Reactions of Oxazole

Reactions of Oxazole include electrophilic substitution at the 5-position, nucleophilic substitution at the 2-position, and ring-opening reactions.

1. Electrophilic Aromatic Substitution (EAS)

   • The ring is electron-deficient (due to N and O), so EAS is more difficult than in pyrrole, furan, or imidazole.
   • Most reactive site: C-5, due to resonance stabilization of the intermediate.
   • Examples:
     • Nitration (HNO₃/H₂SO₄) → 5-nitrooxazole
     • Halogenation (Br₂, I₂) → 5-halooxazole
   • Mechanism Tip: Protonation of oxygen/N destabilizes aromaticity, so mild conditions are essential.

2. Nucleophilic Aromatic Substitution (NAS)

   • Possible if electron-withdrawing groups (e.g., NO₂) are present at C-2 or C-4 to stabilize Meisenheimer complex.
   • Example:
     • 2-chloro-5-nitrooxazole +  NaOMe  →  2-methoxy-5-nitrooxazole

3. Lithiation and Functionalization

   • Directed lithiation possible at C-2 or C-5 using strong base like n-BuLi.
   • Electrophile (E⁺) can be added after lithiation to introduce functional groups.
   • Example:
     • Oxazole +  n-BuLi  →  2-lithiooxazole  →  quenching with CO₂  →  2-carboxyoxazole

4. Ring Opening

   • Under strong acidic or basic conditions, the ring may open, especially at high temperatures or with nucleophilic attack.
   • Example:
     • Oxazole hydrolysis under acid →  open-chain amino acid or diketone derivatives.

5. Cycloaddition Reactions

   • Oxazoles can undergo [4+2] Diels-Alder-type reactions as dienes with reactive dienophiles.
   • Less common due to aromatic stability but possible with electron-deficient oxazoles.

6. Reduction Reactions

   • Catalytic hydrogenation can reduce oxazole → dihydro- or tetrahydro-oxazoles.
   • Rarely used in synthetic planning due to loss of aromaticity.

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