Simple, Efficient Catalyst System for the Palladium-Catalyzed

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 one ligand (or a small class of ligands) that is capable of handling all possible substrate combinations. Our group, and others, have recently reported catalysts based on bulky, electron-rich phosphines that are capable of transforming inexpensive and readily available aryl chlorides (as well as aryl bromides) into aniline derivatives, thereby expanding the substrate scope of the palladium-catalyzed amination methodology.2 Herein we disclose results of a detailed study of the use of these ligands in aryl amination processes. Our first catalysts for the amination of aryl chlorides used ligands 1 and 2 (Figure 1).2e However, the preparation of these phosphines required a multistep synthesis. We recently reported that the simple phosphines 3 and † Present address: Department of Chemistry, University of California, Irvine, CA 92697-2025. ‡ Present address: Department of Chemistry, California Institute of Technology, Pasadena, CA, 91125. (1) (a) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125-146. (b) Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998, 37, 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. 1998, 39, 617-620. (b) Yamamoto, T.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1998, 39, 2367-2370. (c) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38, 4807-4810. (d) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369-7370. (e) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 9722-9723. (f) Bei, X.; Guram, A. S.; Turner, H. W.; Weinberg, W. H. Tetrahedron Lett. 1999, 40, 1237-1240. (g) Bei, X.; Uno, T.; Norris, J.; Turner, H. W.; Weinberg, W. H.; Guram, A. S.; Peterson, J. L. Organometallics 1999, 18, 1840-1853. (h) A procedure employing the Herrmann-Beller palladacycle has been used for some C-N bond-forming reactions of aryl chlorides at 135 °C; mixtures of regioisomers are often observed. Riermeier, T. H.; Zapf, A.; Beller, M. Top. Catal. 1997, 4, 301-309 and references therein.

Figure 1.

4 (Figure 1) are excellent ligands for C-N,3a C-C,3a,b and C-O3c bond-forming reactions of aryl chloride substrates. Catalysts that employ 3 are sufficiently active to promote the room-temperature catalytic amination and Suzuki coupling of aryl chloride substrates,3a,b,d,e and catalysts derived from 4 are effective for the Suzuki coupling of hindered substrates.3b These ligands also promote some Suzuki coupling and catalytic amination reactions at very low catalyst levels (0.000001-0.1 mol % Pd).3a Ligands 3 and 4 are air-stable, crystalline solids that are prepared in a single step and are now commercially available.4 Although 3 is effective for the room-temperature amination of several aryl chloride substrates, the scope of aryl chloride aminations is much broader when ligands 3 or 4 are employed at higher temperatures (80-110 °C). This is particularly relevant for reactions of functionalized aryl halides, as the room-temperature reactions require the use of the strong base NaOt-Bu. Ligand 3 is effective for aminations of electron-rich or -neutral aryl chlorides with a wide variety of amine coupling partners; (3) (a) A portion of this work has been previously communicated. See: Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1999, 38, 2413-2416. (b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550-9561. (c) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369-4378. (d) Hartwig has recently reported examples of room-temperature catalytic amination of aryl bromides and chlorides using P(t-Bu)3. See: Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575-5580. (e) Nolan has also recently reported aminations of aryl chlorides using nucleophilic carbenes as ligand. See: Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307-1309. (4) Ligands 3 and 4 are commercially available from Strem Chemical Co.

10.1021/jo991699y CCC: $19.00 © 2000 American Chemical Society Published on Web 02/02/2000

Palladium-Catalyzed Amination Table 1. Room-Temperature Catalytic Amination of Aryl Chloridesa

a Reaction conditions: 1.0 equiv of aryl chloride, 1.2 equiv of 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 minimized. Yields represent isolated yields (average of two or more experiments) of compounds estimated to be g95 % pure as judged by 1H NMR and GC analysis (known compounds) and combustion analysis (new compounds). b The reaction was conducted with 1.5 equiv of benzylamine. c Pd2(dba)3 used in place of Pd(OAc)2.

reactions involving secondary acyclic amines or aryl chlorides bearing base-sensitive functionality are typically more efficient using 4. Aryl bromides and triflates are also effectively coupled with amines using catalysts based on 3 or 4; the Pd/4 catalyst is the most efficient system reported to date for the coupling of electron-rich aryl bromides with primary anilines. Results Room-Temperature Catalytic Amination of Aryl Chlorides. Initial attempts to effect the room-temperature catalytic amination of aryl chlorides using 2 were in general unsuccessful despite the utility of this ligand for room-temperature Suzuki coupling reactions of aryl chlorides.2e The one exception was when 4-chlorobenzonitrile, an activated aryl chloride, was combined with morpholine. However, use of ligand 3 provided catalysts with higher activity than was previously observed with 2. Catalysts comprised of 3/Pd(OAc)2 were sufficiently reactive to promote the room-temperature catalytic amination of a variety of aryl chloride substrates.3a As shown in Table 1, the reaction is effective for both electron-rich and electron-deficient substrates, and a variety of amines are suitable coupling partners. For example, both p- and o-chloroanisole could be converted to aniline derivatives in g90% yield using 1-2 mol % catalyst (entries 7, 11).

J. Org. Chem., Vol. 65, No. 4, 2000 1159

The reaction of benzylamine with 4-chlorotoluene was 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 benzylamine (1.5 equiv) was employed to minimize the formation 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 reaction 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 reaction of p-toluidine with 4-chlorobenzonitrile, which was effective when 2.5 mol % of Pd2(dba)3 was employed as the palladium source. The functional group tolerance of the process is currently limited owing to the need to employ the strong base NaOt-Bu. However, nitrile functionality was tolerated even for arylations of primary anilines, which react with halobenzonitriles at higher temperatures (80 °C) in the presence of NaOt-Bu to form large amounts of amidine side products. Catalytic Amination of Unactivated Aryl Chlorides at 80-110 °C. As shown in Table 2, the scope of the catalytic amination of aryl chlorides is considerably broader at 80-110 °C than at room temperature. A catalyst system derived from Pd(OAc)2 or Pd2(dba)3 functions well for a variety of substrates including those that are electron-rich and/or ortho-substituted. Even the very hindered 2,6-dimethylchlorobenzene was a suitable substrate, although higher reaction temperatures and/ or larger amounts of catalyst were required for reactions to proceed to completion in e24 h. A variety of amine coupling partners may be used including primary and secondary anilines, primary amines, cyclic secondary amines, and diarylamines. Benzophenone imine, which serves as an NH3 equivalent,7 and (5) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 7215-7216. (6) (a) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1995, 34, 1348-1350. (b) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609-3612. (c) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217-7218. (d) Marcoux, J.-F.; Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1997, 62, 1568-1569. (e) Sadighi, J. P.; Harris, M. C.; Buchwald, S. L. Tetrahedron Lett. 1998, 39, 53275330. (7) Wolfe, J. P.; A° hman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6367-6370.

1160

J. Org. Chem., Vol. 65, No. 4, 2000

Wolfe et al.

Table 2. Palladium-Catalyzed Amination of Unactivated Aryl Chloridesa

a Reaction conditions: 1.0 equiv of aryl halide, 1.2 equiv of amine, 1.4 equiv of NaOt-Bu, cat. Pd(OAc) , cat. 3 (2L/Pd), toluene (2 2 mL/mmol halide), 80 °C. Reaction times have not been minimized. b Pd2(dba)3 used in place of Pd(OAc)2. c The reaction was conducted at 100 °C. d The reaction was conducted at 110 °C. e The reaction was conducted with 1.5 equiv of amine. f A ratio of 1.5 L/Pd was employed.

benzophenone hydrazone8 are also suitable substrates. Use of 2, 5, or 6 as ligands for the coupling of di-nbutylamine with 4-chlorotoluene gave higher yields than were obtained with 3 or 4 (entry 6); use of 3 or 4 resulted in the formation of aryl(tert-butyl)ether byproducts (∼10%).

Reactions of primary aliphatic amines with unhindered aryl halides afforded good yields of the aryl(alkyl)amine products with the 3/Pd catalyst at 80 °C; 1.5 equiv of amine was employed to minimize the formation of diarylated side products in these reactions. The ratios of monoaryl/diaryl products were typically ∼10-20/1 for (8) The Pd-catalyzed arylation of benzophenone hydrazone and the subsequent transformation of the aryl hydrazone products to indoles have been previously reported by this group. See: (a) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 6621-6622. (b) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 10251-10263. (c) Hartwig has also reported the catalyzed arylation step, but not the subsequent conversion into indoles: Hartwig, J. F. Angew. Chem., Int. Ed. Engl. 1998, 37, 2090-2093.

reactions of primary amines with p-substituted aryl chlorides, with n-hexylamine producing more diarylation (12/1 monoaryl/diaryl) than benzylamine (21/1 monoaryl/ diaryl) in reactions with 4-chlorotoluene. Diarylated products were not observed with o-substituted aryl chlorides. Reactions of primary anilines were inefficient if Pd(OAc)2 was employed as a precatalyst, but use of Pd2(dba)3 for these reactions provided excellent results. Some substrate combinations that gave outstanding results with the BINAP catalyst system5 (for the analogous aryl bromides) were either inefficient or required high temperatures or long reaction times. For example, the reaction of 4-bromobenzonitrile with n-hexylamine proceeds to completion rapidly and in essentially quantitative yield using the BINAP catalyst system (0.05 mol % Pd).5 However, the reaction of 4-chlorobenzonitrile with n-hexylamine required 40 h at 110 °C to proceed to completion with 1 mol % Pd (see below in Table 5, entry 11). For some substrates it was possible to conduct reactions with low catalyst loadings (0.05 mol % Pd),3a although to date these conditions are only effective for a limited number of substrate combinations (Table 3). For example, the reaction of N-methylaniline with 4-chlorotoluene proceeds to completion in 22 h using 0.025 mol % Pd2(dba)3 and 0.1 mol % 3 at 100 °C affording the

Palladium-Catalyzed Amination Table 3. Amination of Aryl Chlorides at Low Catalyst Loadinga

J. Org. Chem., Vol. 65, No. 4, 2000 1161 Table 4. Palladium-Catalyzed Amination of Chloropyridinesa

a Reaction conditions: 1.0 equiv of aryl chloride, 1.2 equiv amine, 1.4 equiv of NaOt-Bu, 0.025 mol % Pd2(dba)3, 0.1 mol % 3, toluene (1 mL/mmol halide), 110 °C. Reaction times have not been minimized. Yields represent isolated yields (average of two or more experiments) of compounds estimated to be g95 % pure as judged by 1H NMR and GC analysis (known compounds) and combustion analysis (new compounds). b The reaction was conducted at 100 °C. c The reaction was conducted at 80 °C.

desired product in 95% yield. However, although the reaction of 4-chlorotoluene with p-toluidine is efficient with 0.5 mol % Pd (Table 2, entry 3), it only proceeds to 41% conversion in 48 h at 110 °C using 0.05 mol % Pd. Catalytic Amination of Chloropyridines. Previous studies in our laboratory demonstrated that bromopyridine substrates were effective coupling partners in catalytic amination reactions provided that the chelating phosphine ligands BINAP or DPPP were employed;9 nonchelating triarylphosphines were displaced from the metal by the pyridine substrate leading to catalyst deactivation.9,10 Aminations of 2-chloropyridines were possible, although fairly high catalyst loadings (4 mol % Pd) were required.9 When the mixtures of Pd(OAc)2 and 2, 3, or 4 were employed, 2-, 3-, and 4-chloropyridine proved to be viable substrates in catalytic amination reactions. While the chloropyridine derivatives reacted more slowly than other aryl halides, use of 1 mol % Pd(OAc)2 at 100-110 °C provided acceptable results (Table 4). Despite the diminished reactivity of these substrates relative to other aryl chlorides, a variety of amines proved to be suitable coupling partners. Reactions catalyzed by Pd/3, that provided unacceptable results were usually more efficient if Pd/4 or Pd/2 were employed. Use of the Pd/4 catalyst system necessitated the addition of excess amine (1.53.0 equiv) for reactions with primary amines in order to minimize the formation of doubly arylated products. As expected, aminations of the more reactive 2-chloropyridine were considerably faster than those of 3-chloropyridine. Use of the mild base K3PO4 was effective for the amination of 4-chloropyridine HCl with morpholine. The use of this base gave cleaner but slower reactions. Catalytic Amination of Functionalized Aryl Chlorides. The use of the strong base NaOt-Bu in catalytic amination reactions leads to a relatively low level of functional group tolerance.1 However, employment of (9) Wagaw, S.; Buchwald, S. L. J. Org. Chem. 1996, 61, 7240-7241. (10) Hartwig has also demonstrated the displacement of triarylphosphines by pyridine in LPd(Ar)X complexes. See: Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995, 14, 3030-3039.

a Reaction conditions: 1.0 equiv of chloropyridine, 1.2 equiv of amine, 1.4 equiv of NaOt-Bu, cat. Pd(OAc)2, cat. 3, toluene (2 mL/ mmol halide), 110 °C. b The reaction was conducted at 100 °C.c The reaction was conducted using 1.5 equiv of amine. d The reaction was conducted using 3.0 equiv amine. e 2.8 equiv of K3PO4 used in place of NaOt-Bu. f 1,4-Dioxane (1 mL/mmol halide) was used as the solvent. g 1,4-Dioxane (2 mL/mmol halide) was used as the solvent. h 2.8 equiv of NaOt-Bu was employed.

weaker bases such as Cs2CO311 or K3PO42e greatly improves the functional group compatibility of these reactions. Catalytic amination of aryl chloride substrates bearing a variety of base-sensitive functional groups was achieved using catalysts derived from 2, 3, and 4 when K3PO4 was employed as the stoichiometric base (Table 5). The reaction conditions tolerated the presence of enolizable ketones, methyl esters, nitriles, and nitro groups; a variety of amines were efficient coupling partners, but reactions of primary aliphatic amines usually required longer reaction times, higher temperatures, and/or larger catalyst loadings. Although the Pd/3 catalyst was useful for some substrate combinations, the best results were generally obtained with either 2 or 4; catalysts based on 2 were slightly more reactive than those derived from 4. Reactions that proved to be inefficient when Pd(OAc)2 was employed as a precatalyst usually gave better results when Pd2(dba)3 was used. Substrates that contained functional groups ortho to the aryl chloride were much less reactive. Acceptable yields were obtained for the reaction of 2-chloronitrobenzene or methyl-2-chlorobenzoate with primary anilines (entries 15, 16); however, reactions with aliphatic amines resulted in the formation of large amounts of side products arising from reduction and/or homocoupling of the aryl chloride, and typically proceeded to