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Simple, Efficient Catalyst System for the Palladium-Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates

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Simple, Efficient Catalyst System for the Palladium-Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates 1158 J. Org. Chem. 2000, 65, 1158-1174 Simple, Efficient Catalyst System for the Palladium-Catalyzed Amination of Aryl Chlorides, Bromides, and Triflates John P. Wolfe,† Hiroshi Tomori, Joseph P. Sadighi,‡ Jingjun Yin, and Stephen L. Buchwald* Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 Received October 29, 1999 Palladium complexes supported by (o-biphenyl)P(t-Bu)2 (3)or(o-biphenyl)PCy2 (4) are efficient catalysts for the catalytic amination of a wide variety of aryl halides and triflates. Use of ligand 3 allows for the room-temperature catalytic amination of many aryl chloride, bromide, and triflate substrates, while ligand 4 is effective for the amination of functionalized substrates or reactions of acyclic secondary amines. The catalysts perform well for a large number of different substrate combinations at 80-110 °C, including chloropyridines and functionalized aryl halides and triflates using 0.5-1.0 mol % Pd; some reactions proceed efficiently at low catalyst levels (0.05 mol % Pd). These ligands are effective for almost all substrate combinations that have been previously reported with various other ligands, and they represent the most generally effective catalyst system reported to date. Ligands 3 and 4 are air-stable, crystalline solids that are commercially available. Their effectiveness is believed to be due to a combination of steric and electronic properties that promote oxidative addition, Pd-N bond formation, and reductive elimination. Owing to the many important applications of aniline derivatives, and the limitations of most methods for their synthesis, a considerable amount of effort has been recently devoted to the development of catalysts that are capable of effecting the cross-coupling of amines with aryl halides and sulfonates.1 However, the proper choice of catalyst (Pd source, ligand choice) is crucial for the success of these reactions. It would be desirable to have Figure 1. one ligand (or a small class of ligands) that is capable of 4 (Figure 1) are excellent ligands for C-N,3a C-C,3a,b and handling all possible substrate combinations. Our group, C-O3c bond-forming reactions of aryl chloride substrates. and others, have recently reported catalysts based on Catalysts that employ 3 are sufficiently active to promote bulky, electron-rich phosphines that are capable of the room-temperature catalytic amination and Suzuki transforming inexpensive and readily available aryl coupling of aryl chloride substrates,3a,b,d,e and catalysts chlorides (as well as aryl bromides) into aniline deriva- derived from 4 are effective for the Suzuki coupling of tives, thereby expanding the substrate scope of the 3b 2 hindered substrates. These ligands also promote some palladium-catalyzed amination methodology. Herein we Suzuki coupling and catalytic amination reactions at very disclose results of a detailed study of the use of these low catalyst levels (0.000001-0.1 mol % Pd).3a Ligands ligands in aryl amination processes. 3 and 4 are air-stable, crystalline solids that are prepared Our first catalysts for the amination of aryl chlorides in a single step and are now commercially available.4 2e used ligands 1 and 2 (Figure 1). However, the prepara- Although 3 is effective for the room-temperature ami- tion of these phosphines required a multistep synthesis. nation of several aryl chloride substrates, the scope of We recently reported that the simple phosphines 3 and aryl chloride aminations is much broader when ligands 3 or 4 are employed at higher temperatures (80-110 °C). † Present address: Department of Chemistry, University of Cali- This is particularly relevant for reactions of functional- fornia, Irvine, CA 92697-2025. ized aryl halides, as the room-temperature reactions ‡ Present address: Department of Chemistry, California Institute of Technology, Pasadena, CA, 91125. require the use of the strong base NaOt-Bu. Ligand 3 is (1) (a) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, effective for aminations of electron-rich or -neutral aryl 125-146. (b) Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998, 37, chlorides with a wide variety of amine coupling partners; 2046-2067. (c) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818. (2) (a) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron Lett. (3) (a) A portion of this work has been previously communicated. 1998, 39, 617-620. (b) Yamamoto, T.; Nishiyama, M.; Koie, Y. See: Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1999, Tetrahedron Lett. 1998, 39, 2367-2370. (c) Reddy, N. P.; Tanaka, M. 38, 2413-2416. (b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, Tetrahedron Lett. 1997, 38, 4807-4810. (d) Hamann, B. C.; Hartwig, S. L. J. Am. Chem. Soc. 1999, 121, 9550-9561. (c) Aranyos, A.; Old, J. F. J. Am. Chem. Soc. 1998, 120, 7369-7370. (e) Old, D. W.; Wolfe, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722-9723. (f) Am. Chem. Soc. 1999, 121, 4369-4378. (d) Hartwig has recently Bei, X.; Guram, A. S.; Turner, H. W.; Weinberg, W. H. Tetrahedron reported examples of room-temperature catalytic amination of aryl Lett. 1999, 40, 1237-1240. (g) Bei, X.; Uno, T.; Norris, J.; Turner, H. bromides and chlorides using P(t-Bu)3. See: Hartwig, J. F.; Kawatsura, W.; Weinberg, W. H.; Guram, A. S.; Peterson, J. L. Organometallics M.; Hauck, S. I.; Shaughnessy, K.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 18, 1840-1853. (h) A procedure employing the Herrmann-Beller 1999, 64, 5575-5580. (e) Nolan has also recently reported aminations palladacycle has been used for some C-N bond-forming reactions of of aryl chlorides using nucleophilic carbenes as ligand. See: Huang, aryl chlorides at 135 °C; mixtures of regioisomers are often observed. J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307-1309. Riermeier, T. H.; Zapf, A.; Beller, M. Top. Catal. 1997, 4, 301-309 (4) Ligands 3 and 4 are commercially available from Strem Chemical and references therein. Co. 10.1021/jo991699y CCC: $19.00 © 2000 American Chemical Society Published on Web 02/02/2000 Palladium-Catalyzed Amination J. Org. Chem., Vol. 65, No. 4, 2000 1159 Table 1. Room-Temperature Catalytic Amination of Aryl The reaction of benzylamine with 4-chlorotoluene was Chloridesa slow with 1-2 mol % catalyst; the desired product was obtained in good yield when 5 mol % of the palladium catalyst was employed (Table 1, entry 4). Excess benzyl- amine (1.5 equiv) was employed to minimize the forma- tion of diaryl(alkyl) amine side products. Under these conditions a ratio of 8-9/1 diaryl/monoaryl product was observed. A larger amount of diarylated side product was formed at room-temperature than at 80 °C (see below). This procedure was also effective for the arylation of s-butylamine with m-chloroanisole (entry 12). In this case no diarylation was observed when 1.2 equiv of amine was employed. Use of Pd(OAc)2 as the palladium source was required for most of the room-temperature reactions, although the reaction of n-hexylamine with the highly activated 4-chlorobenzonitrile gave the best results when Pd2(dba)3 was employed. In contrast to what has been previously observed,5,6c the reaction of a primary amine or primary aniline with an electron-deficient aryl halide afforded small amounts of diarylated side products; a ratio of ∼14-15/1 diarylamine/triarylamine was observed in the reaction of 4-chlorobenzonitrile with n-hexylamine or p-toluidine. The weak base K3PO4 was ineffective for the room-temperature reactions, even for highly activated substrates such as 4-chloronitrobenzene. Unfortunately, the scope of the room-temperature reactions was somewhat limited. For example, the reac- tion of m-chloroanisole with n-hexylamine proceeded to only 19% conversion in 18 h. The requirement for Pd- (OAc)2 as a precatalyst precluded the use of primary anilines as coupling partners (see below), except for the a Reaction conditions: 1.0 equiv of aryl chloride, 1.2 equiv of reaction of p-toluidine with 4-chlorobenzonitrile, which amine, 1.4 equiv of NaOt-Bu, 1-2 mol % Pd(OAc)2,2-4 mol % 3, toluene (1 mL/mmol halide), rt. Reaction times have not been was effective when 2.5 mol % of Pd2(dba)3 was employed minimized. Yields represent isolated yields (average of two or more as the palladium source. The functional group tolerance experiments) of compounds estimated to be g95 % pure as judged of the process is currently limited owing to the need to by 1H NMR and GC analysis (known compounds) and combustion employ the strong base NaOt-Bu. However, nitrile func- b analysis (new compounds). The reaction was conducted with 1.5 tionality was tolerated even for arylations of primary equiv of benzylamine. c Pd (dba) used in place of Pd(OAc) . 2 3 2 anilines, which react with halobenzonitriles at higher temperatures (80 °C) in the presence of NaOt-Bu to form reactions involving secondary acyclic amines or aryl large amounts of amidine side products. chlorides bearing base-sensitive functionality are typi- cally more efficient using 4. Aryl bromides and triflates Catalytic Amination of Unactivated Aryl Chlo- are also effectively coupled with amines using catalysts rides at 80-110 °C. As shown in Table 2, the scope of based on 3 or 4; the Pd/4 catalyst is the most efficient the catalytic amination of aryl chlorides is considerably system reported to date for the coupling of electron-rich broader at 80-110 °C than at room temperature. A aryl bromides with primary anilines. catalyst system derived from Pd(OAc)2 or Pd2(dba)3 functions well for a variety of substrates including those Results that are electron-rich and/or ortho-substituted.
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