Hantzsch cyclization

C- (112, 113), 4- C- and 5- C-thiazoles (112) were prepared by the same general pathway from the corresponding " C-labeled 2-aminothiazoles synthesized by the Hantzsch cyclization of C-thiourea, l- C-2-bromoethanal, and 2- C-2-bromoethanal, respectively (112). A mixture of 4- and 5- C-thiazoles was prepared by the same general... 

Hantzsch cyclization of 214 to dihydropyridines 216 can be accomplished by treating 215 with 214 in the presence of NaOEt (Equation 29). Under these conditions, dihydropyridines 216 are obtained in 41-64% yields. A three-component Hantzsch reaction using 214, aldehyde 217, and /3-keto ester 218 under similar conditions affords 219 in 51% yield (Equation 30) <2005JOC5331>. 

A novel series of 2,5-disubstituted boryl thiazoles 10 is prepared by means of Hantzsch cyclizations of thioamides with monohalogenated boryl aldehydes 9a/b (14JA17669).These aldehydes are derived from the unsubstituted a-MIDA boryl aldehyde 8 by means of electrophilic halogenation (NBS or NCS, pyrrolidine). Application of these novel boryl thiazoles 10 is demonstrated in cross-coupling reactions (e.g., 11-12). The optimal coupling conditions utilize the Lipshutz surfactant TPGS-750-M in water. The 2,5-disubstituted boryl thiazole intermediate 10 is a versatile intermediate for medicinal chemistry and material science. 

Aryl-substituted dithiazole thioethers 16 are prepared from aryl methyl ketones 15 with thiourea in the presence of iodine (14T5544).The iodine-promoted reactions presumably proceed through a sequence of iodination of methyl ketone, Hantzsch cyclization, iodination, thio formation, and thioether formation. 

These latter compounds can also be obtained by direct cyclization in a Hantzsch s reaction of the selenosemicarbazone of a /3-ketoester, that is, a l-selenocarbamoyl-3-alkyl-5-pyrazolone (Scheme 21). 

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... 

Combinatorial approaches have been applied to this chemistry. In a method amenable to split and pool, PAL, or Rink resin, 89 is modified with an acetoacetate to generate the solid supported aminocrotonate 90. Either a two- or three-component Hantzsch protocol is followed to produce 91. Treatment with TFA carries out the cleavage from the resin and the cyclization to dihydropyridine 92. 

Various more or less efficient methods have been reported for the synthesis of 2-(l-ami-noalkyl)thiazole-4-carboxylic acids and their suitably protected derivatives. 237,539,541,558-568 Optimal conditions must be selected in these syntheses to prevent racemization at the chiral aminoalkyl moiety, e.g. when applying a modified Hantzsch synthesis 559 racemization has been observed to occur at the level of the starting Na-protected amino acid thioamide as well as in the base-mediated dehydration step of the intermediate hydroxydihydrothiazoles. 558 The 2-(aminoalkyl)thiazole-4-carboxylic acids are incorporated into the linear precursors by standard procedures of peptide synthesis, 237,514,529,539,552,555,558,564,569 and cyclization is pref-... 

Solid-phase syntheses have become increasingly popular during the period of this review, with examples including the synthesis of 5,6,7,8-tetrahydro[l,6]naphthyridines from Meldrum s acids derived from /3-amino alcohols via Hantzsch condensation and cyclization with cyclative cleavage from the resin (using 70% trifluoroacetic acid (TFA)/dichloromethane (DCM) followed by 5% triethylamine/DCM) <1999S1951> and also of isoquinolinones and 5-oxo-5,6-dihydro-[l,6]naphthyridines <1995JOC5748>. 

Among the methods available for the synthesis of the pyridine system, Hantzsch synthesis is probably the most important and widely used synthetic route. However, the pyridine ring can be synthesized from the reaction between pentan-2,4-dione and ammonium acetate. Cyclization of 1,5-diketones is also considered as a convenient method for the synthesis of corresponding pyridine derivatives. Commercially, pyridine is obtained from distillation of coal tar. 

Several significant pyrrole syntheses involve the formal tricomponent cyclization of type III ace (equation 126). The Hantzsch pyrrole synthesis involves a dicarbonyl compound, an a -halo ketone and ammonia or an amine. The mechanistic pattern is similar to that involved in the Knorr synthesis (Section 3.06.3.4.1). In addition to a-halo ketones and a-haloal-dehydes, compounds such as 1,2-dichloroethyl acetate, 1,2-dibromoethyl acetate and 1,2-dichloroethyl ethyl ether can serve as a -haloaldehyde equivalents (equation 127) (70CJC1689, 70JCS(C)285>. It is believed that the initial step in these reactions is the formation of a stabilized enamine from the amine and the /3 -dicarbonyl compound. A structural ambiguity... 

MacMillan s catalysts 56a and 61 allowed also the combination of the domino 1,4-hydride addition followed by intramolecular Michael addition [44]. The reaction is chemoselective, as the hydride addition takes place first on the iminium-activated enal. The enamine-product of the reaction is trapped in a rapid intramolecular reaction by the enone, as depicted in Scheme 2.54. The intramolecular trapping is efficient, as no formation of the saturated aldehyde can be observed. The best results were obtained with MacMillan s imidazolidinium salt 61 and Hantzsch ester 62 as hydride source. As was the case in the cyclization reaction, the reaction affords the thermodynamic trans product in high selectivity. This transformation sequence is particularly important in demonstrating that the same catalyst may trigger different reactions via different mechanistic pathways, in the same reaction mixture. 

MISCELLANEOUS REACTIONS OF DIHYDROPYRIDINES Additional tests for net hydride transfers initiated by single-electron transfer include the use of substrates in which such pathways would necessarily involve readily ring-opened cyclopropylmethyl or readily cyclized 5-hexenyl radicals. Products from these radical reactions are not formed in NAD+/ NADH dependent enzymic reductions or oxidations (Maclnnes et al., 1982, 1983 Laurie et al., 1986 Chung and Park, 1982). Such tests have also been applied in non-enzymic reductions. Thus cyclopropane rings in cyclopropyl 2-pyridyl ketones, or imines of formylcyclopropane (van Niel and Pandit, 1983, 1985 Meijer et al., 1984) survive Mg+2 catalysed reduction by BNAH or Hantzsch esters but are opened by treatment with tributylin hydride. 

Hantzsch dihydropyridine synthesis. The original Hantzsch synthesis2 involves condensation of two equivalents of a keto ester with an aldehyde in the presence of ammonia. In an enantioselective version.5 the chirality is introduced by use of a chiral hydrazone (2) of an alkyl acetoacetate prepared from 1. The anion of 2 is then treated with Michael acceptors to form adducts (3), which cyclize to 4-aryl-l,4-dihydropyridines (4), in 64-72% overall yield and in 84-98% ee. 

First described in 1887 (1887CB3118) by Hantzsch, the cyclization of a-halocarbonyl compounds by a great variety of reactants bearing the N—C—S fragment of the ring is still the most widely used method of synthesis of thiazoles. 

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 gives initially a dihydropyridine from the cyclization reaction. Adaptation of this reaction to the use of a 2-methylenethiazolidine yields the fused tetrahydro derivative (502) (77LA1888). Perhydro derivatives are simply prepared from 2-substituted thiazolidines by cycloalkylation as for (503) (80S387). The thiazolidine may also be generated in situ as in the reaction between y-benzoylbutyric acid and 2-mercaptoethylamines under azeotropic conditions to yield (504) (65JOC1506). 

The most commonly used method for the preparation of fused thiazoles involves the reaction of a-mercapto N-heterocyclic compounds of type (138) with an a-halocarbonyl compound or ester to give S-alkylated intermediates (139) which can be dehydrated to (140). When R2 is alkoxy, thiazolones (141) are formed (Hantzsch synthesis). Strong dehydrating agents are necessary to cyclize aldehydes and ketones (139) to fused thiazoles. The method has been used to prepare (dihydro) imidazo[2,l-6]thiazoIes and thiazolo[3,2- ]-s-triazoles (80JHC1321, 78JHC401, 82IJC(B)243). 

---