Hantzsch reaction

Iminothiobutyramide (30), containing four nucleophilic centers (only two of which might react with two electrophilic sites in phenacylbromide), undergoes the Hantzsch reaction preferentially, yielding the enamine (31) in dry dioxane or (4-phenylthiazol-2-yl)acetone (32) in isopropanol. Other enamines are obtainable from the ketone (32) by standard methods (626) (Scheme 15). 

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. 

Two- and three-component Hantzsch reactions using C-glycosylated reagents have been reported as an alternate method for conducting asymmetric syntheses of 1,4-dihydropyridines." ° Reaction of 109, 110 and 97 generate 111 with Ri = sugar. Alternatively, 112 and 113 produce 111 with Ri = sugar. While the yields were acceptable (60-90%), the diastereomeric ratio varied from 30-60%. 

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... 

Oxa-tetrahydropyridines are interesting intermediates for the preparation of pharmaceuticals and natural product based alkaloid systems. A modified Hantzsch reaction was developed under microwave irradiation for the preparation of 2-oxa-tetrahydropyridines 173 by reaction of Meldrum s acid, a /3-ketoester and an aldehyde, using NH4OAC as the source of ammonia (Scheme 62). Yields ranged from 81 to 91% at temperatures of 100-130 °C depending on the substrate (the aldehyde) employed. All the products obtained have the same structure except for the aromatic substituent in position 4 [109]. 

Scheme 62 A modified Hantzsch reaction for the preparation of 2-oxa-tetrahydropyridines...

Hantzsch cyclization of 214 to dihydropyridines 216 can be accomplished by treating 215 with 214 in the presence of NaOEt (Equation 29). Under these conditions, dihydropyridines 216 are obtained in 41-64% yields. A three-component Hantzsch reaction using 214, aldehyde 217, and /3-keto ester 218 under similar conditions affords 219 in 51% yield (Equation 30) <2005JOC5331>. 

Iron-mediated generation of hydroxyl radical ( 0H) was monitored by the hypoxanthine-xanthine oxidase method as previously described (28). Formaldehyde produced by reaction of 0H with DMSO was determined spectrophotometrically by the Hantzsch reaction (29). 

F. Reche, M.C. Garrigos, A. Sanchez and A. Jimenez, Simultaneous fluid derivatization and extraction of formaldehyde by the Hantzsch reaction. J. ChromatogrA 896 (2000) 51-59. 

In the early Gatterman s preparative chemistry book, " the one-pot synthesis of dUiydropyridine derivatives like those formed by the Hantzsch reaction was one of practical laboratory exercises. 

Schildberg and Fleckenstein observed that calciumantagonists can advantageously influence the peripheric vessels and those of the heart.With the 4-aryldihydropyridine-3,5-dicarboxylic esters 4 (Scheme 1.1) that have such effects, the first pharmaceutical products synthesized by Hantzsch reactions were independently introduced by the Bayer and Smith Cline French. ... 

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]. 

Scheme 3.27 Hantzsch reaction for the synthesis of dihydropyridine derivatives (189) [287],...

Keywords 1,3-Dicarbonyls, Biginelh reaction, Hantzsch reaction, Heterocyclic chemistry, Knoevenagel condensation, Mannich reaction, Michael addition, Multi-component reactions... 

Scheme 3 Acridines and unsymmetric 1,4-DHPs via Hantzsch reaction...

Scheme 9 First organocatalyzed asymmetric three-component variant of Hantzsch reaction...

Wang LM, Sheng J, Zhang L, Han JW, Fan ZY, Tian H, Qian CT (2005) Facile Yb(OTf)(3) promoted one-pot synthesis of polyhydroquinoline derivatives through Hantzsch reaction. Tetrahedron 61 1539-1543... 

Nagarapu L, Kumari MD, Kumari NV, Kantevari S (2007) MCM-41 catalyzed rapid and efficient one-pot synthesis of polyhydroquinolines via the Hantzsch reaction under solvent-free conditions. Catal Commun 8 1871-1875... 

Kumar A, Maurya RA (2007) Bakers yeast catalyzed synthesis of polyhydroquinoline derivatives via an unsymmetrical Hantzsch reaction. Tetrahedron Lett 48 3887-3890... 

Debache A, Ghalem W, Boulcina R, Belfaitah A, Rhouati S, Carboni B (2009) An efficient one-step synthesis of 1,4-dihydropyridines via a triphenylphosphine-catalyzed three-component Hantzsch reaction under mild conditions. Tetrahedron Lett 50 5248-5250... 

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... 

There are some methods that are specific to HCHO. For example, the Hantzsch reaction of HCHO, collected with a diffusion scrubber, with ammonium acetate, acetic acid, and acetylacetone to form diacetyldihydrolutidine, which is measured using its fluorescence at 470 nm, has been applied to air measurements (Dasgupta et al., 1988, 1990 Kleindienst et al., 1988a,b Lawson et al., 1990 Khare et al., 1997). Reaction with 1,3-cyclohexanedione and ammonium acetate to form a dihydropyridine derivative that is measured by fluorescence has been used in conjunction with a diffusion scrubber (Fan and Dasgupta, 1994). Enzymatic methods have been used in which formaldehyde dehydrogenase catalyzes the oxidation of HCHO to HCOOH in the presence of -nicotinamide adenine dinucleotide, NAD+, which is reduced to NADH. The latter is measured by fluorescence at 450 nm (Lazrus et al., 1988 Ho and Richards, 1990). 

The utility of some of these products for side-chain modification has also been demonstrated. For example, 4-chloro-3-formylpyridine undergoes the Hantzsch reaction to give a 4-(3-chloropyridine)-l,4-dihydropyridine derivative (88%). (4-Chloro-3-pyridyl)diphenylmethanol affords aza-analogues (65-70%) of the antimycotic agent chlortrimazol by reaction with thionyl chloride and imidazole derivatives (88JHC81). 

For the preparation of 4-aryI-l,4-dihydropyridine derivatives, there are two general approaches, shown in the Scheme 1, which involve variants of the Hantzsch reaction [ref. 14,15],... 

Kidwai, M., Saxena, S., Mohan, R. and Venkataramanan, R., A novel one pot synthesis of nitrogen containing heterocycles an alternate methodology to the Biginelli and Hantzsch reactions, /. Chem. Soc., Perkin Trans. 1,2002, 1845-1846. 

The classical Hantzsch reaction, the formation of dihydropyridines from an aldehyde, a 5-keto ester and an amine, was first described in 18826. In the 1940s, the interest for this substance class increased due to its pharmacological activity, for example, 4-aryl-1,4-dihydropyrdines form an important class of calcium channel antagonists such as Nifedipin. 

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