DOI: 10.1002/cssc.200700166
Ligand-Free Palladium-Catalysed Direct Arylation of Heteroaromatics Using Low Catalyst Loadings Franc Pozˇgan, Julien Roger, and Henri Doucet*[a] The arylation of heteroaromatics is an important field for research in organic synthesis. Palladium-catalysed Suzuki, Negishi or Stille cross-couplings are among the most important methods to perform such reactions.[1] However, they require the preparation of an organometallic derivative and lead to the production of an organometallic salt (MX) as by-product. In 1990, Ohta et al. reported the direct arylation of thiophenes, furans or thiazoles with aryl halides through C H bond activation in moderate to good yields using 5 mol % [PdACHTUNGRE(PPh3)4] as catalyst.[2] Since these exciting results, the palladium-catalysed direct arylation of heterocyclic derivatives with aryl halides or triflates has proved to be a powerful method for the synthesis of heterobiaryls.[3, 4] This method provides a cost-effective and environmentally attractive procedure for the preparation of arylated heteroaromatics. The major drawback of the reported procedures is that they generally require loadings of 5– 10 mol % catalyst.[3] Recently, Heck and Suzuki reactions under low catalyst loading (0.1–0.01 mol %) using ligand-free catalyst PdACHTUNGRE(OAc)2 have been described by de Vries and co-workers.[5, 6] They demonstrated that soluble palladium(0) colloids or nanoparticles are formed at elevated temperature when PdACHTUNGRE(OAc)2 is employed as catalyst precursor and that the Heck or Suzuki reaction takes place through the interaction of the arylating agent with the palladium atoms in the outer rim of the nanoparticles. This leads to formation of monomeric or dimeric anionic palladium complexes that undergo the usual steps of the Heck or Suzuki reaction mechanisms. So far, to our knowledge, all the procedures reported for the arylation through C H bond activation of heteroaromatics using ligand-free catalysts such as PdACHTUNGRE(OAc)2 have required 5– 10 mol % catalyst,[7–13] except for one procedure in which only 1 mol % was employed.[14] In fact, such couplings under low concentrations of catalyst employ palladium associated to sophisticated ligands.[15, 16] Therefore, the development of more effective conditions for the direct coupling of heteroaromatics with aryl halides under low catalyst loadings (< 0.1 mol %), would be a considerable advantage for industrial applications and for sustainable development. Here, we report on ligandless palladium-catalysed direct arylation of heteroaromatics using low catalyst loadings. First, by employing the low catalyst loading procedure described by
[a] Dr. F. Pozˇgan, J. Roger, Dr. H. Doucet Institut Sciences Chimiques de Rennes UMR 6226 CNRS-Universit$ de Rennes 1, “Catalyse et Organometalliques” Campus de Beaulieu, 35042 Rennes (France) Fax: (+ 33) 223-23-69-39 E-mail:
[email protected] Supporting information for this article is available on the WWW under http://www.chemsuschem.org or from the author.
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de Vries and co-workers (elevated reaction temperature, polar solvent, acetate as base and no ligand on palladium), we observed that the coupling of 4-bromoacetophenone with 2-npropylthiazole using as little as 0.01 mol % PdACHTUNGRE(OAc)2 as catalyst led selectively to the 5-arylated thiazole 1 with complete conversion of the aryl bromide and a very high yield of isolated compound (Scheme 1; Table 1, entry 1).
Scheme 1. Coupling of 2-n-propylthiazole and aryl bromides (DMAc = N,N-dimethylacetamide).
Table 1. Palladium-catalysed coupling of 2-n-propylthiazole and aryl bromides (Scheme 1).[a] Substrate/ Product catalyst
Yield [%][b]
1
10 000
100 (94)
2
10 000
94 (89)
3
10 000
95 (90)
4 5
1000 100
88 (79) 88 (77)
6 7
1000 100
52 (44) 52 (42)
8 9
1000 100
Entry
Aryl bromide
0 0
[a] Conditions: PdACHTUNGRE(OAc)2, ArBr (1 equiv), 2-n-propylthiazole derivative (2 equiv), AcOK (2 equiv), DMAc, 150 8C, 20 h. [b] Yields as determined by GC and NMR spectroscopy. The values in parentheses correspond to the yield of isolated product.
Then, we studied the scope and limitations of this procedure with other aryl bromides. 4-Bromobenzonitrile and 4-fluorobromobenzene reacted with 2-n-propylthiazole gave the expected products 2 and 3 with high turnover numbers (TONs) of 8900 and 9000, respectively, and in high yields (Table 1, entries 2 and 3). On the other hand, with the electron-rich aryl bromides, 4-bromoanisole or 4-bromo-N,N-dimethylaniline,
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0.1 mol % catalyst had to be employed to obtain moderate to high yields of 4 and 5. In the presence of sterically congested 2,6-dimethylbromobenzene, no coupling product was obtained. Interestingly, for these reactions, the yields of 4 and 5 were not improved by an increase in the catalyst loading from 0.1 to 1 mol %, revealing that the concentration of active Pd species is relatively similar at both concentrations of PdACHTUNGRE(OAc)2. At higher palladium concentrations with this ligand-free procedure, so-called “palladium black” forms more rapidly and the conversions of aryl bromides are not improved.
Next, we studied the reactivity of thiophene and furan derivatives using this procedure (Table 2, Scheme 2). The coupling
Scheme 2. Coupling of thiophenes or furans and aryl bromides.
Table 2. Palladium-catalysed coupling of heteroaromatics and aryl halides (Scheme 2).[a] Entry
Heteroaryl
Aryl halide
Substrate/catalyst
Product
Yield [%][b]
1
10 000
100 (85)
2
10 000
100 (86)
3
1000
98 (81)
4
10 000
81 (67)
5 6
1000 100
76 (62) 60 (50)
7 8
10 000 1000
52 (46) 63 (49)
9
10 000
100 (80)
10
10 000
100 (86)
11
10 000
100 (90)
12
10 000
100 (64)
13
10 000
100 (86)
14
1000
90 (54)
15 16
1000 100
44 (18) 33 (12)
17
1000
90 (38)[c]
18
10 000
100 (88)
[a] Conditions: PdACHTUNGRE(OAc)2, heteroaryl (2 equiv), aryl halide (1 equiv), AcOK (2 equiv), DMAc, 150 8C, 20 h. [b] Yields as determined by GC and NMR spectroscopy. The values in parentheses correspond to the yield of isolated product. [c] A significant amount of biphenyl was also formed.
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of 2-n-butylthiophene with the electron-deficient aryl bromides, 4-bromoacetophene and 4-bromobenzophenone, also proceeds in high yields using only 0.01 mol % catalyst (Table 2, entries 1 and 2). Slightly activated 4-fluorobromobenzene was found to be less reactive, and 0.1 mol % catalyst had to be employed to obtain a high conversion and a good yield of 9 (81 %) (Table 2, entry 3). Ortho-substituted 2-bromobenzonitrile reacted with 2-n-butylthiophene also led to the expected product with a high TON of 6700 (Table 2, entry 4). As expected, a lower reactivity of the deactivated aryl bromide 4-bromoanisole was observed. With this substrate, an increase in the catalyst loading led to a lower yield of product 11. Conversions of 76 and 60 % were obtained using 0.1 and 1 mol % catalyst, respectively (Table 2, entries 5 and 6). Surprisingly, this ligand-free procedure was found to give disappointing results using iodobenzene. With this very reactive aryl halide, moderate conversions of 52 and 63 % were observed using 0.01 or 0.1 mol % catalyst, respectively (Table 2, entries 7 and 8). On the other hand, the functionalised thiophene, 2-cyanothiophene, reacted with 4-bromoacetophenone to give the expected product 13 with a very high TON of 8000 and in 80 % yield (Table 2, entry 9). Finally, we examined the reactivity of 2-n-butylfuran using a variety of aryl halides. Very high TONs of 6400–9000 and good yields of products 14–17 were obtained using the electron-deficient aryl bromides 4-bromoacetophenone, 4-bromotrifluoromethylbenzene, 4-bromonitrobenzene or 2-bromobenzonitrile (Table 2, entries 10–13). 2-Bromoacetophenone gave 18 in moderate yield only owing to the formation of unidentified side products (Table 2, entry 14). Electron-rich 4-bromoanisole also led to low yields of coupling product 19. During the course of this reaction, conversions of 44 and 33 % of 4-bromoanisole were observed but the formation of side products was observed which lowered the yield. Again, a lower yield of product 19 was obtained when a higher catalyst loading was employed (Table 2, entries 15 and 16). With the reactive aryl halide, iodobenzene, the formation of a significant amount of biphenyl was observed and the target product 20 was isolated in only 38 % yield (Table 2, entry 17). For challenging substrates such as deactivated aryl bromides, aryl chlorides or iodobenzene, palladium complexes associated to electron-rich monodentate phosphine ligands or to polydentate ligands should be employed.[3, 15–17] In summary, the ligand-free palladium-catalysed procedure under low-catalyst loading as reported by de Vries and coworkers is not limited to Heck or Suzuki reactions. We have demonstrated that by using as little as 0.1–0.01 mol % of PdACHTUNGRE(OAc)2 as catalyst precursor, the direct arylation through C H bond activation of heteroaromatics such as thiophene, furan or thiazole derivatives proceeds in moderate to high yields. Note that a wide range of functions, such as acetyl, benzoyl, nitro, nitrile, fluoro or trifluoromethyl, on the aryl bromide are tolerated. With this procedure, an increase in the catalyst loading to 1 mol % generally led more rapidly to aggregation of palladium to form so-called “palladium black” and gave lower yields of coupling products. Therefore, this procedure is limited to acti-
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vated aryl bromides, even if, in selected cases, deactivated aryl bromides gave satisfactory results. This procedure with low catalyst loading is economically and environmentally attractive. The only by-products are AcOH and KBr instead of metallic salts as with classical coupling procedures. Moreover, the preparation of an organometallic derivative is not required, thus reducing the number of steps to prepare these compounds.
Experimental Section Typical reaction procedure: 4-bromoacetophenone (0.199 g, 1 mmol), 2-n-propylthiazole (0.254 g, 2 mmol) and AcOK (0.196 g, 2 mmol) were heated at 150 8C during 20 h in dry DMAc (3 mL) in the presence of PdACHTUNGRE(OAc)2 (0.0224 mg, 0.0001 mmol) under argon. Extraction of the crude mixture with dichloromethane, evaporation of the solvent, and filtration over silica gel (pentane/ether) afforded the corresponding product 1 in 94 % yield (0.231 g). 1H NMR (200 MHz, CDCl3): d = 7.96 (d, J = 8.5 Hz, 2 H), 7.92 (s, 1 H), 7.60 (d, J = 8.5 Hz, 2 H), 2.99 (t, J = 7.4 Hz, 2 H), 2.60 (s, 3 H), 1.85 (sext., J = 7.4 Hz, 2 H), 1.03 ppm (t, J = 7.4 Hz, 3 H); 13C NMR (50 MHz, CDCl3): d = 197.1, 172.1, 138.9, 137.1, 136.2, 136.1, 129.1, 126.3, 35.6, 26.6, 23.3, 13.6 ppm; elemental analysis (%) calcd for C14H15NOS (245.34): C 68.54, H 6.16; found: C 68.66, H 5.96. See Supporting Information for 1H and 13C NMR data and results of elemental analysis of new compounds.
Acknowledgements This research was supported by a Marie Curie Intra-European Fellowship within the 6th European Community Framework Programme. J.R. is grateful to the Minist?re de la Recherche for a grant. We thank the CNRS and Rennes Metropole for providing financial support and P. H. Dixneuf for useful discussions. Keywords: C H activation heterocycles · palladium
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Received: December 21, 2007 Published online on April 2, 2008
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