Hantzsch synthesis pyridines

Dihydropyridine from the condensation of aldehyde, p-ketoester and ammonia. 

Balogh, M. Hermecz, I. Naray-Szabo, G. Simon, K. Meszaros, Z. J. Chem. Soc., Perkin Trans. 1 1986, 753. 

Chaki abai tty in Oxidation in Organic Chemistry, Part C (Ed. W. S. Traha-novsky), Academic Press, New York, 1978, p. 343-370. 

4-Dihydropyridines from condensation of /3-ketoesters with aldehydes and ammonia 

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  

In general the oxidation does not affect the substituent R at C-4 however if R is a benzyl group PhCha-, this will be cleaved from C-4, and a hydrogen is retained in that position (unusual oxidation to yield pyridine). 

The classical synthesis started from acetoacetic ester (1, R = CH3, R = C2H5) and acetaldehyde (2, R = CH3). By subsequent cleavage of the substituents from C-3 and C-5, the collidine 5 was obtained (R = R = CH3)  

In its simplest form, this consists of the condensation of a 3-ketoester with an aldehyde and ammonia. 

The product is a 1,4-dihydropyridine, which is subsequently transformed into the pyridine by oxidation. Several separate reactions occur during this synthesis, and the precise sequence of events may not be quite as shown below - they may be in a different order. 

The normal Hantzsch synthesis leads to a symmetrical product. The diesters formed may be hydrolysed and decarboxylated using base to give pyridines with less substitution. Note that we are using the ester groups as activating species to facilitate enolate anion chemistry (see Section 10.9) 

Michael-like nucleophilic attack of enamine on to unsaturated ketone note ketone is more electrophilic than ester Me 

Muceniece, D. Zandersons, A. Lusis, V. Bull. Soc. Chim. Belg. 1997,106,467. 

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The Hantzsch pyridine synthesis involves the condensation of two equivalents of a 3-dicarbonyl compound, one equivalent of an aldehyde and one equivalent of ammonia. The immediate result from this three-component coupling, 1,4-dihydropyridine 1, is easily oxidized to fully substituted pyridine 2. Saponification and decarboxylation of the 3,5-ester substituents leads to 2,4,6-trisubstituted pyridine 3. 

Krohnke observed that phenacylpyridinium betaines could be compared to 3-diketones based on their structure and reactivity, in particular, their ability to undergo Michael additions. Since 3-dicarbonyls are important components in the Hantzsch pyridine synthesis, application of these 3-dicarbonyl surrogates in a synthetic route to pyridine was investigated. Krohnke found that glacial acetic acid and ammonium acetate were the ideal conditions to promote the desired Michael addition. For example, N-phenacylpyridinium bromide 50 cleanly participates in a Michael addition with benzalacetophenone 51 to afford 2,4,6-triphenylpyridine 52 in 90% yield. 

The long history associated with the Hantzsch pyridine synthesis has produced numerous approaches and methods to the reaction protocol in order to control the various factors directing the course of the reaction. 

A 1,4-dihydropyridine having coronary vasodilatory activity and, therefore, intended for relief of the intense chest pains of angina pectoris is nifedipine (34). Using a portion of the classical Hantzsch pyridine synthesis, condensation of two moles of... 

The benzo-fused dihydrotetrazolo[2,7]naphthyridine 308 is a minor end-product of a mixed Hantzsch pyridine synthesis involving 2-azido-3-nitrobenzaldehyde, /3-aminocrotononi trile, and methyl /3-aminocrotonate in ethanol (Scheme 76) <2001TL4507>. 

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-... 

Khmelnitsky and coworkers have also examined microwave-assisted parallel Hantzsch pyridine synthesis [28], They have demonstrated the benefits of microwave irradiation in a 96-well plate reactor for high throughput, automated production of a pyridine combinatorial library (Scheme 8.20). 

Scheme 12.23 Microwave-assisted Hantzsch pyridine synthesis.

Handylab, 26 976 Hanford N reactor, 17 572-573 Hanford production reactors, 17 570 Hanksite, 5 785t Hansa yellows, 14 317 Hansch equation, 10 329 Hansenula polymorpha, 12 479 Hantaviruses, 3 137 Hantzsch pyridine synthesis, 16 550 Hantzsch-Widman nomenclature system, 17 399... 

The formation of azine derivatives by condensation of enamines and enamides with 1,3-dielectrophiles has been known for almost a century, and there are a number of reactions (e.g. the Hantzsch pyridine synthesis) which proceed by intermediate formation of such compounds. Examples are shown in equations (117)—(119). The transformations outlined in equations (120) and (121) are mechanistically related processes. 

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... 

Application of part of the classical Hantzsch pyridine synthesis leads to nifedipine (87) (81 AG(E)762, 68SAP6801482), a calcium antagonist useful in the treatment of angina. The pharmacology of a chemically related drug, nisoldipine (88), has recently been studied (80AF2144). Both compounds inhibit the transmembrane movement of calcium into activated smooth and cardiac muscle. Nisoldipine, however, is characterized by a high potency and uniqueness of action and may well prove to be of considerable therapeutic value. 

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. 

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... 

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... 

Various approaches can be used to synthesize pyridines and partially saturated pyridines on insoluble supports. Dihydropyridines can be readily prepared by cyclocondensation of amines with ketones and aldehydes (Hantzsch pyridine synthesis, Figure 15.12). This synthesis proceeds particularly smoothly when using a 3-keto carboxylic acid derivative as the ketone component. This cyclocondensation has been realized on... 

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. 

In support of an hypothesis that clivacetine (188) might be a possible biosynthetic precursor of the unusual alkaloid clivimine (192), a biogenetic-type, partial synthesis of 192 from 188 has been completed, exploiting a classic Hantzsch pyridine synthesis (136). Thus, treatment of 188 with 35% formalin and 25% ammonium hydroxide gave dihydroclivimine, which underwent facile oxidation to clivimine (192) on dehydrogenation with sodium nitrite and acetic acid. 

The enone 90 is an aldol product from an aromatic aldehyde and the same acetoacetate 91, raising the possibility that all these reactions might occur at once. We have rediscovered the Hantzsch pyridine synthesis.18 The three components are reacted with ammonia (often NH4OH or NH4OAC) to give 88 in one step.19... 

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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