[213697-53-1]  · C26H36NP  · (MW 393.55)

(reagent used as a ligand for palladium catalysts in a variety of C-N and C-C bond forming reactions)

Physical Data: mp 115-119 °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 2-(N,N-dimethylamino) phenylmagnesium chloride, 2-bromochlorobenzene, and chlorodicyclohexylphosphine in the presence of magnesium (1).1

Purification: 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 has recently emerged as a powerful method for the formation of aryl carbon-nitrogen bonds and the synthesis of a variety of aniline derivatives.2 The bulky, electron-rich phosphine 2-dicyclohexylphosphino-2 (N,N-dimethylamino) biphenyl (1) has been shown to be one of the generally most effective ligands for this process.3 A broad range of aryl bromides are efficiently coupled with amines in the presence of a stoichiometric amount of base, usually NaOtBu, K3PO4 or Cs2CO3, and catalytic amounts of Pd2(dba)3 or Pd(OAc)2 and 1 (2).3,4 As shown in 1, both electron-rich and electron-poor substrates react with amines in high yield, and aniline derivatives bearing ortho substituents can also be prepared. Catalysts supported by 1 are sufficiently reactive to effect the amination of aryl chlorides, substrates that until recently were believed to be unreactive in palladium-catalyzed cross-coupling reactions;5,6 the scope of these reactions is similar to the corresponding reactions of aryl bromides. Additionally, Pd2(dba)3/1 efficiently catalyzes the coupling of amines with aryl iodides, which often give low yields, react sluggishly or require the use of additives such as 18-crown-6 when triarylphosphine-based catalysts are employed.7 Catalytic aminations of aryl triflates have also been achieved using either 1 or the related compound 2-(dicyclohexylphosphino)biphenyl (2) as the supporting ligand for palladium.4 Use of potassium phosphate as the base is essential for most reactions of aryl triflates; stronger bases such as NaOtBu typically cause cleavage of the triflate moiety.4 A variety of functional groups are tolerated in the amination reactions, including nitriles, esters, and enolizable ketones, provided that either cesium carbonate (for aryl iodides) or potassium phosphate (for aryl bromides, chlorides, and triflates) are used as the base.3,4 Halogenated heterocycles are also suitable substrates for amination reactions catalyzed by Pd/1.4

Arylations of cyclic and acyclic secondary amines or anilines occur in high yields for most substrate combinations.3,4 Primary amines can also be used as substrates, although frequently an excess of the amine (1.5-3.0 equiv) is required to minimize the formation of doubly arylated side products. Reactions of primary amines usually give smaller amounts of overarylated side products with catalysts supported by BINAP,8 or 1,3-bis(2,6-diisopropylphenyl)imidazolyl-2-ylidene.9 In contrast, primary anilines react smoothly with little or no overarylation, although reactions of primary anilines often give slightly higher yields and proceed with low catalyst loadings when mixtures of Pd2(dba)3 and 2-(di-tert-butylphosphino)biphenyl (3) are employed.3,4 The N-arylation of indoles can be effected using palladium catalysts supported by 1 or related biaryl or binaphthyl phosphine ligands.10 Additionally, N-arylations of vinylogous amides have also been described,11 and 1 has been employed in the catalytic amination of halo nucleosides12 and for the synthesis of N-aryl azacrown ethers.13

For most reactions, it is convenient to use catalyst loadings of 0.5-2.0 mol % of the palladium catalyst with 1-2 equiv of ligand for each mole of palladium. However, in some cases it is possible to conduct reactions with as little as 0.05 mol % of the catalyst.3 Reactions that proceed efficiently at low catalyst loadings have also been reported using 2,4,14 BINAP,8 and 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolyl-2-ylidene.15

Reactions are typically conducted at 65-100 °C but some substrates can be transformed at room temperature.3 However, the related ligands 2-(di-tert-butylphosphino)biphenyl (3),4,14 P(t-Bu)3,16 and 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazolyl-2-yli-dene15 are typically more useful for room-temperature catalytic aminations.

Suzuki Coupling of Aryl Halides

The cross coupling of aryl halides with boronic acids (Suzuki coupling) is a powerful method for the formation of sp2-sp2 carbon-carbon bonds.17 In addition to being a highly effective ligand for catalytic amination reactions, phosphine 1 is also an excellent ligand for Suzuki couplings (3).3,18 In contrast to the triphenyl phosphine-based catalysts traditionally employed for these reactions, catalysts comprised of Pd/1 are sufficiently active to promote Suzuki coupling of both electron-rich and electron-deficient aryl bromides and chlorides at room temperature,3,19 although catalysts supported by the related ligand 2-(di-tert-butylphosphino)biphenyl (3)14,18 are typically more active for room-temperature Suzuki coupling reactions. Other catalyst systems have been used for room-temperature Suzuki coupling including Pd/P(t-Bu)320 and sulfur-containing palladacycles,21 although these catalysts do not appear to be as effective as 1,2 or 3 for reactions of electron-rich aryl chloride substrates. Trisubstituted biaryls can be prepared at 80 °C using catalysts based on 1 or the related ligand 2 (2).18 These catalysts are among the best reported for Suzuki coupling of hindered substrates.18 The use of Pd/1 or Pd/2 for Suzuki couplings of alkylboron reagents prepared in situ from olefins and 9-BBN have also been described.3,18

Suzuki reactions catalyzed by Pd/1 or Pd/2 employ either KF or K3PO4 as a base to activate the boronic acid, and are run in organic solvents instead of biphasic solvent systems commonly employed for Suzuki couplings. These mild conditions tolerate the presence of a wide variety of functional groups,3,18 and have also been effective for transformations of substrates such as 1-azulenyl triflates,22 that failed to react efficiently using other catalyst systems. Reactions catalyzed by Pd/1 or Pd/2 can be conducted with low levels of the catalyst (0.005-0.02 mol % Pd), and provide the highest turnover numbers reported to date for Suzuki coupling reactions of unactivated aryl bromides;14,18 P(t-Bu)3 has also been effective at promoting Suzuki coupling with low catalyst loadings.20

In addition to Suzuki coupling reactions, 1 and 2 have been reported to be effective for the cross coupling of aryl chlorides with hypervalent aryl siloxanes (4).23 However, triarylphosphines appear to be the ligands of choice for transformations of aryl iodides and bromides.23

a-Arylation of Ketone Enolates

The synthesis of a-aryl ketones has been a longstanding problem in organic synthesis due to the inability of aryl halides to participate in SN2 reactions and the problems associated with forming arylated ketones using benzyne or radical reactions.24a Methods for the palladium-catalyzed a-arylation of ketone enolates have recently been developed and provide access to a wide variety of a-aryl ketones (5).24 Ligands 1 and 2, as well as related ligands bearing alkyl substituents in place of the dimethylamino substituent at the 2 position are the most effective ligands for this transformation which have been reported to date.24a Although many examples of ketone arylations that employ the related ligand 2-(dicyclohexylphosphino)-2-methylbiphenyl (4) have been described (3, entries 3-5), ligand 1 is also effective for most of these transformations although slightly diminished yields are obtained.24a Both electron-rich and electron-deficient aryl bromides and chlorides can be used as substrates in these reactions, and some functional groups including esters, amides, phenols, and nitriles are tolerated (3). Arylation occurs selectively at the less substituted carbon of the ketone, and monoarylated products are generally obtained in high yields.

Ketone arylation reactions typically employ either NaOtBu or K3PO4 as a base, and require 0.1-2.0 mol % of the palladium catalyst. Most reactions are conducted at 45-100 °C, although examples of Pd/1 catalyzed ketone arylation at room temperature have also been reported.3 Ligand 1 and related biphenyl(dicyclohexyl-phosphine) derivatives such as 2 and 4 efficiently transform a broad class of substrates in ketone arylation reactions, however, aryl di-tert-butyl phosphine derivatives such as 3 and related compounds are more effective for reactions of malonates or arylations of nitroalkanes.24

Related Reagents.

1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene [244187-81-3];9 1,3-bis(2,6-diisopropylphenyl)-4,5-dih-ydroimidazol-2-ylidene [258278-28-3];15,25 2,2-bis(diphenylph-osphino)-1,1-binaphthyl; 1,1-bis(di-tert-butylphosphino)ferroc-ene [84680-95-5];26 2-(2-dicyclohexylphosphinophenyl)-2-me-thyl-1,3-dioxolane [221187-50-4];27 2-(dicyclohexylphosphino) biphenyl [247940-06-3];18 2-(dicyclohexylphosphino)-2-methyl-biphenyl [255837-19-5];1 2-(dicyclohexylphosphino)-2-isopro-pylbiphenyl [255835-84-8];1 2-(di-tert-butylphosphino)biphenyl [224311-51-7];4 di-tert-butylphosphino ferrocene [223655-16-1];28 tricyclohexylphosphine [2622-14-2];29 and tri-tert-butylphosphine [13716-12-6].20

1. Tomori, H., Fox, J. M.; Buchwald, S.L., J. Org. Chem. 2000, 65, 5334.
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. Old, D. W.; Wolfe, J. P.; Buchwald, S. L., J. Am. Chem. Soc. 1998, 120, 9722.
4. Wolfe, J. P.; Tomori, H.; Sadighi, J. P., Yin, J.; Buchwald, S. L., J. Org. Chem. 2000, 65, 1158.
5. Grushin, V. V.; Alper, H., Chem. Rev. 1994, 94, 1047.
6. For reports of the catalytic amination of aryl chlorides using other ligands, see footnote 4 in reference 1.
7. Ali, M. H.; Buchwald, S. L., J. Org. Chem. 2001, 66, 2560.
8. Wolfe, J. P.; Buchwald, S. L., J. Org. Chem. 2000, 65, 1144.
9. Huang, J.; Grasa, G.; Nolan, S. P., Org. Lett. 1999, 1, 1307.
10. Old, D. W.; Harris, M. C.; Buchwald, S. L., Org. Lett. 2000, 2, 1403.
11. Edmondson, S. D.; Mastracchio, A.; Parmee, E. R., Org. Lett. 2000, 2, 1109.
12. (a) De Riccardis, F.; Johnson, F., Org. Lett. 2000, 2, 293. (b) Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q., J. Am. Chem. Soc. 1999, 121, 6090.
13. Zhang, X. X.; Buchwald, S. L., J. Org. Chem. 2000, 65, 8027.
14. Wolfe, J. P.; Buchwald, S. L., Angew. Chem. Int. Ed.1999, 38, 2413.
15. Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.; Hartwig, J. F., Org. Lett. 2000, 2, 1423.
16. Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K.H.; Alcazar-Roman, L. M., J. Org. Chem. 1999, 64, 5575.
17. Suzuki, A., In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998, Chapter 2.
18. Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L., J. Am. Chem. Soc. 1999, 121, 9550.
19. A number of reports describe the Suzuki coupling of aryl chlorides at 60-130 °C, see footnote 5 in reference 1.
20. Littke, A. F.; Dai, C.; Fu, G. C., J. Am. Chem. Soc. 2000, 122, 4020.
21. Zim, D.; Gruber, A. S.; Ebeling, G.; Dupont, J.; Monteiro, A. L., Org. Lett. 2000, 2, 2881.
22. Kane, J. L., Jr; Shea, K. M.; Crombie, A. L.; Danheiser, R. L., Org. Lett. 2001, 3, 1081.
23. Mowery, M. E.; DeShong, P., Org. Lett. 1999, 1, 2137.
24. (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L., J. Am. Chem. Soc. 2000, 122, 1360. (b) Kawatsura, M.; Hartwig, J. F., J. Am. Chem. Soc. 1999, 121, 1473. (c) Palucki, M.; Buchwald, S. L., J. Am. Chem. Soc. 1997, 119, 11108. (d) Hamann, B. C.; Hartwig, J. F., J. Am. Chem. Soc. 1997, 119, 12382.
25. Arduengo, A. J., III; Krafczyk, R.; Schmutzler, R.; Craig, H. A.; Goerlich, J. R.; Marshall, W. J.; Unverzagt, M., Tetrahedron 1999, 55, 14523.
26. (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.
27. (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.
28. Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F., J. Am. Chem. Soc. 1999, 121, 3224.
29. Reddy, N. P.; Tanaka, M., Tetrahedron Lett. 1997, 38, 4807.

John P. Wolfe

University of California, Irvine, CA, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.