Synthesis of Cyclopentadienyl Alkyl Ethers via Pd-Catalyzed. Cyclotrimerization of Diarylacetylenes

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1 Synthesis of Cyclopentadienyl Alkyl Ethers via Pd-Catalyzed Cyclotrimerization of Diarylacetylenes Ranran Cai, a Mengmeng Huang, *a Xiuling Cui, a Jianye Zhang, a Chenxia Du, a Yusheng Wu, b and Yangjie Wu *a a College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of Henan Universities, Zhengzhou University, Zhengzhou, , P.R. China. b Tetranov Biopharm, LLC. 75 Daxue Road, Zhengzhou, Henan , P.R. China, and Tetranov International Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA. Supporting Information Table of contents Experimental Procedures and Spectra Data 2~8 1 H NMR, 13 C NMR and IR Spectra 9~30 X-ray Crystallographic Data of compound 3a, 3f and 4a 31~35

2 General information. All reactions were carried out under air atmospheres. 1,2-diphenylethyne derivatives (1a-1j) were prepared according to the literature procedure 1. Other chemical reagents were purchased from commercial suppliers and used without further purification. All organic solvents were purified prior to use. 1 H NMR and 13 C NMR spectra were recorded on a Bruker DPX-400 instrument using CDCl 3 as the solvent and TMS as the internal standard. Mass spectra were measured on a TRACE GC ULTRA-DSQⅡ spectrometer. High resolution mass spectrometry was measured on an Agilent UHPLC Q-Tof APCI - HRMS. FT-IR data were recorded on a Bruker ALPHA spectrometer. Elemental analyses (EA) data were recorded on Elementar Vario ELIII spectrometer. GC analysis was performed on Agilent 4890D gas chromatograph. Crystal data were collected on a Oxford diffraction Cemimi E diffractometer using Mo Kα radiation ( Å) at K. Fluorescence were recorded on a FluoroMax -P spectrometer. General procedure. Catalysis procedure for synthesis of 3a-3i, 4a-4j and 5j: A solution of 1,2-diphenylethyne (0.50 mmol), Pd(OAc) 2 (5.6 mg, mmol), K 2 S 2 O 8 (81 mg, 0.3 mmol) in methanol (for 3a-3g and 5j) or ethanol (for 3i) (3 ml) was stirred at 60 o C for 24 h in the absence of light. After the completion of the reaction it was cooled to room temperature. The reaction mixture was dissolved in H 2 O and extracted with dichloromethane (3 x 10 ml). The organic layer was collected and dried by Na 2 SO 4, then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the by-product 4a-4j, the desired product 3a-3i and 5j. (5-methoxycyclopenta-1,3-diene-1,2,3,4,5-pentayl)pentabenzene (3a) 2 : Yellow amorphous solid (m.p o C): R f = 0.35 (17:3 petroleum ether/ch 2 Cl 2 ). A suitable crystal of 3a for X-ray diffraction analysis was grown from MeOH. 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (d, J = 7.32 Hz, 2H), 7.24 (t, J = 7.32 Hz, 2H), (m, 7H), (m, 14H), 3.48 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 144.9, 144.5, 139.6, 135.5, 134.0, 131.4, 129.9, 129.0, 128.2, 128.0, 127.6, 127.1, 126.7, 125.3, 95.3, FT-IR (thin film) 2926, 1724, 1594, 1488, 1440, 1277, 1178, 1069, 1025, 742, 697, 548 cm -1. Anal calcd for C 36 H 28 O ( g/mol): C, 90.72; H, 5.92; found C, 90.52; H, APCI-HRMS m/z [M OCH 3 ] + Calcd for C 35 H 25 : ; Found

3 2,3,4,5-tetraphenylfuran (4a) 3 : White solid: R f = 0.61 (17:3 petroleum ether/ch 2 Cl 2 ). A suitable crystal of 4a for X-ray diffraction analysis was grown from 3:1 petroleum ether/ch 2 Cl 2. 1 H NMR (400 MHz, CDCl 3 ) δ (m, 4H), (m, 12H), (m, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ 147.7, 133.2, 130.9, 130.4, 128.4, 128.4, 127.4, 127.2, 125.9, MS (EI, 70 ev) m/z for C 28 H 20 O: 372 (M +, 100), 267 (34), 165 (19), 77 (11). 4,4',4'',4''',4''''-(5-methoxycyclopenta-1,3-diene-1,2,3,4,5-pentayl)pentakis(metho xybenzene) (3b): Yellow amorphous solid (m.p o C): R f = 0.2 (1:1 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 (d, J = 8.61 Hz, 2H), 6.97 (d, J = 9.00 Hz, 4H), 6.91 (d, J = 8.61 Hz, 4H), 6.76 (d, J = 8.61 Hz, 2H), 6.71 (d, J = 9.00 Hz, 4H), 6.58 (d, J = 8.61 Hz, 4H), 3.78 (s, 6H), 3.76 (s, 3H), 3.70 (s, 6H), 3.38 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 158.4, 158.1, 158.0, 143.1, 142.6, 132.3, 131.2, 130.2, 128.3, 127.1, 126.5, 113.5, 113.4, 113.0, 94.8, 55.1, 55.0, 54.9, FT-IR (thin film) 2923, 2851, 1756, 1602, 1508, 1461, 1246, 1172, 1029, 832, 806, 542 cm -1. Anal calcd for C 41 H 38 O 6 ( g/mol): C, 78.57; H, 6.11; found. C, 78.33; H, APCI-HRMS m/z [M OCH 3 ] + Calcd for C 40 H 35 O 5 : ; Found ,3,4,5-tetrakis(4-methoxyphenyl)furan (4b) 3 : White solid: R f = 0.4 (1:1 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 3

4 7.84 (d, J = 8.80 Hz, 4H), 7.11 (d, J = 8.80 Hz, 4H), 6.80 (d, J = 8.80 Hz, 4H), 6.73 (d, J = 8.80 Hz, 4H), 3.79, 3.75 (2s, 12H). 13 C NMR (100 MHz, CDCl 3 ) δ 196.0, 163.3, 159.3, 142.5, 132.5, 131.1, 129.7, 128.1, 114.1, 113.5, 55.4, ,3',3'',3''',3''''-(5-methoxycyclopenta-1,3-diene-1,2,3,4,5-pentayl)pentakis(metho xybenzene) (3c): Yellow amorphous solid (m.p o C): R f = 0.35 (1:1 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ (m, 3H), 7.10 (t, J = 7.92 Hz, 2H), 6.95 (t, J = 7.92 Hz, 2H), (m, 11H), 6.53 (s, 2H), 3.75 (s, 3H), 3.56 (s, 6H), 3.46 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 159.6, 159.3, 158.6, 144.6, 144.4, 141.4, 137.0, 135.0, 129.2, 129.2, 128.5, 122.4, 121.6, 117.8, 114.9, 113.6, 113.5, 113.4, 112.3, 111.4, 95.0, 55.2, 55.1, 54.7, FT-IR (thin film) 2934, 2831, 1597, 1482, 1424, 1284, 1255, 1222, 1041, 863, 780, 690 cm -1. Anal calcd for C 41 H 38 O 6 ( g/mol): C, 78.57; H, 6.11; found. C, 78.36; H, APCI-HRMS m/z [M OCH 3 ] + Calcd for C 40 H 35 O 5 : ; Found ,4',4'',4''',4''''-(5-methoxycyclopenta-1,3-diene-1,2,3,4,5-pentayl)pentakis(methy lbenzene) (3d): Yellow amorphous solid (m.p o C): R f = 0.37 (17:3 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 (d, J = 7.83 Hz, 2H), 7.03 (d, J = 7.82 Hz, 3H), (m, 11H), 6.83 (d, J = 7.82 Hz, 4H), 3.42 (s, 3H), 2.30 (s, 6H), 2.26 (s, 3H), 2.19 (s, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 144.1, 143.9, 136.9, 136.4, 136.0, 135.8, 132.9, 131.4, 129.8, 128.9, 128.8, 128.7, 128.3, 125.2, 95.1, 51.2, 21.3, 21.2, FT-IR (thin film) 2921, 1723, 1608, 1507, 1444, 1277, 1178, 1086, 810, 749, 525 cm -1. Anal calcd for C 41 H 38 O ( g/mol): C, 90.07; H, 7.01; found. C, 89.85; H, APCI-HRMS m/z [M OCH 3 ] + Calcd for C 40 H 35 : ; Found

5 2,3,4,5-tetrap-tolylfuran (4d) 4 : Yellow solid: R f = 0.61 (17:3 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 (d, J = 8.31 Hz, 4H), 7.08 (d, J = 7.83 Hz, 4H), 7.05 (s, 8H), 2.34 (s, 12H). 13 C NMR (100 MHz, CDCl 3 ) δ 147.5, 136.9, 136.5, 130.2, 130.2, 129.1, 129.0, 128.4, 125.8, 124.3, 29.7, MS (EI, 70 ev) m/z for C 32 H 28 O: 428 (M +, 100), 309 (29), 281(25), 119 (15), 91 (18). 5,5',5'',5''',5''''-(5-methoxycyclopenta-1,3-diene-1,2,3,4,5-pentayl)pentakis(1,3-di methylbenzene) (3e): Light yellow amorphous solid (m. p o C): R f = 0.37 (17:3 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.21 (s, 2H), 6.78 (s, 3H), (m, 10H), 3.39 (s, 3H), 2.26 (s, 6H), 2.13 (s, 12H), 2.03 (s, 12H). 13 C NMR (100 MHz, CDCl 3 ) δ 144.8, 143.8, 139.9, 137.0, 136.8, 136.2, 136.0, 134.6, 134.1, 128.2, 128.1, 127.6, 126.8, 123.3, 95.2, 51.0, 21.6, 21.3, FT-IR (thin film) 2918, 1724, 1596, 1458, 1377, 1219, 1104, 850, 701 cm -1. Anal calcd for C 46 H 48 O ( g/mol): C, 89.56; H, 7.84; found. C, 89.24; H, APCI-HRMS m/z [M OCH 3 ] + Calcd for C 45 H 45 : ; Found ,3,4,5-tetrakis(3,5-dimethylphenyl)furan (4e) 5 : White solid: R f = 0.62 (17:3 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.17 (s, 4H), 6.86 (s, 4H), 6.81 (s, 4H), 2.25 (s, 12H), 2.21 (s, 12H). 13 C NMR (100 MHz, CDCl 3 ) δ 147.5, 137.6, 137.2, 133.1, 131.0, 128.7, 128.5, 128.2, 125.1, 123.6, 21.4,

6 3,3',3'',3''',3''''-(5-methoxycyclopenta-1,3-diene-1,2,3,4,5-pentayl)pentakis(methy lbenzene) (3f): Yellow amorphous solid (m. p o C): R f = 0.36 (17:3 petroleum ether/ch 2 Cl 2 ). A suitable crystal of 3f for X-ray diffraction analysis was grown from MeOH. 1 H NMR (400 MHz, CDCl 3 ) δ 7.46 (s, 1H), 7.38 (d, J = 7.82 Hz, 1H), (d, J = 7.82 Hz, 1H), (m, 8H), (m, 9H), 3.45 (s, 3H), 2.30 (s, 3H), 2.17 (s, 6H), 2.08 (s, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 144.6, 144.4, 139.7, 137.5, 137.2, 136.6, 135.7, 134.0, 130.5, 129.7, 129.0, 127.9, 127.7, 127.6, 127.3, 127.3, 126.9, 126.2, 126.1, 122.4, 95.2, 51.2, 21.8, 21.4, FT-IR (thin film) 2920, 1599, 1483, 1449, 1378, 1200, 1155, 1126, 1091, 784, 725, 697 cm -1. Anal calcd for C 41 H 38 O ( g/mol): C, 90.07; H, 7.01; found. C, 89.76; H, APCI-HRMS m/z [M OCH 3 ] + Calcd for C 40 H 35 : ; Found ,3,4,5-tetrakis(3-methylphenyl)furan (4f) 6 : White solid: R f = 0.62 (17:3 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.43 (s, 2H), 7.25 (s, 2H), (m, 4H), (m, 4H), 7.00 (s, 2H), 6.96 (d, J = 7.31 Hz, 2H), 2.31 (s, 6H), 2.24 (s, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 147.6, 137.8, 137.6, 133.1, 131.0, 130.9, 128.1, 128.0, 127.9, 127.7, 127.5, 126.4, 125.1, 123.0, 21.5, MS (EI, 70 ev) m/z for C 32 H 28 O: 428 (M +, 100), 309 (21), 119 (65), 91 (18). 4,4',4'',4''',4''''-(5-methoxycyclopenta-1,3-diene-1,2,3,4,5-pentayl)pentakis(fluoro benzene) (3g): 6

7 Light yellow amorphous solid (m. p o C): R f = 0.36 (83/17 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ (m, 2H), (m, 14H), (m, 4H), 3.41 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ (d, J = Hz), (d, J = Hz), (d, J = Hz), 143.9, 142.9, (d, J = 2.9 Hz), (d, J = 2.5 Hz), (d, J = 8.1 Hz), (d, J = 7.9 Hz), (d, J = 7.7 Hz), (d, J = 3.1 Hz), (d, J = 21.3 Hz), (d, J = 21.1 Hz), (d, J = 21.3 Hz), 94.7, FT-IR (thin film) 2924, 1601, 1507, 1465, 1231, 1157, 1014, 836, 531 cm -1. Anal calcd for C 36 H 23 OF 5 ( g/mol): C, 76.32; H, 4.09; found. C, 76.13; H, APCI-HRMS m/z [M OCH 3 ] + Calcd for C 35 H 20 F 5 : ; Found ,3,4,5-tetrakis(4-fluorophenyl)furan (4g) 4 : White solid: R f = 0.63 (83/17 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ (m, 4H), (m, 4H), (m, 8H). 13 C NMR (100 MHz, CDCl 3 ) δ (d, J = Hz), (d, J = Hz), 147.1, (d, J = 7.9 Hz), (d, J = 8.0 Hz), (d, J = 3.5 Hz), (d, J = 3.5 Hz), 123.5, (d, J = 21.5 Hz), (d, J = 21.7 Hz), MS (EI, 70 ev) m/z for C 28 H 16 OF 4 : 444 (M +, 100), 321 (53),123 (29). 2,3,4,5-tetrakis(4-(trifluoromethyl)benzene)furan (4h) 3 : White solid: R f = 0.67 (17:3 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.59 (d, J = 6.85 Hz, 12H), 7.27 (d, J = 7.82 Hz, 4H). 13 C NMR (100 MHz, CDCl 3 ) 148.0, 135.6, 132.9, 131.1, 130.5, (q, J = 32.8 Hz), (q, J = 31.6 Hz), 129.6, (q, J = 3.6 Hz), (q, J = 3.7 Hz), (q, J = Hz), (q, J 7

8 = Hz). MS (EI, 70 ev) m/z for C 32 H 16 OF 12 : 644(M +, 100), 471 (41), 173 (52), 145 (43). (5-ethyoxycyclopenta-1,3-diene-1,2,3,4,5-pentayl)pentabenzene (3i): Light yellow amorphous solid (m. p o C): R f = 0.34 (17:3 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (d, J = 7.34 Hz, 2H), 7.24 (d, J = 7.82 Hz, 2H), (m, 7H), (m, 14H), 3.74 (q, J = 6.36 Hz; 7.34 Hz, 2H), 1.22 (t, J = 7.34 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 145.5, 144.0, 139.9, 135.7, 134.1, 131.4, 129.9, 129.0, 128.2, 128.0, 127.5, 127.0, 126.6, 125.4, 94.7, 58.8, FT-IR (thin film) 2924, 1718, 1629, 1599, 1490, 1442, 1271, 1069, 744, 694, 546 cm -1. Anal calcd for C 37 H 30 O ( g/mol): C, 90.58; H, 6.16; found. C, 90.29; APCI-HRMS m/z [M OCH 2 CH 3 ] + Calcd for: C 35 H 25 : ; Found ,3,4,5-tetrakis(4-chlorophenyl)furan (4j) 7 : Yellow solid: R f = 0.55 (17:3 petroleum ether/ch 2 Cl 2 ). 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 (d, J = 8.53 Hz, 4H), 7.27 (d, J = 8.53 Hz, 8H), 7.05 (d, J = 7.92 Hz, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ 147.4, 133.7, 133.6, 131.5, 130.8, 129.1, 128.8, 128.6, 127.1, ,4',4'',4''',4''''-(5-methoxycyclopenta-1,3-diene-1,2,3,4,5-pentayl)pentakis(chloro benzene) (5j, 5j - D): 8

9 Yellow amorphous solid(m.p o C): R f = 0.31 (17:3 petroleum ether/ch 2 Cl 2 ). 1 H NMR(400 MHz, CDCl 3 ) δ (m, 6H), 7.05 (d, J = 8.53 Hz, 6H), 6.90 (d, J = 8.53 Hz, 4H), 6.83 (d, J = 8.53 Hz, 4H), 4.95 (s, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 145.9, 143.0, 135.4, 133.4, 133.3, 132.9, 132.7, 131.2, 130.1, 129.6, 129.2, 128.8, 128.6, 128.3, FT-IR (thin film) 2924, 1589, 1486, 1396, 1091, 1012, 829, 778, 494 cm -1. Anal calcd for C 35 H 21 Cl 5 ( g/mol): C, 67.93; H, 3.42; Found. C, 68.15; H, APCI-HRMS m/z [M H] Calcd for C 35 H 20 Cl 5 : , Found Reference: 1 (a)m. J. Mio, L. C. Kopel, J. B. Braun, T. L. Gadzikwa, K. L. Hull, R. G. Brisbois, C. J. Markworth and P. A. Grieco, Org. let., 2002, 4, 3199; (b) E. Shirakawa, T. Kitabata, H. Otsuka and T. Tsuchimoto, Tetrahedron, 2005, 61, R. Guy and R. Andre, Compt. Rend., 1962, 254, M. Nakano, H. Tsurugi, T. Satoh and M. Miura, Org. Lett., 2008, 10, Li, Z. F.; Zhang, Y. M.; Liu and Y. K, J. Indian Chem. Soc., 2002, 79, H. Munawar, K. R. Ahmad, N. Thai-hung and L. Peter, Organic&Biomolecular Chemsitry, 2011, 9, Krepski, R. Larry, M.H. Steven, K. R. Jerald, L. T. Michael and K. S. Howell, II. Synth. Commun., 1986, 16, U. Takashi, M. Tomoka, S. Yoshiaka, I. Akihiko and N. Juzo, Heterocycles, 1998, 48, 61. 9

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37 APCI-MS-(+) spectrum for the standard reaction after 1 h, the cation VIII m/z x10 5 +APCI Scan ( min, 10 Scans) Frag=180.0V 60min-0.2uL.d x APCI Scan ( min, 10 Scans) Frag=180.0V 60min-0.2uL.d Counts vs. Mass-to-Charge (m/ z) Counts vs. Mass-to-Charge (m/ z) 37

38 X-ray experimental: single crystals of 3a (CCDC No ), 3f (CCDC No ) and 4a (CCDC No ) were grown from evaporation of a MeOH (for 3a and 3f) or 3:1 petroleum ether/ch 2 Cl 2 (for 4a) solution. A suitable crystal was selected and mounted on a Oxford diffraction Cemimi E diffractometer using Mo Kα radiation ( Å). The crystal was kept at K during data collection. The structures were solved by direct methods and refined by full-matrix least-squares based on F 2 with anisotropic thermal parameters for all non-hydrogen atoms (SHELXTL-Plus). All hydrogen atoms were found from difference Fourier syntheses and refined isotropically. Crystallographic data for complex 3a (CCDC No ). 38

39 Table 1. Crystal data and structure refinement for complex 3a. Identification code Empirical formula C 36 H 28 O Formula weight Temperature/K Crystal system Space group P-1 triclinic a/å (3) b/å (2) c/å (4) α/ 99.93(2) β/ 93.55(2) γ/ (3) Volume/Å (6) Z 2 ρ calc mg/mm m/mm F(000) 504 Crystal size/mm Θ range for data collection 6.18 to Index ranges -12 h 11, -11 k 12, -17 l 17 Reflections collected Independent reflections 4743[R(int) = ] Data/restraints/parameters 4743/0/336 Goodness-of-fit on F Final R indexes [I>=2σ (I)] R 1 = , wr 2 = Final R indexes [all data] R 1 = , wr 2 = Largest diff. peak/hole / e Å / Flack Parameter N/A 39

40 Crystallographic data for complex 3f (CCDC No ). Table 2. Crystal data and structure refinement for complex 3f. Identification code Empirical formula C 41 H 38 O Formula weight Temperature/K Crystal system Space group P2 1 /c monoclinic a/å (9) b/å (3) c/å (14) α/ β/ (3) γ/ Volume/Å (3) Z 4 ρ calc mg/mm m/mm F(000)

41 Crystal size/mm Θ range for data collection 6.9 to Index ranges -23 h 23, -6 k 9, -29 l 30 Reflections collected Independent reflections 5710[R(int) = ] Data/restraints/parameters 5710/5/408 Goodness-of-fit on F Final R indexes [I>=2σ (I)] R 1 = , wr 2 = Final R indexes [all data] R 1 = , wr 2 = Largest diff. peak/hole / e Å /-0.31 Crystallographic data for complex 4a (CCDC No ). Table 3. Crystal data and structure refinement for complex 4a. Identification code Empirical formula C 28 H 20 O Formula weight Temperature/K Crystal system Space group monoclinic C2/c a/å (14) 41

42 b/å (3) c/å (12) α/ β/ (7) γ/ Volume/Å (4) Z 8 ρ calc mg/mm m/mm F(000) Crystal size/mm Θ range for data collection 6 to Index ranges -31 h 32, -4 k 10, -26 l 27 Reflections collected 8377 Independent reflections 4148[R(int) = ] Data/restraints/parameters 4148/0/262 Goodness-of-fit on F Final R indexes [I>=2σ (I)] R 1 = , wr 2 = Final R indexes [all data] R 1 = , wr 2 = Largest diff. peak/hole / e Å /