Bis-Sonogashira Cross-Coupling - Royal Society of Chemistry

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I Catalyst screening: An oven-dried flask was filled with aryl dihalide 1 (0.5 mmol), alkynol. 2 (1.2 mmol) [1] and the appropriate catalyst, solvent as well as ...

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Bis-Sonogashira Cross-Coupling: An Expeditious Approach towards Long-Chain, Phenylene-Modified 1,ω ω-Diols Simon Drescher,ab Susan Becker,a Bodo Dobnera and Alfred Blumeb a

Institute of Pharmacy, Wolfgang-Langenbeck-Str. 4, 06120 Halle (Saale), Germany;

b

Institute of Chemistry, von-Danckelmann-Platz 4, 06120 Halle (Saale), Germany.

Materials and Methods General Procedures Characterization of Products 1

H and 13C NMR Spectra of Final Products

References

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Materials and Methods All chemicals were purchased from Sigma Aldrich Co. (Steinheim, Germany) and were used without further purification. All solvents were dried and distilled before use. The purity of all compounds was checked by thin-layer chromatography (TLC-plates; Merck, Darmstadt, Germany) using silica gel 60 F254 plates (Merck) and common eluents. The plates were visualised under UV (254 nm) light or by usage of Bromothymol Blue. Purification of the products was carried out by recrystallization or by middle pressure liquid chromatography (MPLC; Büchi, Essen, Germany) on silica gel (0.040–0.063 mm, Merck). The MPLC was equipped with a Fraction Collector C-660, Pump Module C-601 (2×), Pump Manager C-615 and UV detector (cut off = 254 nm), and the following solvent was used for elution: 25 min isocratic chloroform, 60 min continuous increase from chloroform/diethyl ether (100/0, v/v) to (60/40, v/v); flow = 20 ml/mL, sample fractions of 20 mL.

Melting points were determined with a Boetius apparatus. Elemental analyses were carried out on a Leco CHNS-932 (Leco-Corporation, St. Joseph, MI, USA). 1H and 13C spectra were recorded on a Varian Gemini 2000 spectrometer or a Varian Inova 500 with the use of CDCl3 as internal standard. Any chemical shifts (δ) are reported as parts per million (ppm). The coupling constants (J) are reported in Hz and signal multiplicities are reported as singlet (s), triplet (t) or multiplet (m). Mass spectrometric data were recorded on an AMD 402 (70 eV; AMD Intecta GmbH, Harpstedt, Germany) spectrometer.

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General Procedures I Catalyst screening: An oven-dried flask was filled with aryl dihalide 1 (0.5 mmol), alkynol 2 (1.2 mmol) [1] and the appropriate catalyst, solvent as well as additives (see Table 1) under argon atmosphere. The mixture was either heated to the temperature stated in Table 1 or not. After several hours (see Table 1) 30 mL H2O was added and the mixture was extracted with chloroform (3× 20 mL). The combined organic layers were washed with brine (20 mL), water (20 mL), dried over sodium sulphate, and evaporated. The residue was purified by middle pressure liquid chromatography using chloroform/diethyl ether as eluents and gradient technique to afford the diol 3a as white crystalline powder.

II Bis-Sonogashira cross-coupling: An oven-dried flask was filled with aryl dihalide 1 (0.5– 1.0 mmol), alkynol 2 (1.2–2.4 mmol)[1], PdCl2(PPh3)2 (6 mol %) and TBAF×3H2O (3 equiv) under argon atmosphere. The mixture was subsequently stirred at 80 °C for 1–2 h until complete consumption of the starting material. Afterwards, 30 mL H2O was added and the mixture was extracted with chloroform (3× 20 mL). The combined organic layers were washed with brine (20 mL), water (20 mL), dried over sodium sulphate, and evaporated. The residue was purified by middle pressure liquid chromatography using chloroform/diethyl ether as eluents and gradient technique to afford the diols 3 as white crystalline powder.

III Hydrogenation reaction: For the hydrogenation of the triple bonds, diol 3 (0.5 mmol) was dissolved in heptane/ethyl acetate/ethanol (100 mL, 3/1/1, v/v/v) and Pd(OH)2 (20% on carbon, 75 mg) was added. The mixture was stirred under hydrogen (10 atm) at room temperature for 18 h. Afterwards, the catalyst was removed by filtration and the solvent was evaporated in vacuo to give the diols 4 as white crystalline powder after recrystallization from heptane.

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Characterization of Products 17,17‘-(1,4-Phenylene)bis(heptadec-16-in-1-ol) (3a, Table 1, Entries 7–9):

OH

HO

Following general procedure II, 1,4-dibromobenzene (1a, 0.188 g, 0.8 mmol) and heptadec16-yn-1-ol (2, 0.480 g, 1.9 mmol) were used. 17,17‘-(1,4-Phenylene)bis(heptadec-16-in-1-ol) was recovered as white solid (0.29 g, 63%) after MPLC (chloroform/diethyl ether. M.p. 86–87 °C; Rf = 0.28 (CHCl3/diethyl ether, 1/1, v/v); 1H NMR (400 MHz, CDCl3, 27 °C):

δ = 1.24–1.45 (m, 44 H, 2× C≡C(CH2)2(CH2)11(CH2)2OH), 1.51–1.61 (m, 8 H, 2× C≡CCH2 CH2(CH2)11CH2CH2OH), 2.37 (t, 3JH/H = 7.1 Hz, 4 H, 2× C≡CCH2), 3.62 (t, 3JH/H = 6.6 Hz, 4 H, 2× CH2OH), 7.27 ppm (s, 4 H, C6H4);

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C NMR (100 MHz, CDCl3, 27 °C): δ = 19.52

(C≡CCH2), 25.79 (CH2(CH2)2OH), 28.77, 28.97, 29.17, 29.47, 29.56, 29.64, 29.67, 32.87 (CH2CH2OH), 63.11 (CH2OH), 80.40 (C≡CCH2), 91.94 (C≡CCH2), 123.17 (1,4-C, C6H4), 131.28 ppm (2,3,5,6-C, C6H4); MS (70 eV): m/z (%): 578 (81) [M+], 422 (18), 380 (98) [M+ − C13H26O], 366 (82) [M+ − C14H28O], 262 (21), 209 (24), 195 (31), 183 (43), 169 (59), 155 (80), 129 (100); elemental analysis calcd (%) for C40H66O2 (578.95): C 82.98, H 11.49; found: C 82.86, H 11.06. Following general procedure II, 1,4-diiodobenzene (1b, 0.264 g, 0.8 mmol) and heptadec-16yn-1-ol (2, 0.480 g, 1.9 mmol) were used (Table 1, Entry 9). 17,17‘-(1,4-Phenylene)bis(heptadec-16-in-1-ol) was recovered as white solid (0.21 g, 45%) after MPLC (chloroform/diethyl ether). Analytical data was consistent with that above.

17,17‘-(1,3-Phenylen)bis(heptadec-16-in-1-ol) (3b Table 1, Entry 10):

HO

OH

Following general procedure II, 1,3-dibromobenzene (1c, 0.188 g, 0.8 mmol) and heptadec16-yn-1-ol (2, 0.480 g, 1.9 mmol) were used. 17,17‘-(1,3-Phenylene)bis(heptadec-16-in-1-ol) was recovered as light yellow solid (0.28 g, 61%) after MPLC (chloroform/diethyl ether).

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M.p. 69–71 °C; Rf = 0.27 (CHCl3/diethyl ether, 1/1, v/v); 1H NMR (400 MHz, CDCl3, 27 °C):

δ = 1.25–1.44 (m, 44 H, 2× C≡C(CH2)2(CH2)11(CH2)2OH), 1.51–1.61 (m, 8 H, 2× C≡CCH2 CH2(CH2)11CH2CH2OH), 2.37 (t, 3JH/H = 7.1 Hz, 4 H, 2× C≡CCH2), 3.62 (t, 3JH/H = 6.6 Hz, 4 H, 2× CH2OH), 7.14–7.19 (m, 1 H, 5-H, C6H4), 7.24 (s, 1 H, 2-H, C6H4), 7.26–7.40 ppm (m, 2 H, 4,6-H, C6H4);

C NMR (100 MHz, CDCl3, 27 °C): δ = 19.45 (C≡CCH2), 25.80

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(CH2(CH2)2OH), 28.78, 28.96, 29.19, 29.48, 29.57, 29.69, 32.89 (CH2CH2OH), 63.11 (CH2OH), 80.00 (C≡CCH2), 90.85 (C≡CCH2), 124.22 (1,3-C, C6H4), 128.02 (5-C, C6H4), 130.49 (4,6-C, C6H4), 134.56 ppm (2-C, C6H4); MS (70 eV): m/z (%): 578.5 (29) [M+], 380.3 (20) [M+ − C13H26O], 237.2 (19), 168.1 (91), 195.0 (18), 181.0 (34); elemental analysis calcd (%) for C40H66O2 (578.95): C 82.98, H 11.49; found: C 82.56, H 11.31. 17,17‘-(1,2-Phenylen)bis(heptadec-16-in-1-ol) (3c Table 1, Entry 11):

OH

OH

Following general procedure II, 1,2-dibromobenzene (1d, 0.188 g, 0.8 mmol) and heptadec16-yn-1-ol (2, 0.480 g, 1.9 mmol) were used. 17,17‘-(1,2-Phenylene)bis(heptadec-16-in-1-ol) was recovered as light yellow solid (0.20 g, 43%) after MPLC (chloroform/diethyl ether). M.p. 72–73 °C; Rf = 0.25 (CHCl3/diethyl ether, 1/1, v/v); 1H NMR (400 MHz, CDCl3, 27 °C):

δ = 1.25–1.35 (m, 40 H, 2× C≡C(CH2)2(CH2)10(CH2)3OH), 1.42–1.65 (m, 12 H, 2× C≡CCH2 CH2(CH2)10(CH2)2CH2OH), 2.43 (t, 3JH/H = 7.1 Hz, 4 H, 2× C≡CCH2), 3.62 (t, 3JH/H = 6.6 Hz, 4 H, 2× CH2OH), 7.13–7.16 (m, 2 H, 4,5-H, C6H4), 7.33–7.35 ppm (m, 2 H, 3,6-H, C6H4); 13C NMR (100 MHz, CDCl3, 27 °C): δ = 19.80 (C≡CCH2), 25.86 (CH2(CH2)2OH), 28.97, 29.06, 29.36, 29.54, 29.68, 29.71, 29.78, 32.93 (CH2CH2OH), 63.13 (CH2OH), 79.62 (C≡CCH2), 94.13 (C≡CCH2), 126.36 (1,2-C, C6H4), 126.97 (4,5-C, C6H4), 131.68 ppm (3,6-C, C6H4); MS (70 eV): m/z (%): 578.4 (64) [M+], 393.2 (19), 380.3 (29) [M+ − C13H26O], 365.2 (36), 351.2 (42), 195.0 (25), 181.0 (68), 167.0 (76), 155.0 (55), 140.9 (100); elemental analysis calcd (%) for C40H66O2 (578.95): C 82.98, H 11.49; found: C 82.67, H 11.51.

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17,17’-(1,4-Phenylene)bis(heptadecan-1-ol) (4a):

OH HO

Following the procedure III, 17,17‘-(1,4-Phenylene)bis(heptadec-16-in-1-ol) (3a, 290 mg, 0.5 mmol) was used. 17,17’-(1,4-Phenylene)bis(heptadecan-1-ol) was recovered as white solid (0.27 g, 93%) after recrystallization from heptane. M.p. 96–97 °C; Rf = 0.29 (CHCl3/diethyl ether, 1/1, v/v); 1H NMR (400 MHz, CDCl3, 27 °C):

δ = 1.24–1.35 (m, 52 H, 2× (CH2)2(CH2)13(CH2)2OH), 1.51–1.61 (m, 8 H, 2× CH2CH2(CH2)13 CH2CH2OH), 2.54 (t, 3JH/H = 7.8 Hz, 4 H, CH2C6H4CH2), 3.62 (t, 3JH/H = 6.6 Hz, 4 H, 2× CH2OH), 7.06 ppm (s, 4 H, C6H4);

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C NMR (100 MHz, CDCl3, 27 °C): δ = 25.74

(CH2(CH2)2OH), 29.40, 29.43, 29.53, 29.60, 29.61, 29.67, 31.59 (CH2CH2C6H4CH2CH2), 32.83 (CH2CH2OH), 35.57 (CH2C6H4CH2), 63.11 (CH2OH), 128.20 (2,3,5,6-C, C6H4), 140.07 ppm (1,4-C, C6H4); MS (70 eV): m/z (%): 586 (100) [M+], 568 (21) [M+ − H2O]; elemental analysis calcd (%) for C40H74O2 (587.01): C 81.84, H 12.71; found: C 81.81, H 12.39.

17,17‘-(1,3-Phenylene)bis(heptadecan-1-ol) (4b):

HO

OH

Following the procedure III, 17,17‘-(1,3-Phenylene)bis(heptadec-16-in-1-ol) (3b, 290 mg, 0.5 mmol) was used. 17,17’-(1,3-Phenylene)bis(heptadecan-1-ol) was recovered as white solid (0.26 g, 90%) after recrystallization from heptane. M.p. 77–78 °C; Rf = 0.26 (CHCl3/diethyl ether, 1/1, v/v); 1H NMR (500 MHz, CDCl3, 27 °C):

δ = 1.24–1.40 (m, 52 H, 2× (CH2)2(CH2)13(CH2)2OH), 1.52–1.59 (m, 8 H, 2× CH2CH2(CH2)13 CH2CH2OH), 2.55 (t, 3JH/H = 7.6 Hz, 4 H, CH2C6H4CH2), 3.62 (t, 3JH/H = 6.6 Hz, 4 H, 2× CH2OH), 6.96–6.97 (m, 2 H, 4,6-H, C6H4), 7.15 („t“, J = 7.5 Hz, 1 H, 5-H, C6H4), 7.40 ppm (s, 1 H, 2-H, C6H4); 13C NMR (125 MHz, CDCl3, 27 °C): δ = 25.74 (CH2(CH2)2OH), 29.39, 29.43, 29.52, 29.60, 29.67, 31.55 (CH2CH2C6H4CH2CH2), 32.82 (CH2CH2OH), 35.97 (CH2C6H4CH2), 63.10 (CH2OH), 125.58 (4,6-C, C6H4), 128.03 and 128.55 (2,5-C, C6H4), 142.81 ppm (1,3-C, C6H4); MS (70 eV): m/z (%): 586.6 (39) [M+], 368.6 (20) [M+ − H2O], 346.3 (16) [M+ − C16H33O], 328.3 (10) [M+ − C16H35O2], 159.1 (16), 145.1 (50), 131.1 (66), 6

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105.0 (100); elemental analysis calcd (%) for C40H74O2 (587.01): C 81.84, H 12.71; found: C 81.75, H 12.59.

17,17‘-(1,2-Phenylene)bis(heptadecan-1-ol) (4c):

OH OH

Following the procedure III, 17,17‘-(1,2-Phenylene)bis(heptadec-16-in-1-ol) (3c, 290 mg, 0.5 mmol) was used. 17,17’-(1,2-Phenylene)bis(heptadecan-1-ol) was recovered as white solid (0.28 g, 95%) after recrystallization from heptane. M.p. 60–61 °C; Rf = 0.26 (CHCl3/diethyl ether, 1/1, v/v); 1H NMR (500 MHz, CDCl3, 27 °C):

δ = 1.24–1.38 (m, 52 H, 2× (CH2)2(CH2)13(CH2)2OH), 1.52–1.58 (m, 8 H, 2× CH2CH2(CH2)13 CH2CH2OH), 2.57 (t, 3JH/H = 7.9 Hz, 4 H, CH2C6H4CH2), 3.62 (t, 3JH/H = 6.7 Hz, 4 H, 2× CH2OH), 7.08–7.12 ppm (m, 4 H, C6H4);

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C NMR (125 MHz, CDCl3, 27 °C): δ = 25.73

(CH2(CH2)2OH), 29.42, 29.54, 29.60, 29.66, 29.68, 29.79, 31.32 (CH2CH2C6H4CH2CH2), 32.69 (CH2C6H4CH2), 32.81 (CH2CH2OH), 63.09 (CH2OH), 125.65 (4,5-C, C6H4), 129.06 (3,6-C, C6H4), 140.55 ppm (1,2-C, C6H4); MS (70 eV): m/z (%): 586.6 (59) [M+], 368.7 (22) [M+ − H2O], 346.4 (8) [M+ − C16H33O], 327.4 (12) [M+ − C16H35O2], 313.3 (18) [M+ − C17H37O2], 145.1 (48), 131.2 (98), 117.0 (51), 105.0 (100); elemental analysis calcd (%) for C40H74O2 (587.01): C 81.84, H 12.71; found: C 81.69, H 12.64.

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1

H and 13C NMR Spectra of Final Products

17,17’-(1,4-Phenylene)bis(heptadecan-1-ol) (4a)

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17,17’-(1,3-Phenylene)bis(heptadecan-1-ol) (4b)

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17,17’-(1,2-Phenylene)bis(heptadecan-1-ol) (4c)

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References [1]

S. Drescher, K. Helmis, A. Langner, B. Dobner, Monatsh. Chem. 2010, 141, 339-349.

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