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Aryl Carboxylic Acids and Derivatives Decarboxylative/Decarbonylative Couplings of (Hetero)Aryl Carboxylic Acids and Derivatives Pr Pr N N Me Me N N Me Me N N N O N OH Telmisartan Yufan Liang MacMillan Group Meeting January 17, 2019 Arylating Reagents ■ New alkylating reagents: innovations for novel alkylating reactions Ph O Ph MeO2C O N OH H N – CO H Boc Ph BF4 2 BocN O O alkyl carboxylic acid alkyl oxalate C–H nucleophile alkyl amine ■ Arylating reagents in cross-couplings: overview I Br Cl B(OH)2 MgBr ZnBr OPiv O NEt2 O N N N N N N N N aryl halide aryl organometallic reagents phenol derivative DG + + N2 NMe3 F OMe SO2M H H N N N N N N N aryl diazonium aniline aryl fluoride aryl ether aryl sulfinate arene Arylating Reagents in New Arylation Reactions ■ Aryl phosphine: heterobiaryl synthesis F C 3 F3C N N H PPh2 Ph2P CO2Me H n-Bu N Br N Br n-Bu N Br O F O F heteroaryl phosphine O F ■ Diaryl iodonium salts: meta-selective C–H arylation t-Bu t-Bu Me OTf HN O HN O I Br Me Me + Cu Br Me Me H diaryl iodonium Hilton, M. C.; Zhang, X.; Boyle, B. T.; Alegre-Requena, J. V.; Paton, R. S.; McNally, A. Science 2018, 362, 799–804 Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593–1597 (Hetero)Aryl Carboxylic Acid ■ Aryl carboxylic acids and derivatives O O ♦Commercially available ♦Easily available OH ♦Structurally diverse ♦One-step, trivial synthesis X X ♦Bench-stable, easy to handle ♦Highly tunatble aryl carboxylic acid aryl amide/ester ■ Carboxylic acids are versatile directing groups for sp2 C–H functionalization R O R O R O R R O 2 X sp C–H X X X functionalization acids or derivatives ortho- meta- para- Drapeau, M. P.; Goossen, L. J. Chem. Eur. J. 2016, 22, 18654 Font, M.; Quibell, J. M.; Perry, G. J. P.; Larrosa, I. Chem. Commun. 2017, 53, 5584 Decarboxylative and Decarbonylative Couplings of Aryl Acids and Derivatives ■ What will be covered O O O OH NR2 OR decarboxylative X decarbonylative X X X –CO2 functionalized –CO acid or carboxylate arenes amide or ester ■ Related review articles ♦Decarboxylative coupling: Igor Larrosa Eur. J. Org. Chem. 2017, 3517 (biaryl synthesis) Jessica M. Hoover Comments Inorg. Chem. 2017, 37, 169 (mechanistic studies) Weiping Su Chem. Rev. 2017, 117 , 8864 (decarboxylative C–H functionalization) Igor Larrosa Synthesis 2012, 653 (C–C bond) Lukas J. Goossen Chem. Soc. Rev. 2011, 40, 5030 (C–C bond) Lukas J. Goossen Isr. J. Chem. 2010, 50, 617 ♦Decarbonylative coupling: Magnus Rueping Chem. Eur. J. 2018, 24, 7794 Michal Szosak Org. Biomol. Chem. 2018, 16, 7998–8010 (amide as substrate) Junichiro Yamaguchi Chem. Soc. Rev. 2017, 46, 5864 Decarboxylative and Decarbonylative Couplings of Aryl Acids and Derivatives ■ What will be covered O O O OH NR2 OR decarboxylative X decarbonylative X X X –CO2 functionalized –CO acid or carboxylate arenes amide or ester ■ Summary of common features ♦High temperature (>150 ºC) ♦Ortho effect in decarboxylation step ♦Concerted mechanism ■ What transformations haven't been accomplished O O O CF3 F N N Y N X X X X X X acid, no reports very limited scope amide or ester Outline ■ Decarboxylative coupling using aryl acid ♦C–C bond formation ♦C–O and C–N bond formation ♦Ortho effect and lower-temperature system ■ Decarbonylative coupling using activated ester and amide ♦C–C bond formation ♦C–heteroatom bond formation and mechanistic study ■ Radical strategy Decarboxylative Arylation for Biaryl Synthesis: Cu/Pd System ■ Biaryl synthesis via Cu/Pd bimetallic catlysis NO2 NO2 Br Cu Pd CO2H Cl Cl aryl acid aryl bromide biaryl product CuI Pd0 reductive elimination CO2 NO2 NO2 PdII Cu to Pd PdII CuI Cl transmetallation Cl oxidative decarboxylation addition Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–664 Goossen, L. J.; Rodriguez, N.; Melzer, B. M.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824–4833 Decarboxylative Arylation for Biaryl Synthesis: Cu/Pd System ■ Optimal contidions stoichiometric in Cu NO2 2 mol% Pd(acac)2, 6 mol% P(i-Pr)Ph2 NO2 Br 1.5 equiv CuCO3, 1.5 equiv KF CO2H Cl 3A MS, NMP, 120 ºC, 24 h Cl 1.5 equiv 96% yield catalytic in Cu 1 mol% Pd(acac)2 3 mol% CuI, 5 mol% Phen NO2 NO2 Br 1.2 equiv K2CO3 CO2H Cl 3A MS, NMP, 160 ºC, 24 h Cl 1.5 equiv 99% yield large scale NO 0.03 mol% Pd(acac)2 2 NO2 Br 0.3 mol% Cu(phen)(PPh3)2NO3 CO K Cl 2 toluene/quinoline, azotropic –H2O 150 ºC, 24 h Cl 1.0 equiv 92% yield 80 mmol >17 g Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–664 Goossen, L. J.; Rodriguez, N.; Melzer, B. M.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824–4833 Decarboxylative Arylation for Biaryl Synthesis: Cu/Pd System ■ Scope of aryl halide 1 mol% Pd(acac)2 3 mol% CuI, 5 mol% Phen NO2 NO2 X 1.2 equiv K2CO3 CO2H 3A MS, NMP, 160 ºC, 24 h 1.5 equiv biaryl product (1.5 equiv Cu yield) Br Br Br Br Br CN CO2Et CHO OMe MeO 93% yield 96% yield 78% yield 68% yield 30% yield (80% yield) Br Br Br Cl Cl N Me Me N Cl CN 23% yield 53% yield 98% yield 66% yield 96% yield (93% yield) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–664 Goossen, L. J.; Rodriguez, N.; Melzer, B. M.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824–4833 Decarboxylative Arylation for Biaryl Synthesis: Cu/Pd System ■ Scope of aryl acid Br Cu Pd 170 ºC Me CO2H or Cu Pd 160 ºC Me (yield with 1.2 equiv Cu) O O OMe CF3 S Me H CO2H CO2H CO2H CO2H CO2H 69% yield 61% yield 46% yield 31% yield 62% yield O O CN H H MeO S N N Me Ac Ph CO2H CO H CO H CO2H CO2H 2 2 34% yield 42% yield 0% yield 0% yield 0% yield (55% yield) (97% yield) (42% yield) (91% yield) (41% yield) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 313, 662–664 Goossen, L. J.; Rodriguez, N.; Melzer, B. M.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824–4833 Decarboxylative Arylation for Biaryl Synthesis: Cu/Pd System ■ Proposed mechanism: synergistic Cu/Pd catalysis Br CO2 X NO2 oxidative PdII addition Cl decarboxylation CuI Cl aryl bromide NO2 Cu Catalytic Pd Catalytic transmetallation Pd0 Cycle Cycle CO2Cu reductive elimination anion exchange NO2 PdII NO CuIX 2 NO2 Cl – CO2 Cl aryl carboxylate biaryl product ■ Anion exchange step determines if turn-over of Cu is possible ■ A suitable Cu catalyst for decarboxylation might still not solve the coupling problem Goossen, L. J.; Rodriguez, N.; Melzer, B. M.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824–4833 Decarboxylative Arylation for Biaryl Synthesis: Cu/Pd System ■ Proposed mechanism: synergistic Cu/Pd catalysis Br CO2 X NO2 oxidative PdII addition Cl decarboxylation CuI Cl aryl bromide NO2 Cu Catalytic Pd Catalytic transmetallation Pd0 Cycle Cycle CO2Cu reductive elimination anion exchange NO2 PdII NO CuIX 2 NO2 Cl – CO2 Cl aryl carboxylate biaryl product ■ Anion exchange step determines if turn-over of Cu is possible ■ A suitable Cu catalyst for decarboxylation might still not solve the coupling problem Goossen, L. J.; Rodriguez, N.; Melzer, B. M.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824–4833 Decarboxylative Arylation for Biaryl Synthesis: Cu/Pd System ■ Influence of bromide anion in decarboxylation step CO2H 7.5 mol% Cu2O, 15 mol% Phen H X NMP/quinoline (3:1), 170 ºC, 6 h X aryl acid arene (yield with 15 mol% KBr) H H NO2 F CN N N Ac Ph CO2H CO2H CO2H CO2H CO2H 100% yield 75% yield 40% yield 48% yield 96% yield (100% yield) (75% yield) (25% yield) (0% yield) (23% yield) O O CN O N MeO S 2 Me S CO2H CO2H CO2H CO2H CO2H 54% yield 52% yield 23% yield 72% yield 44% yield (43% yield) (25% yield) (0% yield) (24% yield) (7% yield) Goossen, L. J.; Rodriguez, N.; Melzer, B. M.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824–4833 Decarboxylative Arylation for Biaryl Synthesis: Cu/Pd System ■ Improved system for biaryl synthesis: ArOTf as electrophile 3 mol% PdI2, 4.5 mol% Tol-BINAP TfO 7.5 mol% Cu2O, 15 mol% Phen CO2K Me NMP, 170 ºC, 24 h Me potassium carboxylate aryl triflate biaryl product NO2 CN Cl O2N CO2K CO2K CO2K CO2K 72% yield 52% yield 40% yield 68% yield H NC N Ac S N CO K CO2K CO2K 2 CO2K 58% yield 53% yield 41% yield 54% yield Goossen, L. J.; Rodriguez, N.; Linder, C. J. Am. Chem. Soc. 2008, 130, 15248–15249 For using ArOTs and ArOMs: Goossen, L. J. et al., Angew. Chem. Int. Ed. 2010, 49, 1111–1114; Angew. Chem. Int. Ed. 2013, 52, 2954–2958 Decarboxylative Arylation for Biaryl Synthesis: Cu/Pd System ■ Cross-couplings of aryl chlorides 2 mol% [Pd(MeCN)4](OTf)2 5 mol% XPhos Cl 10 mol% CuI, 10 mol% Me4-Phen X X CO K Y NMP/quinoline (1:1), 190 ºC, 16 h 2 Y potassium carboxylate aryl chloride biaryl product NC F PhO OMe Me Me Me Me 70% yield 48% yield 50% yield 79% yield O2N O2N Me Ph CN CN OMe F 18% yield 32% yield 40% yield 52% yield Tang, J.; Biafora, A.; Goossen, L.
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