Thiazole

Thiazole
Names
	Preferred IUPAC name 1,3-Thiazole
	Other names Thiazole
Identifiers
CAS Number	288-47-1 ;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:43732 ;
ChEMBL	ChEMBL15605 ;
ChemSpider	8899 ;
ECHA InfoCard	100.005.475
PubChem CID	9256;
UNII	320RCW8PEF ;
CompTox Dashboard (EPA)	DTXSID2059776 ;
	InChI InChI=1S/C3H3NS/c1-2-5-3-4-1/h1-3H Key: FZWLAAWBMGSTSO-UHFFFAOYSA-N ; InChI=1/C3H3NS/c1-2-5-3-4-1/h1-3H Key: FZWLAAWBMGSTSO-UHFFFAOYAI;
	SMILES n1ccsc1;
Properties
Chemical formula	C3H3NS
Molar mass	85.12 g·mol−1
Boiling point	116 to 118 °C (241 to 244 °F; 389 to 391 K)
Acidity (pKa)	2.5 (of conjugate acid) [1]
Magnetic susceptibility (χ)	-50.55·10−6 cm3/mol
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). verify (what is ?) Infobox references

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.[2] 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.

Thiazole rings are planar and aromatic. Thiazoles are characterized by larger pi-electron delocalization than the corresponding oxazoles and have therefore greater aromaticity. This aromaticity is evidenced by the chemical shift of the ring protons in proton NMR spectroscopy (between 7.27 and 8.77 ppm), clearly indicating a strong diamagnetic ring current. The calculated pi-electron density marks C5 as the primary site for electrophilic substitution, and C2 as the site for nucleophilic substitution.

Thiazole electron densities and numbering scheme

Occurrence of thiazoles and thiazolium salts

Bleomycin is a thiazole-containing anti-cancer drug.

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).[3]

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# [6451-12-3]), Algol Yellow GC (CAS# [129-09-9]), Indanthren Rubine B (CAS# [6371-49-9]), Indanthren Blue CLG (CAS# [6371-50-2], and Indanthren Blue CLB (CAS#[6492-78-0]). These thiazole dye are used for dyeing cotton.

Organic 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.[4][5] Another example [6] is given below:

Hantsch Thiazole Synthesis

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 through application of 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.[7] 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).[8]

Deprotonation at C2: the negative charge on this position is stabilized as an ylide; Hauser bases and organolithium compounds react at this site, replacing the proton

Thiazole deprotonation

2-(trimethylsilyl)thiazole [9] (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

Electrophilic aromatic substitution at C5 requires activating groups such as a methyl group in this bromination:

Thiazole bromination

Nucleophilic aromatic substitution often requires a leaving group such as chlorine at C2 with

Thiazole Nucleophilic Aromatic Substitution

Organic 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:[10] 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.[11]

Thiazole oxidation

Thiazoles are formyl synthons; conversion of R-thia to the R-CHO aldehyde takes place with,[9] 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,[6] 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 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.

Thiazole cycloaddition

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[12] and transition metal carbene complexes.

Structure of thiazoles (left) and thiazolium salts (right)

Alagebrium is a thiazolium-based drug.

References

Zoltewicz, J. A.; Deady, L. W. (1978). Quaternization of Heteroaromatic Compounds. Quantitative Aspects. Advances in Heterocyclic Chemistry. Vol. 22. pp. 71–121. doi:10.1016/S0065-2725(08)60103-8. ISBN 9780120206223.
Eicher, T.; Hauptmann, S. (2003). The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications. ISBN 978-3-527-30720-3.
Mak, Jeffrey Y. W.; Xu, Weijun; Fairlie, David P. (2015-01-01). Peptidomimetics I (PDF). Topics in Heterocyclic Chemistry. Vol. 48. Springer Berlin Heidelberg. pp. 235–266. doi:10.1007/7081_2015_176. ISBN 978-3-319-49117-2.
J. R. Byers; J. B. Dickey (1939). "2-Amino-4-methylthiazole". Organic Syntheses. 19: 10. doi:10.15227/orgsyn.019.0010.
George Schwarz (1945). "2,4-Dimethylthiazole". Organic Syntheses. 25: 35. doi:10.15227/orgsyn.025.0035.
Alajarín, M.; Cabrera, J.; Pastor, A.; Sánchez-Andrada, P.; Bautista, D. (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. PMID 16808523.
Kriek, M.; Martins, F.; Leonardi, R.; Fairhurst, S. A.; Lowe, D. J.; Roach, P. L. (2007). "Thiazole Synthase from Escherichia coli: An Investigation of the Substrates and Purified Proteins Required for Activity in vitro" (PDF). J. Biol. Chem. 282 (24): 17413–17423. doi:10.1074/jbc.M700782200. PMID 17403671.
Thomas L. Gilchrist "Heterocyclic Chemistry" 3rd ed. Addison Wesley: Essex, England, 1997. 414 pp. ISBN 0-582-27843-0.
Dondoni, A.; Merino, P. (1995). "Diastereoselective Homologation of D-(R)-Glyceraldehyde Acetonide using 2-(Trimethylsilyl)thiazole". Organic Syntheses. 72: 21.; Collective Volume, vol. 9, p. 952
Amir, E.; Rozen, S. (2006). "Easy Access to the Family of Thiazole N-oxides using HOF·CH₃CN". Chemical Communications. 2006 (21): 2262–2264. doi:10.1039/b602594c. PMID 16718323.
Campeau, Louis-Charles; Bertrand-Laperle, Mégan; Leclerc, Jean-Philippe; Villemure, Elisia; Gorelsky, Serge; Fagnou, Keith (2008-03-01). "C2, C5, and C4 Azole N -Oxide Direct Arylation Including Room-Temperature Reactions". Journal of the American Chemical Society. 130 (11): 3276–3277. doi:10.1021/ja7107068. ISSN 0002-7863.
Arduengo, A. J.; Goerlich, J. R.; Marshall, W. J. (1997). "A Stable Thiazol-2-ylidene and Its Dimer". Liebigs Annalen. 1997 (2): 365–374. doi:10.1002/jlac.199719970213.

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[1] Zoltewicz, J. A.; Deady, L. W. (1978). Quaternization of Heteroaromatic Compounds. Quantitative Aspects. Advances in Heterocyclic Chemistry. Vol. 22. pp. 71–121. doi:10.1016/S0065-2725(08)60103-8. ISBN 9780120206223.

[2] Eicher, T.; Hauptmann, S. (2003). The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications. ISBN 978-3-527-30720-3.

[3] Mak, Jeffrey Y. W.; Xu, Weijun; Fairlie, David P. (2015-01-01). Peptidomimetics I (PDF). Topics in Heterocyclic Chemistry. Vol. 48. Springer Berlin Heidelberg. pp. 235–266. doi:10.1007/7081_2015_176. ISBN 978-3-319-49117-2.

[4] J. R. Byers; J. B. Dickey (1939). "2-Amino-4-methylthiazole". Organic Syntheses. 19: 10. doi:10.15227/orgsyn.019.0010.

[5] George Schwarz (1945). "2,4-Dimethylthiazole". Organic Syntheses. 25: 35. doi:10.15227/orgsyn.025.0035.

[Mateo-6] Alajarín, M.; Cabrera, J.; Pastor, A.; Sánchez-Andrada, P.; Bautista, D. (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. PMID 16808523.

[7] Kriek, M.; Martins, F.; Leonardi, R.; Fairhurst, S. A.; Lowe, D. J.; Roach, P. L. (2007). "Thiazole Synthase from Escherichia coli: An Investigation of the Substrates and Purified Proteins Required for Activity in vitro" (PDF). J. Biol. Chem. 282 (24): 17413–17423. doi:10.1074/jbc.M700782200. PMID 17403671.

[Gilchrist-8] Thomas L. Gilchrist "Heterocyclic Chemistry" 3rd ed. Addison Wesley: Essex, England, 1997. 414 pp. ISBN 0-582-27843-0.

[orgsynth1-9] Dondoni, A.; Merino, P. (1995). "Diastereoselective Homologation of D-(R)-Glyceraldehyde Acetonide using 2-(Trimethylsilyl)thiazole". Organic Syntheses. 72: 21.; Collective Volume, vol. 9, p. 952

[10] Amir, E.; Rozen, S. (2006). "Easy Access to the Family of Thiazole N-oxides using HOF·CH₃CN". Chemical Communications. 2006 (21): 2262–2264. doi:10.1039/b602594c. PMID 16718323.

[11] Campeau, Louis-Charles; Bertrand-Laperle, Mégan; Leclerc, Jean-Philippe; Villemure, Elisia; Gorelsky, Serge; Fagnou, Keith (2008-03-01). "C2, C5, and C4 Azole N -Oxide Direct Arylation Including Room-Temperature Reactions". Journal of the American Chemical Society. 130 (11): 3276–3277. doi:10.1021/ja7107068. ISSN 0002-7863.

[12] Arduengo, A. J.; Goerlich, J. R.; Marshall, W. J. (1997). "A Stable Thiazol-2-ylidene and Its Dimer". Liebigs Annalen. 1997 (2): 365–374. doi:10.1002/jlac.199719970213.