Guillaume Benoit – Charette Group Enantiospecific Trifluoromethyl-Radical-Induced Three-Component Coupling of Boronic Esters with Furans Wang, Y.; Noble, A.; Sandford, C.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2017, 56, 1810. Guillaume Benoit – Charette Group Literature Meeting 2017-04-12

Varinder K. Aggarwal Education: 1980-1983 BA, University of Cambridge 1983-1986 PhD in Organic Chemistry with Dr. Stuart Warren, University of Cambridge (Stereocontrolled Synthesis with Phenylthio Migration) 1986-1988 Postdoctoral position with Prof. Gilbert Stork, Columbia University. Academic Positions: 1988-1991 Lecturer in Chemistry, Bath University 1991-1995 Lecturer in Chemistry, Sheffield University 1995-1997 Reader in Chemistry, Sheffield University 1997-2000 Professor in Chemistry, Sheffield University Professor in Synthetic Chemistry, Bristol University (current position)   Awards: 1997 Royal Society of Chemistry (RSC) Hickinbottom Fellowship; 1999 RSC Corday Morgan Prize and Medal; Novartis Lectureship; Liebig Lectureship, Gesellschaft Deutscher Chemiker (GDCh; German Chemical Society); 2007 RSC/GDCh Alexander Todd/Hans Krebs Lectureship; RSC Tilden Lectureship; 2009 RSC Stereochemistry Award; SCI Award for Process Research (GSK-AZ-Pfizer); 2012 elected Fellow of the Royal Society; 2013 RSC Perkin Award

Aggarwal’s Group : Research Interests Epoxidation and aziridination using new chiral sulfur ylides Annulation reactions Transition metal catalyzed processes Total synthesis of natural products  

Aggarwal’s Group : Research Interests Synthesis of enantioenriched secondary boronate and applications in synthesis   D. Leonori, V. K. Aggarwal, Acc. Chem. Res., 2014, 47, 3174 Stymiest, J. L.; Dutheuil, G.; Mahmood, A.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2007, 46, 7491.

Aggarwal’s Group : Research Interests Synthesis and functionalization of secondary and tertiary boronates   Arylation Nat. Chem. 2014, 6, 584 Protodeboronation JACS 2010, 132, 17096 Quaternary center formation ACIE 2011, 50, 3760 Amination ACIE 2011, 50, 1080 D. Leonori, V. K. Aggarwal, Acc. Chem. Res., 2014, 47, 3174

Aggarwal’s Group : Research Interests Iterative homologations: formation of contiguous stereocenters   Burns, M.; Essafi, S.; Bame, J. R.; Bull, S. P.; Webster, M. P.; Balieu, S.; Dale, J. W.; Butts, C. P.; Harvey, J. N.; Aggarwal, V. K. Nature 2014, 513, 183. D. Leonori, V. K. Aggarwal, Acc. Chem. Res., 2014, 47, 3174

Three-component metal-free coupling : CF3 radical, Fur-Li & Boronate The Paper Main Goal:   Enantioenriched Mono-, Di- & Tri-alkyl-substituted Boronates as starting material Three-component metal-free coupling : CF3 radical, Fur-Li & Boronate

sp2-sp3 Cross Coupling with Secondary & Tertiary-Alkyl Boronates Challenging coupling: slow rates for the transmetallation step and the reductive elimination Reactions lead to retention or Inversion of the stereocenter   Leonori, D.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2015, 54, 1082. (Review)

sp2-sp3 Cross Coupling with Secondary & Tertiary-Alkyl Boronates Activated Substrates Crudden 2009: First example of a cross-coupling of chiral boronate without high retention of enantioselectivity Molander 2010:

sp2-sp3 Cross Coupling with Secondary & Tertiary-Alkyl Boronates  Activated Substrates Ohmura & Suginome 2011: Molander 2012:

sp2-sp3 Cross Coupling with Secondary & Tertiary-Alkyl Boronates  Non-Activated Substrates Biscoe 2014:

Previous Work in the Aggarwal Group Transition Metal Free Enantiospecific sp2-sp3 Coupling of Secondary and Tertiary Boronic Esters with Aromatic Compounds (a) Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K. Nat Chem 2014, 6, 584. (b) Odachowski, M.; Bonet, A.; Essafi, S.; Conti-Ramsden, P.; Harvey, J. N.; Leonori, D.; Aggarwal, V. K. J. Am. Chem. Soc. 2016, 138, 9521. (c) Leonori, D.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2015, 54, 1082. (Review)

Previous Work in the Aggarwal Group Transition Metal Free Enantiospecific Coupling of Secondary and Tertiary Boronic Esters with Aromatic Compounds (a) Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K. Nat Chem 2014, 6, 584. (b) Odachowski, M.; Bonet, A.; Essafi, S.; Conti-Ramsden, P.; Harvey, J. N.; Leonori, D.; Aggarwal, V. K. J. Am. Chem. Soc. 2016, 138, 9521. (c) Leonori, D.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2015, 54, 1082. (Review)

Three-component metal-free coupling : CF3 radical, Fur-Li & Boronate The Paper Main Goal:   Enantioenriched Mono-, Di- & Tri-alkyl-substituted Boronates as starting material Three-component metal-free coupling : CF3 radical, Fur-Li & Boronate

The Trifluoromehtyl-Methyl-Furan Motif  

The Trifluoromehtyl-Furan Motif: General Preparations  

Optimization of the Reaction   Entry[a] Solvent Time (h) Yield (%)[b] 2a/1a[c] 1 MeCN 60 56:44 2 THF Trace 9:91 3 DMSO 56 4 DMF 57 63:37 5 MeOH 17 85:15 6 12 45 86:14 7 MeCN/MeOH (3:1) 49 64:36 8 MeCN/MeOH (1:1) 77 93:7 9 MeCN/MeOH (1:3) 61 92:8 [a] Reactions were conducted using furan-2-yllithium (0.4 mmol), 1a (0.3 mmol) in 1.0 mL THF. After solvent switch (2 mL), CF3 reagent (0.4 mmol) was added. [b] Yield determined by 19F NMR analysis of the crude reaction mixture using Ph-CF3 as an internal standard. [c] Ratio determined by GC-MS analysis of the crude reaction mixture.

Scope Of the Reaction, Alkyl-Bpin Coupling  

Scope Of the Reaction, Aryl-Bpin Coupling  

Scope Of the Reaction, Other Electrophiles  

Limitations: Reaction of Unreactive/Challenging Substrates Trifluomethylation Failed Oxidation of the intermediate failed  

Mechanistic Considerations EPR Spectroscopy to identify the generation of a CF3 radical in the reaction conditions  X-band EPR spectrum obtained in the reaction of boronate complex derived from 1a with Umemoto’s reagent A in the presence of PBN 5 (2 equiv) in DMF at 298 K. g=2.0044, aN=1.411 mT, aH=0.1664 mT, aF=0.1781 mT. CF3 radical, is only formed in the presence of the Umemoto reagent and the B-ate-complex

Proposed Mechanism  

Summary Development of a trifluoromethyl radical-induced 3-component coupling of furans with enantioenriched secondary and tertiary alkyl and aryl boronic esters Wide Scope Moderate yields Demonstrated radical pathway