Hantzsch Cyclocondensations

Alvarez-Builla and coworkers have used microwave irradiation to improve Hantzsch- 

Khadilkar and Madyar [24] have developed a large scale and continuous Hantzsch- 

Nitrendipine (R = 3-N02, R1, R2 = Me) has been obtained in 94% yield (50 g) after 24 min by microwave irradiation of the reaction mixture (final temperature 86 °C) at a flow rate of 100 mL min-1. The reaction mixture was circulated through the 

It should be noted that the Hantzsch-1,4-DHP synthesis can be conducted with a soluble polymer. Successful derivatization of poly(styrene-co-allyl alcohol) under the action of microwave irradiation with a variety of ethyl oxopropanoates and ethyl 3-aminobut-2-enoates were reported by Vanden Eynde s group [27]. 

In each reaction ethyl acetoacetate 51 a was used as one of the components of the Hantzsch synthesis, whereas the second 1,3-dicarbonyl compound 51 (or 53) and the aldehydes 50 were used in all possible combinations (one unique combination per 

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Ducatti DRB, Massi A, Noseda MD, Duarte MER, Dondoni A (2009) Dihydropyridine C-glycoconjugates by organocatalytic Hantzsch cyclocondensation. Stereoselective synthesis of alpha-threofuranose C-nucleoside enantiomers. Org Biomol Chem 7 1980-1986... 

Dondoni, A., Massi, A., Minghini, E., Sabbatini, S., Bertolasi, V. Model Studies toward the Synthesis of Dihydropyrimidinyl and Pyridyl a-Amino Acids via Three-Component Biginelli and Hantzsch Cyclocondensations. J. Org. Chem. 2003, 68, 6172-6183. 

The known but newer, more elaborate approach to 4//-thiopyrans by procedures A, B, and C (Scheme 1) resembles the Hantzsch-like syntheses of 4iT-pyrans (83AHC145, Section III,D). The results are summarized in Table I for 3,5-dicyano products 21. The chemistry of cyanothioacetamide as the key starting component has also been reviewed (86H2023 87H205). Cyclocondensations A to C usually proceed under mild conditions and afford 21 in satisfactory yields. 

The cyclocondensation of an aldehyde, CH-acidic ketone and ammonia provides symmetrical l,4-dihydropyridine-3,5-dicarboxylate derivatives of pharmacological importance, often called Hantzsch 1,4-dihydropyridines (1,4-DHPs) following its original invention over a century ago (Scheme 4) [44,45]. The 1,4-DHP motif is found in a number of chemotherapeutic agents for... 

Preparation of thiazole Hantzsch synthesis can be applied to synthesize the thiazole system from thioamides. The reaction involves initial nucleophilic attack by sulphur followed by a cyclocondensation. 

The more usual cyclocondensations of two identical molecules of 1,3-dicarbonyl or other C-acidic components with a third different oxo compound (mostly an aldehyde) afford exclusively 4//-pyrans and resemble the well-known Hantzsch synthesis of 1,4-dihydropyridines. It usually proceeds... 

Various approaches can be used to synthesize pyridines and partially saturated pyridines on insoluble supports. Dihydropyridines can be readily prepared by cyclocondensation of amines with ketones and aldehydes (Hantzsch pyridine synthesis, Figure 15.12). This synthesis proceeds particularly smoothly when using a 3-keto carboxylic acid derivative as the ketone component. This cyclocondensation has been realized on... 

According to the classical Hantzsch synthesis of pyridine derivatives, an a,(5-unsaturated carbonyl compound is first formed by Knoevenagel condensation of an aldehyde with a P-dicarbonyl compound. The next step is a Michael reaction with another equivalent of the P-dicarbonyl compound (or its enamine) to form a 1,5-diketone, which finally undergoes a cyclocondensation with ammonia to give a 1,4-dihydropyridine with specific symmetry in its substitution pattern. 

A variation of the Hantzsch synthesis uses enaminones instead of / -dicarbonyl derivatives (for another variant, see Section II.A.l.e). Here the method consists of a condensation of two enaminone molecules and one molecule of aromatic or aliphatic aldehyde to give 1,4-dihydropyridines (equation 14). Various dihydropyridines have been synthesized by this method20-22. Enaminonitriles can be cyclocondensed in the same manner23 (equation 15). 

Carbon-11 labelled calcium channel antagonists C-nifedipine, C-nisoldipine, C-nitrendipine and C-CFj-nifedipine possessing vasodilating and hypotensive properties have been synthesized using a modified Hantzsch-type cyclocondensation proce-dure . Condensation of aldehydes 242, 243 and 244 with 3-aminocrotonic acid esters 245, 246, 247 and with acetoacetic ester 248 produced in one pot after 12 hours reflux in dry ethanol the methyl sulphonylethyl protected dihydropyridines 249-252. Deprotection of the carboxylic acids by alkaline hydrolysis followed by conversion into the dihydropyridine monocarboxylic acids 253-256 gave potassium salts in situ, and subsequent methylation with CH3I produced the corresponding labelled title compounds 257-260 (equation 102),... 

The cyclocondensation of or-halocarbonyl compounds with thioamides (Hantzsch synthesis) offers considerable scope ... 

In modifications of the Hantzsch synthesis [65], P-enaminones replace one molecule of the P-dicarbonyl compound, and enones undergo cyclocondensation with P-enaminones or 1,5-dicarbonyl compounds with NH3. Thus, for instance, as an alternative to the classical synthesis (2 mol acetoacetate, benzaldehyde and NH3), the l,4-dihydropyridine-3,5-dicarboxylate 171 is obtained from acetoacetate, benzaldehyde and p-aminocrotonate (1 1 1), as well as from benzylidene acetoacetate and aminocrotonate (1 1). 

In a three-component cyclocondensation, a-halocarbonyl compounds react with P-ketoesters (or P-diketones) and ammonia or primary amines to give pyrrole-3-carboxylates (or 3-acyIpyrroIes), which are substituted either in 1,2,4- or in 1,2,5-position, for example, 43/45 (Hantzsch synthesis) ... 

The Hantzsch synthesis can be conducted directly to the pyridines 167 in one-pot procedures (i) by combining the MCR process with oxidative aromatization by Pd-C/montmorillonite K-10 [123] and (ii) by using [NH4]C103 as a source of NH3 [124]. (b) In a three-component domino process, a,p-unsaturated aldehydes (mainly cinnamaldehydes), aromatic primary amines, and P-ketoesters catalyzed by CAN [125] or L-proline [126] are cyclocondensed to give N-arylsubstituted-5,6-unsubstituted 1,4-dihydropyridines 173 ... 

In 1893,11 years after the publication of the Hantzsch dihydropyridine synthesis, the Italian chemist Pietro Biginelli reported a related three-component reaction based on the cyclocondensation of aldehydes, p-ketoesters, and urea, for the synthesis of... 

Like many other MCRs, the Hantzsch protocol usually commences with a condensation reaction that produces an imine from the amine and aldehyde. In this case, however, the Knoevenagel adduct undergoes addition by the nucleophilic p-keto ester, which generates the intermediary dihydropyranol. Ammonium acetate addition then finally initiates the expected cyclocondensation to give the aminal. Although the... 

The 1,4-dihydropyridines (DHPs) classes of privileged heterocyclic pharmacophores are well known for their calcium channel blocker activity. Other versatile biological profiles of 1,4-DHPs such as anticonvulsant activity, selective adenosine-A3 receptor antagonism, radioprotective activity, sirtuin activation, and inhibition, etc. have also been well known [186]. Conventionally, 1,4-DHPs could be accessed via the Hantzsch reaction, reduction of pyridines, addition to pyridines or cycloadditions, etc. As a facile and broadly tolerable protocol, the Hantzsch reaction consisting of cyclocondensation reaction of ethyl acetoacetate (2 equivalent) with an aldehyde and ammonia remains as a frequently employed tactic for the synthesis of 1,4-DHPs in a large number of areas such as stereoselective synthesis and green chemistry [187]. 

In recent years, synthesis of pyrroles has drawn the attention of chemists. Traditional methods used for pyrrole synthesis include the Hantzsch reaction [45] and the Paal-Knorr condensation reaction [46,47], The latter is the most widely used method, which involves the cyclocondensation reaction of 1,4-dicarbonyl compounds with primary amines to produce substituted pyrroles. In addition, there are several methods such as 1,3-dipolar cydoaddition reaction, aza-Wittig reaction, reductive coupling, and titanium-catalyzed hydroamination of diynes. Scheme 1 shows several catalysts used in this type of reaction [44]. 

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