Hantzsch-type reaction

A number of fused thiopyranopyrazolopyrimidines with potential as potassium channel openers have been prepared by a three-component Hantzsch-type reaction between a ketone, an aldehyde, and an aminopyrazole. These reactions give a mixture of isomers, with and without ring junction heteroatoms (Equation 49) <2002BML1481> among the compounds of particular interest are those in which the ketone is a derivative of thiopyran or its A,A-dioxide. 

Hantzsch-type reaction between 5-amino-3-methyl-l-phenylpyrazole, 4-dimethyl-aminobenzaldehyde, and 2-aroylbenzimidazole is followed by elimination of 4-dimethylaminophelyl substituent [75]. The treatments that were carried out in boiling glacial acetic acids for 2 h yielded pyrazolopyridines 44 when Ry 4-NO2C6H4 (Scheme 19). 

Another application of additions to chiral vinylic sulfoxides constitutes the Hantzsch-type reaction of methyl 3-aminocrotonate with compound (109), yielding the dihydropyridine derivative (110) as a single... 

Reaction of dimedone enamines with a-ketoacids has recently been shown to lead mainly to indole-2,4-dione derivatives64 (equation 47). Glyoxylic acid, however, reacts similarly to other aldehydes in a Hantzsch-type reaction yielding iV-phenylacridinedione in 30% yield64. 

Eq. (11), the selenazole (27) is not formed by the same mechanism as the usual Hantzsch-type reaction. 

Alkynes bearing electron-withdrawing substituents are more suitable for this reaction as was shown earlier by Bohlmann and Rahtz. Pyridines are formed from intermediate Michael adducts in the reaction of a-oxoalkynes having a j8-hydrogen and several primary enaminones in high yield. If, however, jS-substituted propargylaldehyde derivatives are used, a normal Hantzsch-type reaction without attack of the alkyne bond leads to 1,4-dihydropyridines (equation 79). This method was used later for converting cyclic enaminones to pyridine derivatives, however in low yield, and to quinolines in a better yield (equation 80). 

The reactivity of pyridazine-3- and 4-carbaldehydes towards active methylene reagents under the conditions of Knoevenagel, Wittig, and Hantzsch-type reactions has been examined. The 4-aldehyde reacts readily with malononitrile and methyl cyanoacetate, and less readily with triethyl phos-phonoacetate, indane-l,3-dione and alkyl acetoacetates/ammonia (e.g.. Scheme 52). Condensation with nitroethane is successful, but nitromethane gives an unstable intermediate which decomposes. The 3-aldehyde has similar reactivity to the 4-aldehyde, but some reactions are unsuccessful due to reduced reactivity, or instability of the products <90JHC1313>. 

G. C. Nandi, S. Samai, M. S. Singh, J. Org. Chem. 2010, 75, 7785-7795. BigineUi and Hantzsch-type reactions leading to highly functionalized dihydropyrimidinone, thiocoumarin, and pyridopyrimidinone frameworks via ring annulation with... 

Scheme 4i39 Enantioselective sequential Hantzsch-type reaction of conjugated enals, primary anilines, and 1,3-dicarbonyl compounds catalyzed by sterically demanding phosphoric acids.

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

Thiazoles may be prepared by a Hantzsch-type process, by reaction of N-protected thioamino acids with bicarbonate and BrCH2C0C02Et, followed by TFAA in 2,6-lutidine (equation 205). This reaction has been used as one of the important steps in the total synthesis of (—)-bistatramide C721. 

A direct asymmetric reductive Mannich-type reaction that allows for the formation of three contiguous stereocentres with high chemo-, diastereo-, and enantio-selectivity (10 1 to 50 1 dr, 96-99% ee ) has been presented (Scheme 4). The reaction commences with the formation of the corresponding iminium ion from aldehyde (122) and prolinol (g) catalyst (125), followed by conjugate reduction with Hantzsch ester (123) to generate an enamine, which then undergoes Mannich reaction with imine (124) to produce (126).179... 

Although the exact reaction mechanism for this three-component condensation reaction was not confirmed in [193, 194], the hypothesized mechanism is likely to involve the initial base-catalyzed formation of the Michael adduct, and its subsequent reaction with the aminopyrazole component to furnish the tricyclic intermediate (Scheme 3.63). Elimination of water from this intermediate leads to the formation of the classic Hantzsch-type dihydropyridine... 

Under acidic conditions, Hantzsch-type intermediates 414a-d prepared by the reaction of pyrazol-3-one 411 with thionyl chloride and pyridine, followed by addition of ethyl-3-amino-2-butenoates 413a-d, undergo an elimination of the 4-substituent to yield pyrazol-3-one 415 and pyridine 416a d. The salt 412, which was not isolated, was expected to react with butenoates 413 to yield dihydropyridines 414. Cleavage of the C-4 dihydropyridine/C-4 pyrazol-3-one bond could probably occur at C-4 due to the particular electronic delocalization in the enaminone-like moiety (94H815) (Scheme 115). 

The reaction mixture was irradiated in a domestic MW oven for 5 min on a surface of bentonite clay. Not only traditional j8-keto esters, but also, for example, cyclic 1,3-diketones can participate in this MCR, thus enabling a four-component Hantzsch-type synthesis of unsymmetrically substituted 1,4-pyridines 20 (Scheme 17.15) [29, 37]. 

The syntheses of dithiopyr (1), thiazopyr (2) and related compounds [4, 5] begin with a Hantzsch-type base-catalyzed intermolecular cyclization [22], which provides the dihydropyridines 4 (R = Me or Et). Two equivalents of methyl or ethyl trifiuoroacetoacetate (5, R = Me or Et) are allowed to react with one equivalent of isovaleraldehyde (6) in the presence of a base, like piperidine, in a suitable solvent at temperatures varying from room temperature to reflux. The intermediate dihydroxytetrahydropyran (structure not shown) is converted into the dihy-droxypiperidine 7 by reaction with a nitrogen source, such as ammonium hydroxide or ammonia gas. Reaction of 7 with a dehydrating agent, such as concentrated sulfuric acid, toluenesulfonic acid, or trifluoroacetic anhydride, gives a mixture... 

The aldol-type reaction occurs in some processes (i.e. Weiss-Cook and Hantzsch reactions), in tandem with the Michael reaction. Therefore, some significant applications of this last reaction in aqueous media will be illustrated. 

Asymmetric Reduction of Enals by Transfer Hydrogenation. The metal-free reduction of olefins relies on the use of Hantzsch-type dihydropyridines, as hydrogen donors. The asymmetric variant of this reaction can be mediated by catalyst 1. The reduction is enantioconvergent both stereoisomers of... 

Hantzsch Heterocyclization Henry Reaction Hofmann Rearrangement Knoevenagel Condensation Mannich Type Reaction Michael Addition enolate... 

---