Question

Propose a synthesis for 3,5 -dichloro-2-methoxybenzoic acid starting from phenol.

Short answer

Answer: The synthetic route involves the following steps: 1. Protect the hydroxyl group in phenol using tert-butyl-dimethylsilyl (TBS) chloride and imidazole in DMF. 2. Introduce chloro groups at the 3 and 5 positions using N-chlorosuccinimide (NCS) in a suitable solvent. 3. Add a methoxy group at the 2 position using sodium methoxide (NaOMe) in THF. 4. Introduce a carboxylic acid group at the 1 position through the Gattermann-Koch reaction using CO, HCl, and an aluminum chloride (AlCl3) catalyst. 5. Deprotect the hydroxyl group using tetra-n-butylammonium fluoride (TBAF) in THF to obtain 3,5-dichloro-2-methoxybenzoic acid.

Step-by-step solution

Protecting the Hydroxyl Group

In order to protect the hydroxyl group in phenol, we can react it with a protecting group. One common protecting group is tert-butyl-dimethylsilyl (TBS). Phenol can be treated with TBS-Cl and imidazole in DMF (dimethylformamide) to produce TBS-protected phenol: Phenol + TBS-Cl + Imidazole → TBS-protected phenol

Introducing the Chloro Groups

To introduce chloro groups at the 3 and 5 positions, we can use chlorination reagents like N-chlorosuccinimide (NCS) in a solvent, such as CCl\(_4\) or CHCl\(_3\). This step might require careful temperature control to ensure selective substitution only at 3,5 positions: TBS-protected Phenol + 2 NCS → 3,5-dichloro-TBS-protected phenol

Introducing the Methoxy Group

To introduce a methoxy group at the 2 position, react 3,5-dichloro-TBS-protected phenol with sodium methoxide (NaOMe) in an inert solvent like THF. This will result in the formation of 2-methoxy-3,5-dichloro-TBS-protected phenol: 3,5-dichloro-TBS-protected phenol + NaOMe → 2-methoxy-3,5-dichloro-TBS-protected phenol

Introducing the Carboxylic Acid Group

To add the carboxylic acid group at the 1 position, we can perform a Gattermann-Koch reaction using CO, HCl, and an aluminum chloride (AlCl\(_3\)) catalyst. This will transform the benzene ring into benzoic acid with the substituents in the correct positions. 2-methoxy-3,5-dichloro-TBS-protected phenol + CO + HCl + AlCl\(_3\) → 2-methoxy-3,5-dichloro-TBS-protected benzoic acid

Deprotecting the Hydroxyl Group

Finally, to remove the TBS protecting group and unmask the hydroxyl group, we can react the TBS-protected compound with tetra-n-butylammonium fluoride (TBAF) in THF: 2-methoxy-3,5-dichloro-TBS-protected benzoic acid + TBAF → 3,5-dichloro-2-methoxybenzoic acid At the end of this reaction sequence, we have successfully synthesized 3,5-dichloro-2-methoxybenzoic acid starting from phenol.