Palladium(II)-Catalyzed Oxidative C-H/C-H Cross-Coupling of Heteroarenes

Transcription

1 Supporting Information Palladium(II)-Catalyzed xidative C-H/C-H Cross-Coupling of Heteroarenes Peihua Xi, Fan Yang, Song Qin, Dongbing Zhao, Jingbo Lan, Ge Gao, Changwei Hu,* and Jingsong You* Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, and State Key Laboratory of Biotherapy, West China Medical School, Sichuan University, 29 Wangjiang Road, Chengdu , PR China Fax: ; S1

2 Table of contents I. General remarks....s3 II. Synthesis of 1,3-diethylxanthine S3 III. General procedure for the heteroarylation of -heteroarenes (except for -heteroarene -oxides)...s4 IV. General procedure for the cross-coupling of -heteroarene -oxides with thiophene or furan derivatives...s6 V. Procedure for the bench-scale preparation of 2-(5-methylthiophen-2-yl)-quinoline -oxide (2t)......S6 VI. Experimental data for the described substances s7 VII. RTEP diagrams of 2a and 2q S22 VIII. DFT simulation on the heterocoupling reaction of heteroarenes catalyzed by Pd(Ac) S23 IX. References S36 X. Copies of 1 H and 13 C MR spectra s37 S2

3 I. General remarks MR spectra were obtained on a Bruker AMX-400, a Bruker AMX-600, or a Varian Inova 400 spectrometer. The 1 H MR (400 MHz or 600 MHz) chemical shifts were measured relative to CDCl 3 or tetramethylsilane (TMS) as the internal reference (CDCl 3 : δ = 7.26 ppm; TMS: δ = 0.00 ppm). The 13 C MR (100 MHz) chemical shifts were given using CDCl 3 or DMS-d 6 as the internal standard (CDCl 3 : δ = ppm; DMS-d 6 : δ = ppm). High-resolution mass spectra (HR-MS) were obtained with a Waters-Q-TF-Premier (ESI), or a JEL JMS-SX/SX 102A mass spectrometer (EI). X-Ray single-crystal diffraction data were collected on a Bruker SMART 1000 CCD areadetector diffractometer. Melting points were determined with XRC-1 and are uncorrected. Unless otherwise noted, all reagents were obtained from commercial suppliers and used without further purification. Caffeine, thiophenes and furans were purchased from Lancaster, Acros, and Asta Tech in China. Pd(Ac) 2 was purchased from Shanxi Kai Da Chemical Engineering (China) C., Ltd. Cu(Ac) 2 H 2 (99% purity), CuCl (97% purity) and CuBr (99% purity) were purchased from Chengdu Ke Long Chemical Engineering Reagent (China) C., Ltd., Shanghai Ke Feng Chemical Reagent (China) C., Ltd., and Shanghai Xin Bao Fine Chemical Engineering Reagent (China) C., Ltd., respectively. -Heterocycle -oxides 1, n-butyl theophylline, benzylic theophylline, benzylic theobromine, 2 indolizine, 3 and 1-methylbenzimidazole 4 were prepared according to the literature procedures. Pyridine and triethylamine (Et 3 ) were dried over CaH 2 and were freshly distilled prior to use. All solvents were purified and dried according to standard methods prior to use. All syntheses and manipulations were carried out under 2 atmosphere. II. Synthesis of 1,3-diethylxanthine Xanthine (1.06 g, 7.0 mmol) and potassium hydroxide (0.82 g, 14.7 mmol) were suspended in a mixture of ethanol (30 ml) and H 2 (20 ml). Ethyl bromide (1.6 g, S3

4 14.7 mmol) was added in batches. The reaction mixture was kept at 50 ºC for 10 h, and the solvent was then removed under reduced pressure. The residue was diluted with 50 ml of CH 2 Cl 2, filtered through a Celite pad, and then washed with ml of CH 2 Cl 2. The combined organic extracts were dried over a 2 S 4, and the solvent was removed under reduced pressure to give a white solid, which could be purified by column chromatography on silica gel (CH 2 Cl 2 /acetone = 6/1, v/v) to afford the desired product (0.2 g, 13%) as a white solid. mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 1.33 (t, J = 7.2 Hz, 3H), 1.51 (t, J = 7.2 Hz, 3H), 4.12 (q, J = 7.2 Hz, 2H), 4.30 (q, J = 7.2 Hz, 2H), 7.60 (s, 1H), 8.99 (br, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 13.5, 16.5, 38.0, 42.5, 107.5, 140.9, 150.5, 151.0, ppm; HRMS (ESI): calcd for C 9 H [M+H] , found III. General procedure for the heteroarylation of -heteroarenes (except for -heteroarene -oxides) (i). ptimization of the heteroarylation of caffeine with 2-formylthiophene A flame-dried Schlenk test tube with a magnetic stirring bar was charged with Pd(Ac) 2 (2.8 mg, mmol), oxidant (0.75 mmol, 1.5 equiv), caffeine (97 mg, 0.5 mmol), additive (0.5 mmol, 1.0 equiv) and solvent (0.6 ml) under 2. After the reaction mixture was stirred for 10 min at room temperature, 2-formylthiophene (168.2 mg, 1.5 mmol) was added. The resulting mixture was heated at the indicated temperature for 20 h and then cooled to ambient temperature. The mixture was diluted with 30 ml of CH 2 Cl 2, filtered through a Celite pad, and then washed with ml of CH 2 Cl 2. The combined organic extracts were concentrated and the resulting residue was purified by column chromatography on silica gel (CH 2 Cl 2 /acetone = 14/1, v/v) to provide the desired product. S4

5 Table S1. ptimization of the Heteroarylation of Caffeine with 2-Formylthiophene a H + H S CH Pd(Ac) 2 (2.5 mol%) oxidant, additive Solvent S CH 2a Entry xidant (equiv) Additive (equiv) Solvent Yield(%) b 1 Cu(Ac) 2 H 2 (1.5) DMA 55 2 Cu(Ac) 2 H 2 (1.5) K 2 C 3 (1.0) DMA 34 3 Cu(Ac) 2 H 2 (1.5) pyridine (1.0) DMA 70 4 Cu(Ac) 2 H 2 (1.5) Et 3 (1.0) DMA 38 5 Ag 2 C 3 (1.5) pyridine (1.0) DMA 52 6 Cu(Ac) 2 H 2 (1.5) pyridine (1.0) DMF 56 7 Cu(Ac) 2 H 2 (1.5) pyridine (1.0) DMS 48 8 Cu(Ac) 2 H 2 (1.5) pyridine (1.0) 1,4-dioxane 93 9 Cu(Ac) 2 H 2 (1.5) pyridine (1.0) + H 2 (1.5) 1,4-dioxane Cu(Ac) 2 (1.5) pyridine (1.0) 1,4-dioxane c Cu(Ac) 2 H 2 (1.5) pyridine (1.0) 1,4-dioxane 11 a Reaction conditions: caffeine (0.5 mmol), 2-formylthiophene (3 equiv), Pd(Ac) 2 (2.5 mol%), oxidant (1.5 equiv), additive and solvent (0.6 ml) at 120 C for 20 h. b Yield of isolated product based on caffeine after chromatographic purification. c Reaction was carried out at 100 C. (ii). General procedure for the heteroarylation of -heteroarenes (except for -heteroarene -oxides) A flame-dried Schlenk test tube with a magnetic stirring bar was charged with Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), -heterocycle (0.5 mmol), pyridine (39.6 mg, 0.5 mmol) and 1,4-dioxane (0.6 ml) under 2. After the reaction mixture was stirred for 10 min at room temperature, thiophene or furan derivative (1.5 mmol) was added. The resulting mixture was heated at 120 ºC for 20 h and then cooled to ambient temperature. The mixture was diluted with 30 ml of CH 2 Cl 2, filtered through a Celite pad, and then washed with ml of CH 2 Cl 2. The combined organic extracts were concentrated and the resulting residue was purified by column chromatography on silica gel to provide the desired product. S5

6 IV. General procedure for the cross-coupling of -heteroarene -oxides with thiophene or furan derivatives A flame-dried Schlenk test tube with a magnetic stirring bar was charged with Pd(Ac) 2 (2.8 mg, mmol), CuBr (7.2 mg, 0.05 mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), heteroarene -oxide (2.0 mmol), pyridine (39.6 mg, 0.5 mmol) and 1,4-dioxane (1.2 ml) under 2. After the reaction mixture was stirred for 10 min at room temperature, thiophene or furan derivative (0.5 mmol) was added. The resulting mixture was heated at 110 ºC for 30 h and then cooled to ambient temperature. The mixture was diluted with 20 ml of CH 2 Cl 2, filtered through a Celite pad, and then washed with ml of CH 2 Cl 2. The combined organic extracts were concentrated and the resulting residue was purified by column chromatography on silica gel to provide the desired product. V. Procedure for the bench-scale preparation of 2-(5-methylthiophen-2-yl)-quinoline -oxide (2t) A flame-dried Schlenk test tube with a magnetic stirring bar was charged with Pd(Ac) 2 (61.7 mg, mmol), CuBr (157.8 mg, 1.1 mmol), Cu(Ac) 2 H 2 (3.29 g, 16.5 mmol), quinoline -oxide (6.38 g, 44 mmol), pyridine (0.87 g, 11 mmol) and 1,4-dioxane (26.4 ml) under 2. After the reaction mixture was stirred for 10 min at room temperature, 2-methylthiophene (1.08 g, 11 mmol) was added. The resulting mixture was heated at 110 ºC for 30 h and then cooled to ambient temperature. The mixture was diluted with 50 ml of CH 2 Cl 2, filtered through a Celite pad, and then washed with 20 ml of CH 2 Cl 2. The combined organic extracts were concentrated and the resulting residue was purified by column chromatography on silica gel (CH 2 Cl 2 /petroleum ether/etac = 20/40/6-20/40/10, v/v) afforded the desired product 2t (1.71 g, 64%). S6

7 VI. Experimental data for the described substances S CH 1,3,7-Trimethyl-8-(5-formylthiophen-2-yl)-xanthine (2a) Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), caffeine (97.1 mg, 0.5 mmol), 2-formylthiophene (168.2 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography afforded 2a as a yellow solid (93% yield) and 2a as a yellow solid (10% yield) (CH 2 Cl 2 /acetone = 14/1, CH 2 Cl 2 /petroleum ether = 4:1-5:1 v/v, respectively). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 3.43 (s, 3H), 3.62 (s, 3H), 4.27 (s, 3H), 7.70 (d, J = 4.0 Hz, 1H), 7.82 (d, J = 4.0 Hz, 1H), 9.98 (s, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 28.2, 30.0, 34.0, 109.3, 129.1, 136.1, 139.0, 145.0, 145.5, 148.2, 151.6, 155.5, ppm; HRMS (ESI): calcd for C 13 H S [M+H] , found HC S S CH 5,5'-Diformyl-2,2'-bithiophene (2a') mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 7.42 (d, J = 4.0 Hz, 2H), 7.73 (d, J = 4.0 Hz, 2H), 9.92 (s, 2H) ppm; MS (ESI): calcd for C 10 H 7 2 S 2 [M+H] , found S S7

8 1,3,7-Trimethyl-8-(5-methylthiophen-2-yl)-xanthine (2b) Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), caffeine (97.1 mg, 0.5 mmol), 2-methylthiophene (147.3 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /acetone = 30/1, v/v) afforded a white solid (96% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 2.56 (s, 3H), 3.42 (s, 3H), 3.61 (s, 3H), 4.17 (s, 3H), 6.84 (d, J = 3.2 Hz, 1H), 7.38 (d, J = 3.6 Hz, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 15.4, 28.0, 29.8, 33.6, 108.1, 126.5, 128.2, 128.9, 144.6, 146.8, 148.2, 151.7, ppm; HRMS (ESI): calcd for C 13 H S [M+H] , found S 1,3,7-Trimethyl-8-(4-methylthiophen-2-yl)-xanthine (2c) Pd(Ac) 2 (2.8 mg, mmol), CuCl (5.1 mg, 0.05 mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), caffeine (97.1 mg, 0.5 mmol), 3-methylthiophene (147.3 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /acetone/etac = 50/1/2, v/v) afforded a yellowish solid (73% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 2.33 (s, 3H), 3.42 (s, 3H), 3.61 (s, 3H), 4.18 (s, 3H), 7.13 (s, 1H), 7.40 (s, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 15.8, 28.0, 29.9, 33.7, 108.2, 124.9, 130.2, 130.9, 138.9, 146.8, 148.2, 151.7, ppm; HRMS (ESI): calcd for C 13 H S [M+H] , found S8

9 S Me 1,3,7-Trimethyl-8-(5-methoxylthiophen-2-yl)-xanthine (2d) Pd(Ac) 2 (2.8 mg, mmol), CuCl (5.1 mg, 0.05 mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), caffeine (97.1 mg, 0.5 mmol), 2-methoxythiophene (171.3 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /acetone = 30/1, v/v) afforded a white solid (34% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 3.40 (s, 3H), 3.58 (s, 3H), 3.96 (s, 3H), 4.14 (s, 3H), 6.27 (d, J = 4.4 Hz, 1H), 7.22 (d, J = 4.0 Hz, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 28.0, 29.9, 33.6, 60.5, 105.3, 108.0, 116.9, 127.3, 146.9, 148.2, 151.7, 155.2, ppm; HRMS (EI): calcd for C 13 H S [M] , found S C 1,3,7-Trimethyl-8-(5-cyanothiophen-2-yl)-xanthine (2e) Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), caffeine (97.1 mg, 0.5 mmol), 2-cyanothiophene (163.7 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /petroleum ether/acetone = 20/20/5, v/v) afforded a light yellow solid (65% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 3.42 (s, 3H), 3.60 (s, 3H), 4.24 (s, 3H), 7.53 (d, J = 4.0 Hz, 1H), 7.67 (d, J = 4.0 Hz, 1H) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = 28.2, 30.0, 33.9, 109.3, 112.7, 113.4, 127.4, 137.7, 137.9, 144.0, 148.2, 151.6, ppm; HRMS (ESI): calcd for C 13 H S [M+H] , found S9

10 S 1,3,7-Trimethyl-8-(5-acetylthiophen-2-yl)-xanthine (2f) Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), caffeine (97.1 mg, 0.5 mmol), 2-acetylthiophene (189.3 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /acetone = 15/1, v/v) afforded a yellow solid (96% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 2.60 (s, 3H), 3.41 (s, 3H), 3.60 (s, 3H), 4.23 (s, 3H), 7.62 (d, J = 4.0 Hz, 1H), 7.71 (d, J = 4.0 Hz, 1H) ppm. 13 C MR (100 MHz, CDCl 3 ): δ = 27.0, 28.2, 29.9, 33.9, 109.1, 129.2, 132.4, 137.5, 145.3, 146.4, 148.2, 151.6, 155.4, ppm; HRMS (ESI): calcd for C 14 H S [M+H] , found S 1,3,7-Trimethyl-8-(benzothiophen-2-yl)-xanthine (2g) Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), caffeine (97.1 mg, 0.5 mmol), benzothiophene (201.3 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /acetone = 25/1, v/v) afforded a white solid (93% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 3.42 (s, 3H), 3.63 (s, 3H), 4.28 (s, 3H), (m, 2H), 7.77 (s, 1H), (m, 2H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 28.2, 30.0, 34.0, 109.0, 122.4, 124.8, 125.3, 125.3, 126.3, 130.8, 139.6, 140.7, 148.3, 151.8, ppm; HRMS (ESI): calcd for C 16 H S [M+H] , S10

11 found CH 1,3,7-Trimethyl-8-(5-formylfuran-2-yl)-xanthine (2h) Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), caffeine (97.1 mg, 0.5 mmol), furan-2-carbaldehyde (144.1 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /acetone = 12/1, v/v) afforded a yellow solid (85% yield). mp: >258 ºC (dec.); 1 H MR (400 MHz, CDCl 3 ): δ = 3.42 (s, 3H), 3.61 (s, 3H), 4.37 (s, 3H), 7.27 (d, J = 3.6 Hz, 1H), 7.38 (d, J = 4.0 Hz, 1H), 9.75 (s, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 28.2, 29.9, 34.2, 109.1, 115.0, 121.9, 141.1, 148.5, 149.1, 151.7, 153.4, 155.5, ppm; HRMS (ESI): calcd for C 13 H [M+H] , found ,3,7-Trimethyl-8-(4,5-dimethylfuran-2-yl)-xanthine (2i) Pd(Ac) 2 (2.8 mg, mmol), CuCl (5.1 mg, 0.05 mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), caffeine (97.1 mg, 0.5 mmol), 2,3-dimethylfuran (144.2 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /acetone = 20/1, v/v) afforded a white solid (95% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 2.01 (s, 3H), 2.33 (s, 3H), 3.40 (s, 3H), 3.59 (s, 3H), 4.18 (s, 3H), 6.85 (s, 1H) ppm; S11

12 13 C MR (100 MHz, CDCl 3 ): δ = 9.8, 11.8, 28.0, 29.8, 33.6, 107.6, 117.1, 117.1, 141.1, 143.4, 148.4, 151.0, 151.7, ppm; HRMS (ESI): calcd for C 14 H [M+H] , found ,3,7-Trimethyl-8-(benzofuran-2-yl)-xanthine (2j) Pd(Ac) 2 (2.8 mg, mmol), CuCl (5.1 mg, 0.05mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), caffeine (97.1 mg, 0.5 mmol), benzofuran (177.2 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /acetone = 23/1, v/v) afforded a white solid (72% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 3.43 (s, 3H), 3.65 (s, 3H), 4.38 (s, 3H), 7.31 (dd, J = 7.2, 7.2 Hz, 1H), 7.40 (dd, J = 7.6, 7.6 Hz, 1H), 7.45 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 28.0, 29.8, 34.0, 108.5, 109.5, 111.7, 121.9, 124.0, 126.4, 127.4, 142.5, 145.5, 148.3, 151.5, 155.2, ppm; HRMS (ESI): calcd for C 16 H [M+H] , found nbu S C 7-Butyl-1,3-dimethyl-8-(5-cyanthiophen-2-yl)-xanthine (2k) Pd(Ac) 2 (2.8 mg, mmol), CuCl (5.1 mg, 0.05mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), 7-butyl-1,3-dimethylxanthine (118.1 mg, 0.5 mmol), 2-cyanthiophene (163.7 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC S12

13 for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /petroleum ether/acetone = 20/20/2, v/v) afforded a light yellow solid (47% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 0.96 (t, J = 7.6 Hz, 3H), (m, 2H), (m, 2H), 3.42 (s, 3H), 3.59 (s, 3H), 4.53 (t, J = 8.0 Hz, 2H), 7.47 (d, J = 4.0 Hz, 1H), 7.66 (d, J = 4.0 Hz, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 13.7, 19.8, 28.2, 29.9, 32.9, 46.6, 108.9, 112.4, 113.4, 127.3, 137.6, 137.9, 143.2, 148.2, 151.5, ppm; HRMS (ESI): calcd for C 16 H S [M-H] , found Bn S 7-Benzyl-1,3-dimethyl-8-(5-methylthiophen-2-yl)-xanthine (2l) Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), 7-benzyl-1,3-dimethylxanthine (135.1 mg, 0.5 mmol), 2-methylthiophene (147.3 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /EtAc = 20/1, v/v) afforded a white solid (92% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 2.51 (s, 3H), 3.38 (s, 3H), 3.64 (s, 3H), 5.79 (s, 2H), 6.72 (d, J = 3.2 Hz, 1H), 7.10 (d, J = 7.2 Hz, 2H), 7.13 (d, J = 3.6 Hz, 1H), (m, 3H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 15.4, 28.1, 29.9, 49.4, 108.0, 126.1, 126.6, 127.7, 127.9, 129.1, 136.2, 144.9, 147.0, 148.5, 151.7, ppm; HRMS (ESI): calcd for C 19 H S [M+H] , found Bn S 1-Benzyl-3,7-dimethyl-8-(5-methylthiophen-2-yl)-xanthine (2m) S13

14 Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), 1-benzyl-3,7-dimethylxanthine (135.1 mg, 0.5 mmol), 2-methylthiophene (147.3 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /EtAc = 30/1, v/v) afforded a white solid (96% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 2.55 (s, 3H), 3.59 (s, 3H), 4.16 (s, 3H), 5.21 (s, 2H), 6.83 (d, J = 2.8 Hz, 1H), (m, 3H), 7.36 (d, J = 3.6 Hz, 1H), 7.48 (d, J = 7.2 Hz, 2H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 15.4, 29.8, 33.7, 44.5, 108.2, 126.5, 127.5, 128.1, 128.4, 128.8, 128.9, 137.5, 144.6, 147.0, 148.4, 151.6, ppm; HRMS (ESI): calcd for C 19 H S [M+H] , found H S 1,3-Diethyl-8-(5-methylthiophen-2-yl)-xanthine (2n) Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), 1,3-diethylxanthine (104.1 mg, 0.5 mmol), 2-methylthiophene (147.3 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /acetone = 12/1, v/v) afforded a white solid (96% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 1.35 (t, J = 6.8 Hz, 3H), 1.52 (t, J = 7.2 Hz, 3H), 2.56 (s, 3H), 4.13 (q, J = 7.2 Hz, 2H), 4.51 (q, J = 7.2 Hz, 2H), 6.84 (d, J = 3.2 Hz, 1H), 7.34 (d, J = 3.6 Hz, 1H), 8.45 (s, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 13.5, 15.4, 16.2, 38.0, 41.8, 126.5, 127.9, 129.0, 144.6, 146.6, 150.1, 150.8, ppm; HRMS (ESI): calcd for C 14 H S [M+H] , found S14

15 S CH 1-Methyl-2-(5-formylthiophen-2-yl)-benzimidazole (2o) Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), 1-methylbenzimidazole (66.1 mg, 0.5 mmol), 2-formylthiophene (168.2 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /petroleum ether/etac = 6/2/1, v/v) afforded a yellow solid (72% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 4.02 (s, 3H), (m, 3H), 7.71 (d, J = 4.0 Hz, 1H), (m, 2H), 9.95 (s, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 31.9, 109.8, 120.3, 123.3, 124.0, 128.6, 136.1, 136.8, 141.1, 142.9, 145.0, 146.3, ppm; HRMS (ESI): calcd for C 13 H 11 2 S [M+H] , found CH 1-Methyl-2-(5-formylfuran-2-yl)-benzimidazole (2p) Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), 1-methylbenzimidazole (66.1 mg, 0.5 mmol), 2-formylfuran (144.1 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /petroleum ether/etac = 2/2/1.2, v/v) afforded a yellow solid (75% yield). mp: ºC; 1 H MR (600 MHz, CDCl 3 ): δ = 4.16 (s, 3H), 7.32 (dd, J = 7.2, 7.2 Hz, 1H), 7.35 (dd, J = 7.8, 7.8 Hz, 1H), (m, 3H), 7.79 (d, J = 7.8 Hz, 1H), 9.74 (s, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 31.9, 109.9, 114.1, 120.2, 122.5, 123.4, 124.2, 136.4, 142.5, 143.1, 150.7, 152.9, ppm; HRMS (ESI): calcd for C 13 H [M+H] , found S15

16 S CH 1-Methyl-2-(5-formylthiophen-2-yl)-imidazole (2q) Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), 1-methylimidazole (41.1 mg, 0.5 mmol), 2-formylthiophene (168.2 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography afforded 2q as a yellow solid (56% yield), 2q as a brownish yellow solid (10% yield) (CH 2 Cl 2 /EtAc = 6/1-4/1, v/v), and 5,5'-diformyl-2,2'-bithiophene 2a as a yellow solid (11% yield) (CH 2 Cl 2 /petroleum ether = 4:1-5:1, v/v). 2q: mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 3.92 (s, 3H), 7.03 (br, 1H), 7.17 (br, 1H), 7.58 (br, 1H), 7.77 (s, 1H), 9.93 (s, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 35.0, 124.2, 126.0, 129.5, 136.6, 141.1, 142.0, 143.1, ppm; HRMS (ESI): calcd for C 9 H 9 2 S [M+H] , found HC S S CH 1-Methyl-2,5-di(5-formylthiophen-2-yl)-imidazole (2q ) mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 3.98 (s, 3H), 7.28 (d, J = 4.0 Hz, 1H), 7.46 (s, 1H), 7.63 (d, J = 4.0 Hz, 1H), 7.79 (dd, J = 3.6, 3.6 Hz, 2H), 9.93 (s, 1H), 9.96 (s, 1H) ppm; 13 C MR (100 MHz, DMS-d 6 ): δ = 33.9, 127.2, 127.6, 129.0, 130.8, 138.3, 138.5, 138.8, 140.8, 142.5, 143.0, 143.5, 183.9, ppm; HRMS (ESI): calcd for C 14 H S 2 [M+H] , found S CH 2-(5-Formylthiophen-2-yl)-benzoxazole (2r) S16

17 Pd(Ac) 2 (2.8 mg, mmol), CuCl (5.1 mg, 0.05mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), benzoxazole (59.6 mg, 0.5 mmol), 2-formylthiophene (168.2 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and DMA (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /petroleum ether/et 2 = 20/40/3, v/v) afforded a yellow solid (55% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = (m, 2H), 7.58 (d, J = 6.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 4.0 Hz, 1H), 7.96 (d, J = 4.0 Hz, 1H), (s, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 110.9, 120.5, 125.3, 126.3, 130.0, 136.2, 137.7, 141.9, 146.3, 150.7, 157.7, ppm; HRMS (ESI): calcd for C 12 H 8 2 S [M+H] , found S MeC Methyl 3-(5-acetylthiophen-2-yl)-pyrrolo[2,1-a]isoquinoline-1-carboxylate (2s) Pd(Ac) 2 (2.8 mg, mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), methyl 7,8-benzoindolizine-1-carboxylate (112.6 mg, 0.5 mmol), 2-acetylthiophene (189.3 mg, 1.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (0.6 ml) at 120 ºC for 20 h. Purification via silica gel column chromatography (CH 2 Cl 2 /petroleum ether/et 2 = 20/40/3, v/v) afforded a light yellow solid (60% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 2.61 (s, 3H), 3.95 (s, 3H), 7.06 (d, J = 7.2 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 7.49 (s, 1H), 7.54 (dd, J = 7.2, 7.2 Hz, 1H), (m, 2H), 7.73 (d, J = 3.6 Hz, 1H), 8.26 (d, J = 7.2 Hz, 1H), 9.82 (d, J = 8.4 Hz, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 26.7, 51.7, 109.5, 114.6, 119.1, 120.2, 121.6, 125.7, 126.6, 126.8, 127.5, 128.1, 128.3, 128.9, 133.0, 134.1, 140.7, 143.6, 165.4, ppm; HRMS (ESI): calcd for C 20 H 16 3 S [M+H] , found S17

18 S 2-(5-Methylthiophen-2-yl)-quinoline -oxide (2t) Pd(Ac) 2 (2.8 mg, mmol), CuBr (7.2 mg, 0.05 mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), quinoline -oxide (290.3 mg, 2.0 mmol), 2-methylthiophene (49.1 mg, 0.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (1.2 ml) at 110 ºC for 30 h. Purification via silica gel column chromatography (CH 2 Cl 2 /petroleum ether/etac = 20/40/6-20/40/10, v/v) afforded a yellow solid (80% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 2.59 (s, 3H), 6.94 (d, J = 3.6 Hz, 1H), 7.55 (dd, J = 7.2, 7.2 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), (m, 3H), 7.89 (d, J = 8.8 Hz, 1H), 8.79 (d, J = 8.8 Hz, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 15.1, 118.4, 119.7, 125.1, 125.5, 127.7, 127.8, 128.5, 130.2, 130.5, 139.4, 141.2, ppm; HRMS (ESI): calcd for C 14 H 12 S [M+H] , found (4,5-Dimethylfuran-2-yl)-quinoline -oxide (2u) Pd(Ac) 2 (2.8 mg, mmol), CuBr (7.2 mg, 0.05 mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), quinoline -oxide (290.3 mg. 2.0 mmol), 2,3-dimethylfuran (48.1 mg, 0.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (1.2 ml) at 110 ºC for 30 h. Purification via silica gel column chromatography (CH 2 Cl 2 /petroleum ether/etac = 1/6/2, v/v) afforded a yellow solid (60% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 2.06 (s, 3H), 2.35 (s, 3H) 7.53 (dd, J = 7.2, 7.2 Hz, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.72 (dd, J = 7.2, 7.2 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 8.07 (s, 1H), 8.76 (d, J = 8.8 Hz, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 10.0, 11.9, 117.9, 118.5, 119.4, 121.5, 125.0, 127.6, 127.9, 128.0, 130.4, 136.6, 142.1, S18

19 143.2, ppm; HRMS (ESI): calcd for C 15 H 14 2 [M+H] , found S CH 2-(5-Formylthiophen-2-yl)-quinoline -oxide (2v) Pd(Ac) 2 (2.8 mg, mmol), CuBr (7.2 mg, 0.05 mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), quinoline -oxide (290.3 mg. 2.0 mmol), 2-formylthiophene (56.1 mg, 0.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (1.2 ml) at 110 ºC for 30 h. Purification via silica gel column chromatography (CH 2 Cl 2 /petroleum ether/etac = 20/20/8, v/v) afforded a yellow solid (41% yield). mp: >246 ºC (dec.); 1 H MR (400 MHz, CDCl 3 ): δ = 7.66 (dd, J = 7.6, 7.6 Hz, 1H), (m, 2H), (m, 2H), (m, 2H), 8.81 (d, J = 8.4 Hz, 1H), (s, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 118.8, 120.3, 125.7, 127.9, 128.2, 128.7, 129.2, 131.3, 133.2, 138.4, 140.7, 141.6, 144.7, ppm; HRMS (ESI): calcd for C 14 H 9 2 Sa [M+a] , found S 2-(Benzothiophen-2-yl)-quinoline -oxide (2w) Pd(Ac) 2 (2.8 mg, mmol), CuBr (7.2 mg, 0.05 mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), quinoline -oxide (290.3 mg. 2.0 mmol), benzothiophene (67.1 mg, 0.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (1.2 ml) at 120 ºC for 30 h. Purification via silica gel column chromatography (CH 2 Cl 2 /petroleum ether/etac = 10/60/17-10/60/20, v/v) afforded a light yellow solid (50% yield). mp: ºC; 1 H S19

20 MR (400 MHz, CDCl 3 ): δ = (m, 2H), 7.57 (dd, J = 7.2, 7.2 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), (m, 2H), 7.83 (d, J = 7.6 Hz, 1H), 7.95 (dd, J =16.4, 7.6 Hz, 2H), 8.20 (s, 1H), 8.82 (d, J = 8.4 Hz, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 119.4, 120.1, 122.3, 123.9, 124.6, 125.0, 125.7, 125.8, 128.0, 128.6, 130.9, 133.7, 137.8, 139.6, 141.6, ppm; HRMS (EI): calcd for C 17 H 11 S [M] , found S 2-(5-Methylthiophen-2-yl)-pyridine -oxide (2x) Pd(Ac) 2 (2.8 mg, mmol), CuBr (7.2 mg, 0.05 mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), pyridine -oxide (190.2 mg. 2.0 mmol), 2-methylthiophene (49.1 mg, 0.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (1.2 ml) at 110 ºC for 30 h. Purification via silica gel column chromatography (CH 2 Cl 2 /acetone = 7/1, v/v) afforded a yellow solid (78% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 2.54 (s, 3H), 6.86 (d, J = 3.2 Hz, 1H), 7.04 (dd, J = 6.4, 6.4 Hz, 1H), 7.24 (dd, J = 7.6, 7.6 Hz, 1H), 7.66 (d, J = 3.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 8.26 (d, J = 6.4 Hz, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 15.1, 121.6, 121.7, 124.8, 125.7, 127.4, 129.0, 139.4, 143.3, ppm; HRMS (ESI): calcd for C 10 H 10 S [M+H] , found (4,5-Dimethylfuran-2-yl)-pyridine -oxide (2y) Pd(Ac) 2 (2.8 mg, mmol), CuBr (7.2 mg, 0.05 mmol), Cu(Ac) 2 H 2 (150 S20

21 mg, 0.75 mmol), pyridine -oxide (190.2 mg. 2.0 mmol), 2,3-dimethylfuran (48.1 mg, 0.5 mmol), pyridine (39.6 mg, 0.5 mmol) and dioxane (1.2 ml) at 110 ºC for 30 h. Purification via silica gel column chromatography (CH 2 Cl 2 /acetone = 3/1, v/v) afforded a yellow solid (77% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 2.01 (s, 3H), 2.30 (s, 3H), 7.00 (td, J = 7.2, 1.6 Hz, 1H), 7.22 (dd, J = 8.0, 8.0 Hz, 1H), 7.80 (s, 1H), 7.83 (dd, J = 8.0, 1.6 Hz, 1H), 8.22 (d, J = 6.8 Hz, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 9.9, 11.8, 117.5, 120.5, 121.6, 121.8, 125.1, 140.3, 142.3, ppm; HRMS (ESI): calcd for C 11 H 12 2 [M+H] , found S 2-(5-Methylthiophen-2-yl)-6-methyl-pyridine -oxide (2z) Pd(Ac) 2 (2.8 mg, mmol), CuBr (7.2 mg, 0.05 mmol), Cu(Ac) 2 H 2 (150 mg, 0.75 mmol), 2-methylpyridine -oxide (218.3 mg. 2.0 mmol), 2-methylthiophene (49.1 mg, 0.5 mmol), pyridine (39.6 mg, 0.5 mmol), and dioxane (1.2 ml) at 110 ºC for 30 h. Purification via silica gel column chromatography (CH 2 Cl 2 /petroleum ether/ EtAc = 1/4/2, v/v) afforded a yellow solid (65% yield). mp: ºC; 1 H MR (400 MHz, CDCl 3 ): δ = 2.54 (s, 3H), 2.59 (s, 3H), 6.86 (dd, J = 3.6, 0.4 Hz, 1H), 7.06 (dd, J = 7.6, 1.2 Hz, 1H), 7.17 (dd, J= 8.0, 8.0 Hz, 1H), 7.64 (d, J = 4.0 Hz, 1H), 7.76 (dd, J = 8.4, 1.6 Hz, 1H) ppm; 13 C MR (100 MHz, CDCl 3 ): δ = 15.1, 18.4, 119.4, 122.1, 124.7, 125.1, 127.4, 129.7, 143.3, 145.0, ppm; HRMS (ESI): calcd for C 11 H 12 S [M+H] , found S21

22 VII. RTEP diagrams of 2a and 2q Figure S1. RTEP diagrams of a) 2a, and b) 2q. Thermal ellipsoids are shown at the 50% probability level. S22

23 VIII. DFT simulation on the heterocoupling reaction of heteroarenes catalyzed by Pd(Ac) 2 (i) Computational details All calculations were performed within the density functional theory in Gaussian 03 programs. 5 In this section, Becke three-parameter hybrid exchange functional combined with the Lee Yang Parr correlation functional (B3LYP) 6 was used for geometry optimizations and vibrational calculations. The SDD 7 basis set for palladium atom along effective core potential (ECP) and the 6-31G(d, p) 8 basis set for other elements were used. Each optimized structure was analyzed by harmonic vibrational frequencies obtained at the same level and characterized as a minimum (no imaginary frequency) or a transition state (one imaginary frequency). For each transition state, intrinsic reaction coordinate (IRC) calculations were performed in both directions to connect these corresponding intermediates. To obtain more reliable relative energies, the single-point energies calculated at the B3LYP/ G(2d,2p), SDD level on optimized structures were also performed. If other specified, the single-point energies were used in the following discussion. (ii) Energy profile of the reaction calculated as well as discussion respect with to plausible catalytic cycle of C-H/C-H cross-coupling of thiophene and imidazole The predicted reaction mechanism involves the process of bisheteroarylpalladium intermediate IM4 from the reactants of thiophene, -methylimidazole and Pd(Ac) 2. The DFT calculation indicates that the abstraction of hydrogen from thiophene with the formation of α-thienylpalladium(ii) intermediate IM2 might easily take place with a smaller energy barrier of ca kj/mol (Figure S2). n the other hand, we also tried to find out the hydrogen abstraction from -methylimidazole rather than thiophene in the first reaction step, but all attempt to locate the transition state failed. The subsequent metallation step involving the formation of bisheteroarylpalladium intermediate IM4 might be rate-determining in the entire reaction because the corresponding energy barrier is calculated to be kj/mol (Figure S2). S23

24 TS3 TS3 + HAc (122.7) IM4 IM4 + HAc (111.5) TS1 TS1+imidazole IM2 Reactants (0.0) (40.3) IM2+imidazole ( 4.3) IM3 + HAc IM3 ( 58.0) Figure S2. Energy profile of the reaction calculated at the B3LYP/ G(2d,2p), SDD level. Relative energies in kj/mol are listed in parentheses. Color code: C (gray), (blue), (red), S (yellow), Pd (cyan), and H (white). Besides, we also considered the reaction mechanism related to the formation of dithiophene (Figure S3). Although the calculation indicates that dithiophene could be generated from IM2 and an isolated thiophene via the electophilic transition state Side-TS and the energy barrier of the step was predicted to be 91.8 kj/mol, as compared to IM3, Side-IM3 might be an unstable complex as its relative energy is 11.9 kj/mol higher than IM2 and an isolated thiophene. Therefore, when catalyst, thiophene and -methylimidazole co-exist in the reaction system, IM3 might be the predominant intermediate after the formation of IM2. S24

25 Side TS Side TS+HAc (103.7) IM2 IM2+thiophene (0.0) Side IM3 Side IM3+HAc (11.9) Side IM4 Side IM4+HAc (19.9) Figure S3. Energy profile of the reaction to dithiophene from IM2 at the B3LYP/ G(2d,2p), SDD level. Relative energies in kj/mol are listed in parentheses. Color code: C (gray), (blue), (red), S (yellow), Pd (cyan), and H (white). (iii) The optimized geometries of the stationary points Pd(Ac) 2 S25

26 Standard orientation Center Atomic Atomic Coordinates (Angstroms) umber umber Type X Y Z B3LYP/6-31G(d,p), SDD E ZPE = (Hartree/Particle) B3LYP/ G(2d,2p), SDD E SP = (Hartree/Particle) thiophene Standard orientation Center Atomic Atomic Coordinates (Angstroms) umber umber Type X Y Z B3LYP/6-31G(d,p), SDD E ZPE = (Hartree/Particle) B3LYP/ G(2d,2p), SDD E SP = (Hartree/Particle) S26

27 -methylimidazole Standard orientation Center Atomic Atomic Coordinates (Angstroms) umber umber Type X Y Z B3LYP/6-31G(d,p), SDD E ZPE = (Hartree/Particle) B3LYP/ G(2d,2p), SDD E SP = (Hartree/Particle) Acetic acid Standard orientation Center Atomic Atomic Coordinates (Angstroms) umber umber Type X Y Z B3LYP/6-31G(d,p), SDD E ZPE = (Hartree/Particle) B3LYP/ G(2d,2p), SDD E SP = (Hartree/Particle) S27

28 TS1 The transition state TS1 involves the abstraction of hydrogen from thiophene to acetic acid moiety via electrophilic C-H substitution (S E Ar) and links the reactants [thiophene + Pd(Ac) 2 ] and the intermediate IM2. Standard orientation Center Atomic Atomic Coordinates (Angstroms) umber umber Type X Y Z Unique imaginary frequency: i B3LYP/6-31G(d,p), SDD E ZPE = (Hartree/Particle) B3LYP/ G(2d,2p), SDD E SP = (Hartree/Particle) S28

29 IM2: theα-thienylpalladium(ii) intermediate Standard orientation Center Atomic Atomic Coordinates (Angstroms) umber umber Type X Y Z B3LYP/6-31G(d,p), SDD E ZPE = (Hartree/Particle) B3LYP/ G(2d,2p), SDD E SP = (Hartree/Particle) S29

30 IM3: the intermediate with the -methylimidazolyl fragment Standard orientation Center Atomic Atomic Coordinates (Angstroms) umber umber Type X Y Z B3LYP/6-31G(d,p), SDD E ZPE = (Hartree/Particle) B3LYP/ G(2d,2p), SDD E SP = (Hartree/Particle) S30

31 TS3 The transition state TS3 involves the abstraction of hydrogen from -methylimidazole to acetic acid moiety via the concerted metalation-deprotonation (CMD) process and links the intermediate IM3 and the intermediate IM4. TS3 lies on the top of the energy curve for the entire reaction and therefore is the rate-determining step. Standard orientation Center Atomic Atomic Coordinates (Angstroms) umber umber Type X Y Z Unique imaginary frequency: i B3LYP/6-31G(d,p), SDD E ZPE = (Hartree/Particle) B3LYP/ G(2d,2p), SDD E SP = (Hartree/Particle) S31

32 IM4: the key bisheteroarylpalladium intermediate related to the heterocoupling Standard orientation Center Atomic Atomic Coordinates (Angstroms) umber umber Type X Y Z B3LYP/6-31G(d,p), SDD E ZPE = (Hartree/Particle) B3LYP/ G(2d,2p), SDD E SP = (Hartree/Particle) S32

33 Side-IM3: the palladium(ii) π complex intermediate from IM2 and an isolated thiophene Standard orientation Center Atomic Atomic Coordinates (Angstroms) umber umber Type X Y Z B3LYP/6-31G(d,p), SDD E ZPE = (Hartree/Particle) B3LYP/ G(2d,2p), SDD E SP = (Hartree/Particle) S33

34 Side-TS The transition state Side-TS involves the C-C formation between two thiophene molecules by a four-member ring structure. In Side-TS, no distinguishable hydrogen transfer can be detected. Side-TS, as an electrophnic transition state, links the intermediate Side-IM3 and the intermediate Side-IM4. Standard orientation Center Atomic Atomic Coordinates (Angstroms) umber umber Type X Y Z B3LYP/6-31G(d,p), SDD Ezpe= (Hartree/Particle) B3LYP/ G(2d,2p) Esp = (Hartree/Particle) S34

35 Side-IM4: the Heck-type intermediate Standard orientation Center Atomic Atomic Coordinates (Angstroms) umber umber Type X Y Z B3LYP/6-31G(d,p), SDD Ezpe= (Hartree/Particle) B3LYP/ G(2d,2p) Esp = (Hartree/Particle) S35