their chemistry has been thoroughly investigated over the last decades [11-14]. The first synthesis of dihydropyridines 4 was reported by Arthur Rudolf Hantzsch over a century ago and involved the condensation between ammonia, an aldehyde and two molecules of a P-ketoester (Scheme 2.1) [15]. Use of a modified procedure allowed synthesis of unsymmetrical dihydropyridmes starting from two different P-ketoesters [16], Compounds 4 are known as Hantzsch esters and have been extensively used as pyridine precursors in the synthesis of heterocyclic compounds. 

Scheme 2.1 Hantzsch synthesis of dihydropyridines and common Hantzsch esters used in asymmetric organocatafytic transfer hydrogenations...

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