1-chloro-3-methoxybenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:

Procedure: The general procedure A was followed using 1-chloro-3-methoxybenzene (60.4 uL, 0.5 mmol) and B2pin2 (126.9 mg, 0.5 mmol, 1.0 eq.) as starting material. The resulting mixture was allowed to stir 16 hours at 100 oC. 5e was obtained as colorless oil (130.2 mg, 97%) after purification by silica gel flash chromatography (EtOAc/PE=1:40 v/v).

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Chloroanisole (76 mg, 0.54 mmol) reacted with 4-methoxyphenylboronic acid (117 mg, 0.77 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in toluene at 80° C. to give the title compound (112 mg, 97%) as a colorless oil: 1H-NMR (300 MHz CDCl3): δ 7.57 (d, 2H, J=8.7 Hz), 7.37 (t, 1H, J=7.8 and 8.1 Hz), 7.17 (m, 2H), 7.01 (d, 2H, J=8.7 Hz), 6.88-6.97 (m, 1H), 3.89 (s, 3H), 3.88 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 159.86, 159.17, 142.28, 135.51, 129.66, 128.13, 119.21, 114.09, 112.44, 111.93. GC/MS (EI): m/z 214 (M+), 199, 171, 128. Anal. Calcd for C14H4O2: C, 78.48; H, 6.59. Found C, 78.46: H, 6.62. at 80° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Chloroanisole (74 mg, 0.52 mmol) reacted with n-hexylamine (65 mg, 0.64 mmol) according to procedure B using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (58 mg, 0.60 mmol) in toluene at 100° C. to give the title compound (103 mg, 95%) as a colorless oil. Also 3-bromoanisole was converted to the title amine in 85% yield by procedure A: 1H-NMR (400 MHz, CDCl3): δ 6.99 (t, 1H, J=8.0 Hz), 6.19-6.13 (m, 2H), 6.08 (app.t, 1H, J=2.4 Hz), 3.70 (s, 3H), 3.55 (bs, 1H), 3.01 (t, 2H, J=7.2 Hz), 1.53 (m, 2H), 1.33 (m, 2H), 1.24 (m, 4H), 0.83 (t, 3H, J=6.8 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 160.81, 149.91, 129.87, 105.86, 102.09, 98.53, 55.01, 43.95, 31.61, 29.47, 26.81, 22.60, 14.01. GC/MS(EI): m/z 207 (M+), 136. Anal. Calcd for C13H21NO: C, 75.23; H, 10.21; N, 6.76. Found: C,75.25; H, 10.33; N, 6.86. at 100° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 4-chlorobenzoyl chloride (1.0 g, 5.8 mmol) and 1-chloro-3-methoxybenzene(823.7 mmol) in CH2Cl2 (150 mL) at 0° C. was added AlCl3 (841.5 mg, 6.4 mmol). The reaction mixture was warmed to room temperature. After 12h the reaction mixture was poured into aq. NaHCO3 and extracted with CH2Cl2 (twice). The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vaccuo to provide the crude product. Purification by silica gel chromatography provided (2-chloro-4-methoxyphenyl)(4-chlorophenyl)methanone(1.1 g, 4.1 mmol). (2-Chloro-4-methoxyphenyl)(4-chlorophenyl)methanone was dissolved in AcOH (60 mL) and 49% HBr (60 mL) was added. After 12h at 90° C. all volatiles were evaporated in vaccuo to afford (4-chlorophenyl)(2,4-dihydroxyphenyl)methanone in quantitative yield. This was dissolved in MeOH (30 mL) and THF (6 mL) and cooled to 0° C. Into the reaction mixture NaBH4 (235.5 mg, 6.2 mmol) was added. After 30 minutes the reaction was quenched with aq. NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vaccuo. Without purification this was subjected to alkylation with 1,8-dibromoocatane (3.3 g, 12.3 mmol) and K2CO3 (1.7 g, 12.3 mmol) in DMF (45 mL). After 12h the reaction mixture was diluted with water (150 mL) and water phase was extracted with EtOAc (twice). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated in vaccuo to give the crude product. Purification by silica gel chromatography provided (4-(8-bromooctyloxy)-2-chlorophenyl)(4-chlorophenyl)methanol (1.6 g, 3.5 mmol). To a stirred solution of (4-(8-bromooctyloxy)-2-chlorophenyl)(4-chlorophenyl)methanol (1.6 g, 3.5 mmol) in THF (25 mL) was added N-methylprop-2-en-1-amine (746 mg, 10.5 mmol) and NaHCO3 (11.0 mmol). After 36h at room temperature the reaction mixture was filtered through a glass-filter. The filtrate was evaporated in vaccuo. Purification by silica gel chromatography provided (4-(8-(allyl(methyl)amino)octyloxy)-2-chlorophenyl)(4-chlorophenyl)methanol (1.5 g, 3.3 mmol); 1H-NMR (300 MHz, CDCl3); 7.29-7.17 ppm (m, 5H), 6.84 (d, J=10.1 Hz, 1H), 6.74 (s, 1H), 5.98-5.80 (m, 2H), 5.31-5.15 (m, 2H), 3.85 (t, J=7.6 Hz, 2H), 3.20-3.08 (m, 2H), 2.58-2.40 (m, 2H), 2.35 (s, 3H), 1.77-1.45 (m, 4H), 1.32-1.15 (m, 8H); 13C—NMR (75 MHz, CDCl3) 156.3 ppm, 138.3, 134.2, 131.8, 130.0, 129.6, 129.3, 116.2, 74.5, 68.8, 60.4, 43.8, 57.0, 29.6, 29.3, 28.1, 27.3, 25.9; ESI-MS calcd for C25H34Cl2NO2 [M+H]+: 450.2. found 450.2. extracted with CH2Cl2 (twice) The combined extracts were washed with brine dried over Na2SO4 concentrated in vaccuo to provide the crude product Purification by silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The general procedure described in Example 27 was used with 3-chloroanisole (0.063 mL, 0.50 mmol), phenylacetylene (0.072 mL, 0.65 mmol), PdCl2(CH3CN)2 (3.2 mg, 0.0125 mmol, 1.25 mol %), sodium 2′-(dicyclohexyl-phosphanyl)-2,6-diisopropyl-biphenyl-4-sulfonate (20.0 mg, 0.0375 mmol, 3.75 mol %), Cs2CO3 (650 mg, 2.00 mmol), water (1.0 mL), acetonitrile (1.5 mL), 12 h, 100° C. The product was isolated as a white solid (99 mg, 95%). Mp=70° C. (lit. 72-74° C.). 1H NMR (400 MHz, CDCl3) δ: 7.62 (m, 2H), 7.41 (m, 3H), 7.32 (t, 1H, J=7.6 Hz), 7.23 (dt, 1H, J=1.2 Hz, 7.6 Hz), 7.15 (m, 1H), 6.96 (qd, 1H, J=1.2 Hz, 2.4 Hz, 7.6 Hz). 13C NMR (125 MHz, CDCl3) δ: 159.5, 131.8, 129.6, 128.5, 128.48, 124.4, 124.3, 123.3, 116.5, 115.1, 89.5, 89.4, 55.4.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The general procedure described in Example 27 was used with 3-chloroanisole (0.061 mL, 0.50 mmol), 5-hexynoic acid (0.072 mL, 0.65 mmol), PdCl2(CH3CN)2 (3.2 mg, 0.0125 mmol, 1.25 mol %), sodium 2′-(dicyclohexyl-phosphanyl)-2,6-diisopropyl-biphenyl-4-sulfonate (20.0 mg, 0.0375 mmol, 3.75 mol %), Cs2CO3 (650 mg, 2.00 mmol), water (1.0 mL), acetonitrile (1.0 mL), 10 h, 100° C. The product was isolated as a colorless oil (60 mg, 85%). 1H NMR (400 MHz, CDCl3) δ: 7.16 (t, 1H, J=8.0 Hz), 6.96 (dt, 1H, J=1.2 Hz, 7.6 Hz), 6.89 (m, 1H), 6.80 (qd, 1H, J=1.2 Hz, 2.4 Hz, 8.4 Hz), 3.76 (s, 3H), 3.66 (s, 3H), 2.48 (t, 2H, J=7.2 Hz), 2.45 (t, 2H, J=6.8 Hz), 1.90 (q, 2H, J=6.8 Hz). 13C NMR (125 MHz, CDCl3) δ: 173.8, 159.4, 129.5, 124.9, 124.3, 116.6, 114.5, 88.9, 81.6, 55.4, 51.8, 33.1, 24.1, 19.1. IR (neat, cm−1): 2952, 2232, 1737, 1598, 1574, 1481, 1434, 1316, 1287, 1206, 1164, 1045, 854, 786, 688. 1H NMR (CDCl3) is shown in FIG. 8.

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of AlCl3 (42.08 g; 315.60 mmol) in CH2Cl2 (300 mL) was added dropwise 3-chloroanisole (22.50 g; 157.80 mmol), at −30° C. To the resulting mixture was added dropwise a solution of AcCl (10.50 mL; 147.63 mmol) in CH2Cl2 (100 mL) at such a rate to keep the temperature below −15° C. The resulting mixture was stirred for 4 hours at −10° C. Subsequently, the mixture was poured onto ice and extracted with CH2Cl2. The combined organic layers, were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:9) to afford 1-(2-chloro-4-methoxy-phenyl)-ethanone (17.68 g). at −30° C the temperature below −15° C Subsequently, the mixture was poured onto ice extracted with CH2Cl2 The combined organic layers, were dried (MgSO4) filtered concentrated in vacuo The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:9)