Hantzsch studies

Related studies have been made using perchloric acid. From mixtures of anhydrous nitric and perchloric acids in the appropriate proportions, Hantzsch " claimed to have isolated two salts whose structures supported his hypothesis concerning the nature of nitric acid in strong mineral acids. He represented the formation of the salts by the following... 

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... 

The mechanism of the Hantzsch s synthesis was studied at a very early stage by several authors. The intermediates were generally assumed to be open-chain a-thioketones, but in a series of papers by Murav eva and Schukina (470, 490) the isolation of hydroxythiazolines from the reaction between a-haloketones and a variety of thioureas was reported. 

The method has not been studied extensively and is restricted to the preparation of alkyl-, aryl-, or alkoxy-substituted thiazoles mostly in 2-, 5-, or 2,5-positions. Yields ranged from 45 to 80%. Sometimes this method gives good results when the usual Hantzsch s synthesis fails. There has been very little speculation about the mechanism of this reaction. 

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. 

Steps (1) and (2) are fast while the production of nitronium ion in step (3) is slow . A great mass of evidence exists in support of the formation of N02+ in mixed acids of low water content, but there is some controversy about the presence of H2N03+ in MA. Hantzsch s cryo-metric studies (Refs 9 18) were interpreted to be in support, of the existence of the nitra-cidium ion (fijNOj ). These views were later supported by the studies of Hammet coworkers (Refs 20 24). Furthermore, Hantzsch isolated crystalline nitracidium perchlorate (H2N03+)(C104-)(Refs 14a 14b)... 

Euler was the first to suggest the presence of nitronium ions in mixed acids (Ref 12), This view was later supported by the conductometric studies of Walden (Ref 14). Titov (Ref 28) reinterpreted Hantzsch s data and suggested that the simplest way to explain them was ... 

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 relationships between the components of the Hantzsch triangle were considered in-depth in the monograph 2 and references therein. Although the problem of reactivity of ambident substrates has been studied over many years and from different points of view, the complexity of the starting system and its numerous reaction pathways do not allow one to reliably predict the results of O-alkylation in each particular case, because it is necessary to take into account the rates of numerous reversible and irreversible processes as well as the thermodynamic factors responsible for the position of the equilibrium it is necessary to take solvent effects into consideration when estimating the thermodynamic factors. All accumulated observations are approximated by several empirical mles included in monographs 2 and 3. 

For the study of the diazo-compounds we recommend the excellent work Die Diazoverbindunqen, by A. Hantzsch, revised by Reddelien, Leipzig, 1921. 

In 1896 Hantzsch and Schultze obtained the separate nitro and isonitro forms of phenylni-tromethane and studied their properties and their interconversion24. Hantzsch introduced the term pseudo-acid to describe neutral compounds which form alkali metal salts corresponding to their aci forms. 

He was sent by the Japanese Government to Europe in 1910. He first stayed in the laboratory of A. Hantzsch in Leipzig, and soon moved to the laboratory of A. Werner (1866-1919) in Zurich to leam Coordination Chemistry. He also stayed in the laboratory of G. Urban of the University of Paris to study spectroscopy. He returned from Europe in 1913 with a spectrometer made by Adam Hilger Co. in England, which is the first equipment to be able to measure spectra of solution in Japan, and he used the equipment for the measurements of spectra of coordination... 

Bischler, A. Napieralski, B. Ber. Dtsch. Chem. Ges. 1893, 26, 1903. Augustus Bis-chler (1865—1957) was born in South Russia. He studied in Zurich with Arthur Hantzsch. He discovered the Bischler-Napieralski reaction while studying alkaloids at Basel Chemical Works, Switzerland with his coworker, B. Napieralski. 

Detailed mechanistic investigations of transfer hydrogenations with Hantzsch ester by means of DFT computational studies were carried out by the groups of Goodman and Himo [42, 43]. 

Simon L, Goodman JM (2008) Theoretical study of the mechanism of Hantzsch ester hydrogenation of imines catalyzed by chiral BINOL-phosphoric acids. J Am Chem Soc 130 8741-8747... 

The MacMillan laboratory has produced an interesting study on the reductive amination of a broad scope of aromatic and aliphatic methyl ketones catalyzed by ent-lk, utilizing Hantzsch ester as a hydride source (Scheme 5.26) [48]. Apphcation of corresponding ethyl ketones gave very low conversions. Computational studies indicated that while catalyst association with methyl ketones exposes the C=N Si face to hydride addition, substrates with larger alkyl groups are forced to adopt conformations where both enantiofaces of the iminium ir... 

Application of part of the classical Hantzsch pyridine synthesis leads to nifedipine (87) (81 AG(E)762, 68SAP6801482), a calcium antagonist useful in the treatment of angina. The pharmacology of a chemically related drug, nisoldipine (88), has recently been studied (80AF2144). Both compounds inhibit the transmembrane movement of calcium into activated smooth and cardiac muscle. Nisoldipine, however, is characterized by a high potency and uniqueness of action and may well prove to be of considerable therapeutic value. 

Extensive stmcture activity relationship (SAR) studies in this series revealed that unsymmetrical substitution on the heterocyclic ring and hence the introduction of chirality on the central carbon atom led to increased potency. Such asymmetrical dihydro-pyridines can be prepared by stepwise variation of the Hantzsch synthesis, based on the hypothetical alternate route to nifedipine. Thus, aldol condensation of methyl acetoacetate with 2,3-dichlorobenzaldehyde (13-1) gives the cinnamyl ketone (13-2). Reaction of that with the enamine (13-3) from ethyl acetoacetate gives the calcium channel blocker felodipine (13-4) [14]. 

Nitronium Ion (N02+). Nitration is one of the most studied and best understood organic reactions.510-512 The species responsible for electrophilic aromatic nitration was shown to be the nitronium ion (N02+) 219. Since the early 1900s, extensive efforts have been directed toward the identification of this ion, whose existence was first shown by Hantzsch and later firmly established by Ingold and Hughes.510... 

---