thiazole

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.

File:Bleomycin A2.svg 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).{{cite book|last1=Mak|first1=Jeffrey Y. W.|last2=Xu|first2=Weijun|last3=Fairlie|first3=David P.|date=2015-01-01|publisher=Springer Berlin Heidelberg|series=Topics in Heterocyclic Chemistry|pages=235–266|language=en|doi=10.1007/7081_2015_176|title = Peptidomimetics I|volume = 48|isbn = 978-3-319-49117-2|url=http://espace.library.uq.edu.au/view/UQ:386341/UQ386341_OA.pdf}}

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.

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.{{OrgSynth | title = 2,4-Dimethylthiazole | author = George Schwarz| year = 1945| volume = 25 | page = 35 | doi = 10.15227/orgsyn.025.0035}} 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.

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.{{ cite journal |author1=Kriek, M. |author2=Martins, F. |author3=Leonardi, R. |author4=Fairhurst, S. A. |author5=Lowe, D. J. |author6=Roach, P. L. | title = Thiazole Synthase from Escherichia coli: An Investigation of the Substrates and Purified Proteins Required for Activity in vitro | journal = J. Biol. Chem. | year = 2007 | volume = 282 | issue = 24 | pages = 17413–17423 | doi = 10.1074/jbc.M700782200 | url = http://www.jbc.org/content/282/24/17413.full.pdf | pmid = 17403671 | doi-access = free }} Sulfur of the thiazole is derived from cysteine. In anaerobic bacteria, the CN group is derived from dehydroglycine.

With a pK_a of 2.5 for the conjugate acid, thiazoles are far less basic than imidazole (pK_a =7).{{cite book|author=Thomas L. Gilchrist|title=Heterocyclic Chemistry|edition=3|year= 1997|publisher=Addison Wesley|location=Essex, England|page=414| isbn=0-582-27843-0}}

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.{{cite journal | author1 = Dondoni, A. | author2 = Merino, P. | title = Diastereoselective Homologation of D-(R)-Glyceraldehyde Acetonide using 2-(Trimethylsilyl)thiazole | year = 1995 | volume = 72 | pages = 21 | doi = 10.15227/orgsyn.072.0021 }}

Thiazole deprotonation{{clear left}}

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

:Image:Thiazole bromination v2.svg{{clear left}}

:Image:ThiazoleNucleophilicAromaticSubstitution.png{{clear left}}

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:{{cite journal |author1=Amir, E. |author2=Rozen, S. | title = Easy Access to the Family of Thiazole N-oxides using HOF·CH₃CN | journal = Chemical Communications | year = 2006 | volume = 2006 | issue = 21 | pages = 2262–2264 | doi = 10.1039/b602594c | pmid = 16718323 }} 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.{{cite journal |last1=Campeau |first1=Louis-Charles |last2=Bertrand-Laperle |first2=Mégan |last3=Leclerc |first3=Jean-Philippe |last4=Villemure |first4=Elisia |last5=Gorelsky |first5=Serge |last6=Fagnou |first6=Keith |date=2008-03-01 |title=C2, C5, and C4 Azole N -Oxide Direct Arylation Including Room-Temperature Reactions |url=https://pubs.acs.org/doi/10.1021/ja7107068 |journal=Journal of the American Chemical Society |language=en |volume=130 |issue=11 |pages=3276–3277 |doi=10.1021/ja7107068 |pmid=18302383 |issn=0002-7863|url-access=subscription }}

:Image:ThiazoleOxidation.png{{clear left}}

• 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,{{cite journal | title = On the [2+2] Cycloaddition of 2-Aminothiazoles and Dimethyl Acetylenedicarboxylate. Experimental and Computational Evidence of a Thermal Disrotatory Ring Opening of Fused Cyclobutenes |author1=Alajarín, M. |author2=Cabrera, J. |author3=Pastor, A. |author4=Sánchez-Andrada, P. |author5=Bautista, D. | journal = J. Org. Chem. | year = 2006 | volume = 71 | issue = 14 | pages = 5328–5339 | doi = 10.1021/jo060664c | pmid = 16808523 }} 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.

:Image:ThiazoleCycloaddition.png{{clear left}}

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{{cite journal |author1=Arduengo, A. J. |author2=Goerlich, J. R. |author3=Marshall, W. J. | title = A Stable Thiazol-2-ylidene and Its Dimer | journal = Liebigs Annalen | year = 1997 | volume = 1997 | issue = 2 | pages = 365–374 | doi = 10.1002/jlac.199719970213}} and transition metal carbene complexes.

:Image:Thiazoles.png{{clear left}}

Alagebrium is a thiazolium-based drug.

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Category:Aromatic bases

Category:Simple aromatic rings