Thiazolium Salt

Thiazole (), or 1,3-thiazole, is a 5-membered heterocyclic compound that contains both sulfur and nitrogen. The term 'thiazole' also refers to a large family of derivatives. Thiazole itself is a pale yellow liquid with a pyridine-like odor and the molecular formula C₃H₃NS. The thiazole ring is notable as a component of the vitamin thiamine (B₁).

Molecular and electronic structure

Thiazoles are members of the azoles, heterocycles that include imidazoles and oxazoles. Thiazole can also be considered a functional group when part of a larger molecule.

Being planar thiazoles are characterized by significant pi-electron delocalization and have some degree of aromaticity, more so than the corresponding oxazoles. This aromaticity is evidenced by the ¹H NMR chemical shift of the ring protons, which absorb between 7.27 and 8.77 ppm, indicating a strong diamagnetic ring current. The calculated pi-electron density marks C5 as the primary site for electrophilic substitution, and C2-H as susceptible to deprotonation.

Occurrence of thiazoles and thiazolium salts

Thiazoles are found in a variety of specialized products, often fused with benzene derivatives, the so-called benzothiazoles. In addition to vitamin B₁, the thiazole ring is found in epothilone. Other important thiazole derivatives are benzothiazoles, for example, the firefly chemical luciferin. Whereas thiazoles are well represented in biomolecules, oxazoles are not. It is found in naturally occurring peptides, and utilised in the development of peptidomimetics (i.e. molecules that mimic the function and structure of peptides).

Commercial significant thiazoles include mainly dyes and fungicides. Thifluzamide, Tricyclazole, and Thiabendazole are marketed for control of various agricultural pests. Another widely used thiazole derivative is the non-steroidal anti-inflammatory drug Meloxicam. The following anthroquinone dyes contain benzothiazole subunits: Algol Yellow 8 (CAS# 451-12-3, Algol Yellow GC (CAS# 29-09-9, Indanthren Rubine B (CAS# 371-49-9, Indanthren Blue CLG (CAS# 371-50-2 and Indanthren Blue CLB (CAS#492-78-0. These thiazole dye are used for dyeing cotton.

Synthesis

Various laboratory methods exist for the organic synthesis of thiazoles. Prominent is the Hantzsch thiazole synthesis, which is a reaction between haloketones and thioamides. For example, 2,4-dimethylthiazole is synthesized from thioacetamide and chloroacetone. In the Cook-Heilbron synthesis, thiazoles arise by the condensation of α-aminonitrile with carbon disulfide. Thiazoles can be accessed by acylation of 2-aminothiolates, often available by the Herz reaction.

Biosynthesis

Thiazoles are generally formed via reactions of cysteine, which provides the N-C-C-S backbone of the ring. Thiamine does not fit this pattern however. Several biosynthesis routes lead to the thiazole ring as required for the formation of thiamine. Sulfur of the thiazole is derived from cysteine. In anaerobic bacteria, the CN group is derived from dehydroglycine.

Reactions

With a pK_a of 2.5 for the conjugate acid, thiazoles are far less basic than imidazole (pK_a =7).

Deprotonation with strong bases occurs at C2-H. The negative charge on this position is stabilized as an ylide. Hauser bases and organolithium compounds react at this site, replacing the proton. 2-Lithiothiazoles are also generated by metal-halogen exchange from 2-bromothiazole.

Electrophilic aromatic substitution at C5 but require activating groups such as a methyl group, as illustrated in bromination:

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Oxidation at nitrogen gives the aromatic thiazole ''N''-oxide; many oxidizing agents exist, such as mCPBA; a novel one is hypofluorous acid prepared from fluorine and water in acetonitrile; some of the oxidation takes place at sulfur, leading to non-aromatic sulfoxide/sulfone: Thiazole ''N''-oxides are useful in Palladium-catalysed C-H arylations, where the ''N''-oxide is able to shift the reactivity to reliably favor the 2-position, and allows for these reactions to be carried out under much more mild conditions.

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* Thiazoles are formyl synthons; conversion of R-thia to the R-CHO aldehyde takes place with, respectively, methyl iodide (''N''-methylation), organic reduction with sodium borohydride, and hydrolysis with Mercury(II) chloride in water.
* Thiazoles can react in cycloadditions, but in general at high temperatures due to favorable aromatic stabilization of the reactant; Diels-Alder reactions with alkynes are followed by extrusion of sulfur, and the endproduct is a pyridine; in one study, a very mild reaction of a ''2-(dimethylamino)thiazole'' with ''dimethyl acetylenedicarboxylate'' (DMAD) to a pyridine was found to proceed through a zwitterionic intermediate in a formal +2ycloaddition to a cyclobutene, then to a ''1,3-thiazepine'' in a 4-electron electrocyclic ring opening and then to a ''7-thia-2-azanorcaradiene'' in a 6-electron electrocyclic ring, closing before extruding the sulfur atom.

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Thiazolium salts

Alkylation of thiazoles at nitrogen forms a thiazolium cation. Thiazolium salts are catalysts in the Stetter reaction and the Benzoin condensation. Deprotonation of ''N''-alkyl thiazolium salts give the free carbenes and transition metal carbene complexes.
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Alagebrium is a thiazolium-based drug.

References

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Aromatic bases
Simple aromatic rings