Heterocycle synthesis Hantzsch pyridine

Dihydropyridines not only are intermediates for the synthesis of pyridines, but also are themselves an important class of N-heterocycles an example is the coenzyme NADH. Studies on the function of NADH led to increased interest in the synthesis of dihydropyridines as model compounds. Aryl-substituted dihy-dropyridines have been shown to be physiologically active as calcium antagonists. Some derivatives have found application in the therapy of high blood pressure and angina pectoris. For that reason the synthesis of 1,4-dihydropyridines has been the subject of intensive research and industrial use. The Hantzsch synthesis has thus become an important reaction. 

As might be expected, there are relatively few reactions for the preparation of heterocyclic systems which are useful on a laboratory scale and which involve the formation of four ring bonds. The Hantzsch pyridine synthesis (equation 148) (and a number of variations of the original procedure) is perhaps the classic example of this type of reaction, which is... 

The only report concerning the construction of the heterocyclic ring of diazafluorenes was described in CHEC-11(1996) <1996CHEC-II(7)921> using a variant of the Hantzsch pyridine synthesis. Somewhat surprisingly, no further reports using this method have been found. 

A roundabout route is used to prepare tetrahydroquinolines with reduced carbocyclic rings since direct reduction, as noted above, adds hydrogen to the heterocyclic ring. The key reaction in this scheme involves a variant of the Hantzsch pyridine synthesis. Condensation of the imine (37-1) from dihydroresorcinol with ethoxymethylenepropionaldehyde (37-2) can be envisaged as proceeding through... 

As well as being intermediates for the synthesis of pyridines, these dihydropyridines are themselves an important class of heterocycles. For instance, dihydropyridine 5.14 is a drug for lowering blood pressure. In the synthesis of 5.14 note that carrying out the Hantzsch synthesis stepwise allows for the preparation of an unsymmetrical dihydropyridine, having both a methyl and an ethyl ester. 

Standard heterocyclic syntheses tend to have a name associated with them and it is simply not worth while learning these names. Few chemists use any but the most famous of them we will mention the Knorr pyrrole synthesis, the Hantzsch pyridine synthesis, and the Fischer and Reissert indole syntheses. We did not mention that the synthesis of furans from 1,4-dicarbonyl compounds is known as the Feist-Benary synthesis, and there are many more like this. If you are really interested in these other names we suggest you consult a specialist book on heterocyclic chemistry. 

Katritzky, A. R., Ostercamp, D. L., Yousaf, T. I. Mechanism of heterocyclic ring closures. 3. Mechanism of the Hantzsch pyridine synthesis a study by nitrogen-15 and carbon-13 NMR spectroscopy. Tetrahedron 1986, 42, 5729-5738. 

C. Hollins, The Synthesis of Nitrogen Ring Compounds (New York, 1924) p 197 V. Migrdichian, The Chemistry of Organic Cyanogen Compounds (New York, 1947) p 322 H. S. Mosher, Heterocyclic Compounds 1, 466 (1950) R. W. Holder etal, J. Org. Chem. 47, 1445 (1982) D. J. Collins, A. M. James, Aust. J. Chem. 42,215 (1989). Cf Hantzsch (Dihvdro)Pvridine Synthesis KrOhnke Pyridine Synthesis. 

Subsequent to Hantzsch s communication for the construction of pyridine derivatives, a number of other groups have reported their efforts towards the synthesis of the pyridine heterocyclic framework. Initially, the protocol was modified by Beyer and later by Knoevenagel to allow preparation of unsymmetrical 1,4-dihydropyridines by condensation of an alkylidene or arylidene P-dicarbonyl compound with a P-amino-a,P-unsaturated carbonyl compound. Following these initial reports, additional modifications were communicated and since these other methods fall under the condensation approach, they will be presented as variations, although each of them has attained the status of named reaction . 

In Hantzsch s synthesis the condensation product is a derivative of dihydropjndine and is only converted into a true pyridine derivative by dehydrogenation. It is only by the removal of the two hydrogen atoms in the 1 4-positions that the heterocyclic ring system analogous to benzene is produced. The corresponding conversion of ethyl A 2 5-dihydroterephthalate into ethyl terephthalate takes place much more readily. 

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). 

Extensive stmcture activity relationship (SAR) studies in this series revealed that unsymmetrical substitution on the heterocyclic ring and hence the introduction of chirality on the central carbon atom led to increased potency. Such asymmetrical dihydro-pyridines can be prepared by stepwise variation of the Hantzsch synthesis, based on the hypothetical alternate route to nifedipine. Thus, aldol condensation of methyl acetoacetate with 2,3-dichlorobenzaldehyde (13-1) gives the cinnamyl ketone (13-2). Reaction of that with the enamine (13-3) from ethyl acetoacetate gives the calcium channel blocker felodipine (13-4) [14]. 

To make rosoxacin two heterocyclic systems must be constructed. Workers at the pharmaceutical company Sterling decided to build the pyridine in an ingenious version of the Hantzsch synthesis using acetylenic esters on 3-nitrobenzaldehyde. The ammonia was added as ammonium acetate. Oxidation with nitric acid made the pyridine, hydrolysis of the esters and decarboxylation removed the acid groups, and reduction with Fe(TT) and HC1 converted the nitro group into the amino group required for the quinolone synthesis. 

Promothiocin A was initially synthesised by a three-component coupling approach <1998CC2049>. A Bohlmann-Rahtz pyridine synthesis established the oxazoyl-thiazole-pyridine heterocyclic centerpiece. The thiazole building blocks were obtained by the Hantzsch reaction. Two different strategies for macrocylization were successfully employed, with the dedroalanine side-chain being introduced in the last steps of the synthesis <2000JA3301>. 

Combinations of N- and 5-alkylation in 2-imidazoline-2-thiols can lead to 5,6-dihydro-4//-imidazo[2,l-6]thiazoles when the heterocycles are treated with ketones in the presence of a halo-genating agent. This is a variant of the Hantzsch thiazole synthesis <92SC1293>. A further example of A-acylation in combination with nucleophilic substitution is the conversion of 2-chloro-2-imi-dazoline into (131) when it is treated with pyridine and an aryl isocyanate <87JCS(P1)1033>. 2-Imidazolines like clonidine are also known to A-nitrosate <93JCS(P2)59l>. Intramolecular alkylation is exemplified in the base-induced rearrangement of 2,5-diaryl-4-chloromethyl-2-imidazolines (132) into pyrimidines (Scheme 64) <93JOC6354>. 

Knoevenagel reactions are used in the synthesis of a wide variety of O- and N-heterocycles. In the typical Knorr pyrrole synthesis, a 1,3-dicarbonyl compound is condensed with an oximino- or azimino-1,3-dicarbonyl compound followed by reductive cyclization. Thus, catalytic hydrogenation of benzyl acetoacetate (243) and diethyl oximinoacetonedicarboxylate (242) affords pyrrole (244), which is transformed to (245) by another Knoevenagel reaction (Scheme 49). A rational synthesis of all four uropor-phyrines has been achieved by cyclization of appropriate pyrroles such as (245). ° Another typical preparation of a heterocycle that involves a Knoevenagel condensation is the Hantzsch 1,4-dihydro-pyridine synthesis. Here, an aldehyde and two molecules of a 1,3-dicarl30nyl compound react in the... 

A survey of microwave activation in the chemistry of Hantzsch 1,4-dihydropyridines (1,4-DHP) was reported in 2003 [195]. The experimental method proposed more than a century ago remains the most widely used for synthesis of these heterocycles. Since 1992 the process has been adapted to microwave irradiation under a variety of conditions to reduce the reaction time and enhance the yield. Among these experiments, Zhang reported a solvent-free process starting from 3-aminocrotonate (20 mmol), methyl acetoacetate (20 mmol), and aromatic aldehydes (20 mmol) in a domestic oven [196]. Yields from 59 to 77% were reported for 10-min reaction. A variety of conditions (solution, dry media, solvent-free) has been used for microwave-assisted synthesis of Hantzsch 1,4-DHP. Only procedures involving solvent-free conditions under the action of microwave irradiation led to the aromatized pyridine derivatives. 

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... 

Synthesis. The preparation of these heterocycles was accomplished using traditional methodology. 2,4-Disubstituted and 2,4,5-trisubstituted compounds were prepared via the Hantzsch (21) synthesis. The Gabriel (22) and Robinson-Gabriel (23) syntheses were used to prepare the 2,5-disubstituted thiazoles and oxazoles, respectively. The intermediate keto-amides could be converted into thiazoles by heating with P4S] q pyridine or with Lawesson s reagent (24). 

The 1,4-dihydropyridines (DHPs) classes of privileged heterocyclic pharmacophores are well known for their calcium channel blocker activity. Other versatile biological profiles of 1,4-DHPs such as anticonvulsant activity, selective adenosine-A3 receptor antagonism, radioprotective activity, sirtuin activation, and inhibition, etc. have also been well known [186]. Conventionally, 1,4-DHPs could be accessed via the Hantzsch reaction, reduction of pyridines, addition to pyridines or cycloadditions, etc. As a facile and broadly tolerable protocol, the Hantzsch reaction consisting of cyclocondensation reaction of ethyl acetoacetate (2 equivalent) with an aldehyde and ammonia remains as a frequently employed tactic for the synthesis of 1,4-DHPs in a large number of areas such as stereoselective synthesis and green chemistry [187]. 

Dihydropyridines find important applications in medicine (mainly as calcium channel blockers) and their chemistry has been thoroughly investigated over the last decades [11-14]. The first synthesis of dihydropyridines 4 was reported by Arthur Rudolf Hantzsch over a century ago and involved the condensation between ammonia, an aldehyde and two molecules of a P-ketoester (Scheme 2.1) [15]. Use of a modified procedure allowed synthesis of unsymmetrical dihydropyridmes starting from two different P-ketoesters [16], Compounds 4 are known as Hantzsch esters and have been extensively used as pyridine precursors in the synthesis of heterocyclic compounds. 

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