Condensed pyridines, synthesis

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. 

The Guareschi-Thorpe pyridine synthesis is closely related to the Hantzsch protocol. The primary point of difference lies in the use of cyanoacetic esters. This modification assembles pyridine 23 by the condensation of acetoacetic esters 21 with cyanoacetic esters 22 in the presence of ammonia. A second variation of this method involves reaction of cyanoacetic ester 22 with P-diketone 24 in the presence of ammonia to generate the 2-hydroxypyridine 25. 

The Hantsch pyridine synthesis provides the final step in the preparation of all dihydrop-yridines. This reaction consists in essence in the condensation of an aromatic aldehyde with an excess of an acetoacetate ester and ammonia. Tlie need to produce unsymmetrically subsrituted dihydropyridines led to the development of modifications on the synthesis. (The chirality in unsymmetrical compounds leads to marked enhancement in potency.) Methyl acetoacetate foniis an aldol product (30) with aldehyde 29 conjugate addition of ethyl acetoacetate would complete assembly of the carbon skeleton. Ammonia would provide the heterocyclic atom. Thus, application of this modified reaction affords the mixed diester felodipine 31 [8]. 

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 cobalt-catalyzed cooligomerization of diynes with nitriles allows a simple one-step synthesis222 of condensed pyridine derivatives including difficultly accessible 5,6,7,8-tetrahydroisoquinolines223 The synthesis is a versatile one in that pyridines condensed with five- and seven-membered carbocyclic rings can also be achieved in moderate yield in similar fashion. Additional attractive features of this simple synthesis are the formation of condensed isoquinolines by the use of functionalized nitriles and the pronounced regioselectivity observed when dissymmetrical diacetylenes are employed (Scheme 148).222... 

With the aid of a Knoevenagel condensation and a Staudinger reaction, 2-azidocyclopent-l-ene 1-carbaldehydes (195) can be converted into suitable products for a cyclopenta[b]pyridine synthesis [89JCS(P1)1369], as shown in Scheme 72. In order to bring the ester carbonyl function and the imino-phosphorane group into close proximity suitable for cyclization reactions, the 1,3-diene system 196 should possess the s-cis conformation. Furthermore, the exocyclic double bond should show a cis conformation. To achieve... 

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. 

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... 

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 glycerol was to provide acrolein (CH2=CH-CHO) by dehydration, the nitrobenzene was to act as oxidant, and the wide condenser... All too often Skraup reactions did let rip—with destructive results. A safer approach is to prepare the conjugate adduct first, cyclize it in acid solution, and then oxidize it with one of the reagents we described for pyridine synthesis, particularly quinones such as DDQ. 

The Hantzsch pyridine synthesis affords 1,4-dihydropyridines 214, although spontaneous oxidation to pyridines often occurs. In its simplest form it involves the condensation of two molecules of a -keto ester with an aldehyde and ammonia (Scheme 119) . Compounds resulting from the condensation of ammonia with one of the carbonyl components can be used in the Hantzsch synthesis. Thus, -aminocrotonic ester 215 can replace the ammonia and one mole of acetoacetic ester in Scheme 119. The mechanism of the Hantzsch synthesis has been clarified by 13C and 1SN NMR spectroscopy <1987T5171>. 

The above equation represents the classical pyridine synthesis of Hantzsch, the starting materials being an aldehyde, a /S-keto ester, and ammonia. The over-all yield of 3,5-dicarbethoxy-2,6-dimethylpyridine from formaldehyde, acetoacetic ester, and ammonia is 4S>-58%. A study of substituted aromatic aldehydes in this synthesis has been made. This is one of many condensations of aliphatic compounds that leads to pyridine derivatives. Although these condensations have been subdivided in various ways for purpose of discussion, the lines of de-... 

In the laboratory of P. Kocovsky, novel pyridine-type P,A/-ligands were prepared from various monoterpenes. The key step was the Krohnke pyridine synthesis, and the chirality was introduced by the a,(3-unsaturated ketone component, which was derived from enantiopure monoterpenes. One of these ligands was synthesized from (+)-pinocarvone which was condensed with the acylmethylpyridinium salt under standard conditions to give good yield of the trisubstituted pyridine product. The benzylic position of this compound was deprotonated with butyllithium, and upon addition of methyl iodide the stereoselective methylation was achieved. The subsequent nucleophilic aromatic substitution (Sw/ r) gave rise to the desired ligand. 

Krohnke pyridine synthesis Condensation of an unsaturated ketone with an a-halo ketone to give highly substituted pyridines. 254... 

Chichibabin pyridine synthesis. Condensation of carbonyl compounds with ammonia or amines under pressure to form pyridine derivatives the reaction is reversible and produces different pyridine derivatives and by-products. 

This very old synthesis of l,4-dihydropyrimidin-2-ones, which is analogous to the Hantzsch pyridine synthesis (8.14.1.2), is much used, particularly for library synthesis, and many variants of the reaction conditions have been described most often the condensation is acid or Lewis-acid catalysed. The products are important in their own right, but can also be dehydrogenated to give pyrimidin-2-ones. If guanidine is used instead of the urea component, 2-amino-1,4-dihydropyrimidines result. ... 

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... 

Halogenation-dehydrohalogenation Synthesis of an alkyne through an alkenyl halide intermediate. Hantzsch pyridine synthesis Condensation of two 3-dicarbonyl molecules, an aldehyde, and ammonia... 

The first reactions are an aldol condensation and a conjugate addition. We have shown just the first steps, but make sure that you can draw full mechanisms for both. The last step is a standard pyridine synthesis. 

When using cyanoacetic esters instead of aldehydes, the Guareschi-Thorpe pyridine synthesis assembles pyridines 155 by the condensation of acetoacetic esters 153 with cyanoacetic esters 154 in the presence of ammonia. A variation of this method involves the reaction of cyanoacetic ester 156 with 3-diketone 157 in the presence of ammonia to generate 2-hydroxypyridine 158." The mechanism of this reaction has been studied, and it was initiated by an ester/amide exchange on cyanoacetic ester 156 with... 

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