1

Kumada Coupling [Mg]

Huang, J.; Nolan, S. P., "Efficient cross-coupling or aryl chlorides with aryl Grignardreagents (Kumada reaction) mediated by a palladium/imidazolium chloride system."J. Am. Chem. Soc. 1999, 121, 9889-9890.

Stille Coupling [Sn]

JOC 1991, 56, 2883. TH 1992, 48, 2957. Organometallics 1991, 10, 1993.

P. Wipf 1/30/2007

2

JACS 1984, 106, 7500: capnellene

Negishi Coupling [Zn]Tius, M. A.; Gomez-Galeno, J.; Gu, X.; Zaidi, J. H., "C-glycosylanthraquinone synthesis: Totalsynthesis of vineomycinone B2 methyl ester." J. Am. Chem. Soc. 1991, 113, 5775-5783.

P. Wipf 1/30/2007

3

Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 117, 558; Wipf, P.; Lim, S. Chimia 1996, 50, 157.

Mori, Y.; Seki, M., "Highly efficient phosphine-free Pd(OAc)2-catalyzedFukuyama coupling reaction: Synthesis of a key intermediate for (+)-biotin underlow catalyst loading." Synlett 2005, 2233-2235.

P. Wipf 1/30/2007

4

Suzuki Coupling [B]

esp. for biaryl couplings:

Ligand selection: It is often crucial to optimize ligand selection by empirical screeningof ligands and catalyst/ligand ratios:

P. Wipf 1/30/2007

5

For difficult substrates in the Suzuki coupling, it is useful to apply the followingconditions:

Review: Frisch, A. C.; Beller, M., "Catalysts for cross-coupling reactions with non-activatedalkyl halides." Angew. Chem., Int. Ed. 2005, 44, 674-688.

As the C(sp3)-X bond in alkyl halides is more electron rich than the C(sp2)-X bond in aryl andvinyl halides, the propensity of alkyl halides to undergo oxidative addition to a low-valenttransition-metal complex (i.e. formal reduction of C(sp3)-X) is much lower than that of aryl andvinyl halides. The resulting alkyl–metal complex is highly reactive owing to the absence ofstabilizing electronic interactions with the metal d-orbitals. The fast and thermodynamicallyfavored β-hydride elimination leads to the predominant formation of olefinic by-products withmost catalyst systems. The relatively slow reductive elimination of the cross-coupling productfrom the catalyst (aryl–aryl>aryl–alkyl>alkyl–alkyl) makes side reactions even more likely.Therefore, the design of new, more active catalyst systems and the development of suitablereaction conditions for cross coupling reactions of alkyl halides have generally been aimed atfacilitating the oxidative-addition and reductive-elimination steps and preventing the competingβ-hydride elimination.

P. Wipf 1/30/2007

6

Postulated mechanism of the alkyl–alkyl cross-coupling and the β-H elimination as aside reaction:

Organohalosilanes (Hiyama, Hatanaka) & Siloxanes (DeShong,Tamao, Shibata, Denmark):

Denmark, S. E.; Sweis, R. F., "Design and implementation of new, silicon-based,cross-coupling reactions: Importance of silicon-oxygen bonds." Acc. Chem. Res.2002, 35, 835-846.

P. Wipf 1/30/2007

7

Alternative Preparation of Organocopper/palladium species byDecarboxylation:

Goossen, L. J.; Deng, G.; Levy, L. M., "Synthesis of biaryls via catalyticdecarboxylative coupling." Science 2006, 313, 662-664. An ortho-activatingfunction such as nitro is generally required for good yield.

Proposed mechanism:

P. Wipf 1/30/2007

8

Sonogashira Coupling [Cu]

Over the past few decades, the Pd-catalyzed alkynylation has emerged as one of themost general and reliable methods for the synthesis of alkynes. Currently, the mostwidely used by far is a hybrid of the Cu-promoted Castro-Stephens reaction and thealkyne version of the Heck reaction, which is known as the Sonogashira reactionoriginally reported in 1975. This reaction is considered generally superior to eitherthe Castro-Stephens reaction or the Heck protocol without the use of a Cu salt, and itis normally used without checking the comparative merits among them, even thoughthe Heck protocol, which is inherently simpler than the Sonogashira reaction, hasbeen shown to be highly satisfactory in a number of cases. For a review, see:Negishi, E.-I.; Anastasia, L. Palladium-catalyzed alkynylation. Chem. Rev. 2003,103, 1979-2017.

Calicheamicin/esperamicin studies:

P. Wipf 1/30/2007

9

Related: sp2 - sp Couplings:

π-Allyl Palladium ChemistryTrost, Tsuji; catalytic cycle:

X = Cl > OCO2R > OAc >> OH

P. Wipf 1/30/2007

10

J. E. Bäckvall ... JACS 1990, 112, 3683:

P. Wipf 1/30/2007

11

B. M. Trost, THL 1986, 27, 5695:

Wipf, P.; Rector, S. R.; Takahashi, H., "Total synthesis of (-)-tuberostemonine." J.Am. Chem. Soc. 2002, 124, 14848-14849.

P. Wipf 1/30/2007

12

Decarboxylation – Propargylation

- Rayabarapu, D. K.; Tunge, J. A., "Catalytic decarboxylative sp-sp3 coupling." J.Am. Chem. Soc. 2005, 127, 13510-13511.

P. Wipf 1/30/2007

13

Asymmetric O-Alkylation

- Trost, B. M.; Toste, F. D., "A catalytic enantioselective approach to chromans andchromanols. A total synthesis of (-)-calanolides A and B and the vitamin E nucleus." J. Am.Chem. Soc. 1998, 120, 9074.

Asymmetric Allylic Alkylation

Trost, B. M.; Schroeder, G. M., "Palladium-catalyzed asymmetric alkylation of ketoneenolates." J. Am. Chem. Soc. 1999, 121, 6759-6760.

P. Wipf 1/30/2007

14

Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J., "Asymmetric synthesis ofactive pharmaceutical ingredients." Chem. Rev. 2006, 106, 2734-2793.

Cylization-Anion Capture Cascade

- Grigg, R.; Rasul, R.; Savic, V. Tetrahedron Lett. 1997, 38, 1825.

P. Wipf 1/30/2007

15

Sequential Asymmetric Allylic Alkylation – Intramolecular Heck Reaction

- Trost, B. M.; Toste, F. D., "Enantioselective total synthesis of (-)-galanthamine." J. Am. Chem.Soc. 2000, 122, 11262-11263.

Amination [N]

Recent advances in the palladium-catalyzed amination of aryl halides offerconsiderable advantages for aniline formation over the classical methods, whichrequire either activated substrates or severe reaction conditions.

P. Wipf 1/30/2007

16

Ali, M. H.; Buchwald, S. L., "An improved method for the palladium-catalyzedamination of aryl iodides." J. Org. Chem. 2001, 66, 2560-2565.

Strieter, E. R.;Blackmond, D. G.;Buchwald, S. L.Insights into the originof high activity andstability of catalystsderived from bulky,electron-richmonophosphinobiarylligands in the Pd-catalyzed C-N bondformation. J. Am.Chem. Soc. 2003, 125,13978-13980.

P. Wipf 1/30/2007

17

Ney, J. E.; Wolfe, J. P., "Selective synthesis of 5- or 6-aryloctahydrocyclopenta[b]pyrroles from a common precursor through control ofcompeting pathways in a Pd-catalyzed reaction." J. Am. Chem. Soc. 2005, 127,8644-8651.

A significant challenge in the development of metal-catalyzed reactions is thesuppression of competing mechanistic pathways without inhibiting desired steps in acatalytic cycle. In recent years, several remarkable transformations have beeneffected through the use of palladium catalysts that minimize side reactions (e.g., -hydride elimination) while still allowing reductive elimination or transmetalationprocesses to occur. Despite these achievements, the factors that affect the relativerates of competing mechanistic pathways in catalytic reactions (e.g., reductiveelimination versus olefin insertion, or C-C versus C-N bond-forming reductiveelimination) are not well understood. If these fundamental processes could becontrolled, the selective construction of a diverse array of products from commonstarting materials could be achieved under similar reaction conditions by varyingcatalyst structure.

P. Wipf 1/30/2007

18

P. Wipf 1/30/2007