Hantzschs Synthesis Mechanism

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 use of a reagent bearing a basic center or the addition of a base to the reaction mixture was recognized as necessary to prevent the acid-catalyzed elimination of the elements of water from the intermediates. Since the publication of this work, a number of similar intermediates have been isolated from thioamides and a-halogeno carbonyl compounds (608, 609, 619, 739, 754, 801), and as a result of kinetic studies, the exact mechanism of this reaction has been well established (739, 821). 

In several cases, this intermediate has been successfully isolated at a relatively low temperature, particularly with the following substituents on 98 Rj = Me and Rj = CH2CO2C2H5, and Rj = Me or Ph and R2 = CH2C1(19, 99, 145, 339). 

The next step is attack at the carbon carrying the carbonyl function by the lone pair of nitrogen atom, giving rise to a new cyclic intermediate 

210 General Synthetic Methods for Thiazole and Thiazolium Salts 

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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... 

The mechanism of the Hantzsch synthesis has been established and is shown in Scheme 165. Substitution of the halogen atom of the a-halo ketone by the sulfur atom of the thioamide occurs first to give an open-chain a-thioketone (232), which under transprotonation proceeds to give a 4-hydroxy-A2-thiazoline (233) in aprotic solvents, or a thiazole (234) by acid-catalyzed dehydration of the intermediate thiazoline in protic solvents. 

The mechanism of this cyclization is similar to that proposed for the Hantzsch synthesis. Hydroxythiazoline intermediates have been isolated which, on heating with dilute HC1, lead to A4-thiazoline-2-thione. The precise control of the pH during the reaction permits the isolation of an acyclic intermediate (248) which is in equilibrium with its cyclic isomer (249 Scheme 182). The large influence of steric effects on the 3-position has been demonstrated with R4 = Me and R3 = Bu dealkylation at nitrogen is observed upon dehydration of the intermediate thiazoline (Scheme 183) (67BSF1948). 

The Hantzsch pyridine synthesis affords 1,4-dihydropyridines 214, although spontaneous oxidation to pyridines often occurs. In its simplest form it involves the condensation of two molecules of a -keto ester with an aldehyde and ammonia (Scheme 119) . Compounds resulting from the condensation of ammonia with one of the carbonyl components can be used in the Hantzsch synthesis. Thus, -aminocrotonic ester 215 can replace the ammonia and one mole of acetoacetic ester in Scheme 119. The mechanism of the Hantzsch synthesis has been clarified by 13C and 1SN NMR spectroscopy <1987T5171>. 

The easy specific reduction of 3-acylpyridinium salts giving stable 3-acyl-1,4-dihydropyridines using sodium dithionite is often quoted, because of its perceived relevance to nicotinamide coenzyme activity the mechanism involves addition of sulfur at C-4 as its first step, as shown below.1,4-Dihydropyridines are normally air-sensitive, easily rearomatised molecules the stability of 3-acyl-1,4-dihydropyr-idines is related to the conjugation between ring nitrogen and side-chain carbonyl group (see also Hantzsch synthesis, section 5.15.1.2). However, even simple pyridinium salts, provided the A-substituent is larger than propyl, or for example benzyl, can be reduced to 1,4-dihydropyridines with sodium dithionite. ... 

In the mechanism of the Hantzsch synthesis, primarily nucleophilic displacement of halogen in the a-halogeno carbonyl system by the thioamide C=S functionality takes place. The resulting S-alkyliminium salt 18 cyclizes after proton transfer N O (18 -> 19) and carbonyl activation to the salt 20 ofa 4-hydroxy-4,5-dihydrothiazole, which is converted to the thiazole 17 by elimination of H2O and HX. 

The Hantzsch synthesis of pyridines features 1,4-dihydropyridines in the first step. A variant of the method uses hydroxylamine (Table 17-5), which can be regarded as an oxidized version of ammonia. With this reagent, pyridines are formed directly from 1,5-dicarbonyl compounds, in turn readily made by Michael additions of enolates to a,j8-unsaturated aldehydes and ketones (Section 18-11). Formulate the mechanisms of the two steps in the pyridine synthesis shown. 

Probably the mechanism of this reaction is similar to that proposed for the Hantzsch s synthesis and discussed in Section II.l.D,... 

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. 

Katritzky, A. R., Ostercamp, D. L., Yousaf, T. I. Mechanism of heterocyclic ring closures. 3. Mechanism of the Hantzsch pyridine synthesis a study by nitrogen-15 and carbon-13 NMR spectroscopy. Tetrahedron 1986, 42, 5729-5738. 

The mechanism of this hydrogen migration needs further study. It would be interesting to compare the rates of and substituent influences on this migration with the similar processes in the last step of Hantzsch s synthesis of dihydropyridines (Scheme 3) and in hydrogen migration in the dihydropyri-dazine series (Section IV,C). 

It is possible that the mechanism of the Hantzsch pyrrole synthesis commenced with the condensation between the amine and the ketoester. The resulting imine then undergoes an Sn2 replacement reaction with the a-haloketone via the intermediacy of an enamine. The adduct as an enamine ketone then undergoes an intramolecular C-N bond formation to deliver the final pyrrole after extrusion of a molecule of water. 

Several research laboratories investigated the mechanism of the Hantzsch dihydropyridine synthesis. " A comprehensive discussion on the mechanism is reported recently. ... 

The mechanism for the Hantzsch pyrrole synthesis begins with enamine formation. Condensation of ammonia (or an ammonia surrogate) and 3-ketoester 2 gives intermediate A. Intermediate A then undergoes dehydration and tautomerization (B) to produce enamine C. Michael addition of enamine C and a-haloketone 1 gives D, which forms E via P-elimination. Intramolecular nucleophilic substitution then generates F, which undergoes rapid isomerization to form the desired pyrrole 3. 

The mechanism for the Hantzsch thiazole synthesis begins with deprotonation of thioamide 4 (or thiourea) followed by nucleophilic substitution of the a-haloketone 1 to form G. G then undergoes intramolecular nucleophilic substitution at the ketone to form H, which undergoes rapid base-catalyzed elimination to give the desired thiazole 5. 

SCHEME 13.128 Mechanism of the Hantzsch 1,4-dihydropyridine synthesis—part I. 

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