Additions to Metal-Alkene and -Alkyne Complexes

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1 Additions to tal-alkene and -Alkyne Complexes ecal that alkenes, alkynes and other π-systems can be excellent ligands for transition metals. As a consequence of this binding, the nature of the π-system changes from weakly nucleophilic to electrophilic. vacant d orbital M filled metal d orbital + + filled C=C π-bond as σ-donor + C C + vacant C=C π* orbital A lot of very rich chemistry here. We will focus our attention on reactions promoted by Pd(II) and Au(I). The addition of the nucleophile can be external or internal. Nu L n M + L n M (external) Nu Nu L n M (external) Attack on ligand favored by: saturated metal center π-accepting ligands electron-poor metal centers cationic complexes soft nucleophiles L n M Nu trans-addition L n M Nu cis-addition The resulting σ-alkyl or σ-alkenyl complexes can proceed to do other reactions.

2 Palladium (II)-Catalyzed Additions PdCl 2 and Pd(AC) 2 are commonly used. Strong donor ligands (phosphines) tend to shut down reactivity. Weaker donor ligands (pyridines) can be used. Acceptor ligands (nitriles) also good. PdL 2 X 2 trans-attack at most substituted end X Pd X L π-alkene Pd(II) + Nuc X Nuc L Pd X L σ-alkyl Pd(II) B..E. Nuc + Cl + Pd(0) Z M C 2 or formate Nuc L Pd X Z L Pd L Nuc L Nuc C Pd X Nuc + Pd(0) All transformations involving the σ-alkyl palladium intermediate will eventually generate Pd(0). Either stoichiometric amounts of metal are needed or a reoxidant must be present. B..E..E..E. Pd(0) Pd(0) Pd(0)

3 Stoichiometric xidants for Generating Pd(II) Several stoichiometric reoxidant systems have been developed for convering Pd(0) back to Pd(II). There are advantages/disadvantages with each. Choice determined by what else in going on the system and the stability ofstarting material/products toward the oxidant. CuCl 2 or CuCl 2 w/ 2 : likely involves sequential SET reactions. Catalytic in Cu if 2 (1 atm) is used. Pd(0) + 2 CuCl 2 PdCl CuCl 2 CuCl + 2 Cl + 1/2 2 2 CuCl Benzoquinone (BQ): Very mild and compatible with lots of functional groups. Stoichiometric organic impurity that must be removed. X X + PdX 2 Pd(0) Pd X XPd 2 (1 atm): If the reaction is carried out in DMS or with pyridine ligand, then 2 can be used by itself. (pyr) 2 Pd 2 (pyr) 2 Pd 2 X (pyr) 2 PdX

4 Wacker xidation ne of the first palladium-catalyzed reactions. Discovered by the process group at Wacker Chemie (Angew. Chem. Int Ed. Engl. 1962, 1, 80). rginially developed to convert ethylene into acetaldehyde. as since become a general way to convert a monosubstituted olefin into a methyl ketone. cat. PdCl 2 cat. CuCl 2 (or Cu(Ac) 2 2 (1 atm) DMF, 2 Bn PdCl 2, 2 Bn Bn PG DMF, 45 ºC 60% PG PG C 2 C 2 PdCl 2, CuCl 2 2, 2, DMF 65%

5 Internal olefins are typically much slower to react Wacker xidation Ac PdCl 2, CuCl 2 2, DMF 70 83% Ac In some cases a neighboring group, can alter the regioselectivity and form an aldehdye MPM PdCl 2, CuCl 2 2, 2, DMF 95% MPM C MPM PdCl 2, CuCl 2 2, 2, DMF 93% MPM

6 Wacker-Type Cyclizations Tethered nucleophiles (typically and N) can be used to form heterocycles. Both terminal and internal olefins work well. Can be coupled with other processes. 5 mol% Pd(Ac) 2 DMS, 2 95% PdCl 2 CuCl 2, 2 NTs 2 C 84% 85% ee 86% ee Pd(Ac) 2, pyridine 2 (1 atm), xylene 80 ºC, 87% Ts N Pd(CN)(BF 4 ) 2 chiral ligand, BQ, 90% N Bz PdCl 2 (CN) 2 (20 mol%) 77% Note catalysis without oxidant N Bz 97% ee

7 Wacker-Type Cascades Bz Pd( 2 CCF 3 ) 2 chiral ligand C 2 Cl 2, BQ, 0 ºC 89%, 82% ee Bz Ph PdCl 2, CuCl 2, C NaAc, Ac 90% Ph Pd( 2 CCF 3 ) 2 chiral ligand C 2 C 2 Cl 2, BQ 3.5 days 84%, 96% ee C 2

8 Enol Ether Substrates (Saegusa xidation) Useful C C bond formations can be accomplished with silyl enol ether nucleophiles Piv LDA TBSCl TF, MPA Piv TBS Pd(Ac) 2 2 DMS 74% Piv More commonly, silyl enol ethers are oxidized to enones. riginally used stoichiometric amounts of Pd because turnover was not observed with BQ. Catalysis can be acheived with 2 and DMS. TES EtAlCl 2 TES Pd(Ac) 2 TMS Toluene TMS DMS 64% 10 mol% Pd(Ac) 2 2 (1 atm) DMS, rt 72 hrs

9 Additions to Alkynes Alkynes are also excellent π-lignads for Pd(II). Nucleophilic addition produces an alkenyl Pd intermediate that is more stable than the alkyl Pd intermediates generted from alkenes (B..E. not a problem). This can be intercepted by other processes or undergo protodemetallation (regenerates Pd(II)). C mol% PdCl 2 (PhCN) 2 + C6 13 C % 45% 2 PdCl 2 (PhCN) % NAc PdCl 2 (PhCN) 2 Et 3 N PdCl 2 CN 84-93% TF, Δ 100% N Ac

10 Arylations of Alkynes ydroarylation of alkynes likely invovles initial palladation of aromatic. Similar reactions with alkenes. + C 2 Et Pd(Ac) 2, TFA C 2 Cl 2, rt, 78% C 2 Et Ph + Ph C 2 Et Pd(Ac) 2, Ac C 2 Cl 2, rt, 72% C 2 Et Using Pd(II) formed from oxidative addition. Ph NCCF 3 + Tf 5 mol% Pd(PPh 3 ) 4 Et 3 N C 3 CN, rt, 74% N Ph CCF 3

11 The Pauson-Khand eaction Coupling of an alkyne, alkene, and C to give a cyclopentenone. Both inter - and intramolecular variants are possible. ften use stoichiometric amounts of Co 2 (C) 8, but catalytic versions are known as well as with other metals. ftern requires high temperatures Co 2 (C) 8 solvent, heat Plausible mechanism: Co 2 (C) 8 2 C (C) 3 Co Co(C) 3 C (C) 3 Co Co(C) 2 (C) 3 Co Co C C alkene insertion + C (C) 3 Co(C) 3 Co Co 2 (C) 6 Co(C) 3 Co(C) 3 alkene insertion + C Co(C) 3 Co(C) 3

12 The Pauson-Khand eaction C 2 (C) 8, 4Å ms, Ph then 3 N, 2, Ph 60_70% rg. Lett. 2005, 7, amine oxides and other Lewis bases can be used as a promoter Co 2 (C) 8 C 2 (C) 6 NM 3 Si Et then Et 2 AlCl 82% J. Am. Chem. Soc. 1997, 119, % alkyne-cobalt complexes are quite stable and can be use as a protecting group and to stabilize propargylic cations TIPS C 2 (C) 6 + S N 2 NM CN 62% dr 97:3 S TIPS Ar Chem. Eur. J. 2004, 10, 5443.