Hantzsch 1,4-Dihydropyridine Synthesis

Dihydropyridine from the condensation of aldehyde, P-ketoester and ammonia. 

Balogh, M. Hermecz, L Naray-Szabo, G. Simon, K. Meszaros, Z. J. Chem. Soc., Perkin Trans. 1 1986, 753. 

Galatsis, P. Hantzsch Dihydro-Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 304—307. (Review). 

The rapid synthesis of heteroaromatic Hantzsch pyridines can be achieved by aromatization of the corresponding 1,4-DHP derivative under microwave-assisted conditions [51]. However, the domino synthesis of these derivatives has been reported in a domestic microwave oven [58,59] using bentonite clay and ammonium nitrate, the latter serving as both the source of ammonia and the oxidant, hi spite of some contradictory findings [51,58,59], this approach has been employed in the automated high-throughput parallel synthesis of pyridine libraries in a 96-well plate [59]. In each well, a mixture of an aldehyde, ethyl acetoacetate and a second 1,3-dicarbonyl compound was irradiated for 5 min in the presence of bentonite/ammoniiun nitrate. For some reactions, depending upon the specific 1,3-dicarbonyl compound used. 

4-Dihydropyridine from the condensation of aldehyde, P-ketoester and ammonia. Hantzsch 1,4-dihydropyridines are popular reducing reagents in organocata-lysis. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 119, Springer-Verlag Berlin Heidelberg 2009 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 127, Springer International Publishing Switzerland 2014 

A new strategy for the synthesis of heterocyclic a-amino acids utilizing the Hantzsch dihydropyridine synthesis was developed in the laboratory of A. Dondoni. ° The enantiopure oxazolidinyl keto ester was condensed with benzaldehyde and fert-butyl amino crotonate in the presence of molecular sieves in 2-methyl-2-propanol to give a 85% yield of diastereomeric 1,4-dihydropyridines. The acetonide protecting group was removed and the resulting amino alcohol was oxidized to the target 2-pyridyl a-alanine derivative. 

Lipophilic 1,4-dihydropyridines, such as 4-aryl-1,4-dihydropyridines, exhibit significant calcium channel antagonist activity. N.R. Natale et al. have synthesized a series of 4-isoxazolyl-1,4-dihydropyridines bearing lipophilic side chains at the C5 position of the isoxazole ring. The Hantzsch synthesis was carried out in an aerosol dispersion tube at 110 °C in ethanol in the presence of 2 equivalents of ethyl acetoacetate and aqueous ammonia solution. 

Baley reported the first synthesis of an unsymmetrical 2,2 -6 2 -terpyridine containing two carboxylic acids using 

The furan ring served as a latent carboxylic acid 

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Another well-known method for the preparation of heterocycles is the Hantzsch dihydropyridine synthesis. In 2001, Ohberg and Westman presented a microwave-... 

The Hantzsch dihydropyridine synthesis has been performed [75] in a singlemode microwave cavity. In comparison with both conventional methods and microwave-assisted reactions performed in a domestic oven, reaction times were shorter and yields were higher (Scheme 8.51). 

As discussed in Section 4.2.3.4.1, pentane-1,5-diones (200) can undergo ring closure to give a pyran (199) or, in the presence of ammonia, a dihydropyridine (201). Oxidative aromatization of these products occurs so easily that it frequently takes place prior to isolation, giving a pyrylium salt (198) or a pyridine (202). The Hantzsch dihydropyridine synthesis is described in Section 4.2.3.4.2. 

Ohberg,L. and Westman, J., An efficient and fast procedure for the Hantzsch dihydropyridine synthesis under microwave conditions, Synlett, 2001, 1293—1296. 

A number of MCRs having enolate-derived nucleophilic components were subsequently discovered (Scheme 7.3), including the Hantzsch dihydropyridine synthesis [13], the Biginelli reaction [14, 15] and the Mannich reaction [16-20], An added complication in many of these MCRs is the potential irreversible addition of the nucleophile to the carbonyl component, leading to carbonyl addition products. Such MCRs, however, become feasible by the appropriate selection of components that do not favor such alternative transformations. For example, the use of formaldehyde is more effective in the Mannich reaction, because its greater reactivity towards the amine prevents its undesired reaction with the enolate component. 

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. 

Hantzsch A (1882) Ueber die Synthese pyridinartiger Verbindungen aus Acetessigather und Aldehydammoniak (Hantzsch dihydropyridine synthesis). Justus Liehegs Ann Chem 215 1-82... 

This review deals with the formation of reduced pyridines and their benzo analogs from the parent heteroaromatic bases. Included are acridines, isoquinolines, pyridines and quinolines and their quaternary ammonium salts and N-oxides. The formation of the reduced species by other methods, e.g. Hantzsch dihydropyridine synthesis, is not addressed. 

Hantzsch dihydropyridine synthesis Preparation of dihydropyridines from 1,3-diketones, aldehydes and ammonia. 194... 

Watanabe, Y., Shiota, K., Hoshiko, T., Ozaki, S. An efficient procedure for the Hantzsch dihydropyridine synthesis. Synthesis 1983, 761. 

Enders, D., Mueller, S., Demir, A. S. Enantioseiective Hantzsch dihydropyridine synthesis via metalated chirai aikyi acetoacetate hydrazones. Tetrahedron Lett. 1988, 29, 6437-6440. 

Several research laboratories investigated the mechanism of the Hantzsch dihydropyridine synthesis. " A comprehensive discussion on the mechanism is reported recently. ... 

Several reagents and reaction conditions such as TMSI (generated in situ from TMSCl and Nal), magnesium nitride (Mg3N2), triphenylphosphine (PPhs), thiamine hydrochloride (vitamin mnding under solvent-free conditions, PTSA with ultrasonic irradiation were recently reported to mediate efficiently the Hantzsch dihydropyridine synthesis. For instance, 1,4-dihydropyridines 143 were obtained in good yields using thiamine hydrochloride (vitamin B ) as the catalyst under solvent-free conditions at room temperature. ... 

This reaction is related to the Hantzsch Dihydropyridine Synthesis and Krohnke Pyridine Synthesis. 

Other references related to the Hantzsch dihydropyridine synthesis are cited in the literature. ... 

Dihydropyridines can be prepared via the three-eomponent coupling of cinnamaldehyde, aniline and p-keto esters under solvent-free conditions by means again of L-Pro as catalyst in the transformation. The three-component reaction of 1,3-indanedione, isatins and enamines as the nucleophiles is also possible in the presence of L-Pro for the one-pot synthesis of highly functionalised spirooxindoles derivatives. While only some examples are highlighted here, ° ° the possibilities of L-Pro in multicomponent reactions are tremendous. It has also shown good catalytie activity in classic multicomponent reactions such as Biginelli reactions and Hantzsch dihydropyridine synthesis. 

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