Transition Metal Catalyzed C-C Cross Coupling Reactions: An Introduction Hiroyuki Hattori Crosscoupling reactions refer to reactions that couple two different organic fragments with the aid of metal catalysts (Wikipedia). R-R' Pd(0) R-X Oxidative Addition Reductive Elimination R Pd(II) R R X Pd(II) Pd(II) R' X R-R Transmetallation Homocoupling R'' β-Elimination MX2 MR'X Table of Contents 1. Kumada Coupling 2. Negishi Coupling 3. Stille Coupling 4. Suzuki Coupling X Time Yield X Time Yield 5. Hiyama Coupling I 3 80 Cl 3 95 6. Heck Reaction Br 4.5 54 F 2 31 7. Sonogashira Coupling There is no clear trend in the yield of Kumada coupling using different halides, but the rates of dehalogenation 4 1. Kumada Coupling follow the order I>Br>>Cl>F. The Kumada coupling connects the organic fragments of a Grignard reagent and a halide to produce the product. This coupling was first found to be catalyzed by a nickel If there is more than one halogen group in the substrate, all of these are potential reactive sites unless steric complex and is still used because of its ease of oxidative 5 addition and its lower cost.1 hindrance blocks a halide. However, selective coupling can 2RMgX 2MgX2 be achieved by modulating the catalyst activity. L2NiX2 L2NiR2 R'X" R-R R-MgX R' R-R' NiL2 X R' Yield R' X' NiL Cl Grignard R' 2 1x R 2x R NiL 2 R EtMgBr 71 11 R ortho sec-BuMgBr 45 5 R'-X' n-BuMgBr 68 23 Meta The diagram shown above is the proposed catalytic sec-BuMgBr 21 11 cycle for Kumada coupling. After entering the cycle, the EtMgBr 75 9 para alkyl group from the Grignard reagent is transmetalated sec-BuMgBr 31 13 onto the nickel. Then reductively elimination of the R groups For example, use of a tri-dentate ligand, triphos, is able produces a Nickel (0) species. Oxidative addition of the to stop the reaction at the stage of monoalkylation. alkyl halide reproduces the nickel (II) species. Major side The table above also shows a characteristic of Kumada 2 reactions are homocoupling or β-hydride elimination. coupling that more substituted Grignard reagents tend to 6 MgBr R give poorer yield. Directing groups such as OH are often exploited to Br R 7 Ni(acac)2 (0.2%) selectively couple halide substrate at the ortho halide. Et2O, r.t. R=OMe, Me, Br, e.t.c 50-75% Diphosphine ligands enhance the yield of the Kumada coupling and therefore became common ligands.3 1 / 10 Alkyl halides are seldom used in Kumada coupling successfully. Although Kumada coupling with nickel complexes is common, palladium complexes sometimes have advantages. Shown below is the first Pd catalyzed Kumada coupling. The strong NHC-Pd bond that is formed in situ protects the palladium from oxidation.8 Stereoselective Kumada couplings initially focused on the Pd and Ni complexes ligated by a PP ligand with modest enantiomeric excesses, but the effort has now shifted to PN ligands, which deliver higher ee’s. Compared to the other coupling reactions, the Kumada coupling is superior in terms of the ample availability of Grignard reagents, but many functional groups are incompatible with the conditions, and the reaction is often limited to ether solvents. These limitations have driven a 11 search for alternative coupling reactions. Kumada couplings with vinyl Grignard reagents are possible but may be tricky because the vinyl fragment is •References for Kumada Couplings: prone to isomerization to give an unwanted side product.9 1. C. E. I. Knappke and A. J. von Wangelin, Chem. Soc. Rev., 2011, 40, 4948 MgBr (3 eq) 2. Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, I Pd(PPh ) (5 mol%) 1417. OH 3 4 OH THF 0 oC to r.t., 24 h 3. R. J. P. Corriu and J. P. Masse, J. Chem. Soc., Chem. 89% (E/Z=9:1) Commun., 1972, 144a 4. Tamao, K.; Kumada, M. et al. Bull, Chem. Soc. Jpn. 1976. 49, MgBr (2.5 eq) 1958. I Pd(PPh ) (5 mol%) 5. Eapen, K. C.; Dua, S. S.; Tamborski, C. J. Org. Chem. 1984, 49, OH 3 4 OH THF 0 oC to r.t., 3 h 478. 56% (E/Z=35:65) 6. Reddy, G. S.; Tam, W. Organometallics 1984, 3, 630. Alkynyl magnesium bromide reagents readily undergo 7. Wang, J.-R.; Manabe, K. Org. Lett. 2009, 11, 741. Kumada couplings. Some recent Kumada couplings use 8. J. Huang and S. P. Nolan, J. Am. Chem. Soc., 1999, 121, 9889 LiBr to break down oligometric magnesium halides. A OTf 9. P. Gamez, C. Ariente, J. Gore´ and B. Cazes, Tetrahedron. 1998, 54, 14825 group on benzene is usually stable under coupling 10 10. Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Chem. Rev. conditions, but it is activated for this reaction. 2015, 115, 9587 11. T. Kamikawa and T. Hayashi, J. Org. Chem., 1998, 63, 8922 Entry Br R Temp Time Yield 1 Et3Si 20 1 99 2 para n-C5H11 30 12 92 3 t-Bu 30 20 90 4 Ph 20 4 92 ortho 5 Et3Si 30 4 91 6 Ph 20 1 99 meta 7 Et3Si 20 1 93 2 / 10 2. Negishi Coupling In contrast to Kumada couplings, palladium is used in Negishi coupling most commonly. In addition, the The Negishi coupling is similar to the Kumada coupling, mechanisms for these metals are different. Oxidative except that the reaction is between zinc compounds and a addition of alkyl or aryl halides by Pd(0) produces Pd(II) halide. Because the C-Zn bond is stronger than the Mg-C interaction, organozinc reagents are less reactive, and onto which the alkyl zinc transmetallates. The coupling therefore organozinc reagents don’t react with other partners on palladium are then released in a reductive elimination.6 functional groups such as ester and nitriles. R-X An organozinc reagent was prepared by allowing an Pd0L organohalide to react with powdered zinc in the presence of R-R' 2 lithium chloride, which removes the oxide impurities.1 R R PdLn O O LnPdII X O Br Zn, LiCl O ZnBrLiCl R' EtO THF, 25 oC, 12 h EtO R'ZnX' ZnXX' 91% By understanding the traits of each step of the coupling, Sometimes, the organozinc reagent is prepared via the product yields can be improved. To increase the relative transmetallation from a Grignard reagent. The example speed of oxidative addition, strong electron donating shown below combines regioselective Mg/Br exchange and ligands such as electron rich phosphines or NHC ligands a mild Negishi coupling that does not influence the nitrile. are used. These ligands increase the electron density of the 7 Only the bromide on the less crowded side of the pyridine metal center, and therefore facilitate the oxidative addition. readily couples with the aryl partner.2 1) Br Br CN MgBr TMS N THF 2) ZnCl (1 eq) 2 Br 0 °C, 15 min 3) P(Ph3)4 (4%) TMS N 0 to 25 °C, 2 h 60% I CN Once oxidative addition of the alkyl halide and (0.9 eq) transmetallation are completed, there are two possible Sometimes, n-butylithium is added to the mixture for pathways: reductive elimination that produces the desired lithium/halogen exchange followed by transmetallation with product or β-elimination leading to an alkene by-product. To zinc. Butylithium can also deprotonate the substrate directly obtain the desired product, a ligand with a large bite angle to make a precursor for the transmetallation. is used. In the second example below, the angle of P-Pd-P, Me Me 99°, pushes the coupling partners closer and encourages 1) n-BuLi, -40 oC, 2 h the reductive elimination process.8 S toluene/nBu2O S 2)ZnBr LiBr 2 I 2 Zn 90% F F Tetrabutylammonium iodide is known to be a promoter Catalyst R=H R=p-OMe R=o-Me 4 of some Negishi couplings. One hypothesis is that iodide PdCl2(dppf) 1h, 95% 18 h, 3% 20 h, 0% coordination on Zn creates an active zincate intermediate, PdCl2(PPh3)2 24 h, 5% 19 h, 75% 19 h, 58% whereas another attributes the enhancement to increased The mechanism of the nickel catalyzed Negishi coupling 5 ionic strength. However, the effect of the Bu4NI is not is postulated to involve an electron transfer reaction after perfectly clear. the oxidative addition. R' e- ZnR'X Ni(I) R' R' Ni(III)RR'X Ni(II) R X Entry Additive Eq Time Conversion R-R' ArX (I) 1 None 1 1 0.5% Ni X Ni(0) 2 Bu4NF 1 1 0.7% 3 Bu NBr 1 1 23% 4 Zn ZnX2 4 Bu4NI 0.1 1.5 2.4% The relative readiness of R groups to be transferred was 5 Bu4NI 1 1.5 38% investigated. The result is as shown below. The table 6 Bu4NI 3 1.5 90% 3 / 10 shows that a phenyl group is transferred fastest and an i-Pr •References for Negishi Coupling: group (branched alkane) is slowest. Because zinc parts 1. Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P. with aryl groups quickly, this creates a problem when a Angew. Chem., Int. Ed. 2006, 45, 6040 stereoselective Negishi coupling is the goal. 2. Saemann, C.; Haag, B.; Knochel, P. Chem. Eur. J. 2012, 18, 16145 3. Lemaire, S.; Houpis, I. N.; Xiao, T.; Li, J.; Digard, E.; Gozlan, C.; Liu, R.; Gavryushin, A.; Diene, C.; Wang, Y.; Farina, V.; Knochel, P.