Hantzsch-dihydropyridine synthesis reaction

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). 

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. 

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. 

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. 

Contrary to the general perception, MCR occupies an important position in the development of modern organic chemistry. Indeed, many important named reactions such as the Strecker amino nitrile synthesis (1850) [6], the Hantzsch dihydropyridine synthesis (1882) [7], the Biginelli dihydropyrimidine synthesis (1891) [8], the Mannich reaction (1912) [9], the isocyanide-based Passerini reaction (1921) [10], and the Ugi (1959) reaction [11], among others, are all multicomponent processes. In spite of the significant contribution of MCRs to the state of the art of modern organic chemistry and its demonstrated potential in the synthesis of... 

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. 

I, 000 fold [96-98], Various six-membered heterocyclic compounds are synthesised imder nticrowave conditions with greater yield, enhanced purity and lesser amount of side products. Hantzsch dihydropyridine synthesis is the most common method for the synthesis of a six-membered pyridine ring. The reaction is given in Scheme... 

We found that if 2 equivalents of ethyl 4,4,4-trifluoroacetoacetate (ETFAA) were reacted with one equivalent of an aldehyde and ammonium hydroxide in ethanol under the standard Hantzsch dihydropyridine synthesis conditions, a cis-dihydroxypiperidine 8a was obtained in modest yields after recrystallization. By carefully monitoring the crude reaction mixture with nmr, we were able to identify one of the other products as the trans isomer 8b which is usually more soluble and remains in the mother liquor. The other remaining products were identified as the ammonium salt, enamine, and possibly hydrate, ammonia adduct and hemiketal of ETFAA. We found that better results were obtained if 2 equivalents of ETFAA were reacted with one equivalent of an aldehyde first in a nonprotic solvent followed by passing excess gaseous ammonia into the reaction mixture to form a mixture of cis - and trans-2,6-dihydroxypiperidines 8a and 8b. The nmr shows that, in this manner, the combined yields of cis- and trans-2.6-dihydroxypiperidines 8a and 8b are in excess of 90%. The nmr spectrum also reveals that an isomeric mixture of 2-... 

However, many MCRs result in a single type of scaffold structure, for example, the Biginelli reaction or the Hantzsch dihydropyridine synthesis, which clearly... 

Aqueous solutions of hydrotropes (e.g. NaBMGS, sodium methylcello-solve sulfate) have been used in the Hantzsch dihydropyridine synthesis, a tandem Knoevenagel and Michael reaction, in which acetoacetic ester reacts with benzaldehydes and methyl aminocrotonate or aqueous ammonia at room temperature or heated with microwaves (MW) [16,17] ... 

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 Knoevenagel condensation also plays a part in a number of prominent heterocycle syntheses including the Knorr pyrrole synthesis/ Hantzsch dihydropyridine synthesis/ Feist-Benary furan synthesis and the Gewald reaction, which is used to make 2-aminothiophenes. 

Further adaptation of the Hantzsch dihydropyridine synthesis has opened up synthetic routes to annelated 1,4-dihydropyridines, e.g. (25), in which the nitrogen is at a bridgehead position, " and to 2-amino-l,4-dihydropyridine-3,5-dicarboxylates of type (26)/ The former are prepared by Michael addition of /3-amino-acrylates (27) to alkylideneacetoacetic esters R CH=C(C02Me)C0CH3, whereas the latter involve a similar reaction of the acetoacetate with an amidinoacetic ester (NH2)2C=CHC02R. ... 

With 8-keto esters HCHO is known to undergo Knoevenagel reaction to give 2-acylacrylates, key intermediates in the Hantzsch dihydropyridine synthesis. Application... 

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... 

The synthesis of racemic felodipine (Scheme 11.2) utilizes a stepwise Hantzsch dihydropyridine reaction (Berntsson et al., 1981). 2,3-Dichlorobenzylidineacetyl acetic acid... 

The great majority of 1,4-dihydropyridines are prepared using classical Hantzsch pyridine synthesis or one of its variants. The first dihydropyridine was in fact isolated back in 1882 as a stable intermediate from that method. In its simplest form, the synthesis involves heating an aldehyde such a orf/io-nitrobenzaldehyde (12-1) with ethyl acetoacetate (12-2) and ammonia. The reaction almost certainly involves, as the first... 

Another important reaction of diketene derivatives is the Hantzsch pyridine synthesis (101). This synthesis is the preparation of 1,4-dihydropyridines (14) starting either from two acetoacetic esters, which react with an aldehyde and ammonia or a primary amine or from 3-aminocrotonates and 2-alkylidene acetoacetic esters, both diketene derivatives. Several such dihydropyridines such as nifedipine [21829-25-4] (102), nimodipine [66085-59-4], and nicardipine [55985-32-5] exhibit interesting pharmaceutical activity as vasodilators (blood vessel dilation) and antihypertensives (see Cardiovascularagents). 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

The Hantzsch pyridine synthesis gives initially a dihydropyridine from the cyclization reaction. Adaptation of this reaction to the use of a 2-methylenethiazolidine yields the fused tetrahydro derivative (502) (77LA1888). Perhydro derivatives are simply prepared from 2-substituted thiazolidines by cycloalkylation as for (503) (80S387). The thiazolidine may also be generated in situ as in the reaction between y-benzoylbutyric acid and 2-mercaptoethylamines under azeotropic conditions to yield (504) (65JOC1506). 

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