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1 SUPPRTING INFRMATIN Silver Catalyzed Domino Hydroarylation/Cycloisomerization Reactions of ortho Alkynylbenzaldehydes: an Entry to Functionalized Isochromene Derivatives. Gaëlle Mariaule, a,b Gregory Newsome, c Patrick Y. Toullec, c Philippe Belmont a,b * and Véronique Michelet c *. a Institut Curie, UMR CNRS 176, 26 rue d Ulm, Paris, France. b Université Paris Descartes, Faculté de Pharmacie de Paris, UMR CNRS 8638, 4 avenue de l'bservatoire, Paris, France. c PSL Research University, Chimie ParisTech CNRS, Institut de Recherche de Chimie Paris, 11 rue P. et M. Curie, Paris, France. Table of contents Page N I) General considerations S 2 II) Synthesis of ortho alkynylbenzaldehyde derivatives S 2 General procedure (Sonogashira coupling) S 2 Description of products 1a 1s S 2 to S 7 III) Synthesis of isochromene derivatives S 7 General procedure S 7 Description of products 3a 3k, 3m 3n, 3p 3s, 13 16, 3a d 3 S 7 to S 13 IV) Metal catalyzed Hartwig Buchwald reaction S 14 Description of product 17 S 14 V) Crystal data for 3h S 14 VI) 1 H and 13 C NMR spectra of all new compounds S 14 to S 74 1d (S15 16), 1f (S17 18), 1g (S19 20), 1o (S21 22), 1q (S23 S24), 1r (S25 26), 1s (S27 28) 3a (S29 30), 3a d 3 (S31 32), 3b 3k (S33 S52), 3m 3n (S53 56), 3p 3s (S57 64) (S65 74) S1

2 I) General considerations: Anhydrous DMF, ClCH 2 CH 2 Cl and dioxane were purchased from Sigma Aldrich in a SureSeal bottle and used as received. therwise, all reagents and solvents were used without further purification. 1 H NMR (300 MHz) and 13 C NMR (75 MHz) were recorded on a Bruker ACP 300 spectrometer using the residual peak of chloroform d as internal standard (7.26 ppm for 1 H NMR and ppm for 13 C NMR). Chemical shifts are reported in ppm and coupling constants J in Hertz. Multiplicities were given as: s (singlet); brs (broad singlet); d (doublet); t (triplet); q (quartet); dd (doublets of doublet); td (triplet of doublet); m (multiplets); and etc Flash chromatography was performed using µm silica. Analytical TLC s were performed on Merck pre coated silica 60 F254 plates. Low and High Resolution Mass Spectra (MS and HRMS) were performed on an ESI MicrTFQ II Bruker spectrometer at the Centre Commun de Spectrométrie de Masse of ICBMS UMR 5246 unit (Lyon, France). II) Synthesis of ortho alkynylbenzaldehyde derivatives: General procedure : Sonogashira coupling reactions were performed following a reported method 1 The corresponding 2 bromobenzaldehyde (1 equiv.) was dissolved in Et 3 N (0.25 M) and the mixture was degassed for 5 min by argon bubbling. Then, CuI (1 mol%) and PdCl 2 (PPh 3 ) 2 (2 mol%) were introduced and the mixture was further degassed for 10 min by argon bubbling. Finally, the corresponding alkyne (1.2 equiv.) was added and the reaction was stirred overnight at 50 C. After checking by TLC the completion of the reaction, it was quenched by addition of distilled water and was extracted three times by CH 2 Cl 2. The combined organic layers were washed with brine, dried over MgS 4, filtrated and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (solid deposit) and eluted with the appropriate mixture of cyclohexane and ethyl acetate in order to obtain the purified desired compound. 1 J. H. Park, S. V. Bhilare, S. W. Youn, rg. Lett. 2011, 13, S2

3 2 (phenylethynyl)benzaldehyde, 1a Yield 79 %, Brown oil. TLC R f 0.58 (pentane/ether 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.95 (dd, J = 7.8, 1.3 Hz, 1H), (m, 4H), (m, 4H). Spectral data were consistent with data reported in the literature. 2 2 (p tolylethynyl)benzaldehyde, 1b Yield 80 %, Yellow solid. Mp C (literature: C). 3 TLC R f 0.63 (pentane/ether 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.94 (d, J = 7.8 Hz, 1H), (m, 2H), (m, 3H), 7.20 (d, J = 8.2 Hz, 2H), 2.39 (s, 3H). Spectral data were consistent with data reported in the literature. 3 2 ((3 methoxyphenyl)ethynyl)benzaldehyde, 1c CH 3 Yield 81 %, Yellow solid. Mp C. TLC R f 0.47 (pentane/ether 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 7.08 (s, 1H), 6.95 (dd, J = 8.3, 2.5 Hz, 1H), 3.84 (s, 3H). Spectral data were consistent with data reported in the literature. 4 2 (2 (4 fluorophenyl)ethynyl)benzaldehyde, 1d Yield 90 %, Yellow solid. Mp C (literature: C). 5 TLC R f 0.67 (pentane/ether 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.94 (dd, J = 7.6, 0.9 Hz, 1H), (m, 5H), 7.08 (td, J = 8.7, 2.9 Hz, 2H). 13 C NMR (75 MHz, CDCl 3 ): δ = (CH), (d, J = Hz, CF), (C), (d, J = 7.4 Hz, 2xCH), (CH), (CH), (CH), (CH), (C), (C), (d, J = 22.0 Hz, 2xCH), 95.2 (C), 84.7 (C). MS (m/z): 247 [MNa + ]. HRMS (ESI): m/z [MH + ] calcd. for C 15 H 9 FNa [M+Na] + : found : Reported in the literature but via a different synthetic pathway. 5 2 ((4 (trifluoromethyl)phenyl)ethynyl)benzaldehyde, 1e Yield 71 %, Light brown solid. Mp C (literature: C). 6 TLC R f 0.60 (pentane/ether 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.98 (d, J = 7.4 Hz, 1H), (m, 6H), 7.51 (t, J = 7.4 Hz, 1H). Spectral data were consistent with data reported in the literature. 6 2 G. Dyker, W. Stirner, G. Henkel, Eur. J. rg. Chem. 2000, M. Alfonsi, M. Dell Acqua, D. Facoetti, A. Arcadi, G. Abbiati, E. Rossi, Eur. J. rg. Chem. 2009, N. T. Patil, A. Konala, V. Singh, V. V. N. Reddy, Eur. J. rg. Chem. 2009, P. C. Too, S. Chiba, Chem. Commun. 2012, 48, a) V. Rustagi, R. Tiwari, A. K. Verma, Eur. J. rg. Chem. 2012, b) S. bika, H. Kono, Y. Yasui, R. Yanada, Y. Takemoto, J. rg. Chem. 2007, 72, c) See also reference 8. S3

4 2 (2 (2 fluorophenyl)ethynyl)benzaldehyde, 1f Yield 81 %, Yellow solid. Mp C. TLC R f 0.61 (pentane/ether 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), (m, 4H), (m, 1H), (m, 2H). 13 C NMR (75 MHz, CDCl 3 ): δ = (CH), (d, J = Hz, CF), (C, C 1 ), (CH), (CH), (CH), (d, J = 7.6 Hz, CH), (CH), (CH), (C), (CH), (d, J = 20.6 Hz, CH), (d, J = 15.2 Hz, C), 90.3 (C), 90.0 (C). MS (m/z): 247 [MNa + ]. HRMS (ESI): m/z [MH + ] calcd. for C 15 H 9 FNa [M+Na] + : found : (2 (2 (trifluoromethyl)phenyl)ethynyl)benzaldehyde, 1g Yield 85 %, Light brown solid. Mp C. TLC R f 0.63 (pentane/ether 80:20) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), (m, 7H). 13 C NMR (75 MHz, CDCl 3 ): δ = (CH), (C), (CH), (CH), (CH), (CH), (C), (CH), (CH), (CH), (CH), (C), (d, J = Hz, CF 3 ), (C), 91.8 (C), 90.3 (C). MS (m/z): 297 [MNa + ]. HRMS (ESI): m/z [MH + ] calcd. for C 16 H 9 F 3 Na [M+Na] + : found : ((4 bromophenyl)ethynyl)benzaldehyde, 1h Yield 43 %, Pale yellow solid. Mp C (literature: 87 C). 7 TLC R f 0.53 (pentane/ether 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), (m, 7H). Spectral data were consistent with data reported in the literature. 7 2 (3,4,5 trimethoxyphenylethynyl)benzaldehyde, 1i Yield 75 %, Yellow solid. Mp C (literature: Yellow oil). TLC R f 0.19 (pentane/ether 80:20) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.95 (d, J = 7.8Hz, 1H), (m, 2H), 7.46 (t, J = 7.1 Hz, 1H), 6.80 (s, 2H), 3.90 (s, 9H). Spectral data were consistent with data reported in the literature. 8 7 A. S. K. Hashmi, M. Wieteck, I. Braun, P. Nçsel, L. Jongbloed, M. Rudolph, F. Rominger, Adv. Synth. Catal. 2012, 354, Q. Huang, J. A. Hunter, R. C. Larock, J. rg. Chem. 2002, 67, S4

5 2 ((4 nitrophenyl)ethynyl)benzaldehyde, 1J Yield 60 %, Yellow solid. Mp C (literature: C). 9 TLC R f 0.58 (pentane/ether 70:30) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 8.26 (d, J = 8.3Hz, 2H), 7.98 (d, J = 7.8 Hz, 1H), (m, 5H). Spectral data were consistent with data reported in the literature. 9 2 ethynylbenzaldehyde, 1k Yield 81 %, White solid. Mp C (literature: 65 C 10a or C 10b ). TLC R f 0.38 (pentane/ether 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.93 (d, J = 7.3 Hz, 1H), (m, 2H), 7.48 (t, J = 7.6 Hz, 1H), 3.46 (s, 1H). Spectral data were consistent with data reported in the literature (2 trimethylsilylethynyl)benzaldehyde, 1l Yield 85 %, Pale yellow solid. Mp C (literature: C). 11 TLC R f 0.66 (pentane/ether 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.90 (dd, J = 7.6, 0.8 Hz, 1H), (m, 2H), (m, 1H), 0.27 (s, 9H). Spectral data were consistent with data reported in the literature. 3,11 2 (pent 1 ynyl)benzaldehyde, 1m Yield 83 %, Light yellow oil. TLC R f 0.72 (pentane/ether 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.89 (d, J = 7.6 Hz, 1H), (m, 2H), (m, 1H), 2.47 (t, J = 7.0 Hz, 2H), 1.67 (sext, J = 7.2 Hz, 2H), 1.07 (t, J = 7.3 Hz, 3H). Spectral data were consistent with data reported in the literature. 6b 2 (3,3 dimethylbut 1 ynyl)benzaldehyde, 1n Yield 84 %, il. TLC R f 0.85 (pentane/ether 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), (m, 2H), (m, 1H), 1.35 (s, 9H). Spectral data were consistent with data reported in the literature M. Dell Acqua, D. Facoetti, G. Abbiati, E. Rossi, Synthesis 2010, a) Y. hta, Y. Kubota, T. Watabe, H. Chiba, S. ishi, N. Fujii, H. hno, J. rg. Chem. 2009, 74, b) S. Bhunia, K. C. Wang, R. S. Liu, Angew. Chem. Int. Ed. 2008, 47, T. C. Bedard, J. S. Moore, J. Am. Chem. Soc. 1995, 117, a) A. S. K. Hashmi, M. Bührle, R. Salathé, J. W. Bats, Adv. Synth. Catal. 2008, 350, b) M. Schmittel, S. Kiau, T. Siebert, M. Strittmatter, Tetrahedron Lett. 1996, 37, S5

6 2 (3 (benzyl(methyl)amino)prop 1 ynyl)benzaldehyde, 1o Yield 87 %, range oil. TLC R f 0.35 (pentane/ether 70:30) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.93 (d, J = 7.8 Hz, 1H), (m, 2H), (m, 1H), (m, 5H), 3.66 (s, 2H), 3.60 (s, 2H), 2.44 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ = (CH), (C), (C), (CH), (CH), (CH), (CH), (CH), (CH), (C), 92.1 (C), 81.4 (C), 60.3 (CH 2 ), 45.7 (CH 2 ), 42.2 (CH 3 ). MS (m/z): 264 [MH + ]. HRMS (ESI): m/z [MH + ] calcd. for C 18 H 18 N [M+H] + : found : (3 methoxyprop 1 ynyl)benzaldehyde, 1p Yield 86 %, Yellow oil. TLC R f 0.28 (pentane/ether 90 :10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.91 (d, J = 7.5 Hz, 1H), (m, 2H), (m, 1H), 4.39 (s, 2H), 3.47 (s, 3H). Spectral data were consistent with data reported in the literature. 13 3,4,5 trimethoxy 2 (3 methoxyprop 1 ynyl)benzaldehyde, 1q Yield 90 %, Yellow solid. Mp 30 C. TLC R f 0.52 (pentane/ether 50:50) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 7.24 (s, 1H), 4.41 (s, 2H), 3.97 (s, 3H), 3.95 (s, 3H), 3.91 (s, 3H), 3.48 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ = (CH), (C), (C), (C), (C), (C), (CH), 95.4 (C), 77.2 (C), 61.9 (CH 3 ), 61.6 (CH 3 ), 60.9 (CH 2 ), 58.2 (CH 3 ), 56.6 (CH 3 ). MS (m/z): 287 [MNa + ]. HRMS (ESI): m/z [MH + ] calcd. for C 14 H 16 Na 5 [M+Na] + : found : fluro 2 (3 methoxyprop 1 ynyl)benzaldehyde, 1r Yield 81 %, White solid. Mp C. TLC R f 0.43 (pentane/ether 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), (m, 2H), 7.26 (td, J = 8.5, 2.8 Hz, 1H), 4.37 (s, 2H), 3.46 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ = (d, J = 1.8 Hz, CH), (d, J = Hz, CF), (d, J = 6.7 Hz, C), (d, J = 7.6 Hz, CH), (d, J = 3.5 Hz, C), (d, J = 22.6 Hz, CH), (d, J = 22.8 Hz, CH), 92.3 (C), 81.3 (C), 60.7 (CH 2 ), 58.4 (CH 3 ). MS (m/z): 215 [MNa + ]. HRMS (ESI): m/z [MH + ] calcd. for C 11 H 9 FNa 2 [M+Na] + : ; found : (3 methoxyprop 1 ynyl) 5 (trifluoromethyl)benzaldehyde, 1s Yield 78 %, il. TLC R f 0.41 (pentane/ether 80:20) 1 H NMR (300 MHz, CDCl 3 ): δ = (s, 1H), 8.17 (s, 1), 7.80 (dd, J = 8.2, 0.8 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 4.41 (s, 2H), 3.48 (s, 3H). 13 T. Godet, C. Vaxelaire, C. Michel, A. Milet, P. Belmont, Chem. Eur. J. 2007, 13, S6

7 13 C NMR (75 MHz, CDCl 3 ): δ = (CH), (C), (CH), (d, J = 33.4 Hz, C), (CH), (C), (CH), (d, J = Hz, CF 3 ), 95.0 (C, C 9 ), 80.8 (C), 60.3 (CH 2 ), 58.2 (CH 3 ). MS (m/z): 265 [MNa + ]. HRMS (ESI): m/z [MH + ] calcd. for C 12 H 9 F 3 Na 2 [M+Na] + : found : III) Synthesis of isochromene derivatives: Ar/Het General procedure: R 1 CH R 2 Ar-H/Het-H AgTf 10 mol% DMF (0.5 M) R 1 R 2 To the corresponding ortho alkynylbenzaldehyde (1 equiv.) dissolved in DMF (0.5 M), was added AgTf (10 mol%). Then, the corresponding aromatic/heteroaromatic (Ar H/Het H) moiety was introduced. The reaction mixture was stirred, under argon atmosphere at the requisite temperature (rt, 50 C or 80 C), until the completion of the reaction was attested by TLC analysis. At this point, the reaction mixture was filtered through a pad of silica and celite which was then rinsed with Et 2. The organic filtrate layers were evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel with various solvent mixtures. 3 phenyl 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3a Yield 91 %, White solid. Mp C. TLC R f 0.21 (pentane/ether, 90:10). 1 H NMR (300 MHz, CDCl 3 ): δ = 7.74 (dd, J = 7.7, 1.2 Hz, 2H), (m, 3H), 7.17 (t, J = 7.4 Hz, 1H), (m, 2H), 6.88 (s, 1H), 6.67 (d, J = 7.4 Hz, 1H), 6.42 (s, 1H), 6.25 (s, 2H), 3.88 (s, 3H), 3.72 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = 161.7, (2xC), 154.2, 135.0, 132.2, 132.1, (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH), 108.5, (CH), 91.5 (2xCH), 72.5 (CH), 56.1 (2xCH 3 ), 55.3 (CH 3 ). MS (m/z): 397 [MNa + ]. HRMS (ESI): m/z [MH + ] calcd. for C 24 H 22 Na 4 [M+Na] + : found : (4 methylphenyl) 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3b Yield 83 %, White solid. Mp C. TLC R f 0.29 (pentane/ether, 90:10). 1 H NMR (300 MHz, CDCl 3 ): δ = 7.60 (d, J = 8.1 Hz, 2H), (m, 3H), (m, 2H), 6.82 (s, 1H), 6.62 (d, J = 7.5 Hz, 1H), 6.35 (s, 1H), 6.22 (s, 2H), 3.86 (s, 3H), 3.70 (s, 6H), 2.34 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ = 161.7, (2xC), 154.4, 138.3, 132.5, 132.4, 132.0, (2xCH), (CH), (CH), (2xCH), (CH), (CH), 108.8, 99.3 (CH), 91.6 (2xCH), 72.5 (CH), 56.1 (2xCH 3 ), 55.3 (CH 3 ), 21.3 (CH 3 ). MS (m/z) 389 [MH + ], 411 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 25 H 25 4 [M+H] + : found : S7

8 3 (3 methoxyphenyl) 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3c Yield 86 %, White solid. Mp: C. TLC R f 0.40 (pentane/ether, 70:30). 1 H NMR (300 MHz, CDCl 3 ): δ = 7.34 (dd, J = 7.9, 1.2 Hz, 1H), (m, 2H), 7.16 (t, J = 7.4 Hz, 1H), (m, 2H), (m, 2H), 6.66 (d, J = 7.5 Hz, 1H), 6.39 (s, 1H), 6.24 (s, 2H), 3.87 (s, 3H), 3.82 (s, 3H), 3.71 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = 161.7, (2xC), 159.5, 154.0, 136.5, (2xC), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH), 108.6, (CH), 91.4 (2xCH), 72.5(CH), 56.1 (2xCH 3 ), 55.3 (2xCH 3 ). MS (m/z) 427 [MNa + ]. HRMS (ESI): m/z [MH + ] calcd. for C 25 H 24 Na 5 [M+Na] + : found : (4 fluorophenyl) 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3d Yield 85 %, White solid. Mp C. TLC R f 0.32 (pentane/ether, 90:10). 1 H NMR (300 MHz, CDCl 3 ): δ = 7.69 (dd, J = 8.7, 5.5 Hz, 2H), 7.15 (t, J = 7.5 Hz, 1H), (m, 4H), 6.85 (s, 1H), 6.64 (d, J = 7.5 Hz, 1H), 6.32 (s, 1H), 6.23 (s, 2H), 3.86 (s, 3H), 3.70 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = (d, J = Hz, CF), 161.7, (2xC), 153.4, 132.0, 131.9, 131.2, (d, J = 7.2 Hz, 2xCH), (CH), (CH), (CH), (CH), (d, J = 21.4 Hz, 2xCH), 108.3, 99.8 (CH), 91.4 (2xCH), 72.6 (CH), 56.1 (2xCH 3 ), 55.4 (CH 3 ). MS (m/z) 415 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 24 H 21 FNa 4 [M+Na] + : found : (4 (trifluoromethyl)phenyl) 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3e Yield 98 %, White solid. Mp C. TLC R f 0.26 (pentane/ether, 90:10). 1 H NMR (300 MHz, CDCl 3 ): δ = 7.80 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.2 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H), (m, 2H), 6.89 (s, 1H), 6.66 (d, J = 7.4 Hz, 1H), 6.46 (s, 1H), 6.22 (s, 2H), 3.87 (s, 3H), 3.70 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (C), (C,), (C), (C), (q, J = 32.4 Hz, C), (CH), (CH), (2xCH), (2xCH), (q, J = Hz, CF 3,), (2xCH), (C), (CH), 91.4 (2xCH), 72.6 (CH), 56.0 (2xCH 3 ), 55.4 (CH 3 ). MS (m/z) 465 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 25 H 21 F 3 Na 4 [M+Na] + : found : S8

9 3 (2 fluorophenyl) 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3f Yield 88 %, White solid. Mp C. TLC R f 0.39 (pentane/ether, 80:20) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.70 (td, J = 7.9, 1.5 Hz, 1H), (m, 6H), 6.86 (s, 1H), 6.64 (d, J = 7.6 Hz, 1H), 6.61 (s, 1H), 6.22 (s, 2H), 3.86 (s, 3H), 3.71 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (d, J = 239.1Hz, CF), (C), (C), (C), (d, J = 8.7 Hz, CH), (CH), (CH), (CH), (CH), (CH), (CH), (d, J = 22.9 Hz, CH), (C), (CH), (d, J = 13.9 Hz, C), 91.4 (2xCH), 72.4 (CH), 56.0 (2xCH 3 ), 55.3 (CH 3 ). MS (m/z) 415 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 24 H 21 FNa 4 [M+Na] + : found : (2 (trifluoromethyl)phenyl) 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3g Yield 80 %, White solid. Mp C. TLC R f 0.37 (pentane/ether, 80:20) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.67 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 6.0 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 7.3 Hz, 1H), (m, 3H), 6.63 (d, J = 7.6 Hz), 6.19 (s, 2H), 5.99 (s, 1H), 3.84 (s, 3H), 3.72 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (C), (C), (C), (C), (CH), (CH), (q, J = 30.6 Hz, C), (CH), (CH), (CH), (CH), (q, J = Hz, CF 3 ), (CH), (CH), (C), (CH), 91.7 (2xCH), 73.6 (CH), 56.3 (2xCH 3 ), 55.7 (CH 3 ). MS (m/z) 465 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 25 H 21 F 3 Na 4 [M+Na] + : found : (4 bromophenyl) 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3h Yield 81 %, White solid. Mp C. TLC R f 0.43 (pentane/ether, 80:20) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.59 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.16 (t, J = 6.8 Hz, 1H), (m, 2H), 6.87 (s, 1H), 6.65 (d, J = 7.4 Hz, 1H), 6.38 (s, 1H), 6.23 (s, 2H), 3.87 (s, 3H), 3.70 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (C), (C), (C), (C), (2xCH), (CH), (2xCH), (CH), (CH), (CH), (C), (C), (CH), 91.8 (2xCH), 73.0 (CH), 56.5 (2xCH 3 ), 55.8 (CH 3 ). MS (m/z) 475 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 24 H 21 BrNa 4 [M+Na] + : found : S9

10 1 (2,4,6 trimethoxyphenyl) 3 (3,4,5 trimethoxyphenyl) 1H isochromene, 3i Yield 80 %, White solid. Mp C. TLC R f 0.34 (pentane/ether, 50:50) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.15 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 6.8 Hz, 1H), (m, 2H), 6.93 (s, 2H), 6.84 (s, 1H), 6.61 (d, J = 7.6 Hz, 1H), 6.29 (s, 1H), 6.22 (s, 2H), 3.88 (s, 6H), 3.87 (s, 3H), 3.84 (s, 3H), 3.70 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (C), (2xC), (C), (2xC), (C), (CH), (CH), (CH), (CH), (C), (2xCH), 99.9 (CH), 91.4 (2xCH), 72.7 (CH), 60.9 (CH 3 ), 56.2 (2xCH 3 ), 56.1 (2xCH 3 ), 55.3 (CH 3 ). MS (m/z) 465 [MH + ], 487 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 27 H 29 7 [M+H] + : found : (4 nitrophenyl) 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3j Yield 93 %, White solid. Mp C. TLC R f 0.41 (pentane/ether, 70:30) 1 H NMR (300 MHz, CDCl 3 ): δ = 8.17 (dd, J = 8.9, 0.7 Hz, 2H), 7.84 (dd, J = 8.9, 0.7 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), (m, 2H), 6.92 (s, 1H), 6.67 (d, J = 7.3 Hz, 1H), 6.55 (s, 1H), 6.23 (s, 2H), 3.87 (s, 3H), 3.70 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (C), (C), (C), (C), (C), (2xCH), (2xCH), (CH), (CH), (2xCH), (C), (CH), 91.3 (2xCH), 72.6 (CH), 55.9 (2xCH 3 ), 55.3 (CH 3 ). MS (m/z) 442 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 24 H 21 NNa 6 [M+Na] + : found : (2,4,6 trimethoxyphenyl) 1H isochromene, 3k Yield 45 %, White solid. Mp C. TLC R f 0.20 (pentane/ether, 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.11 (t, J = 7.4 Hz, 1H), (m, 2H), 6.75 (s, 1H), 6.64 (d, J = 5.7 Hz), 6.56 (d, J = 7.5 Hz, 1H), 6.20 (s, 2H), 5.75 (d, J = 5.7 Hz, 1H), 3.85 (s, 3H), 3.71 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (CH), (C), (C), (CH), (CH), (CH), (CH), (C), (CH), 91.6 (2xCH), 72.0 (CH), 56.4 (2xCH 3 ), 55.8 (CH 3 ). MS (m/z) 321 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 18 H 18 Na 4 [M+Na] + : found : S10

11 3 propyl 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3m Yield 34 %, il. TLC R f 0.32 (pentane/ether, 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.08 (t, J = 7.4 Hz, 1H), (m, 2H), 6.70 (s, 1H), 6.53 (d, J = 7.6 Hz, 1H), 6.20 (s, 2H), 5.58 (s, 1H), 3.84 (s, 3H), 3.70 (s, 6H), 2.16 (t, J = 7.5 Hz, 2H), (m, 2H), 0.96 (t, J = 7.5 Hz, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (C), (C), (C), (CH), (CH), (CH), (CH), (C), 99.4 (CH), 91.5 (2xCH), 72.1 (CH), 56.0 (2xCH 3 ), 55.3 (CH 3 ), 36.0 (CH 2 ), 20.4 (CH 2 ), 13.7 (CH 3 ). MS (m/z) 363 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 21 H 24 Na 4 [M+Na] + : found : tert butyl 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3n Yield 65 %, White solid. Mp C. TLC R f 0.55 (pentane/ether, 90:10) 1 H NMR (300 MHz, 45 C, CDCl 3 ): δ = 7.06 (app. t, J = 7.1 Hz, 1H), (m, 2H), 6.67 (s, 1H), 6.54 (d, J = 7.4 Hz, 1H), 6.22 (s, 2H), 5.62 (s, 1H), 3.85 (s, 3H), 3.71 (brs, 6H), 1.16 (s, 9H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (3xC), (C), (C), (CH), (CH), (CH), (CH), (C), 95.5 (CH), 92.5 (CH), 90.5 (CH), 72.1 (CH), 56.1 (2xCH 3 ), 55.3 (CH 3 ), 35.3 (C), 27.9 (3xCH 3 ). MS (m/z) 377 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 22 H 26 Na 4 [M+Na] + : found : (methoxymethyl) 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3p Yield 80 %, White solid. Mp C. TLC R f 0.57 (pentane/ether, 50:50) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.10 (t, J = 7.4 Hz, 1H), (m, 2H), 6.78 (s, 1H), 6.56 (d, J = 7.2 Hz, 1H), 6.18 (s, 2H, H 12 ), 5.83 (s, 1H), 4.05 (d, J = 13.3 Hz, 1H), 3.90 (d, J = 13.3 Hz, 1H), 3.84 (s, 3H), 3.69 (s, 6H), 3.42 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (C), (C), (C), (CH), (CH), (CH), (CH), (C), (CH), 91.3 (2xCH), 72.3 (CH), 71.9 (CH 2 ), 58.3 (CH 3 ), 55.9 (2xCH 3 ), 55.3 (CH 3 ). MS (m/z) 365 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 20 H 22 Na 5 [M+Na] + : found : ,6,7 trimethoxy 3 (methoxymethyl) 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3q Yield 33 %, White solid. Mp C. TLC R f 0.29 (pentane/ether, 50:50) 1 H NMR (300 MHz, CDCl 3 ): δ = 6.67 (s, 1H), 6.17 (s, 2H), 6.04 (s, 1H), 5.96 (s, 1H), 4.05 (d, J = 13.0 Hz, 1H), 3.91 (d, J = 13.0 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 6H), 3.71 (s, 6H), 3.63 (s, 3H), 3.41 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (C), (C), (C), (C), (C), (C), (C), (CH), 96.9 (CH), 91.8 (2xCH), 72.6 (CH 2 ), 72.3 (CH), 61.7 (CH 3 ), 61.3 (CH 3 ), 58.5 (CH 3 ), 56.6 (CH 3 ), 56.4 (2xCH 3 ), 55.7 (CH 3 ). MS (m/z) 455 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 23 H 28 Na 8 [M+Na] + : found : S11

12 7 fluoro 3 (methoxymethyl) 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3r Yield 88 %, White solid. Mp C. TLC R f 0.30 (pentane/ether, 70:30) 1 H NMR (300 MHz, CDCl 3 ): δ = (m, 1H), (m, 2H), 6.30 (d, J = 9.1 Hz, 1H), 6.17 (s, 2H), 5.81 (s, 1H), 4.05 (d, J = 13.3 Hz, 1H), 3.90 (d, J = 13.3 Hz, 1H), 3.84 (s, 3H), 3.70 (s, 6H), 3.41 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ = δ = (C,), (d, J = Hz, CF), (2xC), (C), (d, J = 7.0 Hz, C), (d, J = 2.9 Hz, C), (d, J = 7.7 Hz, CH), (d, J = 21.6 Hz, CH), (d, J = 23.4 Hz, CH), (C), (CH), 91.7 (2xCH), 72.3 (CH), 72.2 (CH 2 ), 58.7 (CH 3 ), 56.3 (2xCH 3 ), 55.8 (CH 3 ). MS (m/z) 383 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 20 H 21 FNa 5 [M+Na] + : found : (methoxymethyl) 7 (trifluoromethyl) 1 (2,4,6 trimethoxyphenyl) 1H isochromene, 3s Yield 88 %, White solid. Mp C. TLC R f 0.17 (pentane/ether, 80:20) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.36 (d, J = 7.8 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), (m, 2H), 6.19 (s, 2H), 5.89 (s, 1H), 4.06 (d, J = 13.8 Hz, 1H), 3.91 (d, J = 13.8 Hz, 1H), 3.84 (s, 3H), 3.69 (s, 6H), 3.42 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (C), (C), (C), (q, J = 31.9 Hz, C), (q, J = Hz, CF 3 ), (CH), (CH), (CH), (C), (CH), 91.3 (2xCH), 72.2 (CH), 71.5 (CH 2 ), 58.5 (CH 3 ), 55.8 (2xCH 3 ), 55.3 (CH 3 ). MS (m/z) 433 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 21 H 21 F 3 Na 5 [M+Na] + : found : (2,4 dimethoxyphenyl) 3 phenyl 1H isochromene, 13 Yield 58 %, il. TLC R f 0.36 (pentane/ether, 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.70 (dd, J = 8.1, 1.7 Hz, 2H), (m, 4H), (m), 6.79 (d, J = 7.5 Hz, 1H), 6.66 (s, 1H), 6.56 (d, J = 2.3 Hz, 1H), 6.49 (s, 1H), 6.45 (dd, J = 8.5, 2.3 Hz, 1H), 3.91 (s, 3H), 3.81 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (C), (C), (C), (C), (C), (CH), (CH), (2xCH), (CH), (CH), (2xCH), (CH), (CH), (C), (CH), (CH), 98.4 (CH), 74.0 (CH), 55.6 (CH 3 ), 55.4 (CH 3 ). MS (m/z) 345 [MH + ] HRMS (ESI): m/z [MH + ] calcd. for C 23 H 21 3 [M+H] + : found : (2,4 dimethoxyphenyl) 7 fluoro 3 (methoxymethyl) 1H isochromene, 14 Yield 47 %, White solid. Mp C. TLC R f 0.29 (pentane/ether, 80:20) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.17 (d, J = 8.5 Hz, 1H), (m, 1H), 6.88 (td, J = 8.5, 2.5 Hz, 1H), (m, 3H), 6.40 (dd, J = 9.3, 2.1 Hz, 1H), 5.92 (s, 1H), 3.99 (d, J = 13.4 Hz, 1H), 3.91 (d, J 13.4 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.33 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ = (d, J = Hz, CF), (C), (C), (C), (d, J = 3.7 Hz, C), (CH), (C), (d, J = 7.4 Hz, CH), (C), (d, J = 21.3 Hz, CH), (d, J = 22.9 Hz, CH), (CH), (CH), 98.4 (CH), 73.6 (CH), 71.6 (CH 2 ), 58.3 (CH 3 ), 55.6 (CH 3 ), 55.4 (CH 3 ). MS (m/z) 353 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 19 H 19 FNa 4 [M+Na] + : found : S12

13 4 (7 fluoro 3 (methoxymethyl) 1H isochromen 1 yl) N,N dimethylaniline, 15 Yield 50 % (71% conversion), il. TLC R f 0.39 (pentane/ether, 80:20) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.21 (d, J = 8.8 Hz, 2H), 7.00 (dd, J = 5.5, 8.3 Hz, 1H), 6.90 (td, J = 2.3, 8.3 Hz, 1H), 6.71 (d, J = 8.8 Hz, 2H), 6.50 (dd, J = 2.3, 8.9 Hz, 1H), 6.03 (s, 1H), 5.91 (s, 1H), 3.94 (x, J = x Hz, 2H), 3.32 (s, 3H), 2.96 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = (d, J = Hz, CF), (C), (C), (d, J = 6.5 Hz, C), (2xCH), (C), (C), (d, J = 7.4 Hz, CH), (d, J = 21.5 Hz, CH), (d, J = 22.4 Hz, CH), (2xCH), (CH), 80.2 (CH), 72.1 (CH 2 ), 58.7 (CH 3 ), 40.9 (2xCH 3 ). MS (m/z) 314 [MH + ] HRMS (ESI): m/z [MH + ] calcd. for C 19 H 21 FN 2 [M+H] + : found : (7 fluoro 3 (methoxymethyl) 1H isochromen 1 yl) 1 methyl 1H indole, 16 Yield 83 %, Pale red solid. Mp C. TLC R f 0.20 (pentane/ether, 80:20) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.69 (d, J = 7.9 Hz, 1H), (m, 2H), 7.12 (t, J = 7.8 Hz, 1H), 7.03 (t, J = 5.6 Hz, 1H), (m, 1H), 6.80 (s, 1H), 6.64 (dd, J = 9.1, 2.1 Hz, 1H), 6.48 (s, 1H), 5.96 (s, 1H), 3.94 (d, J = 13.4 Hz, 1H), 3.86 (d, J = 13.4 Hz, 1H), 3.73 (s, 3H), 3.29 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ): δ = (d, J = Hz, CF), (C), (C), (C), (CH), (C), (C), (d, J = 7.3 Hz, CH), (CH), (CH), (CH), (d, J = 21.4 Hz, CH), (C), (d, J = 22.7 Hz, CH), (CH), (CH), 74.3 (CH), 72.0 (CH 2 ), 58.7 (CH 3 ), 33.3 (CH 3 ). MS (m/z) 346 [MNa + ], 378 [M+MeH+Na + ] HRMS (ESI): m/z [MH + ] calcd. for C 20 H 18 FNNa 2 [M+Na] + : found : phenyl 1 (2,4,6 trimethoxyphenyl 3,5 d 2 ) 1H isochromene 4d 1, 3a d 3 Yield 88 %, White solid. Mp C. TLC R f 0.21 (pentane/ether, 90:10) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.76 (dd, J = 8.2, 1.6 Hz, 2H), (m, 3H), 7.18 (app. t, J = 7.3 Hz, 1H), (m, 2H), 6.91 (s, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.43 (s, 1H), 6.26 (s, 2H), 3.88 (s, 3H), 3.72 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (C), (C), (2xC, C 4 ), (CH), (2xCH), (CH), 126.4(CH), (2xCH), (CH), (CH), (C), (CD), 91.9 (2xCD), 72.9 (CH), 56.5 (2xCH 3 ), 55.8 (CH 3 ). MS (m/z) 378 [MH + ], 400 [MNa + ] HRMS (ESI): m/z [MH + ] calcd. for C 24 H 19 D 3 Na 4 [M+Na] + : found : S13

14 IV) Metal catalyzed Hartwig Buchwald reaction The palladium catalyzed amination reaction was performed following a reported procedure. 14 N benzyl 4 (1 (2,4,6 trimethoxyphenyl) 1H isochrom 3 yl)aniline, 17 Yield 72 %, Pale yellow solid. Mp 101 C. TLC R f 0.15 (pentane/ether, 80:20) 1 H NMR (300 MHz, CDCl 3 ): δ = 7.54 (d, J = 8.6 Hz, 2H), (m, 5H), 7.12 (app. t, J = 7.5 Hz, 1H), 7.01 (d, J = 7.1 Hz, 1H), 6.94 (app. t, J = 7.2 Hz, 1H), 6.75 (s, 1H), (m, 3H), 6.22 (brs, 3H), 4.34 (s, 2H), 4.18 (brs, 1H, NH), 3.86 (s, 3H), 3.69 (s, 6H). 13 C NMR (75 MHz, CDCl 3 ): δ = (C), (2xC), (C, C 2 ), (C), (C), (C), (C), (2xCH), (2xCH), (CH), (CH), (2xCH), (CH), (C), (CH), (CH), (2xCH), (C), 97.7 (CH), 91.9 (2xCH), 72.8 (CH), 56.5 (2xCH 3 ), 55.7 (CH 3 ), 48.5 (CH 2 ). MS (m/z) 480 [MH + ] HRMS (ESI): m/z [MH + ] calcd. for C 31 H 30 N 4 [M+H] + : found : V) Crystal data for 3h Crystal data for 3h. Colorless block-like crystals: C 24 H 21 Br 4,0.25 (C H 2 Cl 2 ), triclinic, P -1, a = (3), b = (3), c = (4) Å, α = (1), β = (1), γ = (1), V = (9) Å 3, Z = 4, T = 200(2) K, = mm -1, reflections measured, 7699 independent (R int = ), 7483 observed [I 2 (I)], 593 parameters, final R indices R 1 [I 2 (I)] = and wr 2 (all data)= , GF on F 2 = 1.221, max/min residual electron density = 0.525/ e.å -3. A single crystal was selected, mounted onto a cryoloop, and transferred in a cold nitrogen gas stream. Intensity data were collected with a BRUKER QUAZAR diffractometer with IµS microfocus Cu-K radiation (λ = Å). Data collection was performed with APEX2 suite (BRUKER). Unit-cell parameters refinement, integration and data reduction were carried out with SAINT program (BRUKER). SADABS (BRUKER) was used for scaling and multi-scan absorption corrections. In the WinGX suite of programs, the structure were solved with SUPERFLIP program and refined by full-matrix least-squares methods using SHELXL All non-hydrogen atoms were refined anisotropically. A model of disorder was introduced for 44 C25 C34 atoms. Hydrogen atoms were placed at calculated positions. 15 CCDC contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via VI) 1 H and 13 C NMR spectra for all new compounds (see following pages) 14 D. S. Surry, S. L. Buchwald, Chem. Sci. 2011, 2, a) Palatinus, L.; Chapuis, G. J. Appl. Cryst. 2007, 40, b) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. J. Appl. Cryst. 1994, 27, 435. c) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, d) Brandenburg, K. Crystal Impact GbR, Bonn, Germany. S14

15 ppm (f1) 1d 2.5 F

16

17 1f ppm (f1) F 2.5 S

18 ppm (f1) f F

19 ppm (f1) g F 3 C

20 1g F 3C 175 ppm (f1) S

21 N 1o ppm (f1)

22

23 ppm (f1) q CH

24

25 F CH 3 1r ppm (f1)

26 ppm (f1) F 1r CH 3

27 F 3 C CH 3 1s ppm (t1)

28

29 ppm (f1) a

30 175 ppm (f1) a

31 ppm (f1) a-d 3 D D D

32 175 ppm (f1) D D 3a-d 3 D 25 S

33 ppm (f1) b

34 175 ppm (f1) b

35 ppm (f1) c

36 175 ppm (f1) c

37

38 175 ppm (f1) d 25 F S

39 ppm (f1) CF3 3e

40

41 ppm (f1) F 3f

42 175 ppm (f1) f 25 F

43 ppm (f1) F 3 C 3g

44 175 ppm (t1) F 3 C 3g

45 ppm (f1) Br 3h

46

47 ppm (f1) i

48 175 ppm (f1) i

49 ppm (f1) j 1.50 N

50 175 ppm (f1) j N 2

51 ppm (f1) k H

52 175 ppm (f1) k 25 H

53 ppm (f1) m

54 175 ppm (f1) m

55 n ppm (f1)

56 175 ppm (f1) n

57 ppm (f1) p

58 175 ppm (f1) p

59 ppm (f1) q

60

61 ppm (f1) r F

62 175 ppm (f1) F 3r

63 175 ppm (f1) F 3 C 3s

64 ppm (f1) ppm (f1) s F 3 C

65 ppm (f1)

66 175 ppm (f1)

67 ppm (f1) F

68 175 ppm (f1) F

69 ppm (f1) N 15 F

70

71 ppm (f1) F N

72 175 ppm (f1) F N 16

73 ppm (f1) N H 17

74