Aryl Carboxylic Acids and Derivatives

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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

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

■ 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)

■ 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)

■ 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. J. Angew. Chem. Int. Ed. 2015, 54, 13130–13133 For first generation conditions: Goossen, L. J.; Zimmermann, B.; Knauber, T. Angew. Chem. Int. Ed. 2008, 47, 7103–7106 Decarboxylative Heck Reaction

■ Pd-catalyzed decarboxylative Heck: ortho-substituted acid

20 mol% Pd(TFA)2 CO H R 2 Ag2CO3 (2–3 equiv) R

FG 5% DMSO–DMF, 80–120 ºC, 1–3 h FG

ortho-substituted acid alkene Heck product

i-Pr OMe Me Me MeO Ph CO2Et Ph O MeO OMe MeO OMe OMe Me Me

91% yield 86% yield 66% yield 99% yield

F Cl Ph F CO2Bu O CO2Bu CO2Bu

F F Me MeO N OMe Cl F

66% yield 47% yield 90% yield 66% yield

Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250–11251 Tanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433–446 Decarboxylative Heck Reaction

■ Pd-catalyzed decarboxylative Heck: proposed mechanism

Me Me O O – – O Me O O Me OMe ArCO2 CF3CO2 S CO2 S

Pd(OCOCF ) II Ar II 3 2 F3C O Pd O F3C O Pd OMe anion exchange decarboxylation S S r.t. O Me 80 ºC O Me OMe Me Me X-ray

catalyst regenation R migratory Ag2CO3 insertion r.t. r.t.

Me reductive elimination β-hydride elimination O Me O O S r.t. r.t. II 0 PdII Pd R Pd Ln F C O F3C O H 3

CF3CO2H Ar X-ray, for norbonene adduct R R = Ph, t1/2 < 15 min at –20 ºC Heck product

Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 10323–10333 Decarboxylative Heck Reaction

■ Pd-catalyzed decarboxylative Heck: proposed mechanism

Me Me O O – – O Me O O Me OMe ArCO2 CF3CO2 S CO2 S

Pd(OCOCF ) II Ar II 3 2 F3C O Pd O F3C O Pd OMe anion exchange decarboxylation S S r.t. O Me 80 ºC O Me OMe Me Me X-ray DMSO O catalyst regenation TFA Pd R MeO O migratory Ag2CO3 insertion r.t. MeO OMe r.t.

Me reductive elimination β-hydride elimination O Me O O S r.t. r.t. II 0 PdII Pd R Pd Ln F C O F3C O H 3

CF3CO2H Ar X-ray, for norbonene adduct R R = Ph, t1/2 < 15 min at –20 ºC Heck product

Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 10323–10333 Decarboxylative Heck Reaction

■ Pd-catalyzed decarboxylative Heck: proposed mechanism

Me Me O O – – O Me O O Me OMe ArCO2 CF3CO2 S CO2 S

Pd(OCOCF ) II Ar II 3 2 F3C O Pd O F3C O Pd OMe anion exchange decarboxylation S S r.t. O Me 80 ºC O Me OMe Me Me X-ray O OBu

catalyst regenation PdII observed by 1H-NMR R migratory H Ag2CO3 insertion r.t. r.t. CO2Bu

Me reductive elimination β-hydride elimination O Me O O S r.t. r.t. II 0 PdII Pd R Pd Ln F C O F3C O H 3

CF3CO2H Ar X-ray, for norbonene adduct R R = Ph, t1/2 < 15 min at –20 ºC Heck product

Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 10323–10333 Decarboxylative C–H Functionalization

■ Biaryl synthesis via decarboxylative C–H arylation

NO2 NO2 H M Pd

CO2H X M = Ag or Cu X aryl acid arene biaryl product

MI PdII reductive elimination

CO2

NO2 NO2 PdII transmetallation PdII

MI X X

decarboxylation C–H activation

Wei, Y.; Hu, P.; Zhang, M.; Su, W. Chem. Rev. 2017, 117 , 8864–8907 Decarboxylative C–H Coupling for Biaryl Synthesis

■ Intramolecular coupling

15 mol% Pd(TFA)2 CO2H H Y 3 equiv Ag2CO3 Y X X O 5% DMSO/dioxane, 150 ºC, 14 h O

diaryl ether dibenzofuran

OMe Br

O O O

85% yield 73% yield 39% yield

Me F O O O Me

69% yield 63% yield 70% yield r.r. = 26:1

Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194–4195 Decarboxylative C–H Coupling for Biaryl Synthesis

■ Selected examples for intermolecular transformation

Ag Pd 110 ºC Cu Pd 140 ºC

H Me S Ph O2N Cl O CO2H N H N N CO2H CO Et Me 2 Piv

Igor Larrosa Org. Lett. 2009, 5506 Michael Greaney ACIE 2010, 2768

Ag Pd 120 ºC Ag Pd 140 ºC

F F OMe S H S CO2H Cl H N CO2H Me OMe F F

Weiping Su ACIE 2012, 227 Weiping Su JOC 2011, 882 Decarboxylative C–O Coupling

■ Etherification with silicate esters

1 equiv Cu(OAc)2 NO2 NO RO OR 25 mol% Ag2CO3, O2 balloon 2 Si OR OR CO2K DMF, 145 ºC, 18 h OR

potassium carboxylate silicate ester ■ Cu is responsible for C–O formation aryl ether ■ Ag to Cu transmetalltion

OMe NO2 NO2 NMe2

Me i-Pr OMe O O OMe OMe

85% yield 81% yield 79% yield 55% yield

F CF3 Cl NO2

Ph OMe OMe O2N OMe O

48% yield 73% yield 58% yield 58% yield with B(OPh)3

Bhadra, S.; Dzik, W. I.; Goossen, L. J. J. Am. Chem. Soc. 2012, 134, 9938–9941 Decarboxylative C–N Coupling

■ With amide and sulfonamide

20 mol% CuCl , 20 mol% Phen NO2 O 2 NO NO2 2 O O 2 equiv NaHCO3, O2 O O HN S N S H N Me CO H 2 anisole, 4A MS, 170 ºC, 14 h N Me 2 H O aryl acid amide or sulfonamide 73% yield 60% yield

■ With aniline

NO Br NO Cl NO 2 2 2 H2N 1 equiv CuSO H H 4 N N

CO2K X NMP, 4A MS, 140 ºC, 12 h Cl potassium aniline carboxylate 61% yield 60% yield

Zhang, Y.; Patel, S.; Mainolfi, N. Chem. Sci. 2012, 3, 3196–3199

Sheng, W.-J.; Ye, Q.; Yu, W.-B.; Liu, R.-R.; Xu, M.; Gao, J.-R.; Jia, Y.-X. Tetrahedron Lett. 2015, 56, 599–601 Decarboxylative C–N Coupling

■ A recent example via bimetallic Cu/Pd system

NO2 NO2 H2N Cu Pd HN H N R 2 N X 120–145 ºC CO2K Y potassium 1º , 2º amine, electron-rich aniline N-aryl product carboxylate

NO2 NO2 OMe NO2

N Ph N N H H OMe CO2Et

63% yield 70% yield 84% yield

MeO NO2 NO2 MeO2C NO2 Cl

MeO N MeO N Ph N H O H

77% yield 74% yield 70% yield

Drapeau, M. P.; Bahri, J.; Lichte, D.; Goossen, L. J. Angew. Chem. Int. Ed. 2019, 58, 892–896 Decarboxylative Couplings: Computational and Mechanistic Studies

■ Ortho effect in decarboxylation step

■ Most groups at ortho positions can destablize substrates (steric effect)

■ Coordinating groups at ortho positions can stablize TS (electronic effect)

Perry, G. J. P.; Larrosa, I. Eur J. Org. Chem. 2017, 3517–3527 Protodecarboxylation via Copper-Catalysis

■ A general platform for protodecarboxylation

CO2H 5 mol% Cu2O, 10 mol% BPhen H

X NMP/quinoline (3:1), 170 ºC, 12–24 h X aryl acid arene

O O H NO2 Me S N Me Ph

CO2H CO2H CO2H CO2H

60% yield 82% yield 89% yield 60% yield

MeO Et OHC HO

CO2H CO2H CO2H CO2H

80% yield 92% yield 65% yield 75% yield

Goosen, L. J.; Thiel, W. R.; Rodriguez, N.; Linder, C.; Melzer, B. Adv. Synth. Catal. 2007, 349, 2241–2246 Decarboxylative Couplings: Efforts toward Lower-Temperature Decarboxylation

■ Comparisons of Cu and Ag-catalyzed systems

≠ ≠ M L G Δ 393 F F F L L L O Cu phen 31.3 kcal/mol M M O M L Ag phen 29.5 kcal/mol L O L O Ag NMP 29.2 kcal/mol TS

Ag 120 ºC ■ Very good for ortho-substituted acids X X ■ CO H H Not applicable to meta and para-acids 2 Cu 170 ºC

NO S 2 NO2 Br MeO OMe CF3

CO2H CO2H Me CO2H CO2H CO2H CO2H

92% yield 78% yield 76% yield 89% yield 91% yield 0% yield 87% yield 73% yield 0% yield 0% yield 22% yield 89% yield

Goossen, L. J.; Rodriguez, N.; Linder, C.; Lange, P. P.; Fromm, A. ChemCatChem 2010, 2, 430–442 Decarboxylative Couplings: Efforts toward Lower-Temperature Decarboxylation

■ Biaryl synthesis based on bimetallic Ag/Pd system

3 mol% PdCl , 9 mol% PPh 2 3 FG FG TfO 5 mol% Ag2CO3 20 mol% 2,6-lutidine

CO2K X NMP, 130 ºC, 16 h X potassium aryl triflate biaryl product carboxylate

OMe Cl Me N N

OMe Cl Cl Cl Cl

74% yield 76% yield 60% yield

Me O NO2 S N N

Me Me Me Cl Me

75% yield 89% yield 36% yield

Goossen, L. J.; Lange, P. P.; Rodriguez, N.; Linder, C. Chem. Eur. J. 2010, 16, 3906–3909 Decarboxylative Couplings: A Recent Example

■ Dynamic Carbon Isotope Exchange with Labeled CO2

20 mol% CuBr O O CN 20 mol% Box ligand 13 O O OCs [ C]CO2 OH DMSO, 150 ºC, 2 h N N FG FG then HCl Ph Ph cesium isotope source carbon labeled Box ligand carboxylate 3 equiv 14 acid [ C]CO2 can also be applied

O O O O O 75% 30% 14% O2N 65% OH OH OH OH N OH O Me NO2 O2N 29% O 50% yield 88% yield 65% yield 72% yield 35% yield

O O O 49% NC F O 54% Me OH 34% N Pr OH OH O N N i-Bu S OH Pr S O O 66% O O O Me 42% yield 26% yield 50% yield 10% yield

Destro, G.; Loreau, O.; Marcon, E.; Taran, F.; Cantat, T.; Audisio, D. J. Am. Chem. Soc. 2019, 141, 780–784 Decarbonylative Couplings of Aryl Amides and Esters: Overview

■ General ideas of mechanistic hypothesis

O O

OPh

X X X functionalized 0 aryl ester M activated ester arenes or amide

reductive oxidative elimination addition O O

MII O X O

MII twisted amide X X ■ Monometallic system transmetallation or decarbonylation ■ Pd0/PdII or Ni0/NiII cycles ligand exchange

■ Decarbonylative step needs high T MII ■ When Ni is used, sometimes CO X the scope is only limited to extended-π substrates Decarbonylative Couplings for C–C Bond Formation

■ From activated esters: coupling with C–H nucleophiles

10 mol% Ni(COD)2 O 20 mol% dcype N N 2 equiv K3PO4 Cy Cy H PhO X P P Cy Cy Z dioxane Z X 150 ºC, 24 h dcype C–H nucleophile aryl ester biaryl product

N N N N S O S O O Boc N

96% yield 96% yield 92% yield Me O N H O N MeO2C N N N N Me

O N O N Ph O N 39% yield

57% yield 52% yield 96% yield

Amaike, K.; Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134, 13573–13576 Decarbonylative Couplings for C–C Bond Formation

■ From activated esters: coupling with aryl boronic acids

5 mol% Ni(OAc)2 O 20 mol% P(n-Bu)3 (HO) B 2 2 equiv Na2CO3 OPh X toluene Y X Y 150 ºC, 24 h aryl ester boronic acid biaryl product

Me OMe OMe Me2N OMe N Me

89% yield 75% yield 63% yield

S Me CO2Me N N N Me

66% yield 72% yield 64% yield

Muto, K.; Yamaguchi, J.; Musaev, D. G.; Itami, K. Nat. Commun. 2015, 6, 7508 A Pd-catalyzed version using azincarboxylates: Muto, K.; Hatakeyama, T.; Itami, K.; Yamaguchi, J. Org. Lett. 2016, 18, 5106–5109 Decarbonylative Couplings for C–C Bond Formation

■ Coupling with aryl boronic acids: the effect of ester aryl groups

5 mol% Ni(COD)2 O 20 mol% P(n-Bu)3 (HO) B 2 1.5 equiv Et3N OAr OMe toluene O O OMe 150 ºC, 24 h aryl ester boronic acid biaryl product

OMe

MeO OMe Me t-Bu

50% yield 20% yield 14% yield 53% yield 20% yield 17% yield

F F Ph Ac

15% yield 30% yield 50% yield 20% yield 3% yield 17% yield

■ Alkyl esters don't work ■ Possible role of phenyl ring: coordination with Ni(0) to facilitate oxidative addition

Muto, K.; Yamaguchi, J.; Musaev, D. G.; Itami, K. Nat. Commun. 2015, 6, 7508 Decarbonylative Couplings for C–C Bond Formation

■ Coupling with aryl boronic acids: applications

O OMe OMe Ni Ni N PivO OPh PivO O decabonylative C–H/C–O Suzuki coupling coupling

74% yield 82% yield

MeO MeO O Ni Ni N PhO N N H decabonylative H decabonylative N O Suzuki coupling O C–H coupling O 57% yield 99% yield

Me decabonylative decabonylative Me O O C–H coupling Suzuki coupling N B N O OPh O N CO2Ph H O N 50% yield 52% yield

Muto, K.; Yamaguchi, J.; Musaev, D. G.; Itami, K. Nat. Commun. 2015, 6, 7508 Decarbonylative Couplings for C–C Bond Formation

■ From activated esters: coupling with alkyl zinc reagents

O 10 mol% Ni(COD)2 10 mol% dcype Cy Cy OPh P P Cy Cy BrZn THF/i-Pr2O X 150 ºC, 18 h X dcype aryl ester alkylzinc reagent alkylated arene ■ extended-π substrates

MeO O n-Bu n-Bu Ph N n-Bu Me2N Me OMe

50% yield 42% yield 68% yield

Me Me Me Me

72% yield 57% yield 71% yield

Liu, X.; Jia, J.; Rueping, M. ACS Catal. 2017, 7, 4491–4496 Decarbonylative Couplings for C–C Bond Formation

■ From activated esters: coupling with alkyl boranes

10 mol% Ni(COD)2 O 20 mol% dcype CsF or Cs2CO3 R Cy Cy OPh 9-BBN R P P Cy Cy toluene X X 150 ºC, 65 h dcype aryl ester alkyl borane alkylated arene

■ Switch ligand to PBu3 or PCy3 can lead to ketone products

PMP PMP PMP

t-Bu F3C

82% yield 84% yield 62% yield

Et PMP CO2Me MeO O Ph

O O

71% yield 43% yield 81% yield with BEt3

Chatupheeraphat, A.; Liao, H.-H.; Srimontree, W.; Guo, L.; Minenkov, Y.; Poater, A.; Cavallo, L.; Rueping, M. JACS 2018, 140, 3724 Decarbonylative Couplings for C–C Bond Formation

■ From activated amides: Heck reaction

O O 3 mol% PdCl2 9 mol% LiBr R N R NMP X X O 160 ºC, 15 h activated amide olefin Heck product

Ph Ph Ph Ph Ph

MeO O2N Br Me

86% yield 81% yield 76% yield 71% yield 91% yield

Ph Ph CONHt-Bu CO2Bu

Me MeO2C OHC F3C F3C

65% yield 75% yield 86% yield 80% yield

Meng, G.; Szostak, M. Angew. Chem. Int. Ed. 2015, 54, 14518–14522 Decarbonylative Couplings for C–C Bond Formation

■ From activated amides: Heck reaction, amide structure effect

O 3 mol% PdCl2 9 mol% LiBr CO2Bu N CO2Bu NMP 160 ºC, 15 h activated amide olefin Heck product

O O O O O Me Me O Me

N N N N Me O O Me Me

95% yield <5% yield <5% yield <5% yield

O O O O Ts Me N N N N Ph OMe Me

<5% yield <5% yield <5% yield <5% yield

Meng, G.; Szostak, M. Angew. Chem. Int. Ed. 2015, 54, 14518–14522 Decarbonylative Couplings for C–C Bond Formation

■ From activated amides: Suzuki coupling

O O 5 mol% Ni(PCy3)Cl2 (HO) B 2 4.5 equiv Na2CO3 N X dioxane Y X Y O 150 ºC, 12 h activated amide boronic acid biaryl product

MeO2C CF3 OHC CF3 CF3

81% yield 46% yield 80% yield

O F3C F F3C OMe F3C N

74% yield 74% yield 52% yield

Shi, S.; Meng, G.; Szostak, M. Angew. Chem. Int. Ed. 2016, 55, 6959–6963 Decarbonylative Couplings for C–Heteroatom Bond Formation

■ C–O formation from ester: unimolecular reaction

5 mol% Ni(COD)2 or Pd(OAc)2 S 10 mol% dcypt or dcppt O Y N O K3PO4 or CsF R R N P P O Y R R toluene X X 140–150 ºC, 12–26 h dcypt, R = Cy 2-azine ester diaryl ether dcppt, R = Cyp

N O N O Me Me N O N O OMe N

O O Me F

64% yield 72% yield 80% yield 54% yield Ni Ni Ni Ni

N O N O N O N O

Me F3C N

72% yield 75% yield 50% yield 93% yield Pd Ni Ni Pd

Takise, R.; Isshiki, R.; Muto, K.; Itami, K.; Yamaguchi, J. J. Am. Chem. Soc. 2017, 139, 3340–3343 Decarbonylative Couplings for C–Heteroatom Bond Formation

■ C–O formation from ester: applications intermolecule C–O formation

5 mol% Ni(COD)2 Me Me 10 mol% dcypt O HO N O 1.5 equiv K3PO4 N O OMe toluene OMe Me 150 ºC, 18 h 2 equiv 75% yield sequential chemoselective decarbonylation

N O O N O N Ni Ni O

decabonylative decabonylative C–O coupling PhO O Suzuki coupling PhO O OMe 83% yield OMe 66% yield

(HO)2B

Takise, R.; Isshiki, R.; Muto, K.; Itami, K.; Yamaguchi, J. J. Am. Chem. Soc. 2017, 139, 3340–3343 Decarbonylative Couplings for C–Heteroatom Bond Formation

■ C–N, C–P and C–H formation from activated esters and amides C–N formation Magnus Rueping et al., Angew. Chem. Int. Ed. 2017, 56, 4282–4285

O Ni HN Ph 170 ºC NH2 OPh + Ph then acidic hydrolysis

C–P formation Michal Szostak et al., Angew. Chem. Int. Ed. 2017, 56, 12718–12722

O O O O O Ni or Pd 160 ºC OEt Ts + OEt P N or N P OEt H OEt Ph O

C–H formation Magnus Rueping et al., Angew. Chem. Int. Ed. 2017, 56, 3972–3976

O O O Ni 170 ºC H OPh or N PMHS O Decarbonylative Couplings for C–Heteroatom Bond Formation

■ Mechanistic study: from ester to Ar–Bnep

5 mol% Ni(COD)2 10 mol% L•HCl, 10 mol% NaOt-Bu Me O O Me 2 equiv Na2CO3, 2 equiv NaCl B (nep) B N N OPh 2 2 Cy Cy dioxane O 160 ºC, 12 h L aryl ester 78% yield

1 equiv Ni(COD)2 1 equiv Ni(COD)2 2 equiv L•HCl O 2 equiv L•HCl O 2 equiv NaOt-Bu O L 2 equiv NaOt-Bu 1.25 equiv Al(Ot-Bu)3 OPh NiII OMe Cl toluene L toluene 31% yield 12% yield r.t., 12 h X-ray 60 ºC, 12 h

CO (1 atm) toluene, 60 ºC, 24 h toluene, 60 ºC, 24 h 85% yield 80% yield ■ Both Ni(II) complexes are chemical competent under B2(nep)2 Me catalytic conditions at 160 ºC L 2 equiv Na2CO3 Cl O Me 2 equiv NaCl ■ A related amide borylation NiII B O mechanistic study was also L dioxane, 80 ºC conducted by the same group 68% yield X-ray see ACIE 2016, 55, 8718 Pu, X.; Hu, J.; Zhao, Y.; Shi, Z. ACS Catal 2016, 6, 6692–6698 Decarboxylation Coupling: Radical Pathway

■ General consideration: decarboxylation is a kinetically less favoured pathway O trapping by ArH OAr k ~ 108 M-1s-1

O O –H+, SET decarboxylation OH O k ~ 106 M-1s-1

O HAT OH k ~ 107 M-1s-1

■ Using aryl carboxylic acid as HAT reagent in photoredox catalysis

O 1 mol% Ir[dF(CF )ppy] (dtbbpy)PF Me 3 2 6 Me 5 mol% PhCO2Na Me Me OBz N SCF3 OBz H F3CS Me Me O MeCN, r.t.

96% yield

Candish, L.; Freitag, M.; Gensch, T.; Glorius, F. Chem. Sci. 2017, 8, 3618–3622 Mukherjee, S.; Maji, B.; Tlahuext-Aca, A.; Glorius, F. J. Am. Chem. Soc. 2016, 138, 16200–16203 Decarboxylation Coupling: Radical Pathway

■ Protodecarboxylation platform using Ag/persulfate

20 mol% AgOAc CO H H 2 5 equiv K2S2O8

X MeCN, 100 ºC, 24 h X

CO H CO2H CO2H 2 CO2H CO2H

Ac MeO2C Br I

52% yield 78% yield 82% yield 67% yield 40% yield

CO H MeO2C CO2H MeO CO2H Br CO2H 2 CO2H

F MeO NO2 MeO

81% yield 45% yield 74% yield 58% yield 34% yield

O CO2H H

SET O –CO2 HAT X AgII X MeCN X

Seo, S.; Taylor, J. B.; Greaney, M. F. Chem. Commun. 2012, 48, 8270–8272 Quenching the radical with arenes: Kan, J.; Huang, S.; Lin, J.; Zhang, M.; Su, W. Angew. Chem. Int. Ed. 2015, 54, 2199–2203 Decarboxylation Coupling: Radical Pathway

■ An alternative strategy: avoid generating oxygen-center radical

O O O X X O SET O O X– CO2 not formed

■ Benzoyl hypohalites as intermediates

EtO C CO Et O O 2 2 O Br Me Br OH SET O O SET

in-situ generated

Candish, L.; Freitag, M.; Gensch, T.; Glorius, F. Chem. Sci. 2017, 8, 3618–3622 Decarboxylation Coupling: Radical Pathway

■ Proposed mechanism: decarboxylative arylation with arenes O

III *Ir O

X O decarboxylation O SET photoredox not favored X X catalytic cycle IrIII IrII

EtO2C CO2Et

Br Me SET O Br O O Br X O

–CO , –Br– H 2 X arene trapping rearomatization X X biaryl product

Candish, L.; Freitag, M.; Gensch, T.; Glorius, F. Chem. Sci. 2017, 8, 3618–3622 Decarboxylation Coupling: Radical Pathway

■ Decarboxylative C–H coupling via radical decarboxylation

3 mol% Ir[dF(CF3)2ppy](dtbbpy)PF6 CO H H 2 2 equiv Cs2CO3, 3.5 equiv BrC(CH3)(CO2Et)2

X arene as (co)solvent, 55 ºC, 22 h X aryl acid arene biaryl product

N MeO t-Bu N Br Cl

52% yield 68% yield 57% yield 78% yield 67% yield

t-Bu t-Bu Cl t-Bu t-Bu

Cl N t-Bu t-Bu Br Br Br

56% yield 59% yield 79% yield 21:50:29

Candish, L.; Freitag, M.; Gensch, T.; Glorius, F. Chem. Sci. 2017, 8, 3618–3622 Decarboxylation Coupling: Radical Pathway

■ Using redox ester: decarboxylative borylation under mild condition

Me O 1.5 equiv pyridine Me O 0.5 equiv CsOAc O Me N B2pin2 B O O Me O 400 nm irradiation, EtOAc, 35 ºC X X aryl redox ester aryl boronic ester

Bpin Bpin Bpin Bpin MeO Bpin

MeO MeO2C I

84% yield 72% yield 61% yield 52% yield 72% yield

Cl Bpin Bpin Bpin Bpin Bpin

N Me N Boc N

35% yield 34% yield 78% yield 59% yield 66% yield

Candish, L.; Teders, M.; Glorius, F. J. Am. Chem. Soc. 2017, 139, 7440–7443 Decarboxylation Coupling: Radical Pathway

■ Mechanistic hypothesis

* O O O O N N Ar O Ar O O O O O N CO + Phth– e– acceptor Ar O 2 O Bpin SET X Me Me •+ Me Me Me Me Bpin Me O N Me O N O B Bpin B pin O B Bpin 2 2 N N

e– donor

Candish, L.; Teders, M.; Glorius, F. J. Am. Chem. Soc. 2017, 139, 7440–7443