Question

Sotalol is a \(\beta\)-adrenergic blocker used to treat certain types of cardiac arrhythmias. Its hydrochloride salt is marketed under several trade names, including Betapace. Following is a retrosynthetic analysis. (a) Propose a synthesis for sotalol from aniline. (b) Is sotalol chiral? If so, which of the possible stereoisomers are formed in this synthesis?

Short answer

Short Answer: Sotalol is synthesized from aniline in three main steps: (1) protection of the NH2 group using Boc2O, (2) a nucleophilic aromatic substitution reaction with tert-butyl methyl sulfoxide, and (3) deprotection by removing the Boc protecting group using trifluoroacetic acid. Sotalol is not chiral, as it does not contain chiral carbon atoms. Therefore, there are no stereoisomers formed during its synthesis, and only one isomer of sotalol will be obtained.

Step-by-step solution

Identify the main structure and functional groups in sotalol

Sotalol has the following structure: C12H20N2O3S. The main functional groups present in sotalol are: - A secondary amine: -NH-CH3 - An aromatic ring (phenyl group) which is connected to the nitrogen atom of the secondary amine - A sulfur atom single-bonded to a oxygen atom (sulfoxide group) - An isopropyl group attached to the sulfoxide group's sulfur atom - A tert-butyl group connected to the oxygen atom of the sulfoxide group

Propose a step-by-step synthesis of sotalol from aniline

Starting from aniline, we will carry out the following steps: 1. Protect the NH2 group in aniline using the Boc protecting group by reacting aniline with di-tert-butyl dicarbonate (Boc2O). This will form N-Boc-aniline. 2. Perform a nucleophilic aromatic substitution with the N-Boc-aniline by reacting with tert-butyl methyl sulfoxide in the presence of a strong base. This will cause the formation of the C-N bond between the phenyl group of N-Boc-aniline and nitrogen atom of tert-butyl methyl sulfoxide. This will yield the intermediate compound N-Boc-sotalol. 3. Deprotect N-Boc-sotalol to remove the Boc protecting group. This can be done by treating N-Boc-sotalol with trifluoroacetic acid. The amine group is released, forming the final compound, sotalol.

Determine the chirality of sotalol

To determine if sotalol is chiral, we need to check if it has a carbon atom that is connected to four different substituents. The sulfur atom in sotalol is bonded to four different groups: two directly (oxygen and isopropyl) and two others through the oxygen atom (tert-butyl and phenyl). However, chirality is defined by the presence of chiral carbon atoms. Sotalol does not contain any chiral carbon atoms. Therefore, sotalol is not chiral.

Identify the possible stereoisomers formed in the synthesis

Since sotalol is not chiral, there will be no stereoisomers formed during the synthesis. Therefore, only one isomer of sotalol will be obtained.