1. 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

2. Varinder K. Aggarwal Education: 1980-1983 BA, University of Cambridge
PhD in Organic Chemistry with Dr. Stuart Warren, University of Cambridge (Stereocontrolled Synthesis with Phenylthio Migration)
Postdoctoral position with Prof. Gilbert Stork, Columbia University.
Academic Positions:
Lecturer in Chemistry, Bath University
Lecturer in Chemistry, Sheffield University
Reader in Chemistry, Sheffield University
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

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

4. 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.

5. 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

6. 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

7. 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

8. 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, (Review)

9. 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:

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

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

12. 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, (c) Leonori, D.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2015, 54, (Review)

13. 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, (c) Leonori, D.; Aggarwal, V. K. Angew. Chem. Int. Ed. 2015, 54, (Review)

14. 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

15. The Trifluoromehtyl-Methyl-Furan Motif

16. The Trifluoromehtyl-Furan Motif: General Preparations

17. 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.

18. Scope Of the Reaction, Alkyl-Bpin Coupling

19. Scope Of the Reaction, Aryl-Bpin Coupling

20. Scope Of the Reaction, Other Electrophiles

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

22. 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= mT, aF= mT.
CF3 radical, is only formed in the presence of the Umemoto reagent and the B-ate-complex

23. Proposed Mechanism

24. 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