Hantzsch synthesis, 4-component reactions

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... 

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... 

The idea of coupling two keto-esters together with a nitrogen atom also works for pyridines except that an extra carbon atom is needed. This is provided as an aldehyde and another important difference is that the nitrogen atom is added as a nucleophile rather than an electrophile. These are features of the Hantzsch pyridine synthesis. This is a four-component reaction that goes like this. 

Sheng and co-workers [113] described an efficient Hantzsch reaction for the synthesis of polyhydroquinolines 67 applying a solvent-free microwave-assisted one-pot four-component reaction of PEG-bound acetoacetate, 1,3-cyclohexane-dione, an aromatic aldehyde and ammonium acetate in the presence of a catalytic amount of PPA. The target compounds 67 were obtained in excellent yields and purities, after cleavage from the PEG support using NaOEt in EtOH. The reactions were carried out in domestic microwave oven (Scheme 51). 

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). 

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... 

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. 

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. 

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). 

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. 

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... 

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... 

In a 1998 publication, the concept of microwave-assisted parallel synthesis in plate format was introduced for the first time. Using the three-component Hantzsch pyridine synthesis as a model reaction, libraries of substituted pyridines were pre-... 

Scheme 7 Synthesis of 1,4-dihydropyricline derivatives by the three-component Hantzsch-like reaction...

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