Synthesis Hantzsch

GlaxoSmithKline Pharmaceuticals in Harlow, UK, performed the Hantzsch synthesis of 2-bromo-4 -methylacetophenone and l-acetyl-2-thiourea in NMP (N-methyl-2-pyrrolidone) using a microchip reactor under EOF [17] (for EOF see Ref. [18]). This is claimed to be the first example of a heated organic reaction performed on a glass chip reactor under electroosmotic flow control, while earlier only room-temperature reactions were used. In a wider scope, the Hantzsch synthesis is a further example to evaluate the potential of microfluidic systems for high-throughput screening. 

Yields from 42 to 99% were reported. Comparative and better yields were achieved when using a microchip reactor as compared to conventional laboratory batch technology. In case of improvement, the increase in yield amounted to about 10-20% [17,19]. 

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Hantzsch synthesis The formation of pyridine derivatives by the condensation of ethyl acetoacetate with ammonia and an aldehyde. Also applied to similar syntheses of pyrroles. 

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The immediate outcome of the Hantzsch synthesis is the dihydropyridine which requires a subsequent oxidation step to generate the pyridine core. Classically, this has been accomplished with nitric acid. Alternative reagents include oxygen, sodium nitrite, ferric nitrate/cupric nitrate, bromine/sodium acetate, chromium trioxide, sulfur, potassium permanganate, chloranil, DDQ, Pd/C and DBU. More recently, ceric ammonium nitrate (CAN) has been found to be an efficient reagent to carry out this transformation. When 100 was treated with 2 equivalents of CAN in aqueous acetone, the reaction to 101 was complete in 10 minutes at room temperature and in excellent yield. 

An obvious outcome of the Hantzsch synthesis is the symmetrical nature of the dihydropyridines produced. A double protection strategy has been developed to address this issue. The protected chalcone 103 was reacted with an orthogonally protected ketoester to generate dihydropyridine 104. Selective deprotection of the ester at C3 could be accomplished and the resultant acid coupled with the appropriate amine. Iteration of this sequence with the C5 ester substituent ultimately gave rise to the unsymmetrical 1,4-dihydropyridine 105. 

A modihed Hantzsch synthesis has been utilized for the preparation of 1,4-dihydropyridines (Scheme 66). Thus, condensation of formylfurazans 116 with an acetoacetic ester and aminocrotonic acid ester in isopropanol at reflux led to 1,4-dihydropyridine derivatives 117 in about 70% yield (92AE921). Both isomeric furoxan aldehydes reacted in a similar way. 

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 ... 

Dihydropyridines not only are intermediates for the synthesis of pyridines, but also are themselves an important class of N-heterocycles an example is the coenzyme NADH. Studies on the function of NADH led to increased interest in the synthesis of dihydropyridines as model compounds. Aryl-substituted dihy-dropyridines have been shown to be physiologically active as calcium antagonists. Some derivatives have found application in the therapy of high blood pressure and angina pectoris. For that reason the synthesis of 1,4-dihydropyridines has been the subject of intensive research and industrial use. The Hantzsch synthesis has thus become an important reaction. 

Garcia-Egido, E., Wong, S. Y. E., A Hantzsch synthesis of 2-aminothiazoles performed in a microreactor system, in Ramsey, J. M., van den Berg, A. (Eds.), Micro Total Analysis Systems,... 

The Hantzsch synthesis was primarily chosen to evaluate the potential of a micro-mixing-tee chip reactor for carrying out reactions above room temperature (e.g. 

In a wider sense, the Hantzsch synthesis is a further example for evaluating the potenhal of microfluidic systems for high-throughput screening [9]. 

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]. 

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... 

A modification of the Hantzsch synthesis of thiazoles has been reported. The reaction of alkoxyoxiranes 16 with A-arylthioureas 17 affords thiazoles such as 20. The mechanism involves the initial P-cleavage of the oxirane to give the hemiacetal... 

A-Thiazolyl a-amino acids 56 have been prepared. The preferred route to these compounds would utilise the Hantzsch synthesis, however in this case the in situ formation of the required thiourea derivatives of a-aminoacids 52 failed. A variety of isothiocyanate reagents were tried, with the result being either no reaction, decomposition or the corresponding thiohydantoin 53. A modified version of the Hantzsch synthesis was developed. If the bromoketone 54 is initially treated with sodium thiocyanate an a-thiocyanatoketone 55 is formed, subsequent addition of the amino acid ester 51 yields A-thiazolyl a-amino acids 56 <00T3161>. 

A one pot procedure for the preparation of 1,3-sclenazoles has been reported. The method, a variation on the Hantzsch synthesis, involves the a-tosylation of ketones 90 with [hydroxy(tosyloxy)iodo]benzene followed by treatment with selenoamides to give 1,3-selenazoles 91 in moderate to high yields <00S1219>. 

Sugar Based Low Melting Mixtures as Green Solvents in The Hantzsch Synthesis of Substituted 1,4-Dihydropyridines... 

Scheme 1.1 Hantzsch synthesis of 4-aryldihydropyridine-3,5-dicarboxylic esters.

Hansa yellow org chem Group of organic azo pigments with strong tinting power, but poor opacity in paints used where nontoxIcIty Is Important. han-sa yel o ) Hantzsch synthesis org chem The reaction whereby a pyrrole compound is formed when a p-ketoester, chloroacetone, and a primary amine condense. hansh, sin-tha-sas ... 

The normal Hantzsch synthesis leads to a symmetrical product. The diesters formed may be hydrolysed and decarboxylated using base to give pyridines with less substitution. Note that we are using the ester groups as activating species to facilitate enolate anion chemistry (see Section 10.9)... 

Evans CG, Gestwicki JE (2009) Enantioselective organocatalytic Hantzsch synthesis of polyhydroquinolines. Org Lett 11 2957-2959... 

Ways in which pyridines and N-alkylpiperidines are synthesized. The importance of the Hantzsch synthesis of pyridines... 

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