Hantzsch synthesis of pyridines

Ways in which pyridines and N-alkylpiperidines are synthesized. The importance of the Hantzsch synthesis of pyridines... 

According to the classical Hantzsch synthesis of pyridine derivatives, an a,(5-unsaturated carbonyl compound is first formed by Knoevenagel condensation of an aldehyde with a P-dicarbonyl compound. The next step is a Michael reaction with another equivalent of the P-dicarbonyl compound (or its enamine) to form a 1,5-diketone, which finally undergoes a cyclocondensation with ammonia to give a 1,4-dihydropyridine with specific symmetry in its substitution pattern. 

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 ... 

The Hantzsch synthesis of pyridines features 1,4-dihydropyridines in the first step. A variant of the method uses hydroxylamine (Table 17-5), which can be regarded as an oxidized version of ammonia. With this reagent, pyridines are formed directly from 1,5-dicarbonyl compounds, in turn readily made by Michael additions of enolates to a,j8-unsaturated aldehydes and ketones (Section 18-11). Formulate the mechanisms of the two steps in the pyridine synthesis shown. 

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. 

The rapid synthesis of heteroaromatic Hantzsch pyridines can be achieved by aromatization of the corresponding 1,4-DHP derivative under microwave-assisted conditions [51]. However, the domino synthesis of these derivatives has been reported in a domestic microwave oven [58,59] using bentonite clay and ammoniiun nitrate, the latter serving as both the source of ammonia and the oxidant, hi spite of some contradictory findings [51,58,59], this approach has been employed in the automated high-throughput parallel synthesis of pyridine libraries in a 96-well plate [59]. In each well, a mixture of an aldehyde, ethyl acetoacetate and a second 1,3-dicarbonyl compound was irradiated for 5 min in the presence of bentonite/ammonium nitrate. For some reactions, depending upon the specific 1,3-dicarbonyl compound used. 

The Hantzsch reaction that allows the synthesis of pyridine derivatives, is a condensation involving two equivalents of a yS-ketoester or a yS-ketoamide, one equivalent of an aldehyde and ammonia. The Hantzsch reaction was used by Patel et al. for the synthesis of a 300 member dihydropyridine library (Scheme 3.27) [287]. 

The most famous synthesis of pyridines is undoubtedly due to Hantzsch (1882LA(215)1), who used ethyl acetoacetate, an aldehyde and ammonia (or an aldehyde ammonia) to obtain... 

There are several significant ring syntheses for pyridines, of which the most important is the Hantzsch synthesis of dihydropyridines (Section 4.2.3.4.2). However, the majority of substituted pyridines are prepared from pyridine itself or from a simple alkyl derivative. 

In addition to procedures for pyridine ring closure based on the use of 3-amino-thiophene derivatives, there are alternative methods for the construction of thieno [3,2-Z>]pyridines. One approach made use of cyclic (3-keto sulfones, which proved to be convenient synthons for the modified Hantzsch synthesis of fused pyridines (1986KGS1563, 1990JHC1453, 2000MI1, 2002USP6191140). For example, the reactions of benzothiophene 1,1-dioxide 168 with enamines 169 or methylene-active compounds 170 in the presence of NH4OAc produced fused dihydropyridines 171 (1990JHC1453). 

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. 

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). 

Hantzsch, A. Synthesis of pyridine derivatives from acetoacetic ester and aldehydeammoniak. Liebigs Ann. Chem. 1882, 215,1-82. 

The Hantzsch-type of pyridine synthesis was also used in the total synthesis and stereochemical assignment of the thiopeptide antibiotic micrococcin Pl. ... 

Hantzsch s first important research was the synthesis of pyridine from acetoacetic ester and aldehyde ammonia, a general method of synthesis of pyridine derivatives. Coumarone, discovered by Fittig and Ebert (see p. 768), was (with some derivatives) synthesised by Hantzsch, who called it the fur-furane of the naphthalene series . He synthesised thiazole, and benzene, pyridine, and thiophen derivatives from derivatives of pentamethylene, and pyrrole, investigated tetrazoles, and perthiocyanic acid C2N2S3H2 (discovered by Wohler), giving it a cyclic structure." ... 

Romanelli and coworkers reported the solvent-free mnlti-component synthesis of pyridines nsing the Wells-Dawson (WD) heteropoly acid as the catalyst [59], The reaction of 3-formy Ichromones 80 with acetoacetic esters 81 and ammonium acetate gave the corresponding pyridines 83 in good yields (64-99%). As shown in Scheme 11.12, Hantzsch esters 82 were obtained in variable yields (0-36%) as the by-products. 

What starting materials would you use in the Hantzsch synthesis of the following pyridines ... 

SCHEME 35 Hantzsch reaction in aqueous medium for the synthesis of pyridines. 

Hantzsch synthesis The formation of pyridine derivatives by the condensation of ethyl acetoacetate with ammonia and an aldehyde. Also applied to similar syntheses of pyrroles. 

While there are a number of related reactions that can assemble the pyridine nucleus, the oldest of these classical reactions is due to Arthur Hantzsch. In 1882 he reported the first synthesis of l,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylates from a refluxing... 

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 . 

The immediate outcome of the Hantzsch synthesis is the dihydropyridine which requires a subsequent oxidation step to generate the pyridine core. Classically, this has been accomplished with nitric acid. Alternative reagents include oxygen, sodium nitrite, ferric nitrate/cupric nitrate, bromine/sodium acetate, chromium trioxide, sulfur, potassium permanganate, chloranil, DDQ, Pd/C and DBU. More recently, ceric ammonium nitrate (CAN) has been found to be an efficient reagent to carry out this transformation. When 100 was treated with 2 equivalents of CAN in aqueous acetone, the reaction to 101 was complete in 10 minutes at room temperature and in excellent yield. 

A general method for the construction of a pyridine ring is the Hantzsch synthesis. A condensation reaction of two equivalents of a /3-ketoester 1 with an aldehyde 2 and ammonia leads to a 1,4-dihydropyridine 3, which can be oxidized to the corresponding pyridine 4—for example by nitric acid ... 

Schemes Combinatorial domino synthesis of Hantzsch pyridines 21-23...

Formation of the central six-membered ring is the key to the synthesis of the highly substituted irnidazo[4,5-r]-[2,7]naphthyridines, 67 and 68 (Equations 15 and 16) the bicyclic precursors 65 and 66 are themselves the products of Hantzsch pyridine syntheses <1999PHA814>. 

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