Grignard reagents on a tab: Direct magnesium insertion under flow conditions

Transcription

1 Grignard reagents on a tab: Direct magnesium insertion under flow conditions Supporting information Lena Huck, Antonio de la Hoz, Angel Díaz-Ortiz and Jesus Alcázar* Janssen Research and Development, Janssen-Cilag, S.A., C/ Jarama 75, Toledo, Spain. Fax: ; Tel: ; jalcazar@its.jnj.com. S1

2 Table of contents 1. General Information S3 2. Preparation of Mg column S4 3. General procedure for organomagnesium synthesis and titration S4 4. Scale up of synthesis of phenyl magnesiumbromide S5 5. General procedures for DOS reactions under flow and characterization of products S6 6. General procedures for DOS reactions in batch and characterization of products S14 7. NMR Spectra of products S16 S2

3 General Information: GC measurements were performed using a 689 Series Gas Chromatograph (Agilent Technologies) system comprising a 7683 Series injector and autosampler, J&W HP-5MS column (2 m x.18 mm,.18 m) from Agilent Technologies coupled to a 5973N MSD Mass Selective Detector (single quadrupole, Agilent Technologies). The MS detector was configured with an electronic impact ionization source/chemical ionization source (EI/CI). EI low-resolution mass spectra were acquired by scanning from 5 to 55 at a rate of scan. The source temperature was maintained at 23 C. Helium was used as the nebulizer gas. Data acquisition was performed with Chemstation-Open Action software. Thin layer chromatography (TLC) was carried out on silica gel 6 F254 plates (Merck) using reagent grade solvents. Unless otherwise specified, reagents were obtained from commercial sources and used without further purification. The magnesium used is Sigma Aldrich 2-23 mesh, reagent grade 98%, CAS: , g. Flow reactions were carried out in a Omnifit column fixed on a R2/R4 Vapourtec equipment. 1 H NMR spectra were recorded on Bruker DPX-4 or Bruker AV-5 spectrometers with standard pulse sequences, operating at 4MHz and 5MHz respectively. Chemical shifts ( ) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS), which was used as an internal standard. S3

4 Preparation of Mg column: a SolventPlusTM column (bore: 1 mm, length: 1 mm, AF; Omnifit, cat. no. 6SCC-1-1-AF) is filled with 4g of magnesium (2-23 mesh, Sigma Aldrich Cat. N.: ) weight in a beaker using a filter funnel. General flow procedure for magnesium activation and organomagnesium synthesis: 5 ml of DIBAL- H 1M in toluene was passed through a 1 mm internal diameter Omni-fit column containing Mg (4 g) at 1 ml/min at room temperature. After that, a solution of TMSCl 2M and 1-bromo-2-chloroethane.24M in 1 ml THF/toluene (1:1) was passed through the column at 1 ml/min at room temperature. After the activation, a solution of bromobenzene.5m in LiCl.5M in THF was passed through the column at.5 ml/min and at room temperature. The solution was collected in a sealed vial under nitrogen. Titration of organomagnesium reagent A: An accurately weighed sample of salicylaldehyde phenyl hydrazone (typically between 2. and 3. mg) is dissolved in 1 ml of THF and stirred at room temperature under nitrogen while the organomagnesium reagent is added slowly until the pale yellow color of the solution turned orange. The calculated concentration of the organozinc reagent was.34m. Titration of organomagnesium reagent B: An accurately weighed sample of menthol (typically between 2. and 3. mg) and 1 mg of phenantroline is dissolved in 1 ml of THF and stirred at room temperature under nitrogen while the organomagnesium reagent is added slowly until the pale yellow color of the solution turned orange. The calculated concentration of the organozinc reagent was.38m. S4

5 Scale up of the synthesis of phenyl magnesium bromide: 5mL of DIBAL-H 1M in toluene was passed through a 1 mm internal diameter Omni-fit column containing Mg (4 g) at 1 ml/min at room temperature. After that, a solution of TMSCl 2M and 1-bromo-2-chloroethane.24M in 1 ml THF/toluene (1:1) was passed through the column at 1 ml/min at room temperature. After the activation, a solution of bromobenzene (4 ml, 37.5 mmol).5m in LiCl.5M in THF (75 ml) was passed through the column at.5 ml/min and at room temperature. The solution was collected in a sealed vial under nitrogen. A sample was taken every 3 min from the outcome and titrated using method A concentration concentration S5

6 General flow procedure: A solution of the correspondent haloderivative (.1 ml,.86mmol) in.7 ml of dry LiCl.5 M in THF was passed through a 1 mm internal diameter Omni-fit column containing Mg (4 g) using the Vapourtec R2+R4 system at room temperature and a flow rate of.5 ml/min. The outlet solution was combined with a solution of the correspondent electrophile and pumped through a 1 ml coil at room temperature at.5 ml/min (Rt = 1 min). The outcome was collected in a saturated solution of ammonium chloride and extracted with AcOEt. The organic layer was separated, dried (Na 2SO 4), filtered and the solvents evaporated in vacuo. The crude was purified by automated flash chromatography in silica gel (Si35, 4 g) from AcOEt in heptane :1 to 2:8. The desired fractions were collected and concentrated in vacuo to yield the final compound. General flow procedure for synthesis of alcohols (procedure A): A solution of the correspondent haloderivative (1 mmol) in 2 ml of dry LiCl.5 M in THF was passed through a 1 mm internal diameter Omni-fit column containing Mg (4 g) using the Vapourtec R2+R4 system at room temperature and a flow rate of.5 ml/min. The outlet solution was combined with a solution of the benzaldehyde (.8 mmol) in THF (2 ml) and pumped through a 2 ml coil at room temperature at.5 ml/min each line (Rt = 2 min). The outcome was collected in a saturated solution of ammonium chloride and extracted with AcOEt. The organic layer was separated, dried (Na 2SO 4), filtered and the solvents evaporated in vacuo. The crude was purified by automated flash chromatography in silica gel (Si35, 4 g) from AcOEt in heptane :1 to 2:8. The desired fractions were collected and concentrated in vacuo to yield the final compound. General flow procedure for synthesis of tert-butyl ester derivatives (procedure B): A solution of the correspondent haloderivative (.65 mmol) in 1.2 ml of dry LiCl.5 M in THF was passed through a 1 mm internal diameter Omni-fit column containing Mg (4 g) using the Vapourtec R2+R4 system at room temperature and a flow rate of.5 ml/min. The outlet solution was combined with a solution of bocanhydride in THF (.45 mmol) and pumped through a 1 ml chip at ºC at.5 ml/min each line (Rt = 1 min). The outcome was collected in a saturated solution of ammonium chloride and extracted with AcOEt. The organic layer was separated, dried (Na 2SO 4), filtered and the solvents evaporated in vacuo. The crude was purified by automated flash chromatography in silica gel (Si35, 4 g) from AcOEt in heptane :1 to 2:8. The desired fractions were collected and concentrated in vacuo to yield the final compound. General flow procedure for synthesis of ketones (procedure C): A solution of the correspondent haloderivative (2 mmol) in 4 ml of dry LiCl.5 M in THF was passed through a 1 mm internal diameter Omni-fit column containing Mg (4 g) using the Vapourtec R2+R4 system at room temperature and a flow rate of.5 ml/min. The outlet solution was combined with a solution of Weinreb-amide (.8) in 4.1 ml diethyleter and pumped through a 2 ml coil at room tempearture at.5 ml/min each line (Rt = 2 min). S6

7 The outcome was collected in a saturated solution of ammonium chloride and extracted with AcOEt. The organic layer was separated, dried (Na 2SO 4), filtered and the solvents evaporated in vacuo. The crude was purified by automated flash chromatography in silica gel (Si35, 4 g) from AcOEt in heptane :1 to 2:8. The desired fractions were collected and concentrated in vacuo to yield the final compound. General flow procedure for synthesis of amides (procedure D): A solution of the correspondent haloderivative (2.5 mmol) in 5 ml of dry LiCl.5 M in THF was passed through a 1 mm internal diameter Omni-fit column containing Mg (4 g) using the Vapourtec R2+R4 system at room temperature and a flow rate of.5 ml/min. The outlet solution was combined with a solution of phenyl-isocyanate (1.25 mmol) in 5 ml of dry THF and pumped through a 2 ml coil at room tempearture at.5 ml/min each line (Rt = 2 min). The outcome was collected in a saturated solution of ammonium chloride and extracted with AcOEt. The organic layer was separated, dried (Na 2SO 4), filtered and the solvents evaporated in vacuo. The crude was purified by automated flash chromatography in silica gel (Si35, 4 g) from AcOEt in heptane :1 to 25:75. The desired fractions were collected and concentrated in vacuo to yield the final compound. Diphenylmethanol (7a): was obtained as colorless oil (12 mg, 94% yield) using procedure A. MS (EI): mass calcd. for C 14H 14O 2, 214.1; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = - (m, 8H), - (m, 2H), (d, J=3. Hz, 1H), ppm (br s, 1H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 143.8, 128.5, 127.6, 126.6, 76.3 ppm. tert-butyl benzoate (8a): was obtained as colorless oil (158 mg, 97% yield) using procedure A. MS (EI): mass calcd. for C 11H 14O 2, ; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = -8.2 (m, 2H), (m, 1H), - (m, 2H), 1.6 ppm (s, 9H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 165.8, 132.4, 132.1, 129.4, 128.2, 81., 28.2 ppm. S7

8 5-Chloro-1-phenylpentan-1-one (9a): was obtained as colorless oil (123 mg, 79% yield) using procedure C changing the temperature of the Mg column to 5ºC. MS (EI): mass calcd. for C 11H 13ClO, 196.1; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = (m, 2H), -7.6 (m, 1H), (m, 2H), (t, J=6.1 Hz, 2H), 3.2 (t, J=6.8 Hz, 2H), - ppm (m, 4H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 199.6, 136.9, 133.1, 128.6, 128., 44.8, 37.6, 32.1, 2 ppm. N-Phenylbenzamide (1a): was obtained as colorless oil (21 mg, 84% yield) using procedure C. MS (ES): mass calcd. for C 11H 13ClO, 196.1; m/z found, [M+H]+. 1 H NMR (CHLOROFORM-d, 4MHz): δ = (m, 2H), (br s, 1H), (dd, J=8.4, 1. Hz, 2H), (m, 1H), (m, 2H), - (m, 2H), ppm (m, 1H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 165.8, 137.9, 135., 131.9, 129.1, 128.8, 127., 124.6, 12.2 ppm. (3-chlorophenyl)(pyridin-3-yl)methanol (7b): was obtained as colorless oil (87 mg, 74% yield) using procedure A. MS (EI): mass calcd. for C 12H 1ClNO, 219.; m/z found, H NMR (CHLOROFORMd, 4MHz): δ = (s, 1H), (m, 1H), 7.68 (dt, J=7.9, 1.7 Hz, 1H), (s, 1H), 7.2- (m, 4H), (s, 1H), 3.94 ppm (br s, 1H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 148.5, 148.4, 145.1, 139.1, 134.7, 134.4, 13., 128.1, 126.6, 124.6, 123.7, 73.3 ppm. S8

9 tert-butyl 4-fluorobenzoate (8c): was obtained as colorless oil (71 mg, 79% yield) using procedure B. MS (EI): mass calcd. for C 11H 13FO 2, 196.1; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = -8.5 (m, 2H), 7.5- (m, 2H), ppm (s, 9H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 166.7, 131.9, 131.8, 125.5, 122.7, 115.3, 115.1, 81.2, 28.2 ppm. Phenyl(3-(trifluoromethyl)phenyl)methanol (7d): was obtained as colorless oil (289 mg, 97% yield) using procedure A. MS (EI): mass calcd. for C 14H 11F 3O, 252.1; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = (s, 1H), - (m, 2H), - (m, 1H), (d, J=4.4 Hz, 4H), - (m, 1H), (d, J=3.2 Hz, 1H), ppm (d, J=3.2 Hz, 1H). 13 C NMR (CHLOROFORMd, 11MHz): δ = 144.6, 143.1, 13.9 (q, J=19.1 Hz, 1C), 129.9, 128.9, 128.8, 128.1, 126.7, (q, J=4.1 Hz, 1C), (q, J=3.9 Hz, 1C), 75.8 ppm. tert-butyl 3-(trifluoromethyl)benzoate (8d): was obtained as colorless oil (1 mg, 88% yield) using procedure B. MS (EI): mass calcd. for C 12H 13F 3O 2, 246.1; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = (s, 1H), (d, J=7.9 Hz, 1H), 7.78 (dd, J=7.9,.7 Hz, 1H), (t, J=7.9 Hz, 1H), ppm (s, 9H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 164.4, 132.8, 132.6,129., (q, J=3.7 Hz, 1C), (q, J=4. Hz, 1C), 13.6, 82., 28.2 ppm. S9

10 (2-Methoxyphenyl)(phenyl)methanol (7e): was obtained as colorless oil (1 mg, 95% yield) using procedure A. MS (EI): mass calcd. for C 14H 14O 2, 214.1; m/z found, H NMR (CHLOROFORM-d, 5MHz): δ = -7.4 (m, 2H), - (m, 2H), - (m, 3H), (td, J=7.5,.9 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 6.5 (d, J=5.5 Hz, 1H), (s, 3H), 3.3 ppm (d, J=5.5 Hz, 1H). 13 C NMR (CHLOROFORM-d, 126MHz): δ = 156.8, 143.3, 132., 128.8, 128.2, 127.9, 127.2, 126.6, 12.8, 11.8, 72.3, 55.5 ppm. (3-Methoxyphenyl)(phenyl)methanol (7f): was obtained as colorless oil (87 mg, 83% yield) using procedure A. MS (EI): mass calcd. for C 14H 14O 2, 214.1; m/z found, H NMR (CHLOROFORM-d, 5MHz): δ = - (m, 2H), - (m, 2H), - (m, 2H), (m, 1H), (m, 1H), (d, J=3.2 Hz, 1H), (s, 3H), ppm (m, 1H). 13 C NMR (CHLOROFORM-d, 126MHz): δ = 159.8, 145.5, 143.7, 129.5, 128.5, 127.6, 126.6, 118.9, 113., 112.1, 76.2, 55.3 ppm. (4-Methoxyphenyl)(phenyl)methanol (7g): was obtained as colorless oil (93 mg, 88% yield) using procedure A. MS (EI): mass calcd. for C 14H 14O 2, 214.1; m/z found, H NMR (CHLOROFORM-d, 5MHz): δ = - (m, 4H), - (m, 3H), 6.85 (d, J=8.7 Hz, 2H), (d, J=3.2 Hz, 1H), (s, 3H), ppm (br d, J=2.3 Hz, 1H). 13 C NMR (CHLOROFORM-d, 126MHz): δ = 159.1, 144.1, 136.2, 128.5, 127.9, 127.5, 126.4, 113.9, 75.8, 55.3 ppm. S1

11 5-Chloro-1-(2,3-dimethoxyphenyl)pentan-1-one (9h): was obtained as colorless oil (85 mg, 74% yield) using procedure C. MS (EI): mass calcd. for C 14H 14O 2, 214.1; m/z found, [M+H] +. 1 H NMR (CHLOROFORM-d, 5MHz): δ = - (m, 1H), (t, J=7.8 Hz, 1H), (m, 1H), (s, 3H), (s, 3H), (m, 2H), -3.2 (m, 2H), ppm (dt, J=6.2, 3.3 Hz, 4H). 13 C NMR (CHLOROFORM-d, 126MHz): δ = 22.9, 153., 148., 134.1, 124.2, 12.6, 115.5, 61.6, 56., 44.8, 42.4, 32.1, 21.6 ppm. 2-(Hydroxy(phenyl)methyl)benzonitrile (7i): was obtained as colorless oil (165 mg, 83% yield) using procedure A. MS (EI): mass calcd. for C 14H 11NO, 29.1; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = 7.93 (br d, J=6.9 Hz, 1H), (m, 2H), - (m, 4H), - (m, 3H), 7.2- (m, 1H), ppm (s, 1H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 147.2, 138., 132.4, 129.1, 129., 128.9, 127., 122.9, 84.9 ppm. (6-Methoxy-2-methylpyridin-3-yl)(phenyl)methanol (7j): was obtained as colorless oil (4mg, 62% yield) using procedure A. MS (EI): mass calcd. for C 14H 15NO 2, 229.1; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = (d, J=8.6 Hz, 1H), - (m, 5H), 6.58 (d, J=8.6 Hz, 1H), (d, J=2.8 Hz, 1H), (m, 3H), 2.4 (s, 3H), ppm (d, J=2.8 Hz, 1H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 162.7, 153.4, 142.8, 137.5, 129.4, 128.6, 127.7, 126.7, 17.5, 72.4, 53.4, 22. ppm. S11

12 (2-Methoxypyridin-3-yl)(phenyl)methanol (7k): was obtained as colorless oil (153 mg, 75% yield) using procedure A. MS (EI): mass calcd. for C 13H 13NO 2, 215.1; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = 8.5 (dd, J=5.1, 1.8 Hz, 1H), (ddd, J=7.4, 1.8,.7 Hz, 1H), - (m, 4H), - (m, 1H), (dd, J=7.4, 5.1 Hz, 1H), (d, J=3.9 Hz, 1H), 3.92 (s, 3H), ppm (d, J=4.6 Hz, 1H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 16.9, 145.7, 142.3, 135.9, 128.4, 127.6, 126.6, 126.4, 117., 71.3, 53.5 ppm. 1-Phenylpentan-1-ol (7l): was obtained as colorless oil (79 mg, 98% yield) using procedure A. MS (EI): mass calcd. for C11H16O, 164.1; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = - (m, 3H), - (m, 1H), (ddd, J=7.5, 5.8, 3.4 Hz, 1H), (m, 2H), (m, 4H),.89 ppm (t, J=7.1 Hz, 3H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 145., 128.4, 127.5, 125.9, 74.7, 38.9, 28., 22.6, 14. ppm. 5,5,5-Trifluoro-1-(pyridin-3-yl)pentan-1-ol (7m): was obtained as colorless oil (174mg, 85% yield) using procedure A. MS (EI): mass calcd. for C 1H 12F 3NO, 219.1; m/z found, H NMR (CHLOROFORMd, 4MHz): δ = (td, J=4.8, 1.7 Hz, 2H), 7.71 (dt, J=7.9, 1.8 Hz, 1H), (dd, J=7.9, 4.9 Hz, 1H), (dd, J=7.7, 4.3 Hz, 1H), (m, 2H), 1.7- (m, 2H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 148.9, 147.5, 139.9, 132.7, 123.7, (q, J=276.5), 71.6, 37.8, 33.5 (q, J=28.6), 18.4 ppm. S12

13 4,4,4-Trifluoro-1-(pyridin-3-yl)butan-1-ol (7n): was obtained as colorless oil (134mg, 7% yield) using procedure A. MS (EI): mass calcd. for C 9H 1F 3NO, 25.1; m/z found, H NMR (CHLOROFORMd, 4MHz): δ = (m, 2H), 7.73 (dt, J=7.9, 1.8 Hz, 1H), - (m, 1H), (dd, J=7.6, 5.3 Hz, 1H), (br s, 1H), - (m, 2H), -2.8 ppm (m, 2H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 149.2, 147.5, 139.2, 133.6, 128.5, 123.7, 7.4, 31.2, 3.1(q, J=29.1Hz) ppm. (1-Methylpiperidin-4-yl)(phenyl)methanol (7o): was obtained as colorless oil (82 mg, 81% yield) using procedure A. MS (EI): mass calcd. for C 13H 19NO, 25.1; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = - (m, 5H), 4.32 (d, J=7.6 Hz, 1H), (m, 1H), 2.73 (br d, J=11.1 Hz, 1H), (d, J=1.8 Hz, 3H), 2. (br d, J=12.9 Hz, 1H), - (m, 1H), (td, J=11., 4.4 Hz, 1H), - (m, 1H), (m, 1H), 1.2- ppm (m, 2H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 143.5, 128.7, 128.3, 127.6, 126.7, 78.8, 55.7, 55.6, 46.3, 42.6, 28.7, 28.5 ppm. N-Phenylcyclopentanecarboxamide (1p): was obtained as colorless oil (132 mg, 55% yield) using procedure D. MS (EI): mass calcd. for C 12H 15NO, 189.1; m/z found, H NMR (CHLOROFORM-d, 5MHz): δ = (br d, J=8.1 Hz, 2H), (t, J=7.8 Hz, 3H), 7.8 (t, J=7.4 Hz, 1H), (quin, J=8.1 Hz, 1H), - (m, 4H), (m, 2H), ppm (m, 2H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 174.7, 138.2, 129., 124., 119.7, 46.9, 3.6, 26. ppm. S13

14 (Benzylsulfonyl)benzene (11a): A solution of bromobenzene (1 mg,.64 mmol) in 1.25 ml of dry LiCl.5 M in THF was passed through a 1 mm internal diameter Omni-fit column containing Mg (4 g) using the Vapourtec R2+R4 system at room temperature and a flow rate of.5 ml/min. The outlet solution was collected in a vial containing DABSO (153 mg,.64mmol). The resulting mixture was stirred vigorously for 1h at room temperature. After this time, a strong flow of nitrogen gas was applied to remove the solvent. Then, DMF (5 ml) and benzyl bromide (.23 ml, 1.9 mmol) were added and the reaction was stirred 2h at 12ºC. After cooling Et 2O was added and the solids filtered off before removing the solvent in vacuo. The crude was purified by automated flash chromatography in silica gel (Si35, 4 g) from AcOEt in heptane :1 to 2:8. The desired fractions were collected and concentrated in vacuo to yield 135 mg of 11a (89%). MS (EI): mass calcd. for C 13H 12O 2S, 232.; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = (m, 3H), (m, 2H), - (m, 3H), 7.5- (m, 2H), ppm (s, 2H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 133.7, 13.8, 128.9, 128.8, 128.7, 128.6, 62.9 ppm. 2,2-Diphenyltetrahydrofuran (12a): A solution of bromobenzene (1 mg,.64 mmol) in 1.25 ml of dry LiCl.5 M in THF was passed through a 1 mm internal diameter Omni-fit column containing Mg (4 g) using the Vapourtec R2+R4 system at room temperature and a flow rate of.5 ml/min. The outlet solution was collected in a vial containing 4-chlorobutyrophenone (.5 ml,.3 mmol) in THF (.5 ml) at ºC. The resulting mixture was stirred vigorously for 1h at room temperature. A saturated solution of ammonium chloride was added and extracted with AcOEt. The organic layer was separated, dried (Na 2SO 4), filtered and the solvents evaporated in vacuo. The crude was purified by automated flash chromatography in silica gel (Si35, 4 g) from AcOEt in heptane :1 to 2:8. The desired fractions were collected and concentrated in vacuo to yield 36mg of 12a (51%). MS (EI): mass calcd. for C 16H 16O, m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = - (m, 4H), - (m, 4H), (m, 2H), 4.5 (t, J=7.1 Hz, 2H), (t, J=7.2 Hz, 2H), 1.9- ppm (q, J=7.1 Hz, 2H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 146.4, 128.2, 126.7, 125.8, 88., 67.4, 38.6, 25.5 ppm S14

15 3-Phenylcyclohexan-1-one (13a): A solution of bromobenzene (.5 ml, 4.7 mmol) in 9.4 ml of dry LiCl.5 M in THF was passed through a 1 mm internal diameter Omni-fit column containing Mg (4 g) using the Vapourtec R2+R4 system at room temperature and a flow rate of.5 ml/min. The outlet solution was collected in a vial containing 2-cyclohexen-1-one (15 mg, 6 mmol), CuI (3 mg,.15mmol) and TMSCl (.2 ml, 6 mmol) in dry LiCl.5 M in THF (1.25 ml) at room temperature. The resulting mixture was stirred vigorously overnight at room temperature. Water was added and extracted with AcOEt. The organic layer was separated, dried (Na 2SO 4), filtered and the solvents evaporated in vacuo. The crude was purified by automated flash chromatography in silica gel (Si35, 4 g) from AcOEt in heptane :1 to 2:8. The desired fractions were collected and concentrated in vacuo to yield 146 mg of 13a (56%). MS (EI): mass calcd. for C1 2H 14O, 174.1; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = - (m, 2H), 7.2- (m, 3H), 3.1 (tt, J=11.7, 4. Hz, 1H), - (m, 4H), (ddt, J=9.4, 6.2, 3.1 Hz, 1H), (m, 1H), ppm (m, 2H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 211., 144.4, 128.7, 126.7, 126.6, 49., 44.8, 41.2, 32.8, 25.6 ppm. 4-Methoxy-1,1'-biphenyl (14a): A solution of bromobenzene (.25 ml, 2.5 mmol) in 5 ml of dry LiCl.5 M in THF was passed through a 1 mm internal diameter Omni-fit column containing Mg (4 g) using the Vapourtec R2+R4 system at room temperature and a flow rate of.5 ml/min. The outlet solution was combined with a solution of 4-iodoanisole (15 mg,.65 mmol), Pd 2(dba) 3 (3mg,.32 mmol), tri(2- furyl) phosphine (15mg,.65 mmol), ZnCl 2 (1.8 ml,.9 mmol) in 3 ml of THF and pumped through a 2 ml coil at 5 ºC at.5 ml/min each line (Rt = 2 min). The outcome was collected in water and extracted with AcOEt. The organic layer was separated, dried (Na 2SO 4), filtered and the solvents evaporated in vacuo. The crude was purified by automated flash chromatography in silica gel (Si35, 4 g) from AcOEt in heptane :1 to 25:75. The desired fractions were collected and concentrated in vacuo to yield 78 mg of 14a (66%). MS (EI): mass calcd. for C 13H 12O, 184.1; m/z found, H NMR (CHLOROFORM-d, 4MHz): δ = (m, 4H), - (m, 2H), - (m, 1H), -7.1 (m, 2H), ppm (s, 3H). 13 C NMR (CHLOROFORM-d, 11MHz): δ = 159.2, 14.8, 133.8, 128.7, 128.2, 126.8, 126.7, 114.8, 114.2, 55.4 ppm. S15

16 S16 UCLM_lhuck3_63_1.1.jdx UCLM_lhuck3_63_1.2.jdx Compound 7a

17 S17 UCLM_lhuck3_569_1.3.jdx UCLM_lhuck3_569_1.4.jdx Compound 8a

18 S18 UCLM_lhuck3_267_1.1.jdx UCLM_lhuck3_267_1.2.jdx Compound 9a

19 S19 UCLM_lhuck3_281_1.3.jdx UCLM_lhuck3_281_.jdx Compound 1a

20 S2 UCLM_lhuck3_184_1.2.jdx UCLM_lhuck3_184_1.3.jdx Compound 7b

21 S21 UCLM_lhuck3_21_1.2.jdx UCLM_lhuck3_21_1.3.jdx Compound 8c

22 S22 UCLM_lhuck3_156_1.1.jdx UCLM_lhuck3_156_1.2.jdx Compound 7d

23 S23 UCLM_lhuck3_155_1.1.jdx UCLM_lhuck3_155_1.2.jdx Compound 8d

24 S24 UCLM_lhuck3_171_1.1.jdx UCLM_lhuck3_171_1.2.jdx Compound 7e

25 S25 UCLM_lhuck3_174_1.1.jdx UCLM_lhuck3_174_1.2.jdx Compound 7f

26 S26 UCLM_lhuck3_175_1.1.jdx UCLM_lhuck3_175_1.2.jdx Compound 7g

27 S27 UCLM_lhuck3_166_1.1.jdx UCLM_lhuck3_166_1.2.jdx Compound 9h

28 S28 UCLM_lhuck3_197_1.2.jdx UCLM_lhuck3_197_1.3.jdx Compound 7i

29 S29 UCLM_lhuck3_238_1.3.jdx UCLM_lhuck3_238_1.4.jdx Compound 7j

30 S3 UCLM_lhuck3_268_1.1.jdx UCLM_lhuck3_268_1.2.jdx Compound 7k

31 S31 UCLM_lhuck3_163_1.2.jdx UCLM_lhuck3_163_1.3.jdx Compound 7l

32 S32 UCLM_lhuck3_189_1.1.jdx UCLM_lhuck3_189_1.2.jdx Compound 7m

33 S33 UCLM_lhuck3_266_1.1.jdx UCLM_lhuck3_266_1.2.jdx Compound 7n

34 S34 UCLM_lhuck3_192_1.2.jdx UCLM_lhuck3_192_1.1.jdx Compound 7o

35 S35 UCLM_lhuck3_288_1.1.jdx UCLM_lhuck3_288_1.1.jdx Compound 1p

36 S36 UCLM_lhuck3_792_1.2.jdx UCLM_lhuck3_792_1.3.jdx Compound 11a

37 S37 UCLM_lhuck3_826_1.4.jdx UCLM_lhuck3_826_.jdx Compound 12a

38 S38 UCLM_lhuck3_282_1.1.jdx UCLM_lhuck3_282_1.2.jdx Compound 13a

39 S39 UCLM_lhuck3_28_1.2.jdx UCLM_lhuck3_28_1.3.jdx Compound 14a