Direct sequential C-H iodination/organoyl-thiolation of quinonoid deactivated systems: A new frontier for potent trypanocidal quinones

1 ,4-Naphthoquinones (1 ,4-NQs) are considered privileged structures implicated in important biological processes.1 Due of their biological importance, scientific endeavor has been devoted aiming at new synthetic methods for preparing 1 ,4-NQs with potential applicability against illness such as Chagas disease. 2 Recently, our research group have demonstrated the effectiveness of [RhCp*CI2]2 for the first catalytic directed orthofunctionalizations of simple (non-bias) 1 ,4-NQs by using different electrophilic iodine or bromine sources. 3 This methodology opened way for new modification on the benzenoid ring of 1 ,4-NQs as for example, copper catalyzed organoyl-thiolation reactions. Herein our strategy was based on the general and powerful method to install iodine at C-5 with high yield and regioselectivity and subsequently to combine AgSR salts with a copper source, achieving the thiolated adducts in only two steps via a direct sequential C-H iodination/organoyl-thiolation protocol. Sixteen new compounds were synthesised and tested against T. cruzi, showing remarkable activity (examples showed values almost 40 times more active than benznidazole. the standard drug). Eleven structures were solved by Xray crystallography and electrochemical studies were also performed. Exploratory reactions were conducted and the mechanism of the reaction was also proposed.