Selective, Catalytic and Metal-Free Coupling of Electron-rich Phenols and Anilides Using Molecular Oxygen as Terminal Oxidant

Transcription

1 Supporting Information for Selective, Catalytic and Metal-Free Coupling of Electron-rich Phenols and Anilides Using Molecular Oxygen as Terminal Oxidant Luis Bering, 1,2 Melina Vogt, 2 Felix M. Paulussen 2 and Andrey P. Antonchick 1,2 * 1 Max-Planck-Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Straße 11, Dortmund, Germany 2 TU Dortmund, Faculty of Chemistry and Chemical Biology, Chemical Biology, Otto-Hahn-Straße 4a, Dortmund, Germany * Andrey.Antonchick@mpi-dortmund.mpg.de Contents General... S2 Optimization... S3 General Synthetic Procedures... S6 Details on the control experiments... S8 Physical Data of Starting Materials... S12 Physical Data of Products... S18 Copies of 1 H and 13 C NMR spectra... S34 References... S81 S1

2 General All reactions were carried out in an oven dried screw cap vial. Unless otherwise noted, all commercially available compounds were used as provided without any further purification. Solvents for chromatography were laboratory grade. Analytical thin-layer chromatography (TLC) was performed on Merck silica gel aluminum plates with F 254 indicator, visualized by irradiation with UV light. Column chromatography was performed using silica gel Merck 60 (particle size mm). Nitrosyl tetrafluoroborate was purchased from VWR Germany (VWR International GmbH, Hilpertstraße 20a, Darmstadt) with a claimed purity of 98%. 1 H NMR and 13 C NMR were recorded on a Bruker DRX400 (400 MHz), DRX500 (500MHz) and DRX700 (700 MHZ) spectrometer in CD2Cl2, Aceton-d6 or DMSO-d6. Data are reported in the following order: chemical shift (δ) in ppm; multiplicities are indicated s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet); coupling constants (J) are given in Hertz (Hz). Low resolution mass spectra (MS-EI, 70 ev) were collected using a GC-MS (GC system 7890A equipped with 5975C detector) produced by Agilent Technologies (column: HP-5MS, 30 m mm 0.25 μm). Fourier transform infrared spectroscopy (FT IR) spectra were obtained with a Bruker Tensor 27 spectrometer (ATR, neat) and are reported in terms of frequency of absorption (cm 1 ). High resolution mass spectra were recorded on a LTQ Orbitrap mass spectrometer coupled to an Accela HPLC System (HPLC column: Hypersyl GOLD, 50 mm 1 mm, 1.9 μm). S2

3 Optimization Table S1. Full details on the optimization for the dehydrogenative coupling of 1a a Entry Solvent TFA (v/v) Loading Time Temperature Conc. Yield 2a b Yield 2q b 1 MeCN - 10 mol% 1 h 0 C 0.1 M DCM - 10 mol% 24 h 0 C 0.1 M TFE - 10 mol% 24 h 0 C 0.1 M PhCl 20% 10 mol% 24 h 0 C 0.1 M HFIP - 10 mol% 1 h 0 C 0.1 M ,4-dioxane 20% 10 mol% 24 h 0 C 0.1 M MeNO 2 20% 10 mol% 1 h 0 C 0.1 M EtOAc 20% 10 mol% 24 h 0 C 0.1 M Me 2O 20% 10 mol% 24 h 0 C 0.1 M % 10 mol% 1 h 0 C 0.1 M :1 DCM / HFIP - 10 mol% 1 h 0 C 0.1 M 15% 32% 12 MeCN 20% 10 mol% 1 h 0 C 0.1 M DCM 20% 10 mol% 1 h 0 C 0.1 M - 33% 14 c DCM 20% 10 mol% 1 h 0 C 0.1 M - 33% 15 DCM 10% 10 mol% 1 h 0 C 0.1 M - 29% 16 DCM 5% 10 mol% 1 h 0 C 0.1 M - 32% 17 DCM 2.5% 10 mol% 1 h 0 C 0.1 M - 14% 18 DCM 20% 5 mol% 1 h 0 C 0.1 M 33% - 19 DCM 20% 2.5 mol% 1 h 0 C 0.1 M 58% - 20 DCM 20% 1 mol% 1 h 0 C 0.1 M 44% - 21 DCM 20% 2.5 mol% 1 h 0 C 0.2 M 30% - 22 DCM 20% 2.5 mol% 1 h 0 C 0.05 M 73% - 23 DCM 20% 2.5 mol% 1 h 0 C M 51% - 24 DCM 20% 2.5 mol% 1 h -15 C 0.05 M 84% - 25 d DCM 20% 2.5 mol% 1 h -15 C 0.05 M 55% - a Optimization performed using phenol 1a (0.2 mmol, 1 equiv.) as model substrate. b Yields are given for isolated products after column chromatography. c NaNO 2 (10 mol%) instead of NOBF 4 was used. d Under O 2 atmosphere. S3

4 Table S2. Optimization for the dehydrogenative coupling of 1a in the presence of KB(C 6F 5) 4 as additive a Entry Solvent TFA (v/v) Loading Additive Time Temperature Concentration Yield b 1 DCM 20% 2.5 mol% KB(Ph) 4 (5 mol%) 24 h 0 C 0.1 M traces 2 DCM 20% 2.5 mol% KBPhF 3 (5 mol%) 24 h 3 DCM 20% 2.5 mol% KB(C 6F 5) 4 (5 mol%) 1 h 0 C 0.1 M 55% 4 DCM 20% 5 mol% KB(C 6F 5) 4 (10 mol%) 1 h 0 C 0.1 M 37% 5 DCM mol% KB(C 6F 5) 4 (5 mol%) 24 h 0 C 0.1 M 14% 6 DCM mol% KB(C 6F 5) 4 (5 mol%) 24 h 0 C 0.1 M 15% 7 HFIP mol% KB(C 6F 5) 4 (5 mol%) 1 h 0 C 0.1 M 30% 8 HFIP - 5 mol% KB(C 6F 5) 4 (10 mol%) 1 h 0 C 0.1 M 36% 9 HFIP - 10 mol% KB(C 6F 5) 4 (20 mol%) 1 h 0 C 0.1 M 58% 10 HFIP - 20 mol% KB(C 6F 5) 4 (40 mol%) 1 h 0 C 0.1 M 58% 11 MeNO 2 20% 2.5 mol% KB(C 6F 5) 4 (5 mol%) 24 h 0 C 0.1 M 32% 12 PhCl 20% 2.5 mol% KB(C 6F 5) 4 (5 mol%) 24 h 0 C 0.1 M 14% a Optimization performed using phenol 1a (0.2 mmol, 1 equiv.) as model substrate. b Yields are given for isolated products after column chromatography. S4

5 Table S3. Details on the optimization for the dehydrogenative coupling of 3a a Entry Solvent TFA (v/v) Loading Yield b 1 MeCN 20% 10 mol% 34% 2 MeCN 20% 20 mol% 52% 3 DCM 20% 20 mol% 65% 4 DCM 10% 20 mol% 48% 5 DCM 33% 20 mol% 94% 6 DCM 50% 20 mol% 26% 7 c DCM 33% 20 mol% 51% a Optimization performed using anilide 3a (0.2 mmol, 1 equiv.) as model substrate. b Yields are given for isolated products after column chromatography. c Under O 2 atmosphere. S5

6 General Synthetic Procedures General Procedure A: Synthesis of Anilides To a solution of the amine (2 mmol, 1 equiv.) and 4-(dimethylamino)pyridine (0.02 mmol, 1 mol%) in 1:1 DCM / pyridine (10 ml) the acyl chloride (2.4 mmol, 1.2 equiv.) was slowly added at 0 C and the reaction was stirred at room temperature for overnight. The reaction was neutralized adding 1 M HCl solution (40 ml), the aqueous phase was extracted three times with DCM (3x50 ml) and the combined organic layers were dried over MgSO4. The crude product was purified by silica gel column chromatography (elute: petroleum ether / EtOAc). General Procedure B: Synthesis of Biphenols B1) To a stirring solution of phenol (0.5 mmol, 1 equiv.) in 4:1 DCM / TFA (10 ml), NOBF4 (1.5 mg, 12.5 μmol, 2.5 mol%) was added at -15 C. The reaction was vigorously stirred until full conversion of starting material was monitored by TLC. The reaction was slowly quenched with saturated NaHCO3 solution (30 ml) and extracted three times with DCM (3x40 ml). The combined organic layers were dried over MgSO4 and the crude product was purified by silica gel column chromatography (elute: petroleum ether / EtOAc). B2) To a stirring solution of KB(C6F5)4 (28 mg, 0.04 mmol, 20 mol%) in HFIP (4 ml) was added NOBF4 (2.34 mg, 0.02 mmol, 10 mol%) at room temperature. The reaction mixture was stirred at room temperature for 15 Minutes and subsequently cooled to 0 C. The phenol (0.2 mmol, 1 equiv.) was added and the reaction was vigorously stirred until full conversion of starting material was monitored by TLC. The solvent was removed under reduced pressure and the crude product was purified by silica gel column chromatography (elute: petroleum ether / EtOAc). S6

7 General Procedure C: Cross-Dehydrogenative Coupling of Phenols To a stirring solution of phenol (0.25 mmol, 1 equiv.) and arenes (0.75 mmol, 3 equiv.) in 4:1 DCM / TFA (2.5 ml), NOBF4 (2.24 mg, 18.5 μmol, 7.5 mol%) was added at 0 C. The reaction was vigorously stirred until full conversion of starting material was monitored by TLC. The reaction was slowly quenched with saturated NaHCO3 solution (15 ml) and extracted three times with DCM (3x20 ml). The combined organic layers were dried over MgSO4 and the crude product was purified by silica gel column chromatography (elute: petroleum ether / EtOAc). Phenol-anilide cross-coupling was conducted in the same manner, using phenol (0.2 mmol, 1 equiv.) and anilide (0.6 mmol, 3 equiv.) in 4:1 DCM / TFA (2 ml). General Procedure D: Synthesis of Bisanilides To a stirring solution of anilide (0.2 mmol, 1 equiv.) in 2:1 DCM / TFA (2 ml), NOBF4 (4.76 mg, 0.04 mmol, 20 mol%) was at 0 C. The reaction was vigorously stirred until full conversion of starting material was monitored by TLC. The reaction was slowly quenched with saturated NaHCO3 solution (10 ml) and extracted three times with DCM (3x20 ml). The combined organic layers were dried over MgSO4 and the crude product was purified by silica gel column chromatography (elute: petroleum ether / EtOAc or DCM / MeOH). S7

8 Details on the control experiments Scheme S1. Examination of butylated hydroxytoluene (BHT) as suitable radical scavenger. We selected butylated hydroxytoluene as radical trap, since it did not show any reactivity in the presence of nitrosonium tetrafluoroborate. This finding is in contrast to other radical traps such as TEMPO or N,α-diphenyl-nitrone, which directly oxidize NO-species and do not prove the formation of radical intermediates. Scheme S2. Control experiments for the dehydrogenative coupling of phenols. The control experiments for the homo coupling of phenol 1a show, that ambient oxygen is required to maintain the catalytic cycle, since no conversion was observed, when the reaction was conducted under argon atmosphere (S2a). This result shows, that oxygen is the terminal oxidant and consequently water is formed as the by-product. Further, methylated phenol analogue 1r did not show any conversion (S2b). This result shows, that oxidation of weak O-H bonds is required to achieve coupling and a direct S8

9 single-electro-transfer process is unlikely. Finally, when performing the reaction in the presence of radical trap BHT, no formation of 2a was observed and the formation of radical trapping adduct 2s was detected (S2c). This result supports the generation of radical intermediates during the course of reaction. Scheme S3. Mass spectrum of 2s. S9

10 Details on the control experiments Scheme S4. Examination of butylated hydroxytoluene (BHT) as radical scavenger. We selected butylated hydroxytoluene as radical trap as well, since it did not show any reactivity in the presence of nitrosonium tetrafluoroborate, even when the catalyst loading was increased to 20 mol%. This finding is in contrast to other radical traps such as TEMPO or N,α-diphenyl-nitrone, which directly oxidize NO-species and do not prove the formation of radical intermediates. Scheme S5. Control experiments for the dehydrogenative coupling of anilides. The control experiments for the homo coupling of anilide 3a show, that ambient oxygen is required to maintain the catalytic cycle, since no conversion was observed, when the reaction was conducted under argon atmosphere (S5a). This result shows, that oxygen is the terminal oxidant and consequently water is formed as the by-product. Further, methylated phenol analogue 3o did not show any conversion (S5b). This result shows, that oxidation of weak N-H bonds is required to achieve coupling and a direct S10

11 single-electro-transfer process is unlikely. Finally, when performing the reaction in the presence of radical trap BHT, no formation of 4a was observed and the formation of radical trapping adduct 4p was detected (S5c). This result supports the generation of radical intermediates during the course of reaction and further demonstrate the homology between phenols and anilides. Scheme S6. Mass spectrum of 4p. S11

12 Physical Data of Starting Materials N-(3,4-dimethoxyphenyl)acetamide (3a) Prepared according to the general procedure A using 3,4-dimethoxyanilide (306 mg, 2 mmol, 1 equiv.) and acetyl chloride (170 µl, 2.4 mmol, 1.2 equiv.); the product was obtained as brownish solid (223 mg, 1.14 mmol, 57%). Rf = 0.52 (cyclohexane / EtOAc = 1:1). 1 H NMR (500 MHz, DMSO) δ 9.78 (s, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 8.6, 2.4 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 3.70 (s, 3H), 3.70 (s, 3H), 1.99 ppm (s, 3H). 13 C NMR (126 MHz, DMSO) δ , , , , , , , 60.89, 60.50, ppm. N-(benzo[d][1,3]dioxol-5-yl)acetamide (3b) Prepared according to the general procedure A using benzo[d][1,3]dioxol-5-amine (306 mg, 2 mmol, 1 equiv.) and acetyl chloride (170 µl, 2.4 mmol, 1.2 equiv.); the product was obtained as brownish solid (304 mg, 1.7 mmol, 85%). Rf = 0.61 (DCM / MeOH = 20:1). 1 H NMR (500 MHz, DMSO) δ 9.84 (s, 1H), 7.28 (d, J = 2.0 Hz, 1H), 6.92 (dd, J = 8.4, 2.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 5.96 (s, 2H), 1.99 ppm (s, 3H). 13 C NMR (126 MHz, DMSO) δ , , , , , , , , ppm. N-(2,4-dimethoxyphenyl)acetamide (3c) Prepared according to the general procedure A using 2,3-dimethoxyanilide (306 mg, 2 mmol, 1 equiv.) and acetyl chloride (170 µl, 2.4 mmol, 1.2 equiv.); the product was obtained as brownish solid (304 mg, 1.7 mmol, 85%). Rf = 0.5 (cyclohexane / EtOAc = 1:2). 1 H NMR (500 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 6.59 (d, J = 2.7 Hz, 1H), 6.46 (dd, J = 8.7, 2.7 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 2.02 ppm (s, 3H). 13 C NMR (126 MHz, DMSO) δ , , , , , , 98.73, 55.66, 55.32, ppm. S12

13 N-(3,4-dimethoxyphenyl)-4-methylbenzenesulfonamide (3d) To a solution of 3,4-dimethoxyanilide (383 mg, 2.5 mmol, 1 equiv.) in distilled water (25 ml) paratoluenesulfonyl chloride (572, 3 mmol, 1 equiv.) was added and the reaction was stirred for overnight at room temperature. The aqueous phase was three times extracted with EtOAc (3x30 ml) and the combined organic layers were washed with brine and dried over MgSO4. The crude product was purified by silica gel column chromatography (elute: petroleum ether / EtOAc); the product was obtained as white solid (369 mg, 1.2 mmol, 48%). Rf = 0.68 (cyclohexane / EtOAc = 1:1). 1 H NMR (500 MHz, DMSO) δ 9.85 (s, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 6.77 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 2.5 Hz, 1H), 6.53 (dd, J = 8.7, 2.5 Hz, 1H), 3.65 (s, 3H), 3.62 (s, 3H), 2.33 ppm (s, 3H). 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , 55.54, 55.35, ppm. N-(3,4-dimethoxyphenyl)benzamide (3e) Prepared according to the general procedure A using 3,4-dimethoxyanilide (306 mg, 2 mmol, 1 equiv.) and benzoyl chloride (277 µl, 2.4 mmol, 1.2 equiv.); the product was obtained as brownish solid (253 mg, 0.98 mmol, 48%). Rf = 0.61 (cyclohexane / EtOAc = 1:1). 1 H NMR 600 MHz, DMSO) δ (s, 1H), (m, 2H), 7.57 (d, J = 7.3 Hz, 1H), 7.52 (t, J = 7.3 Hz, 2H), 7.48 (d, J = 2.3 Hz, 1H), 7.34 (dd, J = 8.7, 2.3 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 3.75 (s, 3H), 3.74 ppm (s, 3H). 13 C NMR (151 MHz, DMSO) δ , , , , , , , , , , , 56.18, ppm. S13

14 N-(3,4-dimethoxyphenyl)-4-nitrobenzamide (3f) Prepared according to the general procedure A using 3,4-dimethoxyanilide (306 mg, 2 mmol, 1 equiv.) and 4-nitrobenzoyl chloride (445 mg, 2.4 mmol, 1.2 equiv.); the product was obtained as yellow solid (235 mg, 0.78 mmol, 39%). Rf = 0.7 (cyclohexane / EtOAc = 1:1). 1 H NMR 500 MHz, DMSO) δ (s, 1H), 8.37 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 2.3 Hz, 1H), 7.34 (dd, J = 8.8, 2.3 Hz, 1H), 6.96 (d, J = 8.8 Hz, 1H), 3.75 ppm (s, 6H). 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , 56.11, ppm. N-(3,4-dimethoxyphenyl)-4-fluorobenzamide (3g) Prepared according to the general procedure A using 3,4-dimethoxyanilide (306 mg, 2 mmol, 1 equiv.) and 4-fluorobenzoyl chloride (284 µl, 2.4 mmol, 1.2 equiv.); the product was obtained as white solid (290 mg, 1.05 mmol, 53%). Rf = 0.77 (cyclohexane / EtOAc = 1:2). 1 H NMR (500 MHz, DMSO-d6) δ (s, 1H), 8.10 (dd, J = 8.7, 5.5 Hz, 2H), 7.53 (d, J = 2.4 Hz, 1H), 7.44 (t, J = 8.8 Hz, 2H), 7.39 (dd, J = 8.7, 2.4 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 3.83 (s, 3H), 3.81 ppm (s, 3H). 13 C NMR (126 MHz, DMSO) δ (d, JCF = Hz), , , , , , (d, JCF = 9.1 Hz), (d, JCF = 21.8 Hz), , , , 56.13, ppm. 4-chloro-N-(3,4-dimethoxyphenyl)benzamide (3h) Prepared according to the general procedure A using 3,4-dimethoxyanilide (306 mg, 2 mmol, 1 equiv.) and 4-chlorobenzoyl chloride (307 µl, 2.4 mmol, 1.2 equiv.); the product was obtained as brownish solid (319 mg, 1.63 mmol, 82%). Rf = 0.5 (cyclohexane / EtOAc = 1:2). 1 H NMR (500 MHz, DMSOd6) δ (s, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 2.4 Hz, 1H), 7.33 (dd, J = 8.7, 2.4 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 3.76 (s, 3H), 3.74 ppm (s, 3H). 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , 56.12, ppm. S14

15 N-(3,4-dimethoxyphenyl)adamantane-1-carboxamide (3g) Prepared according to the general procedure A using 3,4-dimethoxyanilide (306 mg, 2 mmol, 1 equiv.) and 1-adamantanecarbonyl chloride (394 µl, 2.4 mmol, 1.2 equiv.); the product was obtained as white solid (520 mg, 1.64 mmol, 82%). Rf = 0.66 (cyclohexane / EtOAc = 1:2). 1 H NMR 500 MHz, DMSO) δ 8.95 (s, 1H), 7.34 (d, J = 2.3 Hz, 1H), 7.21 (dd, J = 8.7, 2.3 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H), ppm (m, 15H). 13 C NMR (126 MHz, DMSO) δ 176.0, 148.7, , , , , , 56.12, 55.75, 41.24, 38.94, 38.85, 36.51, 28.16, ppm. N-(3,4-dimethoxyphenyl)-2-(naphthalen-2-yloxy)acetamide (3h) To a solution of 3,4-dimethoxyanilide (306 mg, 2 mmol, 1 equiv.) and 2-bromoacetic acid (417 mg, 3 mmol, 1.5 equiv.) in THF (4 ml) a solution of ethylcarbodiimide hydrochloride (421.7 mg, 2.2 mmol, 1.1 equiv.) and 4-aminopyridine (2.44 mg, 0.02 mmol, 1 mol%) was added dropwise at 0 C and the reaction was stirred for 12 h at room temperature. The reaction was acidified with 1 M HCl solution (50 ml) and the aqueous phase was three times extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was subjected to the next reaction step without further purification. To the solution of the crude 2-bromo-N-(3,4-dimethoxyphenyl)acetamide in acetone (8 ml) successively 2- naphthol (284 µl, 2.4 mmol, 1.2 equiv.) and K2CO3 (553 mg, 4 mmol, 2 equiv.) were added and the reaction was stirred at 60 C for overnight. Then, the reaction mixture was quenched with water (20 ml) and three times extracted with DCM (3x30 ml). The combined organic layers were dried over MgSO4 and the crude product was purified by column chromatography; the product was obtained as orange solid (493 mg, 1.3 mmol, 65%). Rf = 0.61 (cyclohexane / EtOAc = 1:1). 1 H NMR (500 MHz, DMSO) δ (s, 1H), 7.88 (d, J = 8.9 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), (m, 1H), 7.35 (m, 4H), 7.21 (dd, J = 8.7, 2.4 Hz, 1H), 6.91 (d, J = 8.7 Hz, 1H), 4.79 (s, 2H), 3.72 (s, 3H), 3.72 ppm (s, 3H). 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , , 67.68, 56.12, ppm. S15

16 N-(4-Methoxy-3-methylphenyl)acetamide Prepared according to the general procedure A using 4-methoxy-3-methylaniline (354 mg, 2.5 mmol, 1 equiv.) and acetyl chloride (213 µl, 3 mmol, 1.2 equiv.); the product was obtained as white solid (430 mg, 2.4 mmol, 96%). Rf = 0.38 (cyclohexane / EtOAc = 1:1). 1 H NMR (500 MHz, DMSO-d6) δ 9.87 (s, 1H), 7.26 (d, J = 1.8 Hz, 1H), (m, 2H), 3.73 (s, 3H), 2.07 (s, 3H), 2.02 ppm (s, 3H). 13 C NMR (126 MHz, DMSO) δ , , , , , , , 55.42, 24.48, ppm. N-(3,4-dimethoxyphenyl)-N-methylacetamide (3o) To a solution of N-(3,4-dimethoxyphenyl)acetamide (78 mg, 0.4 mmol, 1 equiv.) in DMF (2 ml) was added NaH, 60% in mineral oil (24 mg, 0.6 mmol, 1.5 equiv.) at 0 C in portions. The reaction was stirred for 30 Minutes at 0 C and after that time iodomethane (37 µl, 0.6 mmol, 1.5 equiv.) was added and the reaction was stirred at 60 C for overnight. After cooling to room temperature, water (20 ml) and DCM (10 ml) were successively added and the phases were separated. The aqueous phase was two more times extracted with DCM (2x10 ml), the combined organic layers were dried over MgSO4 and the crude product was purified by silica gel column chromatography (elute: petroleum ether / EtOAc); the product was obtained as orange solid (52 mg, 0.25 mmol, 62%). Rf = 0.5 (cyclohexane / EtOAc = 1:2). 1 H NMR (500 MHz, DMSO) δ 6.96 (m, 2H), 6.83 (dd, J = 8.4, 2.3 Hz, 1H), 3.76 (s, 3H), 3.76 (s, 3H), 3.10 (s, 3H), 1.75 ppm (s, 3H). 13 C NMR (126 MHz, DMSO) δ , , , , , , , 56.10, 56.05, 37.12, ppm. S16

17 1,2-Dimethoxy-4-methylbenzene (1r) To a solution of 2-methoxy-4-methylphenol (258 µl, 2 mmol, 1 equiv.) in DMF (5 ml) was added NaH, 60% in mineral oil (120 mg, 3 mmol, 1.5 equiv.) at 0 C in portions. The reaction was stirred for 30 Minutes at 0 C and after that time iodomethane (254 µl, 4 mmol, 2 equiv.) was added and the reaction was stirred at 60 C for overnight. After cooling to room temperature, water (50 ml) and DCM (30 ml) were successively added and the phases were separated. The aqueous phase was two more times extracted with DCM (2x30 ml), the combined organic layers were dried over MgSO4 and the crude product was purified by silica gel column chromatography (elute: petroleum ether / EtOAc); the product was obtained as yellow oil (292 mg, 1.92 mmol, 96%). Rf = 0.59 (cyclohexane / EtOAc = 10:1). 1 H NMR (500 MHz, Chloroform-d) δ 6.77 (d, J = 8.6 Hz, 1H), 6.71 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 2.31 ppm (s, 3H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , 55.96, 55.77, ppm. S17

18 Physical Data of Products 3,4'-Dimethoxy-5,6'-dimethyl-[1,1'-biphenyl]-2,3'-diol (2a) Prepared according to the general procedure B1 using 2-methoxy-4-methylphenol (64.5 μl, 0.5 mmol, 1 equiv.); the product was obtained as white solid (57 mg, 0.21 mmol, 84%). Rf = 0.29 (cyclohexane / EtOAc = 10:1). 1 H NMR (500 MHz, Chloroform-d) δ 6.82 (s, 1H), 6.78 (s, 1H), 6.70 (d, J = 1.6 Hz, 1H), 6.57 (d, J = 1.6 Hz, 1H), 3.92 (s, 6H), 2.32 (s, 3H), 2.15 ppm (s, 3H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , , , , , , , 55.98, 55.92, 21.10, ppm. FT-IR: ν = , , , , , , , cm -1. HR-MS: calc. for [M+H] + C16H19O4 = found Spectral data matched literature characterization. 1 3,3'-Dibromo-5,5'-dimethyl-[1,1'-biphenyl]-2,2'-diol (2b) Prepared according to the general procedure B2 using 2-bromo-4-methylphenol (25.5 µl, 0.2 mmol, 1 equiv.); the product was obtained as white solid (22 mg, 0.06 mmol, 60%). Rf = 0.45 (cyclohexane / EtOAc = 10:1). 1 H NMR (500 MHz, Chloroform-d) δ 7.28 (d, J = 2.1 Hz, 2H), 6.94 (d, J = 2.1 Hz, 2H), 5.74 (s, 2H), 2.23 ppm (s, 6H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , ppm. FT-IR: ν = , , , , , , cm -1. HR-MS: calc. for [M+H] + C14H13O2 79 Br2 = found , C14H13O2 81 Br2 = found Spectral data matched literature characterization. 1 S18

19 3,3',5,5'-Tetramethyl-[1,1'-biphenyl]-2,2'-diol (2c) Prepared according to the general procedure B2 using 2,4-dimethylphenol (24 µl, 0.2 mmol. 1 equiv.); the product was obtained as white solid (10 mg, mmol, 41%). Rf = 0.42 (cyclohexane / EtOAc = 10:1). 1 H NMR (600 MHz, Chloroform-d) δ 6.93 (d, J = 2.2 Hz, 2H), 6.79 (d, J = 2.2 Hz, 2H), 5.01 (s, 2H), 2.21 (s, 6H), 2.20 ppm (s, 6H). 13 C NMR (151 MHz, CDCl3) δ , , , , , , 20.45, ppm. FT-IR: ν = , , , , , , , cm -1. HR-MS: calc. for [M+H] + C16H19O2 = found Spectral data matched literature characterization. 1 3,3',5,5'-Tetra-tert-butyl-[1,1'-bi(cyclohexylidene)]-2,2',5,5'-tetraene-4,4'-dione (2d) Prepared according to the general procedure B1 using 2,6-di-tert-butylphenol (105 mg, 0.5 mmol, 1 equiv.); the product was obtained as red crystalline solid (75 mg, mmol, 73%). Rf = 0.75 (cyclohexane / EtOAc = 10:1). 1 H NMR (400 MHz, Chloroform-d) δ 7.64 (s, 4H), 1.29 ppm (s, 36H). 13 C NMR (101 MHz, CDCl3) δ , , , , 36.18, ppm. FT-IR: ν = , , , , , , cm -1. HR-MS: calc. for [M+H] + C28H41O2 = found Spectral data matched literature characterization. 2 S19

20 3,3',5,5'-Tetraisopropyl-[1,1'-bi(cyclohexylidene)]-2,2',5,5'-tetraene-4,4'-dione (2e) Prepared according to the general procedure B1 using 2,6-diisopropylphenol (76 mg, 0.43 mmol, 1 equiv.); the product was obtained as red crystalline solid (76 mg, 0.22 mmol, 86%). Rf = 0.72 (cyclohexane / EtOAc = 10:1). 1 H NMR (500 MHz, Chloroform-d) δ 7.59 (s, 4H), (m, 4H), 1.15 ppm (d, J = 6.9 Hz, 24H). 13 C NMR (126 MHz, CDCl3) δ , , , , 27.70, ppm. FT-IR: ν = , , , , , , cm -1. HR-MS: calc. for [M+H] + C24H33O2 = found Spectral data matched literature characterization. 3 3,3',5,5'-Tetramethyl-[1,1'-bi(cyclohexylidene)]-2,2',5,5'-tetraene-4,4'-dione (2f) Prepared according to the general procedure B2 using 2,6-dimethylphenol (0.2 mmol, 1 equiv.); the product was obtained as red crystalline solid (11 mg, mmol, 46%). Rf = 0.63 (cyclohexane / EtOAc = 10:1). 1 H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 4H), 2.07 ppm (s, 12H). 13 C NMR (126 MHz, DMSO) δ , , , , ppm. FT-IR: ν = , , , , , , cm -1. HR-MS: calc. for [M+H] + C16H17O2 = found Spectral data matched literature characterization. 3 S20

21 2,3',4,5'-Tetramethoxy-[1,1'-biphenyl]-3,4'-diol (2g) Prepared according to the general procedure B2 using 2,6-dimethoxyphenol (31.5 mg, 0.2 mmol, 1 equiv.); the product was obtained as white solid (14 mg, mmol, 46%). Rf = 0.18 (cyclohexane / EtOAc = 10:1). 1 H NMR (500 MHz, Chloroform-d) δ 6.76 (d, J = 8.5 Hz, 1H), 6.72 (s, 2H), 6.65 (d, J = 8.5 Hz, 1H), 5.68 (s, 1H), 5.49 (s, 1H), 3.86 (s, 3H), 3.85 (s, 6H), 3.50 ppm (s, 3H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , , , , 77.25, 60.54, 56.36, ppm. FT-IR: ν = , , , , , , , , cm -1. HR-MS: calc. for [M+H] + C16H19O6 = found Spectral data matched literature characterization. 1 [1,1'-Binaphthalene]-2,2'-diol (2h) Prepared according to the general procedure B1 using 2-naphthol (73.5 mg, 0.5 mmol, 1 equiv.); the product was obtained white solid (60 mg, 0.21 mmol, 83%). Rf = 0.36 (cyclohexane / EtOAc = 10:1). 1 H NMR (400 MHz, Chloroform-d) δ 7.88 (d, J = 8.9 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.29 (m, 4H), 7.22 (td, J = 7.6, 6.9, 1.2 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 4.97 ppm (s, 2H). 13 C NMR (101 MHz, CDCl3) δ , , , , , , , , , ppm. FT-IR: ν = , , , , , , cm -1. HR-MS: calc. for [M+H] + C20H15O2 = found Spectral data matched literature characterization. 1 S21

22 [1,1'-Binaphthalene]-2,2',7,7'-tetraol (2i) Prepared according to the general procedure B1 using naphthalene-2,7-diol (82.5 mg, 0.5 mmol, 1 equiv.); the product was obtained white solid (60.5 mg, 0.19 mmol, 76%). %). Rf = 0.37 (cyclohexane / EtOAc = 3:1). 1 H NMR (500 MHz, Acetone-d6) δ 8.41 (s, 2H), 7.75 (m, 6H), 7.10 (d, J = 8.8 Hz, 2H), 6.89 (dd, J = 8.8, 2.4 Hz, 2H), 6.37 (d, J = 2.4 Hz, 2H). 13 C NMR (126 MHz, Acetone) δ , , , , , , , , , ppm. FT-IR: ν = , , , , , , , cm -1. HR-MS: calc. for [M+H] + C20H15O4 = found Spectral data matched literature characterization. 1 Dimethyl 2,2'-dihydroxy-[1,1'-binaphthalene]-3,3'-dicarboxylate (2j) To a stirring solution of methyl 3-hydroxy-2-naphthoate (41.3 mg, 0.2 mmol, 1 equiv.) and sodium nitrite (2.7 mg, 0.04 mmol, 20 mol%) in CH3CN (2 ml) CF3SO3H (36 μl, 0.4 mmol, 2 equiv.) was added at 0 C. Stirring was continued for 1 h and the reaction was slowly quenched with saturated NaHCO3 solution (15 ml) and extracted three times with DCM (3x20 ml). The combined organic layers were dried over MgSO4 and the crude product was purified by silica gel column chromatography (elute: petroleum ether / EtOAc); the product was obtained as white solid (16 mg, 0.04 mmol, 40%). 1 H NMR (400 MHz, Chloroform-d) δ (s, 2H), 8.61 (s, 2H), (m, 2H), 7.26 (dd, J = 6.3, 3.3 Hz, 4H), 7.08 (dd, J = 6.0, 3.6 Hz, 2H), 3.97 ppm (s, 6H). 13 C NMR (101 MHz, CDCl3) δ , , , , , , , , , , , ppm. FT-IR: ν = , , , , , cm -1. HR-MS: calc. for [M+H] + C24H19O6 = found Spectral data matched literature characterization. 4 S22

23 2-Methoxy-6-(2-methoxynaphthalen-1-yl)-4-methylphenol (2k) Prepared according to the general procedure C using 2-methoxy-4-methylphenol (37.2 µl, 0.25 mmol, 1 equiv.) and 2-methoxynaphthalene (122 mg, 0.75 mmol, 3 equiv.) in CH3CN / TFA; the product was obtained as white solid (54 mg, mmol, 74%). Rf = 0.41 (cyclohexane / EtOAc = 5:1). 1 H NMR (500 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.94 (d, J = 9.0 Hz, 1H), 7.87 (dd, J = 6.4, 3.0 Hz, 1H), 7.48 (d, J = 9.0 Hz, 1H), (m, 2H), (m, 1H), 6.82 (d, J = 1.6 Hz, 1H), (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H), 2.26 ppm (s, 3H). 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , 56.24, 55.64, ppm. FT-IR: ν = , , , , , , cm -1. HR-MS: calc. for [M+H] + C19H19O3 = found Spectral data matched literature characterization. 5 3-Methoxy-2',3',5,6'-tetramethyl-[1,1'-biphenyl]-2,4'-diol (2l) Prepared according to the general procedure C using 2-methoxy-4-methylphenol (37.2 µl, 0.25 mmol, 1 equiv.) and 2,3,5-trimethylphenol (105 mg, 0.75 mmol, 3 equiv.); the product was obtained as white solid (30 mg, 0.11 mmol, 44%). Rf = 0.17 (cyclohexane / EtOAc = 10:1). 1 H NMR (400 MHz, Chloroform-d) δ 6.61 (d, J = 1.9 Hz, 1H), 6.50 (s, 1H), 6.35 (d, J = 1.9 Hz, 1H), 3.84 (s, 3H), 2.23 (s, 3H), 2.09 (s, 3H), 1.90 ppm (s, 6H). 13 C NMR (101 MHz, CDCl3) δ , , , , , , , , , , , , 55.87, 21.19, 20.32, 17.30, ppm. FT-IR: ν = , , , , , , cm -1. HR-MS: calc. for [M+H] + C17H21O3 = found S23

24 3,4'-Dimethoxy-2',3',5-trimethyl-[1,1'-biphenyl]-2-ol (2m) Prepared according to the general procedure C using 2-methoxy-4-methylphenol (37.2 µl, 0.25 mmol, 1 equiv.) and 2,3-dimethoxyanisole (107 µl, 0.75 mmol, 3 equiv.); the product was obtained as colorless oil (56 mg, 0.21 mmol, 82%). Rf = 0.39 (cyclohexane / EtOAc = 10:1). 1 H NMR (500 MHz, Chloroform-d) δ 7.08 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 6.60 (d, J = 2.0, 1H), 5.41 (s, 1H), 3.93 (s, 3H), 3.87 (s, 3H), 2.35 (s, 3H), 2.25 (s, 3H), 2.13 ppm (s, 3H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , , , , , , , 56.00, 55.54, 21.19, 17.21, ppm. FT-IR: ν = , , , , , cm -1. HR-MS: calc. for [M+H] + C17H21O3 = found (tert-Butyl)-4-methoxy-6-(2-methoxynaphthalen-1-yl)phenol (2n) Prepared according to the general procedure C using 3-tert-butyl-4-hydroxyanisole (46 mg, 0.25 mmol, 1 equiv.) and 2-methoxynaphthalene (122 mg, 0.75 mmol, 3 equiv.); the product was obtained as colorless oil (60 mg, 0.18 mmol, 71%). Rf = 0.48 (cyclohexane / EtOAc = 10:1). 1 H NMR (500 MHz, Chloroform-d) δ 7.85 (d, J = 9.1 Hz, 1H), (m, 1H), (m, 1H), (m, 3H), 6.92 (d, J = 3.1 Hz, 1H), 6.52 (d, J = 3.1 Hz, 1H), 4.69 (s, 1H), 3.80 (s, 3H), 3.66 (s, 3H), 1.37 ppm (s, 9H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , , , , , , , , , , , 56.79, 55.63, 35.13, ppm. FT-IR: ν = , , , , , cm -1. HR-MS: calc. for [M+H] + C22H25O3 = found S24

25 3-(tert-Butyl)-4',5-dimethoxy-2',3'-dimethyl-[1,1'-biphenyl]-2-ol (2o) Prepared according to the general procedure C using 3-tert-butyl-4-hydroxyanisole (46 mg, 0.25 mmol, 1 equiv.) and and 2,3-dimethoxyanisole (107 µl, 0.75 mmol, 3 equiv.); the product was obtained as white solid (53 mg, 0.17 mmol, 67%). Rf = 0.28 (petroleum ether / DCM = 2:1). 1 H NMR (500 MHz, Chloroform-d) δ 7.03 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 3.1 Hz, 1H), 6.75 (d, J = 8.3 Hz, 1H), 6.43 (d, J = 3.1 Hz, 1H), 4.59 (s, 1H), 3.79 (s, 3H), 3.67 (s, 3H), 2.14 (s, 3H), 1.98 (s, 3H), 1.34 ppm (s, 9H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , , , , , , , 55.64, 55.60, 34.99, 29.46, 16.83, ppm. FT-IR: ν = , , , , , cm -1. HR-MS: calc. for [M+H] + C20H27O3 = found ,6-Dimethoxy-4-(2-methoxynaphthalen-1-yl)phenol (2p) Prepared according to the general procedure C using 2,6-dimethoxyphenol (40 mg, 0.25 mmol, 1 equiv.) and 2-methoxynaphthalene (122 mg, 0.75 mmol, 3 equiv.); the product was obtained as white solid (73 mg, 0.24 mmol, 93%). Rf = 0.29 (cyclohexane / EtOAc = 5:1). 1 H NMR (500 MHz, DMSOd6) δ 8.44 (s, 1H), 7.95 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), (m, 2H), 6.49 (s, 2H), 3.80 (s, 3H), 3.73 ppm (s, 6H). 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , 56.84, ppm. FT-IR: ν = , , , , , cm -1. HR-MS: calc. for [M+H] + C19H19O4 = found Spectral data matched literature characterization. 6 S25

26 3,6-Dimethoxy-4a,8-dimethyldibenzo[b,d]furan-2(4aH)-one (2q) A) To a stirring solution of 2-methoxy-4-methylphenol (25 μl, 0.2 mmol, 1 equiv.) in 1:1 DCM / HFIP (2 ml), NOBF4 (3.6 mg, 0.3 mmol, 15 mol%) was added with the help of a glass capillary at 0 C. The reaction was vigorously stirred until full conversion of starting material was monitored by TLC. The solvent was reduced under reduced pressure and the crude product was purified by silica gel column chromatography (elute: petroleum ether / EtOAc); the product was obtained as yellow solid (16 mg, 0.12 mmol, 59%). B) To a stirring solution of 3,4'-dimethoxy-5,6'-dimethyl-[1,1'-biphenyl]-2,3'-diol (55 mg, 0.2 mmol, 1 equiv.) in in 1:1 DCM / HFIP (4 ml), NOBF4 (1.2 mg, 0.1 mmol, 5 mol%) was added with the help of a glass capillary at 0 C. The reaction was vigorously stirred until full conversion of starting material was monitored by TLC. The solvent was reduced under reduced pressure and the crude product was purified by silica gel column chromatography (elute: petroleum ether / EtOAc); the product was obtained as yellow solid (44 mg, mmol, 81%). Rf = 0.59 (cyclohexane / EtOAc = 1:1). 1 H NMR (500 MHz, Chloroform-d) δ 6.94 (s, 1H), 6.78 (s, 1H), 6.32 (s, 1H), 6.16 (s, 1H), 3.91 (s, 3H), 3.70 (s, 3H), 2.36 (s, 3H), 1.74 ppm (s, 3H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , , , , , , 87.90, 56.20, 55.55, 33.29, ppm. FT-IR: ν = , , , , , , , cm -1. HR-MS: calc. for [M+H] + C16H17O4 = found S26

27 N,N'-(4,4',5,5'-tetramethoxy-[1,1'-biphenyl]-2,2'-diyl)diacetamide (4a) Prepared according to the general procedure D using N-(3,4-dimethoxyphenyl)acetamide (39 mg, 0.2 mmol, 1 equiv.); the product was obtained as brownish solid (37 mg, mmol, 94%). Rf = 0.32 (cyclohexane / EtOAc = 1:2). 1 H NMR (500 MHz, DMSO) δ 8.65 (s, 2H), 7.19 (s, 2H), 6.71 (s, 2H), 3.75 (s, 6H), 3.73 (s, 6H), 1.83 ppm (s, 6H). 13 C NMR (101 MHz, DMSO) δ , , , , , , , 56.13, 56.04, ppm. FT-IR: ν = , , , , , , , cm -1. HR-MS: calc. for [M+H] + C20H25N2O6: found: Spectral data matched literature characterization. 7 Scale up experiment In a 250 ml round-bottom flask N-(3,4-dimethoxyphenyl)acetamide (1 g, 5.12 mmol, 1 equiv.) was dissolved in 2:1 CH3CN / TFA (51.2 ml) and cooled to 0 C. To the stirring solution NOBF4 (122 mg, 1.02 mmol, 0.2 equiv.) was added at 0 C and stirring was continued for 1 h. After that time, the reaction was slowly quenched with 1 M NaOH solution (150 ml) and extracted three times with DCM (3x150 ml). The combined organic layers were dried over MgSO4 and the crude product was purified by silica gel column chromatography (elute: petroleum DCM/ MeOH), affording the title compound as brownish solid (850 mg, 2.19 mmol, 85%). N,N'-([5,5'-bibenzo[d][1,3]dioxole]-6,6'-diyl)diacetamide (4b) Prepared according to the general procedure D using N-(benzo[d][1,3]dioxol-5-yl)acetamide (36 mg, 0.2 mmol, 1 equiv.); the product was obtained as orange solid (21 mg, 0.06 mmol, 59%). Rf = 0.33 (cyclohexane / EtOAc = 1:2). 1 H NMR (500 MHz, CDCl3) δ 7.46 (s, 2H), 6.99 (s, 2H), 6.60 (s, 2H), 6.01 (dd, J = 8.2, 1.2 Hz, 4H), 1.96 (s, 6H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , , , ppm. FT-IR: ν = , , , , , , , , cm -1. HR-MS: calc. for [M+H] + C18H17N2O6: found: S27

28 N,N'-(3,3',5,5'-tetramethoxy-[1,1'-biphenyl]-2,2'-diyl)diacetamide (4c) Prepared according to the general procedure D using N-(2,4-dimethoxyphenyl)acetamide (39 mg, 0.2 mmol, 1 equiv.) using NOBF4 (1.19 mg, 0.01 mmol, 5 mol%); the product was obtained as brownish solid (21.5 mg, mmol, 55%). Rf = 0.36 (cyclohexane / EtOAc = 1:2). 1 H NMR (500 MHz, DMSO-d6) δ 9.03 (s, 2H), 7.49 (s, 2H), 6.72 (s, 2H), 3.88 (s, 6H), 3.71 (s, 6H), 2.02 ppm (s, 6H). 13 C NMR (126 MHz, DMSO) δ , , , , , , 97.02, 56.29, 56.26, ppm. FT-IR: ν = , , , , , cm -1. HR-MS: calc. for [M+H] + C20H25O6N2 = found: N,N'-(4,4',5,5'-tetramethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(4-methylbenzenesulfonamide) (4d) Prepared according to the general procedure D using N-(3,4-dimethoxyphenyl)-4- methylbenzenesulfonamide (61 mg, 0.2 mmol, 1 equiv.); the product was obtained as brownish solid (33 mg, mmol, 53%). Rf = 0.5 (cyclohexane / EtOAc = 1:1). 1 H NMR (500 MHz, CDCl3) δ 7.62 (d, J = 8.2 Hz, 4H), 7.36 (d, J = 8.2 Hz, 4H), 6.24 (s, 2H), 5.99 (s, 2H), 4.03 (s, 6H), 3.81 (s, 6H), 2.55 ppm (s, 6H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , , , , , 56.13, 56.02, ppm. FT-IR: ν = , , , , , , , cm -1. HR-MS: calc. for [M+H] + C30H33N2O8S2: found: S28

29 N,N'-(4,4',5,5'-tetramethoxy-[1,1'-biphenyl]-2,2'-diyl)dibenzamide (4e) Prepared according to the general procedure D using N-(3,4-dimethoxyphenyl)benzamide (51 mg, 0.2 mmol, 1 equiv.); the product was obtained as light brown solid (38 mg, mmol, 75%). Rf = 0.58 (cyclohexane / EtOAc = 1:2). 1 H NMR (500 MHz, CDCl3) δ 8.11 (s, 2H), 7.87 (s, 2H), 7.57 (d, J = 7.4 Hz, 4H), 7.47 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.6 Hz, 4H), 6.79 (s, 2H), 4.00 (s, 6H), 3.85 ppm (s, 6H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , , , , , , 56.22, ppm. FT-IR: ν = , , , , , , , , , cm -1. HR-MS: calc. for [M+H] + C30H29N2O6: found: Spectral data matched literature characterization. 7 N,N'-(4,4',5,5'-tetramethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(4-nitrobenzamide) (4f) Prepared according to the general procedure D using N-(3,4-dimethoxyphenyl)-4-nitrobenzamide (60 mg, 0.2 mmol, 1 equiv.); the product was obtained as yellow solid (34 mg, mmol, 58%). Rf = 0.41 (cyclohexane / EtOAc = 1:2). 1 H NMR (400 MHz, DMSO) δ 9.99 (s, 2H), 8.64 (d, J = 8.7 Hz, 4H), 8.27 (d, J = 8.7 Hz, 4H), 7.52 (s, 2H), 7.16 (s, 2H), 4.10 (s, 6H), 4.04 ppm (s, 6H). 13 C NMR (101 MHz, DMSO) δ , , , , , , , , , , , ppm. FT-IR: ν = , , , , , , , , cm -1. HR-MS: calc. for [M+H] + C30H27N4O10: found: S29

30 N,N'-(4,4',5,5'-tetramethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(4-fluorobenzamide) (4g) Prepared according to the general procedure D using N-(3,4-dimethoxyphenyl)-4-fluorobenzamide (55 mg, 0.2 mmol, 1 equiv.) in CH3CN / TFA; the product was obtained as reddish solid (21 mg, 0.04 mmol, 39%). Rf = 0.44 (cyclohexane / EtOAc = 1:2). 1 H NMR (500 MHz, Chloroform-d) δ 7.91 (s, 2H), 7.81 (s, 2H), (m, 4H), 7.04 (t, J = 8.6 Hz, 4H), 6.76 (s, 2H), 3.96 (s, 6H), 3.83 ppm (s, 6H). 13 C NMR (126 MHz, Chloroform-d) δ (d, JCF = Hz), , , , (d, JCF = 3.1 Hz), (m), , , , , , 56.29, ppm. FT- IR: ν = , , , , , , , , cm -1. HR- MS: calc. for [M+H] + C30H27F2N2O6: found: N,N'-(4,4',5,5'-tetramethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(4-chlorobenzamide) (4h) Prepared according to the general procedure D using 4-chloro-N-(3,4-dimethoxyphenyl)benzamide (58 mg, 0.2 mmol, 1 equiv.); the product was obtained as yellow solid (37 mg, mmol, 63%). Rf = 0.61 (cyclohexane / EtOAc = 1:2). 1 H NMR (500 MHz, Chloroform-d) δ 7.92 (s, 2H), 7.79 (s, 2H), 7.50 (d, J = 8.5 Hz, 4H), 7.34 (d, J = 8.5 Hz, 4H), 6.76 (s, 2H), 3.97 (s, 6H), 3.84 ppm (s, 6H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , , , , , , 56.33, ppm. FT-IR: ν = , , , , , , , , cm -1. HR-MS: calc. for [M+H] + C30H27Cl2N2O6: found: S30

31 N,N'-(4,4',5,5'-tetramethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(1-((1S,3s)-adamantan-1-yl)formamide) (4i) Prepared according to the general procedure D using N-(3,4-dimethoxyphenyl)adamantane-1- carboxamide (63 mg, 0.2 mmol, 1 equiv.); the product was obtained as brownish solid (49 mg, mmol, 75%). Rf = 0.66 (cyclohexane / EtOAc = 1:1). 1 H NMR (500 MHz, CDCl3) δ 8.08 (s, 2H), 7.19 (s, 2H), 6.69 (s, 2H), 3.95 (s, 6H), 3.85 (s, 6H), ppm (m, 30H). 13 C NMR (126 MHz, CDCl3) δ , , , , , , , 56.19, 56.15, 41.55, 38.96, 36.26, ppm. FT-IR: ν = , , , , , , , , , cm -1. HR-MS: calc. for [M+H] + C38H49N2O6: found: N,N'-(4,4',5,5'-tetramethoxy-[1,1'-biphenyl]-2,2'-diyl)bis(2-(naphthalen-2-yloxy)acetamide) (4j) Prepared according to the general procedure D using N-(3,4-dimethoxyphenyl)-2-(naphthalen-2- yloxy)acetamide (50 mg, 0.15 mmol, 1 equiv.) in CH3CN / TFA; the product was obtained as white solid (24 mg, 0.05 mmol, 48%). Rf = 0.56 (cyclohexane / EtOAc = 1:1). 1 H NMR (500 MHz, DMSO) δ 8.80 (s, 2H), 7.81 (dd, J = 23.0, 8.5 Hz, 4H), (m, 4H), 7.41 (dt, J = 40.3, 7.1 Hz, 4H), 7.18 (d, J = 2.1 Hz, 2H), 6.91 (dd, J = 8.9, 2.4 Hz, 2H), 6.82 (s, 2H), 4.58 (q, J = 14.9 Hz, 4H), 3.82 (s, 6H), 3.65 (s, 6H). 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , , , , , , , 67.40, 56.10, ppm. FT-IR: ν = , , , , , , , , , cm -1. HR-MS: calc. for [M+H] + C40H37N2O8: found: S31

32 N-(4'-Hydroxy-3',4,5'-trimethoxy-5-methyl-[1,1'-biphenyl]-2-yl)acetamide (4k) Prepared according to the general procedure C using 2,6-dimethoxyphenol (31 mg, 0.2 mmol, 1 equiv.) and N-(4-methoxy-3-methylphenyl)acetamide (108 mg, 0.6 mmol, 3 equiv.); the product was obtained as white solid (47 mg, 0.14 mmol, 71%). Rf = 0.36 (cyclohexane / EtOAc = 1:2). 1 H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.39 (s, 1H), 7.12 (s, 1H), 7.07 (s, 1H), 6.57 (s, 2H), 3.76 (s, 3H), 3.75 (s, 6H), 2.15 (s, 3H), 1.92 ppm (s, 3H). 13 C NMR (126 MHz, DMSO) δ , , , , , , , , , , , 56.41, 55.84, 23.62, ppm. FT-IR: ν = , , , , , cm -1. HR-MS: calc. for [M+H] + C18H22O5N = found: N-(2'-Hydroxy-3',4-dimethoxy-5,5'-dimethyl-[1,1'-biphenyl]-2-yl)acetamide (4l) Prepared according to the general procedure C using 2-methoxy-4-methylphenol (26 µl, 0.2 mmol, 1 equiv.) and N-(4-methoxy-3-methylphenyl)acetamide (108 mg, 0.6 mmol, 3 equiv.); the product was obtained as white solid (26 mg, 0.08 mmol, 41%). Rf = 0.33 (cyclohexane / EtOAc = 1:1). 1 H NMR (600 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.54 (s, 1H), 7.32 (s, 1H), 6.97 (s, 1H), 6.80 (s, 1H), 6.50 (s, 1H), 3.83 (s, 3H), 3.77 (s, 3H), 2.25 (s, 3H), 2.13 (s, 3H), 1.90 ppm (s, 3H). 13 C NMR (151 MHz, DMSO) δ , , , , , , , , , , , , , 55.87, 55.27, 23.83, 20.71, ppm. FT-IR: ν = , , , , , cm -1. HR-MS: calc. for [M+H] + C18H22O4N = found: S32

33 N-(5'-Bromo-2'-hydroxy-3',4-dimethoxy-5-methyl-[1,1'-biphenyl]-2-yl)acetamide (4m) Prepared according to the general procedure C using 4-bromo-2-methoxyphenol (40 mg, 0.2 mmol, 1 equiv.) and N-(4-methoxy-3-methylphenyl)acetamide (108 mg, 0.6 mmol, 3 equiv.); the product was obtained as yellow solid (40 mg, 0.11 mmol, 53%). Rf = 0.39 (cyclohexane / EtOAc = 1:1). 1 H NMR (600 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.71 (s, 1H), 7.03 (s, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.56 (s, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 2.08 (s, 3H), 2.03 ppm (s, 3H). 13 C NMR (151 MHz, CDCl3) δ , , , , , , , , , , , , , 56.38, 55.95, 25.02, ppm. FT-IR: ν = , , , , , , , cm -1. HR-MS: calc. for [M+H] + C17H19O4N 79 Br = found: ; C17H19O4N 81 Br = found: N-(6-(4-hydroxy-3,5-dimethoxyphenyl)benzo[d][1,3]dioxol-5-yl)acetamide (4n) Prepared according to the general procedure C using 2,6-dimethoxyphenol (31 mg, 0.2 mmol, 1 equiv.) and N-(benzo[d][1,3]dioxol-5-yl)acetamide (106 mg, 0.6 mmol, 3 equiv.); the product was obtained as pale white solid (33 mg, 0.1 mmol, 50%). Rf = 0.45 (cyclohexane / EtOAc = 1:2). 1 H NMR (600 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.41 (s, 1H), 6.98 (s, 1H), 6.91 (s, 1H), 6.57 (s, 2H), 6.04 (s, 2H), 3.76 (s, 6H), 1.89 ppm (s, 3H). 13 C NMR (151 MHz, DMSO) δ , , , , , , , , , , , , 56.41, ppm. FT-IR: ν = , , , , , , , cm -1. HR-MS: calc. for [M+H] + C17H18O6N = found: S33

34 Copies of 1 H and 13 C NMR spectra 1 H NMR spectrum of 3a. 13 C NMR spectrum of 3a. S34

35 1 H NMR spectrum of 3b. 13 C NMR spectrum of 3b. S35

36 1 H NMR spectrum of 3c. 13 C NMR spectrum of 3c. S36

37 1 H NMR spectrum of 3d. 13 C NMR spectrum of 3d. S37

38 1 H NMR spectrum of 3e. 13 C NMR spectrum of 3e. S38

39 1 H NMR spectrum of 3f. 13 C NMR spectrum of 3f. S39

40 1 H NMR spectrum of 3g. 13 C NMR spectrum of 3g. S40

41 1 H NMR spectrum of 3h. 13 C NMR spectrum of 3h. S41

42 1 H NMR spectrum of 3i. 13 C NMR spectrum of 3i. S42

43 1 H NMR spectrum of 3j. 13 C NMR spectrum of 3j. S43

44 1 H NMR spectrum of N-(4-methoxy-3-methylphenyl)acetamide. 13 C NMR spectrum of N-(4-methoxy-3-methylphenyl)acetamide. S44

45 1 H NMR spectrum of 3o. 13 C NMR spectrum of 3o. S45

46 1 H NMR spectrum of 1r. 13 C NMR spectrum of 1r. S46

47 1 H NMR spectrum of 2a. 13 C NMR spectrum of 2a. S47

48 1 H NMR spectrum of 2b. 13 C NMR spectrum of 2b. S48

49 1 H NMR spectrum of 2c. 13 C NMR spectrum of 2c. S49

50 1 H NMR spectrum of 2d. 13 C NMR spectrum of 2d. S50

51 1 H NMR spectrum of 2e. 13 C NMR spectrum of 2e. S51

52 1 H NMR spectrum of 2f. 13 C NMR spectrum of 2f. S52

53 1 H NMR spectrum of 2g. 13 C NMR spectrum of 2g. S53

54 1 H NMR spectrum of 2h. 13 C NMR spectrum of 2h. S54

55 1 H NMR spectrum of 2i. 13 C NMR spectrum of 2i. S55

56 1 H NMR spectrum of 2j. 13 C NMR spectrum of 2j. S56

57 1 H NMR spectrum of 2k. 13 C NMR spectrum of 2k. S57

58 1 H NMR spectrum of 2l. 13 C NMR spectrum of 2l. S58

59 2D-NMR NOESY spectrum of 2l. S59

60 1 H NMR spectrum of 2m. 13 C NMR spectrum of 2m. S60

61 2D-NMR NOESY spectrum of 2m. S61

62 1 H NMR spectrum of 2n. 13 C NMR spectrum of 2n. S62

63 1 H NMR spectrum of 2o. 13 C NMR spectrum of 2o. S63

64 2D-NMR NOESY spectrum of 2o. S64

65 1 H NMR spectrum of 2p. 13 C NMR spectrum of 2p. S65

66 1 H NMR spectrum of 2p. 13 C NMR spectrum of 2p. S66

67 1 H NMR spectrum of 4a. 13 C NMR spectrum of 4a. S67

68 1 H NMR spectrum of 4b. 13 C NMR spectrum of 4b. S68

69 1 H NMR spectrum of 4c. 13 C NMR spectrum of 4c. S69

70 1 H NMR spectrum of 4d. 13 C NMR spectrum of 4d. S70

71 1 H NMR spectrum of 4e. 13 C NMR spectrum of 4e. S71

72 1 H NMR spectrum of 4f. 13 C NMR spectrum of 4f. S72

73 1 H NMR spectrum of 4g. 13 C NMR spectrum of 4g. S73

74 1 H NMR spectrum of 4h. 13 C NMR spectrum of 4h. S74