Development of Two Synthetic Routes to 4-(N-Boc-N-methylaminomethyl)benzaldehyde: A Versatile Starting Material in Pharmaceutical Synthesis

Two novel synthetic routes to 4-(N-Boc-N-methylaminomethyl)benzaldehyde, an important pharmaceutical starting material, were developed using terephthaloyl chloride and terephthalaldehyde. In the first approach, terephthaloyl chloride was converted to an ester amide. The treatment of the ester amide with LiAlH₄ followed by protection of the resulting amine with tert-butoxycarbonyl anhydride yielded the corresponding benzyl alcohol. The benzyl alcohol was oxidized to the aldehyde completing the first-generation synthesis. The second approach utilized a one-step protocol mono-selective reductive amination of terephthalaldehyde with N-Boc-methylamine using chlorodimethylsilane. Both methods were scalable to 50 mmol and provided the desired aldehyde in a synthetically useful yield, demonstrating their practicality.