· (MW 298.41)
(reagent used as a ligand for palladium catalysts in a variety of C-N, C-O, C-Si, and C-C bond forming reactions)
Physical Data: mp 85 °C.
Solubility: soluble in most organic solvents.
Form Supplied in: white crystals, commercially available.
Analysis of Reagent Purity: 1H and 31P NMR.
Preparative Methods: synthesized from chloro-di-tert-butylphosphine and 2-bromobiphenyl.1
typically used as obtained from commercial sources.
Handling, Storage, and Precautions: incompatible with strong oxidizing agents. Low reactivity towards air oxidation, although commonly stored under nitrogen in a dessicator. Toxic effects are unknown but presumably similar to other aryldialkyl phosphines, which are usually classified as irritants.
Catalytic Amination of Aryl Halides and Triflates
The catalytic amination of aryl halides is one of the most general methods for the formation of aryl carbon-nitrogen bonds and allows for the preparation of a wide variety of aryl amines under mild reaction conditions (1).2 The proper choice of catalyst is essential for the success of these reactions, and 2-(di-tert-butylphosphino)biphenyl (1) has been shown to be a highly effective ligand for catalytic amination reactions.3 A wide variety of aryl bromides, chlorides,4 and triflates are efficiently converted to anilines in the presence of NaOtBu or K3PO4 using this catalyst system, including electron-rich and electron-poor substrates, and ortho-substituted aryl halides (1).3b A number of functional groups are well tolerated, including esters, nitriles, enolizable ketones, and nitro groups, provided that K3PO4 is used as the stoichiometric base.3b
Use of K3PO4 is also necessary to obtain optimal yields in reactions of aryl triflates due to the tendency of NaOtBu to cleave the aryl triflate substrates and liberate the parent phenols.3b
Many different amines can be N-arylated using catalytic amounts of Pd2(dba)3 or Pd(OAc)2 and 1. Primary amines and cyclic secondary amines react in high yields, although acyclic secondary aliphatic amines give lower yields. Acyclic secondary amine substrates are more effectively coupled using 2-(N,N-dimethylamino)-2´-dicyclohexylphosphino biphenyl (2) as the supporting ligand for palladium.3b,5 The conversion of primary anilines to diarylamines is facile and efficient with the Pd/1 catalyst, and secondary anilines are converted to diarylalkylamines in high yields.3b Benzophenone imine can be N-arylated using this catalyst, providing a route to protected primary anilines,3b and benzophenone hydrazine reacts cleanly with aryl halides to afford protected aryl hydrazines3b that can be directly treated with aldehydes or ketones under acidic conditions to give indole products.6 The high reactivity of Pd/1 with aniline substrates allows for the preparation of partially Boc-protected polyaniline by polymerization of N-Boc-4-bromo-4´-aminodiphenylamine (2).7 The use of 1 for the one-pot synthesis of unsymmetrical triarylamines has also been described (3).8 The N-arylation of indoles has been achieved using the closely related ligand 2-(di-tert-butylphosphino)-2´-isopropylbiphenyl.9,10
Most aryl amination reactions are conducted at 80-110 °C; however, Pd(OAc)2/1 or Pd2(dba)3/1 are sufficiently active to catalyze the room-temperature catalytic amination of aryl bromides, chlorides, and triflates.3b A number of substrates can be effectively coupled at ambient temperatures with only 1-2 mol% of the catalyst, although the strong base NaOtBu is required which limits the scope of the transformation. Room-temperature catalytic aminations have also been effected using 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene4a and P(t-Bu)311 although fewer examples of room-temperature reactions have been reported with these ligands.
Despite the utility of Pd/1 for many palladium-catalyzed amination reactions, other catalysts more efficiently transform certain classes of substrates. For example, reactions conducted at low catalyst loading are more efficient with Pd/2;3b other ligands such as BINAP12 and 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene4a have also been used for catalytic amination at low catalyst loadings. The Pd/1 catalyst is also less effective than Pd/2 for reactions of sterically hindered substrates and reactions of functionalized aryl halides.3b The Pd/BINAP catalyst is more effective for the reaction of aryl bromides with primary aliphatic amines.12 1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene has also been used for the coupling of primary aliphatic amines with aryl chlorides.13
Palladium-catalyzed Aryl C-O Bond Formation
Palladium catalysts supported by ligand 1 and related biaryl(di-tert-butyl)phosphine derivatives have also been employed in aryl carbon-oxygen bond forming reactions (4).1
Catalysts of this type are effective for the cross coupling of aryl bromides, chlorides, and triflates with phenols in the presence of K3PO4 or NaH to prepare diaryl ethers (2).1 As observed in aryl C-N bond forming reactions, a variety of electron-rich and electron-poor aryl halides with various substitution patterns are successfully transformed, and the presence of functional groups such as esters, amides, and nitriles is tolerated. In addition to diaryl ethers, tert-butyl ethers can also be prepared by coupling aryl halides with NaOtBu (2).14
Intramolecular C-O bond forming reactions are reported to be most efficient when catalysts supported by 1 and related ligands are employed.15 A variety of 5-, 6-, and 7-membered oxygen heterocycles are formed in good to excellent yields (5).15 Additionally, the cyclization of chiral alcohols occurs without loss of enantiomeric purity.15 Although the use of Pd/BINAP has been described for the cyclization of substrates bearing pendant tertiary alcohols, secondary alcohols typically gave low yields of heterocyclic products, and primary alcohols failed to provide the desired cycloadducts.16 In contrast, 1 and related ligands are highly effective for the cyclization of substrates bearing pendant primary or secondary alcohols.15 Other ligands such as 1,1´-bis(di-tert-butylphosphino)ferrrocene,17 BINAP,16,18 P(t-Bu)3,19 and dppf (diphenyl phosphinoferrocene)20 have also been employed in palladium-catalyzed aryl C-O bond forming reactions; however, 1 and related biaryl(di-tert-butylphosphine) derivatives appear to transform a broader range of substrates in high yields.1,14,15
Suzuki Coupling of Aryl Halides
Catalysts comprised of Pd(OAc)2/1 are highly active in cross coupling reactions of aryl halides with boronic acids (Suzuki coupling),3a,21 which are widely used for the formation of sp2-sp2 C-C bonds.22 In contrast to tetrakis(triphenylphosphine)palladium, which has traditionally been employed as a catalyst for these reactions,22 mixtures of Pd(OAc)2/1 catalyze the Suzuki coupling of aryl bromides and aryl chlorides at room temperature (6).3,21 A wide variety of substrates are transformed in high yields and the reaction conditions tolerate nearly all common functional groups (3). Additionally, most reactions proceed to completion at room temperature in <24 h using only 0.5-1.0 mol % of the palladium catalyst.
Although 1 is superior to most other ligands employed for Suzuki coupling in terms of substrate scope and reactivity,23 2 and 2-(dicyclohexylphosphino)biphenyl (3) are more effective for reactions of sterically hindered substrates and for reactions of alkylboron reagents.21 The Pd/3,3a,21 or Pd/P(t-Bu)323 catalyst systems are frequently more useful than Pd/1 for Suzuki coupling reactions conducted with low levels of the palladium catalyst (0.005-0.02 mol %), although the Suzuki coupling of a highly active substrate required only 0.000 001 mol % Pd/1 to proceed to completion.3a,21
Catalytic Silylation of Aryl Bromides
The preparation of aryltrimethylsilanes by the Pd/1-catalyzed silylation of electron-deficient aryl bromides has recently been reported.24 In contrast to other methods for effecting this transformation, a wide variety of functional groups are tolerated, and the reactions proceed in high yield at 100 °C affording the desired products in under 16 h (7). Phosphine 1 was superior to triarylphosphines for reactions of electron-deficient substrates, although diphenyl-2´-pyridyl phosphine (Ph2Ppy) was found to be more effective for electron-rich substrates.24
a-Arylation of Nitroalkanes and Malonates
The palladium-catalyzed a-arylation of nitroalkanes has been accomplished using catalysts comprised of Pd(OAc)2 and 1 or the related ligand 2-(di-tert-butylphosphino)-2´-methylbiphenyl (4) in the presence of NaOtBu (8).25 The a-arylation of malonates is also effective using palladium catalysts supported by 425 (9) or ligands such as P(t-Bu)3 or 1,1´-bis(di-tert-butylphosphino)ferrocene.26 The a-arylation of ketones has also been reported using Pd/1 as a catalyst, although the related 2-biaryl(dicyclohexylphosphine)-type ligands appear to be more generally useful for a-arylations of ketones.25
2,2´-bis(diphenylphosphino)-1,1´-binaphthyl; 1,1´-bis(di-tert-butylphosphino) ferrocene [84680-95-5];17,28
2-(dicyclohexylphosphino) biphenyl [247940-06-3];21
2-(di-tert-butylphosphino)-o- terphenyl [224311-54-0];1
di-tert-butylphosphino ferrocene [223655-16-1];17
and Tri-tert-butylphosphine [13716-12-6].11,19
- 1. Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L., J. Am. Chem. Soc. 1999, 121, 4369.
- 2. (a) Belfield, A. J.; Brown, G. R.; Foubister, A. J., Tetrahedron 1999, 55, 11399. (b) Yang, B. H.; Buchwald, S. L., J. Organomet. Chem. 1999, 576, 125. (c) Wolfe, J. P., Wagaw, S., Marcoux, J. F.; Buchwald, S. L., Acc. Chem. Res. 1998, 31, 805. (d) Hartwig, J. F., Angew. Chem. Int. Ed. 1998, 37, 2046.
- 3. (a) Wolfe, J. P.; Buchwald, S. L., Angew. Chem. Int. Ed. 1999, 38, 2413. (b) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.; Buchwald, S. L., J. Org. Chem. 2000, 65, 1158.
- 4. (a) Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.; Hartwig, J. F., Org. Lett. 2000, 2, 1423. (b) Footnote 2 of reference 3b.
- 5. Old, D. W.; Wolfe, J. P.; Buchwald, S. L., J. Am. Chem. Soc. 1998, 120, 9722.
- 6. Wagaw, S.; Yang, B. H.; Buchwald, S. L., J. Am. Chem. Soc. 1999, 121, 10251.
- 7. Zhang, X. X.; Sadighi, J. P.; Mackewitz, T. W.; Buchwald, S. L., J. Am. Chem. Soc. 2000, 122, 7606.
- 8. Harris, M. C.; Buchwald, S. L., J. Org. Chem. 2000, 65, 5327.
- 9. Old, D. W.; Harris, M. C.; Buchwald, S. L., Org. Lett. 2000, 2, 1403.
- 10. Tomori, H.; Fox, J. M.; Buchwald, S. L., J. Org. Chem. 2000, 65, 5334.
- 11. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.; Alcazar-Roman, L. M.; J. Org. Chem. 1999, 64, 5575.
- 12. Wolfe, J. P.; Buchwald, S. L., J. Org. Chem. 2000, 65, 1144.
- 13. Huang, J.; Grasa, G.; Nolan, S. P., Org. Lett. 1999, 1, 1307.
- 14. Parrish, C. A.; Buchwald, S. L., J. Org. Chem. 2001, 66, 2498.
- 15. Torraca, K. E.; Kuwabe, S. I.; Buchwald, S. L., J. Am. Chem. Soc. 2000, 122, 12907.
- 16. Palucki, M.; Wolfe, J. P.; Buchwald, S. L., J. Am. Chem. Soc. 1996, 118, 10333.
- 17. (a) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F., J. Am. Chem. Soc. 1999, 121, 3224. (b) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F., J. Am. Chem. Soc. 2000, 122, 10718.
- 18. Palucki, M.; Wolfe, J. P.; Buchwald, S. L., J. Am. Chem. Soc. 1997, 119, 3395.
- 19. Watanabe, M.; Nishiyama, M.; Koie, Y., Tetrahedron Lett. 1999, 40, 8837.
- 20. (a) Mann, G.; Hartwig, J. F., Tetrahedron Lett. 1997, 38, 8005. (b) Mann, G.; Hartwig, J. F., J. Am. Chem. Soc. 1996, 118, 13109.
- 21. Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L., J. Am. Chem. Soc. 1999, 121, 9550.
- 22. Suzuki, A., In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH, Weinheim, Germany, 1998; Chap. 2.
- 23. Littke, A. F.; Dai, C.; Fu, G. C., J. Am. Chem. Soc. 2000, 122, 4020.
- 24. Gooen, L. J.; Ferwanah, A. R. S., Synlett 2000, 1801.
- 25. Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L., J. Am. Chem. Soc. 2000, 122, 1360.
- 26. Kawatsura, M.; Hartwig, J. F., J. Am. Chem. Soc. 1999, 121, 1473.
- 27. Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R.; Craig, H. A.; Goerlich, J. R.; Marshall, W. J.; Unverzagt, M., Tetrahedron 1999, 55, 14523.
- 28. (a) Hamann, B. C.; Hartwig, J. F., J. Am. Chem. Soc. 1998, 120, 7369. (b) Cullen, W. R.; Kim, T. J.; Einstein, F. W. B.; Jones, T., Organometallics 1983, 2, 714.
- 29. (a) Bei, X.; Guram, A. S.; Turner, H. W.; Weinberg, W. H., Tetrahedron Lett. 1999, 40, 1237. (b) Bei, X.; Uno, T.; Norris, J.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.; Petersen, J. L., Organometallics 1999, 18, 1840.
- 30. Reddy, N. P.; Tanaka, M., Tetrahedron Lett. 1997, 38, 4807.
John P. Wolfe
University of California, Irvine, CA, USA
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