1.5 Experimental section
1.5.5 Synthesis of dialkyne substrates
1.5.5 Synthesis of dialkyne substrates
Figure 1.42 1H NMR spectrum of dialkyne 1 (in DMSO-d6).
Figure 1.43 13C NMR spectrum of dialkyne 1 (in DMSO-d6).
- Synthesis of dialkyne 2
4-ethynyl-N,N-dimethyl-N-(prop-2-yn-1-yl)benzenaminium bromide. To a stirred solution of 4- ethynyl-N,N-dimethylaniline (1 g, 6.89 mmol) in acetonitrile (30 mL) was added 80% propargyl bromide in toluene (1.53 mL, 13.78 mmol) and the resultant mixture was stirred for 24 hours at rt. Then, diethyl ether (100 mL) was added to the reaction mixture to precipitate the product which was further centrifuged. The precipitate was washed and centrifuged 3 times by using diethyl ether (3 × 100 mL).
Drying under high vacuum yielded product as a yellow powder (1.64 g, 90% yield).
1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J = 9.1 Hz, 2H), 7.77 (d, J = 9.06 Hz, 2H), 4.96 (d, J = 2.41 Hz, 2H), 4.48 (s, 1H), 3.90 (t, J = 2.37 Hz, 1H), 3.64 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ 144.7, 133.2, 123.9, 121.9, 83.6, 83.1, 81.5, 72.6, 58.2, 53.7; HRMS (ESI) m/z for C13H14N [M-Br-]+ calcd.
184.1126, found 184.1126.
Figure 1.44 1H NMR spectrum of dialkyne 2 (in DMSO-d6).
Figure 1.45 13C NMR spectrum of dialkyne 2 (in DMSO-d6).
- Synthesis of dialkyne 3.
Methyl 3-bromo-5-iodobenzoate was prepared according to the synthetic procedure from ref.69. 3-bromo-5-(tributylstannyl)pyridine. To a solution of 3-bromo-5-iodopyridine (1.0 g, 3.52 mmol) in THF (14 mL) cooled to -78 °C was added dropwise solution of n-BuLi in hexane (2.3 mL, 1.6 M). 10 min. later, tributyltin chloride (1.05 mL, 3.7 mmol) was added. The mixture was slowly heated up to
room temperature (over ~2 hours) and then concentrated in vacuo. The residue was dissolved in pentane, filtered and concentrated to give the title compound (as a crude mixture with remaining tributyltin chloride) and was used in subsequent step without purification.
Methyl 3-bromo-5-(5-bromopyridin-3-yl)benzoate. Mixture of methyl 3-bromo-5-iodobenzoate (682 mg, 2 mmol), crude 3-bromo-5-(tributylstannyl)pyridine (1.0 g), Pd(PPh3)4 (116 mg, 0.1 mmol, 5%mol), CuI (38 mg, 0.2 mmol, 10%mol) and KF (232 mg, 4 mmol) in DMF (10 mL) was stirred for 24 hours at 60 °C. Afterwards, the mixture was poured into a separatory funnel containing water and was extracted with diethyl ether (2 x 10 mL). Combined organic phases were washed with water (2 x 10 mL), saturated NaCl solution (1 x 10 mL) and dried with MgSO4. Evaporation of solvent gave crude mixture which was purified on silica gel (hexane:ethyl acetate = 9:1) and yielded title compound (347 mg, 47%) as off-white solid.
1H NMR (400 MHz, CDCl3) δ 8.84 (bs, 2H), 8.24 (s, 1H), 8 (s, 1H), 8.06 (s, 1H), 7.90 (s, 1H), 3.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.4, 150.7, 146.4, 142.7, 138.7, 137.1, 134.4, 133.0, 132.8, 127.1, 123.5, 52.7; HRMS (ESI) m/zfor C13H10Br2NO2[M+H]+calcd. 369.9078, found 369.9076.
Methyl 3-((trimethylsilyl)ethynyl)-5-(5-((trimethylsilyl)ethynyl)pyridin-3-yl)benzoate. Mixture of methyl 3-bromo-5-(5-bromopyridin-3-yl)benzoate (260 mg, 0.7 mmol), CuI (27 mg, 0.14 mmol, 20%mol), Pd(PPh3)4 (80 mg, 70 µmol, 10%mol), trimethylsilylacetylene (595 µL, 2.1 mmol), triethylamine (1.9 mL) and THF (5.5 mL) was heated at 50 °C for 5 hours. Evaporation of THF and TEA gave black crude which was purified on silica gel (hexane:ethyl acetate = 9:1) and gave title compound (252 mg, 89%) as yellowish solid.
1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 1.9 Hz, 1H), 8.17 (dt, J = 2.3, 1.6 Hz, 2H), 7.96 (t, J = 2.1 Hz, 1H), 7.84 (t, J = 1.7 Hz, 1H), 3.96 (s, 3H), 0.28 (d, J = 3.8 Hz, 18H); 13C NMR (100 MHz, CDCl3) δ 166.1, 151.9, 147.2, 137.7, 137.3, 134.6, 134.4, 132.9, 131.4, 128.1, 124.8, 120.6, 103.4, 101.2, 99.2, 96.6, 52.7, 0.0 (6); HRMS (ESI) m/zfor C23H27NO2Si2Na [M+H]+ calcd.
406.1659, found 406.1659.
3-ethynyl-5-(5-ethynylpyridin-3-yl)benzoic acid. Product of the previous step (147 mg, 0.36 mmol) was dissolved in MeOH (2.7 mL). To this solution, while stirring, was injected a solution of LiOH (52 mg, 2.16 mmol) in H2O (2.7 mL). This mixture was stirred overnight at room temperature and was then acidified by HClaq (2 M) to pH 4-5. Remaining precipitate was filtered off and washed with water. After drying, white solid product was obtained (76 mg, 86%).
1H NMR (400 MHz, DMSO-d6) δ 13.41 (br s, 1H), 8.95 (d, J = 2.3 Hz, 1H), 8.71 (d, J = 1.8 Hz, 1H), 8.29 (t, J = 2.1 Hz, 1H), 8.23 (t, J = 1.6 Hz, 1H), 8.12 (t, J = 1.6 Hz, 1H), 8.01 (t, J = 1.5 Hz, 1H), 4.51 (s, 1H), 4.39 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 166.2, 151.4, 147.6, 137.3, 137.2, 134.3, 133.6,
132.3, 132.0, 128.2, 123.1, 119.0, 84.6, 82.3, 82.2, 80.2; HRMS (ESI) m/zfor C16H10NO2[M+H]+calcd.
248.0712, found 248.0712.
3-(3-carboxy-5-ethynylphenyl)-5-ethynyl-1-methylpyridin-1-ium iodide. 3-ethynyl-5-(5- ethynylpyridin -3-yl)benzoic acid (62 mg, 0.25 mmol) was dissolved in DMF (2 mL) an methyl iodide (32 µL, 0.5 mmol) was added thereto. After stirring for 24 hours at rt, diethyl ether (10 mL) was added and the mixture was kept in a fridge for several hours. The precipitate formed was filtered off and washed with diethyl ether several times to remove DMF. After drying in vacuum, white solid product was obtained (92 mg, 95 %).
1H NMR (400 MHz, DMSO-d6) δ 9.51 (t, J = 1.5 Hz, 1H), 9.26 (t, J = 1.3 Hz, 1H), 9.09 (t, J = 1.7 Hz, 1H), 8.40 (t, J = 1.7 Hz, 1H), 8.15 (t, J = 1.8 Hz, 1H), 8.09 (t, J = 1.5 Hz, 1H), 4.99 (s, 1H), 4.38 (s, 1H), 4.38 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 166.1, 146.6, 144.6, 144.0, 138.0, 133.6, 132.9 (2), 132.6, 128.6, 122.6, 121.9, 88.5, 82.5, 82.0, 76.9, 48.2; HRMS (ESI) m/zfor C17H12NO2[M-I-]+ calcd. 262.0868, found 262.0865.
3-ethynyl-5-(5-ethynyl-1-methylpyridin-1-ium-3-yl)benzoate. The product of the previous step 3-(3- carboxy-5-ethynylphenyl)-5-ethynyl-1-methylpyridin-1-ium iodide (60 mg, 154 µmol) was dissolved in MeOH (1 mL), and propylene oxide (32 µL, 462 µmol) was added. After stirring for 3 hours, volatiles were evaporated and remaining solid was dried under vacuum to give title compound as a white solid (39 mg, 97%).
1H NMR (400 MHz, D2O) δ 9.10 (s, 1H), 8.99 (s, 1H), 8.81 (s, 1H), 8.15 (t, J = 1.7 Hz, 1H), 8.11 (t, J
= 1.5 Hz, 1H), 7.94 (t, J = 1.7 Hz, 1H), 4.47 (s, 3H), 4.08 (s, 1H), 3.66 (s, 1H); 13C NMR (100 MHz, D2O) δ 171.9, 146.3, 145.2, 142.7, 139.3, 136.9, 134.0, 133.1, 132.8, 128.2, 123.6, 123.1, 86.8, 82.0, 80.0, 75.7, 48.6; HRMS (ESI) m/zfor C17H12NO2[M+H]+calcd. 262.0868, found 262.0865.
Figure 1.46 1H NMR spectrum of dialkyne 3 (in D2O).
Figure 1.47 13C NMR spectrum of dialkyne 3 (in D2O).
- Synthesis of dialkyne 4.
1-nitro-2,4-bis(prop-2-yn-1-yloxy)benzene. A round-bottom flask (100 mL) was charged with K2CO3
(9.453 g, 68.40 mmol), dry DMF (35 mL), then propargyl alcohol (2.39 mL, 41.04 mmol) and 2,4- difluoronitrobenzene (1.50 mL, 13.68 mmol) were added. The flask was equipped with a reflux condenser capped with a rubber septum, established inert Ar atmosphere and the balloon with Ar was set at the top of the reflux condenser. The reaction was stirred overnight at 70 oC. After reaction completion (monitored by TLC, hexane:AcOEt = 4:1), the reaction mixture was cooled down to room temperature and the solids were filtered off, and rinsed by AcOEt. Aqueous, 10% solution of LiCl (50 mL) was added to the filtrate and, after separation, organic phase was dried over anhydrous MgSO4, filtered, and the solvents were removed in vacuo. The remaining oil was purified by the flash column chromatography (hexane:ethyl acetate = 3:1) to yield 1.826 g of product (58%) as a pale yellow solid.
1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 9.1 Hz, 1H), 6.83 (d, J = 2.5 Hz, 1H), 6.66 (dd, J = 9.1, 2.5 Hz, 1H), 4.85 (d, J = 2.4 Hz, 2H), 4.78 (d, J = 2.4 Hz, 2H), 2.60 (q, J = 2.4 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 162.3, 153.4, 134.3, 128.4, 107.0, 102.7, 77.4, 77.3, 76.9, 57.5, 56.5; HRMS (ESI) m/z for C12H9NO4Na [M+Na]+ calcd. 254.0429, found 254.0426.
2,4-bis(prop-2-yn-1-yloxy)aniline. A round-bottom flask (50 mL) was charged with SnCl2×2H2O (1.230 g, 4.870 mmol) and HCl (37%, 4.0 mL). The flask was then cooled to 0 oC before addition of 1- nitro-2,4-bis(prop-2-yn-1-yloxy)benzene (150.0 mg, 0.649 mmol) and THF (4.0 mL). The reaction mixture was stirred for 3.5 hours at rt. After reaction completion (monitored by TLC, hexane:AcOEt = 2:1), the mixture was cooled down to 0 oC, Et2O (20 mL) was added and carefully quenched by portion- wise addition of saturated water solution of NaHCO3 (10 mL) and solid NaHCO3 until quenching with HCl. Water (20 mL) was added to the mixture and the aqueous phase was extracted with Et2O (3 × 20 mL), dried over anhydrous MgSO4, filtered, and the solvents were removed in vacuo. The remaining oil was purified by the flash column chromatography (hexane:ethyl acetate = 2:1) to yield 0.1299 g of product (99%) as a pale brown oil.
1H NMR (500 MHz, DMSO-d6) δ 9.92 (s, 2H), 7.41 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 2.5 Hz, 1H), 6.70 (dd, J = 8.7, 2.5 Hz, 1H), 4.95 (d, J = 2.4 Hz, 2H), 4.83 (d, J = 2.4 Hz, 2H), 3.70 (t, J = 2.4 Hz, 1H), 3.60 (t, J = 2.4 Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 157.5, 151.0, 124.5, 114.4, 106.6, 102.1,
79.4, 78.8, 78.6, 78.4, 56.6, 56.0; HRMS (ESI) m/z for C12H12NO2 [M+H]+ calcd. 202.0868, found 202.0865.
N,N-dimethyl-2,4-bis(prop-2-yn-1-yloxy)aniline. A round-bottom flask (25 mL) was charged with 2,4-bis(prop-2-yn-1-yloxy)aniline (0.6810 g, 3.39 mmol), NaHCO3 (0.8544 g, 10.71 mmol) and dry DMF (4.0 mL). The flask was capped with a rubber septum and inert, Ar atmosphere was established.
MeI (1.005 g, 7.08 mmol) was added to the stirred mixture dropwise. After 30 min. the solution solidified, another portion of DMF (3.0 mL) was added and then stirred for 15 min. After reaction completion (monitored by TLC, hexane:AcOEt = 7:2) AcOEt (50 mL) was added, and organic phases were washed in a separatory funnel with 10% aqueous solution of LiCl (2 × 30 mL), dried over anhydrous MgSO4, filtered, and the solvents were removed in vacuo. The remaining oil was purified by the flash column chromatography (hexane:ethyl acetate = 7:2) to yield 0.3047 g (39%) product as a pale yellow oil.
1H NMR (500 MHz, D2O) δ 7.65 (d, J= 9.1 Hz, 1H), 7.00 (d, J= 2.6 Hz, 1H), 6.89 (dd, J = 9.1, 2.4 Hz, 1H), 5.01 (d, J= 2.4 Hz, 2H), 4.88 (d, J= 2.4 Hz, 2H), 3.26 (s, 6H), 3.05 (t, J= 2.4 Hz, 1H), 3.01 (t, J= 2.4 Hz, 1H); 13C NMR (126 MHz, D2O) δ 158.7, 149.5, 124.8, 121.5, 108.4, 102.0, 78.0, 77.6, 77.5, 77.0, 57.0, 56.3, 45.7 (2); HRMS (ESI) m/z for C14H16NO2 [M+H]+ calcd. 230.1181, found 230.1177.
N,N,N-trimethyl-2,4-bis(prop-2-yn-1-yloxy)benzenaminium iodide. A round-bottom flask (25 mL) was charged with N,N-dimethyl-2,4-bis(prop-2-yn-1-yloxy)aniline (0.3047 g, 1.33 mmol) and dry CH3CN (5.0 mL). The flask was capped with a rubber septum and inert, Ar atmosphere was established.
MeI (1.005 g, 7.08 mmol) was added dropwise to the stirred mixture. The reaction was stirred overnight at room temperature and monitored by TLC (hexane:AcOEt = 2:1), until full conversion of N,N- dimethyl-2,4-bis(prop-2-yn-1-yloxy)aniline and appearance of a pale yellow solid. Et2O (10 mL) was added and the mixture was then filtered using Büchner funnel. Precipitate was dried under vacuum to yield 0.4386 g (89%) of product as a white solid.
1H NMR (400 MHz, D2O) δ 7.70 (d, J = 9.5 Hz, 1H), 7.04 (d, J = 2.7 Hz, 1H), 6.83 (dd, J = 2.8, 9.4 Hz, 1H), 4.88 (d, J = 2.1 Hz, 2H), 3.69 (s, 9H), 3.04 (t, J = 3.0 Hz, 1H), 3.00 (t, J = 3.0 Hz, 1H); 13C NMR (100 MHz, D2O) δ 159.1, 150.7, 128.1, 122.1, 107.3, 103.5, 77.7, 77.1, 56.8, 56.3, 56.0; HRMS (ESI) m/zfor C15H18NO2[M+H]+calcd. 244.1338, found 244.1336.
Figure 1.481H NMR spectrum of dialkyne 4(in D2O).
Figure 1.4913C NMR spectrum of dialkyne 4(in D2O).
1.5.6 Site-selective synthesis of triazoles from dialkynes