The Hantzsch Condensation

In this method, an oligoethylene glycol is treated with 0.3 eq. of sodium bromoace-tate in methanol. The resulting monocarboxylic acid salt is then treated with toluene-sulfonyl chloride, sodium carbonate and dioxane. After heating the reaction mixture at 50° for an hour, the product was obtained either by Kugelrohr distillation or extraction. The two compounds produced in the reaction below (i.e., n = 1 and n = 2) were formed in 38% and 42% yields respectively . 

These authors suggest that the reaction may proceed through the formation of their mixed anhydrides , and illustrate a metal ion templated, mixed carboxylic-sulfonic anhydride. 

H0CH2(CH20CH2)n+30H + BrCH2C02Na - H0CH2(CH20CH2)n+30CH2C02Na 

It should be noted that compounds of this type have been of interest as models for hydride transfer reductions in biological systems. Van Bergen and Kellogg state clearly their hope, if not expectation, that when ions such as H, Zn , Mg, etc. are com-plexed in the vicinity of the donor, beneficial catalytic effects might be forthcoming .  

Similar compounds to those described above have been prepared by the same group using the bis-cesium salts of pyridine-3,5-dicarboxylic acids. In a number of experiments Piepers and Kellogg showed that Cs plays an irreplacable role as compared with Na , K and Rb for the formation of [the macrocycle shown below] . 

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Nearly a century later with the recognition that DHPMs possessed similar pharmacological profiles to the Nifedipine class [9a] of DHP calcium channel modulators 2 (formed via the Hantzsch condensation 1882, Scheme 11.2 [9b]), the Biginelli reaction witnessed a dramatic upsurge in popularity [10],... 

The product of Step 2 was also used in the Hantzsch condensation to prepare phthaloyl amlodipine, a precursor for amlodipine besylate (3). 

A semiautomated fluorometric procedure for quantitating triglycerides was presented by Kessler and Lederer in 1965 (K6). This is based on the Hantzsch condensation reaction between an amine, j8-diketone, and an aldehyde (Bl, Nl). Isopropanolic extracts of serum are prepared manually, and at this point can also be used for the determination of cholesterol and phospholipids. Triglycerides can be determined after treatment with Zeolite, as employed by Van Handel and Zilversmit... 

The reagents stayed in the aqueous phase. The product precipitated as formed. The hydrotropic solution showed no problems after being recycled four times. This method has also been used in the Hantzsch condensation (8.39) where, again, the product was recovered by filtration. 

As an example, we present a solution-phase multigeneration strategy towards highly substituted thiazoles based on the Hantzsch condensation of thioureas 33 with 2-bromomethyl ketones 34 to give 2-aminothiazoles 35 in high yields, as shown in Scheme 3.4.4, using liquid-liquid phase extraction (LPE) and liquid-solid phase extraction (SPE). 

It is also interesting to note that Van Bergen and Kellogg have used the Hantzsch condensation to construct the pyridine ring in situ <76CC964>. Construction of the pyridine unit from the / -keto ester places the pyridine nitrogen exocyclic (12), unlike (9)-(ll) in which the pyridine N is endocyclic. 

The Hantzsch strategy has been applied in the synthesis of the dopamine Da-agonist pramipexole, a molecule comprising a fused bicyclic tetrahydrobenzothiazole substructure. The synthesis starts with a-bromination of protected 4-aminocyclohexanone followed by the Hantzsch condensation with thiourea. Deprotection and then chiral resolution yield the -enantiomer. Reductive amination leads to pramipexole, which is isolated as the dihydrochloride. ... 

If in the Hantzsch s synthesis, selenoamide is replaced by a selenosemi-carbazide (HjJN -NH-CSe-l ). condensation can take place upon... 

Another approach to 2-aminothiazole derivatives was recently developed by Zbiral and Hengstberger (667, 700) thus the condensation of )3-acylvinylphosphonium salts (248) with thiourea affords the thiazolyl-methylphosphonium salt (249) via an acyclic intermediate analogous to the Hantzsch s synthesis. Final alkaline hydrolysis of 249 furnishes the 2-aminothiazoles (250) (Scheme 127) (700). 

The most widely used method for the preparation of carboxylic acids is ester hydrolysis. The esters are generally prepared by heterocyclization (cf. Chapter II), the most useful and versatile of which is the Hantzsch s synthesis, that is the condensation of an halogenated a- or /3 keto ester with a thioamide (1-20). For example ethyl 4-thiazole carboxylate (3) was prepared by Jones et al. from ethyl a-bromoacetoacetate (1) and thioformamide (2) (1). Hydrolysis of the ester with potassium hydroxide gave the corresponding acid (4) after acidification (Scheme 1). 

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. 

While mechanistically this reaction is related to the Robinson-Schopf reaction for the generation of the tropinone skeleton, it also has similarities to the Hantzsch reaction. Here the heterocyclic ring 75 is assembled by the condensation of an equivalent of acetonedicarboxylic ester 72 with 2 equivalents of aldehyde 73 in the presence of ammonia or primary amine 74. 

The preparation of the selenazolyl-pyrazolones was then effected by a second method, in which first the pyrazolone ring and afterward the selenazole ring was formed. For this purpose -ketoester seleno-semicarbazones were first converted to the corresponding 1-seleno-carbamoyl-3-aIkylpyrazol-5-one. These, by condensation with a-halo-genocarbonyl compounds according to the Hantzsch synthesis, formed the selenazole ring as a second step (17). 

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 ... 

The initial step of the Hantzsch synthesis is likely to be a Knoevenagel condensation reaction of aldehyde 2 and /3-ketoester 1 to give the a ,/3-unsaturated ketoester 6 ... 

Pyridines are traditionally prepared using the Hantzsch reaction, a condensation between 2 mol of a 6-ketoester, 1 mol of an aldehyde and 1 mol of ammonia. The product of this reaction is a 1,4-dihydropyridine which can be further oxidized to the corresponding pyridine compound (as 155 in Scheme 54). A first report described the Hantzsch reaction carried out under microwave irradiation on Bentonite clay and ammonium nitrate as ammonia... 

Another modification of the Hantzsch thiazole synthesis afforded C-4 thiazolylmethyl phosphonium salts (49). These ylids could then undergo Wittig condensations to furnish a wide variety of 2,4-disubstituted thiazoles <96TL983>. 

In a related example involving the use of the same instrument (Fig. 12.6) in the Hantzsch multicomponent condensation, the serial synthesis of 24 dihydropyridine... 

The modified Hantzsch condensation of nitroacetone, 2,l,3-benzoxadiazol-4-carboxaldehyde 253, and ( S,ZR)-Z-(3,5-dinitrophenylcarbonylamino)-2-methoxycarbonyl-l-methylethyl 3-aminocrotonate afforded a mixture of the two diastereomers that differ in configuration (S or R) at the C-4 position of the 1,4-DHP ring (DHP - dehydropeptidase) (Equation 49) <2004JME254>. 

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]. 

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... 

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 novel solid-phase synthesis of pyrrolo[3,4- ]pyridines using a sequence of Knoevenagel and Hantzsch condensation reactions has been reported <199981951 >. The reactions lead to a variety of highly substituted pyrrolo[3,4- ]pyridines, 70. 

Solid-phase syntheses have become increasingly popular during the period of this review, with examples including the synthesis of 5,6,7,8-tetrahydro[l,6]naphthyridines from Meldrum s acids derived from /3-amino alcohols via Hantzsch condensation and cyclization with cyclative cleavage from the resin (using 70% trifluoroacetic acid (TFA)/dichloromethane (DCM) followed by 5% triethylamine/DCM) <1999S1951> and also of isoquinolinones and 5-oxo-5,6-dihydro-[l,6]naphthyridines <1995JOC5748>. 

Solid-phase synthesis of pyrido[2,3 pytirtiidines 514 was achieved by Hantzsch condensation of Wang resin-supported Knoevenagel derivative 513 with 6-aminouracil derivatives 512 as an a-oxo enamine component in the presence of ceric ammonium nitrate (CAN) in DMA followed by hydrolysis with TFA in CH2GI2. Compound 513 was prepared by treatment of a hydroxylated polymer, such as Wang or Sasrin resin, with diketene, followed by condensation with benzaldehyde (Equation 41) <1996TL4643>. 

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]. 

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 have been used to prepare pyrroles on insoluble supports (Figure 15.1). These include the condensation of a-halo ketones or nitroalkenes with enamines (Hantzsch pyrrole synthesis) and the decarboxylative condensation of N-acyl a-amino acids with alkynes (Table 15.3). The enamines required for the Hanztsch pyrrole synthesis are obtained by treating support-bound acetoacetamides with primary aliphatic amines. Unfortunately, 3-keto amides other than acetoacetamides are not readily accessible this imposes some limitations on the range of substituents that may be incorporated into the products. Pyrroles have also been prepared by the treatment of polystyrene-bound vinylsulfones with isonitriles such as Tosmic [28] and by the reaction of resin-bound sulfonic esters of a-hydroxy ketones with enamines [29]. 

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. 

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