* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of the American Chemical Society, 1985, vol. 107, p. 6659
[2] Journal of Organic Chemistry, 1986, vol. 51, # 25, p. 4974 - 4979
[3] Journal of the Chemical Society, Chemical Communications, 1982, # 4, p. 242 - 243
[4] Russian Journal of Organic Chemistry, 2012, vol. 48, # 10, p. 1345 - 1352[5] Zh. Org. Khim., 2012, vol. 48, # 10, p. 1350 - 1357,8
2
[ 37860-51-8 ]
[ 111-42-2 ]
[ 33941-15-0 ]
Yield
Reaction Conditions
Operation in experiment
35%
at 40℃; for 1 h; Inert atmosphere; Glovebox
A 3 L, three-neck round bottom flask was charged with a magnetic stir bar, 1.50 L tBuOH, andKOtBu (30.7 g, 274 mmol). The mixture was warmed to 40°C stirred for 30 min to dissolve theKOtBu, and then tetraethylene glycol di(toluene-p-sulphonate) (46 g, 91.5 mmol, in 100 mLdioxane) and diethanolamine (9.6 g, 91.3 mmol, in 100 mL tBuOH) were added dropwise(simultaneously from two different dropping funnels) over the course of 2 h. Note: Slow additionof the solutions is crucial; the slower the addition, the higher the yield After addition, the reactionmixture was stirred for 1h and allowed to cool. The reaction mixture was then filtered twicethrough a Büchner funnel and the solvent was removed on a rotary evaporator. Deionized water(100 mL) was added to the brown, sticky residue and the resulting solution was first extracted withhexane (1×60 mL, hexane phase discarded), followed by CH2Cl2 (5×60 mL). The CH2Cl2 phaseswere collected, dried over MgSO4, and solvent was removed on a rotary evaporator. The resultingdark brown residue was distilled through a bulb-to-bulb distillation under high static vacuum usinga heat gun to yield the product as a colorless liquid (8.4 g, 35percent). The NMR spectra are consistentwith published data. We have found that the tBuOH used in this preparation can be distilled andre-used for subsequent azacrown syntheses despite the presence of small amounts of dioxane(<5percent).
Reference：
[1] Bulletin of the Chemical Society of Japan, 1983, vol. 56, # 1, p. 212 - 218
[2] Polyhedron, 2018, vol. 141, p. 385 - 392
[3] Phosphorus, Sulfur and Silicon and the Related Elements, 2006, vol. 181, # 1, p. 219 - 225
[4] Journal of the Chemical Society, Chemical Communications, 1981, # 10, p. 471 - 472
3
[ 118798-05-3 ]
[ 33941-15-0 ]
Reference：
[1] Journal of Organic Chemistry, 1986, vol. 51, # 25, p. 4974 - 4979
With potassium <i>tert</i>-butylate In 1,4-dioxane; <i>tert</i>-butyl alcohol at 40℃; for 2h;
35%
With potassium <i>tert</i>-butylate; <i>tert</i>-butyl alcohol at 40℃; for 1h; Inert atmosphere; Glovebox;
Synthesis of 1-Aza-18-Crown-6 (1b)
A 3 L, three-neck round bottom flask was charged with a magnetic stir bar, 1.50 L tBuOH, andKOtBu (30.7 g, 274 mmol). The mixture was warmed to 40°C stirred for 30 min to dissolve theKOtBu, and then tetraethylene glycol di(toluene-p-sulphonate) (46 g, 91.5 mmol, in 100 mLdioxane) and diethanolamine (9.6 g, 91.3 mmol, in 100 mL tBuOH) were added dropwise(simultaneously from two different dropping funnels) over the course of 2 h. Note: Slow additionof the solutions is crucial; the slower the addition, the higher the yield After addition, the reactionmixture was stirred for 1h and allowed to cool. The reaction mixture was then filtered twicethrough a Büchner funnel and the solvent was removed on a rotary evaporator. Deionized water(100 mL) was added to the brown, sticky residue and the resulting solution was first extracted withhexane (1×60 mL, hexane phase discarded), followed by CH2Cl2 (5×60 mL). The CH2Cl2 phaseswere collected, dried over MgSO4, and solvent was removed on a rotary evaporator. The resultingdark brown residue was distilled through a bulb-to-bulb distillation under high static vacuum usinga heat gun to yield the product as a colorless liquid (8.4 g, 35%). The NMR spectra are consistentwith published data. We have found that the tBuOH used in this preparation can be distilled andre-used for subsequent azacrown syntheses despite the presence of small amounts of dioxane(<5%).
30%
With potassium <i>tert</i>-butylate In 1,4-dioxane; <i>tert</i>-butyl alcohol for 12h;
24%
With sodium t-butanolate In 1,4-dioxane; <i>tert</i>-butyl alcohol at 20 - 40℃; for 1h;
With potassium <i>tert</i>-butylate In <i>tert</i>-butyl alcohol at 40℃; Yield given;
<i>N</i>,<i>N</i>-diethyl-4-(1,4,7,10,13-pentaoxa-16-aza-cyclooctadec-16-yl)-benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
Stage #1: 1-aza-18-crown-6 With n-butyllithium In tetrahydrofuran; hexane cooling;
Stage #2: N,N-diethyl-4-fluorobenzenesulfonamide In tetrahydrofuran; hexane at 20℃;
3-(1,4,7,10,13-pentaoxa-16-aza-cyclooctadec-16-yl)-propionic acid 3-(3-1,4,7,10,13-pentaoxa-16-aza-cyclooctadec-16-yl-propionyloxy)-2,2-bis-(3-1,4,7,10,13-pentaoxa-16-aza-cyclooctadec-16-yl-propionyloxymethyl)-propyl ester[ No CAS ]
3-(1,4,7,10,13-pentaoxa-16-aza-cyclooctadec-16-yl)-propionic acid 2,2-bis-(3-1,4,7,10,13-pentaoxa-16-aza-cyclooctadec-16-yl-propionyloxymethyl)-butyl ester[ No CAS ]
With sodium hydroxide In ethanol at 0 - 5℃; for 2 - 3h;
VI
To a cold solution of 1-aza-18-crown-6 (0.276 g, 95%, 1.0 mmol) and sodium hydroxide (0.04 g, 1.0 mmol) in 3 mL of ethanol was added carbon disulfide (0.076 g, 1.0 mmol) dropwise. The resulting mixture was stirred at 0-5 °C for another 2-3 h. Upon addition of 20 mL of diethyl ether with vigorous stirring, a white precipitate was formed, which was isolated by decanting the upper supernatant. Then it was washed twice with ether (2 x 10 mL) and dried under vacuum to give the product as a white solid (0.32 g, yield 84%).'H NMR (D2O, chemical shift 5 in ppm): 4.19 (t, 4H, J = 6.0 Hz), 3.70 (t, 4H, J = 6.0 Hz), and 3.52 (m, 16H). 13C NMR (D2O, DMSO-d6 as internal reference, chemical shift 5 in ppm): 205.7 (C=S), 71.9, 70.9 (m), 69.5, 56.7 (crown ether ring carbons).
16-(prop-2-ynyl)-1,4, 7, 10, 13-pentaoxa-16-azacyclooctadecane (29)29The synthesis followed the literature according to a modified procedure. Monoaza-18-crown-6 ether22 (0.6 g, 2.28 mmol) and propargylbromide (0.206 ml, 2.74 mmol) were dissolved in dry acetonitrile (70 ml) before CS2CO3 (1 .48 g, 4.56 mmol) was added. The suspension was stirred overnight at 85°C. After cooling to room temperature, the suspension was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with CHC /MeOH (9/1 v/v) yielding 29 as a red oil (64 %)1H NMR (CDCI3, 300 MHz): δ = 2.18 (t, 1 H, J = 2,45Hz), 2.82 (t, 4H, J = 5.28Hz), 3.61 -3.74 (m, 22H); 13C (CDCI3, 75 MHz): δ = 43.42, 53.29, 68.94, 70.52, 73.61 , 78.85; IR (ATR, cm"1): 1 1 15, 2867, 3189; HRMS (+ESI): m/z calcd. for (M+H)+,302.20; found, 302.21 .
Stage #1: di-<i>tert</i>-butyl dicarbonate With C12H24KO6(1+)*Br3H(1-) In ethanol at 20℃; for 0.0166667h;
Stage #2: 1-aza-18-crown-6 In ethanol at 20℃; for 0.0833333h;
For the N-boc protection of amines, to solution of diboc (1 mmol) in ethanol (5 ml) was added {K*18-crown-6]Br3}n (0.001 mmol). The solution was stirred at room temperature for 1 min. The amine (1 mmol) was then added and solution as stirred at room temperature for an appropriate time (table 1). After completion of the reaction, the solvent was removed by water bath distillation. To the residue was added ethyl acetate (5 ml) and the mixture was filtered (the catalyst is insoluble in n-hexane and ethyl acetate). The solid was washed with ethyl acetate ()10 ml*2) amd combined filtrates were reduced to dryness to yield the pure products.
83%
With [H2-cryptand 222](Br3)2 In acetonitrile at 20℃; for 0.16h; chemoselective reaction;
With triethylamine In N,N-dimethyl-formamide at 50℃;
4.2.3. Preparation of 5
Compound 4 (1.94 g, 2.86 mmol), 1-aza-18-crown-6 (752 mg, 2.86 mmol) and triethylamine (0.398 cm3, 2.86 mmol) were dissolved in dry DMF (500 cm3). The solution was stirred overnight at 50 °C. The solvent was removed under vacuo, then CH3CN (30 cm3) was added to the residue and the mixture stirred for more 30 min. After cooling the mixture to 0 °C, a white precipitate was collected by filtration, washed three times with diethyl ether and dried in vacuo. This operation was repeated twice giving 5 as a white powder (1.90 g, 77%). Found: C, 56.92; H, 6.35; N, 7.98. Calcd for C41H59N5O5Br2: C, 57.14; H, 6.90; N, 8.13%. δH (400.13 MHz; D2O; Me3Si(CH2)3SO3Na) 3.12 (4H, m, CH2Nether), 3.30-3.90 (38H, m, CH2Ncyclen+CH2Oether+CH2Nether), 4.36 (2H, m, CH2Ncyclen), 4.80-5.10 (4H, m, Haminal+CH2Ncyclen), 7.58-7.68 (7H, m), 7.97 (2H, d, 3J=8.6 Hz), 8.04 (1H, d, 3J=7.5 Hz), 8.13 (1H, s). δC (100.61 MHz; D2O; Me3Si(CH2)3SO3Na) 42.7, 42.8, 46.1, 52.5, 54.0, 54.7, 54.8, 55.0 (CH2N), 60.2, 61.1, 63.5 (CBn), 69.4, 69.5 (2C), 69.6, 69.8 (CH2O), 77.7, 77.9 (Caminal), 123.5, 127.5, 127.8 (2C), 128.1, 128.2, 128.4, 129.6 (2C), 132.6, 132.7, 133.1, 133.2, 133.8 (Car). m/z (ESI-MS; CHCl3; positive ion mode) 861.9 [MBr2+H]+, 782.2 [MBr]+, m/z 700.1 [M-H]+.
With sodium carbonate In acetonitrile at 20℃; for 24h; Inert atmosphere; Reflux;
3 4.3 1,3,5-Tris[(1′-aza-4′,7′,10′,13′,16′-pentaoxaoctadec-1′-yl)methyl]benzene (7)16
A mixture of 1 (0.20 g, 0.56 mmol), 1-aza-18-crown-6 (0.50 g, 1.9 mmol) and sodium carbonate (0.52 g, 5.0 mmol) in dry acetonitrile (15 mL) was stirred at room temperature under an atmosphere of nitrogen for 20 h. The mixture was then heated at reflux for 4 h. After cooling, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (9:1 v/v chloroform/methanol elution), to give 7 (0.47 g, 93%) as a yellow oil. Found: [M+H]+, 904.5741. C45H82N3O15 requires 904.5746; found: C, 55.2; H, 8.8; N, 4.3. C45H81N3O15·4H2O requires C, 55.4; H, 9.2; N, 4.3%; 1H NMR (300 MHz, CD3OD) δ 7.26 (s, 3H), 3.73-3.63 (complex m), 2.80 (t, J=5.3 Hz, 12H); 13C NMR (75.5 MHz, CD3OD) δ 139.7 (C), 130.6 (CH), 71.6 (CH2), 71.5 (CH2), 71.3 (CH2), 70.3 (CH2), 60.5 (CH2), 54.7 (CH2), one signal obscured or overlapping; IR νmax (NaCl)/cm-1 3495 (m), 2867 (s), 1116 (s); MS (ESI) m/z 927 [(M+Na)+, 10%] 905 (100) 657 (10)
With sodium carbonate In acetonitrile at 20℃; for 24h; Inert atmosphere; Reflux;
5 4.5 1,3,5-Tris[(1′-aza-4′,7′,10′,13′,16′-pentaoxaoctadec-1′-yl)methyl]-2,4,6-trimethylbenzene (9)
A mixture of 2 (0.13 g, 0.33 mmol), 1-aza-18-crown-6 (0.27 g, 1.03 mmol) and sodium carbonate (58 mg, 0.55 mmol) in dry acetonitrile (15 mL) was stirred at room temperature under an atmosphere of nitrogen for 20 h. The mixture was then heated at reflux for 4 h. After cooling, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (9:1 v/v chloroform/methanol elution), to give 9 (0.29 g, 95%) as a pale yellow oil. Found: (M+H)+, 946.6211. C48H88N3O15 requires 946.6215; found: C, 60.75; H, 9.49; N, 4.36. C48H87N3O15·0.25H2O requires C, 60.64; H, 9.28; N, 4.42%; 1H NMR (300 MHz, CD3OD) δ 3.74-3.52 (complex m, 66H), 2.72 (t, J=5.8 Hz, 12H), 2.47 (s, 9H); 13C NMR (75.5 MHz, CD3OD) δ 138.8 (C), 134.6 (C), 71.9 (CH2), 71.8 (CH2), 71.7 (CH2), 71.3 (CH2), 55.4 (CH2), 54.7 (CH2), 17.2 (CH3), one signal overlapping; IR νmax (NaCl)/cm-1 3511 (w), 2864 (s), 1119 (s); MS (ESI) m/z 948 [(M+H)+, 40%] 947 (100) 684 (10).
With sodium carbonate; In acetonitrile; at 20℃; for 24h;Inert atmosphere; Reflux;
A mixture of 3 (1.00 g, 2.27 mmol), 1-aza-18-crown-6 (1.84 g, 6.99 mmol) and sodium carbonate (2.94 g, 27.7 mmol) in dry acetonitrile (15 mL) was stirred at room temperature under an atmosphere of nitrogen for 20 h. The mixture was then heated at reflux for 4 h. After cooling, the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (9:1 v/v chloroform/methanol elution), to give 11 (2.08 g, 93%) as a pale yellow oil. Found: (M+H)+, 988.6680. C51H94N3O15 requires 988.6685; found: C, 58.7; H, 9.2; N, 4.0. C51H93N3O15.3H2O requires C, 58.8; H, 9.6; N, 4.0%; 1H NMR (300 MHz, CD3OD) delta 3.70-3.52 (complex m, 66H), 3.10 (q, J=7.3 Hz, 6H) 2.75 (t, J=5.5 Hz, 12H), 1.09 (t, J=7.3 Hz, 9H); 13C NMR (75.5 MHz, CD3OD) delta 146.1 (C), 133.3 (C), 71.9 (CH2), 71.75 (CH2), 71.71 (CH2), 71.4 (CH2), 54.8 (CH2), 53.8 (NCH2), 23.2 (CH2), 16.5 (CH3), one signal overlapping; IR numax (NaCl)/cm-1 3459 (s), 2867 (s), 1117 (s); MS (ESI) m/z 991 [(M+H)+, 15%] 990 (100) 726 (5), 462 (3).
With caesium carbonate In toluene at 80℃; for 24h;
General procedure: The syntheses of 1-(1,4,7-trioxa-10-azacyclododecan-10-yl)-9,10-anthraquinone (A12C4AQN) and 1-(1,4,7,10,13-pentaoxa-16-azacyclooctadecan-16-yl)-9,10-anthraquinone (A18C6AQN) were performed according to analogous procedure as for A15C5AQN. For A12C4AQN to asolution of 1-fluoro-9,10-anthraquinone (710 mg, 3.138 mM) and cesium carbonate (1.859 g, 5.706 mM) in 20 mL of toluene, 1,4,7-trioxa-10-azacyclododecane (500 mg,2.853 mM) was added. For A18C6AQN to a solution of 1-fluoro-9,10-anthraquinone (473 mg, 2.090 mM) and cesium carbonate (1.238 g, 3.800 mM) in 15 mL of toluene, 1,4,7,10,13-pentaoxa-16-azacyclooctadecane (500 mg, 1.900 mM) was added. The reaction mixture was stirred at 80 °C for 24 h. The resulting mixture was cooled to room temperature, filtered, and washed with dichloromethane. The solvents were removed in vacuo and the residuewas dissolved in 150 mL of dichloromethane. The solution was washed with 40% solution of tetrabutylammonium hydroxide in water (1100 mL) and with water (1100 mL).The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure,obtaining a red solid residue. The crude product was purified by flash chromatography (SiO2, eluent : dichloromethane : methanol, 50 : 2 v/v) to afford 774 mg (yield : 71%) as a red solid for A12C4AQN and 723 mg (yield : 83%) as a red solid for A18C6AQN.
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 16h;
4 General procedure for the alkylation of an amine by 3-bromoacetyltetronic acid
General procedure: To a solution of amine (0.45mmol, 1equiv) in DMF (3mL) was added K2CO3 (188mg, 1.36mmol, 4equiv). After cooling at 0°C, a solution of 3-bromoacetyltetronic acid 1 (221mg, 1mmol, 2.2equiv) in DMF (2mL) was added dropwise. The reaction mixture was stirred at 0°C for 1h and at room temperature for 15h. Solvent was removed under vacuum and the residue was purified by reversed phase chromatography (aqueous 0.01N HCO2NH4 buffer, pH 9/MeOH 100/0 to 80/20) to afford the desired product.
Stage #1: C73H80N4O8 With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 5h;
Stage #2: 1-aza-18-crown-6 With triethylamine In dichloromethane at 20℃;
2.1. General procedure for the synthesis of metalloporphyrin receptors
General procedure: 2.1. General procedure for the synthesis of metalloporphyrin receptorsTo a solution of porphyrin acid 5 in dichloromethane oxalylchloride and several drops of DMF were added. The mixture wasstirred at room temperature for 5 h. After evaporating the solventsunder vacuum, the residue was dissolved in dichloromethane andthen aza-crown ether and triethyl amine were added and stirredovernight at room temperature. After removal of solvent, theresulting residue was purified by column chromatography to affordaza-crown ether porphyrin. The free base porphyrin was dissolved indichloromethane/methanol (3:1) and zinc acetate was added withstirring. The mixture was stirred under reflux overnight. The solventwas removed in vacuo and the resulting residue was subjected tocolumn chromatography to afford metalloporphyrin receptor as apurple solid in high yield (Scheme 2).;_This compound was prepared (71%) as purple solid from the reaction ofcompound 7 and aza-18-crown-6 by a method analogous to compound 10. Mp > 230 °C. 1H NMR (300 M,CDCl3): d -2.67 (s, 2 H), -1.17 (br, 4 H), -0.82 (br, 4 H), -0.53 (br, 4 H), 0.67(br, 4 H), 0.91 (t, 6 H), 1.24-1.43 (m, 20 H), 1.92 (p, 4 H), 3.43-3.88 (m, 24H), 4.50 (t, J = 6.75 Hz, 4 H), 7.28 (m, 1 H), 7.46 (m, 1 H), 7.76 (m, 1 H),7.90 (m, 1 H), 8.14 (m, 2 H), 8.32 (m, 1 H), 8.44 (m, 8 H), 8.81 (d-d, J = 4.95Hz and 22.6 Hz, 8 H).13CNMR (400 M, CDCl3):d 14.1, 22.7, 25.1, 26.2, 29.1,29.3, 29.4, 29.7, 31.9, 65.4, 70.4, 112.8, 113.8, 116.3, 117.7, 119.4, 119.9, 127.6,128.9, 129.5, 129.8, 131.4, 131.6, 131.8, 132.1, 134.3, 134.7, 147.8, 149.5, 150.5,150.9, 159.8, 160.5, 167.0, 171.8, 172.0. MS (MALDI-TOF) (m/e): 1387 (M+H+).
Stage #1: 1-aza-18-crown-6; 2,3-dichloro-5,6-dicyanopyrazine In tetrahydrofuran for 0.0833333h; Cooling;
Stage #2: With potassium carbonate In tetrahydrofuran at 20℃; for 2h;
2.2 2.2.2 5-chloro-6-(1,4,7,10,13-pentaoxa-16-azacyclooctadecan-16-yl)pyrazine-2,3-dicarbonitrile (2c)
5,6-dichloropyrazine-2,3-dicarbonitrile (600 mg, 3.02 mmol) was dissolved in THF (50 mL), and the solution was cooled down in a NaCl/ice bath. Then, a cold solution of 1-aza-18-crown-6 (790 mg, 3.00 mmol) in THF (15 mL) was slowly added, the mixture was stirred for 5 min. Finely ground anhydrous K2CO3 (542 mg, 3.92 mmol) was added in one portion and suspension was stirred for another 2 h at rt. THF was evaporated, chloroform (50 mL) and one drop of hydrochloric acid were added and the product was washed three times with brine (3 * 50 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered and evaporated to dryness. The product was purified by column chromatography on silica with diethyl ether/acetone 2:1 (Rf of 2b = 0.28) as the eluent. Yield: 1.02 g (79%) of light yellow oil; 1H NMR (500 MHz, CDCl3, 25 °C): δ = 3.61-3.67 (m, 16 H, crown-H), 3.82 (t, J = 6 Hz, 4 H, crown-H) and 4.10 ppm (t, J = 6 Hz, 4 H, crown-H); 13C NMR (125 MHz, CDCl3, 25 °C): δ = 51.9, 69.2, 70.52, 70.56, 70.65, 70.73, 112.9, 113.1, 117.9, 129.0, 135.6 and 152.0 ppm; IR (ATR): 2868, 2228 (CN), 1549, 1441, 1384, 1350, 1299, 1233, 1118, 1045, 987 and 944 cm-1; HR MS (ESI+): calcd for C18H24ClN5O5m/z = 426.1539 [M+H]+; found m/z = 426.1543 [M+H]+.
Stage #1: 1-aza-18-crown-6 With sodium hydride In tetrahydrofuran at 0℃; for 0.0833333h; Schlenk technique; Inert atmosphere;
Stage #2: C77H98ClN2OP In tetrahydrofuran at 0 - 20℃; for 18h; Schlenk technique; Inert atmosphere;
General procedure for the amination of phosphane oxide 11
General procedure: The amine is placed in a Schlenk tube under argon containing distilled THF (1 equiv., 0.04 M) and the solution was cooled to 0 °C. Sodium hydride (1.3 equiv.) was added and the reaction mixture stirred at 0 °C for 5 min. Phosphane oxide 11 (1 equiv., 0.04 M) in distilled THF is added dropwise. The reaction mixture was allowed to warm up to room temperature and stirred for 18 h. The reaction is quenched by addition of water and extracted with CH2Cl2. The organic layer is dried over MgSO4 and the solvents removed under reduced pressure.
With triethylamine In dichloromethane at 0 - 20℃; Cooling with ice;
97%
With triethylamine In dichloromethane at 0 - 20℃; for 24.5h;
3.2. General Procedure A-For Preparation of Compounds 1a-3a
General procedure: Firstly, 1-aza-18-crown-6 (0.72 g, 2.69 mmol) at 0 °C (ice bath) was added to a solution ofcorresponding nitrobenzoyl chloride (0.36 mL, 2.72 mmol) and TEA (0.38 mL, 2.72 mmol) in DCM(20 mL). The reaction mixture was stirred for 30 min and then left at room temperature (r.t.) overnight.The organic phase was then washed with distilled water (2 x 30 mL), 1 M HCl (30 mL), saturatedaqueous solution of NaHCO3 (30 mL), and dried over MgSO4. After evaporation of DCM, the residuewas purified by silica gel column chromatography using a mixture of MeOH in CHCl3 (5:95 v/v) togive the title product as a colorless oil.
With potassium carbonate; potassium iodide In tetrahydrofuran at 66℃; for 72h;
With triethylamine In dichloromethane at 0 - 20℃; for 24.5h;
3.2. General Procedure A-For Preparation of Compounds 1a-3a
General procedure: Firstly, 1-aza-18-crown-6 (0.72 g, 2.69 mmol) at 0 °C (ice bath) was added to a solution ofcorresponding nitrobenzoyl chloride (0.36 mL, 2.72 mmol) and TEA (0.38 mL, 2.72 mmol) in DCM(20 mL). The reaction mixture was stirred for 30 min and then left at room temperature (r.t.) overnight.The organic phase was then washed with distilled water (2 x 30 mL), 1 M HCl (30 mL), saturatedaqueous solution of NaHCO3 (30 mL), and dried over MgSO4. After evaporation of DCM, the residuewas purified by silica gel column chromatography using a mixture of MeOH in CHCl3 (5:95 v/v) togive the title product as a colorless oil.
With dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃;
To a solution of Boc-4-nitro-L-phenylalanine (620 mg, 2.00 mmol) and 1,3-dicyclohexylocarbodiimide (DCC) (430 mg, 2.09 mmol) in 10 ml of dry dichloromethane 526 mg, 2.00 mmol of 1-aza-18-crown-6 in 10 ml of dry dichloromethane at 0 C (ice bath) was added. The reaction mixture was stirred for 30 min and then left at room temperature overnight. The precipitate was filtered off, washed with dichloromethane and solvent was evaporated. The residue was purified by silica gel column chromatography (2% methanol in chloroform) to give the title product as a colorless oil (788 mg, 71% yield).
Stage #1: Boc-Arg(Z)2-OH With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;
Stage #2: 1-aza-18-crown-6 In N,N-dimethyl-formamide at 5 - 20℃; Inert atmosphere;
4.1. Boc-Arg-(diZ)-1-aza-18-crown-6 (2)
Boc-Arg-(diZ)-OH (3 g, 5.53 mmol) was dissolved in 50 ml of anhydrous DMF. To this solution of coupling reagent HATU (2.52 g, 6.65 mmol, 1.2 eq) and of N,N-diisopropylethylamine (2.7 mL, 16.6 mmol, 3 eq) were added. The resulting mixture was stirred under argon at room temperature for one hour. After this time the solution became orange. This mixture was then cooled to 5 °C in an ice/water bath and solution of 1-aza-18-crown-6 (1.50 g, 5.53 mmol, 1 eq) in DMF (5 ml) was added dropwise. The reaction mixture was then stirred overnight at room temperature under argon atmosphere (the solution became dark orange). TLC analysisin 10% MeOH/DCM confirmed the formation of the desired product. TLC plate was visualized in a solution of ninhydrin, product spot (Rf = 0.63) tinged brown. Then, the solvent was evaporated and the residue (dark oil) was re-dissolved in 80 ml of CHCl3 and washed three times with distilled water. The combined aqueous phases were back extracted with CHCl3 (2 x 20 mL). The organic phases were combined and dried over MgSO4, filtered, and the solvent was evaporated. The dark brown oil obtained was purified by column chromatography with 2% methanol/chloroform to give a Boc-Arg-(diZ)-1-aza-18-crown-6 (2) (3.65 g, 5,08 mmol) as oil in 92% yield. 1H NMR 300 MHz in CDCl3 δ (ppm): 1.38 (s, 9H, tert-butyl group), 1.67-1.63 (m, 4H, β-CH2 and γ-CH2), 3.54-3.59 (m, 24H, crown ether), 3.98-3.89 (m, 2H, δ-CH2), 4.55-4.59 (m, 1H, α-CH), 5.10 (s, 2H, CH2 -Cbz group), 5.21 (s, 2H, CH2-Cbz), 5.27 (s, 1H, NH α-C), 7.26-7.39 (m, 10H, Ar-Cbz), 9.25 (s, 1H, NH guanidine group), 9.42 (s, 1H, NH guanidine group). 13C NMR 75 MHz in CDCl3 δ (ppm): 14.4 (Cb), 25.0 (Cγ), 28.5 (tert-butyl group), 31.0 (Cδ), 44.7, 47.2, 48.9 (crown ether), 50.2 (Cα), 67.2 (CH2-Cbz), 69.7 (CH2-Cbz), 70.763, 70.8, 70.9 (crown ether),79.6 (tert-butyl group), 128.0, 128.5, 128.6, 129.0, 134.887, 137.112 (Ar-Cbz), 156.072, 164.057 (C=O), 160.680 (C guanidine group), 172.704 (C=O).
General procedure: N-Phenylaza-crown ether conjugates (1-8) are new compounds that were synthesized as follows. To a solution of 3.8mmol of an appropriate aza-crown ether (1.00g of 1-aza-18-crown-6 or 0.83g of 1-aza-15-crown-5) in 50ml of dry diethyl ether, a portion of 3.8mmol of fluoronitroarene was added (0.81g of pentafluoronitrobenzene (for ligand 8), 0.74g of 2,3,4,6-tetrafluoronitrobenzene (for ligands 1-6) or 0.74g of <strong>[5580-79-0]2,3,4,5-tetrafluoronitrobenzene</strong> (for ligand 7)). The mixture obtained was refluxed over 24h. Then the solvent was evaporated and the products were purified by column chromatography on silica, using hexane-chloroform (1:1v/v) or chloroform as eluents.
(2-(1,4,7,10,13-pentaoxa-16-azacyclooctadecan-16-yl)pyrimidin-4-yl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90 - 105℃; for 6h; Sealed tube; Microwave irradiation;
116.116A (2-(1,4,7,10,13-pentaoxa-16-azacyclooctadecan-16-yl)pyrimidin-4-yl)methanol
A 10 mL microwave tube was charged with (2-chloropyrimidin-4-yl)methanol (140 mg), 1 ,4,7, 10, 13 -pentaoxa- 16-azacyclooctadecane (265 mg) and acetonitrile (5 mL). NJN-Diisopropylethylamine (0.25 mL) was added, the vessel was capped and heated in a Biotage microwave for 2 hours to 90 °C and for 4 hours to 105 °C. Water (5 mL) and dichloromethane (50 mL) were added, the mixture stirred for 10 minutes, the layers separated via Chromabond PTS cartridge and the organic layer concentrated in vacuo. Purification by chromatography using an ISCO CombiFlash Companion MPLC (24 g RediSep Gold column, eluting with 0-50% dichloromethane/methanol; in a second step 15 g Chromabond RP-C18 column, eluting with 0-100% water/acetonitrile) gave the title compound. MS (APCI) m/z 372.2 (M+H)+.
With triethylamine In dichloromethane at 0 - 20℃; for 24.5h;
3.2. General Procedure A-For Preparation of Compounds 1a-3a
General procedure: Firstly, 1-aza-18-crown-6 (0.72 g, 2.69 mmol) at 0 °C (ice bath) was added to a solution ofcorresponding nitrobenzoyl chloride (0.36 mL, 2.72 mmol) and TEA (0.38 mL, 2.72 mmol) in DCM(20 mL). The reaction mixture was stirred for 30 min and then left at room temperature (r.t.) overnight.The organic phase was then washed with distilled water (2 x 30 mL), 1 M HCl (30 mL), saturatedaqueous solution of NaHCO3 (30 mL), and dried over MgSO4. After evaporation of DCM, the residuewas purified by silica gel column chromatography using a mixture of MeOH in CHCl3 (5:95 v/v) togive the title product as a colorless oil.
With potassium carbonate In tetrahydrofuran at 80℃; for 12h; Inert atmosphere;
83%
With potassium carbonate In tetrahydrofuran at 80℃; for 24h; Inert atmosphere;
10 Synthesis of compound 14
Compound 13 (1.0 g, 2.18 mmol), potassium carbonate (336mg, 2.4mmol) was added to a 50mL two-necked flask and ventilated three times under the protection of argon. Add 20 mL of tetrahydrofuran, heat to 80°C, slowly add 1-aza-18-crown-6 (574 mg, 518 mmol) in tetrahydrofuran solution (10 mL) dropwise, and react for 24 hours. After the reaction, the reaction solution was cooled to room temperature, purification by direct column chromatography (eluent: dichloromethane: methanol = 15:1), compound 21 was obtained as a pale yellow liquid (996 mg, 83%).
16,16-di(octan-3-yl)-1,4,7,10,13-pentaoxa-16-azacyclooctadecan-16-ium chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
for 24h; Reflux;
1 Route A:
3-(chloromethyl)heptane was added to a solution of 1-aza-18-crown-6 as a solvent. The mixture was heated to reflux and was reacted for about 24 hours. 16,16-di(octan-3-yl)-1,4,7,10,13 -pentaoxa-16-azacyclooctadecan-16-ium chloride salt was obtained
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