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. Org. Chem. 2006, 71, 6135.
David Arnold @ Wipf Group Page 18 of 35 5/18/2008 Horner-Wadsworth-Emmons Olefination
O i. n-BuLi, 0 oC O THF/DMF/hexanes R1 H P R1 + EtO ii. n-Bu OH R2 EtO 4 Bu N F B KF3B CH Cl , H O, rt 4 3 R2 2 2 2
Phosphonate Product
O CN P CN EtO EtO Bu4N F3B Yield 70% E:Z 9:1 O O O OCH3 P EtO OCH3 EtO Bu4N F3B Yield 91% E:Z 125:1
O O O OEt P EtO OEt EtO Bu4N F3B Yield 65% E:Z 20:1 • Good yields and generally high E-selectivities J. Org. Chem. 2006, 71, 6135.
David Arnold @ Wipf Group Page 19 of 35 5/18/2008 Click Chemistry and Reductive Amination • 1,3-dipolarcycloaddition reactions, synthesis of potassium organotrifluoroborates containing the pharmaceutically important [1,2,3]-triazole subunit
BF3K BF K 3 N i. NaN3/DMSO N o N Cl 80 C, 30 min ii. ethynylbenzene iii. CuI (10 mol %) 97% 18 examples, Yields: 85-98%
• One Pot Reaction. General for aromatic and alkyl-alkynes containing alcohols, esters, nitriles and ethers. Org. Lett. 2006, 8, 2767.
• Reductive amination, access to amine-substituted organotrifluoroborates
O NR2 amine
Pyr.BH3 KHF2 BF3K BF3K n-butylamine 76%, pyrrolidine 76%, morpholine 89%
J. Org. Chem. 2008, 73, 3885.
David Arnold @ Wipf Group Page 20 of 35 5/18/2008 Selected Reactions of Potassium Organotrifluoroborates
Organodifluoroboranes •Petasis Reaction •Allylation and Crotylation Reactions •Preparation of Chiral Secondary Amines
Potassium Organotrifluoroborates •Rhodium-Catalyzed 1,2- and 1,4-Additions •Rhodium-Catalyzed Cross-Coupling Reactions •Diels-Alder/Cross-Coupling Reactions •Palladium Catalyzed Cross-Coupling Reactions
David Arnold @ Wipf Group Page 21 of 35 5/18/2008 Petasis Reactions of Difluoroorganoboranes: Three-Component Reactions to Synthesize Heavily Functionalized Amines Proposed Mechanism
R4 R5 R R O H R R4 R5 N R 4 5 + N 5 N 1 N R R - R R 3 2 +B OH 2 3 R4 O R R R2 OH R3 OH 1 3 R1 H R2 B OH HO
O Ph Ph H NH . 25 mol% BF3 OEt + OH N Toluene, 90 oC, 1h BF3K
OH 75 % The reaction can accommodate electron rich aryl-, heteroaryl-, vinyl- and allyltrifluoroborates in moderate to good yields
Tetrahedron. Lett. 2004, 45, 3471.
David Arnold @ Wipf Group Page 22 of 35 5/18/2008 Difluoroorganoboranes: Allylation and Crotylation Reactions • Allylation of aldehydes
. O 2 eq BF3 OEt OH + BF3K R H R CH2Cl2, rt, 3-6 h R: O O O
H H H
O2N NC 95% 91% 95% • Crotylation of aldehydes O OH R BF K 0.05 eq BF .OEt BF2 1 3 3 R2 H + O R R3 2 CH2Cl2, rt, 3-6 h R1 R1 R2
Crotyltrifluoroborate Product OH
Me BF3K 92% yield Me H d.r. >98:2 H OH H BF3K 93% yield Me d.r. >98:2 Me H Synthesis 2000, 7, 990.
David Arnold @ Wipf Group Page 23 of 35 5/18/2008 Difluoroorganoboranes: Preparation of Chiral Secondary Amines
Cy i. LiCHCl 2, ZnCl2 Cy + - o NaN 3, B u 4N Br THF, - 100 C to r t, 15h O O Cy B Cy B O EtOA c, H 2O O ii. PhM gB r B r N3 80 oC, 8 h 88%
Cy KHF S iCl O 2 BF3K 4 N 3 B Cy Ph N O MeOH/H O Ph P hCH /CH CN N 3 2 3 3 H o P h 22 C, 10 h; H 2O
73% 82% 77%, 90% ee
Org. Lett. 2002, 4, 2153.
David Arnold @ Wipf Group Page 24 of 35 5/18/2008 Reactions of Potassium Organotrifluoroborates: Rh-Catalyzed Addition to Aldehydes and Enones
O M OH 3.0 mol % Rh(acac)(CO)2 H + 3.0 mol % dppf o DME/H2O, 80 C
M = -B(OH)2 or -BF3K
O M OH 3.0 mol % Rh(acac)(CO)2 + 3.0 mol % dppf o MeOH/H2O, 50 C
M = -B(OH)2 or -BF3K
Org. Lett. 1999, 1, 1683
David Arnold @ Wipf Group Page 25 of 35 5/18/2008 Rhodium-Catalyzed Cross-Coupling Reaction with Potassium Organotrifluoroborates: Conversion of Aldehydes to Ketones
O BF K 3 1.5 mol% [Rh(CH CH ) Cl] O 2 2 2 2 HO D D + + t 3.0 mol % P( Bu)3 80 oC, 1,4-dioxane/acetone 65% 64% ?
O O Ph Ph [Rh]-H(D)
[Rh] O Ph [Rh] O H(D) Ph H(D)
Ph-BF K [Rh]-Ph 3
O ROBF3K Ph D
J. Am. Chem. Soc. 2004, 126, 15356.
David Arnold @ Wipf Group Page 26 of 35 5/18/2008 Diels-Alder/Cross-Coupling Reactions of 2-BF3- Substituted 1,3-Dienes • Limitations to the use of 1,3-dienyl-2-boronates
B(OR) dimerization 2
(RO)2B (RO)2B • Preparation of stable 2-potassium trifluoroborate 1,3-dienes
i. Mg, cat ZnCl2
Cl ii. B(OMe)3 KF3B iii. aq KHF 2 Stable
• Diels-Alder/Cross-Coupling Reactions
O O i. EtOH, 95-100 oC OEt + OEt + OEt KF3B ii. Ph-I, Pd(OAc)2 (0.5%) Ph Ph K2CO3 (3 eq), ROH, ! O para meta 60% yield, para:meta 2.5:1 • 13 examples, moderate yields and regioselectivities Org. Lett. 2005, 7, 2481
David Arnold @ Wipf Group Page 27 of 35 5/18/2008 Palladium Catalyzed Cross-Coupling Reactions of Organotrifluoroborates
• Mechanism of the Suzuki Reaction
David Arnold @ Wipf Group Page 28 of 35 5/18/2008 Palladium Catalyzed Cross-Coupling Reactions of Organotrifluoroborates
• General overall transformation:
Pd(0) R X + R' BF3K R R' Base, H O X = I, Br, OTf 2
R = Aryl, alkenyl, allyl R' = Alkyl, alkenyl, alkynyl, Aryl
• Palladium catalyzed cross-coupling reactions have been one of the most highly investigated areas involving reactions of potassium organotrifluoroborates
• For recent reviews see: Chem. Rev. 2008, 108, 288. Tetrahedron 2007, 63, 3623.
David Arnold @ Wipf Group Page 29 of 35 5/18/2008 Palladium-Catalyzed Cross-Coupling of Acetates of Baylis-Hillman Adducts
O BF3K OAc O R OMe Pd(OAc)2 + R OMe MeOH, rt
R R C8H17-R Cl 84% 83% 48%
• This cross-coupling reaction has been used to generate densely functionalized molecules in moderate to good yields with high stereoselectivity
Org. Lett. 2003, 5, 3803
David Arnold @ Wipf Group Page 30 of 35 5/18/2008 Setreoselective Cross-Coupling Reactions of Potassium Alkenyltrifluoroborates with Alkenyl Bromides
Reaction Conditions: 5 mol% Pd(OAc)2/2PPh3, 3 eq Cs2CO3, THF-H2O (10:1)
Br Cl Ph Cl 2 h, 86% E,E BF K Br Ph 3 Cl Cl E,Z 2 h, 88% Ph
Br Cl Ph Cl 2 h, 85% Z,E Ph Br BF K Cl 3 Cl
4 h, 86% Ph Z,Z
• Stereospecific synthesis (>99%) of the four geometrical isomers of 9-chloronona- 3,5-dienylbenzene J. Org. Chem. 2005, 70, 3950.
David Arnold @ Wipf Group Page 31 of 35 5/18/2008 From Methodology to Utility: Potassium Organotrifluoroborates in Natural Product Synthesis: Oximidine II
H N
O N OH O OH OMe O
Oximidine II • First isolated in 1999 from Pseudomonas sp. Potential cancer therapeutics
• Key step: macrolactonization via esterification did not succeed
Steps
J. Am. Chem. Soc. 2004, 126, 10317.
David Arnold @ Wipf Group Page 32 of 35 5/18/2008 Oximidine II
• Palladium catalyzed cross-coupling of the organotrifluoroborate furnished the macrolactone portion of Oximidine II
OBn BnO
OH O OMOM Pd(PPh3)4, Cs2CO3 O OMOM O OH
THF:H2O (10:1), ! O 42% Br BF3K
J. Am. Chem. Soc. 2004, 126, 10317.
David Arnold @ Wipf Group Page 33 of 35 5/18/2008 Trityrosine • Isolated from bacteria, plants and yeast. Target of interest for biological studies.
H2N CO2H
HO OH
NH2
CO2H HO2C NH2 HO
trityrosine
• Key step: Palladium catalyzed trimerization CbzHN CO2Bn
CbzHN CO2B n Cbz HN CO2Bn . P dCl 2( dppf) CH 2Cl2 BnO K F3B I K2CO3 OH + B nO2C BnO HO THF, H 2O NHCbz reflux, 26 h Cbz HN I 67% CO Bn B nO 2 • The corresponding Suzuki Reaction using the pinacoleboronate ester gave none of the desired product, highlighting the higher reactivity of organotrifluoroboranes
J. Org. Chem. 2005, 18, 7353
David Arnold @ Wipf Group Page 34 of 35 5/18/2008 Conclusion
• Potassium organotrifluoroborates have been demonstrated to be viable reagents in contemporary organic synthesis. Their ease of preparation coupled with their often higher reactivities vs. other organoborane reagents has highlighted their use in a number of transition metal catalyzed reactions.
• This class of organoboron reagents has a high utility due to the overall stability of the C-B bond towards oxidation, proteodeboronation and nucleophilic attack allowing the organic portions of the reagent to be further elaborated. Thus expanding their use as valuable organic synthons in retrosynthetic strategies.
• While there are a host of transition metal catalyzed reactions known for potassium organotrifluoroborates, in many cases the specific mechanisms by which these reagents participate are not fully understood. Further knowledge of the reactive organoboron species in these reactions may lead to the development of new transition metal catalyzed reactions.
David Arnold @ Wipf Group Page 35 of 35 5/18/2008