Diversinates™: Any-Stage Functionalization of (Hetero)aromatic Scaffolds

Figure 1.

Introduction

The synthesis of heteroaromatic and aromatic compounds is at the heart of the chemical industry. With the ever-growing demand of new chemical entities coupled to the dwindling resources and time constraints allotted to any given research project, a rapid way to diversify (hetero)aromatic scaffolds is needed. With operational simplicity (reactions that are not sensitive to air and moisture) in mind, a series of reagents that can append a variety of useful functionalities onto (hetero)aromatic cores was designed. Diversinates™ can functionalize heteroaromatic C–H bonds without the need for pre-functionalization, further saving time for the discovery chemist.

Advantages

Although metal-catalyzed cross-coupling chemistry is robust and undeniably useful, it relies on pre-functionalized (often halogenated) starting materials. Metal-catalyzed C–H activation is of recent research interest; and achieving the (fluoro)alkylation of heteroarene scaffolds in this manner is still a challenge. The Baran Diversinates™ can react with (hetero)arene cores that do not have apparent chemical handles—only heteroaromatic C–H bonds are needed. These powerful reagents take advantage of the innate reactivity of the substrate and react under practical reaction conditions (without the need to exclude air and moisture).

Representative Applications

Figure 2. Representative Applications

References

1. Fujiwara Y, Dixon JA, Rodriguez RA, Baxter RD, Dixon DD, Collins MR, Blackmond DG, Baran PS. 2012. A New Reagent for Direct Difluoromethylation. J. Am. Chem. Soc.. 134(3):1494-1497. https://doi.org/10.1021/ja211422g

2. Fujiwara Y, Dixon JA, O?Hara F, Funder ED, Dixon DD, Rodriguez RA, Baxter RD, Herlé B, Sach N, Collins MR, et al. 2012. Practical and innate carbon?hydrogen functionalization of heterocycles. Nature. 492(7427):95-99. https://doi.org/10.1038/nature11680

3. Zhou Q, Ruffoni A, Gianatassio R, Fujiwara Y, Sella E, Shabat D, Baran PS. 2013. Direct Synthesis of Fluorinated Heteroarylether Bioisosteres. Angew. Chem. Int. Ed.. 52(14):3949-3952. https://doi.org/10.1002/anie.201300763

4. Gui J, Zhou Q, Pan C, Yabe Y, Burns AC, Collins MR, Ornelas MA, Ishihara Y, Baran PS. 2014. C?H Methylation of Heteroarenes Inspired by Radical SAM Methyl Transferase. J. Am. Chem. Soc.. 136(13):4853-4856. https://doi.org/10.1021/ja5007838

5. Gianatassio R, Kawamura S, Eprile CL, Foo K, Ge J, Burns AC, Collins MR, Baran PS. 2014. Simple Sulfinate Synthesis Enables C?H Trifluoromethylcyclopropanation. Angew. Chem. Int. Ed.. 53(37):9851-9855. https://doi.org/10.1002/anie.201406622