Thiazole
| Thiazole | |
|---|---|
| 200px | |
| 200px | |
| Identifiers | |
| CAS number | |
| SMILES | N1=CSC=C1 |
| Properties | |
| Boiling point |
116-118 °C |
| Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references | |
Thiazole, or 1,3-thiazole, is a clear to pale yellow flammable liquid and pyridine-like odor with the molecular formula C3H3NS. It is a 5-membered ring, in which two of the vertices of the ring are nitrogen and sulfur, and the other three are carbons [1].
Thiazole is used for manufacturing biocides, fungicides, pharmaceuticals, and dyes.
Thiazoles and thiazolium salts
Thiazoles are a class of organic compounds related to azoles with a common thiazole functional group.
Thiazoles are aromatic
The thiazole moiety is a crucial part of vitamin B1 (thiamine) and epothilone. Other important thiazoles are Benzothiazoles for example the firefly chemical luciferin.
When the amino atom is alkylated the resulting thiazolium salt is a salt. Thiazolium salts are catalysts in the Stetter reaction and the Benzoin condensation. Thiazole dyes are used for dying cotton.
Oxazoles are related compound with sulfur replaced by oxygen. Thiazoles are well represented in biomolecules, oxazoles are not.
Organic synthesis
Various laboratory methods exist for the organic synthesis of thiazoles.
- The Hantzsch thiazole synthesis (1889) is a reaction between haloketones and thioamides. For example, 2,4-dimethylthiazole is synthesized from acetamide, phosphorus pentasulfide and chloroacetone [2]. Another example [3] is given below:
- In an adaptation of the Robinson-Gabriel synthesis a 2-acylamino-ketones reacts with phosphorus pentasulfide
- In the Cook-Heilbron synthesis an α-aminonitrile reacts with carbon disulfide.
- Certain thiazoles can be accessed though application of the Herz reaction.
Organic reactions
Thiazoles are characterized by larger pi-electron delocalization than the corresponding oxazoles and have therefore greater aromaticity. This is evidenced by the position of the ring protons in proton NMR (between 7.27 and 8.77 ppm) clearly indicating a strong diamagnetic ring current.
The calculated pi-electron density marks C5 as the primary electrophilic site and C2 as the nucleophilic site.
The reactivity of a thiazole can be summarized as follows:
- Deprotonation at C2, the negative charge on this position is stabilized as an ylide. Grignard reagents and organolithium compounds react at this site replacing the proton.
- 2-(trimethylsiliyl)thiazole [4] (with a trimethylsilyl group in the 2-position) is a stable substitute and reacts with a range of electrophiles such as aldehydes, acyl halides and ketenes.
- Alkylation at nitrogen forms a thiazolium salt.
- Electrophilic aromatic substitution at C5 requires activating groups such as a methyl group in this bromination:
- Nucleophilic aromatic substitution often requires an electrofuge at C2 such as chlorine with
- Organic oxidation at nitrogen gives the 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 a sulfoxide [5]:
- Thiazoles are formyl synthons. Conversion of R-thia to the R-CHO aldehyde takes place with [4] respectively methyl iodide (N-methylation), organic reduction with sodium borohydride and hydrolysis with mercury 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 [3] 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 [2+2]cycloaddition to a cyclobutene, then to a 1,3-thiazepine in an 4-electron electrocyclic ring openening and then to a 7-thia-2-azanorcaradiene in an 6-electron electrocyclic ring closing before extruding the sulfur atom.
References
- ↑ The Chemistry of Heterocycles : Structure, Reactions, Syntheses, and Applications Theophil Eicher, Siegfried Hauptmann ISBN 3-527-30720-6
- ↑ George Schwarz (1955). "2,4-Dimethylthiazole". Org. Synth.; Coll. Vol. 3: 332.
- ↑ 3.0 3.1 Mateo Alajarín, José Cabrera, Aurelia Pastor, Pilar Sánchez-Andrada, and Delia Bautista (2006). "On the [2+2] Cycloaddition of 2-Aminothiazoles and Dimethyl Acetylenedicarboxylate. Experimental and Computational Evidence of a Thermal Disrotatory Ring Opening of Fused Cyclobutenes". J. Org. Chem. 71 (14): 5328 - 5339. doi:10.1021/jo060664c.
- ↑ 4.0 4.1 Alessandro Dondoni and Pedro Merino (1998). "Diastereoselective Homologation of D-(R)-Glyceraldehyde Acetonide using 2-(Trimethylsilyl)thiazole". Org. Synth.; Coll. Vol. 9: 952.
- ↑ Elizabeta Amir and Shlomo Rozen (2006). "Easy access to the family of thiazole N-oxides using HOF·CH3CN". Chemical Communications 2006: 2262 - 2264. doi:10.1039/b602594c.
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