Hantzsch derivatives

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. 

Hoffmann (1). a student of Hantzsch, used the condensation of selenobenzamide with a-halogenated carbonyl derivatives to prepare a series of 2-phenylselenazoles according to the Scheme 1,... 

As in the case of the thiazoles, a variation on the Hantzsch s method has been used. This consists of using a nonhalogenated carbonyl derivative directly in the presence of iodine in the reaction with selenourea (Scheme 7) (20). However, in this case the reaction with selenourea is slower than with thiourea, and normally an excess of carbonyl compound is used. 

The general formula of the 2-(2- or 4-furyl. thienyl, or selenienyljselenazoles is shown in Scheme 24 (40, 105. 106). (Selenienyl-2), (furyl-2), (thienyl-2), and (chloromethyi-4)selenazoles may be prepared by Hantzsch s reaction from selenoamides as described in Scheme 25. Hydrolysis give hydroxymethyl derivatives. 

The controversy seemed then to be closed. In 1890 Hantzsch had already started his work on the structure of oximes, and his synthetic work on heterocycles was practically ended. However, 27 years later, in July 1919, Tcherniac published a new paper entitled TTiiocyanoacetone and its derivatives as isomerides (33), where, after the description of improved and generalized methods for the preparation of thiocyanoacetone he came to the explosive conclusion that the substance which has been known since 1887 as hydroxymethylthiazole is not a thiazole at all. It might be called 2-imino-4-methylthioxole, but for the sake of simplicity, and in view of the now proved existence of two other isomerides of thiocyanoacetone, it seems preferable to adopt the generic... 

Probably first obtained by Hantzsch and Arapides (105) by condensation of a,/3-dichlorether with barium thiocyanate, and identified by its pyridine-like odor, thiazole was first prepared in 1889 by G. Popp (104) with a yield of 10% by the reduction in boiling ethanol of thiazol-2-yldiazonium sulfate resulting from the diazotization of 2-aminothiazole. prepared the year before by Traumann (103). The unique cyclization reaction affording directly the thiazole molecule was described in 1914 by Gabriel and Bachstez (106). They applied the method of cyclization, developed by Gabriel (107, 108), to the diethylacetal of 2-formylamino-ethanal and obtained thiazole with a yield of 62% - Thiazole was also formed in the course of a study on the ease of decarboxylation of the three possible monocarboxylic acids derived from it (109). On the other... 

Extension of the Hantzsch s Synthesis to Thiazole Carboxylic and Thiazole Acetic Acids (Table II-IO). Mono-, di-, and tricarboxylic acids are among the most easily prepared thiazole derivatives. 

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 three thiazoleacetic acids and higher homologs such as the derivatives of propionic acid have been synthesized (5), They are usually prepared by the Hantzsch s method, either as the free acid or as the ester from which the free acid is obtained by hydrolysis (49, 73). 

Systematic names of the Hantzsch-Widman type, as well as fusion names, imply unsaturation to the extent of the maximum number of noncumulative double bonds. Suitable suffixes (Table 3) serve to identify the fully saturated derivatives. Partially unsaturated rings may be designated by hydro prefixes with locants and an even-numbered multiplier, such as 2,3-dihydro , applied to a fully unsaturated name, or by dehydro prefixes applied to the saturated name, e.g. (116). 

Subsequent to Hantzsch s communication for the construction of pyridine derivatives, a number of other groups have reported their efforts towards the synthesis of the pyridine heterocyclic framework. Initially, the protocol was modified by Beyer and later by Knoevenagel to allow preparation of unsymmetrical 1,4-dihydropyridines by condensation of an alkylidene or arylidene P-dicarbonyl compound with a P-amino-a,P-unsaturated carbonyl compound. Following these initial reports, additional modifications were communicated and since these other methods fall under the condensation approach, they will be presented as variations, although each of them has attained the status of named reaction . 

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. 

Attempts to prepare selenazole derivatives were first described by Hofmann,2 a student of Hantzsch, in connection with investigations in the thiazole series. By reaction of selenobenzamide with a-halogeno compounds corresponding to the general reaction (2, R" = CeHg), he synthesized a series of 2-phenylselenazoles. In the same way, several... 

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. 

Enantioselective synthesis of Hantzsch 1,4-dihydropyridines was developed based on similar 1,4-additions of /1-oxoester derivatives to 2-(arylmethylene)-3-oxopropanoates. High enantiomeric excess (84-98%) was achieved when (5 )-l-amino-2-(l-methoxy-l-methylethyl)pyrrolidine was used at the auxiliary202. 

Bamberger s arguments were based mainly on classical organic chemistry, e.g., formation of derivatives, whereas Hantzsch was already using physicochemical methods. It took Bamberger 18 years to abandon his negative attitude towards the diazoate stereoisomerism (Bamberger and Baudisch, 1912). 

Since diazoates can be considered to be derived from oximes by substitution of nitrogen for the methine group, Hantzsch (1894) put forward the hypothesis that configurational isomerism was also occurring here. He therefore represented the isomeric diazoates by the structures 7.1 and 7.2, assigning the syn structure (7.1) to the labile diazoate and the anti (7.2) to the stable isomer. Nowadays the description recommended by IUPAC (1979) for such configurational isomers, namely (Z) instead of syn and (E) instead of anti, should be used. 

All the same, lasting credit is due to Hantzsch for refuting the proposals, made so often since 1894, to interpret the isomerism of diazo derivatives using other than stereochemical arguments. For his purpose Hantzsch used the methods of physical chemistry, such as conductivity measurements and spectroscopy, at a time when these were most unusual in the organic field. 

Certain problems, for example, the differentiation between the (is)-diazohydroxide (7.3) and the nitrosoamine (7.4), were quite insoluble in Hantzsch s day because of the lack of appropriate methods. The observation that the sodium salt of the anti-diazoate reacts with methyl iodide to yield the TV-derivative (A-methylnitrosoamine), whereas the silver salt gives the O-ether (diazo ether) was often taken to support the presence of constitutional isomerism, but Hantzsch, quite rightly, disagreed. 

The earliest work on selenazole dates back to 1889. but intensive studies of the compound and its derivatives only really started in 1940. In 1889, the question of the existence under normal conditions of nonsubsti-tuted selenazole was posed as a result of the first studies of the azoles by the group led by Hantzsch. 

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... 

The rapid synthesis of heteroaromatic Hantzsch pyridines can be achieved by aromatization of the corresponding 1,4-DHP derivative under microwave-assisted conditions [51]. However, the domino synthesis of these derivatives has been reported in a domestic microwave oven [58,59] using bentonite clay and ammoniiun nitrate, the latter serving as both the source of ammonia and the oxidant, hi spite of some contradictory findings [51,58,59], this approach has been employed in the automated high-throughput parallel synthesis of pyridine libraries in a 96-well plate [59]. In each well, a mixture of an aldehyde, ethyl acetoacetate and a second 1,3-dicarbonyl compound was irradiated for 5 min in the presence of bentonite/ammonium nitrate. For some reactions, depending upon the specific 1,3-dicarbonyl compound used. 

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. 

Thiazole and its derivatives are conventionally prepared from lachrymatory, a-halo-ketones and thioureas (or thioamides) by Hantzsch procedure [146]. In a marked improvement, Varma et al. have synthesized the title compounds by the simple reaction of in situ-generated a-tosyloxyketones, from arylmethyl ketones and [hydroxy(tosyl-oxy)iodo]benzene (HTIB), with thioamides in the presence of K 10 clay using micro-wave irradiation (Scheme 6.43) the process is solvent-free in both the steps [147]. 

A variety of conditions (solution, dry media, solvent-free) has been used for microwave-assisted synthesis of Hantzsch 1,4-DHP only procedures involving solvent-free conditions under the action of irradiation led to the aromatized pyridine derivatives. 

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>. 

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