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Efficient and C2-selective arylation of indoles, benzofurans, and benzothiophenes with iodobenzenes in water at room temperature
Tetrahedron xxx (2015) 1e6
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Efficient and C2-selective arylation of indoles, benzofurans, and benzothiophenes with iodobenzenes in water at room temperature Zhongmiao Xu a, Yulong Xu b, Hongfu Lu a, Ting Yang a, Xichen Lin a, Liming Shao b, Feng Ren a, * a b
Research and Development, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China School of Pharmacy, Fudan University, 826 Zhangheng Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 January 2015 Received in revised form 8 March 2015 Accepted 13 March 2015 Available online xxx
A mild, efficient, and C2-selective palladium-catalyzed arylation reaction of indoles, benzofurans, and benzothiophenes with iodobenzenes at room temperature has been developed. The methodology allows the use of water, the most environmentally friendly solvent, as the reaction solvent with the addition of Tween 80 (2% w/w) to increase the solubility of starting materials. The protocol demonstrated wide substrate scope and good yields were obtained for all the 32 examples evaluated (52e93%). Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: CeH Arylation Indole Benzofuran Benzothiophene Aqueous micelles
1. Introduction Functionalized indoles, benzofurans, and benzothiophenes serve as important building blocks of natural products and biologically active unnatural molecules.1 Among the known methods in the functionalization of indoles, benzofurans, and benzothiophenes, CeH activation/arylation reactions have attracted tremendous interests due to their high atom efficiency.2 However, the reported methods always suffered from low regio-selectivities (C-2 over C-3) when no directing groups were pre-installed and/or high reaction temperatures (100e150 C), which significantly limited the substrate scope and functional group tolerance. Several C2selective arylation reactions of indoles using boronic acids or trifluoroborate salts as arylation agents at room temperature were developed, whereas in these conditions acetic acid had to be used as the solvent/co-solvent and oftentimes the trifluoroborates were not commercially available.3 Recently Larrosa has reported the C2arylation of N-alkylated indoles at room temperature using more readily available iodobenzenes as arylation agents.4 However, when free indoles were used as the substrates, the arylation reactions required higher temperature (50 C).4 C2-selective arylations of benzofurans and benzothiophenes were less extensively reported
* Corresponding author. Tel.: þ86 186 1674 3377; fax: þ86 021 6159 0730; e-mail address: [email protected] (F. Ren).
compared with indoles, and elevated reaction temperatures (>100 C) were always required for the limited cases in literature.2a,e,h Herein, we report a mild, efficient, and C2-selective arylation reaction of indoles, benzofurans, and benzothiophenes at room temperature with a wide scope of substrates. To the best of our knowledge, this is the first time the C2-selective arylation of benzofurans and benzothiophenes with iodobenzenes could be achieved at room temperature. In addition, our methodology allows the use of water as the reaction solvent, which makes it even more attractive in the aspect of reducing the hazardous organic waste.5 To develop organic reactions in aqueous solution has been one of the research focuses in our group.6 A challenge for aqueous reactions is the poor solubility of starting materials, and adding surfactants to water has been a widely used strategy to improve solubility.7 Among the surfactants used, polysorbates (also called Tweens) offer cheap and environmentally friendly choices8 and we focused our solvents on the Tweens/water micelle system. 2. Result and discussion We started our exploration of the CeH arylation using 1-methyl1H-indole (1a) and iodobenzene (2a) as starting materials and Tween 80/water (2% w/w) micelle as the solvent (Table 1). To our delight, our initial attempt using Pd(OAc)2 as the catalyst and AgOAc as the additive at room temperature led to the formation of C2-arylation product (3a) in 39% conversion (Table 1, entry 1).
http://dx.doi.org/10.1016/j.tet.2015.03.051 0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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Z. Xu et al. / Tetrahedron xxx (2015) 1e6
Table 1 Optimization of the Pd-catalyzed direct arylation conditions of N-methylindole (1a) with iodobenzene (2a)a
Entry
Pd(OAc)2 (mol %)
Surfactant
Additive
Conv (%)c
1 2 3 4b 5 6 7 8 9 10
2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 5 5
Tween Tween Tween Tween Tween Tween Tween Tween Tween none
AgOAc K2CO3 CF3COOAg Ag2OþTFA CF3COOAg CF3COOAg CF3COOAg CF3COOAg CF3COOAg CF3COOAg
39 4 85 24 81 83 73 68 97 38
80 80 80 80 20 40 60 85 80
Table 2 Substrate scope of Pd-catalyzed direct CeH arylation of indolesa
a Conditions: N-methylindole 1a (1 mmol), iodobenzene 2a (2 mmol), additive (1.5 mmol), 2% of surfactant/H2O (w/w, 2 ml). b 0.75 equiv of Ag2O followed by 1.5 equiv of trifluoroacetic acid. c Conversions measured by HPLC.
Encouraged by the result, we started to evaluate the effects of different additives to the reaction including K2CO3, CF3COOAg, and Ag2O plus TFA (Table 1, entries 2e4). Among them, CF3COOAg provided the best conversion (85%) to the desired product 3a (Table 1, entry 3). Tweens of different sizes were also explored (Table 1, entries 5e8) and they all resulted in similar or lower conversions than Tween 80. Increasing the catalyst loading from 2.5 mol % to 5 mol % accelerated the reaction to provide 97% conversion within 1 h (Table 1, entry 9). In comparison, removal of Tween 80 from the reaction mixture gave a much decreased conversion (38%, Table 1, entry 10) at otherwise the same reaction condition, and this was believed to due to the insolubility of starting materials without the micelle formation of the surfactant in water. With the optimized reaction condition of C2-selective arylation of indoles developed, the substrate scope was examined. As shown in Table 2, iodobenzenes with a variety of different substitutions were well tolerated for the reaction. Both electron-withdrawing and electron-donating substitutions were tolerated at the paraposition of the iodobenzene, providing C2-arylation products in good isolated yields (67e90%, 3beg). Substitution at the meta-position also demonstrated high reactivity to afford the desired product (3h) in high yield (93%). Increasing the steric hindrance of the iodobenzene by introducing ortho-substitutions resulted in lower yields (52% and 65% for 3i and 3j, respectively). These results suggested the reactivities of iodobenzenes for the C2-arylation reaction were sensitive to steric rather than electronic effects. The scope of indole substrates was also evaluated, and the reaction showed good tolerability for different substitutions including both electron-withdrawing and electron-donating groups (3jen). The electron-withdrawing substituent at the 4-position of the indole (3n) resulted in a much slower arylation reaction compared with the electron-donating substituent (3l) and a much longer reaction time was required (3 days for 3n and 3 h for 3l). It was noteworthy that for the free indole substrate (3o) high yield (62%) was also obtained at room temperature whereas elevated temperature was required in the reported procedure.4 In addition, the high C2selectivity of our arylation reactions was striking and there was no C3-arylation product observed in all the tested substrates, even for the steric hindered ones (3i and 3j). The mechanistic studies of palladium-catalyzed arylation of indoles had been reported and the palladium migration from the 3-position to the 2-position of the indoleepalladium(II) intermediate was the key to give C2selectivity.9 Our aqueous condition must have strongly favored
Unless otherwise stated, the reaction was conducted with 1 (1 mmol), 2 (2 equiv.), CF3COOAg (1.5 equiv.) and Pd(OAc)2 (0.05 equiv.) in Tween 80/H2O (2 mL, 2% w/w) at room temperature for 1 hour. Isolated yields. b Reaction runs for 3 hours. c Reaction runs for 3 days. a
the C3/C2 migration of palladium to provide the high C2selectivity of the arylation products. We then expanded the substrate scope to benzofurans, which are less electron-rich than indoles. As expected, the CeH arylation reactions of benzofurans were much slower (Table 3) compared with indoles, and extended reaction time (overnight) was required for the reaction to be completed. In addition, TFA had to be used to accelerate the arylation reactions.10 The substituted iodobenzenes were well tolerated and generally good isolated yields of C2arylation products were obtained at room temperature (5aee), although para-CF3 iodobenzene was less effective and a prolonged reaction time was required for high yield (5e). On the other hand, both electron-withdrawing and electron-donating substitutions on benzofurans were tolerated. Prolonged reaction times were required for the full conversions to 5f and 5g, due to poor solubility of starting materials in the reaction mixtures. Again, our arylation condition for benzofurans was highly C2-selective, and there was no C3-arylation product observed for all cases. We further expanded the substrate scope to benzothiophenes, which are even less electron-rich. To our delight, both substituted iodobenzenes and substituted benzothiophenes were welltolerated and high yields of desired C2-arylation products were obtained at room temperature, albeit more prolonged reaction time was required (Table 4). Electron-withdrawing substitutions on the iodobenzene made the reactions less efficient and extremely slow, but good yields could still be obtained (7b and 7e).
3. Conclusion In summary, we have developed a mild, efficient, and highly C2selective palladium-catalyzed arylation reaction of indoles,
Please cite this article in press as: Xu, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.03.051
Z. Xu et al. / Tetrahedron xxx (2015) 1e6 Table 3 Substrate scope of Pd-catalyzed direct CeH arylation of benzofuransa
a
Unless otherwise stated, the reaction was conducted with 4 (1 mmol), 2 (2 equiv.), CF3COOAg (1.5 equiv.), TFA (2 equiv.) and Pd(OAc)2 (0.05 equiv.) in Tween 80/H2O (2 mL, 2% w/w) at room temperature overnight. Isolated yields. bReaction runs for 5 days. c Reactions run for 2 days.
Table 4 Substrate scope of Pd-catalyzed direct CeH arylation of benzothiophenesa
3
as the internal standard. DMSO-d6 is hexadeuteriodimethylsulfoxide, CDCl3 is deuteriochloroform. Chemical shifts are given in parts per million (d) downfield from the NMR solvent. Abbreviations for NMR data are as follows: s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet, dd¼doublet of doublets, dt¼doublet of triplets, app¼apparent, br¼broad. J indicates the NMR coupling constant measured in Hertz. High resolution mass (HRMS) was operated in positive mode of electrospray ionization (ESI) at an orthogonal acceleration time-of-flight (oa-TOF), SYNAPT G2 HDMSTM (Waters, Manchester, UK). LCMS (Agilent 1200SL-6110) analysis was conducted for all compound on acidic condition: acidic condition refers to water containing 0.05% TFA/acetonitrile as mobile phase on Agilent SB-C18 column (1.8 mm, 4.630 mm), with MS and photodiode array detector (PDA). The following conditions were used: a gradient from 5 to 95% in 5 min (or 6 min) and held at 95% for 1 min; UV detection at 214 and 254 nm; a flow rate of 1.5 ml/min; full scan; mass range from 100 to 1000 amu. All the compounds possess 95% purity determined using LC/MS analysis. Column chromatography was performed on Isco or Biotage using a pre-packed silica gel column, a detector with UV wavelength at 254 nm and 280 nm. 4.2. General procedure for the CeH arylation of indoles with iodobenzenes To a microwave reaction vial, Pd(OAc)2 (5 mol %), CF3COOAg (1.5 mmol), iodobenzene (2.0 mmol), N-methylindole (1.0 mmol), and Tween-80/H2O (2 ml, 2 wt %) were added. The reaction mixture was allowed to react at room temperature. After 1 h (or otherwise stated), the mixture was concentrated under reduced pressure, and the residue was purified on a silica gel chromatography to afford the desired product. 4.2.1. 1-Methyl-2-phenyl-1H-indole (3a).4b Yield: 85%; 1H NMR (400 MHz, CDCl3) d 7.69 (td, J¼1.2, 7.8 Hz, 1H), 7.58e7.54 (m, 2H), 7.54e7.49 (m, 2H), 7.47e7.39 (m, 2H), 7.34e7.27 (m, 1H), 7.23e7.15 (m, 1H), 6.62 (d, J¼0.8 Hz, 1H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) d 141.9, 138.7, 133.2, 129.7, 128.8, 128.3, 128.2, 122.0, 120.8, 120.2, 109.9, 102.0, 31.4; HRMS (ESI): calculated for C15H14N [MþH]þ, 208.1126. Found [MþH]þ, 208.1127.
a
Unless otherwise stated, the reaction was conducted with 6 (100 mg), 2 (2 equiv.), silver(I) trifluoroacetate (1.5 equiv.), trifluoroacetic acid (2 equiv.) and diacetoxypalladium (0.05 equiv.) in Tween 80/H2O (2 mL, 2% w/w) at room temperature for 2 days. Isolated yields. bReactions run for 7 days.
benzofurans, and benzothiophenes with iodobenzenes at room temperature. To the best of our knowledge, this is the first time C2selective arylation of benzofurans and benzothiophenes with iodobenzenes could be achieved at room temperature. Our methodology allows the use of water, the most environmentally friendly solvent, as the reaction solvent with the addition of Tween 80 (2% w/w) to increase the solubility of starting materials. In addition, our protocol demonstrated wide substrate scope, and good yields were obtained for all the 32 examples evaluated (52e93%). 4. Experimental section 4.1. General 1
H NMR and 13C NMR spectra were recorded on a Bruker 400/600 NMR spectrometer with CDCl3 or DMSO-d6 as the solvent and TMS
4.2.2. 1-Methyl-2-(p-tolyl)-1H-indole (3b).11 Yield: 90%; 1H NMR (400 MHz, CDCl3) d 7.66 (d, J¼8.0 Hz, 1H), 7.40 (d, J¼8.0 Hz, 2H), 7.35 (d, J¼8.0 Hz, 1H), 7.26e7.30 (m, 3H), 7.18 (t, J¼7.6 Hz, 1H), 6.53 (br s, 1H), 3.78 (s, 3H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) d 141.7, 138.2, 137.8, 129.9, 129.3 (2C), 129.2 (2C), 128.0, 121.5, 120.4, 119.8, 109.6, 101.3, 31.1, 21.3; HRMS (ESI): calculated for C16H16N [MþH]þ, 222.1283. Found [MþH]þ, 222.1285. 4.2.3. 2-(4-Methoxyphenyl)-1-methyl-1H-indole (3c).4b Yield: 85%; 1 H NMR (400 MHz, CDCl3) d 7.65 (d, J¼8.0 Hz, 1H), 7.47 (d, J¼8.0 Hz, 2H), 7.38 (d, J¼8.0 Hz,1H), 7.30 (t, J¼8.0 Hz,1H), 7.20 (t, J¼8.0 Hz,1H), 7.04 (d, J¼8.0 Hz, 2H), 6.54 (s, 1H), 3.91 (s, 3H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.4, 141.4, 138.1, 130.6 (2C), 128.0, 125.3, 121.4, 120.2, 119.7, 114.0 (2C), 109.5, 101.0, 55.4, 31.0; HRMS (ESI): calculated for C16H16NO [MþH]þ, 238.1232. Found [MþH]þ, 238.1229. 4.2.4. 2-(4-Chlorophenyl)-1-methyl-1H-indole (3d).11 Yield: 87%; 1 H NMR (400 MHz, CDCl3) d 7.66 (d, J¼8.0 Hz, 1H), 7.48 (m, 4H), 7.39 (d, J¼8.0 Hz, 1H), 7.24e7.27 (m, 1H), 7.15 (t, J¼8.0 Hz, 1H), 6.59 (s, 1H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) d 140.2, 138.4, 134.0, 131.3 (2C), 130.5 (2C), 128.8, 127.8, 122.0, 120.6, 120.0, 109.6, 102.0, 31.2; HRMS (ESI): calculated for C15H13ClN [MþH]þ, 242.0737. Found [MþH]þ, 242.0737. 4.2.5. 2-(4-Fluorophenyl)-1-methyl-1H-indole (3e).11 Yield: 89%; 1H NMR (400 MHz, CDCl3) d 7.63 (d, J¼7.6 Hz, 1H), 7.45e7.48 (m, 2H),
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7.36 (d, J¼8.4 Hz, 1H), 7.24e7.27 (m, 1H), 7.13e7.18 (m, 3H), 6.53 (s, 1H), 3.71 (s, 3H); 13C NMR (100 MHz, CDCl3) d 162.6 (d, J¼246 Hz), 140.5, 138.3, 131.1 (d, J¼8.0 Hz), 128.9, 127.9, 121.8, 120.5, 120.0, 115.6 (d, J¼21.5 Hz), 109.7, 101.7, 31.1; 19F NMR: (376 MHz, CDCl3) d 113.8; HRMS (ESI): calculated for C15H13FN [MþH]þ, 226.1032. Found [MþH]þ, 225.1030. 4 . 2 . 6 . 1 - M e t hyl - 2 - ( 4 - ( t r i fl u o ro m e t hyl ) p h e nyl ) - 1 H - i n d o l e (3f).11 Yield: 83%; 1H NMR (400 MHz, CDCl3) d 7.76 (d, J¼8.0 Hz, 2H), 7.66e7.71 (m, 3H), 7.42 (d, J¼8.4 Hz, 1H), 7.31 (t, J¼7.4 Hz, 1H), 7.20 (t, J¼8.0 Hz, 1H), 6.68 (s, 1H), 3.81 (s, 3H); 13C NMR (150 MHz, CDCl3) d 139.9, 138.8, 136.7, 130.0 (q, J¼21.0 Hz), 129.7 (2C), 128.0, 125.7 (d, J¼4.5 Hz), 125.0 (q, J¼270.0 Hz), 122.4 (2C), 121.0, 120.5, 110.0, 103.0, 31.5; 19F NMR: (376 MHz, CDCl3) 62.5; HRMS (ESI): calculated for C16H13F3N [MþH]þ, 276.1000. Found [MþH]þ, 276.0995. 4.2.7. 1-Methyl-2-(4-nitrophenyl)-1H-indole (3g).13 Yield: 67%; 1H NMR (400 MHz, CDCl3) d 8.34 (d, J¼8.0 Hz, 2H), 7.70 (d, J¼8.0 Hz, 2H), 7.67 (d, J¼8.0 Hz, 1H), 7.40 (d, J¼8.3 Hz, 1H), 7.32 (t, J¼8.0 Hz, 1H), 7.19 (t, J¼8.0 Hz, 1H), 6.72 (s, 1H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) d 147.0, 139.2, 139.2, 138.9, 129.5, 127.7, 123.9, 123.0, 121.0, 120.5, 109.9, 104.1, 31.5; HRMS (ESI): calculated for C15H13N2O2 [MþH]þ, 253.0977. Found [MþH]þ, 253.0967. 4.2.8. 1-Methyl-2-(3-nitrophenyl)-1H-indole (3h).12 Yield: 93%; 1H NMR (400 MHz, CDCl3) d 8.42 (t, J¼1.8 Hz, 1H), 8.31e8.25 (m, 1H), 7.89e7.87 (m, 1H), 7.73e7.65 (m, 2H), 7.46e7.20 (m, 3H), 6.72 (s, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) d 148.3, 138.7, 138.6, 134.9, 134.5, 129.5, 127.6, 123.7, 122.6, 122.4, 120.9, 120.3, 109.8, 103.2, 31.3; HRMS (ESI): calculated for C15H13N2O2 [MþH]þ, 253.0977. Found [MþH]þ, 253.0974. 4.2.9. 2-(1-Methyl-1H-indol-2-yl)benzonitrile (3i).4b Yield: 52%; LCeMS: tR¼3.738 min, m/z¼233 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.83 (dd, J¼1.2, 7.8 Hz, 1H), 7.70e7.74 (m, 2H), 7.55 (dd, J¼1.2, 7.8 Hz, 1H), 7.52 (dd, J¼1.2, 7.8 Hz, 1H), 7.41 (d, J¼8.0 Hz, 1H), 7.32 (dt, J¼1.2, 7.8 Hz, 1H), 7.23e7.15 (m, 1H), 6.76 (s, 1H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3) d 138.5, 136.6, 136.3, 133.6, 132.4, 131.4, 128.4, 127.6, 122.6, 121.1, 120.2, 118.0, 113.3, 109.8, 104.4, 31.2. 4.2.10. 1-Methyl-2-(o-tolyl)-1H-indole (3j).4b Yield: 65%; 1H NMR (400 MHz, CDCl3) d 7.73 (d, J¼8.0 Hz, 1H), 7.34e7.45 (m, 6H), 7.23e7.28 (m, 1H), 6.49 (s, 1H), 3.59 (s, 3H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) d 140.5, 138.1, 137.3, 132.6, 131.1, 130.0, 128.6, 128.0, 125.5, 121.3, 120.4, 119.6, 109.4, 101.5, 30.3, 20.0; HRMS (ESI): calculated for C16H16N [MþH]þ, 222.1283. Found [MþH]þ, 222.1289. 14
4.2.11. 5-Methoxy-1-methyl-2-phenyl-1H-indole (3k). Yield: 70%; 1 H NMR (400 MHz, CDCl3) d 7.44e7.51 (m, 4H), 7.37e7.40 (m, 1H), 7.24 (d, J¼3.6 Hz, 1H), 7.10 (d, J¼8.0 Hz, 1H), 6.91 (dd, J¼8.8, 2.0 Hz, 1H), 6.48 (s, 1H), 3.87 (s, 3H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3) d 154.4, 142.1, 133.8, 132.9, 129.3, 128.5, 128.3, 127.8, 111.9, 110.3, 102.2, 101.3, 55.9, 31.3; HRMS (ESI): calculated for C16H16NO [MþH]þ, 238.1232. Found [MþH]þ, 238.1231. 4.2.12. 4-Methoxy-1-methyl-2-phenyl-1H-indole (3l).9a Yield: 79%; 1 H NMR (400 MHz, CDCl3) d 7.36e7.53 (m, 5H), 7.18 (t, J¼8.0 Hz, 1H), 7.00 (d, J¼8.2 Hz, 1H), 6.58 (s, 1H), 3.98 (s, 3H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) d 153.9, 140.9, 140.2, 133.4, 129.8, 128.9, 128.1, 122.9, 119.2, 103.6, 100.3, 99.3, 55.8, 31.2; HRMS (ESI): calculated for C16H16NO [MþH]þ, 238.1232. Found [MþH]þ, 238.1225. 4.2.13. 5-Fluoro-1-methyl-2-phenyl-1H-indole (3m). Yield: 78%; 1H NMR (400 MHz, CDCl3) d 7.62 (d, J¼8.0 Hz, 1H), 7.45e7.49 (m, 2H),
7.35 (d, J¼8.0 Hz, 1H), 7.24 (t, J¼8.0 Hz, 1H), 7.13e7.17 (m, 3H), 6.53 (s, 1H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3) d 156.9 (d, J¼233 Hz), 143.1, 134.9, 132.5, 129.3, 128.5, 128.1, 128.0 (d, J¼11 Hz), 110.1 (d, J¼10 Hz), 109.7 (d, J¼26 Hz), 105.0 (d, J¼24 Hz), 101.5 (d, J¼5 Hz), 31.3; 19F NMR: (376 MHz, CDCl3) d 124.8; HRMS (ESI): calculated for C15H13FN [MþH]þ, 226.1032. Found [MþH]þ, 226.1032. 4.2.14. 2-(4-Chlorophenyl)-1-methyl-1H-indole-4-carbonitrile (3n). Yield: 72%; 1H NMR (400 MHz, CDCl3) d 7.59 (d, J¼8.0 Hz, 1H), 7.47e7.54 (m, 5H), 7.31 (d, J¼8.0 Hz, 1H), 6.80 (s, 1H), 3.80 (s, 3H); 13 C NMR (100 MHz, CDCl3) d 142.9, 138.0, 135.0, 130.6, 130.0, 129.3, 129.0, 125.3, 121.4, 118.7, 114.3, 102.8, 100.9, 31.5; HRMS (ESI): calculated for C16H12ClN2 [MþH]þ, 267.0689. Found [MþH]þ, 267.0685. 4.2.15. 2-Phenyl-1H-indole (3o).3b Yield: 62%; 1H NMR (400 MHz, CDCl3) d 8.32 (br s, 1H), 7.62e7.66 (m, 3H), 7.38e7.45 (m, 3H), 7.32 (t, J¼7.2 Hz, 1H), 7.19 (t, J¼7.2 Hz, 1H), 7.12 (t, J¼7.2 Hz, 1H), 6.82 (s, 1H); 13C NMR (150 MHz, CDCl3) 137.9, 136.3, 132.3, 129.2, 129.0, 127.7, 125.2, 122.4, 120.7, 120.3, 110.9, 100.0; HRMS (ESI): calculated for C14H12N [MþH]þ, 194.0970. Found [MþH]þ, 194.0964.
4.3. General procedure for the CeH arylation of benzofurans and benzothiophenes with iodobenzenes To a microwave reaction vial, Pd(OAc)2 (5 mol %), CF3COOAg (1.5 mmol), iodobenzene (2.0 mmol), N-methylindole (1.0 mmol), trifluoroacetic acid (2 mmol), and Tween-80/H2O (2 ml, 2 wt %) were added. The reaction mixture was allowed to react at room temperature. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified on silica gel chromatography to afford the desired product. 4.3.1. 2-Phenylbenzofuran (5a).14 Yield: 88%; LCeMS: tR¼4.169 min, m/z¼195 [MþH]þ; 1H NMR (400 MHz, DMSO-d6) d 7.92 (d, J¼8.0 Hz, 2H), 7.66 (d, J¼8.0 Hz, 1H), 7.63 (d, J¼8.0 Hz, 1H), 7.50 (t, J¼8.0 Hz, 2H), 7.46 (s, 1H), 7.40 (t, J¼8.0 Hz, 1H), 7.31 (t, J¼8.0 Hz, 1H), 7.25 (t, J¼8.0 Hz, 1H). 4.3.2. 2-(4-Chlorophenyl)benzofuran (5b).15 Yield: 87%; LCeMS: tR¼4.508 min, m/z¼229 [MþH]þ; 1H NMR (600 MHz, CDCl3) d 7.78 (d, J¼8.6 Hz, 2H), 7.57 (d, J¼7.6 Hz, 1H), 7.51 (d, J¼8.2 Hz, 1H), 7.40 (d, J¼8.6 Hz, 2H), 7.25e7.27 (m, 2H), 6.99 (s, 1H); 13C NMR (150 MHz, CDCl3) d 155.0, 154.8, 134.4, 129.1, 129.1, 129.0, 126.2, 124.6, 123.1, 121.0, 111.2, 101.8. 4.3.3. 2-(p-Tolyl)benzofuran (5c).14 Yield: 88%; LCeMS: tR¼ 4.385 min, m/z¼209 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.75 (d, J¼8.0 Hz, 1H), 7.55 (d, J¼8.0 Hz, 1H), 7.50 (d, J¼8.0 Hz, 1H), 7.29e7.18 (m, 4H), 6.94 (s, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) d 156.2, 154.8, 138.6, 129.5 (2C), 129.3, 127.7, 124.9 (2C), 124.0, 122.8, 120.7, 111.1, 100.5, 21.4. 4.3.4. 2-(4-Methoxyphenyl)benzofuran (5d).15 Yield: 78%; LCeMS: tR¼4.133 min, m/z¼225 [MþH]þ; 1H NMR (CDCl3, 400 MHz) d 7.79 (d, J¼8.0 Hz, 2H), 7.54 (d, J¼7.8 Hz, 1H), 7.49 (d, J¼8.0 Hz, 1H), 7.26e7.19 (m, 2H), 6.96 (d, J¼8.0 Hz, 2H), 6.87 (s, 1H) 3.85 (s, 3H). 4.3.5. 2-(4-(Trifluoromethyl)phenyl)benzofuran (5e).16 Yield: 83%; LCeMS: tR¼4.524 min, m/z¼263 [MþH]þ; 1H NMR: (400 MHz, CDCl3) d 7.96 (d, J¼8.0 Hz, 2H), 7.70 (d, J¼8.0 Hz, 2H), 7.62 (d, J¼8.0 Hz, 1H), 7.55 (d, J¼8.0 Hz, 1H), 7.34 (dd, J¼8.0, 7.8 Hz, 1H), 7.27 (dd, J¼8.0, 7.8 Hz, 1H), 7.14 (s, 1H); 13C NMR (100 MHz, CDCl3) d 155.1, 154.2, 133.7, 130.1 (q, J¼33 Hz), 128.8, 125.8 (q, J¼5 Hz),
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125.1, 124.9, 124.0 (q, J¼271 Hz), 123.3, 121.3, 111.3, 103.2; (376 MHz, CDCl3) d 62.6.
19
F NMR
4.3.6. Methyl 2-phenylbenzofuran-5-carboxylate (5f).17 Yield: 84%; LCeMS: tR¼4.181 min, m/z¼253 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 8.32 (d, J¼1.6 Hz, 1H), 8.02 (dd, J¼1.6, 8.4 Hz, 1H), 7.88e7.86 (m, 2H), 7.54 (d, J¼8.8 Hz, 1H), 7.49e7.45 (m, 2H), 7.41e7.37 (m, 1H), 7.06 (d, J¼0.8 Hz, 1H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) d 167.2, 157.3, 157.3, 129.8, 129.2, 128.9, 128.2, 126.0, 125.3, 125.0, 123.2, 110.9, 101.5, 52.0. 4.3.7. 5-Methoxy-2-phenylbenzofuran (5g).17 Yield: 87%; LCeMS: tR¼4.138 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 8.88 (d, J¼7.8 Hz, 2H), 7.49e7.44 (m, 3H), 7.39e7.37 (m, 1H), 7.06 (d, J¼2.0 Hz, 1H), 6.98 (s, 1H), 6.93 (dd, J¼2.0, 7.8 Hz, 1H), 3.88 (s, 3H); 13 C NMR (100 MHz, CDCl3) d 156.6, 156.0, 149.8, 130.5, 129.7, 128.7, 128.4, 124.8, 112.9, 111.6, 103.2, 101.4, 55.8. 4.3.8. 5-Methyl-2-phenylbenzofuran (5h).15 Yield: 85%; LCeMS: tR¼4.416 min, m/z¼209 [MþH]þ; 1H NMR (400 MHz, DMSO-d6) d 7.85 (d, J¼7.8 Hz, 2H), 7.43 (t, J¼7.8 Hz, 2H), 7.39 (d, J¼8.0 Hz, 1H), 7.35e7.31 (m, 2H), 7.08 (d, J¼8.0 Hz, 1H), 6.94 (s, 1H), 2.44 (s, 3H). 4.3.9. 7-Methoxy-2-phenylbenzofuran (5i).15 Yield: 80%; LCeMS: tR¼4.022 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, DMSO-d6) d 7.89 (d, J¼8.0 Hz, 2H), 7.43 (t, J¼8.0 Hz, 2H), 7.34 (t, J¼8.0 Hz, 1H), 7.19e7.13 (m, 3H), 7.01 (s, 1H), 6.80 (d, J¼8.0 Hz, 1H), 4.04 (s, 3H); 13 C NMR (150 MHz, CDCl3) d 156.1, 145.4, 144.2, 131.0, 130.3, 128.6, 125.1, 123.6, 113.4, 106.7, 101.7, 56.2. 4.3.10. 2-Phenylbenzo[b]thiophene (7a).18 Yield: 76%; LCeMS: tR¼4.299 min, m/z¼211 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.82 (d, J¼8.0 Hz, 1H), 7.76 (d, J¼8.0 Hz, 1H), 7.71 (d, J¼8.0 Hz, 2H), 7.54 (s, 1H), 7.43e7.40 (m, 2H), 7.36e7.27 (m, 3H); 13C NMR (150 MHz, CDCl3) d 140.8, 138.2, 138.0, 136.1, 128.8, 127.6, 124.5, 124.4, 123.5, 123.4, 123.0, 129.9. 4.3.11. 2-(4-Chlorophenyl)benzo[b]thiophene (7b).18 Yield: 70%; LCeMS: tR¼4.385 min, m/z¼209 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.80 (d, J¼8.0 Hz, 1H), 7.75 (d, J¼8.0 Hz, 1H), 7.61 (d, J¼8.0 Hz, 2H), 7.49 (s, 1H), 7.37 (d, J¼8.0 Hz, 2H), 7.33e7.30 (m, 2H); 13 C NMR (150 MHz, CDCl3) d 140.8, 137.7, 136.6, 134.5, 133.5, 129.9, 128.9, 124.6, 124.5, 123.8, 123.0, 122.7. 4.3.12. 2-(p-Tolyl)benzo[b]thiophene (7c).18 Yield: 70%; LCeMS: tR¼4.531 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, CDCl3): d 7.94e7.96 (m, 2H), 7.52 (d, J¼8.0 Hz, 2H), 7.40e7.44 (m, 3H), 7.33 (d, J¼8.0 Hz, 2H), 2.47 (s, 3H), 13C NMR (150 MHz, CDCl3): d 140.7, 138.1, 138.0, 137.4, 133.2, 129.5, 129.4, 128.6, 124.4, 124.3, 122.9, 21.3. 4.3.13. 2-(4-Methoxyphenyl)benzo[b]thiophene (7d).18 Yield: 72%; LCeMS: tR¼4.244 min, m/z¼241 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.91 (s, 1H), 7.54 (d, J¼8.0 Hz, 2H), 7.40 (m, 2H), 7.36 (s, 1H), 7.04e7.07 (m, 2H), 3.91 (s, 3H); 13C NMR (150 MHz, CDCl3) d 159.2, 140.6, 138.2, 137.7, 129.8, 128.6, 124.3, 123.0, 122.9, 122.6, 114.2, 55.4. 4.3.14. 4-(Benzo[b]thiophen-2-yl)benzonitrile (7e).18 Yield: 74%; LCeMS: tR¼3.964 min, m/z¼236 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.35e7.44 (m, 2H), 7.63 (s, 1H), 7.66 (d, J¼8.0 Hz, 2H), 7.75 (d, J¼8.0 Hz, 2H), 7.79e7.86 (m, 2H); 13C NMR (150 MHz, CDCl3) d 141.6, 140.3, 139.9, 138.5, 132.7, 126.7, 125.4, 125.0, 124.2, 122.4, 121.8, 118.7, 111.3. 4.3.15. 5-Methyl-2-phenylbenzo[b]thiophene (7f). Yield: 75%; LCeMS: tR¼4.513 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.82 (d, J¼8.0 Hz, 1H), 7.73 (s, 1H), 7.60 (d, J¼8.0 Hz, 2H),
5
7.50 (t, J¼8.0 Hz, 1H), 7.44 (d, J¼8.0 Hz, 1H), 7.40 (s, 1H), 7.24 (d, J¼8.0 Hz, 1H), 2.49 (s, 3H); 13C NMR (150 MHz, CDCl3) d 141.7, 138.2, 137.8, 129.9, 129.3, 129.2, 128.0, 121.5, 120.4, 119.8, 109.6, 101.3, 31.1, 21.3. 4.3.16. 5-Chloro-2-phenylbenzo[b]thiophene (7g).19 Yield: 60%; LCeMS: tR¼4.590 min, m/z¼245 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.90 (d, J¼2.0 Hz, 1H), 7.84 (d, J¼8.0 Hz, 1H), 7.57 (d, J¼8.0 Hz, 2H), 7.51 (t, J¼8.0 Hz, 2H), 7.45e7.48 (m, 2H), 7.37 (dd, J¼8.0, 2.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) d 139.2, 138.8, 137.7, 135.4, 130.9, 128.9, 128.7, 127.9, 125.2, 125.0, 123.9, 122.6. 4.3.17. 5-Methoxy-2-phenylbenzo[b]thiophene (7h).20 Yield: 84%; LCeMS: tR¼4.187 min, m/z¼241 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.81 (d, J¼8.0 Hz, 1H), 7.63 (d, J¼6.0 Hz, 2H),7.53 (t, J¼6.0 Hz, 2H), 7.44e7.47 (m, 3H), 7.41 (d, J¼2.4 Hz, 1H), 6.99 (dd, J¼8.0, 2.4 Hz, 1H), 3.88 (s, 3H); 13C NMR (150 MHz, CDCl3) d 157.6, 139.0, 137.8, 136.2, 133.1, 128.8 (2C), 128.6 (2C), 127.5, 124.8, 114.7, 105.7, 55.6. Acknowledgements We thank Dr. Ruina Gao for HRMS analysis and Mr. Morris Sui for NMR analysis. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2015.03.051. References and notes 1. (a) Garg, N. K.; Sarpong, R.; Stolz, B. M. J. Am. Chem. Soc. 2002, 124, 13179; (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (c) Qin, Z.; Kastrati, I.; Chandrasena, R. E. P.; Liu, H.; Yao, P.; Petukhov, P. A.; Bolton, J. L.; Thatcher, G. R. J. J. Med. Chem. 2007, 50, 2682. 2. For selected recent reviews on CeH functionalization, see: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094; (b) WencelDelord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740; (c) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588; (d) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879; (e) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Adv. Synth. Catal. 2014, 356, 17; (f) Giri, R.; Thapa, S.; Kafle, A. Adv. Synth. Catal. 2014, 356, 1395; (g) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744 For selected examples of C-2 arylation of benzofurans and benzothiophenes: (h) Tamba, S.; Okubo, Y.; Tanaka, S.; Monguchi, D.; Mori, A. J. Org. Chem. 2010, 75, 6998 For selected examples of C-2 arylation of indoles: (i) Feng, J.; Lu, G.; Lv, M.; Cai, C. J. Organomet. Chem. 2014, 761, 28; (j) Lu, G.-P.; Cai, C. Synlett 2012, 2992. 3. (a) Yang, S. D.; Sun, C. L.; Fang, Z.; Li, B. J.; Li, Y. Z.; Shi, Z. J. Angew. Chem., Int. Ed. 2008, 47, 1473; (b) Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428; (c) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972; (d) Nimje, R. Y.; Leskinen, M. V.; Pihko, P. M. Angew. Chem., Int. Ed. 2013, 52, 4818. 4. (a) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926; (b) Islam, S.; Larrosa, I. Chem.dEur. J. 2013, 19, 15093. 5. Sheldon, R. A.; Arens, I. W. C. E.; Hanefeld, U. Green Chemistry and Catalysis; Wiley-VCH: Weinheim, Germany, 2007. 6. Xu, Z.; Yang, T.; Lin, X.; Elliott, J.; Ren, F. Tetrahedron Lett. 2015, 56, 475. 7. (a) Bai, L.; Wang, J.-X.; Zhang, Y. Green Chem. 2003, 5, 615; (b) Li, C.-J. Acc. Chem. Res. 2010, 43, 581; (c) Li, C. J. Metal-Mediated CeC Bond Formation in Aqueous Media In Organic Reactions in Water: Principles, Strategies, and Applications; € m, U. M., Ed.; Blackwell: Oxford, UK, 2007; (d) Li, C.-J.; Chen, L. Chem. Lindstro Soc. Rev. 2006, 35, 68; (e) Jones, M. N. Int. J. Pharm. 1999, 177, 137; (f) Klumphu, P.; Lipshutz, B. H. J. Org. Chem. 2014, 79, 888; (g) Dwars, T.; Paetzold, E.; Oehme, G. Angew. Chem., Int. Ed. 2005, 44, 7174. cile, D.; Alexandre, 8. Hubert, S.; Albert, B.; Roland, V.; Eugen, S.; Markwart, K.; Ce C.; Caterine, L.; Bernd, L.; Matthias, M.; Siegfried, P. “Sugar Alcohols” Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, Germany, 2012. 9. (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050; (b) Joucla, L.; Batail, N.; Djakovitch, L. Adv. Synth. Catal. 2010, 352, 2929. 10. (a) Wang, B.; Nack, W. A.; He, G.; Zhang, S. Y.; Chen, G. Chem. Sci. 2014, 5, 3952; (b) Wang, X.; Truesdale, L.; Yu, J. Q. J. Am. Chem. Soc. 2010, 132, 3648; (c) Taniguchi, Y.; Yamaoka, Y.; Nakata, K.; Takaki, K.; Fujiwara, Y. Chem. Lett. 1995, 345; (d) Lu, W.; Yamaoka, Y.; Taniguchi, Y.; Kitamura, T.; Takaki, K.; Fujiwara, Y. J. Organomet. Chem. 1999, 580, 290. 11. Liang, Z.; Yao, B.; Zhang, Y. Org. Lett. 2010, 12, 3185.
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12. Susanto, W.; Chu, C.-Y.; Ang, W. J.; Chou, T.-C.; Lo, L.-C.; Lam, Y. J. Org. Chem. 2012, 77, 2729. 13. Denmark, S. E.; Baird, J. D.; Regens, C. S. J. Org. Chem. 2008, 73, 1440. 14. Ruan, L.; Shi, M.; Mao, S.; Yu, L.; Yang, F.; Tang, J. Tetrahedron 2014, 70, 1065. 15. Wang, X.; Liu, M.; Xu, L.; Wang, Q.; Chen, J.; Ding, J.; Wu, H. J. Org. Chem. 2013, 78, 5273.
16. Denmark, S. E.; Smith, R. C.; Chang, W.-T. T.; Muhuhi, J. M. J. Am. Chem. Soc. 2009, 131, 3104. 17. Wang, S.; Li, P.; Yu, L.; Wang, L. Org. Lett. 2011, 13, 5968. 18. Sun, L.-L.; Deng, C.-L.; Tang, R.-Y.; Zhang, X.-G. J. Org. Chem. 2011, 76, 7546. € nig, B. Org. Lett. 2012, 14, 5334. 19. Hari, D. P.; Hering, T.; Ko 20. Yu, H.; Zhang, M.; Li, Y. J. Org. Chem. 2013, 78, 8898.
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Efficient and C2-selective arylation of indoles, benzofurans, and benzothiophenes with iodobenzenes in water at room temperature Zhongmiao Xu a, Yulong Xu b, Hongfu Lu a, Ting Yang a, Xichen Lin a, Liming Shao b, Feng Ren a, * a b
Research and Development, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China School of Pharmacy, Fudan University, 826 Zhangheng Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 January 2015 Received in revised form 8 March 2015 Accepted 13 March 2015 Available online xxx
A mild, efficient, and C2-selective palladium-catalyzed arylation reaction of indoles, benzofurans, and benzothiophenes with iodobenzenes at room temperature has been developed. The methodology allows the use of water, the most environmentally friendly solvent, as the reaction solvent with the addition of Tween 80 (2% w/w) to increase the solubility of starting materials. The protocol demonstrated wide substrate scope and good yields were obtained for all the 32 examples evaluated (52e93%). Ó 2015 Elsevier Ltd. All rights reserved.
Keywords: CeH Arylation Indole Benzofuran Benzothiophene Aqueous micelles
1. Introduction Functionalized indoles, benzofurans, and benzothiophenes serve as important building blocks of natural products and biologically active unnatural molecules.1 Among the known methods in the functionalization of indoles, benzofurans, and benzothiophenes, CeH activation/arylation reactions have attracted tremendous interests due to their high atom efficiency.2 However, the reported methods always suffered from low regio-selectivities (C-2 over C-3) when no directing groups were pre-installed and/or high reaction temperatures (100e150 C), which significantly limited the substrate scope and functional group tolerance. Several C2selective arylation reactions of indoles using boronic acids or trifluoroborate salts as arylation agents at room temperature were developed, whereas in these conditions acetic acid had to be used as the solvent/co-solvent and oftentimes the trifluoroborates were not commercially available.3 Recently Larrosa has reported the C2arylation of N-alkylated indoles at room temperature using more readily available iodobenzenes as arylation agents.4 However, when free indoles were used as the substrates, the arylation reactions required higher temperature (50 C).4 C2-selective arylations of benzofurans and benzothiophenes were less extensively reported
* Corresponding author. Tel.: þ86 186 1674 3377; fax: þ86 021 6159 0730; e-mail address: [email protected] (F. Ren).
compared with indoles, and elevated reaction temperatures (>100 C) were always required for the limited cases in literature.2a,e,h Herein, we report a mild, efficient, and C2-selective arylation reaction of indoles, benzofurans, and benzothiophenes at room temperature with a wide scope of substrates. To the best of our knowledge, this is the first time the C2-selective arylation of benzofurans and benzothiophenes with iodobenzenes could be achieved at room temperature. In addition, our methodology allows the use of water as the reaction solvent, which makes it even more attractive in the aspect of reducing the hazardous organic waste.5 To develop organic reactions in aqueous solution has been one of the research focuses in our group.6 A challenge for aqueous reactions is the poor solubility of starting materials, and adding surfactants to water has been a widely used strategy to improve solubility.7 Among the surfactants used, polysorbates (also called Tweens) offer cheap and environmentally friendly choices8 and we focused our solvents on the Tweens/water micelle system. 2. Result and discussion We started our exploration of the CeH arylation using 1-methyl1H-indole (1a) and iodobenzene (2a) as starting materials and Tween 80/water (2% w/w) micelle as the solvent (Table 1). To our delight, our initial attempt using Pd(OAc)2 as the catalyst and AgOAc as the additive at room temperature led to the formation of C2-arylation product (3a) in 39% conversion (Table 1, entry 1).
http://dx.doi.org/10.1016/j.tet.2015.03.051 0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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Table 1 Optimization of the Pd-catalyzed direct arylation conditions of N-methylindole (1a) with iodobenzene (2a)a
Entry
Pd(OAc)2 (mol %)
Surfactant
Additive
Conv (%)c
1 2 3 4b 5 6 7 8 9 10
2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 5 5
Tween Tween Tween Tween Tween Tween Tween Tween Tween none
AgOAc K2CO3 CF3COOAg Ag2OþTFA CF3COOAg CF3COOAg CF3COOAg CF3COOAg CF3COOAg CF3COOAg
39 4 85 24 81 83 73 68 97 38
80 80 80 80 20 40 60 85 80
Table 2 Substrate scope of Pd-catalyzed direct CeH arylation of indolesa
a Conditions: N-methylindole 1a (1 mmol), iodobenzene 2a (2 mmol), additive (1.5 mmol), 2% of surfactant/H2O (w/w, 2 ml). b 0.75 equiv of Ag2O followed by 1.5 equiv of trifluoroacetic acid. c Conversions measured by HPLC.
Encouraged by the result, we started to evaluate the effects of different additives to the reaction including K2CO3, CF3COOAg, and Ag2O plus TFA (Table 1, entries 2e4). Among them, CF3COOAg provided the best conversion (85%) to the desired product 3a (Table 1, entry 3). Tweens of different sizes were also explored (Table 1, entries 5e8) and they all resulted in similar or lower conversions than Tween 80. Increasing the catalyst loading from 2.5 mol % to 5 mol % accelerated the reaction to provide 97% conversion within 1 h (Table 1, entry 9). In comparison, removal of Tween 80 from the reaction mixture gave a much decreased conversion (38%, Table 1, entry 10) at otherwise the same reaction condition, and this was believed to due to the insolubility of starting materials without the micelle formation of the surfactant in water. With the optimized reaction condition of C2-selective arylation of indoles developed, the substrate scope was examined. As shown in Table 2, iodobenzenes with a variety of different substitutions were well tolerated for the reaction. Both electron-withdrawing and electron-donating substitutions were tolerated at the paraposition of the iodobenzene, providing C2-arylation products in good isolated yields (67e90%, 3beg). Substitution at the meta-position also demonstrated high reactivity to afford the desired product (3h) in high yield (93%). Increasing the steric hindrance of the iodobenzene by introducing ortho-substitutions resulted in lower yields (52% and 65% for 3i and 3j, respectively). These results suggested the reactivities of iodobenzenes for the C2-arylation reaction were sensitive to steric rather than electronic effects. The scope of indole substrates was also evaluated, and the reaction showed good tolerability for different substitutions including both electron-withdrawing and electron-donating groups (3jen). The electron-withdrawing substituent at the 4-position of the indole (3n) resulted in a much slower arylation reaction compared with the electron-donating substituent (3l) and a much longer reaction time was required (3 days for 3n and 3 h for 3l). It was noteworthy that for the free indole substrate (3o) high yield (62%) was also obtained at room temperature whereas elevated temperature was required in the reported procedure.4 In addition, the high C2selectivity of our arylation reactions was striking and there was no C3-arylation product observed in all the tested substrates, even for the steric hindered ones (3i and 3j). The mechanistic studies of palladium-catalyzed arylation of indoles had been reported and the palladium migration from the 3-position to the 2-position of the indoleepalladium(II) intermediate was the key to give C2selectivity.9 Our aqueous condition must have strongly favored
Unless otherwise stated, the reaction was conducted with 1 (1 mmol), 2 (2 equiv.), CF3COOAg (1.5 equiv.) and Pd(OAc)2 (0.05 equiv.) in Tween 80/H2O (2 mL, 2% w/w) at room temperature for 1 hour. Isolated yields. b Reaction runs for 3 hours. c Reaction runs for 3 days. a
the C3/C2 migration of palladium to provide the high C2selectivity of the arylation products. We then expanded the substrate scope to benzofurans, which are less electron-rich than indoles. As expected, the CeH arylation reactions of benzofurans were much slower (Table 3) compared with indoles, and extended reaction time (overnight) was required for the reaction to be completed. In addition, TFA had to be used to accelerate the arylation reactions.10 The substituted iodobenzenes were well tolerated and generally good isolated yields of C2arylation products were obtained at room temperature (5aee), although para-CF3 iodobenzene was less effective and a prolonged reaction time was required for high yield (5e). On the other hand, both electron-withdrawing and electron-donating substitutions on benzofurans were tolerated. Prolonged reaction times were required for the full conversions to 5f and 5g, due to poor solubility of starting materials in the reaction mixtures. Again, our arylation condition for benzofurans was highly C2-selective, and there was no C3-arylation product observed for all cases. We further expanded the substrate scope to benzothiophenes, which are even less electron-rich. To our delight, both substituted iodobenzenes and substituted benzothiophenes were welltolerated and high yields of desired C2-arylation products were obtained at room temperature, albeit more prolonged reaction time was required (Table 4). Electron-withdrawing substitutions on the iodobenzene made the reactions less efficient and extremely slow, but good yields could still be obtained (7b and 7e).
3. Conclusion In summary, we have developed a mild, efficient, and highly C2selective palladium-catalyzed arylation reaction of indoles,
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Z. Xu et al. / Tetrahedron xxx (2015) 1e6 Table 3 Substrate scope of Pd-catalyzed direct CeH arylation of benzofuransa
a
Unless otherwise stated, the reaction was conducted with 4 (1 mmol), 2 (2 equiv.), CF3COOAg (1.5 equiv.), TFA (2 equiv.) and Pd(OAc)2 (0.05 equiv.) in Tween 80/H2O (2 mL, 2% w/w) at room temperature overnight. Isolated yields. bReaction runs for 5 days. c Reactions run for 2 days.
Table 4 Substrate scope of Pd-catalyzed direct CeH arylation of benzothiophenesa
3
as the internal standard. DMSO-d6 is hexadeuteriodimethylsulfoxide, CDCl3 is deuteriochloroform. Chemical shifts are given in parts per million (d) downfield from the NMR solvent. Abbreviations for NMR data are as follows: s¼singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet, dd¼doublet of doublets, dt¼doublet of triplets, app¼apparent, br¼broad. J indicates the NMR coupling constant measured in Hertz. High resolution mass (HRMS) was operated in positive mode of electrospray ionization (ESI) at an orthogonal acceleration time-of-flight (oa-TOF), SYNAPT G2 HDMSTM (Waters, Manchester, UK). LCMS (Agilent 1200SL-6110) analysis was conducted for all compound on acidic condition: acidic condition refers to water containing 0.05% TFA/acetonitrile as mobile phase on Agilent SB-C18 column (1.8 mm, 4.630 mm), with MS and photodiode array detector (PDA). The following conditions were used: a gradient from 5 to 95% in 5 min (or 6 min) and held at 95% for 1 min; UV detection at 214 and 254 nm; a flow rate of 1.5 ml/min; full scan; mass range from 100 to 1000 amu. All the compounds possess 95% purity determined using LC/MS analysis. Column chromatography was performed on Isco or Biotage using a pre-packed silica gel column, a detector with UV wavelength at 254 nm and 280 nm. 4.2. General procedure for the CeH arylation of indoles with iodobenzenes To a microwave reaction vial, Pd(OAc)2 (5 mol %), CF3COOAg (1.5 mmol), iodobenzene (2.0 mmol), N-methylindole (1.0 mmol), and Tween-80/H2O (2 ml, 2 wt %) were added. The reaction mixture was allowed to react at room temperature. After 1 h (or otherwise stated), the mixture was concentrated under reduced pressure, and the residue was purified on a silica gel chromatography to afford the desired product. 4.2.1. 1-Methyl-2-phenyl-1H-indole (3a).4b Yield: 85%; 1H NMR (400 MHz, CDCl3) d 7.69 (td, J¼1.2, 7.8 Hz, 1H), 7.58e7.54 (m, 2H), 7.54e7.49 (m, 2H), 7.47e7.39 (m, 2H), 7.34e7.27 (m, 1H), 7.23e7.15 (m, 1H), 6.62 (d, J¼0.8 Hz, 1H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) d 141.9, 138.7, 133.2, 129.7, 128.8, 128.3, 128.2, 122.0, 120.8, 120.2, 109.9, 102.0, 31.4; HRMS (ESI): calculated for C15H14N [MþH]þ, 208.1126. Found [MþH]þ, 208.1127.
a
Unless otherwise stated, the reaction was conducted with 6 (100 mg), 2 (2 equiv.), silver(I) trifluoroacetate (1.5 equiv.), trifluoroacetic acid (2 equiv.) and diacetoxypalladium (0.05 equiv.) in Tween 80/H2O (2 mL, 2% w/w) at room temperature for 2 days. Isolated yields. bReactions run for 7 days.
benzofurans, and benzothiophenes with iodobenzenes at room temperature. To the best of our knowledge, this is the first time C2selective arylation of benzofurans and benzothiophenes with iodobenzenes could be achieved at room temperature. Our methodology allows the use of water, the most environmentally friendly solvent, as the reaction solvent with the addition of Tween 80 (2% w/w) to increase the solubility of starting materials. In addition, our protocol demonstrated wide substrate scope, and good yields were obtained for all the 32 examples evaluated (52e93%). 4. Experimental section 4.1. General 1
H NMR and 13C NMR spectra were recorded on a Bruker 400/600 NMR spectrometer with CDCl3 or DMSO-d6 as the solvent and TMS
4.2.2. 1-Methyl-2-(p-tolyl)-1H-indole (3b).11 Yield: 90%; 1H NMR (400 MHz, CDCl3) d 7.66 (d, J¼8.0 Hz, 1H), 7.40 (d, J¼8.0 Hz, 2H), 7.35 (d, J¼8.0 Hz, 1H), 7.26e7.30 (m, 3H), 7.18 (t, J¼7.6 Hz, 1H), 6.53 (br s, 1H), 3.78 (s, 3H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) d 141.7, 138.2, 137.8, 129.9, 129.3 (2C), 129.2 (2C), 128.0, 121.5, 120.4, 119.8, 109.6, 101.3, 31.1, 21.3; HRMS (ESI): calculated for C16H16N [MþH]þ, 222.1283. Found [MþH]þ, 222.1285. 4.2.3. 2-(4-Methoxyphenyl)-1-methyl-1H-indole (3c).4b Yield: 85%; 1 H NMR (400 MHz, CDCl3) d 7.65 (d, J¼8.0 Hz, 1H), 7.47 (d, J¼8.0 Hz, 2H), 7.38 (d, J¼8.0 Hz,1H), 7.30 (t, J¼8.0 Hz,1H), 7.20 (t, J¼8.0 Hz,1H), 7.04 (d, J¼8.0 Hz, 2H), 6.54 (s, 1H), 3.91 (s, 3H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) d 159.4, 141.4, 138.1, 130.6 (2C), 128.0, 125.3, 121.4, 120.2, 119.7, 114.0 (2C), 109.5, 101.0, 55.4, 31.0; HRMS (ESI): calculated for C16H16NO [MþH]þ, 238.1232. Found [MþH]þ, 238.1229. 4.2.4. 2-(4-Chlorophenyl)-1-methyl-1H-indole (3d).11 Yield: 87%; 1 H NMR (400 MHz, CDCl3) d 7.66 (d, J¼8.0 Hz, 1H), 7.48 (m, 4H), 7.39 (d, J¼8.0 Hz, 1H), 7.24e7.27 (m, 1H), 7.15 (t, J¼8.0 Hz, 1H), 6.59 (s, 1H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) d 140.2, 138.4, 134.0, 131.3 (2C), 130.5 (2C), 128.8, 127.8, 122.0, 120.6, 120.0, 109.6, 102.0, 31.2; HRMS (ESI): calculated for C15H13ClN [MþH]þ, 242.0737. Found [MþH]þ, 242.0737. 4.2.5. 2-(4-Fluorophenyl)-1-methyl-1H-indole (3e).11 Yield: 89%; 1H NMR (400 MHz, CDCl3) d 7.63 (d, J¼7.6 Hz, 1H), 7.45e7.48 (m, 2H),
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7.36 (d, J¼8.4 Hz, 1H), 7.24e7.27 (m, 1H), 7.13e7.18 (m, 3H), 6.53 (s, 1H), 3.71 (s, 3H); 13C NMR (100 MHz, CDCl3) d 162.6 (d, J¼246 Hz), 140.5, 138.3, 131.1 (d, J¼8.0 Hz), 128.9, 127.9, 121.8, 120.5, 120.0, 115.6 (d, J¼21.5 Hz), 109.7, 101.7, 31.1; 19F NMR: (376 MHz, CDCl3) d 113.8; HRMS (ESI): calculated for C15H13FN [MþH]þ, 226.1032. Found [MþH]þ, 225.1030. 4 . 2 . 6 . 1 - M e t hyl - 2 - ( 4 - ( t r i fl u o ro m e t hyl ) p h e nyl ) - 1 H - i n d o l e (3f).11 Yield: 83%; 1H NMR (400 MHz, CDCl3) d 7.76 (d, J¼8.0 Hz, 2H), 7.66e7.71 (m, 3H), 7.42 (d, J¼8.4 Hz, 1H), 7.31 (t, J¼7.4 Hz, 1H), 7.20 (t, J¼8.0 Hz, 1H), 6.68 (s, 1H), 3.81 (s, 3H); 13C NMR (150 MHz, CDCl3) d 139.9, 138.8, 136.7, 130.0 (q, J¼21.0 Hz), 129.7 (2C), 128.0, 125.7 (d, J¼4.5 Hz), 125.0 (q, J¼270.0 Hz), 122.4 (2C), 121.0, 120.5, 110.0, 103.0, 31.5; 19F NMR: (376 MHz, CDCl3) 62.5; HRMS (ESI): calculated for C16H13F3N [MþH]þ, 276.1000. Found [MþH]þ, 276.0995. 4.2.7. 1-Methyl-2-(4-nitrophenyl)-1H-indole (3g).13 Yield: 67%; 1H NMR (400 MHz, CDCl3) d 8.34 (d, J¼8.0 Hz, 2H), 7.70 (d, J¼8.0 Hz, 2H), 7.67 (d, J¼8.0 Hz, 1H), 7.40 (d, J¼8.3 Hz, 1H), 7.32 (t, J¼8.0 Hz, 1H), 7.19 (t, J¼8.0 Hz, 1H), 6.72 (s, 1H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) d 147.0, 139.2, 139.2, 138.9, 129.5, 127.7, 123.9, 123.0, 121.0, 120.5, 109.9, 104.1, 31.5; HRMS (ESI): calculated for C15H13N2O2 [MþH]þ, 253.0977. Found [MþH]þ, 253.0967. 4.2.8. 1-Methyl-2-(3-nitrophenyl)-1H-indole (3h).12 Yield: 93%; 1H NMR (400 MHz, CDCl3) d 8.42 (t, J¼1.8 Hz, 1H), 8.31e8.25 (m, 1H), 7.89e7.87 (m, 1H), 7.73e7.65 (m, 2H), 7.46e7.20 (m, 3H), 6.72 (s, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) d 148.3, 138.7, 138.6, 134.9, 134.5, 129.5, 127.6, 123.7, 122.6, 122.4, 120.9, 120.3, 109.8, 103.2, 31.3; HRMS (ESI): calculated for C15H13N2O2 [MþH]þ, 253.0977. Found [MþH]þ, 253.0974. 4.2.9. 2-(1-Methyl-1H-indol-2-yl)benzonitrile (3i).4b Yield: 52%; LCeMS: tR¼3.738 min, m/z¼233 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.83 (dd, J¼1.2, 7.8 Hz, 1H), 7.70e7.74 (m, 2H), 7.55 (dd, J¼1.2, 7.8 Hz, 1H), 7.52 (dd, J¼1.2, 7.8 Hz, 1H), 7.41 (d, J¼8.0 Hz, 1H), 7.32 (dt, J¼1.2, 7.8 Hz, 1H), 7.23e7.15 (m, 1H), 6.76 (s, 1H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3) d 138.5, 136.6, 136.3, 133.6, 132.4, 131.4, 128.4, 127.6, 122.6, 121.1, 120.2, 118.0, 113.3, 109.8, 104.4, 31.2. 4.2.10. 1-Methyl-2-(o-tolyl)-1H-indole (3j).4b Yield: 65%; 1H NMR (400 MHz, CDCl3) d 7.73 (d, J¼8.0 Hz, 1H), 7.34e7.45 (m, 6H), 7.23e7.28 (m, 1H), 6.49 (s, 1H), 3.59 (s, 3H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) d 140.5, 138.1, 137.3, 132.6, 131.1, 130.0, 128.6, 128.0, 125.5, 121.3, 120.4, 119.6, 109.4, 101.5, 30.3, 20.0; HRMS (ESI): calculated for C16H16N [MþH]þ, 222.1283. Found [MþH]þ, 222.1289. 14
4.2.11. 5-Methoxy-1-methyl-2-phenyl-1H-indole (3k). Yield: 70%; 1 H NMR (400 MHz, CDCl3) d 7.44e7.51 (m, 4H), 7.37e7.40 (m, 1H), 7.24 (d, J¼3.6 Hz, 1H), 7.10 (d, J¼8.0 Hz, 1H), 6.91 (dd, J¼8.8, 2.0 Hz, 1H), 6.48 (s, 1H), 3.87 (s, 3H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3) d 154.4, 142.1, 133.8, 132.9, 129.3, 128.5, 128.3, 127.8, 111.9, 110.3, 102.2, 101.3, 55.9, 31.3; HRMS (ESI): calculated for C16H16NO [MþH]þ, 238.1232. Found [MþH]þ, 238.1231. 4.2.12. 4-Methoxy-1-methyl-2-phenyl-1H-indole (3l).9a Yield: 79%; 1 H NMR (400 MHz, CDCl3) d 7.36e7.53 (m, 5H), 7.18 (t, J¼8.0 Hz, 1H), 7.00 (d, J¼8.2 Hz, 1H), 6.58 (s, 1H), 3.98 (s, 3H), 3.74 (s, 3H); 13C NMR (100 MHz, CDCl3) d 153.9, 140.9, 140.2, 133.4, 129.8, 128.9, 128.1, 122.9, 119.2, 103.6, 100.3, 99.3, 55.8, 31.2; HRMS (ESI): calculated for C16H16NO [MþH]þ, 238.1232. Found [MþH]þ, 238.1225. 4.2.13. 5-Fluoro-1-methyl-2-phenyl-1H-indole (3m). Yield: 78%; 1H NMR (400 MHz, CDCl3) d 7.62 (d, J¼8.0 Hz, 1H), 7.45e7.49 (m, 2H),
7.35 (d, J¼8.0 Hz, 1H), 7.24 (t, J¼8.0 Hz, 1H), 7.13e7.17 (m, 3H), 6.53 (s, 1H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3) d 156.9 (d, J¼233 Hz), 143.1, 134.9, 132.5, 129.3, 128.5, 128.1, 128.0 (d, J¼11 Hz), 110.1 (d, J¼10 Hz), 109.7 (d, J¼26 Hz), 105.0 (d, J¼24 Hz), 101.5 (d, J¼5 Hz), 31.3; 19F NMR: (376 MHz, CDCl3) d 124.8; HRMS (ESI): calculated for C15H13FN [MþH]þ, 226.1032. Found [MþH]þ, 226.1032. 4.2.14. 2-(4-Chlorophenyl)-1-methyl-1H-indole-4-carbonitrile (3n). Yield: 72%; 1H NMR (400 MHz, CDCl3) d 7.59 (d, J¼8.0 Hz, 1H), 7.47e7.54 (m, 5H), 7.31 (d, J¼8.0 Hz, 1H), 6.80 (s, 1H), 3.80 (s, 3H); 13 C NMR (100 MHz, CDCl3) d 142.9, 138.0, 135.0, 130.6, 130.0, 129.3, 129.0, 125.3, 121.4, 118.7, 114.3, 102.8, 100.9, 31.5; HRMS (ESI): calculated for C16H12ClN2 [MþH]þ, 267.0689. Found [MþH]þ, 267.0685. 4.2.15. 2-Phenyl-1H-indole (3o).3b Yield: 62%; 1H NMR (400 MHz, CDCl3) d 8.32 (br s, 1H), 7.62e7.66 (m, 3H), 7.38e7.45 (m, 3H), 7.32 (t, J¼7.2 Hz, 1H), 7.19 (t, J¼7.2 Hz, 1H), 7.12 (t, J¼7.2 Hz, 1H), 6.82 (s, 1H); 13C NMR (150 MHz, CDCl3) 137.9, 136.3, 132.3, 129.2, 129.0, 127.7, 125.2, 122.4, 120.7, 120.3, 110.9, 100.0; HRMS (ESI): calculated for C14H12N [MþH]þ, 194.0970. Found [MþH]þ, 194.0964.
4.3. General procedure for the CeH arylation of benzofurans and benzothiophenes with iodobenzenes To a microwave reaction vial, Pd(OAc)2 (5 mol %), CF3COOAg (1.5 mmol), iodobenzene (2.0 mmol), N-methylindole (1.0 mmol), trifluoroacetic acid (2 mmol), and Tween-80/H2O (2 ml, 2 wt %) were added. The reaction mixture was allowed to react at room temperature. After the completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified on silica gel chromatography to afford the desired product. 4.3.1. 2-Phenylbenzofuran (5a).14 Yield: 88%; LCeMS: tR¼4.169 min, m/z¼195 [MþH]þ; 1H NMR (400 MHz, DMSO-d6) d 7.92 (d, J¼8.0 Hz, 2H), 7.66 (d, J¼8.0 Hz, 1H), 7.63 (d, J¼8.0 Hz, 1H), 7.50 (t, J¼8.0 Hz, 2H), 7.46 (s, 1H), 7.40 (t, J¼8.0 Hz, 1H), 7.31 (t, J¼8.0 Hz, 1H), 7.25 (t, J¼8.0 Hz, 1H). 4.3.2. 2-(4-Chlorophenyl)benzofuran (5b).15 Yield: 87%; LCeMS: tR¼4.508 min, m/z¼229 [MþH]þ; 1H NMR (600 MHz, CDCl3) d 7.78 (d, J¼8.6 Hz, 2H), 7.57 (d, J¼7.6 Hz, 1H), 7.51 (d, J¼8.2 Hz, 1H), 7.40 (d, J¼8.6 Hz, 2H), 7.25e7.27 (m, 2H), 6.99 (s, 1H); 13C NMR (150 MHz, CDCl3) d 155.0, 154.8, 134.4, 129.1, 129.1, 129.0, 126.2, 124.6, 123.1, 121.0, 111.2, 101.8. 4.3.3. 2-(p-Tolyl)benzofuran (5c).14 Yield: 88%; LCeMS: tR¼ 4.385 min, m/z¼209 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.75 (d, J¼8.0 Hz, 1H), 7.55 (d, J¼8.0 Hz, 1H), 7.50 (d, J¼8.0 Hz, 1H), 7.29e7.18 (m, 4H), 6.94 (s, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) d 156.2, 154.8, 138.6, 129.5 (2C), 129.3, 127.7, 124.9 (2C), 124.0, 122.8, 120.7, 111.1, 100.5, 21.4. 4.3.4. 2-(4-Methoxyphenyl)benzofuran (5d).15 Yield: 78%; LCeMS: tR¼4.133 min, m/z¼225 [MþH]þ; 1H NMR (CDCl3, 400 MHz) d 7.79 (d, J¼8.0 Hz, 2H), 7.54 (d, J¼7.8 Hz, 1H), 7.49 (d, J¼8.0 Hz, 1H), 7.26e7.19 (m, 2H), 6.96 (d, J¼8.0 Hz, 2H), 6.87 (s, 1H) 3.85 (s, 3H). 4.3.5. 2-(4-(Trifluoromethyl)phenyl)benzofuran (5e).16 Yield: 83%; LCeMS: tR¼4.524 min, m/z¼263 [MþH]þ; 1H NMR: (400 MHz, CDCl3) d 7.96 (d, J¼8.0 Hz, 2H), 7.70 (d, J¼8.0 Hz, 2H), 7.62 (d, J¼8.0 Hz, 1H), 7.55 (d, J¼8.0 Hz, 1H), 7.34 (dd, J¼8.0, 7.8 Hz, 1H), 7.27 (dd, J¼8.0, 7.8 Hz, 1H), 7.14 (s, 1H); 13C NMR (100 MHz, CDCl3) d 155.1, 154.2, 133.7, 130.1 (q, J¼33 Hz), 128.8, 125.8 (q, J¼5 Hz),
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Z. Xu et al. / Tetrahedron xxx (2015) 1e6
125.1, 124.9, 124.0 (q, J¼271 Hz), 123.3, 121.3, 111.3, 103.2; (376 MHz, CDCl3) d 62.6.
19
F NMR
4.3.6. Methyl 2-phenylbenzofuran-5-carboxylate (5f).17 Yield: 84%; LCeMS: tR¼4.181 min, m/z¼253 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 8.32 (d, J¼1.6 Hz, 1H), 8.02 (dd, J¼1.6, 8.4 Hz, 1H), 7.88e7.86 (m, 2H), 7.54 (d, J¼8.8 Hz, 1H), 7.49e7.45 (m, 2H), 7.41e7.37 (m, 1H), 7.06 (d, J¼0.8 Hz, 1H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) d 167.2, 157.3, 157.3, 129.8, 129.2, 128.9, 128.2, 126.0, 125.3, 125.0, 123.2, 110.9, 101.5, 52.0. 4.3.7. 5-Methoxy-2-phenylbenzofuran (5g).17 Yield: 87%; LCeMS: tR¼4.138 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 8.88 (d, J¼7.8 Hz, 2H), 7.49e7.44 (m, 3H), 7.39e7.37 (m, 1H), 7.06 (d, J¼2.0 Hz, 1H), 6.98 (s, 1H), 6.93 (dd, J¼2.0, 7.8 Hz, 1H), 3.88 (s, 3H); 13 C NMR (100 MHz, CDCl3) d 156.6, 156.0, 149.8, 130.5, 129.7, 128.7, 128.4, 124.8, 112.9, 111.6, 103.2, 101.4, 55.8. 4.3.8. 5-Methyl-2-phenylbenzofuran (5h).15 Yield: 85%; LCeMS: tR¼4.416 min, m/z¼209 [MþH]þ; 1H NMR (400 MHz, DMSO-d6) d 7.85 (d, J¼7.8 Hz, 2H), 7.43 (t, J¼7.8 Hz, 2H), 7.39 (d, J¼8.0 Hz, 1H), 7.35e7.31 (m, 2H), 7.08 (d, J¼8.0 Hz, 1H), 6.94 (s, 1H), 2.44 (s, 3H). 4.3.9. 7-Methoxy-2-phenylbenzofuran (5i).15 Yield: 80%; LCeMS: tR¼4.022 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, DMSO-d6) d 7.89 (d, J¼8.0 Hz, 2H), 7.43 (t, J¼8.0 Hz, 2H), 7.34 (t, J¼8.0 Hz, 1H), 7.19e7.13 (m, 3H), 7.01 (s, 1H), 6.80 (d, J¼8.0 Hz, 1H), 4.04 (s, 3H); 13 C NMR (150 MHz, CDCl3) d 156.1, 145.4, 144.2, 131.0, 130.3, 128.6, 125.1, 123.6, 113.4, 106.7, 101.7, 56.2. 4.3.10. 2-Phenylbenzo[b]thiophene (7a).18 Yield: 76%; LCeMS: tR¼4.299 min, m/z¼211 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.82 (d, J¼8.0 Hz, 1H), 7.76 (d, J¼8.0 Hz, 1H), 7.71 (d, J¼8.0 Hz, 2H), 7.54 (s, 1H), 7.43e7.40 (m, 2H), 7.36e7.27 (m, 3H); 13C NMR (150 MHz, CDCl3) d 140.8, 138.2, 138.0, 136.1, 128.8, 127.6, 124.5, 124.4, 123.5, 123.4, 123.0, 129.9. 4.3.11. 2-(4-Chlorophenyl)benzo[b]thiophene (7b).18 Yield: 70%; LCeMS: tR¼4.385 min, m/z¼209 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.80 (d, J¼8.0 Hz, 1H), 7.75 (d, J¼8.0 Hz, 1H), 7.61 (d, J¼8.0 Hz, 2H), 7.49 (s, 1H), 7.37 (d, J¼8.0 Hz, 2H), 7.33e7.30 (m, 2H); 13 C NMR (150 MHz, CDCl3) d 140.8, 137.7, 136.6, 134.5, 133.5, 129.9, 128.9, 124.6, 124.5, 123.8, 123.0, 122.7. 4.3.12. 2-(p-Tolyl)benzo[b]thiophene (7c).18 Yield: 70%; LCeMS: tR¼4.531 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, CDCl3): d 7.94e7.96 (m, 2H), 7.52 (d, J¼8.0 Hz, 2H), 7.40e7.44 (m, 3H), 7.33 (d, J¼8.0 Hz, 2H), 2.47 (s, 3H), 13C NMR (150 MHz, CDCl3): d 140.7, 138.1, 138.0, 137.4, 133.2, 129.5, 129.4, 128.6, 124.4, 124.3, 122.9, 21.3. 4.3.13. 2-(4-Methoxyphenyl)benzo[b]thiophene (7d).18 Yield: 72%; LCeMS: tR¼4.244 min, m/z¼241 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.91 (s, 1H), 7.54 (d, J¼8.0 Hz, 2H), 7.40 (m, 2H), 7.36 (s, 1H), 7.04e7.07 (m, 2H), 3.91 (s, 3H); 13C NMR (150 MHz, CDCl3) d 159.2, 140.6, 138.2, 137.7, 129.8, 128.6, 124.3, 123.0, 122.9, 122.6, 114.2, 55.4. 4.3.14. 4-(Benzo[b]thiophen-2-yl)benzonitrile (7e).18 Yield: 74%; LCeMS: tR¼3.964 min, m/z¼236 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.35e7.44 (m, 2H), 7.63 (s, 1H), 7.66 (d, J¼8.0 Hz, 2H), 7.75 (d, J¼8.0 Hz, 2H), 7.79e7.86 (m, 2H); 13C NMR (150 MHz, CDCl3) d 141.6, 140.3, 139.9, 138.5, 132.7, 126.7, 125.4, 125.0, 124.2, 122.4, 121.8, 118.7, 111.3. 4.3.15. 5-Methyl-2-phenylbenzo[b]thiophene (7f). Yield: 75%; LCeMS: tR¼4.513 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.82 (d, J¼8.0 Hz, 1H), 7.73 (s, 1H), 7.60 (d, J¼8.0 Hz, 2H),
5
7.50 (t, J¼8.0 Hz, 1H), 7.44 (d, J¼8.0 Hz, 1H), 7.40 (s, 1H), 7.24 (d, J¼8.0 Hz, 1H), 2.49 (s, 3H); 13C NMR (150 MHz, CDCl3) d 141.7, 138.2, 137.8, 129.9, 129.3, 129.2, 128.0, 121.5, 120.4, 119.8, 109.6, 101.3, 31.1, 21.3. 4.3.16. 5-Chloro-2-phenylbenzo[b]thiophene (7g).19 Yield: 60%; LCeMS: tR¼4.590 min, m/z¼245 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.90 (d, J¼2.0 Hz, 1H), 7.84 (d, J¼8.0 Hz, 1H), 7.57 (d, J¼8.0 Hz, 2H), 7.51 (t, J¼8.0 Hz, 2H), 7.45e7.48 (m, 2H), 7.37 (dd, J¼8.0, 2.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) d 139.2, 138.8, 137.7, 135.4, 130.9, 128.9, 128.7, 127.9, 125.2, 125.0, 123.9, 122.6. 4.3.17. 5-Methoxy-2-phenylbenzo[b]thiophene (7h).20 Yield: 84%; LCeMS: tR¼4.187 min, m/z¼241 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.81 (d, J¼8.0 Hz, 1H), 7.63 (d, J¼6.0 Hz, 2H),7.53 (t, J¼6.0 Hz, 2H), 7.44e7.47 (m, 3H), 7.41 (d, J¼2.4 Hz, 1H), 6.99 (dd, J¼8.0, 2.4 Hz, 1H), 3.88 (s, 3H); 13C NMR (150 MHz, CDCl3) d 157.6, 139.0, 137.8, 136.2, 133.1, 128.8 (2C), 128.6 (2C), 127.5, 124.8, 114.7, 105.7, 55.6. Acknowledgements We thank Dr. Ruina Gao for HRMS analysis and Mr. Morris Sui for NMR analysis. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2015.03.051. References and notes 1. (a) Garg, N. K.; Sarpong, R.; Stolz, B. M. J. Am. Chem. Soc. 2002, 124, 13179; (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (c) Qin, Z.; Kastrati, I.; Chandrasena, R. E. P.; Liu, H.; Yao, P.; Petukhov, P. A.; Bolton, J. L.; Thatcher, G. R. J. J. Med. Chem. 2007, 50, 2682. 2. For selected recent reviews on CeH functionalization, see: (a) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094; (b) WencelDelord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740; (c) Li, B.-J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588; (d) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879; (e) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Adv. Synth. Catal. 2014, 356, 17; (f) Giri, R.; Thapa, S.; Kafle, A. Adv. Synth. Catal. 2014, 356, 1395; (g) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744 For selected examples of C-2 arylation of benzofurans and benzothiophenes: (h) Tamba, S.; Okubo, Y.; Tanaka, S.; Monguchi, D.; Mori, A. J. Org. Chem. 2010, 75, 6998 For selected examples of C-2 arylation of indoles: (i) Feng, J.; Lu, G.; Lv, M.; Cai, C. J. Organomet. Chem. 2014, 761, 28; (j) Lu, G.-P.; Cai, C. Synlett 2012, 2992. 3. (a) Yang, S. D.; Sun, C. L.; Fang, Z.; Li, B. J.; Li, Y. Z.; Shi, Z. J. Angew. Chem., Int. Ed. 2008, 47, 1473; (b) Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428; (c) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 4972; (d) Nimje, R. Y.; Leskinen, M. V.; Pihko, P. M. Angew. Chem., Int. Ed. 2013, 52, 4818. 4. (a) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926; (b) Islam, S.; Larrosa, I. Chem.dEur. J. 2013, 19, 15093. 5. Sheldon, R. A.; Arens, I. W. C. E.; Hanefeld, U. Green Chemistry and Catalysis; Wiley-VCH: Weinheim, Germany, 2007. 6. Xu, Z.; Yang, T.; Lin, X.; Elliott, J.; Ren, F. Tetrahedron Lett. 2015, 56, 475. 7. (a) Bai, L.; Wang, J.-X.; Zhang, Y. Green Chem. 2003, 5, 615; (b) Li, C.-J. Acc. Chem. Res. 2010, 43, 581; (c) Li, C. J. Metal-Mediated CeC Bond Formation in Aqueous Media In Organic Reactions in Water: Principles, Strategies, and Applications; € m, U. M., Ed.; Blackwell: Oxford, UK, 2007; (d) Li, C.-J.; Chen, L. Chem. Lindstro Soc. Rev. 2006, 35, 68; (e) Jones, M. N. Int. J. Pharm. 1999, 177, 137; (f) Klumphu, P.; Lipshutz, B. H. J. Org. Chem. 2014, 79, 888; (g) Dwars, T.; Paetzold, E.; Oehme, G. Angew. Chem., Int. Ed. 2005, 44, 7174. cile, D.; Alexandre, 8. Hubert, S.; Albert, B.; Roland, V.; Eugen, S.; Markwart, K.; Ce C.; Caterine, L.; Bernd, L.; Matthias, M.; Siegfried, P. “Sugar Alcohols” Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, Germany, 2012. 9. (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050; (b) Joucla, L.; Batail, N.; Djakovitch, L. Adv. Synth. Catal. 2010, 352, 2929. 10. (a) Wang, B.; Nack, W. A.; He, G.; Zhang, S. Y.; Chen, G. Chem. Sci. 2014, 5, 3952; (b) Wang, X.; Truesdale, L.; Yu, J. Q. J. Am. Chem. Soc. 2010, 132, 3648; (c) Taniguchi, Y.; Yamaoka, Y.; Nakata, K.; Takaki, K.; Fujiwara, Y. Chem. Lett. 1995, 345; (d) Lu, W.; Yamaoka, Y.; Taniguchi, Y.; Kitamura, T.; Takaki, K.; Fujiwara, Y. J. Organomet. Chem. 1999, 580, 290. 11. Liang, Z.; Yao, B.; Zhang, Y. Org. Lett. 2010, 12, 3185.
Please cite this article in press as: Xu, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.03.051
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12. Susanto, W.; Chu, C.-Y.; Ang, W. J.; Chou, T.-C.; Lo, L.-C.; Lam, Y. J. Org. Chem. 2012, 77, 2729. 13. Denmark, S. E.; Baird, J. D.; Regens, C. S. J. Org. Chem. 2008, 73, 1440. 14. Ruan, L.; Shi, M.; Mao, S.; Yu, L.; Yang, F.; Tang, J. Tetrahedron 2014, 70, 1065. 15. Wang, X.; Liu, M.; Xu, L.; Wang, Q.; Chen, J.; Ding, J.; Wu, H. J. Org. Chem. 2013, 78, 5273.
16. Denmark, S. E.; Smith, R. C.; Chang, W.-T. T.; Muhuhi, J. M. J. Am. Chem. Soc. 2009, 131, 3104. 17. Wang, S.; Li, P.; Yu, L.; Wang, L. Org. Lett. 2011, 13, 5968. 18. Sun, L.-L.; Deng, C.-L.; Tang, R.-Y.; Zhang, X.-G. J. Org. Chem. 2011, 76, 7546. € nig, B. Org. Lett. 2012, 14, 5334. 19. Hari, D. P.; Hering, T.; Ko 20. Yu, H.; Zhang, M.; Li, Y. J. Org. Chem. 2013, 78, 8898.
Please cite this article in press as: Xu, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.03.051