Synthesis of 2H-indazoles via the Cadogan Reaction in Batch and Flow Mode

Voiceover

Presenter(s)

Matilda Duffy

Abstract or Description

2H-indazoles, common building blocks in many modern anti-cancer drugs, are synthesized primarily via the thermal Cadogan reaction. This reaction, when carried out in batch requires high temperatures, long reaction times, and excess amounts of hazardous reagents. The uniformity and unique reaction environment provided by the system of peristaltic pumps and coils of thin tubing employed in continuous flow protocol provided optimal conditions for the Cadogan reaction to be carried out. Most notably, reaction times were reduced from days to hours, and the reaction itself was carried out under more mild temperatures. The success of the reaction in flow can be attributed to the contained reaction environment in combination with a back-pressure regulator which mitigated loss of the phosphite reagent due to boiling. Triethyl phosphite proved to be the most successful deoxygenation reagent in flow, providing high chemical yield. The flow process was successfully scaled on a 20 mmol scale and generated 4.8 g of the desired 2H-indazole product; seven other 2H-indazole analogs were also synthesized. Using a Vapourtec UV-150 flow photoreactor with a high-powered LED at 365 nm, the 2H-indazole scaffold underwent photochemical and regiospecific acetylation via a hydrogen atom transfer. This additional functionalization reinforces the medicinal potential of the 2H-indazoles and thus the importance of synthesizing these compounds in a more effective manner.

Mentor

Marcus Baumann