Thiazole thiazoline synthesis

Chemistry and heterocyclization of thiosemicarbazones. Synthesis of pyrrohdine, thiazole, thiazoline, thiazohdine, pyrazole, thiadiazole, oxa-(hazole, triazole, pyridazine, thiazine, and triazine derivatives and fused heterocycles 12JHC21. 

A-4-Thiazoline-2-ones and ring substituted derivatives are usually prepared by the general ring-closure methods described in Chapter II. Some special methods where the thiazole ring is already formed have been used, however. An original synthesis of 4- 2-carboxyphenyl)-A-4-thiazoline-2-one (18) starting from 2-thiocyanato-2-halophenyl-l-3-indandione (19) has been proposed (Scheme 8) (20, 21). Reaction of bicyclic quaternary salts (20) may provide 3-substituted A-4-thiazoline-2-one derivatives (21) (Scheme 9) (22). Sykes et al. (23) report the formation of A-4-thiazoline-2-ones (24) by treatment ef 2-bromo (22) or 2-dimethylaminothiazole (23) quaternary salts with base (Scheme 10). 

Of all the methods described for the synthesis of thiazole compounds, the most efficient involves the condensation of equimolar parts of thiourea (103) and a-haloketones or aldehydes to yield the corresponding 2-aminothiazoles (104a) or their 2-imino-A-4-thiazoline tautomers (104b) with no by-products (Method A, Scheme 46). 

Hansa Yellows, 1, 334 5, 299 Hantzsch synthesis, 2, 87-88 1,4-dihydropyridine, 2, 482 thiazoles, 6, 294-299 A -thiazolines, 6, 314 Hantzsch-Widman names parent names, 1, 35 stem suffixes, 1, 12 Hantzsch-Widman system nomenclature, 1, 11-12 Hardeners in photography... 

The ion 133 also reacts with epoxides to form y-hydroxy aldehydes after reduction and hydrolysis,and with aldehydes and ketones (16-41). Similar aldehyde synthesis has also been carried out with thiazoles " and thiazolines (five-... 

Oxidation of thiazolines represents another approach to thiazoles. This method has been applied to the synthesis of A -Boc-/.-thiazole methyl ester 22 <06JA10513>. Conversion of resin-bound thiazolines 23 to thiazoles 24 is also reported <06OL2417>. 

In NRPS, the cyclization domain catalyzes cyclization of the side-chain nucleophile from a dipeptide moiety such as AA-Ser or AA-Cys (AA = amino acids) to form a tetrahedral intermediate, followed by dehydration to form oxazolines and thiazolines (Scheme 7.1) [20]. The synthesis of a 2-methyl oxazoline from threonine follows a similar mechanism. Once a heterocycle is formed, it can be further modified by reductase to form tetrahydro thiazolidine in the case of pyochelin biosynthesis. Conversely, oxidation of the dehydroheterocycles lead to heteroaro-mahc thiazoles or oxazoles as in the case of epothilone D (Figure 7.2) [21]. 

Oxazoles have been found in relatively few cooked foods, although over 30 have been reported in coffee and cocoa, and 9 in cooked meat. Oxazolines have been found in cooked meat and roast peanuts, but not to any extent in other foods. 2,4,5-Trimethyl-3-oxazoline has been regularly detected in cooked meat [26], and when it was first identified in boiled beef [27] it was thought that the compound possessed the characteristic meat aroma however, on synthesis it was shown to have a woody, musty, green flavour with a threshold value of 1 mg/kg [28]. Other 3-oxazolines have nutty, sweet or vegetable-like aromas and the oxazoles also appear to be green and vegetable-like [28]. The contribution of these compounds to the overall aroma of heated foods is probably not as important as the closely related thiazoles and thiazolines. 

The synthesis of thiazoles from dihydrothiazoles (thiazolines) has experienced broad application as a method for incorporating thiazoles into the backbone of peptides (see also Vol. E 22 b, Section 6.8.5.2.2). The ability to incorporate thiazoles into the backbone of peptides by oxidation of dihydrothiazole precursors is consequently limited to the methods available for the synthesis of the required dihydrothiazole precursors. The most straightforward approach would allow for a peptide containing natural amino acids to serve as a precursor to... 

As opposed to ketones, the same low-temperature action of sulfur and ammonia on aldehydes received very little attention presumably because the results of the initial exploration discouraged utilization in synthetic chemistry. Again in reference to unpublished work, the product mixture was claimed to contain 3-thiazoline, formed in 10% yield (3). The low-temperature synthesis of aldehyde-generated thiazolines (2, Rj = R2 = H), as depicted in Figure 1, possibly may have some geochemical interest when viewed in the Tight of reports that such thiazolines are dehydrogenated to thiazoles by sulfur at 130 6C ( -10). 

The photochemical rearrangement of the mesoionic thiazole (33) provides an original synthesis of the 4-methylthio-derivatives of the A-4-thiazoline-2-one (34) (Scheme 15) (33). 

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 reaction of phosphorus pentasulfide with a-acylamino carbonyl compounds of type Ilia also yields thiazoles. Even more commonly, a mercaptoketone is condensed with a nitrile of type IVa or a-mercaptoacids or their esters with Schiff bases. This ring closure is limited to the thiazolidines. In the Va ring-closure type, /3-mercaptoalkylamines serve as the principal starting materials, and ethylformate is the reactant that supplies the carbon at the 2-position of the ring. These syntheses constitute the most important route for the preparation of many thiazolidines and 2-thiazolines. In the Vb type of synthesis, one of the reactant supplies only the carbon at the 5-position of the resultant thiazole. Then in these latter years new modern synthetic methods of thiazole ring have been developed (see Section 7 also Refs. 515, 758, 807, 812, 822). 

In a similar manner, D-camphor-lO-sulfonic acid (10-CSA) has heen used in the synthesis of 2-thiazolines. In the example shown in Scheme 82, endothiopeptide 208 was converted into thiazol-5(4//)-one 209 . 

The first phase of the total synthesis of thiostrepton 303, a highly complex thiopeptide antibiotic, has been described. Retrosynthetic analysis of thiostrepton revealed units 304-308 as potential key building blocks. Concise and stereoselective constructions of all these intermediates have been achieved. The synthesis of the dehydropiperidine core 308 was based on a biosynthetically inspired aza-Diels-Alder dimerization of an appropriate azadiene system, an approach that was initially plagued with several problems which were, however, resolved satisfactorily by systematic investigations. The quinaldic acid fragment 305 and the thiazoline-thiazole segment 306 were synthesized by a series of reactions that included asymmetric and other stereoselective processes (Scheme 113) <2005JA11159>. 

Major metabolite (in faeces) is 5,6-dihydro-6-(2-thienyl)imidazo[2,1-b]thiazole more potent antihelmintic than parent drug. Finding led to synthesis of tetramisole (corresp. 6-phenyl-thiazoline deriv.), potent broad-spectrum antihelmintic (39 0). 

Thiazoles can be prepared from thiazolines by oxidation with activated manganese dioxide. This approach has been applied to the synthesis of dimethyl sulfomycinnamate (11 to 12) <05JOC1389>, the polyoxazole-thiazole based cyclopeptide YM-216391 (13 to YM-216391) <05CC797>, and didmolamides A and B (14 to 15) <05TL2567>. A facile preparation of thiazole 17 from thiazolidine 16 involves a brornmation-elirnination protocol <05JMC2584>. 

As described previously, thiazohnes are versatile intermediates to thiazoles. In addition, thiazoline rings are structural motifs found in numerous natural products. Among a variety of methods for the construction of thiazolines, the cyclodehydration protocol is perhaps most popular. In the total synthesis of cyclopeptide YM-216391, (diethylamino)sulfur trifluoride (DAST) is used as the cyclodehydrating agent for the conversion of P-hydroxy thioamide 76 to thiazoline 13 <05CC797>. A similar strategy has been used in the construction of the thiazoline moiety in two independent total syntheses of hahpeptin A (77 to 78 79 to 80)... 

Heterocydes are common motifs in natural products, which may occur as single, tandem, and multiple moieties within a given molecule (Scheme 8.5) [35-37]. These motifs often provide molecular interaction with nudeotide and protein targets. In the biosynthesis of NRPs, an oxazoline was usually formed from a dipeptide containing serine in the second position upon dehydration (Scheme 8.5) [38]. The syntheses of a thiazoline from cysteine and a 2-methyloxazoline from threonine follow a similar mechanism. These heterocycles can be further custom-made to provide thiazolidines/oxazolidines upon reduction or thiazoles/oxazoles upon oxidation. Enzymatic heterocyclization can be portable, as demonstrated in the synthesis of novel chiral heterocyclic carboxylic adds by hybrid enzymes [39]. 

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