The Downey Group at the University of Richmond studies the ability of trimethylsilyl trifluoromethanesulfonate (TMSOTf) to mediate new reactivity or increase the efficiency of known reactions. The most likely downstream application of this new chemistry is in the fields of pharmaceuticals, pesticides, and herbicides. For example, the processes that we discover might be used to synthesize previously inaccessible drug candidates or streamline the production of known biologically active compounds so that drug prices can lowered or environmental waste minimized.
The ability of TMSOTf to act as both a Lewis acid and a silylating agent makes it a powerful choice in new reaction development. Because it can play two or more roles in a reaction, it can be used to develop so-called “one-pot” reactions, where two or more reactions take place in a single reaction flask without the need for purification of any intermediate compounds. This process greatly increases the efficiency of a synthetic route by shortening the time required and reducing the waste that would be generated in purification processes. Furthermore, the reaction products are often isolated as protected O-silylated products, which are useful for further synthetic steps.
FUNDING
Our work is currently funded by generous contributions from the Camille & Henry Dreyfus Foundation and the University of Richmond. Previous sources of funding include the National Science Foundation, The American Chemical Society-Petroleum Research Fund, Research Corporation, Organic Syntheses, Inc., and the Thomas F. and Kate Miller Jeffress Trust.
PUBLICATIONS
University of Richmond undergraduate coauthors are denoted with an asterisk (*).
23. Tyler G. Chong,* Alex V. Helbling,* Remi D. Graff,* C. Wade Downey. One-pot silyl imidate formation-N-alkylation reactions of amides with propargyl propionates. Tetrahedron Letters 2023, 128, Article 154718. link
22. Elizabeth D. Heafner,* Xuechun Lin,* Alexa H. Connors,* Hanyu Zhong,* R. Joseph Coyle,* Yiqi Liu,* C. Wade Downey. One-pot enol silane formation-allylation of ketones promoted by trimethylsilyl trifluoromethanesulfonate. Synthesis 2023, 55, 2377-2389. link
21. Grant J. Dixon,* Michael R. Rodriguez,* Tyler G. Chong,* Kevin Y. Kim,* C. Wade Downey. Synthesis of beta,beta-Disubstituted Styrenes via Trimethylsilyl Trifluoromethanesulfonate-Promoted Aldehyde-Aldehyde Aldol Addition-Deformylative Elimination. The Journal of Organic Chemistry 2022, 87, 14846-14854. link
20. Zachary Z. Oracheff,* Helen L. Xia,* Christopher D. Poff,* Scott E. Isaacson,* C. Wade Downey. Friedel–Crafts addition of indoles to nitrones promoted by trimethylsilyl trifluoromethanesulfonate. The Journal of Organic Chemistry 2021, 86, 17328-17336. link
19. Danielle E. Sklar,* Alex V. Helbling,* Yiqi Liu,* C. Wade Downey. One-Pot Synthesis of 2-Methylfurans from 3-(Trimethylsilyl)propargyl Acetates Promoted by Trimethylsilyl Trifluoromethanesulfonate. Tetrahedron Letters 2021, 87, Article 153424. link
18. C. Wade Downey, Grace Ann L. Robertson,* Jhonmattew Santa,* Kari. R. Flicker,* William M. Stith.* One-pot silyl ketene imine formation-nucleophilic addition reactions of acetonitrile with acetals and nitrones. Tetrahedron Letters 2020, 61, Article 151537. link
17. C. Wade Downey, Grant J. Dixon,* Jared A. Ingersoll,* Claire N. Fuller,* Kenneth W. MacCormac,* Anna Takashima,* Rohina Sediqui.* One-pot enol silane formation-Mukaiyama aldol reactions: crossed aldehyde-aldehyde coupling, thioester substrates, and reactions in ester solvents. Tetrahedron Letters 2019, 60, Article 151192. link
16. C. Wade Downey, Danielle N. Confair,* Yiqi Liu,* Elizabeth D. Heafner.* One-Pot Enol Silane Formation-Alkylation of Ketones with Propargyl Carboxylates Promoted by Trimethylsilyl Trifluoromethanesulfonate. The Journal of Organic Chemistry 2018, 83, 12931-12938. link
15. C. Wade Downey, Hadleigh M. Glist,* Anna Takashima,* Samuel R. Bottum,* Grant J. Dixon.* Chalcone and cinnamate synthesis via one-pot enol silane formation-Mukaiyama aldol reactions of ketones and acetate esters. Tetrahedron Letters 2018, 59, 3080-3083. link
14. C. Wade Downey, Alice Y.-K. Lee,* John R. Goodin,* Courtney J. Botelho,* William M. Stith.* Mukaiyama addition of (trimethylsilyl)acetonitrile to dimethyl acetals mediated by trimethylsilyl trifluoromethanesulfonate. Tetrahedron Letters 2017, 58, 3496-3499. link
13. C. Wade Downey, Jared A. Ingersoll,* Hadleigh M. Glist,* Carolyn M. Dombrowski,* Adam T. Barnett.* One-pot silyl ketene acetal-formation-Mukaiyama–Mannich additions to imines mediated by trimethylsilyl trifluoromethanesulfonate. European Journal of Organic Chemistry 2015, 7287-7291. link
12. C. Wade Downey, Christopher D. Poff,* Alissa N. Nizinski.* Friedel−Crafts Hydroxyalkylation of Indoles Mediatedby Trimethylsilyl Trifluoromethanesulfonate. The Journal of Organic Chemistry 2015, 80, 10364-10369. link
11. C. Wade Downey, Sarah E. Covington,* Derek C. Obenschain,* Evan Halliday,* James T. Rague,* Danielle N. Confair.* Silyl trifluoromethanesulfonate-activated para-methoxybenzyl methyl ether as an alkylating agent for thiols and aryl ketones. Tetrahedron Letters 2014, 55, 5213-5215. link
10. C. Wade Downey, Erin N. Maxwell,* Danielle N. Confair* Silyl Triflate-Accelerated Additions of Catalytically Generated Zinc Acetylides to N-Phenyl Nitrones. Tetrahedron Letters 2014, 55, 4959-4961. link
9. C. Wade Downey, Carolyn M. Dombrowski,* Erin N. Maxwell,* Chelsea L. Safran,* Odamea A. Akomah.* One-Pot Enol Silane Formation-Mukaiyama–Mannich Addition of Ketones, Amides, and Thioesters to Nitrones in the Presence of Trialkylsilyl Trifluoromethanesulfonates. European Journal of Organic Chemistry 2013, 5716-5720. link
8. Lutz F. Tietze, Holger Geissler, C. Wade Downey. “Diethyl Ethoxymethylenemalonate” In Encyclopedia of Reagents in Organic Synthesis [Online] 2013, Tomislav Rovis, Ed.; Wiley & Sons: New York.
7. C. Wade Downey, Smaranda Craciun,* Christina A. Vivelo,* Ana M. Neferu,* Carly J. Mueller,* Stephanie Corsi.* One-Pot Three-Step Thioconjugate Addition-Oxidation-Diels–Alder Reactions of Ethyl Propiolate. Tetrahedron Letters 2012, 53, 5766-5768. link
6. C. Wade Downey, Smaranda Craciun,* Ana M. Neferu,* Christina A. Vivelo,* Carly J. Mueller,* Brian C. Southall,* Stephanie Corsi,* Eric W. Etchill,* Ryan J. Sault.* One-Pot Synthesis of (Z)--Sulfonyl Enoates from Ethyl Propiolate. Tetrahedron Letters 2012, 53, 5763-5765. link
5. C. Wade Downey, Alan S. Fleisher,* James T. Rague,* Chelsea L. Safran,* Megan E. Venable,* Robert D. Pike. Synthesis of N-Acyl-N,O-Acetals from N-Aryl Amides and Acetals in the Presence of TMSOTf. Tetrahedron Letters 2011, 52, 4756-4759. link
4. C. Wade Downey, Miles W. Johnson,* Daniel H. Lawrence,* Alan S. Fleisher,* Kathryn J. Tracy.* Acetic Acid Aldol Reactions in the Presence of Trimethylsilyl Trifluoromethanesulfonate. The Journal of Organic Chemistry 2010, 75, 5351-5354. link
3. C. Wade Downey, Brian D. Mahoney,* Vincent R. Lipari.* Trimethylsilyl Trifluoromethanesulfonate-Accelerated Addition of Catalytically Generated Zinc Acetylides to Aldehydes. The Journal of Organic Chemistry 2009, 74, 2904-2906. link
2. C. Wade Downey, Miles W. Johnson,* Kathryn J. Tracy.* One-Pot Enol Silane Formation-Mukaiyama Aldol-Type Addition to Dimethyl Acetals Mediated by TMSOTf. The Journal of Organic Chemistry 2008, 73, 3299-3302. link
1. C. Wade Downey, Miles W. Johnson.* A Tandem Enol Silane Formation-Mukaiyama Aldol Reaction Mediated by TMSOTf. Tetrahedron Letters 2007, 48, 3559-3562. link