Cu-Catalyzed Direct Arylation of Benzothiazoles with Diaryliodonium Salts

Huaigui Li Peng Yang Zheng Xu Zhengyin Du Ying Fu

Citation:  Li Huaigui, Yang Peng, Xu Zheng, Du Zhengyin, Fu Ying. Cu-Catalyzed Direct Arylation of Benzothiazoles with Diaryliodonium Salts[J]. Chinese Journal of Organic Chemistry, 2020, 40(8): 2476-2482. doi: 10.6023/cjoc202002042 shu

铜催化苯并噻唑与二芳基碘鎓盐的芳基化反应

    通讯作者: 杜正银, clinton_du@126.com
    傅颖, fu_yingmail@126.com
  • 基金项目:

    国家自然科学基金 21762040

    国家自然科学基金 21762039

    国家自然科学基金 21262028

    国家自然科学基金(Nos.21262028,21762039,21762040)资助项目

摘要: 二芳基碘盐具有毒性低、反应条件温和及选择性高的优点,在有机合成中一直受到关注,已被广泛用作芳基化试剂,可用于芳杂环化合物的交叉偶联反应和芳基化反应等.发展了一种铜催化下苯并噻唑与二芳基碘鎓盐反应合成2-芳基苯并噻唑衍生物的方法.该方法具有底物范围广泛、基团耐受性良好及产率高等优点.

English

  • 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

    Scheme 1

    Scheme 1.  Synthetic methods of 2-arylbenzothiazoles

    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.

    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 conditionsa
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    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 1aa
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    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 2aa
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    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 saltsa
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    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 . Subsequent oxidative addition of to diphenyliodonium tetrafluoroborate delivers to an electrophilic Cu(Ⅲ)-aryl species with the removal of iodobenzene. Then product 3a is obtained upon reductive elimination of , and the Cu(Ⅰ) catalyst is released simutaneously.

    Scheme 2

    Scheme 2.  Proposed reaction mechanism for the arylation of benzothiazoles

    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.

    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).

    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.


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  • Figure 1  Representative bioactive 2-arylbenzothiazole compounds

    Scheme 1  Synthetic methods of 2-arylbenzothiazoles

    Scheme 2  Proposed reaction mechanism for the arylation of benzothiazoles

    Table 1.  Optimization of the reaction conditionsa

    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 1aa

    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 2aa

    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 saltsa

    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.
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  • 发布日期:  2020-08-01
  • 收稿日期:  2020-02-29
  • 修回日期:  2020-05-10
  • 网络出版日期:  2020-05-19
通讯作者: 陈斌, bchen63@163.com
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