Reactions of Thiazole

Reactions of Thiazole include electrophilic substitution, metalation, oxidation, and reduction pathways significant in medicinal chemistry.

Reactions of Thiazole

1. Electrophilic Aromatic Substitution (EAS)

   • Like oxazole, C-5 is the most reactive site.
   • Easier than oxazole due to lower electronegativity of sulfur.
   • Examples:
     • Bromination: Thiazole + Br₂ → 5-bromothiazole
     • Nitration: HNO₃/H₂SO₄ → 5-nitrothiazole
     • Friedel–Crafts acylation: Rare, can occur at C-5 under mild Lewis acid conditions.

2. Nucleophilic Substitution (NAS)

   • Requires activating groups (e.g., NO₂) on ring.
   • Substitution typically at C-2 or C-4 positions with halogen leaving group.

3. N-Lithiation and Functionalization

   • Directed lithiation at C-2 or C-5 using n-BuLi, followed by electrophilic quench.
   • Example:
     • Thiazole + n-BuLi → 2-lithiothiazole → quenching with CH₃I → 2-methylthiazole

4. Reduction

   • Catalytic hydrogenation can reduce the ring → dihydro- or tetrahydrothiazoles.
   • Strong reducing agents can cleave C–S bond under harsh conditions.

5. Metal Coordination and Complexation

   • Thiazole acts as a bidentate ligand through N and S atoms.
   • Common in bioinorganic chemistry and coordination chemistry (e.g., Zn²⁺ binding sites in proteins).

6. Ring Opening

   • Less common but can occur under strong acid or base.
   • Leads to thiourea derivatives or other linear fragments.

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