Organotrifluoroborate Salts: Versatile Reagents in Organic Synthesis Frontiers in Chemistry: May 17, 2008 David Arnold http://periodictable.com/Elements/005/index.html David Arnold @ Wipf Group Page 1 of 35 5/18/2008 Exponential Growth in the Number of Publications Dedicated to Potassium Organotrifluoroborates Over the Last 10 Years - F K+ R = alkyl, alkenyl, alkynyl, R B F allyl, crotonyl, aryl F Chem. Rev. 2008, 108, 288 David Arnold @ Wipf Group Page 2 of 35 5/18/2008 Outline • A Brief History on the Preparation of Organotrifluoroborate Salts • General Preparation of Organotrifluoroborate Salts • Functionalization of Potassium Organotrifluoroborates • Selected Reactions of Potassium Organotrifluoroborates • Applications to Natural Product Synthesis • Conclusions David Arnold @ Wipf Group Page 3 of 35 5/18/2008 A Brief History on the Preparation of Organotrifluoroborate Salts • Laboratory curiosities in the 1960: Preparation of the first organotrifluoroborate salt and the first stable compound containing a trifluoromethyl-boron linkage: h! BF3 gas KF Me3Sn SnMe3 + CF3I Me3SnCF3 Me3Sn(CF3BF3) CF3BF3K CCl4 H2O J. Am. Chem. Soc. 1960, 82, 5298. • Preparation from dihaloorganoboranes: BBr2 KF (3 eq.) BF3K H2O, 89% J. Organomet. Chem. 1988, 340, 267. • A breakthrough in the preparation of organotrifluoroborate salts lies dormant: Thierig and Umland 1967 Ph O KHF2 B PhBF K Ph 3 N AcOH, ! H2 Naturwissenschaften 1967, 54, 563. David Arnold @ Wipf Group Page 4 of 35 5/18/2008 Revisiting the Past, Vedejs 1995: The Revolution Begins • Convenient preparation of aryltrifluoroborate salts from boronic acids and in situ conversion to arylboron difluoride Lewis acids Excess KHF2 (aq) Me3SiCl PhB(OH)2 PhBF3K PhBF2 MeOH, rt, 15 min THF 82% in situ BF K BF K 3 BF3K 3 BF3K F O F Cl Cl BF3K F3C CF3 94% 68% 53% 76% 48% • All salts were found to be air and moisture stable crystalline solids which could be synthesized on a multigram scale and purified by simple recrystallization from acetonitrile or actone/diethyl ether. • Currently there are 90 commercially available potassium organotrifluoro- borates and over 2000 commercially available organoboronic acids. J. Org. Chem. 1995, 60, 3020. David Arnold @ Wipf Group Page 5 of 35 5/18/2008 General Preparation of Organotrifluoroborate Salts: Lithium and Magnesium Reagents • Grignard reagents: • Lithium/halogen exchange: o i. RLi (aq) KHF2 i. B(OR')3, -78 C Ar-Br Ar-B(OH)2 Ar-BF3K R-MgX R-BF K 3 ii. B(OR')3 ii. KHF2, H2O + iii. H3O R = alkyl, aryl, vinyl, allyl, alkynyl BF3K BF3K BF3K F F • Notably, potassium vinyltrifluoroborate CHO is stable at room temperature. CF3 OBn 91% 82% 78% • Ortho-lithiation: • Deprotonation of alk-1-ynes: (aq) KHF i. RLi 2 i. n-BuLi Ar-H Ar-B(OH)2 Ar-BF3K R H R BF3K ii. B(OR')3 + ii. B(OMe)3 iii. H3O iii. (aq) KHF2 F BF3K TBDMSO F F Cl BF K 3 BF3K O BF3K 80% 66% F N F 76% 70% • First air and moisture stable compounds containing an sp-B bond. Chem. Rev. 2008, 108, 288. David Arnold @ Wipf Group Page 6 of 35 5/18/2008 General Preparation of Organotrifluoroborate Salts: Hydroboration of Alkenes and Alkynes i. HBR'''2 R R' R'' R Or R' R'' Or ii. KHF (aq) 2 BF3K BF3K Tetrahedron 2007, 63, 3623. David Arnold @ Wipf Group Page 7 of 35 5/18/2008 General Preparation of Organotrifluoroborate Salts: Zr-Catalyzed Hydroboration of Alkynes O 5 mol% Cp2ZrHCl O R + H B H B O O CH2Cl2, rt, 16h R R = -(CH2)3Cl, -SiMe3, -cyclopentyl, -CH2OMe, -Ph Yields: 75-94%, (E)-selectivities: 90-98% O Cp2ZrHCl H B O R R R O H B O H ZrCp2Cl •Organometallics 1995, 14, 3127. David Arnold @ Wipf Group Page 8 of 35 5/18/2008 General Preparation of Organotrifluoroborate Salts: Rh- Catalyzed trans-Hydroboration of Alkynes H i i. [Rh(cod)Cl]2-4P Pr3 B O O Et3N, cyclohexne rt, 1-4 h R + R Bpin ii. pinacol R = -(CH2)7CH3, -(CH2)3OTBDMS, -TMS, -Ph Yields: 60-79%, (Z)-selectivities: 98-99% cis-hydroboration Mechanism D R D H Rh B Rh+ Rh R Et3N D D Rh H B R R B O O D H H D Rh R Rh B B R • J. Am. Chem. Soc. 2000, 122, 4990. David Arnold @ Wipf Group Page 9 of 35 5/18/2008 General Preparation of Organotrifluoroborate Salts: C-H Activation, Borylation of Arenes and Alkanes • Iridium-catalyzed borylation of arenes: i. 0.1 mol % [Ir(COD)(OMe)]2/dtbpy O O THF, 80 oC B B + Ar-H Ar BF3K O O ii. KHF2 THF/H2O BF K BF3K BF3K BF3K 3 BF3K O Br Br MeO Cl Me CO2Me 61% 97% 94% 75% 78% • Generation of 3,5-disubstituted arenes. Org. Lett. 2007, 9, 757. • Borylation of methyl C-H bonds in alkyl groups containing heteroatom functionality 4 i. 5 mol % Cp*Rh(! -C6Me6) O O 150 oC, 24 h B B + R-CH3 RCH2-BF3K O O ii. KHF2 MeOH 1 eq 10 eq O BF3K BF3K N 86% 69% J. Am. Chem. Soc. 2004, 126, 15334. David Arnold @ Wipf Group Page 10 of 35 5/18/2008 Potassium Organotrifluoroborates • The salts can be prepared according to the methodologies developed for the preparation of substituted boronic acids and esters followed by reaction with KHF2 • Potassium organotrifluoroborates: • Easily prepared • KHF2 is cheap (~0.07 $/g) vs. pinacol (~0.70 $/g) • Generally easily purified by recrystallization • Generally air and moisture stable at room temperature • Known stoichiometries • Reaction byproducts have low toxicities • Reagents show good functional group compatibilities • Reagents are nucleophilic • Can be further elaborated by oxidative processes • Soluble in polar solvents: MeOH, CH3CN, DMF and acetone • Counter ion exchange: TBA salts soluble in organic solvents such as CH2Cl2 + - nBu4N OH (aq) - + BF3K BF3 nBu4N CH2Cl2/H2O rt, 1 min 95% Tetrahedron Letters 2001, 42, 9099 David Arnold @ Wipf Group Page 11 of 35 5/18/2008 Expanding the Utility: Functionalization of Potassium Organotrifluoroborates • Halomethyltrifluoroborates • Lithium-Halogen Exchange • Oxidation Reactions • Wittig Reactions • Horner-Wadsworth-Emmons Olefination • Click Chemistry • Reductive Amination • The functionalization of potassium organotrifluoroborates opens the door to a wide variety of unique and potentially valuable boron containing organic synthons for incorporation into retrosynthetic strategies. David Arnold @ Wipf Group Page 12 of 35 5/18/2008 Synthesis and Elaboration of Halomethyltrifluoroborates • Similar reaction with boronate esters Cl - Cl O + Cl - - O LiCHCl 2 O Li O Nu: O -Cl B R B Cl B CHR B R B CHRNu O R -LiCl O O O O Nu Nu: = RLi, RMgX, alky lamines , enam ines, enolates... • Halomethyltrifluoroborates i. THF, n-BuLi -78 oC, 1h NaI / acetone i) Nu: i NuCH BF K CH2Br2 + B(O Pr)3 BrCH2BF3K ICH2BF3K 2 3 ii. KHF /H O rt, 2h ii) KHF2 2 2 88% 96% S- Li+ H Nu: S N O- Na+ Li MgCl KCN Br 86% 83% 95% 86% 94% 98% Org. Lett. 2006, 8, 2031. David Arnold @ Wipf Group Page 13 of 35 5/18/2008 Lithium-Halogen Exchange Reaction of Potassium Aryltrifluoroborates • One literature reference using magnesium-halogen exchange of arylboronates . O O i. iPrMgCl LiCl O O B THF, -78 oC B ii. E+ I -78 oC -> rt, 1h E 11 examples Angew. Chem. Int. Ed. 2005, 44, 3133. ii. E+, -78 oC -> rt BF K BF K 3 i. n-BuLi, THF 3 45 min BF3K o Br -78 C, 1h Li iii. KHF2 (aq) E rt, 10 min O O E+ O NCO TMSCl I H H 2 exclusive 84% 1,2-addition 65% 67% 64% 68% 94% J. Org. Chem. 2006, 71, 7491. David Arnold @ Wipf Group Page 14 of 35 5/18/2008 Epoxidation of Potassium Organotrifluoroborates • In 2003, it was discovered that m-CPBA could oxidize a thioether to a sulfone in the presence of a C-BF3K bond. m-CPBA PhS BF3K PhO2S BF3K CH2Cl2, rt, 1h 70% • This methodology was then extended to alkene epoxidation O BF3K 1.2 eq DMDO BF K R R 3 R' acetone, rt R' Products O O O O BF3K BF3K Cl BF3K BF K C8H17 3 85% 71% 80% 70% • Potassium organotrifluoroborate epoxides were found to be stable avoiding α -elimination and α-transfer processes J. Am. Chem. Soc. 2003, 125, 11148. David Arnold @ Wipf Group Page 15 of 35 5/18/2008 Cis-Dihydroxylation of Potassium Organotrifluoroborates R3 OsO4 (1.3 mol%) OH R R BF K NMO (1-1.5 eq) 3 1 ( ) 3 R1 BF3K n ( )n R2 R2 Acetone/t-BuOH/H2O OH rt, 1-6 h BF K 3 OH OH HO HO BF K HO BF3K 3 ( )8 HO 75% 56% 71% OH BF3K OH 69% i. OsO4 (1.3 mol%) NMO (1-1.5 eq) Acetone/t-BuOH/H O 2 OH ! "elimination rt, 2h BF3K HO BF3 n-Bu4N X ii. n-Bu NOH, H O 4 2 70% CH2Cl2, rt, 0.5 h Org. Lett. 2006, 8, 75. David Arnold @ Wipf Group Page 16 of 35 5/18/2008 Oxidation of Hydroxyl-Substituted Organotrifluoroborates O OH [O] H Bu4N F3B Bu4N F3B Entry Conditions % isolated yield 1 1% TPAP/NMO 91 2 Swern 90 3 Dess-Martin 86 OH O Bu4N F3B Bu N F B 1-2% TPAP 4 3 94% 1.1 eq NMO HO O BF NBu 3 4 Molecular sieves BF3 NBu4 CH2Cl2, rt, 18-20 h OH O 78% ( ) BF NBu 7 3 4 ( )7 BF3 NBu4 96% J. Am. Chem. Soc. 128, 128, 9634 David Arnold @ Wipf Group Page 17 of 35 5/18/2008 Wittig Reactions • Wittig reactions with stabilized ylides gave good yields and E-selectivities O Stabilized Ylides H R PhH/DMF KF B 3 90 oC, 2h KF3B O O Ph P OCH Ph3P CN 3 3 Ph3P N OCH3 OCH3 Yield 92%, E:Z 24:1 Yield 78%, E:Z 39:1 Yield 82%, E:Z 76:1 • Wittig reactions with unstabilized ylides gave good yields and good to moderate z-selectivities O Unstabilized Ylides H R THF/DMF/hexanes KF3B KF3B -78 oC -> rt, 3h O CN Ph3P Ph3P O Yield 82%, E:Z 1:28 Yield 65%, E:Z 1:4 J.