English

• 1.   Introduction

  Arylbenzothiazole is an important structural motif which can be seen in many organic compounds. 2-Arylbenzo- thiazole derivatives always show some bioactivities and are used as pharmaceuticals, such as antineoplastic agents, ^[1] neurological drugs, ^[2] hematology drugs^[3] and cardiovascular drugs^[4] (Figure 1). Scientists are highly concerned about the synthesis of 2-arylbenzothiazole derivatives, ^[5] and always try to develop some efficient synthetic methods. In the past years, scientists have reported many protocols for the synthesis of 2-arylbenzothiazoles, as seen in Scheme 1.^[6-8] However, some of them have major drawbacks, such as poor tolerance of functional groups, high temperatures and strong oxidants. Therefore, it is urgent to find a suitable, convenient and safe method for the syntheses of 2-arylbenzothiazoles.

  Figure 1

  

  Figure 1.  Representative bioactive 2-arylbenzothiazole compounds

  下载: 全尺寸图片 幻灯片

  Scheme 1

  

  Scheme 1.  Synthetic methods of 2-arylbenzothiazoles

  下载: 全尺寸图片 幻灯片

  Diaryliodonium salts have low toxicity and good stability, their mediated reactions often have advantages of mild reaction conditions and high selectivity since diaryliodonium salts were prepared and used in organic synthesis for the first time.^[9] In recent years, diaryliodonium salts have been widely used as arylating agents in organic synthesis.^[10-13] They can also be successfully used for cross- coupling arylation reaction of hetero atom nucleophilic compounds.^[14-18]

  With continuous research interests in C—H activation and functionalization, some transition metal-catalyzed C—H arylation protocols of aromatics and heteroaromatics by using diaryliodonium salts and aryl halides as coupling partners were developed and good results were obtained.^[19-21] Herein, a copper-catalyzed direct C—H arylation of benzothiazoles with diaryliodonium salts as arylating reagents (Scheme 1) is reported. It is a simple, cheap and efficient method to synthesize 2-arylbenzothiazole derivatives.

  2.   Results and discussion

  In order to explore the best conditions for the reaction, our study was initiated with the reaction of benzothiazole (1a) and diphenyliodonium tetrafluoroborate (2a). The results of the reaction condition optimization are listed in Table 1. The reaction was first conducted in acetonitrile at 80 ℃ with K₂CO₃ as a base, (o-tolyl)₃P as a ligand and copper powder as a catalyst. Unfortunately, there is no target product generation (Entry 1). Then the catalyst was replaced with CuI, only trace of target product was formed (Entry 2). To our delight, when the amount of K₂CO₃ was doubled, the desired 2-phenylbenzothiazole (3a) was obtained in 22% yield (Entry 3). Next, different bases and the dosage of bases were examined in the reaction (Entries 4~8). When 3 equiv. of Cs₂CO₃ were used, the yield of the product was up to 43% (Entry 8). Then we continued to screen catalysts (Entries 9~13) and ligands (Entries 14~19). The results showed that the yield could reach 65% when using CuI as a catalyst and 2, 2'-bipyridine as a ligand (Entry 19). The screening result of organic solvents showed N, N-dimethylformamide (DMF) was the best choice in terms of product yield and reaction time (Entries 20~27). Finally, we found that the optimal conditions for this reaction were: benzothiazole (1a) (1.0 equiv.), diphenyliodonium tetrafluoroborate (2a) (1.0 equiv.), Cs₂CO₃ (3.0 equiv.), CuI (10 mol%), 10 mol% of bipyridine and 3 mL of DMF at 140 ℃ for 24 h and the best product yield was 86% (Entry 22).

  Table 1

  

  Table 1.  Optimization of the reaction conditions^a

  下载: 导出CSV

  Entry	Base (equiv.)	Catalyst	Ligand	Solvent	Temp./℃	Yield of 3a/%
  1	K2CO3 (1.0)	Cu	(o-tolyl)3P	CH3CN	80	NR
  2	K2CO3 (1.0)	CuI	(o-tolyl)3P	CH3CN	80	Trace
  3	K2CO3 (2.0)	CuI	(o-tolyl)3P	CH3CN	80	22
  4	Na2CO3 (2.0)	CuI	(o-tolyl)3P	CH3CN	80	10
  5	NaHCO3 (2.0)	CuI	(o-tolyl)3P	CH3CN	80	12
  6	K2PO4 (2.0)	CuI	(o-tolyl)3P	CH3CN	80	25
  7	Cs2CO3 (2.0)	CuI	(o-tolyl)3P	CH3CN	80	32
  8	Cs2CO3 (3.0)	CuI	(o-tolyl)3P	CH3CN	80	43
  9	Cs2CO3 (3.0)	CuBr	(o-tolyl)3P	CH3CN	80	trace
  10	Cs2CO3 (3.0)	CuCl	(o-tolyl)3P	CH3CN	80	NR
  11	Cs2CO3 (3.0)	Cu-MOF	(o-tolyl)3P	CH3CN	80	NR
  12	Cs2CO3 (3.0)	Fe2O3	(o-tolyl)3P	CH3CN	80	NR
  13	Cs2CO3 (3.0)	NiCl2(PPh3)2	(o-tolyl)3P	CH3CN	80	trace
  14	Cs2CO3 (3.0)	CuI	PPh3	CH3CN	80	28
  15	Cs2CO3 (3.0)	CuI	1, 10-Phenanthroline	CH3CN	80	31
  16	Cs2CO3 (3.0)	CuI	dppp	CH3CN	80	52
  17	Cs2CO3 (3.0)	CuI	TCHP	CH3CN	80	45
  18	Cs2CO3 (3.0)	CuI	dppe	CH3CN	80	47
  19	Cs2CO3 (3.0)	CuI	bpy	CH3CN	80	65
  20	Cs2CO3 (3.0)	CuI	bpy	DMSO	140	30
  21	Cs2CO3 (3.0)	CuI	bpy	1, 4-Dioxane	80	55
  22	Cs2CO3 (3.0)	CuI	bpy	DMF	140	86
  23	Cs2CO3 (3.0)	CuI	bpy	Toulene	80	72
  24	Cs2CO3 (3.0)	CuI	bpy	THF	80	26
  25	Cs2CO3 (3.0)	CuI	bpy	CH2Cl2	80	trace
  26	Cs2CO3 (3.0)	CuI	bpy	DCE	80	58
  27	Cs2CO3 (3.0)	CuI	bpy	Pyridine	115	trace
  a Reagents and conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (10 mol%), ligand (10 mol%), solvent (3 mL) at reflux temperature (140 ℃ for N, N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)) for 24 h. NR means no reaction. Yield is isolated yield. TCHP＝tricyclohexylphosphine, dppe＝bis(diphenylphosphino)ethane, bpy＝2, 2'-bipyridine.

  With the optimized reaction conditions in hand, the effect of different substituents of diaryliodonium salts on 2-arylation of benzothiazoles was investigated. Three symmetric diaryliodonium tetrafluoroborates bearing a variety of functional groups, such as 2-methyl, 4-bromo and 2-fluoro, on the aromatic ring worked well in the protocol to get the corresponding products in the yield of 72%, 81% and 78%, respectively (Table 2, Entries 2~4). When phenyl(2, 6-dimethylphenyl)iodonium salt was used in this reaction, 3a was formed exclusively in 63% yield. It may be due to the large steric hindrance of 2, 6-dimethylphenyl (Entry 5). Using (4-nitrophenyl)phenyliodonium salt as an arylating coupling partner, 2-(4-nitrophenyl)benzothiazole (3e) was formed in 69% yield and 3a was not observed in this reaction (Entry 6). However, when benzothiazole was treated with unsymmetrical (2-methylphenyl)phenyl- iodonium tetrafluoroborate and (2-fluorophenyl)phenyl- iodonium tetrafluoroborate respectively, two arylation products were obtained in total yield of about 80% (Entries 7 and 8). It is obvious that mixed arylation products will be obtained when electron and hindrance effect of substituents of unsymmetrical diaryliodonium salts are not manifest.

  Table 2

  

  Table 2.  Scope of diaryliodonium salts in arylation of 1a^a

  下载: 导出CSV

  Entry	Ar1	Ar2	3	Yield/%
  1	C6H5	C6H5		86
  2	2-MeC6H4	2-MeC6H4		72
  3	4-BrC6H4	4-BrC6H4		81
  4	2-FC6H4	2-FC6H4		78
  5	C6H5	2, 6-Me2C6H3	3a	63
  6	4-O2NC6H4	C6H5		59
  7	2-MeC6H4	C6H5	3a, 3b	55 (3a), 23 (3b)
  8	2-FC6H4	C6H5	3d, 3a	57 (3d), 21 (3a)
  a Reagents and conditions:1a (0.2 mmol), 2 (0.2 mmol), CuI (0.02 mmol), Cs2CO3 (0.6 mmol), bpy (0.02 mmol) in DMF (3 mL) at 140 ℃ for 24 h.

  Next, the scope and group tolerance of benzothiazoles were investigated. As seen from the results in Table 3, the different substituents attached to benzothiazole produced corresponding 2-arylation products 3f~3l in moderate to good yields (42%~83%). These substituents include alkyl, alkyloxy, halo atom and nitro group. Among of them, 6-ethoxybenzothiazole delivered the product 3l yield of 83% and 6-nitrobenzothiazole delivered 42% of 2-phenylation product 3h. Manifestly, both electron-deficient and electron-rich benzothiazoles can participate in the reaction, affording 2-arylbenzothiazole compounds in satisfactory yields, whereas electron-donating groups on benzothiazole ring are more beneficial for the reaction. The reason may be that electron-donating groups increase the electron cloud density of aromatic ring to improve the nucleophilicity of C(2) of benzothiazoles.

  Table 3

  

  Table 3.  2-Arylation of substituted benzothiazoles with 2a^a

  下载: 导出CSV

  Entry	R	3	Yield/%
  1	6-Me		71
  2	6-Br		70
  3	6-NO2		42
  4	6-Cl		68
  5	4, 6-Me2		58
  6	6-MeO		76
  7	6-EtO		83
  a Reagents and conditions: 1 (0.2 mmol), 2a (0.2 mmol), CuI (0.02 mmol), Cs2CO3 (0.6 mmol), and bpy (0.02 mmol) in DMF (3 mL) at 140 ℃ for 24 h. Yield is isolated yield.

  Finally, substituted benzothiazoles were encountered with various symmetric and unsymmetric diaryliodonium tetrafluoroborates under optimized reaction conditions and the results are summarized in Table 4. It can be seen that most of substrates can be smoothly converted into corresponding 2-arylation products in good yields. The reaction results of substituted benzothiazoles with phenyl(2, 6- dimethylphenyl)iodonium salt further confirmed that steric hindrances severely affected the reactivity and chemoselectivity of unsymmetrical diaryliodonium salts.

  Table 4

  

  Table 4.  Reaction of substituted benzothiazoles with various diaryliodonium salts^a

  下载: 导出CSV

  Entry	R	Ar1	Ar2	3	Yield/%
  1	4, 6-Me2	4-BrC6H4	4-BrC6H4		65
  2	4, 6-Me2	C6H5	2-FC6H4		78
  3	6-MeO	2-FC6H4	2-FC6H4		72
  4	6-Me	4-BrC6H4	4-BrC6H4		80
  5	6-Br	4-BrC6H4	4-BrC6H4		58
  6	6-MeO	4-BrC6H4	4-BrC6H4		70
  a Reagents and conditions: 1 (0.2 mmol), 2 (0.2 mmol), CuI (0.02 mmol), Cs2CO3 (0.6 mmol), bpy (0.02 mmol) in DMF (3 mL) at 140 ℃ for 24 h.

  Finally, a possible reaction mechanism for Cu-catalyzed direct arylation of benzothiazoles with diaryliodonium salts was proposed based on our experimental observations and previous literatures (Scheme 2).^[19,21-22] An initial cupration of benzothiazole (1a) with CuI in the presence of Cs₂CO₃ affords thiazolyl-copper species Ⅰ. Subsequent oxidative addition of Ⅰ to diphenyliodonium tetrafluoroborate delivers to an electrophilic Cu(Ⅲ)-aryl species Ⅱ with the removal of iodobenzene. Then product 3a is obtained upon reductive elimination of Ⅱ, and the Cu(Ⅰ) catalyst is released simutaneously.

  Scheme 2

  

  Scheme 2.  Proposed reaction mechanism for the arylation of benzothiazoles

  下载: 全尺寸图片 幻灯片

  3.   Conclusions

  In summary, a simple and low-cost copper-catalyzed C—H direct arylation of benzothiazoles with diaryliodonium salts as arylation reagents to synthesize 2-aryl- benzothiazoles was developed. This method shows wide scope of substrates and good group tolerance as well as high product yields.

  4.   Experimental section

  4.1   General information

  All of ¹H NMR and ¹³C NMR spectra were performed in 600 MHz and 150 MHz Bruker spectrometers (unless special instructions are used for 400 MHz and 100 MHz) and CDCl₃ was used as solvent and TMS as internal standard. All chemicals were used as received without further purification. All solvents were dried and degassed by standard methods before use. Reactions were monitored by thin- layer chromatography (TLC) and high performance liquid chromatography (HPLC).

  4.2   Experimental procedure for Cu-catalyzed direct arylation of benzothiazoles

  Catalyst (0.02 mmol, 10 mol%), ligand (0.02 mmol, 10 mol% for mono-P ligand; 0.01 mmol, 5 mol% for di-P ligand), benzothiazoles (0.2 mmol), diaryliodonium salts (0.2 mmol) and solvent (3.0 mL) were sequentially added into a 10 mL reaction tube, and the resulting mixture was stirred in a preheated oil bath at 140 ℃ for 24 h. Reaction mixture was cooled to room temperature and the solvent was removed in vacuum. The crude product was purified by column chromatography on silica gel (ethyl acetate/ dichloromethane/petroleum ether, V:V:V＝1:1:20) to give the desired 2-arylbenzothiazoles. The byproduct iodobenzene was recovered to prepare diaryliodonium salts.

  Phenylbenzothiazole (3a): White solid. m.p. 113~115 ℃ (lit.^[23] 110.5~111 ℃); ¹H NMR (600 MHz, CDCl₃) δ: 8.10 (dd, J＝2.4, 3.6 Hz, 3H), 7.90 (d, J＝7.6 Hz, 1H), 7.50~7.45 (m, 4H), 7.38 (t, J＝7.6 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 168.0, 154.2, 135.1, 133.6, 131.0, 130.9, 129.0, 128.8, 127.6, 126.3, 125.2, 123.2, 121.6.

  2-(2-Methylphenyl)benzothiazole (3b):^[24] Colorless solid. m.p. 56~58 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.11~8.04 (m, 2H), 7.98 (d, J＝7.6 Hz, 1H), 7.92~7.88 (m, 1H), 7.49 (d, J＝4.2 Hz, 2H), 7.40~7.35 (m, 1H), 7.30 (d, J＝7.8 Hz, 1H), 2.42 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 168.2, 154.2, 141.4, 134.9, 133.6, 129.7, 129.0, 127.5, 126.2, 125.0, 123.0, 121.6, 121.6, 21.5.

  2-(4-Bromophenyl)benzothiazole (3c): Colorless solid. m.p. 130~132 ℃ (lit.^[25] 129~131 ℃); ¹H NMR (600 MHz, CDCl₃) δ: 8.07 (d, J＝8.4 Hz, 1H), 7.96 (d, J＝8.4 Hz, 2H), 7.90 (d, J＝8.4 Hz, 1H), 7.63 (d, J＝8.4 Hz, 2H), 7.52~7.48 (m, 1H), 7.42~7.38 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 166.7, 154.1, 135.0, 133.8, 132.6, 132.2, 129.9, 128.9, 126.5, 125.4, 123.4, 123.3, 121.6.

  2-(2-Fluorophenyl)benzothiazole (3d): Light yellow solid. m.p. 67~68 ℃ (lit.^[26] 67~68 ℃); ¹H NMR (600 MHz, CDCl₃) δ: 8.42 (t, J＝7.8 Hz, 1H), 8.13 (d, J＝8.4 Hz, 1H), 7.95 (d, J＝7.8 Hz, 1H), 7.52 (t, J＝7.6 Hz, 1H), 7.48 (q, J＝13.8, 6.5 Hz, 1H), 7.42 (t, J＝7.6 Hz, 1H), 7.32 (t, J＝7.6 Hz, 1H), 7.25~7.21 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 161.4, 159.7 (d, J＝5.7 Hz), 152.6, 135.8 (d, J＝8.2 Hz), 132.1 (d, J＝8.7 Hz), 129.8 (d, J＝2.4 Hz), 126.3, 125.3, 124.7, 123.3, 121.5, 121.4, 116.3 (d, J＝22.0 Hz).

  2-(4-Nitrophenyl)benzothiazole (3e):^[27] Yellow solid. m.p. 229~230 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.36 (d, J＝8.4 Hz, 2H), 8.30 (d, J＝9.0 Hz, 2H), 7.80 (d, J＝8.4 Hz, 2H), 7.18 (d, J＝9.0 Hz, 2H); ¹³C NMR (150 MHz, CDCl₃) δ: 160.7, 148.0, 145.0, 144.2, 130.9, 128.8, 128.3, 126.2, 124.4, 124.4, 119.3.

  Methyl-2-phenylbenzothiazole (3f): White solid. m.p. 124~125 ℃ (lit.^[28] 126~128 ℃); ¹H NMR (600 MHz, CDCl₃) δ: 8.14~8.04 (m, 2H), 7.78 (d, J＝32.4 Hz, 1H), 7.68 (s, 1H), 7.63~7.60 (m, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 2.47 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 167.0, 152.3, 135.3, 135.2, 133.7, 130.7, 128.9, 128.8, 127.9, 127.6, 127.4, 122.7, 121.3, 21.5.

  6-Bromo-2-phenylbenzothiazole (3g):^[24] Pale brown solid. m.p. 151~152 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.11~8.01 (m, 3H), 7.95~7.89 (m, 1H), 7.59 (dd, J＝1.8, 2.4 Hz, 1H), 7.54~7.47 (m, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 167.2, 152.9, 139.2, 136.6, 132.3, 131.9, 130.0, 128.9, 128.6, 125.8, 124.4, 124.2, 119.0.

  6-Nitro-2-phenylbenzothiazole (3h):^[29] Pale orange solid. m.p. 190~192 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.84 (d, J＝2.4 Hz, 1H), 8.37 (dd, J＝9.0, 2.4 Hz, 1H), 8.14 (t, J＝7.6 Hz, 3H), 7.56 (dd, J＝12.8, 7.2 Hz, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 173.7, 157.8, 135.3, 132.7, 132.2, 129.3, 127.9, 123.3, 121.9, 118.2.

  6-Chloro-2-phenylbenzothiazole (3i): Light yellow solid. m.p. 157~158 ℃ (lit.^[24] 156~157 ℃); ¹H NMR (600 MHz, CDCl₃) δ: 8.06 (dd, J＝1.8, 3.6 Hz, 1H), 7.96 (d, J＝9.0 Hz, 1H), 7.87 (d, J＝1.8 Hz, 1H), 7.52~7.47 (m, 3H), 7.44 (dd, J＝1.8, 2.4 Hz, 1H), 7.33 (t, J＝7.8 Hz, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 168.5, 152.7, 136.2, 133.2, 131.2, 131.1, 129.7, 129.1, 127.5, 127.1, 123.9, 121.2, 118.9.

  4, 6-Dimethyl-2-phenylbenzothiazole (3j):^[30] Yellow solid. m.p. 188~191 ℃; ¹H NMR (400 MHz, CDCl₃) δ: 8.09 (d, J＝6.0 Hz, 2H), 7.51 (s, 1H), 7.47 (d, J＝5.2 Hz, 3H), 7.10 (s, 1H), 2.76 (s, 3H), 2.45 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 165.5, 151.7, 135.2, 135.1, 134.1, 132.7, 130.4, 129.7, 128.9, 128.8, 128.4, 127.4, 118.7, 21.5, 18.3.

  6-Methoxy-2-phenylbenzothiazole (3k): White solid. m.p. 113~114 ℃ (lit.^[31] 112~114 ℃); ¹H NMR (600 MHz, CDCl₃) δ: 8.07~8.02 (m, 2H), 7.97~7.93 (m, 1H), 7.50~7.44 (m, 3H), 7.35 (d, J＝3.0 Hz, 1H), 7.12~7.07 (m, 1H), 3.89 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 165.5, 157.8, 148.7, 136.4, 133.8, 130.9, 130.5, 128.9, 128.8, 127.2, 123.7, 115.6, 104.2, 55.8.

  6-Ethyoxyl-2-phenylbenzothiazole (3l): White solid. m.p. 113~115 ℃ (lit.^[32] 113~115 ℃); ¹H NMR (400 MHz, CDCl₃) δ: 8.87 (d, J＝8.4 Hz, 1H), 7.58 (d, J＝2.0 Hz, 1H), 7.44~7.38 (m, 2H), 7.35 (dd, J＝2.4, 2.4 Hz, 2H), 7.17 (q, J＝2.8 Hz, 1H), 6.59 (d, J＝2.0 Hz, 1H), 4.09 (q, J＝6.8 Hz, 2H), 1.46 (t, J＝7.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ: 157.6, 151.8, 146.2, 145.0, 135.5, 134.3, 134.2, 131.9, 129.6, 128.6, 119.5, 114.6, 104.3, 64.5, 14.7.

  2-(4-Bromophenyl)-4, 6-dimethylbenzothiazole (3m): White solid. m.p. 110~113 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.95 (dd, J＝1.2, 1.2 Hz, 2H), 7.63~7.58 (m, 2H), 7.51 (s, 1H), 7.11 (s, 1H), 2.75 (s, 3H), 2.45 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 164.1, 151.6, 147.2, 135.5, 135.2, 133.0, 132.8, 132.1, 128.7, 128.6, 126.0, 124.8, 118.7, 21.5, 18.3; HRMS (ESI) calcd. for C₁₅H₁₃BrNS (M+H)⁺ 317.9947, found 317.9944.

  4, 6-Dimethyl-2-(2-fluorophenyl)benzothiazole (3n): White solid. m.p. 122~124 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.45 (t, J＝7.2 Hz, 1H), 7.55 (s, 1H), 7.43 (q, J＝6.0 Hz, 1H), 7.30 (t, J＝7.6 Hz, 1H), 7.21 (dd, J＝8.4, 8.4 Hz, 1H), 7.13 (s, 1H), 2.78 (s, 3H), 2.46 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 161.3, 158.5 (d, J＝5.7 Hz), 150.1, 135.3 (d, J＝7.6 Hz), 132.7, 131.5 (d, J＝8.6 Hz), 129.7 (d, J＝2.6 Hz), 128.4, 124.6 (d, J＝3.4 Hz), 121.9 (d, J＝11.1 Hz), 121.8, 118.4, 116.2 (d, J＝21.9 Hz), 21.5, 18.2; HRMS (ESI) calcd for C₁₅H₁₃FNS (M+H)⁺ 258.0747, found 258.0744.

  2-(2-Flurophenyl)-6-methoxybenzothiazole (3o):^[33] Light yellow solid. m.p. 104~107 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.36 (t, J＝7.8 Hz, 1H), 7.99 (d, J＝9.0 Hz, 1H), 7.43 (dd, J＝6.6, 6.6 Hz, 1H), 7.37 (s, 1H), 7.28 (t, J＝7.6 Hz, 1H), 7.24~7.17 (m, 1H), 7.14~7.09 (m, 1H), 3.90 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 161.1, 159.5 (d, J＝5.8 Hz), 157.8, 147.2, 137.2 (d, J＝7.8 Hz), 131.6 (d, J＝8.7 Hz), 129.4 (d, J＝2.5 Hz), 124.6, 124.6, 123.8, 116.2, 116.0 (d, J＝21.9 Hz), 103.6, 55.8.

  2-(4-Bromophenyl)-6-methylbenzothiazole (3p):^[34] White solid. m.p. 156~159 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.87 (d, J＝8.4 Hz, 2H), 7.61 (d, J＝10.8 Hz, 2H), 7.55 (d, J＝3.0 Hz, 2H), 7.24 (d, J＝7.8 Hz, 1H), 2.43 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 135.7, 132.7, 132.2, 132.0, 131.9, 128.8, 128.1, 127.3, 125.1, 122.8, 121.4, 21.6.

  6-Bromo-2-(4-bromophenyl)benzothiazole (3q):^[33] Light yellow solid. m.p. 168~171 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 8.02 (s, 1H), 7.91 (dd, J＝7.8, 9.6 Hz, 2H), 7.64~7.57 (m, 3H), 7.52~7.46 (m, 1H); ¹³C NMR (150 MHz, CDCl₃) δ: 167.2, 152.9, 139.2, 136.6, 132.3, 131.9, 130.0, 128.9, 128.6, 125.8, 124.4, 124.2, 119.0.

  2-(4-Bromophenyl)-6-methoxybenzothiazole (3r): White solid. m.p. 137~140 ℃; ¹H NMR (600 MHz, CDCl₃) δ: 7.92 (dd, J＝9.0, 8.4 Hz, 2H), 7.61 (d, J＝7.8 Hz, 2H), 7.47 (dd, J＝7.8, 7.8 Hz, 1H), 7.35 (s, 1H), 7.10 (d, J＝8.4 Hz, 1H), 3.90 (s, 3H); ¹³C NMR (150 MHz, CDCl₃) δ: 164.1, 157.9, 148.6, 136.4, 132.7, 132.3, 132.1, 128.7, 128.6, 124.8, 123.8, 115.9, 104.1, 55.8; HRMS (ESI) calcd for C₁₄H₁₁BrOSN (M+H)⁺ 319.9739, found 319.9735.

  Supporting Information ¹H NMR and ¹³C NMR spectra of products 3a~3r. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

  
  
• 1. [1]

     Matysiak, J.; Skrzypek, A.; Głaszcz, U.; Matwijczuk, A.; Senczyna, B.; Wietrzyk, J.; Krajewska-Kułak, E.; Niewiadomy, A. Res. Chem. Intermed. 2018, 44, 6169. doi: 10.1007/s11164-018-3483-0
     

  2. [2]

     Choi, S.; Park, H.; Lee, S.; Kim, S.; Hanc G.; Choo, H. Bioorg. Med. Chem. 2006, 14, 1229. doi: 10.1016/j.bmc.2005.09.051
     

  3. [3]

     Guo, H.; Li, J.; Shang, Y. Chin. Chem. Lett. 2009, 20, 1408. doi: 10.1016/j.cclet.2009.06.037
     

  4. [4]

     Benazzouz, A.; Boraud, T.; Dubédat, P.; Boireau, A.; Stutzmann, J.; Gross, C. Eur. J. Pharmacol. 1995, 284, 299. doi: 10.1016/0014-2999(95)00362-O
     

  5. [5]

     Bheeter, C. B.; Chen, L.; Soulé, J.-F.; Doucet, H. Catal. Sci. Technol. 2016, 6, 2005. doi: 10.1039/C5CY02095F
     

  6. [6]

     (a) Hu, R.; Li, X.; Tong, Y.; Miao, D.; Pan, Q.; Jiang, Z.; Gan, H.; Han, S. Synlett 2016, 27, 1387.
     (b) Yuen, O. Y.; So, C. M.; Wong, W. T.; Kwong, F. Y. Synlett 2013, 1549.
     (c) Nagao, I.; Ishizaka T.; Kawanami, H. Green Chem. 2016, 18, 3494.
     

  7. [7]

     (a) Zhang, G.; Liu, C.; Yi, H.; Meng, Q.; Bian, C.; Chen, H.; Jian, J.; Wu, L.; Lei, A. J. Am. Chem. Soc. 2015, 137, 9273.
     (b) Inamoto, K.; Nozawa, K.; Kondo, Y. Synlett 2012, 1678.
     (c) Inamoto, K.; Hasegawa, C.; Kawasaki, J.; Hiroya, K.; Dohi, T. Adv. Synth. Catal. 2010, 352, 2643.
     (d) Urzua, J. I.; Contreras, R.; Salas, C. O.; Tapia, R. A. RSC Adv. 2016, 6, 82401.
     (e) Wang, P.; Tang, S. Green Chem. 2017, 19, 2092.
     (f) Xu, Z.; Li, H.; Li, D. H.; Lang. J. Org. Lett. 2019, 21, 237.
     

  8. [8]

     (a) Huang, C.; Wu, J.; Song, C.; Ding, R.; Qiao, Y.; Hou, H.; Chang, J.; Fan, Y. Chem. Commun. 2015, 51, 10353.
     (b) Kirchberg, S.; Tani, S.; Ueda, K.; Yamaguchi, J.; Studer, A.; Itami, K. Angew. Chem., Int. Ed. 2011, 50, 2387.
     (c) Zhang, F.; Greaney. M. Angew. Chem., Int. Ed. 2010, 49, 2768.
     (d) Khake, S. M.; Soni, V.; Gonnade, B. R.; Punji, B. Dalton Trans. 2014, 43, 16084.
     (e) Yang, J. Tetrahedron 2019, 75, 2182.
     (f) Liu, C.; Yang, F. Chin. J. Chem. 2016, 34, 1213.
     (g) Feng, J.; Li, B.; Jiang, J. Chin. J. Chem. 2018, 36, 11.
     

  9. [9]

     (a) Wirth, T. Angew. Chem., Int. Ed. 2005, 44, 3656.
     (b) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052.
     

  10. [10]

      (a) Wirth, T. Angew. Chem., Int Ed. 2001, 40, 2812.
      (b) Cai, Q.; Ma, H. Acta Chim. Sinica 2019, 77, 213(in Chinese). (蔡倩, 马浩文, 化学学报, 2019, 77, 213.)
      (c) Wang, M.; Jiang, X. Acta Chim. Sinica 2018, 76, 377(in Chinese). (王明, 姜雪峰, 化学学报, 2018, 76, 377.)
      

  11. [11]

      Kalyani, D.; Deprez, N. R.; Desai, N. R.; Sanford, L. V.; Kalyani, D.; Deprez, N. R.; Desai, L.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. doi: 10.1021/ja051402f
      

  12. [12]

      Wu, X.; Yang, Y.; Han, J.; Wang, L. Org. Lett. 2015, 17, 5654. doi: 10.1021/acs.orglett.5b02938
      

  13. [13]

      Suero, M. G.; Bayle, E. D.; Collins, B. L.; Gaunt, M. J. Am. Chem. Soc. 2013, 135, 5332. doi: 10.1021/ja401840j
      

  14. [14]

      Margraf, N.; Manolikakes, G. J. Org. Chem. 2015, 80, 2582. doi: 10.1021/jo5027518
      

  15. [15]

      Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn, J. Angew. Chem., Int. Ed. 2011, 50, 8605. doi: 10.1002/anie.201102984
      

  16. [16]

      Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. doi: 10.1021/ja801767s
      

  17. [17]

      Qian, X.; Han, J.; Wang, L. Tetrahedron Lett. 2016, 57, 607. doi: 10.1016/j.tetlet.2015.12.100
      

  18. [18]

      Zhu, D.; Liu, P.; Lu, W.; Wang, H.; Luo, B.; Hu, Y.; Huang, P.; Wen, S. Chem.-Eur. J. 2015, 21, 18915. doi: 10.1002/chem.201503791
      

  19. [19]

      Yang, P.; Wang, R.; Wu, H.; Du, Z.; Fu, Y. Asian J. Org. Chem. 2017, 6, 184. doi: 10.1002/ajoc.201600514
      

  20. [20]

      Gang, F.; Che, Y.; Du, Z.; Feng, H.; Fu, Y. Synlett 2017, 28, 1624. doi: 10.1055/s-0036-1588815
      

  21. [21]

      (a) Zhang, W.; Dong, T.; Wang, T.; Du, Z. J. Liaocheng Univ. (Nat. Sci. Ed.) 2019, 32, 35(in Chinese).
      (张文莹, 董涛生, 王天昀, 杜正银, 聊城大学学报(自然科学版), 2019, 32, 35.)
      (b) Hu, B.; Zhang, Y.; Wang, T.; Du, Z. J. Liaocheng Univ. (Nat. Sci. Ed.) 2020, 33, 67(in Chinese).
      (胡贝, 张源民, 王天昀, 杜正银, 聊城大学学报(自然科学版), 2020, 33, 67.)
      (c) Gang, F.; Xu, G.; Dong, T.; Yang, L.; Du, Z. Chin. J. Org. Chem. 2015, 35, 1428(in Chinese).
      (刚芳莉, 徐光利, 董涛生, 杨丽, 杜正银, 有机化学, 2015, 35, 1428.)
      

  22. [22]

      (a) Kumar, D.; Pilania, M.; Arun, V.; Pooniya, S. Org. Biomol. Chem. 2014, 12, 6340.
      (b) Zhou, B.; Hou, W.; Yang, Y.; Feng, H.; Li, Y. Org. Lett. 2014, 16, 1322.
      

  23. [23]

      Deng, H.; Li, Z.; Ke, F.; Zhou, X. Chem.-Eur. J. 2012, 18, 4840. doi: 10.1002/chem.201103525
      

  24. [24]

      Yang, Z.; Chen, X.; Wang, S.; Liu, J.; Xie, K.; Wang, A.; Tan, Z. J. Org. Chem. 2012, 77, 7086. doi: 10.1021/jo300740j
      

  25. [25]

      Duan, Z.; Ranjit, S.; Liu, X. Org. Lett. 2010, 12, 2430. doi: 10.1021/ol100816g
      

  26. [26]

      Song, Q.; Feng, Q.; Zhou, M. Org. Lett. 2013, 15, 5990. doi: 10.1021/ol402871f
      

  27. [27]

      Pratap, U. R.; Mali, J. R.; Jawale, D. W.; Mane, R. A. Tetrahedron Lett. 2009, 50, 1352. doi: 10.1016/j.tetlet.2009.01.032
      

  28. [28]

      Prasad, D.; Sekar, G. Org. Lett. 2011, 13, 1008. doi: 10.1021/ol103041s
      

  29. [29]

      Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10, 5147. doi: 10.1021/ol802033p
      

  30. [30]

      Alla, S. K.; Sadhu, P.; Punniyamurthy, T. J. Org. Chem. 2014, 79, 7502. doi: 10.1021/jo501216h
      

  31. [31]

      Liu, S.; Chen, R.; Guo, X.; Yang, H.; Deng, G.; Li. C. Green Chem. 2012, 14, 1577. 
      

  32. [32]

      Auld, D. S.; Zhang, Y. Q.; Southal, N. T.; Rai, G.; Landsman, M.; MacLure, D.; Langevin, C. J.; Thomas, C. P.; Inglese, J. J. Med. Chem. 2009, 52, 1450. doi: 10.1021/jm8014525
      

  33. [33]

      Weekes. A. A.; Bagley, M. C.; Westwell, A. D. Tetrahedron 2011, 67, 7743. doi: 10.1016/j.tet.2011.08.004
      

  34. [34]

      Sayama, S. Heterocycles 2011, 83, 1267. doi: 10.3987/COM-11-12178
      

• 

  Figure 1  Representative bioactive 2-arylbenzothiazole compounds

  下载: 全尺寸图片 幻灯片
  

  Scheme 1  Synthetic methods of 2-arylbenzothiazoles

  下载: 全尺寸图片 幻灯片
  

  Scheme 2  Proposed reaction mechanism for the arylation of benzothiazoles

  下载: 全尺寸图片 幻灯片

  Table 1.  Optimization of the reaction conditions^a

  Entry	Base (equiv.)	Catalyst	Ligand	Solvent	Temp./℃	Yield of 3a/%
  1	K2CO3 (1.0)	Cu	(o-tolyl)3P	CH3CN	80	NR
  2	K2CO3 (1.0)	CuI	(o-tolyl)3P	CH3CN	80	Trace
  3	K2CO3 (2.0)	CuI	(o-tolyl)3P	CH3CN	80	22
  4	Na2CO3 (2.0)	CuI	(o-tolyl)3P	CH3CN	80	10
  5	NaHCO3 (2.0)	CuI	(o-tolyl)3P	CH3CN	80	12
  6	K2PO4 (2.0)	CuI	(o-tolyl)3P	CH3CN	80	25
  7	Cs2CO3 (2.0)	CuI	(o-tolyl)3P	CH3CN	80	32
  8	Cs2CO3 (3.0)	CuI	(o-tolyl)3P	CH3CN	80	43
  9	Cs2CO3 (3.0)	CuBr	(o-tolyl)3P	CH3CN	80	trace
  10	Cs2CO3 (3.0)	CuCl	(o-tolyl)3P	CH3CN	80	NR
  11	Cs2CO3 (3.0)	Cu-MOF	(o-tolyl)3P	CH3CN	80	NR
  12	Cs2CO3 (3.0)	Fe2O3	(o-tolyl)3P	CH3CN	80	NR
  13	Cs2CO3 (3.0)	NiCl2(PPh3)2	(o-tolyl)3P	CH3CN	80	trace
  14	Cs2CO3 (3.0)	CuI	PPh3	CH3CN	80	28
  15	Cs2CO3 (3.0)	CuI	1, 10-Phenanthroline	CH3CN	80	31
  16	Cs2CO3 (3.0)	CuI	dppp	CH3CN	80	52
  17	Cs2CO3 (3.0)	CuI	TCHP	CH3CN	80	45
  18	Cs2CO3 (3.0)	CuI	dppe	CH3CN	80	47
  19	Cs2CO3 (3.0)	CuI	bpy	CH3CN	80	65
  20	Cs2CO3 (3.0)	CuI	bpy	DMSO	140	30
  21	Cs2CO3 (3.0)	CuI	bpy	1, 4-Dioxane	80	55
  22	Cs2CO3 (3.0)	CuI	bpy	DMF	140	86
  23	Cs2CO3 (3.0)	CuI	bpy	Toulene	80	72
  24	Cs2CO3 (3.0)	CuI	bpy	THF	80	26
  25	Cs2CO3 (3.0)	CuI	bpy	CH2Cl2	80	trace
  26	Cs2CO3 (3.0)	CuI	bpy	DCE	80	58
  27	Cs2CO3 (3.0)	CuI	bpy	Pyridine	115	trace
  a Reagents and conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (10 mol%), ligand (10 mol%), solvent (3 mL) at reflux temperature (140 ℃ for N, N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO)) for 24 h. NR means no reaction. Yield is isolated yield. TCHP＝tricyclohexylphosphine, dppe＝bis(diphenylphosphino)ethane, bpy＝2, 2'-bipyridine.

  下载: 导出CSV

  Table 2.  Scope of diaryliodonium salts in arylation of 1a^a

  Entry	Ar1	Ar2	3	Yield/%
  1	C6H5	C6H5		86
  2	2-MeC6H4	2-MeC6H4		72
  3	4-BrC6H4	4-BrC6H4		81
  4	2-FC6H4	2-FC6H4		78
  5	C6H5	2, 6-Me2C6H3	3a	63
  6	4-O2NC6H4	C6H5		59
  7	2-MeC6H4	C6H5	3a, 3b	55 (3a), 23 (3b)
  8	2-FC6H4	C6H5	3d, 3a	57 (3d), 21 (3a)
  a Reagents and conditions:1a (0.2 mmol), 2 (0.2 mmol), CuI (0.02 mmol), Cs2CO3 (0.6 mmol), bpy (0.02 mmol) in DMF (3 mL) at 140 ℃ for 24 h.

  下载: 导出CSV

  Table 3.  2-Arylation of substituted benzothiazoles with 2a^a

  Entry	R	3	Yield/%
  1	6-Me		71
  2	6-Br		70
  3	6-NO2		42
  4	6-Cl		68
  5	4, 6-Me2		58
  6	6-MeO		76
  7	6-EtO		83
  a Reagents and conditions: 1 (0.2 mmol), 2a (0.2 mmol), CuI (0.02 mmol), Cs2CO3 (0.6 mmol), and bpy (0.02 mmol) in DMF (3 mL) at 140 ℃ for 24 h. Yield is isolated yield.

  下载: 导出CSV

  Table 4.  Reaction of substituted benzothiazoles with various diaryliodonium salts^a

  Entry	R	Ar1	Ar2	3	Yield/%
  1	4, 6-Me2	4-BrC6H4	4-BrC6H4		65
  2	4, 6-Me2	C6H5	2-FC6H4		78
  3	6-MeO	2-FC6H4	2-FC6H4		72
  4	6-Me	4-BrC6H4	4-BrC6H4		80
  5	6-Br	4-BrC6H4	4-BrC6H4		58
  6	6-MeO	4-BrC6H4	4-BrC6H4		70
  a Reagents and conditions: 1 (0.2 mmol), 2 (0.2 mmol), CuI (0.02 mmol), Cs2CO3 (0.6 mmol), bpy (0.02 mmol) in DMF (3 mL) at 140 ℃ for 24 h.

  下载: 导出CSV
•