Classic vs. C–H functionalization strategies in the synthesis of APIs: a sustainability comparison

Abstract

The landscape of organic synthesis has changed in the last two decades, especially in areas such as pharmaceutical synthesis and large-scale industrial synthesis. The progress and development of synthetic methodologies together with increasing attention to environmental and safety problems, have led many researchers to study procedures that could be compatible with the sustainable development of industrial production. Until a few years ago, the production of APIs was substantially dominated by reliable and solid chemistry but which nevertheless attracted some criticism from the point of view of the length of the synthetic procedures in terms of steps, and therefore in terms of waste production. In recent years, however, we have been witnessing the adoption, even by large industrial groups, of step-economical methodologies based on direct C–H functionalization reactions which, compared to reactions such as cross-coupling or aromatic nucleophilic substitutions, promise better sustainaibility as they do not require pre-functionalized substrates, and therefore offer the intriguing possibility of reducing the number of steps to attain the target. This review presents exemplary case studies analyzed holistically on the basis of waste production (E-factor) and on the basis of environmental and safety hazard scores (ES and SHS scores) with the aim of quantifying whether the adoption of direct C–H functionalization technology is actually always the most effective strategy compared to classic approaches. It will, therefore, ultimately give the reader a quantitative evaluation of how promising in terms of sustainability the current direction of chemical production actually is compared to previous methodologies.