Palladium Catalyzed Cross Coupling Reactions

General Introduction:

During the second half of the 20th century, transition metals have come to play an important role in organic chemistry and this has led to the development of a large number of transition metal-catalyzed reactions for creating organic molecules. Transition metals have a unique ability to activate various organic compounds and through this activation they can catalyze the formation of new bonds. One metal that was used early on for catalytic organic transformations was palladium. One event that stimulated research into the use of palladium in organic chemistry was the discovery that ethylene is oxidized to acetaldehyde by air in a palladium-catalyzed reaction and this became the industrially important Wacker process. Subsequent research on palladium-catalyzed carbonylation led to new reactions for the formation of carbon-carbon bonds. In general, transition metals, and in particular palladium, have been of importance for the development of reactions for the formation of carbon-carbon bonds. In 2005 the Nobel Prize in chemistry was awarded to metal-catalyzed reactions for the formation of carbon-carbon double bonds. This year(2010) the Nobel Prize in chemistry is awarded to the formation of carbon-carbon single bonds through palladium-catalyzed cross-coupling reactions.

Palladium catalyzed cross coupling reactions:

In general, palladium-catalyzed cross couplings is that two molecules are assembled on the metal via the formation of metal-carbon bonds. In this way the carbon atoms bound to palladium are brought very close to one another. In the next step they couple to one another and this leads to the formation of a new carbon-carbon single bond. Thus, palladium catalysis has gained widespread use in industrial and academic synthetic chemistry laboratories as a powerful methodology for the formation of C-C and C-Heteroatom bonds.

There are many palladium catalyzed coupling reactions are developed with various coupling partners.

1. SUZUKI-MIYAURA

2. STILLE

3. NEGISHI

4. KUMADA

5. HIYAMA

6. SONOGASHIRA

7. HECK

8. BUCHWALD-HARTWIG

9. CYANATION

10. CARBONYLATION

Most palladium catalysed reactions are believed to follow a similar catalytic cycle.

The Suzuki-Miyaura coupling

In 1979, A. Suzuki and N. Miyaura reported the stereoselective synthesis of arylated (E)-alkenes by the reaction of 1- alkenylboranes with aryl halides in the presence of a palladium catalyst. The palladium-catalyzed cross-coupling reaction between organoboron compounds and organic halides or triflates provides a powerful and general method for the formation of carbon-carbon bonds known as the Suzuki cross-coupling.

There are several advantages to this method:

1) mild reaction conditions;

2) commercial availability of many boronic acids;

3) the inorganic by-products are easily removed from the reaction mixture, making the reaction suitable for industrial processes;

4) boronic acids are environmentally safer and much less toxic than organostannanes (see Stille coupling);

5) starting materials tolerate a wide variety of functional groups, and they are unaffected by water;

6) the coupling is generally stereo- and regioselective;  

7) sp3-hybridized alkyl boranes can also be coupled by the B-alkyl Suzuki-Miyaura cross-coupling.

Mechanism:

References

1. Galardon,E.; Ramdeehul, S.; Brown, J.M.; Cowley, A.; Hii, K.K.; Jutand, A.; Angew. Chem, Int. Ed. 2002 41, 1760-1763

2. Tolman, C. A. Chem. Rev., 1977, 77, 313–348

3. For a review see: Hillier, A.C.; Grasa, G. A.; Viciu, M.S.; Lee, H. M.; Yang, C; Nolan, S. P. J. Organomet. Chem. 2002, 69-82

Stille coupling

The Pd(0)-catalyzed coupling reaction between an organostannane and an organic electrophile to form a new C-C sigma bond is known as the Stille cross coupling. The Stille reaction is an extremely versatile alternative to the Suzuki reaction. It replaces the organoboron reagents with organostannanes. As the tin bears four organic functional groups, understanding the rates of transmetallation of each group is important. Relative rate of transmetallation: Alkynyl > vinyl > aryl > allyl ~ benzyl >> alkyl

The reaction also has the advantage that it is run under neutral conditions making it even more tolerant of different functional groups than the Suzuki reaction.The precursor organotin compounds have many advantages because they:

1) are tolerate a wide variety of functional groups;

2) are not sensitive to moisture or oxygen unlike other reactive organometallic compounds; and

3) are easily prepared, isolated, and stored.

The main disadvantages are their toxicity and the difficulty to remove the traces of tin by-products from the reaction mixture.

Mechanism:

References

1. Jung, D; Shimogawa, H.; Kwon, Y.; Mao, Q.; Sato, S.-I. Kamisuki, S.; Kigoshi, H.; Uesugi, M. J. Am. Chem. Soc. 2009, 131, 4774-4782.

2. van Niel, M. B.; Wilson, K.; Adkins, C. H.; Atack, J. R.; Castro, J. L.; Clarke, D. E.; Fletcher, S.; Gerhard, U.; Mackey, M. M.; Malpas, S.; Maubach, K.; Newman, R.; O’Connor, D.; Pillai, G. V.; Simpson, P. B.; Thomas, S. R.; MacLoed, A. M. J. Med. Chem. 2005, 48, 6004-6011.

3. Giri, R.; Maugel, N; Li, J.J; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu J.-O. J. Am. Chem. Soc. 2007, 129, 3510-3511.

4. Molander, G.A.; Canturk, B. Angew. Chem. Int. Ed. 2009; 48; 9240-9261

Stille-Kelly coupling.

The Pd-catalyzed intramolecular biaryl coupling of aryl halides or aryl triflates in the presence of distannanes is known as the Stille-Kelly coupling.

Mechanism:

Reference:

Yue, W. S.; Li, J. J. Org.Lett. 2002, 13, 2201-2204.

Negishi coupling

The Negishi coupling utilises organo-zinc reagents as starting materials to cross couple with organohalides and equivalents. The method is compatible with a good range of functional groups on the organohalide including ketones, esters, amines and nitriles. The organo-zinc reagent can be prepared in situ by a variety of methodologies, such as transmetallation of the corresponding organo-lithium or Grignard reagent, or via oxidative addition of activated Zn(0) to an organohalide.

Mechanism:

Reference:

1) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem. Int. Ed. 2006, 45, 2958-2961.

2) Prasad, A. S. B.; Stevenson, T. M.; Citineni, J. R.; Nyzam, V.; Knochel, P. Tetrahedron 1997, 53, 7237-7254

Kumada coupling

The cross coupling of organohalides with Grignard reagents is known as the Kumada coupling. Although it suffers from a limited tolerance of different functional groups, the higher reactivity and basicity of the Grignard reagent allows viable reactions to take place under mild conditions.

The Mechanism is similar as Negishi coupling.

Reference:

1) Anastasia, L., Negishi, E.-i. Palladium-catalyzed aryl-aryl coupling. Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 311-334.

2) Anctil, E. J. G., Snieckus, V. The directed ortho metalation-cross coupling symbiosis. Regioselective methodologies for biaryls and heterobiaryls. Deployment in aromatic and heteroaromatic natural product synthesis. J. Organomet. Chem. 2002, 653, 150-160.

3) Banno, T., Hayakawa, Y., Umeno, M. Some applications of the Grignard cross-coupling reaction in the industrial field. J. Organomet. Chem. 2002, 653, 288-291.

4) Hayashi, T. Palladium-catalyzed asymmetric cross-coupling. Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 791- 806.

Hiyama coupling

The Hiyama Coupling is the palladium-catalyzed C-C bond formation between aryl, alkenyl, or alkyl halides or pseudohalides and organosilanes. This reaction is comparable to the Suzuki Coupling and also requires an activating agent such as fluoride ion or a base.

Mechanism:

Crucial for the success of the Hiyama Coupling is the polarization of the Si-C bond. Activation of the silane with base or fluoride ions (TASF, TBAF) leading to a pentavalent silicon compound is a first necessary step. The use of a silanol as the organosilane is one recent method that has managed to negate the requirement for the reaction to contain fluoride as an activator. This has helped to enlarge the substrate scope available to organic chemists.

Reference:

1) Li, J.-H.; Deng, W.-J.; Liu, Y.-X. Synthesis 2005, 3039-3044.

2) For a recent review on silanols in the Hiyama coupling see: Denmark, S. E.; Regens, C. S. Acc. Chem. Res. 2008, 41, 1486-1499.

Sonogashira coupling

The Sonogashira reaction offers an extremely useful route into aryl- and alkenyl-alkynes. The alkyne moiety is usually introduced via its copper salt. This is generated in situ from a Cu(I) salt, such as CuI or CuCN, and a terminal alkyne in the presence of an amine base. Recent improvements in this reaction have led to the development of copper and amine free couplings.

The general features of the reaction are:

1) the coupling can usually be conducted at or slightly above room temperature, and this is a major advantage over the forcing conditions required for the alternative Castro-Stephens coupling;

 2) the handling of the shock-sensitive/explosive copper acetylides is avoided by the use of a catalytic amounts of copper(I) salt;

3) the copper(I) salt can be the commercially available CuI or CuBr and are usually applied in 0.5-5 mol% with respect to the halide or alkyne;

4) the best palladium catalysts are Pd(PPh3)2Cl2 or Pd(PPh3)4;

5) the solvents and the reagents do not need to be rigorously dried. However, a thorough deoxygenation is essential to maintain the activity of the Pd-catalyst;

6) often the base serves as the solvent but occasionally a co-solvent is used;

7) the reaction works well on both very small and large scale (>100g);

8) the coupling is stereospecific; the stereochemical information of the substrates is preserved in the products;

9) the order of reactivity for the aryl and vinyl halides is I ≈ OTf > Br >> Cl;

10) the difference between the reaction rates of iodides and bromides allows selective coupling with the iodides in the presence of bromides;

11) almost all functional groups are tolerated on the aromatic and vinyl halide substrates.

Mechanism:

The mechanism of the Sonogashira cross-coupling follows the expected oxidative addition-reductive elimination pathway. However, the structure of the catalytically active species and the precise role of the CuI catalyst is unknown. The reaction commences with the generation of a coordinatively unsaturated Pd(0) species from a Pd(II) complex by reduction with the alkyne substrate or with an added phosphine ligand. The Pd(0) then undergoes oxidative addition with the aryl or vinyl halide followed by transmetallation by the copper(I)-acetylide. Reductive elimination affords the coupled product and the regeneration of the catalyst completes the catalytic cycle.

References

1) Cassar, L. J. Organomet. Chem. 1975, 93, 253-257.

2) Dieck, H. A., Heck, F. R.  J. Organomet. Chem. 1975, 93, 259-263.      

3) Sonogashira, K., Tohda, Y., Hagihara, N. Tetrahedron Lett. 1975, 4467-4470.

4)  Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551-8553.

5)  Liang, Y.; Xie, Y.-X.; Li, J.-H. J. Org. Chem. 2006, 71, 379-380.

6) Schiedel, M.-S., Briehn, C. A., Bauerle, P. C-C J. Organomet. Chem. 2002, 653, 200-208.

Heck reaction

In the early 1970s, T. Mizoroki and R.F. Heck independently discovered that aryl, benzyl and styryl halides react with olefinic compounds at elevated temperatures in the presence of a hindered amine base and catalytic amount of Pd(0) to form aryl-, benzyl-, and styryl-substituted olefins. Today, the palladium-catalyzed arylation or alkenylation of olefins is referred to as the Heck reaction. Since its discovery, the Heck reaction has become one of the most widely used catalytic carbon-carbon bond forming tools in organic synthesis.

The Heck reaction follows a slightly different pathway to other palladium catalysed couplings. For intermolecular reactions with monosubstituted olefins, the olefin insertion step is usually directed by steric hindrance. This intermediate then undergoes β-hydride elimination under thermodynamically controlled conditions, leading to preferential formation of the E product.

Reference:

1) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518- 5526.

2) Mizoroki, T., Mori, K., Ozaki, A.  Bull. Chem. Soc. Jpn. 1971, 44, 581.

3) Heck, R. F., Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320-2322.

4) Shibasaki, M., Miyazaki, F. Asymmetric Heck reactions. in Handbook of Organopalladium Chemistry for Organic Synthesis (eds. Negishi, E.-i.,De Meijere, A.), 1, 1283-1315 (Wiley-Interscience, New York, 2002).

5)  Dounay, A. B., Overman, L. E. Chem. Rev. 2003, 103, 2945-2963.

6) Braese, S., de Meijere, A. Cross-coupling of organic halides with alkenes: The Heck reaction. Metal-Catalyzed Cross-Coupling Reactions (2nd Edition) 2004, 1, 217-315.

Buchwald-Hartwig coupling

Palladium catalysis has also been expanded to the formation of C-N bonds. In 1995 Buchwald and Hartwig independently reported the palladium catalysed coupling of aryl halides with amine nucleophiles in the presence of stoichiometric amounts of base.

Mechanism:

The first step in the catalytic cycle is the oxidative addition of Pd(0) to the aryl halide (or sulfonate). In the second step the Pd(II)-aryl amide can be formed either by direct displacement of the halide (or sulfonate) by the amide via a Pd(II)- alkoxide intermediate. Finally, reductive elimination results in the formation of the desired C-N bond and the Pd(0) catalyst is regenerated. Below is the catalytic cycle for the formation of an arylamine.

References

1)  a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem. Int. Ed. 1995, 34, 1348-1350. b) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609-3612.

2). Hillier, A.C.; Grasa, G. A.; Viciu, M.S.; Lee, H. M.; Yang, C; Nolan, S. P. J. Organomet. Chem. 2002, 69-82.

3)  Shen, Q.; Hartwig, J. J. Am. Chem. Soc. 2006, 128, 10028-10029.

Palladium catalysed cyanation

The palladium catalysed cyanation of aromatic halides offers a convenient alternative to the Rosemund-Von Braun reaction, which often employs harsh reaction conditions and can have a labour intensive workup. As the cyanide nucleophile is a strong σ-donor and can poison the catalyst, it is necessary to keep its concentration low during the reaction. To achieve this Zn(CN)2 is often employed as the cyanide source as its solubility in DMF (a common solvent for this reaction) is limited.

An alternative, non-toxic, source of cyanide has also been reported. K4[Fe(CN)6] can be used in combination with palladium catalysts to synthesise aryl nitriles from their corresponding halides.

Reference:

1) Schareina, T.; Zapf, A.; Beller, M. Chem. Comm. 2004, 1388-1389

2) Weissman, S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1508-1510

Palladium catalysed carbonylation

As with most palladium mediated C-C bond forming reactions palladium catalysed carbonylation is compatible with a range of functional groups. This gives it significant advantages over standard organolithium and Grignard chemistry for the synthesis of aryl aldehydes, acids, esters and amides.

References

1) Beller, M.; Magerlein, W.; Indolese, A. F.; Fischer C. Synthesis, 2001, 1098-1110.

2) Kumar K.; Zapf, A.; Michalik, D; Tillack, A.; Heinrich, T.; Bottcher, H.; Arlt, M.; Beller, M. Org. Lett., 2004, 6, 7-10.

3) Ashfield, L.; Barnard, C. F. J.; Org. Process Res. Dev., 2007, 11, 39-43.