1. 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

2. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

3. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

4. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

5. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

6. 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

7. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

8. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

9. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

10. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

11. 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

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

13. 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 ( ,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

14. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

15. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

16. TranMetalRxn 2

17. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

18. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

19. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

20. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

21. 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

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

23. 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

24. 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

25. 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

26. 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

27. 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

28. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

29. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

30. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

31. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2

32. Transition Metal Catalyzed Rxns 2
Spring 2006
TranMetalRxn 2
Chap 2