Hantzsch synthesis, 4-component

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]. 

In each reaction ethyl acetoacetate 51 a was used as one of the components of the Hantzsch synthesis, whereas the second 1,3-dicarbonyl compound 51 (or 53) and the aldehydes 50 were used in all possible combinations (one unique combination per... 

Debache A, Boulcina R, Belfaitah A, Rhouati S, Carboni B (2008) One-pot synthesis of 1,4-dihydropyridines via a phenylboronic acid catalyzed Hantzsch three-component reaction. Synlett 509-512... 

Cherkupally SR, Mekala R (2008) P-TSA catalyzed facile and efficient synthesis of polyhydroquinoline derivatives through Hantzsch multi-component condensation. Chem Pharm Bull 56 1002-1004... 

The more usual cyclocondensations of two identical molecules of 1,3-dicarbonyl or other C-acidic components with a third different oxo compound (mostly an aldehyde) afford exclusively 4//-pyrans and resemble the well-known Hantzsch synthesis of 1,4-dihydropyridines. It usually proceeds... 

The Hantzsch pyridine synthesis affords 1,4-dihydropyridines 214, although spontaneous oxidation to pyridines often occurs. In its simplest form it involves the condensation of two molecules of a -keto ester with an aldehyde and ammonia (Scheme 119) . Compounds resulting from the condensation of ammonia with one of the carbonyl components can be used in the Hantzsch synthesis. Thus, -aminocrotonic ester 215 can replace the ammonia and one mole of acetoacetic ester in Scheme 119. The mechanism of the Hantzsch synthesis has been clarified by 13C and 1SN NMR spectroscopy <1987T5171>. 

Cyclic 1,3 diketones could also participate in this MCR allowing for a four-component Hantzsch synthesis of unsymmetrically substituted 1, 4-dihydropyri-dines or pyridines depending upon reaction conditions [36, 37] (Scheme 14). 

The product from the classical Hantzsch synthesis is necessarily a symmetrically substituted 1,4-dihydro-pyridine, since two mole equivalents of one dicarbonyl component are utilised, the aldehyde carbonyl carbon becoming the pyridine C-4. The precise sequence of intermediate steps is not known for certain, and may indeed vary from case to case, for example the ammonia may become involved early or late, but a reasonable sequence would be aldol condensation followed by Michael addition generating, in situ, a... 

More often, unsymmetrical 1,4-dihydropyridines are produced by conducting the Hantzsch synthesis in two stages, i.e. by making the (presumed) aldol condensation product separately, then reacting with ammonia and a different 1,3-dicarbonyl component, or an enamino-ketone, in a second step. ... 

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 of pyridine is a method of considerable scope and flexibility. In a condensation of four components, two molecules of a p-dicarbonyl compound react with an aldehyde and ammonia giving 1,4-dihydropyridines 165 which can be dehydrogenated to pyridines 166 ... 

Simple examples of this strategy, which for the synthesis of thiazoles is known as the Hantzsch synthesis, are shown below the syntheses of 2,4-dimethylthiazole where the heteroatoms are provided by thioacetamide, " and 2-aminothiazole, in which 1,2-dichloroethyl ethyl ether is utilised as a synthon for chloroethanal and the heteroatoms derive from thiourea. " The use of thioureas as the sulfur component with 2-chloroacetamides as the second unit gives rise to 2,4-diaminothiazoles. " Conversion of 1,3-diketones into their 2-phenyliodonium derivatives and reaction of these with thioureas produces 2-amino-5-acylthiazoles. The first step in such ring syntheses is 5-alkylation. " A useful variant is the use of an a-diazo ketone in place of the a-halocarbonyl component. " ... 

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... 

The traditional Hantzsch pyrrole synthesis consists of a one-pot reaction between P-ketoesters with ammonia, ammonia derivatives or primary amines, and a-haloketones. This process, known as the three-component (3CP) Hantzsch pyrrole synthesis, has been largely replaced by a two component (2CP) Hantzsch synthesis using preformed enamines. Preformed enamines help provide better control over the regioselectivity of the reaction. In addition, the use of preformed enamines helps reduce the side products produced from the self condensation of P-ketoesters. 

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). 

Dondoni and co-workers also prepared unsymmetrical carbohydrate-based 1,4-dihydropyridines using a two component Hantzsch synthesis. Treatment of unsaturated ketone 243 with P-aminocrotonate derivative 244 in DMF at 100 C for 48 h gave the corresponding 1,4-dihydropyridine derivative 245 in 61% with only 30% diastereoselectivity. Ribose and mannose analogs were also prepared in 71% and 66% yields, respectively (not shown). A similar diastereoselectivity of 20% was observed when the ribose based P-aminocrotonate was employed. However, no enantioselectivity was obtained with mannose. 

Su, Li and Li used 5-pyrrolidin-2yl-tetrazole as a promoter in their one-pot Hantzsch synthesis of polyhydroquinoline 273. These compounds are found as structural components in a number of natural products, and therefore are of significant interest to synthetic organic chemists. Reaction of ethyl acetoacetate 8 and dimedone 270 in the presence of 5-pyrrolidin-2yl-tetrazole and ammonium carbonate in ethanol at room temperature gave the corresponding polyhydroquinoline 273 in near quantitative yield. 

K. Arundhathi, K. Sudhakar, B. S. Sastry, J. S. Yadav, Synth. Commun. 2009, 39, 2843—2851. Ced YH O-catalyzed one-pot synthesis of Hantzsch 1,4-dihydropyridines at room temperature, (f) E. Mosaddegh, A. Hassankhani, Bull. Chem. Soc. Ethiop. 2012, 26, 461—465. One-pot synthesis of polyhydropyridine derivatives via Hantzsch four component condensation in water medium use of a recyclable Lewis acid CelSO ) catalyst, (g) M. Hong, C. Cai, W. B. Yi, J. Eluor. Chem. 2010, 131, 111-114. Hafnium (IV) bis(perfluorooctanesulfonyl)imide complex catalyzed synthesis of polyhydro-quinoline derivatives via unsymmetrical Hantzsch reaction in fluorous medium. 

Heravi MM, Bakhtiari K, Javadi NM, Bamoharram FF, Saeedi M, Oskooie HA (2007) K [PWjjCo0 j]-catalyzed one-pot synthesis of polyhydroquinoline derivatives via the Hantzsch three component condensation. J Mol Catal A Chem 264 50-52 Hideo T, Chem. Abstr (1981) 95, 80922b Hideo T, Jpn. Tokkyo Koho JP 56005480 1981 Poupelin J P, Saint-Rut G, Foussard-Blanpin O, Narcisse G, Uchida-Ernouf G, Lacroix R (1978) Synthesis and anti-inflammatory properties of bis (2-hydroxy-l-naphthyl) methane derivatives 1. Eur J Med Chem 13 67-71... 

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... 

In a three-component cyclocondensation, a-halocarbonyl compounds react with P-ketoesters (or P-diketones) and ammonia or primary amines to give pyrrole-3-carboxylates (or 3-acyIpyrroIes), which are substituted either in 1,2,4- or in 1,2,5-position, for example, 43/45 (Hantzsch synthesis) ... 

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 ... 

A three-component reaction related to the Hantzsch-synthesis of dihydropyrid-ines was recently reported by Yuan and colleagues who developed a domino cascade Knoevenagel/Michael/cyclization sequence converting isatin derivatives 182, malonitrile (183), and symmetrical acyclic 1,3-diketones or (3-ketoesters 184... 

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