Mechanochemical chlorination of acetamides via chemometric optimization

Statistics helps researchers and practitioners in chemistry and other fields understand the results of their experiments. In this context, Chemometrics is a consolidated area in the activities of chemists. Despite the importance and variety of its applications, the use of chemometric optimization in synthetic organic chemistry are still rare.1 Besides, the use of mechanochemistry is a new frontier of synthetic methodology.2 For inserting parameters of green chemistry as reactions in the absence of solvents, this leads to explore synthesis of compounds with wide significance as building blocks. Aromatic halogenated compounds have key applications as precursors for a variety of cross-coupling, including Suzuki, Heck and Ulmann couplings.3 Thus, we investigated the chlorination of aromatic acetamides using TCCA (trichloroisocyanuric acid) in a planetary mechanochemical equipment with agate reactor, applying the Doehlert Matrix, which is a planning widely used in methodological optimization. The factors studied were: Frequency (RPM) and Time (min.), since the previously applied two level Full factorial design showed that the number of balls is not significant. The response surface applied by the Doehlert Matrix Figure 1 showed that the critical factors were 446 RPM and 77 min. This condition was applied to other acetamides Scheme 1.4-6 The method will be applied to others acetamides.