Question

Following is the structural formula of musk ambrette, a synthetic musk, essential in perfumes to enhance and retain odor. Propose a synthesis of this compound from \(m\)-cresol (3-methylphenol). COc1c(C(C)C)cc([N+](=O)[O-])c(C)c1[N+](=O)[O-]

Short answer

Question: Outline the steps to synthesize musk ambrette from m-cresol. Answer: The synthesis of musk ambrette from m-cresol involves the following steps: 1. Nitration of m-cresol to form 2-nitro-m-cresol using concentrated nitric acid in the presence of concentrated sulfuric acid. 2. Reduction of the nitro group to an amine group to form 2-amino-m-cresol using a reducing agent like iron filings and hydrochloric acid or tin and HCl. 3. Acetylation of the amine group using acetic anhydride and a base like pyridine to form N-acetyl-2-amino-m-cresol. 4. Diazotization of the remaining amine group using sodium nitrite and hydrochloric acid to form N-acetyl-2-diazonium-m-cresol. 5. Rearrangement of N-acetyl-2-diazonium-m-cresol to form ambrettolides using a Lewis acid catalyst like anhydrous aluminum chloride. 6. Nitration of ambrettolide using concentrated nitric acid and concentrated sulfuric acid to form musk ambrette.

Step-by-step solution

Nitration of m-cresol

Nitrate the m-cresol (3-methylphenol) to form 2-nitro-m-cresol. This can be achieved by using a nitrating agent such as concentrated nitric acid (HNO3) in the presence of a concentrated sulfuric acid (H2SO4) catalyst. The reaction will proceed via electrophilic aromatic substitution, with the phenolic oxygen donating electron density to the ring and directing the nitration ortho and para to itself.

Reduction of the nitro group to an amine

Reduce the nitro group of the 2-nitro-m-cresol to an amine by treating it with a reducing agent, such as iron filings (Fe) and hydrochloric acid (HCl) or tin (Sn) and HCl. This reaction will form 2-amino-m-cresol, where the nitro group is replaced with an amine group (-NH2).

Acetylation of the amine group

Acetylate the amine group of the 2-amino-m-cresol by reacting it with acetic anhydride (CH3CO)2O) in the presence of a base like pyridine. The amine will attack the carbonyl, and the acetyl group will be transferred to the nitrogen atom. This step will produce N-acetyl-2-amino-m-cresol.

Diazotization of the remaining amine group

Convert the remaining amine group in N-acetyl-2-amino-m-cresol to a diazonium salt by treating it with a nitrosating agent like nitrous acid (HNO2). This can be generated in situ by using sodium nitrite (NaNO2) and hydrochloric acid (HCl). The reaction will occur under cold conditions (around 0-5°C) to prevent unwanted side reactions. The resulting compound is N-acetyl-2-diazonium-m-cresol.

Rearrangement to form ambrettolides

Then, rearrange the N-acetyl-2-diazonium-m-cresol to form ambrettolides by heating the reaction mixture to about 110-120°C or using a Lewis acid catalyst such as anhydrous aluminum chloride (AlCl3) at a lower temperature (50-60°C). This rearrangement involves a [3,3]-sigmatropic shift, where the carbocation intermediate formed by losing nitrogen gas rearranges to give ambrettolide.

Nitration of ambrettolide

Finally, nitrate ambrettolide to form musk ambrette by using a nitrating agent such as concentrated nitric acid (HNO3) in the presence of a concentrated sulfuric acid (H2SO4) catalyst. This electrophilic aromatic substitution reaction results in the loss of a proton and addition of a nitro group to the aromatic ring. Following these six steps, musk ambrette is synthesized from m-cresol.