Synthesis and Reactions of Thiazole: It is a pale yellow liquid having a boiling point of 116-118°C. It is an aromatic compound with having odor similar to pyridine. It is a weaker base than pyridine. Thiazole was first described by Hantzsch and Weber in 1887. The partially reduced thiazoles are called thiazolines and completely reduced thiazole is called thiazolidine.
Chemical Synthesis of Thiazole
(i) Treatment of N, N-di-formyl aminomethyl aryl ketones with phosphorus pentasulfide and triethylamine in chloroform gives 5-aryl thiazoles.
(ii) Hantzsch’s Synthesis: It is a condensation reaction between α – halo carbonyl compound with an appropriate thioamide or thiourea. The thioamide can be obtained by reacting phosphorus pentasulfide and formamide at room temperature.
Chloroacetaldehyde on condensation with thioformamide yields unsubstituted thiazole.
(iii) Gabriel synthesis: The α-acylamino ketones react with phosphorus pentasulfide to give 2- or 5- or 2, 5-disubstituted thiazoles.
(iv) From thioamides: Thioamide is reacted with substituted 2-chloroxiranes to give thiazole derivatives.
(v) Cook-Heilborn’s synthesis: Under mild conditions, α-aminonitriles are treated with dithioacids or esters, carbon disulfide, carbon oxysulfide, or isothiocyanates to yield 5-amino thiazoles.
(vi) Tcherniac’s Synthesis: The 2-substituted thiazoles are obtained either from acidic hydrolysis of α-thiocyanic ketones or its treatment with sulfur compounds.
(vii) A copper-catalyzed condensation of oximes, anhydrides in the presence of potassium thiocyanate (KSCN) under mild reaction conditions, produces thiazoles in very good yields.
Chemical Reactions of Thiazole
Thiazole contains thiophene type sulfur atom at position-1 and pyridine type nitrogen at position-3. Its chemical reactivity is similar to other 1, 3-azoles (i.e., imidazole and oxazole).
(i) Protonation: Thiazoles get easily protonated at the N3 position due to the lone pair of electrons available with nitrogen. In the thiazole ring, position-2 is most electron-deficient, position-4 almost neutral and position-5 is slightly electron-rich.
(ii) Deprotonation at C2: The organolithium compounds cause the removal of proton at C2. The resulting nucleophilic site at C2 then reacts with a range of electrophiles such as aldehydes, alkyl halides, and ketones.
(iii) N – Alkylation: Thiazoles react with alkyl halides to form thiazolium cations. This cation is resonance stabilized with the positive charge residing mostly on the sulfur atom.
(iv) Electrophilic substitution reactions: Thiazole has the following resonating structures. All electrophilic and nucleophilic reactions of thiazole can be explained based on these resonance structures.
The 4, 5-double bond is aromatic and undergoes electrophilic substitution at 4- or 5- position depending on the nature of a substituent occupied by 2-position. The sulfur atom always behaves as an electron donor to its adjacent carbons.
(a) At N3-atom: The loan pair of electrons on N3-atom is less reactive. Hence, N-alkylation occurs at a slower rate in thiazole.
(b) Nitration: In acidic media, the attack usually takes place through the formation of thiazolium (N – protonated) cation. The positive charge on the protonated nitrogen of the thiazolium ion deactivates the ring considerably towards electrophilic attack. Nitration of thiazole is rather difficult and is not nitrated even in the oleum at 160°C.
However, 4-methyl thiazole is nitrated at position – 5 under relatively mild conditions.
(c) Sulphonation and halogenation: In the thiazole ring, C5 is the preferred position of attack for all electrophiles. If the C5 position is already substituted, electrophile does not attack other positions. The presence of electron-donating substituent at C2-position makes easy the attack of electrophile at C5-position even under mild conditions. e.g.,
(v) Mercuration: On treatment with mercury acetate, thiazole is mercurated at a preference order of C5 > C4 > C2.
(vi) Diazo Coupling: Thiazoles easily react with diazonium salts to give colored dyes.
(vii) Condensation reactions: The 2-methyl thiazole and 2-amino thiazole undergo a condensation reaction with aromatic aldehydes to give heterocycles.
(viii) Nucleophilic Substitution reaction: In thiazole, the C2 – position is prone to nucleophilic attack due to its electron-deficient nature and hence most suitable for the nucleophilic attack. For nucleophilic reactions to occur, either we need a strong nucleophile or activation of the ring. e.g., quaternization of the ring nitrogen significantly enhances the rate of nucleophilic attack at C2 making C2-hydrogens more acidic.
Similarly, nucleophiles attack the thiazole ring by displacing the halogen atom attached to any of C2–, C4– or C5– positions.
(ix) Oxidation: Thiazole ring is generally stable to oxidation by permanganate, chromic acid, selenium dioxide, and concentrated nitric acid.
(x) Reduction: It is also stable towards catalytic hydrogenation platinum and to the reduction by metal in hydrochloric acid. Reduction using activated Raney nickel leads to desulfuration of thiazole ring followed by decomposition of resulting intermediate.
Applications in Drug Synthesis
Vitamin thiamine (B1) contains both pyrimidine and thiazole ring systems. The ring is also present in meloxicam (non-steroidal anti-inflammatory). It is also an important scaffold in antibacterial, antifungal, antidiabetic, anticancer, and anticonvulsant drug design. These include nitazoxanide (anti-viral), thiabendazole, (anthelmintic), fanetizole (immunomodulator), fentiazac (NSAID), sulfathiazole (antibacterial), nizatidine (H2 – receptor blocker), thiamethoxam (systemic insecticide), etc Penicillins contain reduced thiazole ring (thiazolidine).
Make sure you also check our other amazing Article on : Synthesis and Reactions of Imidazole