Hantzsch heterocyclization

Hantzsch heterocyclization Henry reaction Knoevenagel condensation Michael addition enolate... 

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

The first member of the series. 2-imino-3,4-dimethyl-4-thiazoline (363) is obtained when the di-HBr salt of bis(methylformamidine)disulfide (362i is refluxed for 16 hr in acetone (Scheme 209) (700). The most common preparative methods involve direct heterocyclization by the Hantzsch method (see Chapter II. Section II.4), though the mechanism of this reaction suggests certain limitations according to the respective natures of R2, R3, and in 364 (Scheme 210). 

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... 

The most widely used method for the preparation of carboxylic acids is ester hydrolysis. The esters are generally prepared by heterocyclization (cf. Chapter II), the most useful and versatile of which is the Hantzsch s synthesis, that is the condensation of an halogenated a- or /3 keto ester with a thioamide (1-20). For example ethyl 4-thiazole carboxylate (3) was prepared by Jones et al. from ethyl a-bromoacetoacetate (1) and thioformamide (2) (1). Hydrolysis of the ester with potassium hydroxide gave the corresponding acid (4) after acidification (Scheme 1). 

For such purposes as locating substituents, monocyclic heterocycles having only one non-carbon atom are numbered starting with the hetero atom as 1. If there is more than one hetero atom of the same kind, the more saturated hetero atom takes precedence (cf. imidazole in Table 1). In isoxazole and isothiazole, the divalent atom takes precedence, in conformity with the pnaciples of the Hantzsch-Widman system (Section 1.02.2.2). 

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 . 

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. 

Hantzsch 2 gave the name pseudo bases to those carbinols that gave salts with acids by the elimination of water and a simultaneous change of constitution. Such carbinols are common among the nitrogen heterocyclic compounds and the naturally occurring alkaloids e.g., berberine, sanguinarine, chelerythrine. 

A -(l-Haloalkyl)pyridinium halides have been advantageously employed in the Hantzsch multicomponent synthesis, yielding alkyl 1,4-dihydropyri-dine-3,5-dicarboxylates, which are a well-known class of calcium channel modulators (81AGE762). Tire halides readily interact with an excess of an ethyl 3-aminobut-2-enoate 82 (R = H) in dichloromethane at room temperature to afford the heterocycles 83 (R = H) in good to excellent yields (65-95%) (92T1263). Tliis observation has been exploited to perform a quantitative study of the reactivity of the salts (93CB1251).Tlie results have... 

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. 

Oxepin is the Hantzsch-Widman name for a seven-membered unsaturated heterocycle with one oxygen atom and the numbering follows the convention for monocyclic heterocycles. However, the isomeric benzene oxide has different numbering in agreement with the 7-oxabi-cyclo[4.1.0]hepta-2,4-diene structure, position 1 now corresponds to position 2 in the oxepin. 

Another well-known method for the preparation of heterocycles is the Hantzsch dihydropyridine synthesis. In 2001, Ohberg and Westman presented a microwave-... 

A survey of microwave activation in the chemistry of Hantzsch 1,4-dihydropyridines (1,4-DHP) has recently been reported [98]. The experimental method proposed more than a century ago remains the most widely used to synthesize these heterocycles. Since 1992 this process has been adapted to microwave irradiation under a variety of conditions to reduce the reaction time and enhance the yield. Among these experiments, Zhang [99] reported a solvent-free process starting from 3-aminocrotonate... 

In Hantzsch s synthesis the condensation product is a derivative of dihydropjndine and is only converted into a true pyridine derivative by dehydrogenation. It is only by the removal of the two hydrogen atoms in the 1 4-positions that the heterocyclic ring system analogous to benzene is produced. The corresponding conversion of ethyl A 2 5-dihydroterephthalate into ethyl terephthalate takes place much more readily. 

Galatsis, P. Hantzsch Dihydro-Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 304—307. (Review). 

A general scheme, which constructs the thiazolo variety of various bridgehead heterocycles, is basically an extension of HTIB-mediated modification of Hantzsch thiazole synthesis (Scheme 51). Thus, synthesis of 3-substituted-5,6-dihydro-4//-imidazo[2,l-b]thiazoles 202 has been achieved by the treatment of a-tosyloxyacetophenones (generated by the oxidation of 51 with HTIB) with ethylenethiourea [92JCS(P1)707], The method is successfully extended to synthesize 4,5,6,7-tetrahydrothiazolo[3,2-a]pyrimidines 203... 

MCRs of Hantzsch and Biginelli-types with participation of aldehydes, aminoa-zoles, and cyclic CH-acids, first of all 1,3-diketones and Meldrum acid, as well as the treatments discussed in the previous sub-chapter, are in the focus of interest due to high biological activity of their products. However, on the other hand, in many cases these processes can give several final heterocycles with different position or regiodirection. Moreover, sometimes for the same reactions carried out under similar conditions contradictory facts were published with high level of credibility. 

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

The two most important methods for naming heterocyclic parent hydrides are the extended Hantzsch-Widman system and replacement nomenclature. 

In one method, the non-detachable prefixes hydro- and dehydro- (in the case of mancudes only) can be used to indicate the addition or subtraction of one hydrogen atom. As even numbers of hydrogen atoms are involved when a carbon-carbon single bond becomes a double or triple bond, the multiplicative prefixes di-, tetra-, etc., as well as the appropriate locants, are used. The prefix dehydro- is always used to indicate the subtraction of hydrogen atoms from saturated heterocycles having Hantzsch-Widman names. 

The known types of five-membered heterocycles are presented at the beginning of each main section. Possible structural types with all heteroatomic combinations conceivable are almost unbounded, their presentation here would be worthless and is therefore avoided. The nomenclature of these heterocycles is defined by lUPAC rules (both Hantzsch-Widmann and replacement nomenclature are used) which are adhered to throughout the chapter. 

This method is useful when dealing with simple heterocycles, but it can become clumsy with more complex ones. An alternative is the Hantzsch-Widman system, which uses the same prefixes, but adds a stem name designed to indicate not only the ring size but also the state of unsaturation or saturation (note when the stem name begins with a vowel the last letter, a, of the prefix is dropped). The stem names for rings containing up to 10 atoms are shown in Table 1.1. 

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