Supporting Information. High-Throughput Screening Protocol for the Coupling Reactions of Aryl Halides Using a Colorimetric Chemosensor for Halide Ions

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1 Supporting Information High-Throughput Screening Protocol for the Coupling Reactions of Aryl Halides Using a Colorimetric Chemosensor for Halide Ions Min Sik Eom, a Jieun Noh b, Han-Sung Kim b, Soyeon Yoo, a Min Su Han a* and Sunwoo Lee b* a Department of Chemistry, Gwangju Institute of Science and Technology (GIST), 61005, Republic of Korea b Department of Chemistry, Chonnam National University, Gwangju, 61186, Republic of Korea List of Contents S1. Chemical and Apparatus S2 S2. Preparation of PAR-2Hg 2+ sensor S2 S3. Job Plot between PAR and Hg 2+ S2 S4. Plot between the absorbance and the concentration of iodide and chloride S3 S5. Preparation of sample solutions of reaction mixtures for HTS S5 S6. Procedure for results obtained in Table 1 S5 S7. Procedure of Williamson Ether Synthesis S10 S8. The C-H activated coupling reaction with 4-bromotoluene S12 Spectral Copies of 1H and 13C NMR of the Compounds S18 S1

2 S1. Chemicals and Apparatus All chemicals used were of analytical grade or of the highest purity available. All chemicals purchased from Sigma Aldrich (USA). Milli-Q water was used to prepare all the solutions in this study. UV/Vis spectrometry was carried out with S-3100 purchased from SCINCO. S2. Preparation of PAR-2Hg 2+ sensor The 500 L of PAR solution (100 M) in ethanol was diluted with 200 μl of the sodium phosphate buffer (50 mm, ph 7.2 Tween %) and then 100 μl amount of freshly prepared Hg(NO 3 ) 2 solution in distilled water (1 mm) was added to this solution. So that final concentrations of PAR and Hg(NO 3 ) 2 were 62.5 μm and 125 μm respectively. S3 Job Plot between PAR and Hg 2+ Figure S1. Job plot for binding mode between PAR and Hg 2+ in ph 7.2 sodium phosphate buffer 0.01M (EtOH: H 2 O = 1:1, Tween %). Solutions of PAR (50 M) were mixed with solutions of Hg 2+ (50 M) at varying ratios, and the absorbance changes of the solutions were measured at 408 nm. S2

S4. Plot between the absorbance and the concentration of iodide and chloride S4-1. Iodine titration Figure S2.

01 M (EtOH: H 2 O = 1:1, Tween 20 0.1%) containing PAR (50 μm) and Hg 2+ (100 μm).

A) Absorbance spectra were measured by addition of various concentrations of Cl - to ph 7.2 phosphate buffer solution 0.

3 S4. Plot between the absorbance and the concentration of iodide and chloride S4-1. Iodine titration Figure S2. A) Absorbance spectra were measured by addition of various concentrations of I - to ph 7.2 phosphate buffer solution 0.01 M (EtOH: H 2 O = 1:1, Tween %) containing PAR (50 μm) and Hg 2+ (100 μm). B) Plot of absorbance intensities at 408 nm versus various concentrations of I -. S4-2. Chloride titration Figure S3. A) Absorbance spectra were measured by addition of various concentrations of Cl - to ph 7.2 phosphate buffer solution 0.01 M (EtOH: H 2 O = 1:1, Tween %) containing PAR (50 μm) and Hg 2+ (100 μm). B) Plot of absorbance intensities at 408 nm versus various concentrations of Cl -. S3

S4-3. Selectivity assay for I - Figure S4. A) Absorbance spectra at 408 nm were measured by addition of various anions (0.2 mm) to ph 7.2 phosphate buffer solution 0.

B) Absorbance spectra at 408 nm of PAR- 2Hg 2+ sensor in the presence of various anions. S4-4. Selectivity assay for Cl - Figure S5.

4 S4-3. Selectivity assay for I - Figure S4. A) Absorbance spectra at 408 nm were measured by addition of various anions (0.2 mm) to ph 7.2 phosphate buffer solution 0.01 M (EtOH: H 2 O = 1:1, Tween %) containing PAR (50 μm) and Hg 2+ (100 μm). B) Absorbance spectra at 408 nm of PAR- 2Hg 2+ sensor in the presence of various anions. S4-4. Selectivity assay for Cl - Figure S5. A) Absorbance spectra were measured by addition of various anions (30 mm) to ph 7.2 phosphate buffer solution 0.01 M (EtOH: H 2 O = 1:1, Tween %) containing PAR (50 μm) and Hg 2+ (100 μm). B) Absorbance spectra at 408 nm of PAR-2Hg 2+ sensor in the presence of various anions S4

5 S5. Preparation of sample solutions of reaction mixtures for HTS All reactions tested were carried out with 0.3 mmol of aryl halide in 1 ml solvent. After completing the reactions, distilled water and EtOAc (1:5) was added to the reaction mixture to extract halide ions. With the assumption of all halide ions extracted from the reaction mixture, the extracted solutions were diluted with calculated amount of distilled water to obtain final concentrations of I - (1 mm), Br - (5 mm), and Cl - (150 mm) respectively. 200 µl of the samples were added to 800 L of ph 7.2 phosphate buffer solution 12.5 mm (EtOH: H 2 O = 1:1, Tween %) containing PAR (62.5 μm) and Hg 2+ (125 μm). The resulting sample was analyzed via UV/Vis spectrometry. The absorbance intensities of all samples were recorded at 408nm 30min after the preparation of sample. All conversion extents were determined from titration curve, obtained from the standard samples. S6. Procedure for results obtained in Table 1 S6-1. Suzuki coupling with aryl iodide 4-iodotoluene ( mg, 1.0 mmol) and phenylboronic acid ( mg, 1.0 mmol) were dissolved in 2.0 ml of dimethyl sulfoxide (DMSO) followed by the addition of Pd(OAc) 2 (1.12 mg, mmol), ligand (0.01 mmol) and K 2 CO 3 ( mg, 1.5 mmol), subsequently. The glass vial should be capped. The reaction mixture was heated and stirred at 80 o C for 3 h. S6-2. Suzuki coupling with aryl bromide 4-bromoanisole (93.52 mg, 0.5 mmol) and phenylboronic acid (60.95 mg, 0.5 mmol) were dissolved in 1.0 ml of dimethylformamide (DMF) followed by the addition of Pd(OAc) 2 (1.12 mg, mmol), ligand (0.01 mmol) and Cs 2 CO 3 ( mg, 0.75 mmol), subsequently. The glass vial should be capped. The reaction mixture was heated and stirred at 110 o C for 3 h. S6-3. Suzuki coupling with aryl chloride 4-chloronitrile ( mg, 1.0 mmol) and phenylboronic acid ( mg, 1.0 mmol) were dissolved in 2.0 ml of tetrahydrofuran (THF) followed by the addition of Pd(OAc) 2 (1.12 mg, mmol), ligand (0.01 mmol) and KOAc ( mg, 1.5 mmol), subsequently. The glass vial should be capped. The reaction mixture was heated and stirred at 80 o C for 3 h. S5

6 Figure S6. Correlation between GC conversion and UV conversion in Table 1. Table S1. Conversion Data from the coupling reactions in Figure 2 entry sample Sub. Ligand Base S6 Abs. [a] conv. UV (%) [b] conv. GC (%) [c] Deviation [d] 1 A1 7 L1 K 3 PO A2 7 L2 K 3 PO A3 7 L3 K 3 PO A4 7 L4 K 3 PO A5 7 L5 K 3 PO A6 7 L6 K 3 PO A7 7 L7 K 3 PO A8 7 L8 K 3 PO A9 7 L9 K 3 PO A10 7 L10 K 3 PO A11 7 L11 K 3 PO A12 7 L12 K 3 PO B1 7 L6 K 3 PO B2 7 L6 K 2 HPO B3 7 L6 Na 3 PO B4 7 L6 K 2 CO B5 7 L6 KHCO B6 7 L6 Na 2 CO B7 7 L6 NaHCO B8 7 L6 KOAc [e] B9 7 L6 [e] Cs 2 CO B10 7 L6 NaOAc B11 7 L6 Pyridine

7 24 B12 7 L6 morpholine C1 8 L1 Cs 2 CO C2 8 L2 Cs 2 CO C3 8 L3 Cs 2 CO C4 8 L4 Cs 2 CO C5 8 L5 Cs 2 CO C6 8 L6 Cs 2 CO C7 8 L7 Cs 2 CO C8 8 L8 Cs 2 CO C9 8 L9 Cs 2 CO C10 8 L10 Cs 2 CO C11 8 L11 Cs 2 CO C12 8 L12 Cs 2 CO D1 8 L6 K 3 PO D2 8 L6 K 2 HPO D3 8 L6 Na 3 PO D4 8 L6 K 2 CO D5 8 L6 KHCO D6 8 L6 Na 2 CO D7 8 L6 NaHCO D8 8 L6 Cs 2 CO D9 8 L6 KOAc D10 8 L6 NaOAc D11 8 L6 Pyridine D12 8 L6 morpholine E1 9 L1 Cs 2 CO E2 9 L2 Cs 2 CO E3 9 L3 Cs 2 CO E4 9 L4 Cs 2 CO E5 9 L5 Cs 2 CO E6 9 L6 Cs 2 CO E7 9 L7 Cs 2 CO E8 9 L8 Cs 2 CO E9 9 L9 Cs 2 CO E10 9 L10 Cs 2 CO E11 9 L11 Cs 2 CO E12 9 L12 Cs 2 CO F1 9 L11 K 3 PO F2 9 L11 K 2 HPO F3 9 L11 Na 3 PO F4 9 L11 K 2 CO F5 9 L11 KHCO F6 9 L11 Na 2 CO F7 9 L11 NaHCO F8 9 L11 Cs 2 CO F9 9 L11 KOAc S7

70 F10 9 L11 NaOAc 0.6161 9 9 0 71 F11 9 L11 Pyridine 0.3866 0 14 14 72 F12 9 L11 morpholine 0.3360 0 6 6 73 G1 10 L1 K 3 PO 4 0.7344 15 24 9 74 G2 10 L2 K 3 PO 4 0.

8 70 F10 9 L11 NaOAc F11 9 L11 Pyridine F12 9 L11 morpholine G1 10 L1 K 3 PO G2 10 L2 K 3 PO G3 10 L3 K 3 PO G4 10 L4 K 3 PO G5 10 L5 K 3 PO G6 10 L6 K 3 PO G7 10 L7 K 3 PO G8 10 L8 K 3 PO G9 10 L9 K 3 PO G10 10 L10 K 3 PO G11 10 L11 K 3 PO G12 10 L12 K 3 PO H1 10 L7 K 3 PO H2 10 L7 K 2 HPO H3 10 L7 Na 3 PO H4 10 L7 K 2 CO H5 10 L7 KHCO H6 10 L7 Na 2 CO H7 10 L7 NaHCO H8 10 L7 Cs 2 CO H9 10 L7 KOAc H10 10 L7 NaOAc H11 10 L7 Pyridine H12 10 L7 morpholine [a] Absorbance at 408 nm. [b] Conversion from UV absorbance. [c] Conversion from GC analysis. [d] {GC conversion}-{uv conversion}. [e] The order was different from the others a) S8

in Figure 2. b) The experimental results in Figure 2. Figure S8.

9 b) Figure S7. a) The expected colors of samples which are defined from the GC conversion data of reactions in Figure 2. b) The experimental results in Figure 2. Figure S8. Absorbance spectra at 408 nm were measured by addition of diluted reaction mixture to ph 7.2 phosphate buffer solution 0.01 M (EtOH: H 2 O = 1:1, Tween %) containing PAR (50 µm) and Hg 2+ (100 µm). S9

After 2 h reaction, distilled water and EtOAc (1:5) was added to the reaction mixture to extract halide

10 S7 Procedure of Williamson Ether Synthesis Alkyl chloride (1.0 mmol), phenol derivative (1.1 mmol) and base (1.1 mmol) were stirred in solvent (3.0 ml) at 100 oc for 2h. After 2 h reaction, distilled water and EtOAc (1:5) was added to the reaction mixture to extract halide ions. Scheme S1 Reaction of Williamson ether synthesis from alkyl chloride Figure S9. The detected color in the experimental results of Table S2 S10

Figure S10. Correlation between absorbance and the concentration of chloride. Table S2 The results of Williamson ether synthesis in Scheme S1 Entry RCl ArOH Cond. Abs. [a] UV conv. (%) [b] conv.

11 Figure S10. Correlation between absorbance and the concentration of chloride. Table S2 The results of Williamson ether synthesis in Scheme S1 Entry RCl ArOH Cond. Abs. [a] UV conv. (%) [b] conv. GC Dev. [d] (%) [c] Product Yield(%) [e] 1 S-1 S-A a S-1A 97 2 S-1 S-A b S-1A 88 3 S-1 S-B a S-1B 96 4 S-1 S-B b S-1B 80 5 S-1 S-C a S-1C 99 6 S-1 S-C b S-1C 77 7 S-2 S-A a S-2A trace 8 S-2 S-A b S-2A 10 9 S-2 S-B a S-2B S-2 S-B b S-2B S-2 S-C a S-2C S-2 S-C b S-2C S-3 S-A a S-3A S-3 S-A b S-3A S-3 S-B a S-3B S-3 S-B b S-3B S-3 S-C a S-3C S-3 S-C b S-3C 98 [a] Absorbance at 408 nm. [b] Conversion from UV absorbance. [c] Conversion from GC analysis. [d] {GC conversion}-{uv conversion}. [e] Determined by GC with internal standard. S11

12 S8. The C H activated coupling reaction with 4-bromotoluene Table S3. C H activated coupling reactions with azole and 4-bromotoluene Entry substrate Condition (ligand/base) Conv. Product 1 7 I (dppbz/k 3 PO 4 ) 99 12a II (dppbz/cs 2 CO 3 ) 99 13a III (phen/cs 2 CO 3 ) a IV (Xantphos/K 3 PO 4 ) 99 15a 69 Yield [a] Reaction condition : azoles (3.0 mmol), 11a (3.0 mmol), Pd(OAc) 2 (0.15 mmol), ligand (0.3 mmol), t-bucooh (0.3 mmol), and base (6.0 mmol) were reacted in DMF (10.0 ml) at 120 o C for 15 h. [b] Determined by gas chromatography with internal standard. [c] Isolated yield. (%) c S8-1. General procedure of coupling reaction Heteroaromatic substrates (3.0 mmol) and aryl bromides (3.0 mmol) were dissolved in 10.0 ml of dimethylformamide (DMF) followed by the addition of Pd(OAc) 2 (33.68 mg, 0.15 mmol), ligand (0.3 mmol), base (6.0 mmol) and pivalic acid (30.64 mg, 0.3 mmol). The glass vial should be capped. The reaction mixture was heated and stirred at 120 o C for 15 h. The crude was purified by flash column chromatography on silica gel (eluent : ethyl acetate/hexane = 4/1). S8-2. Coupling with benzoxazole and aryl bromides Benzoxazole ( mg, 3.0 mmol) and aryl bromides (3.0 mmol) were dissolved in 10.0 ml of dimethylformamide (DMF) followed by the addition of Pd(OAc) 2 (33.68 mg, 0.15 mmol), 1,2-bis(diphenylphosphino)benzene (dppbz, mg, 0.3 mmol), K 3 PO 4 ( mg, 6.0 mmol) and pivalic acid (30.64 mg, 0.3 mmol). The glass vial should be capped. The reaction mixture was heated and stirred at 120 o C for 15 h. 2-p-tolylbenzo[d]oxazole (12a) S12

13 4-Bromotoluene (513 mg, 3.0 mmol) provided 12a (577 mg, 2.76 mmol, 92% yield) as white solid. Mp: ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 8.15 (d, J = 8.2 Hz, 2H), (m, 1H), (m, 1H), (m, 4H), 2.45 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 163.2, 150.6, 142.1, 129.6, 127.5, 124.8, 124.4, 119.8, 110.5, (benzo[d]oxazol-2-yl)benzonitrile (12b) 4-Bromobenzonitrile (546 mg, 3.0 mmol) provided 12b (601 mg, 2.73 mmol, 91%) as a white solid. Mp: 205~206 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 8.35 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 8.7 Hz, 3H), 7.61 (d, J = 9.3 Hz, 1H), (m, 2H); 13 C NMR (75 MHz, CDCl 3 ) δ 160.8, 150.8, 141.8, 132.6, 131.1, 127.9, 126.1, 125.1, 120.5, 118.1, 114.7, (benzo[d]oxazol-2-yl)phenyl)ethanone (12c) 4 -Bromoacetophenone (597 mg, 3.0 mmol) provided 12c (491 mg, 2.07 mmol, 69%) as a white solid. Mp: 97~98 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 8.34 (d, J = 8.7 Hz, 2H), 8.09 (d, J = 8.7 Hz, 2H), (m, 1H), 7.60 (t, J = 3.5 Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H), 2.66 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 197.2, 161.8, 150.8, 141.9, 138.9, 131.0, 128.8, 127.7, 125.7, 124.9, 120.3, 110.7, ([1,1'-biphenyl]-4-yl)benzo[d]oxazole (12d) 4-Bromobiphenyl (699 mg, 3.0 mmol) provided 12d (781 mg, 2.88 mmol, 96%) as a white solid. Mp: 167~168 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 8.32 (d, J = 8.5 Hz, 2H), 7.79 (dd, J = 4.1, 2.4 Hz, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 7.1 Hz, 2H), (m, 1H), 7.47 (t, J = 7.3 Hz, 2H), 7.40 (d, J = 7.2 Hz, 1H), 7.35 (dd, J = 6.0, 3.2 Hz, 2H); 13 C NMR (75 MHz, CDCl 3 ) δ 162.9, 150.8, 144.2, 142.2, 139.9, 128.9, 128.0, 127.5, 127.1, 125.9, 125.1, 124.6, 119.9, (naphthalen-1-yl)benzo[d]oxazole (12e) 1-Bromonaphthalene (621 mg, 3.0 mmol) provided 12e (662 mg, 2.70 mmol, 90%) as a light yellow solid. Mp: 151~152 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 9.47 (d, J = 7.6 Hz, 1H), 8.44 S13

14 (dd, J = 7.3, 1.3 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), (m, 1H), 7.71 (ddd, J = 8.5, 6.8, 1.5 Hz, 1H), (m, 1H), (m, 2H), (m, 2H); 13 C NMR (75 MHz, CDCl 3 ) δ 162.8, 150.2, 142.3, 134.0, 132.3, 130.7, 129.3, 128.6, 127.9, 126.4, 125.3, 124.9, 124.5, 123.6, 120.3, S8-3. Coupling with benzothiazole and aryl bromides Benzothiazole ( mg, 3.0 mmol) and aryl bromides (3.0 mmol) were dissolved in 10.0 ml of dimethylformamide (DMF) followed by the addition of Pd(OAc) 2 (33.68 mg, 0.15 mmol), 1,2-bis(diphenylphosphino)benzene (dppbz, mg, 0.3 mmol), Cs 2 CO 3 ( mg, 6.0 mmol) and pivalic acid (30.64 mg, 0.3 mmol). The glass vial should be capped. The reaction mixture was heated and stirred at 120 o C for 15 h. 2-p-tolylbenzo[d]thiazole (13a) 4-Bromotoluene (513 mg, 3.0 mmol) provided 13a (642 mg, 2.85 mmol, 95%) as a white solid. Mp: 85~87 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 8.05 (d, J = 6.5 Hz, 1H), 7.99 (s, 2H), 7.87 (d, J = 7.9 Hz, 1H), (m, 3H), 7.28 (d, J = 8.4 Hz, 2H), 2.41 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 168.2, 154.1, 141.4, 134.9, 130.9, 129.7, 129.0, 127.4, 126.2, 125.0, 123., 121.5, (4-(benzo[d]thiazol-2-yl)phenyl)ethanone (13c) 4 -Bromoacetophenone (597 mg, 3.0 mmol) provided 13c (669 mg, 2.64 mmol, 88%) as a white solid. Mp: 179~180 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 8.19 (d, J = 8.7 Hz, 2H), 8.11 (d, J = 7.6 Hz, 1H), 8.08 (t, J = 6.8 Hz, 2H), 7.93 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 1H), 2.66 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 197.3, 166.4, 154.1, 138.5, 137.5, 135.3, 128.9, 127.6, 126.6, 125.7, 123.6, 121.7, 29.7, (quinolin-3-yl)benzo[d]thiazole (13f) 3-Bromoquinoline (624 mg, 3.0 mmol) provided 13f (512 mg, 1.95 mmol, 65%) as a white solid. Mp: 198~200 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 9.60 (s, 1H), 8.76 (s, 1H), 8.14 (t, J = 9.1 Hz, 2H), 7.93 (d, J = 8.0 Hz, 2H), 7.78 (t, J = 7.1 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ) δ 164.8, 154.0, 148.9, 134.9, 134.6, 130.9, 129.5, 128.5, 127.5, 126.6, 125.7, 123.4, S14

15 2-(4-tert-butylphenyl)benzo[d]thiazole (13g) 1-Bromo-4-tert-butylbenzene (639 mg, 3.0 mmol) provided 13g (570 mg, 2.13 mmol, 71%) as a light yellow solid. Mp: 104~106 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 8.06 (d, J = 7.6 Hz, 1H), 8.02 (d, J = 8.7 Hz, 2H), 7.89 (d, J = 7.3 Hz, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 6.9 Hz, 1H), (m, 1H), 1.37 (s, 9H); 13 C NMR (75 MHz, CDCl 3 ) δ 168.1, 154.5, 154.2, 135.0, 130.9, 129.0, 127.4, 126.1, 125.0, 123.0, 121.5, 35.0, (2,4,5-trimethylphenyl)benzo[d]thiazole (13h) 5-Bromo-1,2,4-trimethylbenzene (597 mg, 3.0 mmol) provided 13h (464 mg, 1.83 mmol, 61%) as a sticky oil; 1 H NMR (300 MHz, CDCl 3 ) δ 8.08 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.57 (s, 1H), (m, 1H), (m, 1H), 7.10 (s, 1H), 2.61 (s, 3H), 2.29 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ 168.2, 153.8, 138.9, 135.5, 134.3, 132.9, 131.5, 130.4, 126.0, 124.8, 123.2, 121.2, 20.8, 19.6, S8-4. Coupling with N-methylindole and aryl bromides N-methylindole ( mg, 3.0 mmol) and aryl bromides (3.0 mmol) were dissolved in 10.0 ml of dimethylformamide (DMF) followed by the addition of Pd(OAc) 2 (33.68 mg, 0.15 mmol), 1,10-phenanthroline (54.06 mg, 0.3 mmol), Cs 2 CO 3 ( mg, 6.0 mmol) and pivalic acid (30.64 mg, 0.3 mmol). The glass vial should be capped. The reaction mixture was heated and stirred at 120 o C for 15 h. 1-methyl-2-p-tolyl-1H-indole (14a) 4-Bromotoluene (513 mg, 3.0 mmol) provided 14a (558 mg, 2.52 mmol, 84%) as a white solid. Mp: 88~89 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 7.62 (d, J = 7.8 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.36 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.22 (dd, J = 8.2, 1.2 Hz, 1H), 7.13 (t, J = 6.9 Hz, 1H), 6.53 (s, 1H), 3.74 (s, 3H), 2.43 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 141.6, 138.2, 137.7, 129.9, 129.2, 127.9, 121.4, 120.3, 119.7, 109.5, 101.3, 31.1, (4-(1-methyl-1H-indol-2-yl)phenyl)ethanone (14c) S15

16 4 -Bromoacetophenone (597 mg, 3.0 mmol) provided 14c (434 mg, 1.74 mmol, 58%) as a white solid. Mp: 148~149 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 8.05 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 7.9 Hz, 1H), 7.62 (t, J = 5.9 Hz, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.28 (t, J = 7.0 Hz, 1H), 7.16 (t, J = 6.9 Hz, 1H), 6.53 (s, 1H), 3.77 (s, 3H), 2.65 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 197.5, 140.2, 138.9, 137.4, 136.0, 129.1, 128.5, 127.8, 122.3, 120.7, 120.1, 109.7, 103.0, 31.4, methyl-2-(naphthalen-2-yl)-1H-indole (14i) 2-Bromonaphthalene (621 mg, 3.0 mmol) provided 14i (672 mg, 2.61 mmol, 87%) as a white solid. Mp: 85~87 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 7.91 (dd, J = 17.5, 9.1 Hz, 4H), (m, 2H), (m, 2H), 7.38 (d, J = 8.2 Hz, 1H), (m, 1H), (m, 1H), 6.66 (s, 1H), 3.79 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 141.5, 138.5, 133.2, 132.7, 130.2, 128.1, 127.7, 127.2, 126.4, 121.7, 120.5, 119.9, 109.6, 102.1, (4-methoxyphenyl)-1-methyl-1H-indole (14j) 4-Bromoanisole (561 mg, 3.0 mmol) provided 14j (527 mg, 2.22 mmol, 74%) as a white solid. Mp: 135~136 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 7.62 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.1 Hz, 1H), 7.22 (t, J = 6.9 Hz, 1H), 7.13 (t, J = 6.8 Hz, 1H), 6.99 (d, J = 11.7 Hz, 2H), 6.53 (s, 1H), 3.86 (s, 3H), 3.71 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 159.4, 141.4, 138.1, 130.6, 128.0, 125.2, 121.3, 120.2, 119.7, 113.9, 109.5, 101.0, 55.3, S8-5. Coupling with benzothiophene and aryl bromides Benzothiophene ( mg, 3.0 mmol) and aryl bromides (3.0 mmol) were dissolved in 10.0 ml of dimethylformamide (DMF) followed by the addition of Pd(OAc) 2 (33.68 mg, 0.15 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos, mg, 0.3 mmol), K 3 PO 4 ( mg, 6.0 mmol) and pivalic acid (30.64 mg, 0.3 mmol). The glass vial should be capped. The reaction mixture was heated and stirred at 120 o C for 15 h. 2-p-tolylbenzo[b]thiophene (15a) S16

17 4-Bromotoluene (513 mg, 3.0 mmol) provided 15a (464 mg, 2.07 mmol, 69%) as a white solid. Mp: 167~168 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 7.79 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 2H), 7.47 (s, 1H), 7.30 (td, J = 13.1, 5.8 Hz, 2H), 7.20 (d, J = 7.8 Hz, 2H), 2.37 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 144.3, 140.7, 139.3, 138.2, 131.4, 129.6, 126.3, 124.4, 124.1, 123.4, 122.2, 118.8, (benzo[b]thiophen-2-yl)pyridine (15k) 3-Bromopyridine (474 mg, 3.0 mmol) provided 15k (304 mg, 1.44 mmol, 48%) as a light yellow solid. Mp: 127~128 ºC; 1 H NMR (300 MHz, CDCl 3 ) δ 8.97 (d, J = 1.7 Hz, 1H), 8.56 (d, J = 3.3 Hz, 1H), 7.93 (d, J = 8.7 Hz, 1H), 7.80 (dd, J = 14.4, 7.6 Hz, 2H), 7.57 (d, J = 0.6 Hz, 1H), (m, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 149.1, 147.3, 140.2, 139.6, 133.4, 130.2, 124.8, 123.7, 122.3, 120. S17

18 1 H NMR, 2-p-tolylbenzo[d]oxazole (12a) 13 C NMR, 2-p-tolylbenzo[d]oxazole (12a) S18

19 1 H NMR, 4-(benzo[d]oxazol-2-yl)benzonitrile (12b) 13 C NMR, 4-(benzo[d]oxazol-2-yl)benzonitrile (12b) S19

20 1 H NMR, 1-(benzo[d]oxazol-2-yl)ethanone (12c) 13 C NMR, 1-(benzo[d]oxazol-2-yl)ethanone (12c) S20

21 1 H NMR, 2-([1,1'-biphenyl]-4-yl)benzo[d]oxazole (12d) 13 C NMR, 2-([1,1'-biphenyl]-4-yl)benzo[d]oxazole (12d) S21

22 1 H NMR, 2-(naphthalen-1-yl)benzo[d]oxazole (12e) 13 C NMR, 2-(naphthalen-1-yl)benzo[d]oxazole (12e) S22

23 1 H NMR, 2-p-tolylbenzo[d]thiazole (13a) 13 C NMR, 2-p-tolylbenzo[d]thiazole (13a) S23

24 1 H NMR, 1-(4-(benzo[d]thiazol-2-yl)phenyl)ethanone (13c) 13 C NMR, 1-(4-(benzo[d]thiazol-2-yl)phenyl)ethanone (13c) S24

25 1 H NMR, 2-(quinolin-3-yl)benzo[d]thiazole (13f) 13 C NMR, 2-(quinolin-3-yl)benzo[d]thiazole (13f) S25

26 1 H NMR, 2-(4-tert-butylphenyl)benzo[d]thiazole (13g) 13 C NMR, 2-(4-tert-butylphenyl)benzo[d]thiazole (13g) S26

27 1 H NMR, 2-(2,4,5-trimethylphenyl)benzo[d]thiazole (13h) 13 C NMR, 2-(2,4,5-trimethylphenyl)benzo[d]thiazole (13h) S27

28 1 H NMR, 1-methyl-2-p-tolyl-1H-indole (14a) 13 C NMR, 1-methyl-2-p-tolyl-1H-indole (14a) S28

29 1 H NMR, 1-(4-(1-methyl-1H-indol-2-yl)phenyl)ethanone (14c) 13 C NMR, 1-(4-(1-methyl-1H-indol-2-yl)phenyl)ethanone (14c) S29

30 1 H NMR, 1-methyl-2-(naphthalen-2-yl)-1H-indole (14i) 13 C NMR, 1-methyl-2-(naphthalen-2-yl)-1H-indole (14i) S30

31 1 H NMR, 2-(4-methoxyphenyl)-1-methyl-1H-indole (14j) 13 C NMR, 2-(4-methoxyphenyl)-1-methyl-1H-indole (14j) S31

32 1 H NMR, 2-p-tolylbenzo[b]thiophene (15a) 13 C NMR, 2-p-tolylbenzo[b]thiophene (15a) S32

33 1 H NMR, 3-(benzo[b]thiophen-2-yl)pyridine (15k) 13 C NMR, 3-(benzo[b]thiophen-2-yl)pyridine (15k) S33

Efficient Pd-Catalyzed Amination of Heteroaryl Halides

1 Efficient Pd-Catalyzed Amination of Heteroaryl Halides Mark D. Charles, Philip Schultz, Stephen L. Buchwald* Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 Supporting