The Suzuki-Miyaura coupling reaction is widely recognized as one of the most powerful and broadly utilized synthetic methods developed over the past thirty years. Thousands of papers employing the reaction have been published during that time, and many of these have been devoted to improvements on the original procedure. Among the latter contributions, the vast majority of these studies have dealt with improving the transformation by optimizing important characteristics of the reaction such as the catalyst/ligand complex, the electrophile (aryl, heteroaryl, alkenyl, alkynyl, alkyl), the nucleofuge (chlorides, sulfonates, phosphates), the solvent (e.g., water, ionic liquids), the bases required, and the conditions of the reaction (e.g., by using sonication or microwaves). Curiously, little effort has been expended to expand the scope of the reaction by altering the essential organoboron reagent, which is clearly a key ingredient. To provide more versatile, easily functionalized organoborons that would create more structurally diverse reagents for cross-coupling, we initiated a program on the development of organotrifluoroborates, which have the potential to transform the implementation of Suzuki coupling in a very powerful way.
The aim of the currently proposed research is to build on this foundation in a demonstration of the breadth of complementarity and, in some cases, orthogonal reactivity between organotrifluoroborates and boronic acids and their derivatives. In the current investigations we will build and couple novel and unique organoboron reagents (e.g., 2-homoenolates, oxiranyltrifluoroborates, aziridinyltrifluoroborates, and acyltrifluoroborates). We will continue to take advantage of the ability to operate on other functional groups within the organoboron reagent itself as a means to build molecular complexity into the organotrifluoroborates while retaining the valuable carbon-boron bond for further transformations (i.e., using the trifluoroborate as a protected boronic acid). We will also examine challenging, paradigm-changing strategies for C-C bond formation (reactions of chiral secondary alkyltrifluroborate, synthesis of dibora compounds and bidirectional synthesis) as well as novel reactivity patterns (intramolecular reactions with activated electrophiles).

Public Health Relevance

Success in the efforts proposed will provide enabling technologies for new drug discovery, and will also result in the development of robust synthetic transformations for the synthesis of complex target structures required for pharmaceutical process research and development, pilot plant technologies, and drug manufacturing. In this way, new drug entities can be delivered to the public more rapidly and efficiently at lower cost.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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University of Pennsylvania
Schools of Arts and Sciences
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Presset, Marc; Fleury-Brégeot, Nicolas; Oehlrich, Daniel et al. (2013) Synthesis and minisci reactions of organotrifluoroborato building blocks. J Org Chem 78:4615-9
Molander, Gary A; Traister, Kaitlin M; Barcellos, Thiago (2013) Palladium-catalyzed ?-arylation of 2-chloroacetates and 2-chloroacetamides. J Org Chem 78:4123-31
Tschaen, Brittany A; Schmink, Jason R; Molander, Gary A (2013) Pd-catalyzed aldehyde to ester conversion: a hydrogen transfer approach. Org Lett 15:500-3
Molander, Gary A; Cavalcanti, Livia N (2013) Synthesis of trifluoromethylated isoxazolidines: 1,3-dipolar cycloaddition of nitrosoarenes, (trifluoromethyl)diazomethane, and alkenes. Org Lett 15:3166-9
Presset, Marc; Oehlrich, Daniel; Rombouts, Frederik et al. (2013) Complementary regioselectivity in Rh(III)-catalyzed insertions of potassium vinyltrifluoroborate via C-H activation: preparation and use of 4-trifluoroboratotetrahydroisoquinolones. Org Lett 15:1528-31
Molander, Gary A; Barcellos, Thiago; Traister, Kaitlin M (2013) Pd-catalyzed cross-coupling of potassium alkenyltrifluoroborates with 2-chloroacetates and 2-chloroacetamides. Org Lett 15:3342-5
Argintaru, O Andreea; Ryu, DaWeon; Aron, Ioana et al. (2013) Synthesis and applications of ?-trifluoromethylated alkylboron compounds. Angew Chem Int Ed Engl 52:13656-60
Molander, Gary A; Traister, Kaitlin M (2013) Pd-catalyzed alkynylation of 2-chloroacetates and 2-chloroacetamides with potassium alkynyltrifluoroborates. Org Lett 15:5052-5
Colombel, Virginie; Presset, Marc; Oehlrich, Daniel et al. (2012) Synthesis and reactivity of solid-supported organotrifluoroborates in Suzuki cross-coupling. Org Lett 14:1680-3
Devulapally, Rammohan; Fleury-Bregeot, Nicolas; Molander, Gary A et al. (2012) Synthesis and cross-coupling reactions of imidomethyltrifluoroborates with aryl chlorides. Tetrahedron Lett 53:1051-1055

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