Hantzsch dihydro -pyridine 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. 

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 

Once formed, 7 and 8 undergo a Michael reaction that gives rise to ketoenamine 9. Ring closure, to form 10, and loss of water then afforded 1,4-dihydropyridine 11. The presence of 9 and 10 could not be detected thus ring closure and dehydration were deduced to proceed faster than the Michael addition. This has the result of making the Michael addition the rate-determining step in this sequence. Conversely, if the reaction is run in the presence of a small amount of diethylamine, compounds related to 10 could be isolated. Diol 20 has been isolated in an unique case (R = CFb). Attempts to dehydrate this compound under a variety of conditions were unsuccessful. Stereoelectronic effects related to the dehydration may be the cause. In related heterocyclic ring formations, it has been determined that dehydration (20 — 10) is about 10 times slower than diol formation (19 — 20). Therefore, one would expect 20 to 

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 . 

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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). 

Ohberg, L. and Westman, J., An efficient and fast procedure for the Hantzsch dihydro pyridine synthesis under microwave conditions, Synlett, 2001, 8, 1296-1298. 

Hantzsch Dihydro pyridine Synthesis (Pyridine Synthesis)... 

Hantzsch (dihydro)-pyridine synthesis Description Historical perspective Mechanism Variations... 

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... 

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]. 

Synthetic ways to dihydropyridines can be classified into ring-forming processes and ring transformations, liie first general approach is best represented by the versatile Hantzsch synthesis. This method conveniently affords 1,4-dihydro- or 3,4-dihydro-, but not 1,2-dihydro-pyridines. The second approach may be illustrated by partial reduction of pyridines or pyridinium salts and nucleophilic addition of organometallic reagents to pyridines and pyridinium salts leading to 1,2- or l,4-dihydropyridines . 

The product from the classical Hantzsch synthesis is necessarily a symmetrically substituted 1,4-dihydro-pyridine, since two mole equivalents of one dicarbonyl component are utilised, the aldehyde carbonyl carbon becoming the pyridine C-4. The precise sequence of intermediate steps is not known for certain, and may indeed vary from case to case, for example the ammonia may become involved early or late, but a reasonable sequence would be aldol condensation followed by Michael addition generating, in situ, a... 

Our own approach to the combination of crown ether and dihydropyridine chemistry has involved constructing the dihydropyridine as an integral portion of the macrocyclic crown ether ring (see 24b, for example). The first synthetic approach involved ring-closure of an alicyclic precursor by means of the Hantzsch 1,4-dihydropyridine synthesis as illustrated for the preparation of (50, eq. 24). Such Hantzsch esters (general type 46) are attractive in that the acid functionalities at the 3,5-positions can be used as handles for attaching the (dihydro)pyridine... 

A one-pot Hantzsch reaction in aqueous medium without any solvent or catalyst is known for the synthesis of 1,4-dihydropyridines. Tamaddon and coworkers have reported the synthesis of 1,4-dihydropyridines 107 by the reaction of aldehydes 51 and methyl/ethyl acetoacetates 106 in aqueous ammonium carbonate at 55-60 °C (Scheme 35) [88]. Recently, a similar study has also been carried out by Yang and coworkers to obtain dihydro-pyridines [89]. Another example of dihydro pyridine ring formation in water employs methyl/ethyl acetoacetates and aromatic aldehydes with 6-amino-l,3-dimethyluracil in the presence of thiourea dioxide as the catalyst [90]. The utilization of water as a solvent and indium(III) chloride as a promoter for the formation of dihydropyridine ring is reported by Khurana and coworkers in the reaction of with 6-amino-l,3-dimethyluracil, aldehydes, and 1,3-diketones [91]. 

Pyridine, 6-cyano-l,2-dihydro-thermal dimerization, 2, 370 Pyridine, 2-cyanomethyl-tautomerism, 2, 159 Pyridine, 4-cyanomethyl-tautomerism, 2, 159 Pyridine, 2-cyano-2,3,4,5-tetrahydro-metallation, 2, 387 Pyridine, 2,5-diacetyl-ipso substitution, 2, 301 Pyridine, 3,5-diacetyl-l,4-dihydro-Hantzsch synthesis, 2, 482 Pyridine, 4-dialkylamino-as acylation catalysts, 2, 34 Pyridine, 2,2-dialkyl-l,2-dihydro-... 

To complete the section on the synthesis of 4,4 -bipyridines, we summarize the methods reported for the preparation of some substituted 4,4 -bi-pyridines and 4,4 -bipyridinones. These methods are closely analogous to syntheses already discussed for some of the isomeric bipyridines. Thus the Hantzsch reaction using pyridine-4-aldehyde, ethyl acetoacetate, and ammonia gives 3,5-di(ethoxycarbonyl)-1,4-dihydro-2,6-dimethyl-4,4 -bipyridine, which after oxidation, followed by hydrolysis and decarboxylation, afforded 2,6-dimethyl-4,4 -bipyridine. Several related condensations have been reported. Similarly, pyridine-4-aldehyde and excess acetophenone gave l,5-diphenyl-3-(4-pyridyl)pentane-l,5-dione, which with ammonium acetate afforded 2,6-diphenyl-4,4 -bipyridine. Alternatively, 1-phenyl-3-(4-pyridyl)prop-2-enone, A-phenacylpyridinium bromide, and ammonium acetate gave the same diphenyl-4,4 -bipyridine, and extensions of this synthesis have been discribed. Condensation of pyridine-4-aldehyde with malononitrile in the presence of an alcohol and alkaline catalyst produced compounds such as whereas condensations of... 

An iron-catalyzed reaction of an a,P-unsaturated oxime such as 68 with a P-oxo ester also gave pyridine derivatives such as nicotinic acid 69 [99]. Under the reaction conditions (150-160 °C, without solvent) first Michael adducts such as intermediate 70 are presumably formed, which further condense via intermediate 71. This method is not restricted to a centric symmetry in the substitution pattern, which is an advantage compared with the Hantzsch synthesis. Moreover, the method starts with hydroxylamine being two oxidation stages above ammonia therefore, no oxidation in the final stage from dihydro- to pyridine is necessary (Scheme 8.31). 

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>. 

In carbon-14 chemistry, Knoevenagel-Michael sequences with alkyl acetoacetates have found widest application in the synthesis of labeled 1,4-dihydropyridines (Hantzsch dihydropyridine synthesis). 4-Aryl-l,4-dihydro[ C]pyridine derivatives constitute a class of calcium antagonists and calcium channel blockers that play an important role in the treatment of cardiovascular diseases. The basic sequence, depicted in Figure 6.90, involves first the Knoevenagel condensation of an aromatic aldehyde with an alkyl... 

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