Synthesis of thiazoles

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 . 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles 06AG(E)7235 . Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

A series of 2-(thiazol-5-yl)acetamides and acetates 35a/b has been prepared in one pot from the reactions of benzotriazolylthione derivatives 32 with A,A-dimethyl-4-A ,A -bis(trimethylsilyl)aminobut-2-yne amide 31a and ethyl 4-A,A-bis(trimethylsilyl)aminobut-2-ynoate 31b, respectively 06TL8661 . Presumably, the initial adducts 33a/b undergo intramolecular thia-Michael addition to give 34a/b, which isomerize to thiazoles 35a/b. 

A novel synthesis of iodothiazole 38 takes advantage of Wiemer s protocol for the synthesis of vinyl iodides from ketones 06JOC5031 . The thiazolyl phosphate 37, prepared from 2-isopropylaminothiazoline-4-one 36, is converted to the desired iodothiazole 38 upon treatment with in situ generated trimethylsilyl iodide. This iodide is a key intermediate in the synthesis of the quinolone substructure of the protease inhibitor BILN 2061. 

The Holzapfel-Meyers-Nicolaou modification is a significant improvement over the traditional Hantzsch conditions. However, racemization can still occur in some circumstances. For example, the two-step Hantzsch reaction of thioamide 12 with bromide 

11 furnishes thiazole 13 with 60-85% enantiomeric excess (ee) due to partial epimerization at the a-stereogenic center 07JOC4205 . The epimerization issue is obviated when thioamide 

12 is replaced with the ketal-protected thioamide 14. Reaction of 11 with 14 delivers 15 with good optical purity ( 96% ee). This thiazole represents the core structure of the potent thiopeptide antibiotic nosiheptide 07JOC4205 . 

Other progress in the Hantzsch thiazole synthesis includes a,a-dibromoketones as a superior alternative to a-dibromoketones 07SC2501 and ionic liquid as reaction medium 07T11066 . 

---

Because of the easy and versatile synthesis of thiazoles (cf. Chapter II), this reaction could have interesting synthetic applications (481). 

Several methods for the synthesis of thiazole compounds are available, which can be classified into the partial structures illustrated in Scheme 1. The first of these structures (la) is by far the most useful and versatile of all the thiazole syntheses. By a judicious choice of reactants it allows... 

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). 

The condensation of thioacetic acid with amino acids under drastic conditions provides a useful new synthesis of thiazoles (Scheme 146) (668, 669). Instead of the amino acid, Af-acyl <279) or N-thioacylamino acids (278) are used. 

These a-acylaminoketones also provided a convenient synthesis of thiazoles on treatment with phosphorus pentasulfide (Gabriel s method). Although yields range from 45 to 80%, substituents are usually restricted to alkyl, aryl and alkoxy derivatives. Thus, reaction of the a-acylaminoketone (4) with P4S1Q gave the thiazole (5), and thiazole (7) itself was prepared in this manner in 62% yield from formylaminoacetal (6) (14CB3163). The corresponding 5-ethoxy compound was obtained from the a-formamidoester and phosphorus pentasulfide in an inert solvent. 

The most widely used method for the synthesis of thiazoles (see Chapter 4.19) is of this type and involves the reaction of a-halo compounds (Y = halogen in Scheme 2) with a reactive component containing an —C(=S)— structural entity. Reaction of the a-... 

Scheme 22 summarizes the present stage of our knowledge of the synthesis of thiazole in yeasts. The existence of two biosynthetic pathways for thiazole is commented on in Sections VII and VIII. 

A solvent-free strategy for the synthesis of thiazoles involved mixing of thioamides with a-tosyloxy ketones in a clay-catalyzed reaction (Scheme 7). The typical procedure entailed mixing of thioamides and in situ produced a-tosyloxy ketones with montmorillonite K-10 clay in an open glass container. The reaction mixture was irradiated in a microwave oven for 2-5 min with intermittent irradiation and the product was extracted into ethyl acetate to afford 2-substituted thiazoles in 88-96% yields [8]. 

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... 

Commercially available 2,5-dibromothiazole can be alternatively generated by bromination of thiazole or 2-bromothiazole [5]. 2,4-Dibromothiazole and 2,5-dibromothiazole are among the most useful building blocks in the synthesis of thiazole-containing molecules. Regioselective bromination was achieved at C(4) when 2-amino-6-trifluoromethoxythiazole (4) was treated with bromine in acetic acid to afford 4-bromobenzothiazole 5 [6],... 

Care must be taken in the choice of organic solvent. Chloroform should never be used under the basic conditions due to the risk of the formation of isocyanides (see Chapter 7) and the use of carbon disulphide can lead to formation of dithiocarba-mates, e.g. dimethyl A -(ethoxycarbonylmethyl)iminodithiocarbonate is formed (35-39%), as the major product in high purity, in the liquiddiquid two-phase methyl-ation of ethyl glycinate in carbon disulphide [15]. The product is useful as an intermediate in the synthesis of thiazoles [15] and dihydrooxazoles [16]. 

Other examples of Ugi reactions combined with RCM have been described in the literature. Hebach and Kazmaier reported the synthesis of conformationally fixed cyclic peptides [70] and Beck and Domling synthesized biaryl-containing natural product-like macrocycles using this method [41]. The same group also reported combination of Passerini and Horner-Wadsworth-Emmons reactions to obtain butenolides [67] and another variation for the combinatorial synthesis of thiazoles [69]. 

JPR711). Also, nitroenamines can be used as the starting materials for the synthesis of thiazoles (85JOC1547) (Scheme 12). 

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... 

Baxendale et al. (2008) reported a bifurcated approach to the synthesis of thiazoles and imidazoles by coupling a glass microreactor and a packed-bed reactor to achieve a base-mediated condensation reaction. As Scheme 32 illustrates, reactions focused on the use of ethyl isocyanoacetate 123, as the cyanide source, with variations made via the isothiocyanate reagent, as illustrated in Table 13. 

Scheme 32 Schematic illustrating the general reaction conditions employed for the continuous flow synthesis of thiazoles and imidazoles.

Building on the bifurcated pathway, developed to enable the selective synthesis of thiazoles or imidazoles (Scheme 73), Baxendale et al. (2005) subsequently demonstrated the synthesis of a HIV-1 RTI analog 255 using the same reaction methodology. 

The forward process is the Hantzsch synthesis of thiazoles which, despite its antiquity (it is around 100 years old), is still very widely used. 

Synthesis of thiazole amino acids as precursors of marine cytotoxic cyclic peptides 91YZ1. 

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. 

Of all the methods described for the synthesis of thiazole compounds, the most efficient involves the condensation of equimolar quantities of thiourea and a-halo ketones or aldehydes to yield the corresponding 2-aminothiazoles (Scheme 167) (l888LA(249)3l). The reaction occurs more readily than that of thioamides and can be carried out in aqueous or alcoholic solution, even in a distinctly acid medium, an advantage not shared by thioamides which are often unstable in acids. The yields are usually excellent. A derived method condenses the thiourea (2 mol) with the non-halogenated methylene ketone (1 mol) in the presence of iodine (1 mol) or another oxidizing agent (chlorine, bromine, sulfuryl chloride, chlorosulfonic acid or sulfur monochloride) (Scheme 168) (45JA2242). 

Another approach to the solid phase synthesis of thiazoles involves an interesting C-sulfanylation step. The starting material for this synthesis is a resin bound piperazine 55 which is converted into a thiourea and then treated with an a-bromoketone to give the thiazole 56. Treatment of 56 with either thiols or disulfides and iodine or sulfonyl chlorides with iodine and triphenylphosphine afforded 5-sulfanylthiazoles 57, which could be obtained in high yields and purity after cleavage from the resin <02EJOC2953>. 

The Hantzsch synthesis of thiazoles is an excellent method for the synthesis of simple thiazoles, however for some substituted examples low yields have been reported as a result of dehalogenation of the a-haloketone. An alternative method for the synthesis of highly substituted thiazoles has been reported, thus starting from the 2-bromo-5-chlorothiazole 76 it was possible to introduce substituents selectively at the 2-position by a palladium-catalysed cross coupling reaction to give 77 (74-92%). In order to introduce a substituent into the 5-position,... 

The synthesis of thiazoles is particularly interesting because of a regioselectivity problem. If we try out the two strategies we have just used for pyrimidines, the first requires the reaction of a carboxylic acid derivative with a most peculiar enamine that is also a thioenol. This does not look like a stable compound. 

Acylamino ketones also provide a convenient synthesis of thiazoles on treatment with phosphorus pentasulfide (Gabriels method). Substituents are usually restricted to alkyl, aryl, and alkoxy derivatives. Thus, the -acylamino ketone 234 with P4S10 gave the thiazole 240. Lawessons reagent (LR) can be effectively used as the source of sulfur in these cyclizations (e.g., Scheme 116) <1996JME957, 2006TL2361, CHEC-III(4.06.9.1.3)682>. 

---