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. 2012 Jul 15;711:62–67. doi: 10.1016/j.jorganchem.2012.03.030

Pd(II)-catalyzed ortho arylation of 2-arylbenzothiazoles with aryl iodides via benzothiazole-directed C–H activation

Qiuping Ding 1,∗, Huafang Ji 1, Dan Wang 1, Yuqing Lin 1, Weihua Yu 1, Yiyuan Peng 1,∗
PMCID: PMC3363328  PMID: 22807586

Abstract

A novel and efficient method for the arylation of 2-arylbenzothiazoles is described via C–H activation. The desired CAr–CAr bond formation proceeded efficiently with good functional-group tolerance and high regioselectivity. Proposed mechanism for the arylation of 2-arylbenzothiazole is depicted.

Keywords: Arylbenzothiazoles, C–H activation, Arylation, Aryl iodide

Graphical abstract

A novel and efficient method for the arylation of 2-arylbenzothiazoles is described via C–H activation. The desired CAr–CAr bond formation proceeded efficiently with good functional-group tolerance and high regioselectivity. Proposed mechanism for the arylation of 2-arylbenzothiazole is depicted.

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Highlights

► Novel arylation of 2-arylbenzothiazoles is described via palladium-catalyzed C–H activation. ► CAr–CAr bond formation proceeded efficiently with good functional-group tolerance and high regioselectivity. ► Proposed mechanism for the arylation of 2-arylbenzothiazole is depicted.

1. Introduction

Construction of carbon–carbon bond is fundamental to all of organic chemistry. Aryl–aryl bonds are founded in diverse natural products, medicinal agents, and organic materials. Metal complexes-catalyzed reactions for the formation of CAr–CAr bonds are widely used in organic synthesis. Transition metal-catalyzed cross-couplings are among the most traditional synthetic methods [1–9], such as the Suzuki–Miyaura reaction, Stille reaction, Kumada reaction, and Negishi reaction. However, the formation of these bonds involved nucleophilic aromatic substitution reactions between electron-deficient organic halides and stoichiometric amounts of organometallic reagents, both coupling components must be functionalized. The required organometallic nucleophilic reagents are often not commercially available or are relatively expensive. Their preparation process usually involves many synthetic steps, during which undesired byproducts are formed. Therefore, transition metal-catalyzed direct arylation reaction through cleavage of C–H bond is an alternative to the traditional strategy. The C–H activation [10–17] progress involves just one or no functionalized coupling components, which represent an environmentally and economically more attractive method. The most widely studied area in this field is transitional metal-catalyzed ligand-directed C–H activation followed by cross-coupling to form C(sp2)–C(sp2), C(sp2)–C(sp3), and C(sp3)–C(sp3) bonds. For example, amide [18], oxime ether [19], pyridine [20–22], oxazoline [23,24], and carboxylic acid [25,26] serve as directing groups for Pd-catalyzed ortho-arylation have been extensively studied.

As a privileged fragment, 2-arylbenzothiazole core is found in many natural products and pharmaceuticals that exhibit remarkable biological activities [27–30]. Typical examples include [11C]PIB (an agent in clinical trials for early diagnosis of Alzheimer's disease) [31,32] GW610 (antitumor agent) [30], and 5F203 (antitumor agent) [33] (Fig. 1). Many efforts continue to be given to the development of new 2-arylbenzothiazole structures and new methods for their constructions [34–38]. As a part of our continuing efforts for the expeditious synthesis of biologically relevant heterocyclic compounds [39–46], herein we would like to report our recent efforts towards the synthesis of diverse 2-arylbenzothiazoles via Pd-catalyzed C–H activation reactions.

Fig. 1.

Fig. 1

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Potential therapeutic/diagnostic 2-arylbenzothiazoles.

2. Experimental

2.1. General remarks

All reactions were performed in reaction tubes under nitrogen atmosphere. Flash column chromatography was performed using silica gel (60-Å pore size, 32–63 μm, standard grade). Analytical thin-layer chromatography was performed using glass plates pre-coated with 0.25 mm 230–400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Thin layer chromatography plates were visualized by exposure to ultraviolet light. Organic solutions were concentrated on rotary evaporators at ∼20 Torr (house vacuum) at 25–35 °C. Commercial reagents and solvents were used as received. 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded in CDCl3 using a Bruker Avance (AV400) spectrometer in parts per million from internal tetramethylsilane on the δ scale. HRMS were obtained using a Nova NanoSEM 200 (FEI) instrument with ESI ionization.

2.2. General procedure for C–H bond activation/arylation of 2-arylbenzothiazoles 1 with aryl iodides 2

In a 20 mL Teflon tube, a mixture of 2-phenylbenzothiazole 1 (0.3 mmol, 1.0 equiv), aryl iodides 2 (1.2 mmol, 4.0 equiv), AgOAc (1.5 mmol, 5.0 equiv), and Pd(OAc)2 (10 mol%) in dried TFA (2.0 mL) was stirred at 90 °C for 12–72 h. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature, the resulting mixture was extracted with ethyl acetate (3 × 20 mL), The organic layer was evaporated under vacuum, and then the residue was purified by flash column chromatography on silica gel to provide the corresponding pure product 3 and (or) 4.

2.2.1. 2-(4,4″-Dimethyl-[1,1′:3′,1″-terphenyl]-2′-yl)benzo[d]thiazole, 3a

White powder; yield: 97 mg (83%); mp 159–161 °C; 1H NMR (400 MHz, CDCl3) δ 2.23 (s, 6H), 6.96 (d, J = 7.6 Hz, 4H), 7.14 (d, J = 7.6 Hz, 4H), 7.26 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.44 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.1, 121.3, 123.3, 124.7, 125.5, 128.7, 129.2, 129.4, 129.6, 131.4, 136.5, 136.6, 137.8, 142.9, 152.6, 167.2; HRMS (ESI): m/z [M + H]+ calcd for C27H22NS: 392.1473; found: 392.1468.

2.2.2. 2-([1,1′:3′,1″-Terphenyl]-2′-yl)benzo[d]thiazole, 3b

Colorless oil; yield: 67.7 mg (63%); 1H NMR (400 MHz, CDCl3) δ 7.14–7.17 (m, 7H), 7.24–7.27 (m, 4H), 7.33 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 121.3, 123.3, 124.8, 125.6, 127.0, 127.9, 129.3, 129.6, 129.8, 131.5, 136.5, 140.7, 142.9, 152.5, 167.0; HRMS (ESI): m/z [M + H]+ calcd for C25H18NS: 364.116; found: 364.1156.

2.2.3. 2-(4,4″-Dimethyl-[1,1′:3′,1″-terphenyl]-2′-yl)-6-methylbenzo[d]thiazole, 3c

Yellow powder; yield: 82.6 mg (68%); mp 153–155 °C; 1H NMR (400 MHz, CDCl3) δ 2.13 (s, 6H), 2.29 (s, 3H), 6.86 (d, J = 8.0 Hz, 4H), 7.06 (d, J = 8.0 Hz, 5H), 7.31 (s, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.43–7.47 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.1, 21.5, 121.0, 122.8, 127.1, 128.6, 129.2, 129.4, 129.5, 131.6, 134.7, 136.5, 136.8, 137.9, 142.9, 150.8, 166.1; HRMS (ESI): m/z [M + H]+ calcd for C28H24NS: 406.1629; found: 406.1630.

2.2.4. 2-(4,4″-Dimethoxy-[1,1′:3′,1″-terphenyl]-2′-yl)-6-methylbenzo[d]thiazole, 3d

Yellow powder; yield: 69.5 mg (53%); mp 163–165 °C; 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 3.68 (s, 6H), 6.68 (d, J = 7.2 Hz, 4H), 7.14–7.18 (m, 5H), 7.39–7.43 (m, 3H), 7.51 (t, J = 8.0 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.5, 55.1, 113.3, 121.0, 122.8, 127.1, 129.3, 129.6, 130.4, 131.6, 133.2, 134.8, 136.8, 142.6, 150.8, 158.5, 166.2; HRMS (ESI): m/z [M + H]+ calcd for C28H24NO2S: 438.1528; found: 438.1522.

2.2.5. 2-(4,4″-Dichloro-[1,1′:3′,1″-terphenyl]-2′-yl)-6-methylbenzo[d]thiazole, 3e

Yellow powder; yield: 80.1 mg (60%); mp 176–178 °C; 1H NMR (400 MHz, CDCl3) δ 2.31 (s, 3H), 7.03 (d, J = 8.4 Hz, 4H), 7.08–7.12 (m, 5H), 7.32–7.37 (m, 3H), 7.47 (t, J = 7.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.5, 121.1, 122.9, 127.6, 128.2, 129.7, 129.8, 130.6, 131.7, 133.2, 135.3, 136.6, 139.0, 141.9, 150.7, 164.9; HRMS (ESI): m/z [M + H]+ calcd for C26H18Cl2NS: 446.0537; found: 446.0540.

2.2.6. 6-Chloro-2-(4,4″-dimethyl-[1,1′:3′,1″-terphenyl]-2′-yl)benzo[d]thiazole, 3f

Yellow powder; yield: 105.8 mg (83%); mp 82–83 °C; 1H NMR (400 MHz, CDCl3) δ 2.12 (s, 6H), 6.86 (d, J = 8.0 Hz, 4H), 7.04 (d, J = 8.0 Hz, 4H), 7.17 (dd, J = 2.0, 8.8 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.42–7.47 (m, 2H), 7.64 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.1, 120.9, 124.0, 126.4, 128.7, 129.2, 129.4, 129.8, 130.7, 131.1, 136.7, 137.7, 137.8, 142.9, 151.2, 167.8; HRMS (ESI): m/z [M + H]+ calcd for C27H21ClNS: 426.1083; found: 426.1078.

2.2.7. 2-([1,1′:3′,1″-Terphenyl]-2′-yl)-6-chlorobenzo[d]thiazole, 3g

Yellow oil; yield: 89.3 mg (75%); 1H NMR (400 MHz, CDCl3) δ 7.04–7.05 (m, 6H), 7.13–7.17 (m, 5H), 7.36 (d, J = 7.6 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 120.9, 124.0, 126.5, 127.1, 128.0, 129.3, 129.6, 129.9, 130.8, 131.2, 137.7, 140.6, 143.0, 151.2, 167.5; HRMS (ESI): m/z [M + H]+ calcd for C25H17ClNS: 398.077; found: 398.0765.

2.2.8. 6-Chloro-2-(4,4″-dichloro-[1,1′:3′,1″-terphenyl]-2′-yl)benzo[d]thiazole, 3h

Yellow powder; yield: 86.3 mg (62%); mp 82–83 °C; 1H NMR (400 MHz, CDCl3) δ 7.12–7.18 (m, 8H), 7.33 (dd, J = 2.0, 8.8 Hz, 1H), 7.43 (d, J = 7.6 Hz, 2H), 7.58 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 121.0, 124.2, 126.8, 128.3, 129.8, 130.1, 130.6, 131.1, 131.2, 133.4, 137.6, 138.8, 141.9, 151.1, 166.7; HRMS (ESI): m/z [M + H]+ calcd for C25H15Cl3NS: 465.9991; found: 465.9985.

2.2.9. 2-(4,4″-Dimethyl-[1,1′:3′,1″-terphenyl]-2′-yl)-6-fluorobenzo[d]thiazole, 3i

Yellow oil; yield: 92.0 mg (75%); 1H NMR (400 MHz, CDCl3) δ 2.11 (s, 6H), 6.85 (d, J = 8.0 Hz, 4H), 6.93 (dt, J = 2.4, 8.8 Hz, 1H), 7.04 (d, J = 8.0 Hz, 4H), 7.15 (dd, J = 2.4, 8.0 Hz, 1H), 7.32 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.2 Hz, 1H), 7.67 (dd, J = 9.2, 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.1, 107.4 (d, 2JC–F = 27.0 Hz), 114.2 (d, 2JC–F = 24.0 Hz), 124.1 (d, 3JC–F = 9.0 Hz), 128.7, 129.2, 129.4, 129.8, 131.2, 136.7, 137.6 (d, 3JC–F = 11.0 Hz), 137.8, 143.0, 149.3, 160.1 (d, 1JC–F = 244.0 Hz), 166.9 (d, 4JC–F = 4.0 Hz); HRMS (ESI): m/z [M + H]+ calcd for C27H21FNS: 410.1379; found: 410.1373.

2.2.10. 2-([1,1′:3′,1″-Terphenyl]-2′-yl)-6-fluorobenzo[d]thiazole, 3j

Yellow oil; yield: 83.4 mg (73%); 1H NMR (400 MHz, CDCl3) δ 6.91–6.96 (m, 2H), 7.04–7.08 (m, 6H), 7.11–7.16 (m, 4H), 7.37 (d, J = 7.6 Hz, 2H), 7.47 (t, J = 7.2 Hz, 1H), 7.62–7.65 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 107.3 (d, 2JC–F = 27.0 Hz), 114.3 (d, 2JC–F = 24.0 Hz), 124.1 (d, 3JC–F = 9.0 Hz), 127.1, 127.9, 129.3, 129.6, 129.8, 131.3, 137.5 (d, 3JC–F = 12 Hz), 140.6, 143.0, 149.2, 161.2 (d, 1JC–F = 244.0 Hz), 166.6; HRMS (ESI): m/z [M + H]+ calcd for C25H17FNS: 382.1066; found: 382.1060.

2.2.11. 6-Chloro-2-(5′-methoxy-4,4″-dimethyl-[1,1′:3′,1″-terphenyl]-2′-yl)benzo[d]thiazole, 3k

Yellow powder; yield: 71 mg (52%); mp 158–160 °C; 1H NMR (400 MHz, CDCl3) δ 2.23 (s, 6H), 3.88 (s, 3H), 6.92–7.00 (m 6H), 7.13 (d, J = 8.0 Hz, 4H), 7.27 (dd, J = 2.0, 8.8 Hz, 1H), 7.56 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.1, 55.5, 114.9, 120.8, 123.8, 123.9, 126.3, 128.7, 129.1, 130.5, 136.8, 137.8, 137.9, 144.5, 151.2, 160.1, 168.0; HRMS (ESI): m/z [M + H]+ calcd for C28H23ClNOS: 456.1189; found: 456.1183.

2.2.12. 6-Chloro-2-(5′-methoxy-[1,1′:3′,1″-terphenyl]-2′-yl)benzo[d]thiazole, 3l

Yellow powder; yield: 76.8 mg (60%); mp 143–145 °C; 1H NMR (400 MHz, CDCl3) δ 3.79 (s, 3H), 6.91 (s, 2H), 7.01–7.11 (m, 6H), 7.12–7.20 (m, 5H), 7.45 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 55.6, 115.1, 120.8, 123.9, 124.0, 126.4, 127.2, 128.0, 129.2, 130.6, 137.9, 140.7, 144.6, 151.2, 160.2, 167.7; HRMS (ESI): m/z [M + H]+ calcd for C26H19ClNOS: 428.0876; found: 428.0870.

2.2.13. 6-Chloro-2-(4,4″,5′-trimethoxy-[1,1′:3′,1″-terphenyl]-2′-yl)benzo[d]thiazole, 3m

Yellow oil; yield: 96.4 mg (66%); 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 6H), 3.90 (s, 3H), 6.70 (d, J = 8.4 Hz, 4H), 6.95 (s, 2H), 7.16 (d, J = 8.4 Hz, 4H), 7.29 (dd, J = 2.0, 8.8 Hz, 1H), 7.60 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 55.1, 55.5, 113.4, 114.8, 120.8, 123.9, 126.3, 130.3, 130.5, 133.1, 137.9, 144.2, 151.2, 158.7, 160.1, 168.0; HRMS (ESI): m/z [M + H]+ calcd for C28H23ClNO3S: 488.1087; found: 488.1082.

2.2.14. 2-(5′-Methoxy-[1,1′:3′,1″-terphenyl]-2′-yl)benzo[d]thiazole, 3n

Colorless oil; yield: 62.5 mg (53%); 1H NMR (400 MHz, CDCl3) δ 3.88 (s, 3H), 6.99 (s, 2H), 7.05–7.18 (m, 6H), 7.19–28 (s, 5H), 7.32 (t, J = 7.6 Hz, 1H), 7.71(d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 53.6, 112.9, 119.5, 120.9, 121.8, 122.9, 123.7, 125.2, 125.9, 126.6, 127.1, 134.4, 138.5, 142.1, 150.4, 157.9, 164.4; HRMS (ESI): m/z [M + H]+ calcd for C26H20NOS: 394.1266; found: 394.1260.

2.2.15. 2-(4′-Methyl-[1,1′-biphenyl]-2-yl)benzo[d]thiazole, 4a

Colorless oil; yield: 11.7 mg (13%); 1H NMR (400 MHz, CDCl3) δ 2.39 (s, 3H), 7.16 (d, J = 7.6 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 8.0 Hz, 1H), 7.41–7.52 (m, 4H), 7.72 (d, J = 7.6 Hz, 1H), 8.08 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 20.2, 120.3, 121.1, 123.8, 124.8, 126.5, 128.0, 128.8, 129.0, 129.3, 129.9, 131.5, 135.6, 136.1, 136.5, 140.6, 151.6, 167.0; HRMS (ESI): m/z [M + H]+ calcd for C20H16NS: 302.1003; found: 302.0998.

2.2.16. 2-([1,1′-Biphenyl]-2-yl)benzo[d]thiazole [47], 4b

Colorless oil; yield: 8.6 mg (10%); 1H NMR (400 MHz, CDCl3) δ 7.30–7.39 (m, 6H), 7.42–7.57 (m, 4H), 7.71 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.08 (d, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 121.3, 123.2, 124.9, 125.9, 127.8, 128.3, 130.0, 130.1, 130.5, 130.9, 132.6, 136.6, 140.2, 141.7, 152.7, 167.9; HRMS (ESI): m/z [M + H]+ calcd for C19H14NS: 288.0847; found: 288.0840.

2.2.17. 6-Chloro-2-(5-methoxy-4′-methyl-[1,1′-biphenyl]-2-yl)benzo[d]thiazole, 4k

Yellow powder; yield: 10.9 mg (10%); mp 147–148 °C; 1H NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 3.81 (s, 3H), 6.81 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 2.4, 8.4 Hz, 1H), 7.08–7.20 (m, 4H), 7.29 (dd, J = 2.0, 8.8 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.3, 55.5, 113.6, 116.0, 120.8, 123.5, 125.1, 126.5, 129.2, 129.8, 130.4, 131.9, 137.0, 137.7, 138.1, 143.5, 151.3, 160.9, 168.3; HRMS (ESI): m/z [M + H]+ calcd for C21H17ClNOS: 366.0719; found: 366.0715.

2.2.18. 6-Fluoro-2-(4-methyl-[1,1′-biphenyl]-2-yl)benzo[d]thiazole, 4o

Colorless powder; yield: 59.3 mg (62%); mp 105–107 °C; 1H NMR (400 MHz, CDCl3) δ 2.47 (s, 3H), 7.16–7.20 (m, 1H), 7.24–7.40(m, 8H), 7.88 (s, 1H), 7.97 (dd, J = 4.8, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.0, 106.3 (d, 2JC–F = 27.0 Hz), 113.5 (d, 2JC–F = 24.0 Hz), 122.9 (d, 3JC–F = 9.0 Hz), 126.7, 127.3, 129.0, 129.6, 129.8, 130.0, 131.0, 136.5 (d, 3JC–F = 11.0 Hz), 136.7, 137.9, 139.0, 148.3 (d, 4JC–F = 1.0 Hz), 159.2 (d, 1JC–F = 244.0 Hz), 166.8 (d, 4JC–F = 3.0 Hz); HRMS (ESI): m/z [M + H]+ calcd for C20H15FNS: 320.0909; found: 320.0903.

2.2.19. 2-(4′-Chloro-4-methyl-[1,1′-biphenyl]-2-yl)-6-fluorobenzo[d]thiazole, 4p

Colorless powder; yield: 62.5 mg (59%); mp 113–114 °C; 1H NMR (400 MHz, CDCl3) δ 2.46 (s, 3H), 7.16–7.34 (m, 7H), 7.40 (dd, J = 2.4, 8.0 Hz, 1H), 7.84 (s, 1H), 7.98 (dd, J = 4.8, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.0, 106.5 (d, 2JC–F = 26.0 Hz), 113.6 (d, 2JC–F = 24.0 Hz), 123.1 (d, 3JC–F = 9.0 Hz), 127.5, 129.7, 129.8, 130.0, 130.2, 131.0, 132.8, 136.4 (d, 3JC–F = 11.0 Hz), 136.5, 137.0, 137.5, 148.3, 159.2 (d, 1JC–F = 244.0 Hz), 166.3; HRMS (ESI): m/z [M + H]+ calcd for C20H14ClFNS: 354.052; found: 354.0515.

2.2.20. 2-(4-Chloro-[1,1′-biphenyl]-2-yl)benzo[d]thiazole, 4q

Yellow powder; yield: 84.7 mg (88%); mp 134–135 °C; 1H NMR (400 MHz, CDCl3) δ 7.16–7.29 (m, 7H), 7.31–7.38 (m, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 120.3, 122.4, 124.2, 125.0, 127.1, 127.5, 128.8, 128.9, 129.1, 131.1, 132.9, 133.1, 135.7, 138.2, 139.2, 151.7, 165.0; HRMS (ESI): m/z [M + H]+ calcd for C19H13ClNS: 322.0457; found: 322.0452.

2.2.21. 2-(4-Chloro-4′-methoxy-[1,1′-biphenyl]-2-yl)benzo[d]thiazole, 4r

Yellow powder; yield: 50.5 mg (48%); mp 91–92 °C; 1H NMR (400 MHz, CDCl3) δ 3.72 (s, 3H), 6.78 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 7.20–7.26 (m, 2H), 7.33–7.36 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 54.3, 113.0, 120.3, 122.4, 124.1, 125.0, 128.9, 129.0, 130.1, 130.4, 131.3, 132.6, 133.2, 135.7, 138.9, 151.6, 158.8, 165.3; HRMS (ESI): m/z [M + H]+ calcd for C20H15ClNOS: 352.0563; found: 352.0057.

2.2.22. 2-(4,4′-Dichloro-[1,1′-biphenyl]-2-yl)benzo[d]thiazole, 4s

Yellow powder; yield: 59.6 mg (56%); mp 89–91 °C; 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J = 8.4 Hz, 2H), 7.20–7.27 (m, 4H), 7.35–7.39 (m, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 120.4, 122.4, 124.4, 125.2, 127.7, 129.0, 129.3, 130.1, 131.0, 133.0, 133.2, 133.4, 135.4, 136.6, 137.7, 151.6, 164.6; HRMS (ESI): m/z [M + H]+ calcd for C19H12Cl2NS: 356.0068; found: 356.0062.

2.2.23. 2-(3-Methoxy-[1,1′-biphenyl]-2-yl)-6-methylbenzo[d]thiazole, 4t

Colorless oil; yield: 67.5 mg (68%); 1H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 3.77 (s, 3H), 6.97 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 7.10–7.17 (m, 3H), 7.21 (d, J = 9.2 Hz 1H), 7.23–7.27 (m, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.89 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.5, 56.1, 110.1, 121.0, 122.1, 122.6, 122.9, 127.0, 127.2, 127.9, 129.3, 130.8, 134.8, 136.9, 140.3, 143.9, 151.2, 158.0, 163.3; HRMS (ESI): m/z [M + H]+ calcd for C21H18NOS: 332.1109; found: 332.1105.

3. Results and discussion

Initially, we studied the coupling of 2-phenylbenzo[d]thiazole 1a with 1-iodo-4-methylbenzene 2a in the presence of Pd(OAc)2 to afford 3a (Table 1). The effects of different oxidants, temperatures, and solvents were systematically investigated. Unfortunately, it failed to provide the desired arylated product when Cu(OAc)2, BQ (1,4-benzoquinone), and oxone were used as oxidant (Table 1, entries 1–3). The use of PhI(OAc)2 as oxidant delivered the desired ortho-diarylated product 3a in 5% yield, and trace of monoarylated product 4a (Table 1, entry 4), while AgOAc afforded the 3a in an encouraged 31% yield (Table 1, entry 5). Further study showed that elevated amount of Pd(OAc)2 led to higher 41% yield (Table 1, entry 5). Examination of the loading of oxidant revealed that the yield was found to grow with increasing oxidant amount (Table 1, entries 6 and 7). Lower yield was obtained when combination of AgOAc and Cu(OAc)2 as oxidant (Table 1, entry 8). No reaction occurred without catalysts or oxidants. Examination of the temperature effect showed that the best results being obtained at relatively high temperature 90 °C (Table 1, entry 9), while inferior results were obtained when the reaction temperature was more than 100 °C (Table 1, entry 11). When trifluoroacetic acid (TFA) was changed to HOAc or 1,4-dioxane, only trace desired product was observed (Table 1, entries 12 and 13). Thus, under optimized conditions [Pd(OAc)2 (10 mol %), AgOAc (5.0 equiv), TFA, 90 °C], the ortho-diarylated product 3a, was obtained in 83% isolated yield, with 13% yield of ortho-monoarylated product 4a.

Table 1.

Optimization of reaction conditions.aInline graphic

Entry x Oxidant (equiv) T/°C Yield (%)b/3 Yield (%)b/4
1 5 Cu(OAc)2 (2.5) 80 – –
2 5 BQ (2.5) 80 – –
3 5 Oxone (2.5) 80 – –
4 5 PhI(OAc)2 (2.5) 80 5 Trace
5 5 AgOAc (2.5) 80 31 3
6 10 AgOAc (2.5) 80 41 5
7 10 AgOAc (5.0) 80 49 8
8 10 AgOAc/Cu(OAc)2(5.0/2.5) 80 44 6
9 10 AgOAc (2.5) 90 73 11
10 10 AgOAc (5.0) 90 83 13
11 10 AgOAc (5.0) 100 60 9
12c 10 AgOAc (5.0) 90 Trace –
13d 10 AgOAc (5.0) 90 Trace –
Open in a new tab
a

Reaction conditions: 2-phenylbenzo[d]thiazole 1a (0.3 mmol), 1-iodo-4-methylbenzene 2a (1.2 mmol, 4.0 equiv), solvent (2 mL), 48 h.

b

Isolated yield based on 2-phenylbenzo[d]thiazole 1a.

c

HOAc as solvent.

d

1,4-Dioxane as solvent.

With this promising result in hand, we started to investigate the scope of this reaction under the optimized conditions. As summarized in Table 2, benzothiazole-directed C–H activation can be extended to a wide variety of substrates. A range of 2-arylbenzothiazoles coupled with aryl iodides to give the corresponding arylated products in moderate to good yields. Electron factors determined the reactivity of the substrates. Substrates aryl iodides or 2-arylbenzothiazoles could tolerate various functional groups such as CH3, OCH3, and Cl. Better results were obtained when aryl iodide containing a moderately electron-donating group (CH3) 2a or electron-neutral group (H) 2b was employed. To strong electron-withdrawing group such as NO2, the desired product was not observed (Table 2, entry 9). For example, 6-chloro-2-phenylbenzo[d]thiazole 1c reacted with 1-iodo-4-methylbenzene 2a led to the desired product 3f in 83% yield (Table 2, entry 6), while 62% yield of 3h was afforded when 1-chloro-4-iodobenzene 2d was utilized in the reaction (Table 2, entry 8). Good results were observed when 6-fluoro-2- phenylbenzo[d]thiazole 1d reacted with 2a and 2b (Table 2, entries 10 and 11). When R2 was a strong electron-donating group (OCH3), the reactions also occurred smoothly to afford the corresponding products, just in relatively low yield. For instance, reaction of 6-chloro-2-(4-methoxyphenyl)benzo[d]thiazole 1e with 2a gave rise to the diarylated cross-coupling product 3k in 52% yield (Table 2, entry 12). The position of substituent R2 had a critical effect on the arylation reaction. The arylation showed high regioselectivity for cross-coupling at the less hindered ortho-position for 2-arylbenzothiazoles containing a meta-substituent (Table 2, entries 16–20). In case of ortho-substituted 2-arylbenzothiazole, the arylation occurred at the other ortho-position in good yield (Table 2, entry 21).

Table 2.

C–H bond activation/arylation of 2-arylbenzothiazoles 1 with aryl iodides 2.aInline graphic

Entry Substrate 1 2 t [h] Yield (%)b/3 Yield (%)b/4
1 graphic file with name fx4.gif 2a 48 83/3a 13/4a
2 1a 2b 72 62/3b 10/4b
3 graphic file with name fx5.gif 2a 48 68/3c Trace
4 1b 2c 24 53/3d Trace
5 1b 2d 72 60/3e Trace
6 graphic file with name fx6.gif 2a 48 83/3f Trace
7 1c 2b 72 75/3g Trace
8 1c 2d 72 62/3h Trace
9 1c 2e 72 – Trace
10 graphic file with name fx7.gif 2a 48 75/3i Trace
11 1d 2b 72 73/3j Trace
12 graphic file with name fx8.gif 2a 72 52/3k 10/4k
13 1e 2b 72 60/3l Trace
14 1e 2c 72 66/3m Trace
15 graphic file with name fx9.gif 2b 72 53/3n Trace
16 graphic file with name fx10.gif 2b 36 – 62/4o
17 1g 2d 48 – 59/4p
18 graphic file with name fx11.gif 2b 36 – 88/4q
19 1h 2c 36 – 48/4r
20 1h 2d 48 – 56/4s
21 graphic file with name fx12.gif 2b 12 – 68/4t
Open in a new tab
a

Reaction conditions: 2-arylbenzothiazole 1 (0.3 mmol), aryl iodide 2 (1.2 mmol, 4.0 equiv), CF3COOH (2 mL), 90 °C, 12–72 h.

b

Isolated yield based on 2-arylbenzothiazole 1.

Based on known metal-catalyzed directing-group-assisted C–H bond activation reaction and an analogy for the reaction of 2-arylbenzoxazole [18–24], a possible reaction mechanism for the arylation of 2-arylbenzothiazole is depicted in Scheme 1. The proposed catalytic cycle involves the following steps: (ⅰ) cyclopalladation of 2-arylbenzothiazole via C–H activation, (ii) oxidation addition of Pd(II) to Pd(IV), (iii) reductive elimination affording monoarylated product 4 and Pd(II). The monoarylated product 4 could re-enter the catalytic cycle to ultimately yield the corresponding diarylated compound 3.

Scheme 1.

Scheme 1

Open in a new tab

Proposed mechanism for Pd-catalyzed directed arylation with AgI/Ar–I.

4. Conclusion

In summary, we have described a novel and efficient method for the arylation of 2-arylbenzothiazoles via C–H activation. The desired CAr–CAr bond formation proceeded efficiently with good functional-group tolerance and high regioselectivity. Proposed mechanism for the arylation of 2-arylbenzothiazole is depicted. The application of benzothiazole as a directing group to construct a C-heteroatom bond is underway in our laboratory.

Acknowledgments

Financial Supported from National Natural Science Foundation of China (No. 21002042 and 21162012), Jiangxi Educational Committee (GJJ12169), and Natural Science Foundation of Jiangxi Province of China (2009GQH0054) is gratefully acknowledged.

Footnotes

Appendix A

Supplementary data related to this article can be found online at doi:10.1016/j.jorganchem.2012.03.030.

Contributor Information

Qiuping Ding, Email: dqpjxnu@gmail.com.

Yiyuan Peng, Email: yiyuanpeng@yahoo.com.

Appendix A. Supporting information

mmc1.doc (2.4MB, doc)

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