Atom‐Efficient Synthesis of Trimethine Cyanines Using Formaldehyde as a Single‐Carbon Source

Abstract Herein, we present an innovative and atom‐efficient synthesis of trimethine cyanines (Cy3) using formaldehyde (FA) as a single‐carbon reagent. The widespread application of Cy3 dyes in bioimaging and genomics/proteomics is often limited by synthetic routes plagued by low atom economy and substantial side‐product formation. Through systematic investigation, we have developed a practical and efficient synthetic pathway for both symmetrical and unsymmetrical Cy3 derivatives, significantly minimizing resource utilization. Notably, this approach yields water as the by‐product, in alignment with sustainable chemistry principles. Moreover, the efficient one‐pot synthesis facilitates the detection of intracellular FA levels, utilizing the fluorescence signal of Cy3 in live cells. It is also possible to detect endogenous FA in the intestinal tissues. We observed a significant decrease in FA in the small intestine of inflammatory bowel disease (IBD) mice as compared to healthy mice. This methodological advancement not only enhances the scope of fluorescent dye synthesis but also contributes to sustainable practices within chemical manufacturing, offering a significant leap forward in the development of environmentally friendly synthetic strategies.