Three-component Hantzsch 1,4-dihydropyridine synthesis

Debache A, Ghalem W, Boulcina R, Belfaitah A, Rhouati S, Carboni B (2009) An efficient one-step synthesis of 1,4-dihydropyridines via a triphenylphosphine-catalyzed three-component Hantzsch reaction under mild conditions. Tetrahedron Lett 50 5248-5250... 

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. 

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. 

Dondoni and co-workers used a three-component Hantzsch synthesis to prepare several symmetrical carbohydrate-based 1,4-dihydropyridine derivatives. Their goal was to evaluate the corresponding C-glycosides as nucleoside mimetics of monastrol, an inhibitor of microtubule-associated protein Eg5. Reaction of ethyl acetoacetate 8, galactosyl aldehyde 241 and P-aminocrotonate 214 in refluxing ethanol gave 242 in 88%. Ribose and mannose based 1,4-dihydopyridine glycoconjugates were also prepared in 71% and 70% yields, respectively (not shown). 

In 1893,11 years after the publication of the Hantzsch dihydropyridine synthesis, the Italian chemist Pietro Biginelli reported a related three-component reaction based on the cyclocondensation of aldehydes, p-ketoesters, and urea, for the synthesis of... 

The Hantzsch pyridine synthesis involves the condensation of two equivalents of a 3-dicarbonyl compound, one equivalent of an aldehyde and one equivalent of ammonia. The immediate result from this three-component coupling, 1,4-dihydropyridine 1, is easily oxidized to fully substituted pyridine 2. Saponification and decarboxylation of the 3,5-ester substituents leads to 2,4,6-trisubstituted pyridine 3. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

This approach, which resembles the well-known Hantzsch synthesis of 7r-isoelectronic 1,4-dihydropyridines usually catalyzed with organic bases (piperidine), has been widely used in the last decade, especially because of pharmaceutical and agrochemical interest in the resulting 4//-pyran derivatives. Two-component procedures starting from a,/3-unsaturated carbonyl compounds or nitriles have been shown to be more effective than three-component procedures using simple aldehydes or ketones. 

The Hantzsch synthesis, which was developed in 1882, is perhaps the best known of several ways to construct the pyridine ring. The original synthesis involved the three-component reaction mixture of a beta-ketoester, ammonia, and an aldehyde. The product is a dihydropyridine, which is easily oxidized to a pyridine. An example is given in Scheme 9.45. Two intermediate compounds have been detected in... 

J. C. Legeay, J. J. Vanden Eynde, J. P. Bazureau, Tetrahedron 2005, 61, 12386-12397. Ionic liquid phase technology supported the three component synthesis of Hantzsch 1,4-dihydropyridines and Biginelli 3,4-dihydropyrimidin-2(l//)-... 

Gordeev MF, Patel DV, Gordon EM (1996) Approaches to combinatorial synthesis of heterocycles a solid-phase synthesis of 1,4-dihdropyridines. J Org Chem 61 924-928 Breitenbucher JG, Figliozzi G (2000) Solid-phase synthesis of 4-aryl-1,4-dihydropyridines via the Hantzsch three component condensation. Tetrahedron Lett41 4311 315... 

The Hantzsch synthesis can be conducted directly to the pyridines 167 in one-pot procedures (i) by combining the MCR process with oxidative aromatization by Pd-C/montmorillonite K-10 [123] and (ii) by using [NH4]C103 as a source of NH3 [124]. (b) In a three-component domino process, a,p-unsaturated aldehydes (mainly cinnamaldehydes), aromatic primary amines, and P-ketoesters catalyzed by CAN [125] or L-proline [126] are cyclocondensed to give N-arylsubstituted-5,6-unsubstituted 1,4-dihydropyridines 173 ... 

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