Hydroboration is unique among the hydrometallation technologies for the versatility of available options for stereospecific conversion of C-B bonds into C-H, C-O, C-N, C-halogen, and C-C bonds. There has been intense recent interest in hydroboration because of the rapidly growing importance of the Suzuki and Heck coupling reactions of boronic acid derivatives. It is clear that these variations of organopalladium coupling technology will be centrally important in the discovery, development, and manufacture of the next generation of pharmaceutical agents, and in the synthesis of complex structures of academic interest. Improved methodology for regiocontrolled or stereocontrolled access to boranes and boronic acids is therefore one of the key challenges for organic synthesis. Boronic acids have advantages over many organometallics in that the reagents can usually be isolated if desired, activation for bond formation occurs under a variety of mild conditions, the intermediates are resistant to water and air, toxicity problems are minimal, and much is known about controlling the regiochemistry of hydroboration based on differences in degree of alkene substitution. However, available hydroboration methodology is not well developed for alkene (or alkyne) substrates where there is little, or no difference in degree of substitution at the unsaturated carbons. Such problems can be addressed by heteroatom substituent directing effects in the substrate, and that will be the focus of the research to be performed. A new concept for nitrogen-directed hydroboration has been demonstrated using electrophilic activation of stable amine borane complexes. The new method involves generation of reactive borenium ion pair intermediates that are capable of regiocontrolled and stereocontrolled hydroboration. The procedure will be used to prepare cyclic amine boranes and to exploit these intermediates for synthesis of a variety of derivatives using palladium catalysis. Methodology for palladium-free introduction of C-C, C-N, C-O and C-X bonds will also be studied. The procedure allows amine-directed internal functionalization of alkenes and alkynes with regio-and stereocontrol. A similar concept will be applied to oxygen-directed borenium hydroboration. Highly selective oxygen-directed hydroboration methodology has been demonstrated using the same principles. A major thrust of the program will be to investigate the stereochemistry of hydroborations directed by ether or alcohol oxygen.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Medicinal Chemistry Study Section (MCHA)
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Schwab, John M
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
United States
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Prokofjevs, Aleksandrs (2015) Thermal Dehydrogenation of Base-Stabilized B2H5(+) Complexes and Its Role in C-H Borylation. Angew Chem Int Ed Engl 54:13401-5
Miller, Daniel K (2013) Facile conversion of chromane-6-triflate to chromane-6-alanines under Palladium conditions. Tetrahedron Lett 54:811-813
Prokofjevs, Aleksandrs; Jermaks, Janis; Borovika, Alina et al. (2013) Electrophilic C-H Borylation and Related Reactions of B-H Boron Cations. Organometallics 32:
Prokofjevs, Aleksandrs; Kampf, Jeff W; Solovyev, Andrey et al. (2013) Weakly stabilized primary borenium cations and their dicationic dimers. J Am Chem Soc 135:15686-9
Cazorla, Clement; De Vries, Timothy S; Vedejs, Edwin (2013) P-directed borylation of phenols. Org Lett 15:984-7
Prokofjevs, Aleksandrs; Boussonniere, Anne; Li, Linfeng et al. (2012) Borenium ion catalyzed hydroboration of alkenes with N-heterocyclic carbene-boranes. J Am Chem Soc 134:12281-8
De Vries, Timothy S; Prokofjevs, Aleksandrs; Vedejs, Edwin (2012) Cationic tricoordinate boron intermediates: borenium chemistry from the organic perspective. Chem Rev 112:4246-82
De Vries, Timothy S; Majumder, Supriyo; Sandelin, Angela M et al. (2012) Mechanistic variations in ionic hydrogenation of unsaturated phosphine and amine boranes. Org Lett 14:688-91
Prokofjevs, Aleksandrs; Vedejs, Edwin (2011) N-Directed aliphatic C-H borylation using borenium cation equivalents. J Am Chem Soc 133:20056-9
Prokofjevs, Aleksandrs; Kampf, Jeff W; Vedejs, Edwin (2011) A boronium ion with exceptional electrophilicity. Angew Chem Int Ed Engl 50:2098-101

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