Amide Directed Cross-Coupling between Alkenes and Alkynes: A Regio- and Stereoselective Approach to Substituted (2Z,4Z)-Dienamides

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1 Supporting Information For the article entitled Amide Directed Cross-Coupling between Alkenes and Alkynes: A Regio- and Stereoselective Approach to Substituted (2Z,4Z)-Dienamides Keke Meng, Jian Zhang,* Feifei Li, Zhenwei Lin, Ke Zhang and Guofu Zhong* College of Material, Chemistry and Chemical Engineering, Hangzhou ormal University, Hangzhou , China zhangjian@hznu.edu.cn; zgf@hznu.edu.cn Supporting Information Table of Contents General methods 2 General Procedure for Ru-Catalyzed Cross-Coupling between Alkenes and Alkynes 2 Characterization of Butadienes 3 Gram-Scale Synthesis 13 Deuterium-Labeled Experiments 14 Competitive reaction of different alkynes and acrylamides 18 References 19 1 H, 13 C MR spectra 20 1

2 General methods Analytical thin layer chromatography (TLC) was performed using Merck 60 F254 precoated silica gel plate (0.2 mm thickness). Subsequent to elution, plates were visualized using UV radiation (254 nm) on Spectroline Model EF-24061/F 254 nm. Further visualization was possible by staining with basic solution of potassium permanganate or acidic solution of ceric molybdate. Flash column chromatography was performed using Merck aluminium oxide 90 active neutral with freshly distilled solvents. Columns were typically packed as slurry and equilibrated with the appropriate solvent system prior to use. Proton nuclear magnetic resonance spectra ( 1 H MR) were recorded on Bruker AMX 400 and 500 spectrophotometer (CDCl 3 as solvent). Chemical shifts for 1 H MR spectra are reported as δ in units of parts per million (ppm) downfield from SiMe 4 (δ 0.0) and relative to the signal of chloroform-d (δ 7.26, singlet). Multiplicities were given as: s (singlet), d (doublet), t (triplet), dd (doublets of doublet) or m (multiplets). The number of protons (n) for a given resonance is indicated by nh. Coupling constants are reported as a J value in Hz. Carbon nuclear magnetic resonance spectra ( 13 C MR) are reported as δ in units of parts per million (ppm) downfield from SiMe 4 (δ 0.0) and relative to the signal of chloroform-d (δ 77.0, triplet). Mass spectrometry was performed by Waters Q-Tof Premier Micromass instrument, using Electro Spray Ionization (ESI) mode. IR spectra were recorded as thin films on KBr or acl plates on a Bio-Rad FTS 165 FTIR spectrometer and are reported in frequency of absorption (cm -1 ). [Ru(p-cymene)Cl 2 ] 2 and AgSbF 6 were purchased from TCI and used directly. ther reagents, unless otherwise noted below, are commercially available from Alfa Aesar (China) Chemical Co., Ltd. and used without further purification. Acrylamides were prepared by previous reported method. 1,2 General Procedure for Ru-Catalyzed Cross-Coupling between Alkenes and Alkynes An oven-dried vial was charged with [Ru(p-cymene)Cl 2 ] 2 (6.1 mg, 5 mol %, 0.01 mmol), AgSbF 6 (13.7 mg, 20 mol %, 0.04 mmol) and THF (1.0 ml). Then, alkyne (0.4 mmol, 2.0 equiv) and acrylamide (0.20 mmol, 1.0 equiv.) were added into the solution in sequence. The vial was sealed under argon and 2

3 heated to 100 with stirring for 16 hours. After cooling down, the mixture was concentrated to give the crude product which was directly applied to a flash column chromatography for purification (EtAc/Petroleum ether mixtures). Characterization of Butadienes (2Z,4Z)-2,4,5-triphenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (3aa) This compound was obtained according to the general procedure as a yellow oil (58.4 mg, yield = 77%). 1 H MR (500 MHz, CDCl 3 ): δ = (m, 2H), (m, 4H), (m, 4H), (m, 3H), 6.90 (s, 1H), (m, 2H), 6.79 (s, 1H), (brs, 4H), (m, 4H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , 46.94, 44.82, 25.61, HR-MS (ESI): m/z calculated for C 27 H 25 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , (2Z,4E)-4-ethyl-2-phenyl-1-(pyrrolidin-1-yl)hepta-2,4-dien-1-one (3ab) This compound was obtained according to the general procedure as a yellow oil (32.3 mg, yield = 57%). 1 H MR (500 MHz, CDCl 3 ): δ = (m, 2H), (m, 2H), (m, 1H), 6.30 (s, 1H), (t, J = 2.5 Hz, 1H), (t, J = 6.5 Hz, 2H), (m, 2H), (m, 2H), (m, 2H), (q, J = 6.5 Hz, 2H), (q, J = 6.5 Hz, 2H), (t, J = 7.5 Hz, 3H), (t, J = 7.5 Hz, 3H). 13 C MR (125 MHz, CDCl 3 ): δ = ,137.45,137.39,135.08, ,130.35,128.66,127.52,125.78,47.16,45.31,25.87,24.47,22.69,21.52,14.27, 3

4 HR-MS (ESI): m/z calculated for C 19 H 25 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , (2Z,4E)-4-methyl-2-phenyl-1-(pyrrolidin-1-yl)hexa-2,4-dien-1-one (3ac) This compound was obtained according to the general procedure as a brown oil (23.1 mg, yield = 45%). 1 H MR (500 MHz, CDCl 3 ): δ = (m, 2H), (m, 3H), (m, 1H), 6.40 (s, 1H), (t, J = 7.0 Hz, 2H), 3.15 (brs, 2H), (m, 3H), 1.75 (m, 4H), (d, J = 7.0 Hz, 3H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , 47.39, 45.25, 25.74, 24.57, 14.30, HR-MS (ESI): m/z calculated for C 17 H 21 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , Methyl (2Z,4Z)-6-oxo-3,5-diphenyl-6-(pyrrolidin-1-yl)hexa-2,4-dienoate (3ad) This compound was obtained according to the general procedure as a yellow oil (38.3 mg, yield = 53%). 1 H MR (500 MHz, CDCl 3 ): δ = 7.50 (s, 1H), (m, 4H), (m, 6H), 6.59 (d, J = 1.5 Hz, 1H), 3.72 (s, 3H), 3.42 (t, J = 6.5 Hz, 2H), 2.97 (t, J = 6.5 Hz, 2H), (m, 2H), (m, 2H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , 51.19, 46.29, 44.61, 24.92, HR-MS (ESI): m/z calculated for C 23 H 23 3 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , ,

5 Me (2Z,4Z)-2,4-diphenyl-1-(pyrrolidin-1-yl)hexa-2,4-dien-1-one(3ae) This compound was obtained according to the general procedure as a light green oil (30.4 mg, yield = 48%). 1 H MR (500 MHz, CDCl 3 ): δ = (m, 2H), (m, 4H), (m, 4H), 6.69 (s, 1H), 6.58 (d, J = 0.5 Hz, 1H), 3.54 (t, J = 7.0 Hz, 2H), 3.20 (brs, 2H), 2.02 (d, J = 1.0 Hz, 3H), (m, 2H), (m, 2H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , 47.48, 45.36, 25.81, 24.56, HR-MS (ESI): m/z calculated for C 22 H 23 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , (2Z,4Z)-4,5-bis(4-butylphenyl)-2-phenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (3af) This compound was obtained according to the general procedure as a yellow oil (65.9 mg, yield = 67%). 1 H MR (500 MHz, CDCl 3 ): δ = (m, 2H), (m, 2H), (m,1h), (m, 4H), 6.82 (d, J = 8.5 Hz, 2H), 6.76 (s, 1H), (m, 3H), 3.13 (brs, 4H), 2.55 (t, J = 7.5 Hz, 2H), 2.42 (t, J = 7.5 Hz, 2H), (m, 6H), (m, 6H), 0.88 (t, J = 7.0 Hz, 3H), 0.81 (t, J = 7.5 Hz, 3H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , , 45.95, 43.84, 34.46, 34.30, 32.59, 32.30, 24.52, 23.14, 21.37, 21.34, 12.97, HR-MS (ESI): m/z calculated for C 35 H 41 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , ,

6 (2Z,4Z)-4,5-bis(4-bromophenyl)-2-phenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (3ag) This compound was obtained according to the general procedure as a yellow oil (73.1 mg, yield = 68%). 1 H MR (500 MHz, CDCl 3 ): δ = (m, 2H), (m, 2H), (m, 2H), (m, 1H), (m, 2H), (m, 2H), 6.73 (s, 1H), (m, 3H), 2.95 (brs, 4H), 1.58 (brs, 4H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , , 45.85, 43.88, 24.57, HR-MS (ESI): m/z calculated for C 27 H 23 Br 2 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , , (2Z,4Z)-4,5-bis(3-bromophenyl)-2-phenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (3ah) This compound was obtained according to the general procedure as a yellow solid (75.6 mg, yield = 70%). Melting point: H MR (500 MHz, CDCl 3 ): δ = (m, 1H), (m, 2H), (m, 3H), (m, 4H), 6.95 (s, 1H), 6.88 (t, J = 8.0 Hz, 4H), 6.73 (s, 1H), (m, 2H), (brs, 4H), (m, 4H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , , , , , , 45.96, 43.94, 24.64, HR-MS (ESI): m/z calculated for C 27 H 23 Br 2 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , ,

7 (2Z,4Z)-2-phenyl-1-(pyrrolidin-1-yl)-4,5-bis(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)penta-2,4-dien-1-one (3ai) This compound was obtained according to the general procedure as a yellow oil (63.1 mg, yield = 50%). 1 H MR (500 MHz, CDCl 3 ): δ = (d, J = 13.0 Hz, 2H), (d, J = 8.0 Hz, 2H), (m, 2H), (m, 5H), 6.85 (s, 1H), 6.80 (d, J = 8 Hz, 2H), 6.69 (s, 1H), 3.04 (brs, 4H), (m, 4H), 1.27 (s, 12H), 1.21 (s, 1H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , 82.75, 82.68, 45.90, 43.86, 24.57, 23.87, 23.82, HR-MS (ESI): m/z calculated for C 39 H 47 B 2 5 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , , (2Z,4Z)-2-(4-fluorophenyl)-4,5-diphenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one(3ba) This compound was obtained according to the general procedure as a yellow oil (50.1 mg, yield = 63%). 1 H MR (500 MHz, CDCl 3 ): δ = (m, 2H), (m, 5H), (m, 5H), 6.82 (s, H), (m, 2H), 6.65 (s, 1H), 3.02 (brs, 4H), (m, 4H). 13 C MR (125 MHz, CDCl 3 ): δ = , (J C-F = Hz), , , , , , (J C-F = 3.3 Hz), (J C-F = 1.5 Hz), , , , , , , , (J C-F = 21.3 Hz), 7

8 46.93, 44.83, 25.57, HR-MS (ESI): m/z calculated for C 27 H 24 F: [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , (2Z,4Z)-4,5-diphenyl-1-(pyrrolidin-1-yl)-2-(4-(trifluoromethyl)phenyl)penta-2,4-dien-1-o ne (3ca) This compound was obtained according to the general procedure as a yellow solid (55.1 mg, yield = 61%). Melting point: H MR (500 MHz, CDCl 3 ): δ = (q, J = 8.5 Hz, 4H), (m, 3H), (m, 2H), (m, 3H), 6.86 (s, 1H), (m, 3H), (brs, 4H), (m, 4H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , (J C-F = 32.3 Hz), , , , , , , (J C-F = 3.8 Hz), (J C-F = Hz), 45.90, 43.84, 24.51, HR-MS (ESI): m/z calculated for C 28 H 24 F 3 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , Cl (2Z,4Z)-2-(3-chlorophenyl)-4,5-diphenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (3da) This compound was obtained according to the general procedure as a yellow oil (105.3 mg, yield = 85%). 1 H MR (500 MHz, CDCl 3 ): δ = 7.37 (s, 1H), (m, 2H), (m, 2H), (m, 4H), (m, 3H), 6.83 (s, 1H), (m, 2H), 6.70 (s, 1H), (brs, 4H), (m, 4H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , , , 8

9 123.22, 45.90, 43.80, 24.51, HR-MS (ESI): m/z calculated for C 27 H 24 Cl: [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , (2Z,4Z)-2-(2-fluorophenyl)-4,5-diphenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (3ea) This compound was obtained according to the general procedure as a yellow oil (45.5 mg, yield = 43%). 1 H MR (500 MHz, CDCl 3 ): δ = (m, 1H), (m, 6H), (m, 5H), (m, 3H), 6.71 (s, 1H), 3.20 (t, J = 7.0 Hz, 2H), (brs, 2H), (m, 2H), (m, 2H). 13 C MR (125 MHz, CDCl 3 ): δ = , (J C-F = Hz), , , , (J C-F = 5.4 Hz), , (J C-F = 1.3 Hz), (J C-F = 2.9 Hz), , , (J C-F = 8.5 Hz), , , , , (J C-F = 11.9 Hz), (J C-F = 3.5 Hz), (J C-F = 22.8 Hz), 46.02, 43.96, 24.59, HR-MS (ESI): m/z calculated for C 27 H 24 F: [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , (2Z,4Z)-2-(4-(tert-butyl)phenyl)-4,5-diphenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (3fa) This compound was obtained according to the general procedure as a yellow solid (62.9 mg, yield = 72%). Melting point: H MR (500 MHz, CDCl 3 ): δ = (m, 5H), (m, 4H), (t, J = 5.0 Hz, 3H), (m, 3H), 6.69 (s, 1H), (brs, 4H), (brs, 4H), 9

10 1.23 (s, 9H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , , 45.93, 43.74, 33.55, 30.22, 24.58, HR-MS (ESI): m/z calculated for C 31 H 33 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , (2Z,4Z)-2-(4-methoxyphenyl)-4,5-diphenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (3ga) This compound was obtained according to the general procedure as a yellow oil (27.2 mg, yield = 33%). 1 H MR (500 MHz, CDCl 3 ): δ = (m, 4H), (m, 3H), (m, 3H), (m, 5H), 6.63 (s, 1H), 3.74 (s, 3H), 3.05 (brs, 2H), (m, 4H), (m, 2H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , , 54.29, 45.89, 43.74, 24.57, HR-MS (ESI): m/z calculated for C 28 H 27 2 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , (2Z,4Z)-2-(naphthalen-2-yl)-4,5-diphenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one (3ha) This compound was obtained according to the general procedure as a yellow oil (59.4 mg, yield = 69%). 1 H MR (500 MHz, CDCl 3 ): δ = (d, J = 8.5 Hz, 1H), (d, J = 8.0 Hz, 1H), (d, J = 8.5 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), (m, 3H), (m, 2H), (m, 3H), (m, 2H), 6.74 (s, 1H), 6.61 (s, 1H), 3.02 (t, J = 6.5 Hz, 2H), (t, J = 7.0 Hz, 2H), (m, 2H), (m, 2H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , 10

11 128.50, , , , , , , , , , , 45.69, 44.05, 24.54, HR-MS (ESI): m/z calculated for C 31 H 27 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , (2Z,4Z)-,-dimethyl-2,4,5-triphenylpenta-2,4-dienamide (3ia) This compound was obtained according to the general procedure as a yellow solid (32.5 mg, yield = 46%). Melting point: H MR (500 MHz, CDCl 3 ): δ = (m, 2H), (m, 3H), (m, 5H), 6.98 (t, J = 3.0 Hz, 3H), (m, 3H), 6.73 (s, 1H), 2.62 (s, 3H), 2.37 (s, 3H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , , 37.92, HR-MS (ESI): m/z calculated for C 25 H 23 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , , (2Z,4Z)-2,4,5-triphenyl-1-(piperidin-1-yl)penta-2,4-dien-1-one (3ja) This compound was obtained according to the general procedure as a yellow oil (20.5 mg, yield = 26%). 1 H MR (500 MHz, CDCl 3 ): δ = (m, 2H), (m, 8H), (m, 3H), 6.87 (s, 1H), (m, 2H), 6.68 (s, 1H), (d, J = 12.5 Hz, 1H), (d, J = 13.0 Hz, 1H), 2.96 (t, J = 11.0 Hz 1H), (q, J = 6.5 Hz, 1H), 1.09 (s, 1H), 1.47 (s, 1H), (m, 4H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , , , , , 47.60, 41.57, 25.89, 25.18, HR-MS (ESI): m/z calculated for C 28 H 27 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , ,

12 (2Z,4Z)-2-(cyclohex-1-en-1-yl)-1-cyclopentyl-4,5-diphenylpenta-2,4-dien-1-one (3ka) This compound was obtained according to the general procedure as a yellow oil (15.0 mg, yield = 21 %). 1 H MR (500 MHz, CDCl 3 ): δ = (m, 5H), (m, 3H), (m, 2H), 6.57 (s, 1H), 3.36 (t, J = 6.5 Hz, 2H), 3.17 (brs, 2H), 2.26 (brs, 2H), 2.02 (brs, 2H), (m, 2H), (m, 6H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , 46.34, 43.91, 28.12, 26.30, 24.92, 23.26, 21.59, HR-MS (ESI): m/z calculated for C 25 H 27 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , , , (3la) (2Z,4Z)-2-methyl-4,5-diphenyl-1-(pyrrolidin-1-yl)penta-2,4-dien-1-one This compound was obtained according to the general procedure as a yellow oil (20.5 mg, yield = 33%). 1 H MR (500 MHz, CDCl 3 ): δ = (m, 3H), (m, 2H), (m, 3H), (m, 2H), 6.61 (s, 1H), 6.10 (s, 1H), (t, J = 7.0 Hz, 2H), (brs, 2H), 1.95 (d, J = 1.5 Hz, 3H ), (t, J = 7.0 Hz, 2H), (t, J = 6.0 Hz, 2H). 13 C MR (125 MHz, CDCl 3 ): δ = , , , , , , , , , , , , , 45.85, 43.69, 24.63, 23.15, HR-MS (ESI): m/z calculated for C 22 H 23 : [M+H] + : , found: FTIR (KBr, cm -1 ): , , , , , ,

13 Gram-Scale Synthesis of 3aa An oven-dried vial was charged with [Ru(p-cymene)Cl 2 ] 2 (92.0 mg, 3 mol %, 0.15 mmol), AgSbF 6 (206.0 mg, 12 mol %, 0.60 mmol) and THF (20 ml). Then, alkyne 2a (1.78 g, 10.0 mmol) and acrylamide 1a (1.00 g, 5.0 mmol) were added into the solution in sequence. The vial was sealed under argon and heated to 100 with stirring for 24 hours. After cooling down, the mixture was concentrated to give the crude product which was directly applied to a flash column chromatography for purification (EtAc/Petroleum ether mixtures). The desired product was obtained as yellow oil (1.76 g, 92% yield). 13

14 Deuterium-Labeled Experiments H/D exchange in 1a 1a + CD 3 CD (10.0 equiv.) Standard Cond. 3 h H H/D 1a-d, 53% 70% D An oven-dried vial was charged with [Ru(p-cymene)Cl 2 ] 2 (6.1 mg, 5.0 mol %, 0.01 mmol), AgSbF 6 (13.7 mg, 20 mol %, 0.04 mmol), THF (1.0 ml) and AcD (10.0 eq, 2.0 mmol). Then, acrylamide 1a (40.2 mg, 0.2 mmol) was added into the solution. The vial was sealed under argon and heated to 100 with stirring for 3 hours. After cooling down, the mixture was directly applied to a flash column chromatography (EtAc/petroleum ether mixtures) on silica gel (22.2 mg, 53% recovered). The D % of 1a-d was estimated by 1 H MR. 14

15 Competitive Deuteration Experiments + D D 1a, 0.1 mmol 1a-d 2, 0.1 mmol 2a, 0,04mmol Standard Cond. k H /k D = D D 3a 3a- d 2 A 10 ml vial was charged with [Ru(p-cymene)Cl 2 ] 2 (3.1 mg, 5.0 mol %), AgSbF 6 (6.9 mg, 20 mol %) and THF (1.0 ml). Then, alkyne 2a (0.04 mmol), acrylamide 1a (20.1 mg, 0.1 mmol) and 1a-d 2 (20.3 mg, 0.1 mmol) were added into the solution in sequence. The vial was sealed under Ar and heated to 100 with stirring for overnight. After cooling down, the mixture was concentrated in vacuo and purified by column chromatography affording the product (19.0 mg, ~25%) as yellow oil. The ratio of 3a/3a-d 2 was determined by 1 H MR (500 MHz, CDCl 3 ) to be

16 Determination of Intermolecular Kinetic Isotope Effect (in parallel) 1a, 0.2 mmol + 2a, 0.4mmol Standard Cond. 1.5 h 1 H MR yield = 19% 3aa D D 1a-d 2, 0.2 mmol + 2a, 0.4mmol Standard Cond. 1.5 h 1 H MR yield = 8% D D 3aa-d 2 An oven-dried 10 ml vial was charged with [Ru(p-cymene)Cl 2 ] 2 (6.2 mg, 0.01 mmol, 5 mol %), AgSbF 6 (13.7 mg, 0.04 mmol, 20 mol %) and THF (1.0 ml). Then, alkyne 2a (71.2 mg, 0.4 mmol, 2.0 equiv) and acrylamide 1a (40.2 mg, 0.20 mmol, 1.0 equiv) were added into the solution in sequence. The vial was sealed under argon and heated to 100 with stirring for 16 hours. Another oven-dried 10 ml vial was also charged with [Ru(p-cymene)Cl 2 ] 2 (6.2 mg, 5 mol %, 0.01 mmol), AgSbF 6 (13.7 mg, 20 mol %, 0.04 mmol) and THF (1.0 ml). Then, alkyne 2a (71.2 mg, 0.4 mmol, 2.0 equiv) and acrylamide 1a-d 2 (40.7 mg, 0.20 mmol, 1.0 equiv.) were added into the solution in sequence. These two reaction mixture was stirred in a preheated oil bath at 100 C for 1.5 h. Two reaction vials were cooled by ice, filtered separately by silica column, washed with EtAc/Hexane. After the removal of solvent, the crude product mixtures were dissolved carefully in CDCl 3 and trimethoxybenzene (0.1 mmol) was added as an internal standard in parallel. 1 H MR was measured for these two samples separately, which shows that 3aa and 3aa-d were obtained in 20% and 8% yields respectively. The primary intermolecular kinetic isotope effect (KIE) was measured as ~

17 D D 1a-d 2 + 2a Standard Cond. 3 h + D D D 1a-d 2, 34% 3a-d 2, 24% D A 10 ml vial was charged with [Ru(p-cymene)Cl 2 ] 2 (3.1 mg, 5.0 mol %), AgSbF 6 (6.9 mg, 20 mol %) and THF (1.0 ml). Then, alkyne (35.7 mg, 0.2 mmol) and 1a-d 2 (20.3 mg, 0.1 mmol) were added into the solution in sequence. The vial was sealed under Ar and heated to 100 with stirring for 3 h. After cooling down, the mixture was concentrated in vacuo and purified by column chromatography affording the product 3a-d 2 (9.1 mg, 24% yield), and 1a-d 2 was recovered (7.0 mg, 34% recovered). 17

18 Competitive reaction of different alkynes with acrylamide 1a A 10 ml vial was charged with [Ru(p-cymene)Cl 2 ] 2 (3.1 mg, 5.0 mol %), AgSbF 6 (6.9 mg, 20 mol %) and THF (1.0 ml). Then, 1,2-diphenylethyne (2a) (35.7 mg, 0.2 mmol ), hex-3-yne (2b) (16.4 mg, 0.2 mmol) and 2-phenyl-1-(pyrrolidin-1-yl) prop-2-en- 1-one (1a) (40.2 mg, 0.2 mmol) were added into the solution in sequence. The vial was sealed under Ar and heated to 100 with stirring for overnight. After cooling down, the mixture was concentrated in vacuo and purified by column chromatography affording the product 3aa (20.0 mg, 26%) and 3ab (19.6 mg, 35%). Competitive reaction of different acrylamides with alkyne 2a A 10 ml vial was charged with [Ru(p-cymene)Cl 2 ] 2 (3.1 mg, 5.0 mol %), AgSbF 6 (6.9 mg, 20 mol %) and THF (1.0 ml). Then, 2-(4-fluorophenyl)-1-(pyrrolidin-1-yl) prop-2-en-1-one (1b) (43.8mg, 0.2 mmol), 2-(4-methoxyphenyl)-1-(pyrrolidin-1-yl) prop-2-en-1-one (1g) (46.2 mg, 0.2 mmol) and 1,2-diphenylethyne (2a) (35.65 mg, 0.2 mmol ) were added into the solution in sequence. The vial was sealed under Ar and heated to 100 with stirring for overnight. After cooling down, the mixture was concentrated in vacuo and purified by column chromatography affording the product 3ba (36.0 mg, 46 %) and 3ga (26.4 mg, 32%). 18

19 References: 1. Zhang, J.; Loh, T. P. Chem. Commun. 2012, 48, Li, F.; Yu, C.; Zhang, J.; Zhong, G. rg. Lett. 2016, 18,

20 MR Spectra 3aa 20

21 3ab 21

22 Me Me 3ac 22

23 CMe 3ad 23

24 Me 3ae 24

25 n Bu n Bu 3af 25

26 Br Br 3ag 26

27 Br Br 3ah 27

28 B B 3ai 28

29 F 3ba 29

30 F 3 C 3ca 30

31 Cl 3da 31

32 F 3ea 32

33 t-bu 3fa 33

34 3ga 34

35 3ha 35

36 Me Me 3ia 36

37 3ja 37

38 3ka 38

39 Me 3la 39

40 D D 1a-d 2 D D 3aa-d 2 40

41 (3aa) E 41