Chapter 2. Cross-coupling Reactions

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Presentation transcript:

Chapter 2. Cross-coupling Reactions Transition Metal Catalyzed Rxns 2 Spring 2006 Chapter 2. Cross-coupling Reactions halides/pseudohalides: aryl/alkenyl/allyl/benzyl-X reactivity: N2+ > I > OTf ≥ Br >> Cl (OMs) >> F M: C(sp2)-X > C(sp3)-X; Mg: C(sp2)-X < C(sp3)-X alkyl halides: facile -H elimination with Pd aryl halides: (hetero)Ar-Pd-X by oxidative addition reactions with alkenes, alkynes, CO: insertion of Ar-Pd reactions with RM’ & Nu-: transmetallation & substitution TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Halides / Pseudohalides (II) Transition Metal Catalyzed Rxns 2 Spring 2006 Halides / Pseudohalides (II) alkenyl halides: alkenyl-Pd-X formation of alkenyl-Pd-X from carbonyl compounds insertion, transmetallation & nucleophilic substitution alkynyl halides: alkynyl-Pd-X Ni-catalyzed couplings: different from [Pd] alternative to Pd: cheap & reactive but sensitive & toxic TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Cross-coupling with Alkenes: (Mizoroki-)Heck Transition Metal Catalyzed Rxns 2 Spring 2006 Cross-coupling with Alkenes: (Mizoroki-)Heck Neutral pathway: oxidative addition reductive elimination syn-elimination syn-insertion internal rotation TranMetalRxn 2 Chap 2

The Heck Reaction: Mechanism (II) Transition Metal Catalyzed Rxns 2 Spring 2006 The Heck Reaction: Mechanism (II) Ionic pathway: elimination TranMetalRxn 2 Chap 2

The Heck Reaction: Scope (I) Transition Metal Catalyzed Rxns 2 Spring 2006 The Heck Reaction: Scope (I) X: N+2 > I > OTf ≥ Br >> Cl (OMs) >> F Cl: Ni(0), high pressure, t-Bu3P/Cs2CO3, PCy3, t-Bu2P(2-biphenyl), [Angew. Chem. Int. Ed. Engl. 1999, 38, 3307 ] alkenes: mono-/disubstituted (intermolecular) intramolecular (tetrasubstituted) / carbonyl substituted allylic alcohols: carbonyls via Pd-H elimination/addition catalysts: high TON (9800-200,000) Pd(OAc)2, PdCl2[(MeCN)2], Pd2(dba)3, Pd(PPh3)4, Pd/C reducing agents: alkene, amine, ligand (phosphane) TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

TranMetalRxn 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

The Heck Reaction: Scope (II) Transition Metal Catalyzed Rxns 2 Spring 2006 The Heck Reaction: Scope (II) solvents: DMF, DMSO, NMP, MeCN, MeOH, THF, dioxane, PhH, PhMe, EDC, CHCl3, NEt3, HNR2, H2O, neat ligand: PPh3, P(o-Tol)3, PR3, TMSPP (P(Ph(m-SO3Na))3), TFP, DPPB, DPPF, DIPPP, chiral ligands (BINAP) bases: TEA, PMP, DABCO, proton sponge,K2CO3, NaHCO3, KOtBu, NaOAc, Cs2CO3 additives: LiCl, NaBr, TBAX (X = Cl, Br), Ag2CO3, Tl2CO3 “Jeffery conditions”: Pd(OAc)2, KHCO3, TBAX, DMSO (DMF) [TL 1985, 26, 2667 & Chem. Comm. 1984, 1287] others: solid support, molecular sieves, high pressure, microwave irradiation, temperature, concentration TranMetalRxn 2 Chap 2

The Heck Reaction: ligands Transition Metal Catalyzed Rxns 2 Spring 2006 The Heck Reaction: ligands TranMetalRxn 2 Chap 2

Cross-coupling via Transmetallation: Principle Transition Metal Catalyzed Rxns 2 Spring 2006 Cross-coupling via Transmetallation: Principle M = Na, Mg, Zn, B, Al, Zr, Sn, Si; Ar’ = R (Ar), H, M’R TranMetalRxn 2 Chap 2

Cross-coupling via Transmetallation (I) Transition Metal Catalyzed Rxns 2 Spring 2006 Cross-coupling via Transmetallation (I) M = MgX; (Tamao-)Kumada-Corriu reaction Grignards: cheap & easy to make but reactive to FGs RMgX with FGs (CN, CO2R, OCOR, Cl): JOC 2000, 5428 transition metals: (L2)NiX2 often preferred to Pd active to Cl & less b-elimination with DPPE / DPPP M = ZnX: Negishi (coupling) reaction preparation of [Zn] reagents: RX(RLi) + Zn(X2)  RZnX R2Zn: R-I + Et2Zn (CuX cat.) / RC=CH2 + Et2BH & Et2Zn tolerance to various FGs: ketone, ester, amine, nitrile incompatible with N3, NO2, OH TranMetalRxn 2 Chap 2

Cross-coupling via Transmetallation (II) Transition Metal Catalyzed Rxns 2 Spring 2006 Cross-coupling via Transmetallation (II) M = BR’2: Suzuki(-Miyaura) reaction tolerance to wider FGs & water / easier disposal unreactive without a base preparation: hydroboration of alkenes and alkynes ArMgX(Li) + B(OR)3  ArB(OR)2  ArB(OH)2 M = SiR’3: Hiyama coupling activation with F- (TBAF / TASF / KF) tolerance to broad FGs & nontoxic but expensive preparation: ArMgX + EtSiCl3  ArSiEtCl2 TranMetalRxn 2 Chap 2

Cross-coupling Reactions: M = SnR’3 Transition Metal Catalyzed Rxns 2 Spring 2006 Cross-coupling Reactions: M = SnR’3 the Stille(-Migita-Kosugi) reaction (coupling) tolerance to broad FGs: aldehyde, amine, alcohol no base needed but toxic  catalyst: mostly ‘Pd’ preparation: transmetallation with R3Sn-SnR3 ArMgX + R3SnCl  ArSnR3 transfer rate of R: CC > C=C > Ar > Allyl  Bn > R ligand effect: TPA (1100) > TFP (105) > TMPA (< 0.07) additives: Cu(I), Ag(I), LiX TranMetalRxn 2 Chap 2

Reactions with Alkynes: Cross-coupling Transition Metal Catalyzed Rxns 2 Spring 2006 Reactions with Alkynes: Cross-coupling Castro(-Stephens) reaction Sonogashira reaction: terminal alkynes mild conditions with CuX: mechanism other metals: Zn, Sn, Mg; [alkynyl-M’] no CuX: TPPTS (TMSPP) in water, piperidine or pyrrolidine, BuN4X, Et3N (Shen, W. OL, 2000, 2857) ‘Living’ alkenylpalladium: cascade reactions TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2

Transition Metal Catalyzed Rxns 2 Spring 2006 TranMetalRxn 2 Chap 2