Palladium-Catalyzed Electrophilic Aromatic C luorination +2 Pd II 2 B 4 C (5 mol %) SI (2 eq) MeC, rt 61%, 69:31 o:p C Yamamoto, K; Li, J.; Garber, J. A..; Rolfes, J. D.; Boursalian, G. B.; Borghs, J. C.; Genicot, C.; Jacq, J.; van Gastel, M.; eese,.; Ritter, T. ature 2018, 554, 511-514 John Milligan Current Literature Wipf Group Meeting March 17, 2018 1
luorination Electrophilic fluorination (Selectfluor, SI, etc.) R 1 R 2 + Radical fluorination (above reagents under radical formation conditions) R 1 R 2 R 1 R 2 ucleophilic fluorination R 1 R ( pyridine, salts; 2 also deoxyfluorination reagents such as DAST, Deoxofluor, Pyluor) 2
Electrophilic fluorination R 1 R 2 + R 1 R 2 Representative reagents: 2 B 4 Ph 2 S S 2Ph R Xe 2 (expensive) Selectfluor TM SI fluoropyridinium salts Representative substrates: Ph Me R Ac Ac Ac C 2 Bn alkanes (w/ heating) alkenes/ alkynes activated arenes activated heterocycles glycals/ enol ethers/ enamines 1,3-dicarbonyl compounds 3 Baudoux, J.; Cahard, D. rg. Reactions. 2007, 69, 347-672.
Catalytic, Electrophilic C luorination B 4 (2.5-4.5 eq) Pd(Ac) 2 (10 mol%) MeC, 150 C (µw) 75% L n Pd C 3 Tf (1.5 eq) Pd(Tf) 2 (MeC) 4 (10 mol %) MP (20 mol %) C 3 MeC, 120 C 65% 4 ull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134-7135. Chan, K. S. L.; Wasa, M.; Wang, X.; Yu, J.-Q. Angew. Chem. Int. Ed. 2011, 50, 9081-9084.
Concept of Current Work Previous Approaches: luorination of a CM bond R M R M + R This Work: ormation of a highly electrophilic M species + M M R R 5
Concept of Current Work R 3 R 3 L L L L Pd II Pd IV L L L (square planar) L L L (octahedral) R R 6
Palladium complexes +2 +3 Pd II 2 B 4 + Pd IV 3 B 4 7 CCDC #1465063, 1536794
Catalyst M +2 2 B 4 Pd II 8
Substrate Scope R Pd catalyst (5 mol %) Selectfluor (2 eq) MeC, 50 C R R o-product p-product C 3 Br C C 3 49%, 52:48 o:p 51%, 59:41 o:p 61%, 69:31 o:p 85%, 69:31 o:p Ph S 2 9 55%, 77:23 o:p 46%, 67:33 o:p 51%, 59:41 o:p 60%, 49:51 o:p
unctional Group Tolerance Pd catalyst (5 mol %) Selectfluor (2 eq) MeC, 0 C 56%, 53:47 Pd catalyst (5 mol %) Selectfluor (2 eq) MeC, 0 C 71%, 72:28 Ac Pd catalyst (10 mol %) Selectfluor (2 eq) MeC, rt 54% Ac 10
SI reactions Pd catalyst (5 mol %) SI (2 eq) Ph Ac C 2 Me MeC, rt 52%, 86:14 Ph Ac C 2 Me Ph Ac C 2 Me ciprofibrate C 2 t-bu Pd catalyst (7.5 mol %) SI (2 eq) MeC, rt 30% C 2 t-bu procymidone Pd catalyst (7.5 mol %) SI (2 eq) MeC, 80 C 35%, 56:44 Pd catalyst (7.5 mol %) SI (2 eq) MeC, 50 C 56%, 51:49 11
Comparison Study 12
Mechanism: Electron Transfer 13
Computational Mechanistic Studies +3 +21.8 kcal 3 B 4 Pd IV +3 +2 3 B 4 0 Pd II 2 B 4 +1.2 kcal Pd IV -7.1 kcal 14
Comparison: Radical-Based C- luorination PhI (6 eq) Ag (3 eq) TBA (0.3 eq) Mn(TMP) (6 mol %) MeC/C 2 2, 50 C 49% 15 Liu, W.; uang, X.; Cheng, M.; ielsen, R. J.; Goddard, W. A. III.; Groves, J. T. Science 2012, 337, 1322-1325.
Potential Application: luoride Scanning previous lead S 2 iterative fluorine incorporation X X X X X X = or X S 2 improved lead structure S 2 yohdoh, I. et al. ACS Med. Chem. Lett. 2013, 4, 1059-1063. 16
Summary +2 Pd II 2 B 4 C (5 mol %) SI (2 eq) MeC, rt 61%, 69:31 o:p C This new method enables the electrophilic fluorination previously unsuitable substrates Amenable for late stage fluorination uture opportunities: Design of catalysts with high selectivity 17