Metal Catalyzed Outer Sphere Alkylations of Unactivated Olefins and Alkynes

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1 Metal Catalyzed uter Sphere Alkylations of Unactivated lefins and Alkynes Stephen Goble rganic Super-Group Meeting Literature Presentation ctober 6,

2 utline I. Background Introduction to Carbometallation Inner Sphere vs. uter Sphere Review of Seminal Work II. III. IV. Catalytic Palladium Systems Catalytic Platinum Systems Catalytic Gold Systems 2

3 I. Background: Carbometallation is the formal addition of a metal and a carbon atom across a double bond. Cis addition would involve olefin insertion in to an σ-alkyl-metal species. This is an Inner Coordination Sphere process. [M] R cis addition olefin insertion The alkyl-metal species could arise from: 1. xidative addition of the metal to an electrophile. 2. Transmetallation of a nucleophile to the metal. 3. irect nucleophilic attack on the palladium. Trans addition would involve an uter Coordination Sphere nucleophilic attack on the metal-olefin coordination complex. trans addition [M] [M] R - R [M] R 3

4 First xample: Carbopalladation of an lefin Tsuji, J. and Takahashi,. J. Am. Chem. Soc (14), R 2 C PdCl 2 R R C 2 R a 2 C 3 Cl Amino and xo-palladations (i.e. Wacker Process) were previously known and have since been much more widely studied. o distinction between cis and trans nucleophilic addition made. 4

5 Carbopalladation on Styrene: ifferent Modes of Attack Proposed different modes of attack based on different observed products with MeLi vs. a-malonate: Murahashi, S. et. al. J. rg. Chem (17), ucleophilic Attack on Pd lefin Insertion B-ydride limination C 3 Li PdX 2 C 3 Inner Sphere Mechanism C 3 - Palladium Coordination ucleophilic Attack B-hydride elimination ac(c 2 R) PdX 2 C 2 R C 2 R - C 2 R C 2 R + uter Sphere attack usually occurs at the more substituted carbon - more stabilization of + charge (In intermolecular processes). - Stoichiometric in Pd 5

6 First irect vidence of Trans Addition Kurosawa,. et. al. Tetrahedron Lett , a + TF -19 C C 2 J=4.2 z = [Pd(n 5 -C 5 5 )(PPh 3 )] + Cl 4 - a + TF -19 C C 2 J=12.3 z = [Pd(n 5 -C 5 5 )(PPh 3 )] + Cl 4-6

7 Palladium-Assisted Alkylation of Unactivated lefins egedus, L. S. et. al. J. Am. Chem. Soc , Wanted general procedure for uter Sphere carbopalladations on unactivated olefins but reduction of Pd (II) was a problem. vercame problem of nucleophilic reduction of Pd (II) by using t 3, in a stepwise, one pot procedure. R' Pd(0) R 1. PdCl 2 (MeC) 2, TF, RT 2. t 3 (2 q), TF, -78 C 2 flush -60 C R R = alkyl PdCl 2 (MeC) 2 TF RT Cl Pd Cl R 3. C(a)C 2 R', TF, -60 C t 3 (2 q) -78 C C(a)C 2 R' TF, -60 C Cl Pd t 3 t 3 R -60 to RT Cl-Pd- Pd (0) R' R 7

8 Palladium-Assisted Alkylation of Unactivated lefins (Continued) egedus, L. S. et. al. J. Am. Chem. Soc , Worked well on a variety of terminal olefins. Internal alkenes gave only traces of reaction. Worked with a variety of malonates. Without triethylamine, reductive dimerization predominates. Using MPA as an additive the reaction works on a variety of un-stabilized nucleophiles: nolates of ketones and esters. Un-stabilized nucleophiles are usually ineffective because they attack the palladium first Inner Sphere. First Intramolecular case: C 2 Me C 2 Me PdCl 2 (MeC) t 3, TF ( 2 flush) C 2 Me C 2 Me In all cases the reaction is stoichiometric in Palladium. 42% Yield 8

9 Problems with Catalysis Since the process is a formal reduction of the metal (Pd (II) to Pd (0) re-oxidation of the metal is necessary. Problem: Carbanions are very easily oxidized. Reductive dimerization is a problem in carbopalladations: Pd (II) + 2 Me 2 C C 2 Me Pd (0) + Me 2 C Me 2 C C 2 Me C 2 Me Therefore, any oxidant strong enough to oxidize the metal will probably oxidize the carbanion preventing any desired reaction. 9

10 Palladium-Promoted Alkylation of lefins by Silyl nol thers Silyl enol ethers transmetallate to Pd (II), β- limination gives α,β-unsaturation: Ito, Y., Aoyama,., irao, T. Mochizuki, A., and Saegusa, T. J. rg. Chem (5), TMS Pd() 2 MeC observed intermediate oxo-π-allylpalladium - When an olefin is present, a formal insertion product is recovered : Ito, Y., Aoyama,., irao, T. Mochizuki, A., and Saegusa, T. J. Am. Chem. Soc (2), R 1 R 2 TMS Pd() 2 n MeC + R 1 R 1 R 2 R 2 Works on a variety of substrates. Since silyl enol ethers don t get oxidized by Pd (II), they could get some weak catalysis (0.5 Molar quiv) using a benzoquinone re-oxidant but yields suffered. 10

11 Palladium-Promoted Alkylation of lefins by Silyl nol thers Ito, Y., Aoyama,., irao, T. Mochizuki, A., and Saegusa, T. J. Am. Chem. Soc (2), By analogy they proposed this Inner Sphere mechanism: R 2 TMS Pd() 2 R 2 olefin R 1 n MeC R 1 n insertion n R 2 R 1 R 1 R 2 n Beta- lim Isomerism But in a footnote they noted another possibility: R 1 TMS n R 2 R 1 n R 2 R 1 R 2 11

12 Palladium-Promoted Alkylation of lefins by Silyl nol thers uring the synthesis of (+/-)-Quadrone, the mechanism of this cyclization was explored: Kende, A. S. et al. J. Am. Chem. Soc , C 2 t Pd() 2 TMS MeC C 2 t Product distributions in a model system are consistent an uter Sphere process: TMS Pd() 2 Me Pd() 2 A MeC 58% 14% Me Pd() 2 MeC o Reaction TBS Pd() 2 C MeC 40% 20% Li Pd() 2 B MeC MeC 45% 22% If desilylation is first step: A and B and should give same distribution, and C should not react (because it doesn t form an enone in ). Cyclization and enone formation does not proceed through same intermediate. vidence supports an uter Sphere mechanism. 12

13 Pt (II) Additions to thylene Fanizzi, F. P et. al. J. Chem. Soc. alton Trans Cl Pt C 2 (C 2 t) a 2 C 3 CM, RT Pt Cl C 2 t C 2 t Addition is irreversible. Also works with inorganic nucleophiles ( 2-, 3-, C - ). eating to 50 ºC gives β-hydride elimination. Treatment of product with acids results in the facile cleavage of the Pt-C bond, regenerating Pt (II). Pt Cl C 2 t C 2 t 0.5 M Cl 2 or C 2 t C 2 t Cl/CCl 3 13

14 Summary Up to ~2001 uter Sphere carbopalladations are stoichiometric in palladium. Pd/amine and Pt/amine complexes are the only known promoters. The products of carbopalladations (alkyl-palladium complexes) undergo β- hydride elimination above -20 ºC. The carbopalladation products can be quenched with 2 by simply flushing the system below -20 ºC. Stabilized and non-stabilized carbon nucleophiles work well. Using silyl enol ethers as the nucleophile allows weak catalysis (50 mol%), but technical problems with the system limit its utility. ne isolated example of a Pt (II) cationic complex adding to ethylene. o other late TM system is known. egedus: [The process] is unlikely to find extensive use in synthesis egedus, L. S. Transition Metals in the Synthesis of Complex rganic Molecules University Science Books, Sausalito, California. 14

15 II. First xample of TM (Pd) Catalysis - ydroalkylation Pei, T. and Widenhoefer, R. A. J. Am. Chem. Soc , Looking at carbopalladations to get cyclopentanones: expected PdCl 2 (MeC) 2 (1 q) TF, 25 C Surprising results: o net oxidation and endo ring closure. 70 % If no net oxidation, then Pd (II) would not be reduced and catalysis is possible: PdCl 2 (MeC) 2 (5%) ioxane, 25 C 81% Mono terminal substitution on olefin is well tolerated. α-substitution is tolerated. β-keto esters give lower yields. But using TMSCl as an additive gives comparable yields (Pei. T and Widenhoefer, R. A. Chem. Comm ) 15

16 Mechanistic Investigation Qian,. and Widenhoefer, R. A. J. Am. Chem. Soc , possible mechanisms: uter vs. Inner Sphere Inner Sphere Path uter Sphere Path + + trans cis Br PdCl 2 (MeC) 2 (5%) Ph 2 S ame Br ioxane, 25 C Me Ph 2 C 2 S Results are consistent with an outer coordination sphere mechanism. 16

17 17 Mechanistic Investigation (Continued) Qian,. and Widenhoefer, R. A. J. Am. Chem. Soc , ther labeling experiments: C 3 C 3 Palladium migration around the ring must occur.

18 Mechanistic Investigation (Continued) Qian,. and Widenhoefer, R. A. J. Am. Chem. Soc , Plausible mechanism with palladium migration: + - Cl L L Pd Cl Cl Cl 18

19 xtension to on-stabilized nolates Wang, X., Pei, t., an, X. and Widenhoefer, R. A. rg. Lett (15), arly Investigations: R PdCl 2 (MeC) 2 (10%) TMSCl CuCl 2 (1 eq) R TMSCl to generate silyl enol ether in situ. CuCl 2 to stabilized oxidation state of Pd. MR analysis of the reaction showed no in situ formation of enol ether concluded that Cl promotes reaction (formed from residual moisture and TMSCl). ptimized conditions: R PdCl 2 (MeC) 2 (10%) Cl/CuCl 2 (1 eq) sealed tube R Worked on a variety of aryl and alkyl R groups. isubstitution to make quaternary centers also tolerated. 19

20 First Pd Catalyzed xidative Alkylation of lefins Pei. T. Wang, X., and Widenhoefer, R. A. J. Am. Chem. Soc (3), Initial investigations with the previous system gave only hydroalkylation. But, extending the chain by one methylene gave the desired conversion. PdCl 2 (MeC) 2 (5%) CuCl 2 (2.5 eq) C, RT CuCl 2 is a stoichiometric re-oxidant. Reaction can be catalytic in CuCl 2 (10%) with 2 atmosphere. 20

21 Proposed Mechanism: PdCl 2 CuCl 2 Pd(0) Cl Cl-Pd- Cl B- lim 21

22 III. Pt (II) Alkylation of lefins with Indoles Liu, C., an, X., Wang, X., Widenhoefer, R. A. J. Am. Chem. Soc xtension of Pd (II) system to indole carbon nucleophiles? Pd(II) system o Reaction As we saw earlier: Cationic Pt (II) complexes are highly reactive toward outer sphere attack. Pt (II) alkyl metal complexes are highly reactive toward protonolysis. Fanizzi, F. P et. al. J. Chem. Soc. alton Trans Using a simple Pt (II) catalyst: [PtCl 2 (C 2 C 2 )] (2.5%) ioxane 90 C, 12 h 87% 22

23 Pt (II) Alkylation of lefins with Indoles Liu, C., an, X., Wang, X., Widenhoefer, R. A. J. Am. Chem. Soc ptimized system: PtCl 2, ioxane, 60 C, h. Works on a variety of indoles. Also found that asymmetric alkylation was possible (69% e.e.) with a Pt (II)- BIPP complex. Is this actually an uter Sphere process? Stoltz has reported a C- activation/olefin insertion mechanism (Inner Sphere) for this related system: Ferreira,. M. and Stoltz, B. J. Am. Chem. Soc (32), % Pd() 2 Bn 40% pyridine PhMe, 2, 80 C Bn Stereochemistry results from a syn addition/syn β- elim pathway. 23

24 Pt (II) Alkylation of lefins with Indoles Liu, C., an, X., Wang, X., Widenhoefer, R. A. J. Am. Chem. Soc [Pt] Inner Sphere Path uter Sphere Path [Pt] [Pt] [Pt] PtCl 2 (2%) Lack of scrambling argues against a reversible β- elimination/addition. 24

25 Pd (II) Alkylation of lefins with Indoles Liu, C. and Widenhoefer, R. A. J. Am. Chem. Soc Palladium system undergoes the same alkylation but protonation does not occur the resulting alkyl-pd species must be quenched with C/alcohol. PdCl 2 (MeC) 2 (5%) R, CuCl 2, C RT C 2 R Mechanism studies once again show an outer-sphere alkylation process followed by syn-c insertion. Pt (II) system does not undergo C insertion. System also works on 3-alkyl indoles. 6-endo cyclization suggests similar outer sphere mechanism (direct contrast to Stoltz systems): PdCl 2 (MeC) 2 (5%) R, CuCl 2, C RT C 2 R 25

26 IV. Gold (I) Catalyzed Conia-ne Reaction Kennedy-Smith, J. J., Staben, S. T., and Toste, F.. J. Am. Chem. Soc (14), Conia-ne Reaction: Au (I) catalyzed version: Me AuTf(PPh 3 ) (5%) C, RT Me 80-95% yield on a variety of terminal alkynyl β-keto ester substrates. Good d.r. observed with 3 and 4 substitutions. Low catalyst loading, short reaction times and open-flask conditions. Is the mechanism consistent with an inner or outer sphere mechanism? 26

27 Gold (I) Catalyzed Conia-ne Reaction (Continued) Kennedy-Smith, J. J., Staben, S. T., and Toste, F.. J. Am. Chem. Soc (14), possible mechanisms: uter Sphere Me Inner Sphere Me 2 C Me 2 C [Au] [Au] Me 2 C Me 2 C Au Au Me euterium label study: Me Me Supports an uter Sphere mechanism Me Me 27

28 Another Gold (I) Catalyzed Carbocyclization Staben, S. T., Kennedy-Smith, J. J., and Toste,. Angew. Chem. Int. d Au (I) also catalyzes the 5-endo-dig cyclization of δ-alkynes: Me Me AuTf(PPh 3 ) (1-5%) CM, RT Works on a variety of β-keto esters and alkynes. The reaction even tolerates terminal halo substitution on the alkyne. By analogy to the previous system, they proposed a outer-coordination sphere mechanism involving initial gold coordination to the alkyne. nce again this reaction is substrate specific. 28

29 Summary Carbopalladations are an effective C-C bond forming reaction. uter Sphere (trans) processes have seen limited use in synthesis. Inherent problem of carbon nucleophiles reducing Pd (II). Prior to 2001, all reactions where stoichiometric in Pd. The past 3 years have seen a revival of uter Sphere carbopalladation chemistry. First catalytic system: ydroalkylations using Pd (II). xidative alkylations were developed and made catalytic using a stoichiometric CuCl 2 re-oxidant. Pt (II) and Au (I) systems have expanded the scope of substrates and nucleophiles. All the systems remain highly substrate specific. The search continues for a general system for efficient catalysis over a range of substrates. 29