Palladium-catalyzed Decarbonylative Alkynylation of Aromatic Esters

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Palladium-catalyzed Decarbonylative Alkynylation of Aromatic Esters Toshimasa Okita, 1 Kazushi Kumazawa, 2 Ryosuke Takise, 2 Kei Muto, 1 Kenichiro Itami,* 2,3 and Junichiro Yamaguchi* 1 1 Department of Applied Chemistry, Waseda University, 3-4-1 Ohkubo, Shinjuku, Tokyo 169-8555 2 Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University, Chikusa, Nagoya, Aichi 464-8602 3 JST-ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya, Aichi 464-8602 (Received November 2, 2016; CL-161001; E-mail: itami@chem.nagoya-u.ac.jp, junyamaguchi@waseda.jp) Copyright The Chemical Society of Japan

Table of Contents 1. General S2 S3 2. Preparation of Starting Materials S3 S4 3. Pd-Catalyzed Decarbonylative Alkynylation S4 S10 4. Orthogonal Cross-coupling S10 S11 5. Effect of Parameters S12 6. The Scope of Alkynes S13 7. 1 H NMR and 13 C NMR Spectra S14 S57 S1

1. General Unless otherwise noted, all materials including dry solvents were obtained from commercial suppliers and used as received. CuI and triisopropylsilylacetylene were obtained from Kanto Chemical. Diethylamine was obtained from Wako Chemicals and freshly distilled before use. Palladium(II) acetylacetonate was obtained from Sigma-Aldrich. Phenyl nicotinate (1A) 1, phenyl picolinate (1B) 1, phenyl isonicotinate (1C) 1, phenyl isoquinoline-1-carboxylate (1D) 2, phenyl quinoline-2-carboxylate (1E) 2, phenyl 2-phenylquinoline-4-carboxylate (1F) 1, phenyl pyrazine-2-carboxylate (1G) 1, phenyl 5-methylpyrazine-2-carboxylate (1H) 2, phenyl 6-(trifluoromethyl)nicotinate (1I) 2, phenyl thiophene-2-carboxylate (1K) 1, phenyl benzo[b]thiophene-2-carboxylate (1L) 3, phenyl thiophene-3-carboxylate (1M) 1, phenyl furan-2-carboxylate (1N) 1, phenyl 2-phenylthiazole-4-carboxylate (1O) 4, phenyl 2-fluorobenzoate (1P) 5, methyl phenyl terephthalate (1Q) 6 and 3,4-bis(dicyclohexylphosphino)thiophene (dcypt) 7 were synthesized according to procedures reported in the literature. Unless otherwise noted, all reactions were performed with dry solvents under an atmosphere of N 2 gas in dried glassware using standard vacuum-line techniques. All coupling reactions were performed in 20-mL glass vessel tubes equipped with J. Young O-ring tap and heated in an 8-well reaction block (heater + magnetic stirrer) unless otherwise noted. All work-up and purification procedures were carried out with reagent-grade solvents in air. Analytical thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F 254 precoated plates (0.25 mm). The developed chromatogram was analyzed by UV lamp (254 nm). Flash column chromatography was performed with E. Merck silica gel 60 (230 400 mesh) or Biotage Isolera equipped with Biotage SNAP Cartridge KP-Sil columns and hexane/etoac as an eluent. Preparative thin-layer chromatography (PTLC) was performed using Wakogel B5-F silica coated plates (0.75 mm) prepared in our laboratory. GCMS analysis was conducted on a Shimadzu GCMS-QP2010 instrument equipped with a HP-5 column (30 m 0.25 mm, Hewlett-Packard). High-resolution mass spectra (HRMS) were obtained from a JMS-T100TD instrument (DART) and Thermo Fisher Scientific Exactive (ESI). Nuclear magnetic resonance (NMR) spectra were recorded on a JEOL JNM-ECA-400 ( 1 H 400 MHz, 13 C 100 MHz) and JNM-ECA-600 ( 1 H 600 MHz, 13 C 150 MHz) spectrometer. Chemical shifts for 1 H NMR are expressed in parts per million (ppm) relative to tetramethylsilane (δ 0.00 ppm). Chemical shifts for 13 C NMR are expressed in ppm relative to CDCl 3 (δ 77.0 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, dd = doublet of doublets, ddd = doublet of doublet of doublets, t = triplet, dt = doublet of triplets, td = 1. Amaike, K.; Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134, 13573. 2. Muto, K.; Hatakeyama, T.; Itami, K.; Yamaguchi, J. Org. Lett. 2016, 18, 5106. 3. Muto, K.; Yamaguchi, J.; Musaev, D. G.; Itami, K. Nat. Commun. 2015, 6, 7508. 4. Chen, H.; O'Connor, S.; Cane, D. E.; Walsh, C. T. Chem. Biol. 2001, 8, 899. 5. Liu, C.; Chen, W.; Shi, W.; Peng, B.; Zhao, Y.; Ma, H.; Xian, M. J. Am. Chem. Soc. 2014, 136, 7257. 6. LaBerge, N. A.; Love, J. A. Eur. J. Org. Chem. 2015, 25, 5546. 7. Takise, R.; Muto, K.; Yamaguchi, J.; Itami, K. Angew. Chem., Int. Ed. 2014, 53, 6791. S2

triplet of doublets, q = quartet, m = multiplet, br = broad signal), coupling constant (Hz), and integration. 2. Preparation of Starting Materials To a round-bottomed flask with arenecarboxylic acid (1.0 equiv) were added phenol (1.0 equiv), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC HCl: 1.5 equiv), N,N-dimethyl-4-aminopyridine (DMAP: 0.25 equiv) and CH 2 Cl 2 (0.5 M). After stirring the mixture at room temperature for several hours with monitoring the reaction progress by TLC, the reaction was quenched with saturated NaHCO 3 aq and extracted three times with CH 2 Cl 2. The combined organic layer was dried over Na 2 SO 4, filtrated, and concentrated in vacuo. The residue was purified by flash column chromatography or Isolera to afford the corresponding phenyl arenecarboxylate 1. Phenyl 2,6-diphenylisonicotinate (1J) Purification by flash column chromatography (hexane/etoac = 5:1) afforded 1J as a white solid (978.3 mg, 93% yield, 3.0 mmol scale). 1 H NMR (CDCl 3, 400 MHz) δ 8.41 (s, 2H), 8.28 8.22 (m, 4H), 7.58 7.52 (m, 4H), 7.51 7.45 (m, 4H), 7.33 (t, J = 7.6 Hz, 1H), 7.30 7.26 (m, 2H); 13 C NMR (CDCl 3, 100 MHz) δ 164.2, 158.1, 150.6, 138.7, 138.5, 129.7, 129.6, 128.8, 127.1, 126.4, 121.5, 118.1; HRMS (ESI) m/z calcd for C 24 H 18 NO 2 [M+H] + : 352.1332, found 352.1332. Phenyl 5-bromopicolinate (5) Purification by Isolera (hexane/etoac = 19:1) and recrystallization from hexane afforded 5 as a white solid (653.6 mg, 80% yield, 2.4 mmol scale). 1 H NMR (CDCl 3, 400 MHz) δ 8.90 (d, J = 2.4 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 8.06 (dd, J = 8.4, 2.4 Hz, 1H), 7.45 (dd, J = 7.6, 7.2 Hz, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.2 Hz, 2H); 13 C NMR (CDCl 3, 100 MHz) δ 163.2, 151.4, 150.7, 145.8, S3

139.9, 129.6, 126.9, 126.3, 125.6, 121.5; HRMS (ESI) m/z calcd for C 12 H 9 BrNO 2 [M+H] + : 277.9811, found 277.9812. 3. Pd-Catalyzed Decarbonylative Alkynylation A 20-mL glass vessel equipped with J. Young O-ring tap containing a magnetic stirring bar and molecular sieves 3A (100 mg) was dried with a heatgun in vacuo and filled with N 2 gas after cooling to room temperature. To this vessel were added phenyl arenecarboxylate 1 (0.40 mmol, 1.0 equiv), Pd(acac) 2 (6.09 mg, 0.020 mmol, 5 mol%), dcypt (19.1 mg, 0.040 mmol, 10 mol%), and CuI (7.62 mg, 0.040 mmol, 10 mol%). The vessel was vacuumed and refilled N 2 gas three times. To this were added triisopropylsilylacetylene (2a: 218.9 mg, 1.20 mmol, 3.0 equiv), diethylamine (117.0 mg, 1.60 mmol, 4.0 equiv), and 1,4-dioxane (1.2 ml). The vessel was sealed with O-ring tap and then heated at 150 170 C for 16 h in an 8-well reaction block with stirring. After cooling the reaction mixture to room temperature, the mixture was passed through a short silica-gel pad with EtOAc. The filtrate was concentrated and the residue was purified by Isolera and PTLC to afford the corresponding cross-coupling product 3. 3-((Triisopropylsilyl)ethynyl)pyridine (3Aa) Purification by Isolera (hexane/etoac = 19:1 to EtOAc) and PTLC (hexane/etoac = 4:1) afforded 3Aa as a yellow liquid (61.5 mg, 59% yield by the reaction at 150 C: 65.6 mg, 63% yield by the reaction at 170 C). 1 H NMR (CDCl 3, 400 MHz) δ 8.70 (s, 1H), 8.53 (dt, J = 5.2, 1.6 Hz, 1H), 7.75 (dt, J = 8.0, 1.6 Hz, 1H), 7.24 (dd, J = 8.0, 5.2 Hz, 1H), 1.16 1.07 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 152.7, 148.5, 138.8, 122.8, 120.6, 103.4, 94.8, 18.6, 11.2; HRMS (ESI) m/z calcd for C 16 H 26 NSi [M+H] + : 260.1829, found 260.1828. S4

2-((Triisopropylsilyl)ethynyl)pyridine (3Ba) 8 Purification by Isolera (hexane/etoac = 19:1 to EtOAc) afforded 3Ba as a yellow liquid (54,6 mg, 52% yield by the reaction at 160 C: 56.8 mg, 55% yield by the reaction at 170 C). 1 H NMR (CDCl 3, 400 MHz) δ 8.59 (d, J = 5.2 Hz, 1H), 7.63 (td, J = 8.0, 2.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.22 (dd, J = 8.0, 5.2 Hz, 1H), 1.17 1.12 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 149.9, 143.4, 136.0, 127.7, 122.8, 105.9, 91.5, 18.6, 11.2; HRMS (ESI) m/z calcd for C 16 H 26 NSi [M+H] + : 260.1829, found 260.1827. 4-((Triisopropylsilyl)ethynyl)pyridine (3Ca) Purification by Isolera (hexane/etoac = 19:1 to EtOAc) or PTLC (hexane/etoac = 5:1) afforded 3Ca as a yellow liquid (56.2 mg, 54% yield by the reaction at 150 C: 64.4 mg, 62% yield by the reaction at 170 C). 1 H NMR (CDCl 3, 400 MHz) δ 8.56 (d, J = 5.2 Hz, 2H), 7.32 (d, J = 5.2 Hz, 2H), 1.15 1.09 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 149.6, 131.5, 125.9, 104.0, 96.7, 18.6, 11.2; HRMS (ESI) m/z calcd for C 16 H 26 NSi [M+H] + : 260.1829, found 260.1831. 1-((Triisopropylsilyl)ethynyl)isoquinoline (3Da) Purification by PTLC (hexane/etoac = 9:1) afforded 3Da as a yellow liquid (52.2 mg, 42% yield by the reaction at 170 C). 1 H NMR (CDCl 3, 400 MHz) δ 8.52 (d, J = 6.0 Hz, 1H), 8.46 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.69 (dd, J = 8.4, 6.8 Hz, 1H), 7.66 (dd, J = 8.2, 6.8 Hz, 1H), 7.60 (d, J = 6.0 Hz, 1H), 1.30 1.17 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 144.1, 142.7, 135.6, 130.4, 129.5, 128.0, 126.9, 126.8, 120.6, 103.6, 96.8, 18.7, 11.2; HRMS (ESI) m/z calcd for C 20 H 28 NSi [M+H] + : 310.1989, found 310.1984. 2-((Triisopropylsilyl)ethynyl)quinoline (3Ea) 8. Tuesuwan, B.; Kerwin, S. M. Biochemistry 2006, 45, 7265. S5

Purification by Isolera (hexane/etoac = 19:1 to EtOAc) or PTLC (hexane/etoac = 10:1) afforded 3Ea as a yellow liquid (56.5 mg, 46% yield by the reaction at 150 C: 69.7 mg, 55% yield by the reaction at 160 C). 1 H NMR (CDCl 3, 600 MHz) δ 8.11 (d, J = 8.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.70 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.55 7.47 (m, 2H); 1.21 1.16 (m, 21H); 13 C NMR (CDCl 3, 150 MHz) δ 148.1, 143.5, 135.8, 129.8, 129.4, 127.4, 127.1, 127.0, 125.0, 106.6, 92.8, 18.6, 11.3; HRMS (ESI) m/z calcd for C 20 H 28 NSi [M+H] + : 310.1986, found 310.1982. 2-Phenyl-4-((triisopropylsilyl)ethynyl)quinoline (3Fa) Purification by PTLC (hexane/etoac = 4:1) afforded 3Fa as a yellow liquid (92.5 mg, 60% yield by the reaction at 150 C: 134 mg, 87% yield by the reaction at 160 C). 1 H NMR (CDCl 3, 400 MHz) δ 8.30 (dd, J = 8.4, 1.2 Hz, 1H), 8.19 8.13 (m, 3H), 8.00 (s, 1H), 7.75 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.59 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.56 7.50 (m, 2H), 7.49 7.44 (m, 1H), 1.26 1.17 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 156.8, 148.1, 139.1, 130.4, 130.1, 130.0, 129.4, 128.8, 127.5, 126.9, 126.8, 125.7, 122.2, 102.6, 101.1, 18.7, 11.3; HRMS (ESI) m/z calcd for C 26 H 32 NSi [M+H] + : 386.2299, found 386.2299. 2-((Triisopropylsilyl)ethynyl)pyrazine (3Ga) Purification by PTLC (hexane/etoac = 10:1) afforded 3Ga as a yellow liquid (61.3 mg, 59% yield by the reaction at 160 C). 1 H NMR (CDCl 3, 600 MHz) δ 8.69 (d, J = 1.2 Hz, 1H), 8.54 (dd, J = 2.4, 1.2 Hz, 1H), 8.47 (d, J = 2.4 Hz, 1H), 1.20 1.12 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 148.2, 144.3, 142.9, 140.2, 102.8, 96.8, 18.6, 11.2; HRMS (ESI) m/z calcd for C 15 H 25 N 2 Si [M+H] + : 261.1782, found 261.1781. 2-Methyl-5-((triisopropylsilyl)ethynyl)pyrazine (3Ha) Purification by PTLC (hexane/etoac = 9:1) afforded 3Ha as a yellow liquid (61.9 mg, 57% yield by the reaction at 160 C). 1 H NMR (CDCl 3, 400 MHz) δ 8.57 (d, J = 1.6 Hz, 1H), 8.42 (d, J = 1.6 Hz, S6

1H), 2.58 (s, 3H), 1.23 1.11 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 152.4, 147.0, 144.0, 136.9, 102.9, 95.4, 21.6, 18.6, 11.1; HRMS (ESI) m/z calcd for C 16 H 27 N 2 Si [M+H] + : 275.1938, found 275.1938. 2-(Trifluoromethyl)-5-((triisopropylsilyl)ethynyl)pyridine (3Ia) Purification by PTLC (hexane/etoac = 20:1) afforded 3Ia as a colorless liquid (74.5 mg, 57% yield by the reaction at 150 C, 121.2 mg, 74% yield by the reaction at 170 C). 1 H NMR (CDCl 3, 400 MHz) δ 8.76 (d, J = 1.6 Hz, 1H), 7.91 (dd, J = 8.0, 1.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 1.19 1.11 (m, 21H); 13 C NMR (CDCl 3, 150 MHz) δ 152.6, 146.6 (q, J C F = 39 Hz), 140.0, 123.6, 121.3 (q, J C F = 275 Hz), 119.7, 102.0, 98.3, 18.6, 11.2; HRMS (ESI) m/z calcd for C 17 H 25 F 3 NSi [M+H] + : 328.1703, found 328.1703. 2,6-Diphenyl-4-((triisopropylsilyl)ethynyl)pyridine (3Ja) Purification by PTLC (hexane/et 2 O = 20:1) afforded 3Ja as a colorless liquid (84.4 mg, 51% yield by the reaction at 150 C, 89.6 mg, 68% yield by the reaction at 170 C). 1 H NMR (CDCl 3, 400 MHz) δ 8.13 (d, J = 7.6 Hz, 4H), 7.71 (s, 2H), 7.48 (t, J = 7.6 Hz, 4H), 7.42 (t, J = 7.6 Hz, 2H), 1.22 1.13 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 157.0, 138.9, 132.8, 129.2, 128.7, 127.0, 120.9, 104.8, 95.7, 18.7, 11.2; HRMS (ESI) m/z calcd for C 28 H 34 NSi [M+H] + : 412.2455, found 412.2454. Triisopropyl(thiophen-2-ylethynyl)silane (3Ka) 9 Purification by PTLC (hexane) afforded 3Ka as a colorless liquid (41.1 mg, 39% yield by the reaction at 170 C). 1 H NMR (CDCl 3, 400 MHz) δ 7.23 7.19 (m, 2H), 6.94 (dd, J = 4.8, 3.6 Hz, 1H), 1.14 1.08 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 132.4, 126.9, 126.8, 123.7, 99.3, 95.3, 18.6, 11.3; HRMS (DART) m/z calcd for C 15 H 25 SSi [M+H] + : 265.1446, found 265.1442. 9. Brand, J. P.; Waser, J. Angew. Chem., Int. Ed. 2010, 49, 7304. S7

(Benzo[b]thiophen-2-ylethynyl)triisopropylsilane (3La) 9 Purification by PTLC (hexane) afforded 3La as a yellow liquid (52.3 mg, 42% yield by the reaction at 150 C). 1 H NMR (CDCl 3, 400 MHz) δ 7.76 7.67 (m, 2H), 7.44 (s, 1H), 7.37 7.30 (m, 2H), 1.18 1.10 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 140.1, 138.9, 129.2, 125.4, 124.6, 123.7, 123.4, 121.9, 99.6, 97.8, 18.6, 11.3; HRMS (DART) m/z calcd for C 19 H 27 SSi [M+H] + : 315.1603, found 315.1603. Triisopropyl(thiophen-3-ylethynyl)silane (3Ma) Purification by PTLC (hexane) afforded 3Ma as a light yellow liquid (45.4 mg, 43% yield by the reaction at 170 C). 1 H NMR (CDCl 3, 400 MHz) δ 7.45 (dd, J = 3.2, 1.2 Hz, 1H), 7.21 (dd, J = 5.2, 3.2 Hz, 1H), 7.11 (dd, J = 5.2, 1.2 Hz, 1H), 1.17 1.09 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 130.2, 129.2, 125.0, 122.8, 101.7, 90.1, 18.6, 11.3; HRMS (DART) m/z calcd for C 15 H 25 SSi [M+H] + : 265.1446, found 265.1446. (Furan-2-ylethynyl)triisopropylsilane (3Na) Purification by PTLC (hexane) afforded 3Na as a yellow liquid (43.1 mg, 43% yield by the reaction at 160 C: 53.3 mg, 54% yield by the reaction at 170 C). 1 H NMR (CDCl 3, 400 MHz) δ 7.34 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 3.2 Hz, 1H), 6.35 (dd, J = 3.2, 2.0 Hz, 1H), 1.17 1.08 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 143.2, 137.4, 115.4, 110.7, 96.1, 96.0, 18.6, 11.2; HRMS (DART) m/z calcd for C 15 H 25 OSi [M+H] + : 249.1675, found 249.1672. 2-Phenyl-4-((triisopropylsilyl)ethynyl)thiazole (3Oa) Purification by PTLC (hexane/etoac = 20:1) afforded 3Oa as a yellow liquid (72.7 mg, 53% yield by the reaction at 150 C: 75.6 mg, 55% yield by the reaction at 160 C). 1 H NMR (CDCl 3, 400 MHz) δ 8.00 7.94 (m, 2H), 7.46 (s, 1H), 7.46 7.41 (m, 3H), 1.20 1.12 (m, 21H); 13 C NMR (CDCl 3, 100 S8

MHz) δ 167.4, 138.5, 133.0, 130.3, 128.9, 126.8, 123.4, 100.5, 91.4, 18.6, 11.3; HRMS (ESI) m/z calcd for C 20 H 27 NSSiNa [M+Na] + : 364.1526, found 364.1526. ((2-Fluorophenyl)ethynyl)triisopropylsilane (3Pa) Purification by PTLC (hexane) afforded 3Pa as a yellow liquid (40.6 mg, 37% yield by the reaction at 170 C). 1 H NMR (CDCl 3, 400 MHz) δ 7.48 7.42 (m, 1H), 7.31 7.23 (m, 1H), 7.10 7.01 (m, 2H), 1.19 1.11 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 163.2 (d, J C F = 254 Hz), 133.9, 129.9 (d, J C F = 8 Hz), 123.7 (d, J C F = 4 Hz), 115.4 (d, J C F = 21 Hz), 112.1 (d, J C F = 16 Hz), 99.8, 96.7 (d, J C F = 3 Hz), 18.6, 11.2; HRMS (DART) m/z calcd for C 17 H 26 FSi [M+H] + : 277.1788, found 277.1788. Methyl 4-((triisopropylsilyl)ethynyl)benzoate (3Qa) Purification by PTLC (hexane/etoac = 9:1) afforded 3Qa as a yellow liquid (52.8 mg, 42% yield by the reaction at 160 C: 58.8 mg, 46% yield by the reaction at 170 C). 1 H NMR (CDCl 3, 400 MHz) δ 7.97 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 3.92 (s, 3H), 1.17 1.11 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 166.5, 131.9, 129.5, 129.3, 128.1, 106.1, 94.3, 52.1, 18.6, 11.2; HRMS (DART) m/z calcd for C 19 H 29 O 2 Si [M+H] + : 317.1937, found 317.1934. Analogous Decarbonylative Alkynylation using 2b A 20-mL glass vessel equipped with J. Young O-ring tap containing a magnetic stirring bar was dried with a heatgun in vacuo and filled with N 2 gas after cooling to room temperature. To this vessel were added 1A (79.7 mg, 0.40 mmol, 1.0 equiv), Pd(OAc) 2 (4.49 mg, 0.020 mmol, 5 mol%) and dcype (16.9 mg, 0.040 mmol, 10 mol%). The vessel was vacuumed and refilled N 2 gas three times. To this were added trimethyl(phenylethynyl)silane (2b: 139.5 mg, 0.80 mmol, 2.0 equiv) and 1,4-dioxane (1.6 ml). The vessel was sealed with O-ring tap and then heated at 170 C for 16 h in an 8-well reaction block with stirring. After cooling the reaction mixture to room temperature, the mixture was passed through a short silica-gel pad with EtOAc. The filtrate was concentrated and the residue was purified S9

by Isolera (hexane/etoac = 19:1 to EtOAc), and then PTLC (hexane/etoac = 3:1) to afford 3-(phenylethynyl)pyridine (3Ab) as a yellow solid (17.0 mg, 24% yield). 1 H NMR (CDCl 3, 400 MHz) δ 8.77 (s, 1H), 8.55 (dd, J = 5.2, 1.6 Hz, 1H), 7.81 (dt, J = 8.0, 1.6 Hz, 1H), 7.58 7.52 (m, 2H), 7.41 7.34 (m, 3H), 7.28 (dd, J = 8.0, 5.2 Hz, 1H); 13 C NMR (CDCl 3, 100 MHz) δ 152.2, 148.5, 138.4, 131.6, 128.8, 128.4, 123.0, 122.4, 120.4, 92.6, 85.9; HRMS (ESI) m/z calcd for C 13 H 10 N [M+H] + : 180.0808, found 180.0809. 4. Orthogonal Cross-coupling Suzuki Miyaura Coupling of 4 and 5 A 20-mL Schlenk tube equipped with rubber septum containing a magnetic stirring bar was dried with a heatgun in vacuo and filled with N 2 gas after cooling to room temperature. To this tube were added (4-methoxyphenyl)boronic acid (4: 227.9 mg, 1.5 mmol, 1.5 equiv), phenyl 5-bromopicolinate (5: 278.1 mg, 1.0 mmol, 1.0 equiv), and Pd(PPh 3 ) 4 (34.7 mg, 30 µmol, 3 mol%). The tube was vacuumed and refilled N 2 gas three times. To this tube were added toluene (4.0 ml) and degassed 2.0 M Na 2 CO 3 aq (1.0 ml, 2.0 equiv). The tube was heated at 80 C with stirring. After stirring the mixture for 2 h with monitoring reaction progress with TLC, the mixture was cooled to room temperature and extracted three times with EtOAc. The combined organic layer was dried over Na 2 SO 4, filtrated, and concentrated in vacuo. The residue was purified by Isolera (hexane/etoac = 19:1) and recrystallization from hexane to afford phenyl 5-(4-methoxyphenyl)picolinate (6) as a white solid (227.8 mg, 75% yield). 1 H NMR (CDCl 3, 400 MHz) δ 9.04 (d, J = 1.6 Hz, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.05 (dd, J = 8.4, 1.6 Hz, 1H), 7.62 (d, J = 9.2 Hz, 2H), 7.45 (dd, J = 8.4, 8.0 Hz, 2H), 7.31 (t, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 9.2 Hz, 2H), 3.89 (s, 3H); 13 C NMR (CDCl 3, 100 MHz) δ 163.7, 160.4, 150.8, 147.9, 145.0, 139.6, 134.2, 129.3, 128.5, 128.4, 125.9, 125.8, 121.5, 114.6, 55.2; HRMS (ESI) m/z calcd for C 19 H 16 NO 3 [M+H] + : 306.1125, found 306.1126. S10

Decarbonylative Alkynylation of 6 with 2a A 20-mL glass vessel equipped with J. Young O-ring tap containing a magnetic stirring bar and molecular sieves 3A (100 mg) was dried with a heatgun in vacuo and filled with N 2 gas after cooling to room temperature. To this vessel were added 6 (122.1 mg, 0.40 mmol, 1.0 equiv), Pd(acac) 2 (6.09 mg, 0.020 mmol, 5 mol%), CuI (7.62 mg, 0.040 mmol, 10 mol%), and dcypt (19.1 mg, 0.040 mmol, 10 mol%). The vessel was vacuumed and refilled N 2 gas three times. To this were added 2a (218.9 mg, 1.20 mmol, 3.0 equiv), and 1,4-dioxane (1.2 ml). The vessel was sealed with O-ring tap and then heated at 170 C for 16 h in an 8-well reaction block with stirring. After cooling the reaction mixture to room temperature, the mixture was passed through a short silica-gel pad with EtOAc. The filtrate was concentrated and the residue was purified by PTLC (hexane/etoac = 9:1) to afford 5-(4-methoxyphenyl)-2-((triisopropylsilyl)ethynyl)pyridine (7) as a yellow solid (66.8 mg, 46% yield). 1 H NMR (CDCl 3, 400 MHz) δ 8.78 (d, J = 2.4 Hz, 1H), 7.78 (dd, J = 8.0, 2.4 Hz, 1H), 7.52 (dd, J = 9.2, 2.4 Hz, 2H), 7.51 (d, J = 8.0 Hz, 1H), 7.01 (dd, J = 9.2, 2.4 Hz, 2H), 3.86 (s, 3H), 1.22 1.12 (m, 21H); 13 C NMR (CDCl 3, 100 MHz) δ 159.9, 147.9, 141.2, 135.2, 133.5, 129.5, 128.1, 127.5, 114.5, 105.9, 91.7, 55.3, 18.6, 11.2; HRMS (ESI) m/z calcd for C 23 H 32 NOSi [M+H] + : 366.2248, found 366.2246. S11

5. Effect of Parameters Ligand Effect The Effect of the Aryl-Substituent of Arenecarboxylates S12

6. The Scope of Alkynes S13

7. 1 H NMR and 13 C NMR Spectra 1 H NMR of 1J (400 MHz, CDCl 3 ) S14

13 C NMR of 1J (100 MHz, CDCl 3 ) S15

1 H NMR of 5 (400 MHz, CDCl 3 ) S16

13 C NMR of 5 (100 MHz, CDCl 3 ) S17

1 H NMR of 3Aa (400 MHz, CDCl 3 ) S18

13 C NMR of 3Aa (100 MHz, CDCl 3 ) S19

1 H NMR of 3Ba (400 MHz, CDCl 3 ) S20

13 C NMR of 3Ba (100 MHz, CDCl 3 ) S21

1 H NMR of 3Ca (400 MHz, CDCl 3 ) S22

13 C NMR of 3Ca (100 MHz, CDCl 3 ) S23

1 H NMR of 3Da (400 MHz, CDCl 3 ) S24

13 C NMR of 3Da (100 MHz, CDCl 3 ) S25

1 H NMR of 3Ea (600 MHz, CDCl 3 ) S26

13 C NMR of 3Ea (150 MHz, CDCl 3 ) S27

1 H NMR of 3Fa (400 MHz, CDCl 3 ) S28

13 C NMR of 3Fa (100 MHz, CDCl 3 ) S29

1 H NMR of 3Ga (600 MHz, CDCl 3 ) S30

13 C NMR of 3Ga (100 MHz, CDCl 3 ) S31

1 H NMR of 3Ha (400 MHz, CDCl 3 ) S32

13 C NMR of 3Ha (100 MHz, CDCl 3 ) S33

1 H NMR of 3Ia (400 MHz, CDCl 3 ) S34

13 C NMR of 3Ia (150 MHz, CDCl 3 ) S35

1 H NMR of 3Ja (400 MHz, CDCl 3 ) S36

13 C NMR of 3Ja (100 MHz, CDCl 3 ) S37

1 H NMR of 3Ka (400 MHz, CDCl 3 ) S38

13 C NMR of 3Ka (100 MHz, CDCl 3 ) S39

1 H NMR of 3La (400 MHz, CDCl 3 ) S40

13 C NMR of 3La (100 MHz, CDCl 3 ) S41

1 H NMR of 3Ma (400 MHz, CDCl 3 ) 13 C NMR of 3Ma (100 MHz, CDCl 3 ) S42

S43

1 H NMR of 3Na (400 MHz, CDCl 3 ) S44

13 C NMR of 3Na (100 MHz, CDCl 3 ) S45

1 H NMR of 3Oa (400 MHz, CDCl 3 ) S46

13 C NMR of 3Oa (100 MHz, CDCl 3 ) S47

1 H NMR of 3Pa (400 MHz, CDCl 3 ) S48

13 C NMR of 3Pa (100 MHz, CDCl 3 ) S49

1 H NMR of 3Qa (400 MHz, CDCl 3 ) S50

13 C NMR of 3Qa (100 MHz, CDCl 3 ) S51

1 H NMR of 3Ab (400 MHz, CDCl 3 ) S52

13 C NMR of 3Ab (100 MHz, CDCl 3 ) S53

1 H NMR of 6 (400 MHz, CDCl 3 ) S54

13 C NMR of 6 (100 MHz, CDCl 3 ) S55

1 H NMR of 7 (400 MHz, CDCl 3 ) S56

13 C NMR of 7 (100 MHz, CDCl 3 ) S57

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