Arenes and heteroarenes form the basis of living organisms and, as a consequence, are ubiquitous in pharmaceuticals and other biologically active compounds. Although there has been sustained interest in (hetero)arene functionalization, ever-growing time and cost constraints of discovery chemistry still demand the development of rapid, efficient and operationally trivial procedures. As this presents an immense task, this proposal will focus on the appendage of fluoroalkyl and alkyl groups onto (hetero)arenes (i.e., C-H to C-C transformations). Many methods are currently available for (hetero)arene functionalization, each of them presenting advantages and disadvantages. Although """"""""programmed"""""""" C-C bond formations such as halogen-metal exchange/electrophilic trap, nucleophilic aromatic substitution and cross-coupling methodology are vital in all aspects of chemistry, these methods require the use of pre-functionalized (typically halogenated) (hetero)arenes, thus adding extra steps to the synthesis. In this regard, one-step methods are more attractive, however, hydrogen-metal exchange/electrophilic trap, electrophilic aromatic substitution and C-H activation methodology all present drawbacks as well, such as the use of highly acidic/basic reagents, cryogenic conditions, or expensive transition metal catalysts. These drawbacks can be potentially overcome by using a radical-based functionalization strategy: recent results have shown that zinc bis(difluoromethanesulfinate) can generate difluoromethyl radicals, which can add to a variety of heterocycles at room temperature under open air. Building upon these results, this proposal aims to generate a series of user-friendly, shelf-stable zinc bis(alkanesulfinate) reagents. These reagents will be made widely accessible and their reactions will be optimized from the vantage point of operational simplicity. This proposal is organized into three parts: 1) the first section details the synthesis of zinc bis(fluoroalkanesulfinate) reagents for direct (hetero)arene fluoroalkylation;2) the second part outlines the development of zinc bis(alkanesulfinate) reagents for (hetero)arene alkylation, as well as the bis- functionalization of hetero(arene)s using a sequential addition strategy;and 3) the final section describes kinetic analysis to guide the optimization process and to elucidate solvent effects on regioselectivity. While these three objectives will be investigated in parallel, they will all contribute in establishing reactivity trends of zinc bis(alkanesulfinate) reagents. Generating an armamentarium of these stable reagents and user- friendly procedures would accelerate discovery in medicinal chemistry, food chemistry, agrochemistry, and other chemical and scientific disciplines.
Arenes and heteroarenes constitute the core skeleton of biologically active compounds in almost every conceivable therapeutic area. This proposal aims to develop a widely accessible toolbox of shelf- stable zinc bis(alkanesulfinate) reagents for the rapid and operationally simple fluoroalkylation and alkylation of (hetero)arenes. This radical-based technology will benefit discovery chemists in both academic and industrial settings in medicinal chemistry and beyond.
|Qin, Tian; Cornella, Josep; Li, Chao et al. (2016) A general alkyl-alkyl cross-coupling enabled by redox-active esters and alkylzinc reagents. Science 352:801-5|
|Gianatassio, Ryan; Lopchuk, Justin M; Wang, Jie et al. (2016) Organic chemistry. Strain-release amination. Science 351:241-6|
|O'Brien, Alexander G; Luca, Oana R; Baran, Phil S et al. (2016) In Situ FTIR Spectroscopic Monitoring of Electrochemically Controlled Organic Reactions in a Recycle Reactor. React Chem Eng 1:90-95|
|Michaudel, Quentin; Ishihara, Yoshihiro; Baran, Phil S (2015) Academia-industry symbiosis in organic chemistry. Acc Chem Res 48:712-21|
|Baxter, Ryan D; Liang, Yong; Hong, Xin et al. (2015) Mechanistic Insights into Two-Phase Radical C-H Arylations. ACS Cent Sci 1:456-462|
|Foo, Klement; Sella, Eran; ThomÃ©, Isabelle et al. (2014) A mild, ferrocene-catalyzed C-H imidation of (hetero)arenes. J Am Chem Soc 136:5279-82|
|Gianatassio, Ryan; Kawamura, Shuhei; Eprile, Cecil L et al. (2014) Simple sulfinate synthesis enables C-H trifluoromethylcyclopropanation. Angew Chem Int Ed Engl 53:9851-5|
|Gui, Jinghan; Zhou, Qianghui; Pan, Chung-Mao et al. (2014) C-H methylation of heteroarenes inspired by radical SAM methyl transferase. J Am Chem Soc 136:4853-6|
|O'Hara, Fionn; Burns, Aaron C; Collins, Michael R et al. (2014) A simple litmus test for aldehyde oxidase metabolism of heteroarenes. J Med Chem 57:1616-20|
|O'Brien, Alexander G; Maruyama, Akinobu; Inokuma, Yasuhide et al. (2014) Radical C-H functionalization of heteroarenes under electrochemical control. Angew Chem Int Ed Engl 53:11868-71|
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