Ketosulfoxonium Ylides

Introduction to Ketosulfoxonium Ylide Chemistry

Since Corey and Chaykovsky first investigated ketosulfoxonium ylides in the 1960s,¹ these reagents have become increasingly popular as stable and safe α-diazocarbonyl equivalents, including for large scale reactions.^2-4 Baldwin initially reported on the transition metal-catalyzed reaction of ketosulfoxonium ylides as carbene equivalents for insertions into heteroatom bonds.⁵ Merck and Co. further advanced this approach,⁶ including for manufacturing processes,^3,4 which resulted in an increased interest in these reagents. In 2017, the labs of Li⁷ and Aïssa⁸ first applied ketosulfoxonium ylides to transition metal-catalyzed C-H functionalization, eliciting a rapid upsurge in the number of applications to give diverse products.⁹ For example, these reagents have been applied to efficient functional group compatible annulations to access privileged [5,6]-bicyclic heterocycles with ring-junction nitrogens, including azolopyridines¹⁰ and azolopyrimidines.^11,12

The first ten ketosulfoxonium ylides below allow researchers to carry out an initial assessment of the scope and limitations of these reagents for new reaction development and potential drug discovery applications.

Advantages of Ketosulfoxonium Ylides

Ketosulfoxonium ylides are readily prepared in one step from the corresponding carboxylic acids and their derivatives. These reagents are well-behaved and are typically crystalline solids. They serve as versatile and convenient carbene equivalents that release dimethyl sulfoxide as a byproduct. In contrast, while the corresponding α-diazocarbonyl compounds are certainly very useful reagents, the high energy release of nitrogen gas can cause safety issues.

Representative Metal-Catalyzed Reaction Products

Special thanks to Andrew Streit, Gia Hoang and Jonathan Ellman for contributing this Technology Spotlight!

References

1. Corey EJ, Chaykovsky M. 1964. Formation and Photochemical Rearrangement of ??-Ketosulfoxonium Ylides. J. Am. Chem. Soc.. 86(8):1640-1641. https://doi.org/10.1021/ja01062a040

2. Wang D, Schwinden MD, Radesca L, Patel B, Kronenthal D, Huang M, Nugent WA. 2004. One-Carbon Chain Extension of Esters to ?-Chloroketones:  A Safer Route without Diazomethane. J. Org. Chem.. 69(5):1629-1633. https://doi.org/10.1021/jo035733r

3. Molinaro C, Bulger PG, Lee EE, Kosjek B, Lau S, Gauvreau D, Howard ME, Wallace DJ, O?Shea PD. 2012. CRTH2 Antagonist MK-7246: A Synthetic Evolution from Discovery through Development. J. Org. Chem.. 77(5):2299-2309. https://doi.org/10.1021/jo202620r

4. Mangion IK, Ruck RT, Rivera N, Huffman MA, Shevlin M. 2011. A Concise Synthesis of a ?-Lactamase Inhibitor. Org. Lett.. 13(20):5480-5483. https://doi.org/10.1021/ol202195n

5. Baldwin JE, Adlington RM, Godfrey CRA, Gollins DW, Vaughan JG. A novel entry to carbenoid species via?-ketosulfoxonium ylides. J. Chem. Soc., Chem. Commun..(18):1434-1435. https://doi.org/10.1039/c39930001434

6. Mangion IK, Nwamba IK, Shevlin M, Huffman MA. 2009. Iridium-Catalyzed X?H Insertions of Sulfoxonium Ylides. Org. Lett.. 11(16):3566-3569. https://doi.org/10.1021/ol901298p

7. Xu Y, Zhou X, Zheng G, Li X. 2017. Sulfoxonium Ylides as a Carbene Precursor in Rh(III)-Catalyzed C?H Acylmethylation of Arenes. Org. Lett.. 19(19):5256-5259. https://doi.org/10.1021/acs.orglett.7b02531

8. Barday M, Janot C, Halcovitch NR, Muir J, Aïssa C. 2017. Cross-Coupling of ?-Carbonyl Sulfoxonium Ylides with C?H Bonds. Angew. Chem. Int. Ed.. 56(42):13117-13121. https://doi.org/10.1002/anie.201706804

9. Cheng J, Wu X, Sun S, Yu J. 2019. Recent Applications of ?-Carbonyl Sulfoxonium Ylides in Rhodium- and Iridium-Catalyzed C?H Functionalizations. Synlett. 30(01):21-29. https://doi.org/10.1055/s-0037-1610263

10. Hoang GL, Ellman JA. 2018. Rhodium(III)-catalyzed C?H functionalization of C-alkenyl azoles with sulfoxonium ylides for the synthesis of bridgehead N-fused [5,6]-bicyclic heterocycles. Tetrahedron. 74(26):3318-3324. https://doi.org/10.1016/j.tet.2018.03.062

11. Halskov KS, Witten MR, Hoang GL, Mercado BQ, Ellman JA. 2018. Rhodium(III)-Catalyzed Imidoyl C?H Activation for Annulations to Azolopyrimidines. Org. Lett.. 20(8):2464-2467. https://doi.org/10.1021/acs.orglett.8b00816

12. Hoang GL, Streit AD, Ellman JA. 2018. Three-Component Coupling of Aldehydes, Aminopyrazoles, and Sulfoxonium Ylides via Rhodium(III)-Catalyzed Imidoyl C?H Activation: Synthesis of Pyrazolo[1,5-a]pyrimidines. J. Org. Chem.. 83(24):15347-15360. https://doi.org/10.1021/acs.joc.8b02606