The direct functionalization of arene C-H bonds can be a powerful way of constructing biaryl motifs found in a variety of medicinally relevant molecules. Despite the potential utility of direct C-H arylation, control of regioselectivity remais a difficulty that limits its synthetic utility. One approach to address this issue is the use of an ortho directing group. Although many such directing groups are currently known, most are synthetically inflexible or require added protection/deprotection steps for their use. Due to the versatility of the amino group, an ortho-arylation using this functional group would be synthetically valuable, allowing access to diverse ortho-substituted biaryl derivatives. However, use of the amino group for ortho direction is challenging, the first example of which having been reported only very recently. The current proposal provides an approach to ortho-arylation of anilines and heteroarylamines utilizing continuous flow technology. Specifically, through the use of carbon dioxide as an abundant and inexpensive reagent, the amino group of an arylamine will be converted to the carbamate salt, which can serve as an in situ protecting and directing group for ortho-arylation. The use of continuous flow methods for this approach is uniquely advantageous, since 1) the thermally labile carbamate salts can be produced and immediately consumed, and 2) high carbon dioxide pressure can be conveniently and safely accessed, a condition necessary to prevent decarboxylation of the carbamate intermediates at the high temperatures required for C-H arylation. Taken together, these two features of continuous flow synthesis allow for an expedient ortho-arylation of anilines that eliminates the need for separate protection/deprotection steps. This advance could lead to more cost-effective syntheses of biaryl scaffolds that are ubiquitous in pharmaceutical agents.
This proposal describes a research plan in the synthesis of a class of organic molecules using reagents flowing in tubes (continuous flow process), rather than mixed in a reaction flask (batch process). The use of this technique will allow a class of molecules that serve as important intermediates to pharmaceutical products and biologically active molecules to be synthesized more efficiently using fewer steps, potentially leading to the less costly manufacture of a variety of current and future drugs.
| Reizman, Brandon J; Wang, Yi-Ming; Buchwald, Stephen L et al. (2016) Suzuki-Miyaura cross-coupling optimization enabled by automated feedback. React Chem Eng 1:658-666 |
| Wang, Yi-Ming; Buchwald, Stephen L (2016) Enantioselective CuH-Catalyzed Hydroallylation of Vinylarenes. J Am Chem Soc 138:5024-7 |
| Pirnot, Michael T; Wang, Yi-Ming; Buchwald, Stephen L (2016) Copper Hydride Catalyzed Hydroamination of Alkenes and Alkynes. Angew Chem Int Ed Engl 55:48-57 |
| Wang, Yi-Ming; Bruno, Nicholas C; Placeres, Ángel L et al. (2015) Enantioselective Synthesis of Carbo- and Heterocycles through a CuH-Catalyzed Hydroalkylation Approach. J Am Chem Soc 137:10524-7 |
