Palladium Catalyzed C-H Amination

Palladium Catalyzed C-H Amination Presented by Ala Bunescu: 1st year PhD student, LSPN, EPFL PhD supervisor : Prof. Jieping Zhu Questions: What is the mechanism of C-H amination? What are the limits of C-H amination? 02/24/2020 2 Plan 1. Introduction 2. Pd-Catalyzed direct C-H amination: Mechanistic overview 3. Examples found in literature: Mechanistical pathway Type of oxidant: internal/external Type of C-H bond: sp3, allylic, aromatic( Inter/Intra Molecular) 02/24/2020 3 Pd-Catalyzed direct C-H amination Advantages: Atom economy /low energy starting material Direct route to complex product An alternative approach for Buchwald-Hartwig Amination 02/24/2020 Desavantages: Inert nature of most C-H carbon bonds: harsh conditions Requirement of site selectivity: directory group Absence of generality 4 Pd-Catalyzed direct C-H amination: Mechanistical Overview Reductive functionalization pathway Electrophilic functionalization pathway 02/24/2020 5

Reductive Functionalization Pathway Pd II/0 Catalytic Cycle Pd 0 Oxidation C-H activation PdII Oxydant +HX L X a I HX L 0 Pd L C-FG b Reductive Elimination 02/24/2020 C L L C C-H PdII II c PdII III FG Ligand Exchange 6 Electrophilic Functionalization Pathway

Direct electrophilic Functionalization of Paladacycle: C-H activation PdII Direct Electrophilic cleavage L X C I Ox-FG PdII L C-FG b II One or Two electron Oxidation of Palladacycle: L C-FG PdII b or c L C C-H C-H activation a I L Reductive Elimination L

X HX FG PdIV L III Ox III (or Pd ~PdIII dimer) II C PdII Pd(II) oxidation : Two / one electron oxidant Internal oxidant /external oxidant Oxydant-FG 02/24/2020 7 Examples: Type of Mechanism Pd(0)/Pd(II): 2 examples Pd(II)/Pd(IV): 2 examples Nitrene insertion: 1 example 02/24/2020 8 C-H Amination to carbazole: Pd(0)/Pd(II) A: 5%-10% Pd(OAc)2 1eq Cu(OAc)2/O2 toluene, 120oC O Ar1 N H Ar1 N B: 5%-10% Pd(OAc)2 DMSO/O2 120oC

Ar2 1 Ar2 O 2 26examples, 41-98% R N O R N N N R 3 R: OMe (92%) F (94%) CF3 (88%) 4 R: OMe (81%) F (78%) CF3 (95%) O O O 5 R: Me (82%) OMe (41%) CF3 (86%) CO2Me (99%) R 6 R: OMe (97%) F (87%) CF3 (94%) SMe (82%)b NO2 (72%)b

Buchwald, S.L. J. Am. Chem.Soc., 2005, 127, 14560-14561 Buchwald, S.L. J. Org. Chem., 2008, 73,7603-7610 02/24/2020 9 Propese Mechanism O O N H 4 a 1 3 Waker-like N Pd AcOH Heck Like OAc I Pd(OAc)2 2 Cu(OAc)2/ O2 N II III O LnPd(0) Pd-OAc AcOH N O Pd-OAc HPdOAc

b N O Electrophylic C-H activation excluded: OMe group in position 3 give just 41% yield At lower temperature just 2-acetamino- 4-metoxybiphenyl (metoxy group in 2) cyclizide in73% (inductive effect of MeO) 02/24/2020 10 C-H amination to oxindole: Pd(0)/Pd(II) R1 R2 H N R1 R2 10% Pd(OAc)2 Cu(OAc)2(1eq) Ts O O N 2 Ts 7exemples, 30-84% 0 p-Xylene, 140 C, O2 1 R O O N 3 Ts 4 84% O O N Ts 5

N Ts R : OMe (30%) Cl (63%) 82% R N Ts 6 R : OMe (61%) Cl (65%) Ph O 7 N Ts 97% O N 8 Ts 39% Non-substituted substrates failed: ThorpeIngold effect MeO in 4 retarded the process : no SEAr for C-H activation Proposed mechanism: via six membered palladacycle in Pd(0)/Pd(II) Murakami, M. Chemistry Lett., 2009, 38, 328-329 02/24/2020 11 Oxidative Pd(II) C-H Bond Amination to Carbazole : Pd(II)/Pd(IV) Ar1 H N Ar2

5%-10% Pd(OAc)2 1.2eq PhI(OAc)2 R R= alky, benzyl,allyl 2 19exemples 56-96% R2 4 3 R1: OMe (85%)b Me (86%)b,a F (79%) CO2Me(95%)a b R3 10 N Bn 4 Ra: Bn (96%) i-Pr (96%) Allyl (79%) Me (80%) Use of 1eq of AcOH Ar2 R1 N R a N R toluene, rt 1 Scope of reaction Ar1 N Bn N Bn

5 R2: OMe (81%) CO2Me(94%) 6 R3: Me (56%)* OMe(75%) Mixture C10/C4 carbazole isomer Gaunt,M. J.Am.Chem.Soc, 2008, 130, 1618416186 02/24/2020 12 Proposed Mechanism: Pd(II)/Pd(IV) Experimental observation: Electron rich substrate react faster: -electrophilic mechanism -stronger interaction of C-H with the metal X ray of IIa : trinuclear complex IIa can be transformed to the carbazole: PhI(OAc)2, PhMe, rt No oxidation in DMSO or in presence of coordinating additive (Py) : monomeric paladacycle 02/24/2020 13 Pd(II) C-H Activation to , , -lactame R1 R2 H N , -lactame : OMe O DCE, 100 C, N2 R1 O 3 R1: OMe(94%) OBn(95%) O N 2 OMe 19 exampels, 58-94%

0 1 N OR' R1 R2 10% Pd(OAc)2 CuCl2(2eq), AgOAc(2eq) O O N OMe R 4 R: OMe(90%) Cl (88%) F(86%) Ph H 5 N OMe 6 R1: Ph (58%) Et (60%) iPr (62%) O N OMe 7 N O OMe 91% 78% N OBn

8 O N OMe 88% 9 N O OMe 72% 10 O N OMe Sp2 CH 72% O 11 Sp3 CH 68% Yu, J.-Q. J.Am.Chem. Soc. 2008, 130, 1405814059 02/24/2020 14 Pd(II) C-H Activation to , , -lactame -lactame H 1 O H N 10% Pd(OAc)2 CuCl2(2eq), AgOAc(2eq) OMe Cl O 0 DCE, 100 C, N2

2 H N N CsF OMe R4N+Cl- OMe O 3 68% One-pot procedure Reductive elimination of R-Cl from five membered palladacycle Strained transition state 02/24/2020 15 Proposed Mechanism: Pd(II)/Pd(IV) 1 2 3 Experimental observation/ hypothesis Using PhI(OAc)2 give 10% of desired oxindole CuCl2 source of Cl+ : 1 or 2 ? PdCl2 ligand exchange with AgOAc Sequential chlorination amination excluded: Cl Cl H N O Cl 4

OMe standard conditions O N OMe Cl 5 40% 02/24/2020 O N OMe Cl 6 Not observed 16 C-H activation via nitrene insertion R1 N R2 OCH3 DCE, 80 0C R: CO2CH3, COCF3, CO2tBu, SO2CH3, SO2(p-Cl-C6H4) NH R 15exampels, 68-96% 2 4 6 O 5% Pd(OAc)2 K2S2O8(5eq) MeOH (3eq) DCE, 80 0C OCH3

5 89% Probe to nitrene intermediacy: NH2 N NHCOCF3 88% O NHSO2(p-Cl-C6H4) N OCH 3 NHSO2(p-Cl-C6H4) 3 OCH3 Sp3 C-H amination N OCH 3 N 2 R H2N R 1 R1 5% Pd(OAc)2 K2S2O8(5eq) 93% O O NH

O NH OMe 7 1) Oxidation to form nitrene 2) Curtius Rearrangement to isocyanate 3) Pd-catalyzed o-methoxylation 8 Proposed mechanism: cyclopalladation then nitrene insertion into Pd-C bond or Pd(II) nitrene. Pd(II)/Pd(IV) is not excluded Chi-Ming Che J.Am. Chem. Soc, 2006, 128, 9048-9049 02/24/2020 17 Examples: Type of oxidant External Oxidant: bystanding oxidant: definition F+ :baystanding oxidant Example1: Indoline synthesis via Pd(II)/Pd(IV) Internal Oxidant: Example1: N-Nosyl carbamate Example2: Oxime esters 02/24/2020 18 External Oxidant Pd(II)/Pd(IV) Octahedral Pd IV: lack of selectivity Bystanding oxidant : A reagent that participates in electron transfer to increase the oxidation state of a transition metal species but is not incorporated into the final product during subsequent reductive elimination Why F+ bystanding oxidant? Yu J.-Q. Angew. Chem. Int. Ed. 2011, 50, 1478 1491

02/24/2020 19 F+: Bystanding Oxidants in Pd(II)/Pd(IV) Catalysis Cl2, CuCl2, NCS, NBS, NIS, IOAc, and PhICl2 source of X + : halogenating agent C-H activation reactions F+ more problematic: F+ reagent : strong sigma donor ligand hamper the C-H activation Highly electronegative, low polarizability : attenuate the reductive elimination 02/24/2020 20 C-H amination using F+ and Ce4+as oxidant: Indoline synthesis 10-15% Pd(OAc)2 oxydant(3eq) R NHTf 1 Oxidant: R DMF(1.25eq or 6eq) DME,1200 C 2 N Tf Ce(SO4)2 or 3 N F OTf 4

Using classical oxidation agent (CuCl2, NCS, NBS, NIS, IOAc) give halogenation/ acetoxylation side product 22 examples, yield 53-91% when F+ (two electron oxidant ) is used: large number of functionalities are tolerated (Br,Cl, F, CN, NO2), quinoline low yield 9 examples, yield 40-80% when Ce(SO4)2 Yu J., Q. J. Am. Chem. Soc., 2009, 131, 1080610807 02/24/2020 21 External-oxidant free oxidative amination: H N R R1 O 1 R1=tBu, Ph, Me NO2 2 R2= Et, Troc, Bn OR2 O O NHCO2R2 85% R R: OMe (45%) F (66%) Br(68%) tBu O N N NH O NHCO2Et NHCO2Et 72% NH

6 O 8 O NHCO2Et R2: Troc (87%) Bn (70%) NHCO2Et 7 tBu NHCO2Et 5 O OR2 21exampels, 45-87% O NH N NH 3 NH R1: t-Bu (84%) Me (52%) Ph (57%) O R 1,4-dioxane, 800C tBu 4 NH Pd(OTs)2(CH3CN)2 Internal oxidant R1 R1

O O O H S N O 9 68% NHCO2Et 10 72% Yu, J. M., J. Am. Chem. Soc., 2010, 132, 1286212864 02/24/2020 22 Proposed mechanism: Pd(II)/Pd(IV) or nitrene: a a-Pd b ab Nitrene insertion or Pd(III)/Pd(IV) intermediate Experimental observation: Isotope effect (kH/kD) =3.7 Stoichiometric amidation of cyclopaladated intermediate afford 45% of ab Anilide stabilized reactive intermediary species Treating a-Pd, a with b in presence of K2CO3(generate nitrene) give 74% desired compound 02/24/2020 23 External-oxidant free oxidative amination: Indole synthesis N R1 OAc R3 1 R2 1% Pd(dba)2 Cs2CO3(1eq)

R Toluene,1500 C R3 R2 13exemples, yield 40-70% 2 Internal oxidant H N R H N H N H N R 3 4 5 n R R1: Me (65%) F (61%) Cl (63%) Br(60%) OMe(40%) R1: Me (65%) Et (51%) n=1(41%) n=2 (51%) Hartwig J., F. J. Am. Chem. Soc., 2010, 132, 36763677 02/24/2020 24 Proposed mechanism Pd(0)/Pd(II) H N

C-N bond reductive elimination N Pd0 Ph b Pd HOAc Experimental observation: N-O bond oxidative addition OAc Pd N NH I Ph IV Ph C-H activation Ph a OAc OAc Pd NH Tautomerization II Ph C6F5 O O Complex V was isolated (X-Ray structure) Complex (1%) catalyzed the reaction with a in 58% By heating V indole b is obtained in 31%

02/24/2020 Cy3P Pd PCy3 N Ph V Ph 25 Type of C-H bond C(sp3)-H Allylic Aromatic Note : Pd(II) catlyzed addition of nitrogen nucleophiles to the alkene is not included in this talk 02/24/2020 26 Sp3-CH Amination : from aniline to indoline R1 R NH 1 O 3 mesytylene,140 0C R2 C(sp3)-H vs C(sp2)-H 4 N R2 O 22exemples, yield 24-80% 2 C(sp3)-H vs benzylic C-H Ph N Ac

NAc R1 10%-Pd(OAc)2 AgOAc, Na2CO3 Ph 5 N Ac N 6 Ac 48:52 39 :0% Large variety of groups is tolerated: Cl, OMe, CHO, ketone N 7 O R2 R2: H(73%) Me(80%) Et (59%) iPr(24%) Glorius, F. Angew. Chem. Int. Ed., 2009, 48, 6892 6895 02/24/2020 27 Allylic intramolecular C-H amination: syn-1,3 and 1,2Aminoalcohols O O S S Ph Ph Pd(OAc)2 10% PhBQ(1.05eq) THF,450C O O R NHTs

1 O NTs O R 2 6 exemples, yield 76-86% O R R: iPr (76%,7/1*) tBu (8%, 18/1) nPr (59%, 1.6/1) NTs O 3 *dr (anti:syn) O O S S Ph Ph Pd(OAc)2 10% PhBQ(1.05eq) DCE,450C O NHNs O R 4 O O NNs O NNs R

5 15exemples, yield 58-87% O O O O O O NNs O NNs O NNs R 6 76%, 3.4/1 7 67%, 4.5/1 8 76%, 3.4/1 9 R: iPr (80%, 6/1) tBu (84%, 6.3/1) Et (87%, 4.3/1) White,C. J.Am.Chem.Soc., 2007, 129, 7274-7276; White,C. J.Am.Chem.Soc., 2009, 131, 11707-11711 Stoichiometric allylic amination: Hegedus,L.S. J. Am. Chem. SOC. 1981, 103, 3037 ; Trost, B.M. Tetrahedron, 1977, 33, 2615 Possible mechanism: Allylic C-H amination / isomerization of double bond followed by aminopalladation O O NHTs 1 O O S S

Ph Ph Pd(TFA)2 10% PhBQ(1.05eq) d8-THF,450C O O O Bu4NOAc NHTs O NTs R 2 LPd(TFA) 3 61% by NMR 75%, dr 6/1 O Alkene 4 give very poor yield (9% for Z, 20% for E) Proposed mechanism: O 4 OH O O LPd(OAc)2 OH R O O

O LPd(0) NTs R O IV LPd(OAc) N Ts O II AcOH R b NHTs R O O Electrophilic C-H cleavage a I 2 AcOH Nucleophilic functionalization NHTs O Catalyst and endogenous base regeneration NHTs Acid/Base exchange +

LPd III 02/24/2020 29 Allylic intermolecular C-H amination Heterobimetallic catalysis : Lewis Acid catalysis Cr bind to BQ -Allyl complex increasing his electrophilicity R Ts H H N OMe O 1 2 O O S Ph Ph S Pd(OAc)2 10% Cr(III)(salen)ClPh(6%) BQ(1.05eq) TBME,450C Ts N R OMe O 3 7exemples, yield 52%-72% Bronsted base activation : Exogenous base will increase the concentration of deprotonated nucleophile nitrogen R Ts H 4 H N

OMe O O O S Ph Ph S Pd(OAc)2 10% R DIPEA(6%),BQ(2eq) TBME,450C O 5 12exemples, yield 55-89% Ts N OMe pKa~3.5 White, C. J.Am.Chem.Soc., 2008, 130, 3316-3318 White, C. J.Am. Chem. Soc., 2009, 131, 1170111706 02/24/2020 30 Aromatic intramolecular amination with amine O NHAr R O Pd(OAc)2 AgOAc, CsF OBz N 2 R1 R DCE,1300 C N R2 18exemples, yield =56-90% Ar=4-CF3-C6H4

1 2 3 O O R tBu N O R: OMe (79%) Br (56%) Cl (60%) Me(82%) N NHAr NHAr tBu 5 tBu N 6 73% NHAr NHAr N tBu N 9 97% Ph 75% O O

tBu N 7 80% 8 O O NHAr NHAr 4 NHAr R1 R NCO2tBu 78% No external oxidant is required Reaction work as well with amine in presence of benzoyl peroxide CsF as base, cycloppaladation, Pd(II)/Pd(IV) or electrophilic amination Pd(dba)2 catalyzed as the reaction: N-O bond oxidative addition Jin-Quan Yu, JACS, 2011 02/24/2020 31 Thank you for your attention! 02/24/2020 32

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