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Synthesis, Reactions and Medicinal Uses of Thiazole

By combining phosphorus pentasulfide with triethylamine, 5-aryl thiazoles are formed.

Thiazole

Synthesis

By combining phosphorus pentasulfide with triethylamine, 5-aryl thiazoles are formed.

Unsubstituted thiazoles are formed by combining chloroacetaldehyde with thioformamide.

From thioamides - Thioamides are converted to thiazole derivatives when second-chloroxiranes are substituted.



Cook – Heilborn's synthesis - α-Aminonitriles are converted into 5-aminothiazoles by treating them with dithioacids, esters, carbon disulfide, carbon oxysulfide, or isothiocyanate under mild conditions.



Tcherniac’s synthesis - The 2-substituted thiazoles are synthesized by hydrolyzing *-thiocyanic ketones with acid or treating them with sulfur compounds.




Reactions

Thiophene sulfur atoms occupy position-1 in thiazole, and pyridine nitrogen atoms occupy position-3 in thiazole. Similar to imidazole, other 1-azoles (e.g., imidazole, oxazole) possess the same chemical reactivity.

Protonation - The lone pair of electrons available in nitrogen makes thiazoles easily protonated at the N3 position. The electron-deficiency of position-2 is highest, position-4 is almost neutral and position-5 is slightly electron-rich in the thiazole ring.

Deprotonation at C2 - Protons are removed from C2 by organolithium compounds. When C2 is nucleophilic, a variety of electrophiles, including aldehydes, alkyl halides, and ketones are able to bind to it.

N – alkylation - Thiazolium cations are formed by the reaction between thiazoles and alkyl halides. Almost all of the positive charge is located on sulfur atoms in this cation, which is resonance stabilized.



Electrophilic substitution reaction - These resonance structures can be used to explain all electrophilic and nucleophilic reactions of thiazole.

The 4- or 5-position of the 4, 5-double bond can be electrophilically substituted depending on which substituent occupies the 2-position. Whenever sulfur is in close proximity to a carbon atom, it behaves as an electron donor.

Sulphonation and halogenation - All electrophiles prefer the C5 position to attack the thiazole ring. Electrophiles do not attack other positions in C5 if it is already substituted. Even under mild conditions, electron-donating substituents at the C2 position facilitate the attack of electrophiles at C5.


Mercuration - In the presence of mercury acetate, thiazole tends to be mercurated in C5 > C4 > C2 order.

Diazo coupling - Colored dyes are produced by combining thiazoles with diazonium salts.

Condensation reaction – To generate heterocycles, 2-methylthiazole and 2-aminothiazole undergo condensation reactions with aromatic aldehydes.


Nucleophilic substitution reaction - C2-positions are vulnerable to nucleophilic attack because of their electron-deficient nature. Either a strong nucleophile or activation of the ring are necessary for nucleophilic reactions to occur. C2-hydrogens become more acidic when the ring nitrogen is quaternized, for example.



The nucleophile changes the position of the halogen atom attached to the thiazole ring by removing the C2–, C4–, or C5– positions.



Reduction - Furthermore, it has good stability with platinum catalytic hydrogenation and with metal reductions in hydrochloric acid. Activated by reaney nickel, it reduces thiazole rings resulting in their desulfuration and subsequent degradation.

Medicinal Uses

A thiazole is a dye or fungicide. The non-steroidal anti-inflammatory is also a commonly used thiazole derivative. The pyrimidine ring system of thiamine (B1) is combined with the thiazole ring system. Meloxicam (non-steroid anti-inflammatory) contains the same ring. In addition, it plays an essential role in the design of antibacterial, antifungal, anti-diabetic, anti-cancer, and anticonvulsant drugs. Penicillin contains the reduced thiazole ring (thiazolidine) which makes them antivirals, anthelmintics, immune-modulators, NSAIDs, sulfathiazole, and other antibiotics.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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