* 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.
With manganese(IV) oxide In N,N-dimethyl-formamide at 28℃; for 2 h;
8.4 mmol of bromopropyne and 8.4 mmol of phthalimide potassium salt were added to 10 mL of N,N-dimethylformamide. Further, 0.2 g of manganese dioxide solid was added. The reaction at a temperature of 28°C for 2h; After adding 100 mL of ethyl acetate, the organic layer was collected by washing with water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and separated by a column. The eluent was selected by petroleum ether-ethyl acetate 5: 1 (v: v) to seperate and purify to obtain pure B.
90%
at 80℃; for 8 h;
Preparation 2:; 2-Prop-2-ynyl-isoindole-1, 3-dione; A mixture of potassium phthalimide (10 grams, 54 mmol) and propargyl bromide (7.65 grams, 65 mmol) was heated in dimethyl formamide (DMF) (50 mL) at 80 °C for 8 hours. The reaction mixture was then poured into ice cold water. White solid obtained was filtered on a Buchner funnel and washed with water and dried (yield is 8.95 grams, 90percent). Melting Point : 138°C. 'H NMR (CDC13) : 6 7.95-7. 85 (m, 2H), 7.75-7. 68 (m, 2H), 4.46 (d, J = 2.5 Hz, 2H), 2.23 (t, J= 2. 5 Hz, 1H). IR (KBr, cm-1): 3294,2925, 1771,1725, 1397. CI-MS (m/z) : 186 (M++1), 148.
80%
at 0 - 20℃;
Step 2: Preparation of acetylene 4: To an ice cold mixture of propargyl bromide (50 g of an 80percent solution in toluene, 336 mmol) in DMF (200 mL) under argon was added potassium phthalimide (64.7 g, 350 mmol) via a funnel. The runnel was rinsed with additional DMF (50 mL). The reaction mixture was allowed to warm to room temperature and then stirred overnight. After solids were removed from the mixture by filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and water and the combined organics were washed with water and saturated aqueous NaHCO3 and dried over MgSO4. The solution was concentrated under reduced pressure to give <n="148"/>an off-white solid. The product was suspended in water, sonicated and the resulting solid was collected by filtration. After drying under vacuum, the solid was triturated with hexanes, collected by filtration and dried to give acetylene 4 as a slightly off-white solid. Yield (49.7 g, 80percent): 1H NMR (400 MHz, DMSO- d6) δ 7.85-7.93 (m, 4H), 4.38 (d, J= 6.0 Hz, 2H), 3.26-3.34 (m, IH).
72%
at 0 - 70℃; for 8 h;
32.3 g (271 mmol) 3-bromopropine are dissolved in 150 ml DMF and 50.3 g (271 mmol) phthalimide potassium salt are added under ice cooling. The suspension is warmed at 70° C. for eight hours. The mixture is concentrated under a vacuum and the residue is distributed between acetic acid ethyl ester and water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is crystallized from acetic acid ethyl ester: Yield 36.4 g (72percent) colorless crystals.
3.15 g
for 5 h; Reflux
Propargyl bromide (1.3 mL, 17.4 mmol) is dissolved in DMF (30 mL) and potassium phtalimide (3.4 g; 18.4 mmol) is added. The mixture is refluxed for 5 h. After cooling at room temperature the mixture is diluted with diethyl ether, washed with water (3x50 mL), dried over Na2SO4 and evaporated under vacuum to give N-propargyl phtalimide as white solid (3.15 g; 17 mmol).
Reference：
[1] Patent: CN105669525, 2016, A, . Location in patent: Paragraph 0062; 0063; 0082
[2] Molecular Crystals and Liquid Crystals Science and Technology Section A: Molecular Crystals and Liquid Crystals, 2002, vol. 377, p. 13 - 18
[3] Phosphorus, Sulfur and Silicon and the Related Elements, 2004, vol. 179, # 8, p. 1611 - 1614
[4] Patent: WO2005/82892, 2005, A2, . Location in patent: Page/Page column 58-59
[5] European Journal of Organic Chemistry, 2017, vol. 2017, # 27, p. 3941 - 3946
[6] Patent: WO2009/45479, 2009, A1, . Location in patent: Page/Page column 145-146
[7] Patent: US6903118, 2005, B1, . Location in patent: Page/Page column 165
[8] Angewandte Chemie - International Edition, 2011, vol. 50, # 32, p. 7354 - 7358
[9] Tetrahedron Asymmetry, 1998, vol. 9, # 24, p. 4419 - 4428
[10] Heterocycles, 2010, vol. 80, # 2, p. 989 - 1002
[11] Journal of the American Chemical Society, 2018, vol. 140, # 27, p. 8448 - 8455
[12] Nippon Kagaku Zasshi, 1955, vol. 76, p. 1404[13] Chem.Abstr., 1957, p. 17760
[14] Annales de Chimie (Cachan, France), 1956, vol. <13>1, p. 161,184,186
[15] Patent: EP1366018, 2016, B1, . Location in patent: Paragraph 0096
[16] Synthetic Communications, 2017, vol. 47, # 7, p. 722 - 733
2
[ 136918-14-4 ]
[ 106-96-7 ]
[ 7223-50-9 ]
Yield
Reaction Conditions
Operation in experiment
89%
With potassium carbonate In acetonitrile for 48 h; Reflux
Propargyl bromide (1 mL, 11.6 mmol) was added to a solution of phthalimide (1 g, 6.8 mmol) and K2CO3 (1.4 g, 10.2 mmol) in CH3CN (25 mL). The reaction mixture was heated at reflux for 48 h and the hot mixture was filtered and cooled at room temperature, the solid was washed with CH3CN (3 × 5 mL), the organic phases were combined and filtered through celite, the solvent was removed in vacuo and the product was purified by crystallisation to afford a white solid (1.12 g, 89percent); m.p. 142–143 °C (lit. 141–143 °C); 20 FTIR (ATR, cm–1): 2145, 1768, 1712, 1468, 1395; 1H NMR (300 MHz, CDCl3) δ 8.15 – 7.75 (m, 4H), 4.60 (dd, J = 2.5, 0.4 Hz, 2H), 2.36 (td, J = 2.5, 0.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.9 (2 × C), 134.2 (2 × CH), 132.0 (2 × C), 123.5 (2 × CH), 77.0 (C), 71.4 (CH), 26.9 (CH2); MS [EI+] m/z (percent): 185 [M]+ (55), 157 [M – CO]+ (40), 129 [C8H4NO] (40), 102 [C7H2O] (60), 76 [C6H4] (100).
89%
With potassium carbonate In acetone for 16 h; Reflux
To a 100 mL round-bottom flask containing vaniline (0.800 g, 5.26 mmol) dissolved in acetone (40 mL), it was added potassium carbonate (1.45 g, 10.5 mmol) and propargyl bromide (957 μL, 10.5 mmol). The resulting mixture was refluxed for 24 h. After cooling to room temperature, it was added to the mixture cold water and CH2Cl2. The layers were separated and the aqueous phase was extracted with ethyl acetate (three times with portions of 30 mL). The organic extracts were combined and the resulting organic layer was washed with brine (25 mL), dried with anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with hexane-ethyl acetate (2:1 v/v). Compound 6 was obtained in 72percent yield (0.716 g, 3.77 mmol). The following data support the structure of compound 6.White solid. Mp 81.3-82.2 oC. TLC: Rf = 0.59 (hexane-ethyl acetate 2:1 v/v). 1H NMR (300 MHz, CDCl3) : 2.56 (t, 1H, J = 2.4 Hz), 3.92 (s, 3H, OCH3), 4.85 (d, 2H, J = 2.4 Hz), 4.85 (d, 1H, J = 8.1 Hz), 7.42-7.47 (m, 2H), 9.85 (s, 1H, CHO). 13C NMR (75 MHz, CDCl3) : 56.0, 56.5, 76.6, 77.4, 109.3, 112.4, 126.2, 130.8, 149.9, 152.0, 190.9 (CHO).
71%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;
General procedure: To a mixture of propargyl bromide (8.47 mmol) and secondary amine (16.94 mmol) in DMF, K2CO3(25.41 mmol) was added and the reaction mixture was allowed to stir at ambient temperature for 10-12 h. The reaction mixture was then quenched with ice cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure to obtain the corresponding products.
69%
With caesium carbonate In acetonitrile at 80℃; for 2 h;
Prepared by the method of Clayton (69percent):34 mp 146–148°C (Lit.36 149–150°C). The spectroscopic data was consistent with the literature:361H NMR (400MHz, CDCl3) δ 7.80–7.91 (m, 2H), 7.74–7.76 (m, 2H), 4.47 (s, 2H), 2.24 (s, 1H).
Reference：
[1] Organic and Biomolecular Chemistry, 2011, vol. 9, # 18, p. 6385 - 6395
[2] Journal of Chemical Research, 2016, vol. 40, # 5, p. 308 - 313
[3] Tetrahedron Letters, 2017, vol. 58, # 6, p. 590 - 595
[4] Angewandte Chemie - International Edition, 2011, vol. 50, # 15, p. 3552 - 3556
[5] Organic Letters, 2018, vol. 20, # 7, p. 2116 - 2119
[6] Angewandte Chemie - International Edition, 2018, vol. 57, # 24, p. 7140 - 7145[7] Angew. Chem., 2018, vol. 130, # 24, p. 7258 - 7263,6
[8] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 7, p. 1795 - 1801
[9] Tetrahedron, 2016, vol. 72, # 40, p. 6136 - 6141
[10] European Journal of Inorganic Chemistry, 2007, # 19, p. 3115 - 3123
[11] Journal of the Brazilian Chemical Society, 2013, vol. 24, # 6, p. 914 - 921
[12] Tetrahedron, 2005, vol. 61, # 36, p. 8705 - 8710
[13] Tetrahedron Letters, 2006, vol. 47, # 31, p. 5547 - 5551
[14] Journal of the Brazilian Chemical Society, 2011, vol. 22, # 3, p. 592 - 597
[15] Helvetica Chimica Acta, 2011, vol. 94, # 12, p. 2194 - 2206
[16] Tetrahedron Letters, 2014, vol. 55, # 4, p. 903 - 909
[17] Tetrahedron Letters, 2015, vol. 55, # 4, p. 903 - 909
[18] Journal of Enzyme Inhibition and Medicinal Chemistry, 2015, vol. 30, # 3, p. 377 - 382
[19] Biochemistry, 2017, vol. 56, # 49, p. 6491 - 6502
3
[ 85-44-9 ]
[ 2450-71-7 ]
[ 7223-50-9 ]
Yield
Reaction Conditions
Operation in experiment
60%
at 115℃; for 2 h; Dean-Stark
Phthalic anhydride (200 mg, 1 .35 mmol) was suspended in toluene (5 mL) and propargylamine (175 iL, 2.73 mmol) was added. The reaction mixture was heated underreflux (115°C) using Dean-stark apparatus. After 2 h the reaction was cooled to rt and concentrated in vacuo. The residue was dissolved in DCM (50 mL) and the organic phase washed with saturated aqueous sodium hydrogen carbonate (diluted 1 in 5, 50 mL). The aqueous layers were further extracted with DCM (2 x 20 mL) before passing through a phase separator cartridge (Biotage) and concentrated in vacuo. The resultingresidue was purified by flash column chromatography (Biotage Isolera Four, 25 g KP-Sil column, 10percent EtOAc I isohexane to 20percent EtOAc I isohexane)to afford the title compound as a white solid (150 mg, 0.81 mmol, 60percent).
With manganese(IV) oxide; In N,N-dimethyl-formamide; at 28℃; for 2h;
8.4 mmol of bromopropyne and 8.4 mmol of phthalimide potassium salt were added to 10 mL of N,N-dimethylformamide. Further, 0.2 g of manganese dioxide solid was added. The reaction at a temperature of 28C for 2h; After adding 100 mL of ethyl acetate, the organic layer was collected by washing with water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and separated by a column. The eluent was selected by petroleum ether-ethyl acetate 5: 1 (v: v) to seperate and purify to obtain pure B.
90%
In DMF (N,N-dimethyl-formamide); at 80℃; for 8h;
Preparation 2:; 2-Prop-2-ynyl-isoindole-1, 3-dione; A mixture of potassium phthalimide (10 grams, 54 mmol) and propargyl bromide (7.65 grams, 65 mmol) was heated in dimethyl formamide (DMF) (50 mL) at 80 C for 8 hours. The reaction mixture was then poured into ice cold water. White solid obtained was filtered on a Buchner funnel and washed with water and dried (yield is 8.95 grams, 90%). Melting Point : 138C. 'H NMR (CDC13) : 6 7.95-7. 85 (m, 2H), 7.75-7. 68 (m, 2H), 4.46 (d, J = 2.5 Hz, 2H), 2.23 (t, J= 2. 5 Hz, 1H). IR (KBr, cm-1): 3294,2925, 1771,1725, 1397. CI-MS (m/z) : 186 (M++1), 148.
80%
In N,N-dimethyl-formamide; toluene; at 0 - 20℃;
Step 2: Preparation of acetylene 4: To an ice cold mixture of propargyl bromide (50 g of an 80% solution in toluene, 336 mmol) in DMF (200 mL) under argon was added potassium phthalimide (64.7 g, 350 mmol) via a funnel. The runnel was rinsed with additional DMF (50 mL). The reaction mixture was allowed to warm to room temperature and then stirred overnight. After solids were removed from the mixture by filtration through Celite, the filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and water and the combined organics were washed with water and saturated aqueous NaHCO3 and dried over MgSO4. The solution was concentrated under reduced pressure to give <n="148"/>an off-white solid. The product was suspended in water, sonicated and the resulting solid was collected by filtration. After drying under vacuum, the solid was triturated with hexanes, collected by filtration and dried to give acetylene 4 as a slightly off-white solid. Yield (49.7 g, 80%): 1H NMR (400 MHz, DMSO- d6) delta 7.85-7.93 (m, 4H), 4.38 (d, J= 6.0 Hz, 2H), 3.26-3.34 (m, IH).
72%
In DMF (N,N-dimethyl-formamide); at 0 - 70℃; for 8h;
32.3 g (271 mmol) 3-bromopropine are dissolved in 150 ml DMF and 50.3 g (271 mmol) phthalimide potassium salt are added under ice cooling. The suspension is warmed at 70 C. for eight hours. The mixture is concentrated under a vacuum and the residue is distributed between acetic acid ethyl ester and water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is crystallized from acetic acid ethyl ester: Yield 36.4 g (72%) colorless crystals.
3.15 g
In N,N-dimethyl-formamide; for 5h;Reflux;
Propargyl bromide (1.3 mL, 17.4 mmol) is dissolved in DMF (30 mL) and potassium phtalimide (3.4 g; 18.4 mmol) is added. The mixture is refluxed for 5 h. After cooling at room temperature the mixture is diluted with diethyl ether, washed with water (3x50 mL), dried over Na2SO4 and evaporated under vacuum to give N-propargyl phtalimide as white solid (3.15 g; 17 mmol).
In water; at 140℃; for 0.15h;Microwave irradiation; Green chemistry;
General procedure: A mixture of a terminal alkyne (2.0 mmol), paraformaldehyde (180.2 mg, 2.0 mmol), amine (2 mmol) and Pt/TiO2 (5.0 mg, 0.25 mol%) loaded in distilled H2O (3 mL) and heated under microwave condition at 140 C and 250 W for appropriate reaction time (the reaction was monitored by TLC). After the completion of the reaction, the mixture was allowed to cool down and then extracted with EtOAc (3*20 mL). The combined organic extracts were dried (MgSO4) and fltered. The solvent was evaporated under reduced pressure and the resulting crude product was purifed by column chromatography (silica gel) to obtain the corresponding products 4a-4l.
In water; at 140℃; for 0.116667h;Microwave irradiation; Green chemistry;
General procedure: A mixture of a terminal alkyne (2.0 mmol), paraformaldehyde (180.2 mg, 2.0 mmol), amine (2 mmol) and Pt/TiO2 (5.0 mg, 0.25 mol%) loaded in distilled H2O (3 mL) and heated under microwave condition at 140 C and 250 W for appropriate reaction time (the reaction was monitored by TLC). After the completion of the reaction, the mixture was allowed to cool down and then extracted with EtOAc (3*20 mL). The combined organic extracts were dried (MgSO4) and fltered. The solvent was evaporated under reduced pressure and the resulting crude product was purifed by column chromatography (silica gel) to obtain the corresponding products 4a-4l.
0.5 g
With copper(l) chloride; In 1,4-dioxane; for 3h;Reflux;
N-propargyl phtalimide (0.64 g; 3.4 mmol) is dissolved in 1,4-dioxane (20 mL), then dimethylamine (8.5 mL; 17 mmol), copper (I) chloride (0.35 g) and paraformaldehyde (1g) are added. The solution is refluxed for 3h. After cooling at room temperature the formed precipitate is filtered off and the filtrate is evaporated under vacuum to give a green oily residue that, after dissolution in CH2Cl2, is washed with sat. sol. NaHCO3 (2x30 mL) and water (2x30 mL). The organic phase is dried over Na2SO4 and evaporated under vacuum. The crude product is purified by treatment with diethyl ether to give N-phtalimido-N',N'-dimethylbutin-2-yl-1,4-diamine as pale yellow solid (0.5 g; 2.05 mmol).
2-{3-[2-amino-7-(4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-4-oxo-4,7-dihydro-3<i>H</i>-pyrrolo[2,3-<i>d</i>]pyrimidin-5-yl]-prop-2-ynyl}-isoindole-1,3-dione[ No CAS ]
2-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
With copper(ll) sulfate pentahydrate; (E)-N-(1-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl][(2E)-2-(hydroxyimino)propyl]amino}propan-2-ylidene)hydroxylamine; sodium L-ascorbate; In methanol; water; at 20℃; for 3h;
General procedure: In 10 ml glass vial were placed azide (0.376 mmol)and acetylene (0.376 mmol) and MeOH (5 ml). Then a solution of TzbetaOx2 (0.0037 mmol in 150 ml MeOH), a solution of CuSO4?5H2O(0.0037 mmol, 0.94 mg in 50 ml H2O) and a solution of sodium ascorbate (3 mg, 0.016 mmolin 50 ml H2O) were added sequentially. The reaction mixture was kept under r.t. with occasional shaking until full consumption of starting compounds(TLC control). The resulting mixture was evaporated and target product was isolated according to one of the following procedures (see Table 2): Procedure (a). Water (7 ml) was added and mixture was sonicated in ultrasonic cleaning bath for 30-60 s. Precipitate was filtered, washed with water or aqueous methanol (50/50) and dried in vacuo (0.5Torr) until constant weight. Procedure (b). The residue was dissolved in minimal amount of CH2Cl2 and placed on short column (2.5 cm) filled with silicagel. Chromatography was performed with hexane/EtOAc or EtOAc/MeOH (for polarproducts) eluents. After evaporation product was dried in vacuo (0.5 Torr)until constant weight. Procedure (c). Water(4 ml) and EtOAc (4 ml) were added and the mixture was vigorously shaken. Organic layer was separated and filtered through Pasteur pipette equipped with anhydrous Na2SO4. Aqueous layer was extracted with EtOAc two times and collected organic fractions were evaporated. The residue was dried in vacuo(0.5 Torr) until constant weight.
76%
With copper(I) oxide; In dichloromethane; water; ethylene glycol; at 40℃; for 2h;
General procedure: In a 10 mL round bottom flask, it was added 0.5 mmol of azide, 0.6 mmol of terminal alkyne, 310 muL of Cu2O spheres suspended in ethylene glycol, 1 mL of distilled water and 1 mL of10dichloromethane. The resulting mixture was stirred at 40 oC until reaction completion, which was monitored by TLC analysis. Then, the mixture was extracted with ethyl acetate (three times with portions of 15 mL). The organic extracts were combined and the resulting organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluted with hexane-ethyl acetate-dichloromethane (3:1:3 v/v). Structures of compounds 10-18 are supported by the following data.
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;
A mixture of phthalimide (3) (0.01 mol), propargyl bromide (0.01 mol), and K2CO3 (0.02 mol) was stirred in DMF at room temperature. The progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction mixture was poured on crushed ice. The solid obtained was filtered, washed with water, and recrystallized from ethanol. Yield: 90%, M.P.: 151-153 C; White Solid. 1H NMR (300 MHz, CDCl3 DMSO-d6) delta ppm 3.17 (s, 1H), 4.43 (d, J3Hz, 2H), 7.78-7.83 (m, 2H), 7.85-7.90 (m, 2H).
89%
With potassium carbonate; In acetonitrile; for 48h;Reflux;
Propargyl bromide (1 mL, 11.6 mmol) was added to a solution of phthalimide (1 g, 6.8 mmol) and K2CO3 (1.4 g, 10.2 mmol) in CH3CN (25 mL). The reaction mixture was heated at reflux for 48 h and the hot mixture was filtered and cooled at room temperature, the solid was washed with CH3CN (3 × 5 mL), the organic phases were combined and filtered through celite, the solvent was removed in vacuo and the product was purified by crystallisation to afford a white solid (1.12 g, 89%); m.p. 142-143 C (lit. 141-143 C); 20 FTIR (ATR, cm-1): 2145, 1768, 1712, 1468, 1395; 1H NMR (300 MHz, CDCl3) delta 8.15 - 7.75 (m, 4H), 4.60 (dd, J = 2.5, 0.4 Hz, 2H), 2.36 (td, J = 2.5, 0.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) delta 166.9 (2 × C), 134.2 (2 × CH), 132.0 (2 × C), 123.5 (2 × CH), 77.0 (C), 71.4 (CH), 26.9 (CH2); MS [EI+] m/z (%): 185 [M]+ (55), 157 [M - CO]+ (40), 129 [C8H4NO] (40), 102 [C7H2O] (60), 76 [C6H4] (100).
89%
With potassium carbonate; In acetone; for 16h;Reflux;
To a 100 mL round-bottom flask containing vaniline (0.800 g, 5.26 mmol) dissolved in acetone (40 mL), it was added potassium carbonate (1.45 g, 10.5 mmol) and propargyl bromide (957 muL, 10.5 mmol). The resulting mixture was refluxed for 24 h. After cooling to room temperature, it was added to the mixture cold water and CH2Cl2. The layers were separated and the aqueous phase was extracted with ethyl acetate (three times with portions of 30 mL). The organic extracts were combined and the resulting organic layer was washed with brine (25 mL), dried with anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with hexane-ethyl acetate (2:1 v/v). Compound 6 was obtained in 72% yield (0.716 g, 3.77 mmol). The following data support the structure of compound 6.White solid. Mp 81.3-82.2 oC. TLC: Rf = 0.59 (hexane-ethyl acetate 2:1 v/v). 1H NMR (300 MHz, CDCl3) : 2.56 (t, 1H, J = 2.4 Hz), 3.92 (s, 3H, OCH3), 4.85 (d, 2H, J = 2.4 Hz), 4.85 (d, 1H, J = 8.1 Hz), 7.42-7.47 (m, 2H), 9.85 (s, 1H, CHO). 13C NMR (75 MHz, CDCl3) : 56.0, 56.5, 76.6, 77.4, 109.3, 112.4, 126.2, 130.8, 149.9, 152.0, 190.9 (CHO).
79.45%
With potassium carbonate; In acetone; at 60℃; for 12h;Inert atmosphere;
Phthalimide (1 g, 6.80 mmol) was dissolved in acetone (50 mL).Then 3-bromopropyne (0.7 mL, 8.16 mmol) and potassium carbonate (2.85 g, 20.39 mmol) were added.Substitute nitrogen, heat to 60 C for 12 hours under nitrogen protection.Stop heating, filter and concentrate.Separation and purification by silica gel column chromatography (PE / EtOAc (v / v) = 4/1) to obtain a milky white liquid 1g, yield: 79.45%.
71%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
General procedure: To a mixture of propargyl bromide (8.47 mmol) and secondary amine (16.94 mmol) in DMF, K2CO3(25.41 mmol) was added and the reaction mixture was allowed to stir at ambient temperature for 10-12 h. The reaction mixture was then quenched with ice cold water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure to obtain the corresponding products.
69%
With caesium carbonate; In acetonitrile; at 80℃; for 2h;
Prepared by the method of Clayton (69%):34 mp 146-148C (Lit.36 149-150C). The spectroscopic data was consistent with the literature:36 1H NMR (400MHz, CDCl3) delta 7.80-7.91 (m, 2H), 7.74-7.76 (m, 2H), 4.47 (s, 2H), 2.24 (s, 1H).
58.1%
Compound 1 (1.71g, 11.6mmol) was suspended in EtOH (20mL) and KOH (0.650g, 11.6mmol) was added. The mixture was stirred at room temperature for 2h, and evaporated to remove EtOH. The residue was dissolved in anhydrous DMF (15mL) and propargyl bromide (1.10mL, 12.8mmol) was added. The mixture was stirred at reflux for 72h. The resulting solution was cooled, diluted with EtOAc and partitioned with saturated NaHCO3. The organic phase was washed with water and brine. The solvent was removed by rotary evaporation. The residue was treated with MeOH, and the suspension was filtered to provide compound 2 (1.25g, 6.75mmol, 58.1%) as a white solid.
With potassium carbonate; In N,N-dimethyl-formamide; toluene; at 0 - 25℃;Inert atmosphere;
General procedure: To a mixture of nucleophile (1 mmol) and potassium carbonate (2.0 mmol) in DMF (10 ml) at 0 C, was added 80 % solution of propargyl bromide in toluene (1.2 mmol) over 5 min. After stirring reaction mixture for 30 min, slowly raised temperature to 25 C and stirred further till completion. The crude mixture was quenched with cold water (15 ml) followed by the addition of diethyl ether (15 ml). The ether layer formed was separated and washed twice with cold water (10 ml), dried over anhydrous Na2SO4. Removal of solvent under vacuum afforded the crude product (1a-1p) which was purified by column chromatography
With potassium carbonate; In N,N-dimethyl-formamide; toluene; at 0 - 25℃;Inert atmosphere;
General procedure: To a mixture of nucleophile (1 mmol) and potassium carbonate (2.0 mmol) in DMF (10 ml) at 0 C, was added 80 % solution of propargyl bromide in toluene (1.2mmol) over 5 min. After stirring reaction mixture for 30 min, slowly raised temperature to 25 C and stirred further till completion. The crude mixture was quenched with cold water (15 ml) followed by the addition of diethyl ether (15 ml). The ether layer formed was separated and washed twice with cold water (10 ml), dried over anhydrous Na2SO4. Removal of solvent under vacuum afforded the crude product (1a-1p) which was purified by column chromatography.
With potassium carbonate; In acetone; for 8h;Reflux;
General procedure: Compound 5 was prepared according to the procedurepreviously reported.35 To a solution of tetrahydrophthalimide 4(1.51 g, 10 mmol) in acetone (20 mL) were added potassiumcarbonate (2.76 g, 20 mmol) and propargyl bromide (1.43 g, 12mmol) sequentially. The resulting mixture was refluxed for 8 h.After the mixture had cooled to room temperature, water (50mL) was added, which was extracted three times with EtOAc(100 mL). The organic layer was washed with brine (50 mL),dried over anhydrous Na2SO4, filtered, and concentrated to givecompounds 5. Under this condition, 8 was also prepared.
With N-Bromosuccinimide; silver nitrate; In acetone; at 20℃; for 16h;Inert atmosphere;
AgNO3 (36.1 mg, 0.21 mmol) and N-bromosuccinimide (576 mg, 3.24mmol) were added to a solution of 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (2a; 371 mg, 2.00 mmol) in acetone (2.0 mL). The reactionmixture was stirred at r.t. for 16 h. Afterwards, the mixture waspoured on ice and extracted with EtOAc. The combined organic layerswere dried (anhyd Na2SO4), concentrated, and the crude product waspurified by flash chromatography (silica gel, PE/EtOAc 8:2). Bromoalkyne3a was isolated as a white solid; yield: 495 mg (1.87 mmol,94%); mp 119-120 C; Rf = 0.35 (PE/EtOAc 7:3).
With copper(II) sulfate; In 1,4-dioxane; at 100℃; for 3h;
15 g (81 mmol) 2-propinyl-isoindolin-1,3-dione, 15 g (52 mmol) [bis-(4-fluorophenyl)-methyl]-piperazine, 2:5 g (81 mmol) paraformaldehyde and 0,2 g copper sulfate are stirred for three hours in 200 ml dioxane at 100 C. The cool solution is concentrated under vacuum and the residue is distributed between acetic acid ethyl ester and saturated NaCl solution. The organic phase is dried over sodium sulfate and concentrated under vacuum until dry. The residue is chromatographically purified over silica gel with acetic acid ethyl ester/petroleum ether (1/1): Yield 23.4 g (93%) yellow amorphous solid.
tert-butyl 4-(4-azido-2-fluorophenyl)piperazine-1-carboxylate[ No CAS ]
[ 7223-50-9 ]
4-{4-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-[1,2,3]triazol-1-yl]-2-fluoro-phenyl}-piperazine-1-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With copper(l) iodide; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 25 - 35℃; for 3h;
Example 15:; 4-f4- [4- (1, 3-Dioxo-1, 3-dihydro-isoindol-2-ylmethyl)- [1, 2,3] triazol-1-yl]-2-fluoro- phenyl}-piperazine-1-carboxylic acid tert-butyl ester; To a solution of 4- (4-azido-2-fluoro-phenyl)-piperazine-1-carboxylic acid tert- butyl ester (10 grams, 31.15 mmol), obtained in preparation 17, N-ethyldiisopropyl amine (8.3 mL, 46.7 mmol) and propargyl phthalimide (6.4 grams, 34.3 mmol) in DMF (50 mL) was added cuprous iodide (3.25 grams, 15. 58 mmol) in small batches at 25-35 C and allowed to stir for 3 hours. Saturated ammonium chloride solution containing 10% ammonium hydroxide was added and stirred for 15 minutes. The aqueous layer was extracted with ethyl acetate (50 mL x 3) and the combined extracts were washed with water and brine successively and dried over sodium sulfate. Evaporation of volatiles left a residue, which was crystallized from 50% ethyl acetate: pet. ether system to get 15 grams of title compound (95%). 'H NMR (CDCl3) : 7.96 (s, 1H), 7.83-7. 90 (m, 2H), 7.71-7. 77 (m, 2H), 7.27-7. 50 (m, 2H), 6. 99 (t, J = 8.7 Hz, 1H), 5.07 (s, 2H), 3.61 (t, J = S. 0 Hz, 4H), 3.07 (t, J = 4.9 Hz, 4H), 1. 49 (bs, 9H). IR (KBr, cm-1) : 3469, 1721, 1685, 1523,1425, 1397,1232. CI-MS (m/z): 507,451, 407.
2-{1-[(4-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-1H-[1,2,3]triazol-4-ylmethyl}isoindole-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With copper(l) iodide; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 25 - 35℃; for 2h;
Example 33:; 2- 1 [4-Benzyl-1, 2,3, 6-tetrahydro-pyridin-4-yl)-3-fluoro-phenyl]-1H- [1, 2,3] triazol-4- ylmethyl isoindole-1, 3-dione :; To a solution of 4-(4-azido-2-fluoro-phenyl)-1-benzyl-1, 2,3, 6-tetrahydro-pyridine (100 mg, 0.324 mmol), obtained in preparation 24, in acetonitrile (10 mL) was added N- Ethyldiisopropylamine (0.11 mL, 0.64 mmol) followed by the addition of 2-prop-2-ynyl- isoindole-1, 3-dione (0.09 grams, 0.48 mmol), obtained in preparation 2, and cuprous iodide (0.067 grams, 0.35 mmol) and stirred at 25-35 C for 2 hours. The reaction mixture was filtered through a celite bed, which was washed thoroughly with 10% methanol in chloroform. The filtrates were concentrated under vacuum and the crude product was purified by silica gel column chromatography (50% ethyl acetate/pet. ether) to get desired product as a yellow solid (150 mg, 93%). IH NMR (CDCl3, 200 MHz): 6 8.01 (s, 1H), 7.93-7. 80 (m, 2H), 7.80-7. 64 (m, 2H), 7.52- 7.19 (m, 8H), 6.11-6. 00 (m, 1H), 5.07 (s, 2H), 3.65 (s, 2H), 3.28-3. 10 (m, 2H), 2.80-2. 62 (m, 2H), 2.62-2. 44 (m, 2H) IR (KBr): 3434,2925, 1721,1393 cm~ CI-MS (m/e): 494 (M++1), 408,400
1-(N-Phthalimido)-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-butyne dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; paraformaldehyde; In tetrahydrofuran; dichloromethane;
EXAMPLE 4 1-(N-Phthalimido)-4-[4-(2-methoxyphenyl)-1-piperazinyl]-2-butyne dihydrochloride A suspension of N-propargylphthalimide (48.5 g), 1-(2-methoxyphenyl)piperazine hydrochloride (61.1 g), paraformaldehyde (11.1 g), triethylamine (29.1 g), and copper (I) chloride (10.4 g), in anhydrous tetrahydrofuran (1200 ml) was heated under reflux for 2.5 hrs. The reaction mixture was washed with 0.43M aqueous sodium hydroxide solution (600 ml), two portions of water (1 l), brine (1 l), dried over anhydrous sodium sulfate, filtered, and the the filtrate was concentrated. The residue was triturated with diethyl ether to give 82.5 g (81%) of product as a free base. The dihydrochloride was prepared by dissolving 19 g of the free base in dichloromethane (300 ml) and treating the solution with excess ethereal hydrogen chloride. The salt was collected, washed with diethyl ether, and dried at 50 C. (150 mm) for 16 hrs to afford 22.5 g of product, mp 191-194 C. Analysis: Calculated for C23 H23 N3 O3.2HCl 59.74% C; 5.45% H; 9.09% N. Found: 59.23% C; 5.59% H; 9.12% N.
Stage #1: N-propargylphthalimide With hydrogen fluoride; antimony pentafluoride at -50℃; for 0.166667h;
Stage #2: With sodium carbonate cooling; Further stages.;
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; tris-(o-tolyl)phosphine; In tetrahydrofuran; at 55℃; for 16h;
A mixture of iodide 3 (1.00 g, 3.16 mmol), acetylene 4 (0.643 g, 3.5 mmol), bis(triphenylphosrhohine)palladium (II) dichloride (0.042 g, 0.06 mmol, copper (I) iodide (0.011 g, 0.06 mmol), tri-(o-tolyl)phosphine (0.037 g, 0.12 mmol) and triethylamine (3 mL) in THF (10 mL) was degassed (vac/argon) and stirred at 55 0C under argon for 16 h. The mixture was concentrated under reduced pressure and then diluted with a small quantity of dichloromethane. Purification by flash chromatography (5 to 40% EtOAc-hexanes gradient) gave phthalimide 5 as a light yellow oil. Yield (0.7 g, 59%): 1H NMR (400 MHz, DMSO-^6) delta 7.85-7.93 (m, 4H), 7.20-7.24 (m, IH), 6.90-6.96 (m, 3H), 4.60 (s, 2H), 3.74 (d, J= 5.6 Hz, 2H), 1.60-1.76 (m, 6H), 0.94-1.26 (m, 5H).
With silica supported cuprous sulfate; In tetrahydrofuran; water; at 20℃; for 0.5h;
To a round bottom flask (50 mL), was added a mixture of alkyne (0.012 mol), CDSCS (0.3 g, 0.05 mol %) and the appropriate beta-azido alcohol (0.01 mol) in a mixture of THF/H2O (1:1 v/v, 20 mL). The reaction mixture was stirred at room temperature until TLC monitoring indicated no further progress in the conversion. The catalyst was filtered off, washed with THF/H2O (5×10 mL) and the filtrate was evaporated under vacuum to remove the solvent. The remaining foam was dissolved in CHCl3 (100 mL) and subsequently washed with water (2×100 mL). The organic layer was dried (Na2SO4) and evaporated. The crude product was purified by column chromatography on silica gel and eluted with proper solvents. Characterization data of all synthesized compounds are described below.
1-azido-3-(naphthalen-2-yloxy)propan-2-ol[ No CAS ]
[ 1394904-05-2 ]
Yield
Reaction Conditions
Operation in experiment
93%
With silica supported cuprous sulfate; In tetrahydrofuran; water; at 20℃; for 0.5h;
To a round bottom flask (50 mL), was added a mixture of alkyne (0.012 mol), CDSCS (0.3 g, 0.05 mol %) and the appropriate beta-azido alcohol (0.01 mol) in a mixture of THF/H2O (1:1 v/v, 20 mL). The reaction mixture was stirred at room temperature until TLC monitoring indicated no further progress in the conversion. The catalyst was filtered off, washed with THF/H2O (5×10 mL) and the filtrate was evaporated under vacuum to remove the solvent. The remaining foam was dissolved in CHCl3 (100 mL) and subsequently washed with water (2×100 mL). The organic layer was dried (Na2SO4) and evaporated. The crude product was purified by column chromatography on silica gel and eluted with proper solvents. Characterization data of all synthesized compounds are described below.
2-((1-(2-methoxyphenyl)-1H-1,2,3-triazol-4-yl)methyl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With copper(ll) sulfate pentahydrate; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; In methanol; dichloromethane; water; at 20℃; for 12h;
General procedure: General Procedure for Cycloaddition of Alkyne-Azide: A solution of CuSO4*5H2O (10 mL, 2 mg, 1 mol % based on azide, with 2.00 g of CuSO4*5H2O in 10 mL H2O) was added to a mixture of azide (0.79 mmol) and alkyne(0.83 mmol), followed by a solution of dihydropyridine Hantzsch ester (10 mL, 2.2 mg, 1 mol % based on azide, with 2.20 g of dihydropyridine in 10 mL CH3OH) and finally methanol (1 mL) via syringes. The mixture was stirred for a period as indicated at roomtemperature. After being checked by thin-layer chromatography (TLC) (CHCl3/CH3OH), the reaction mixture was concentrated to dryness under reduced pressure. A small amount of water was used to wash the solid product followed by petroleumether (1H NMR spectrumshowed it is pure). If needed, the reaction mixture was loaded onto a short plug of silica gel using a fine solvent gradient (CHCl3/CH3OH) to affordthe analytically pure product. For some substrates, the scales were reduced.
2,2'-(1,1'-(2,6-dimethylpyridine-3,5-diyl)bis(methylene)bis(1H-1,2,3-triazole-4,1-diyl))bis(methylene)diisoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With copper(ll) sulfate pentahydrate; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate; In methanol; dichloromethane; water; at 20℃; for 10h;
General procedure: General Procedure for Cycloaddition of Alkyne-Azide: A solution of CuSO4*5H2O (10 mL, 2 mg, 1 mol % based on azide, with 2.00 g of CuSO4*5H2O in 10 mL H2O) was added to a mixture of azide (0.79 mmol) and alkyne(0.83 mmol), followed by a solution of dihydropyridine Hantzsch ester (10 mL, 2.2 mg, 1 mol % based on azide, with 2.20 g of dihydropyridine in 10 mL CH3OH) and finally methanol (1 mL) via syringes. The mixture was stirred for a period as indicated at roomtemperature. After being checked by thin-layer chromatography (TLC) (CHCl3/CH3OH), the reaction mixture was concentrated to dryness under reduced pressure. A small amount of water was used to wash the solid product followed by petroleumether (1H NMR spectrumshowed it is pure). If needed, the reaction mixture was loaded onto a short plug of silica gel using a fine solvent gradient (CHCl3/CH3OH) to affordthe analytically pure product. For some substrates, the scales were reduced.
With bromotris(triphenylphosphine)copper(I); triethylamine; In tetrahydrofuran; at 60℃; for 5h;Inert atmosphere;
General procedure: To a 50 ml two-necked round bottom flask with alkyne function (2 mmol), azide function (2 mmol/alkyne function), [CuBr(PPh3)3] (0.01 mmol/alkyne function), triethylamine (2 ml), and THF (2 ml) were added under nitrogen atmosphere and then the mixture was stirred at 60 C for 5 h. The reaction mixture was allowed to cool, and the solvents were removed under vacuum followed by addition of hexane. The mixture was filtered and washed with 2×5 ml of hexane. The concentration of the filtrate under reduced pressure afforded the title compound in good to excellent yield.
93%
With bromotris(triphenylphosphine)copper(I); triethylamine; In tetrahydrofuran; at 60℃; for 5h;Inert atmosphere;
General procedure: To a 50 ml two-necked round bottom flask with alkyne function (2 mmol), azide function (2 mmol/alkyne function), [CuBr(PPh3)3] (0.01 mmol/alkyne function), triethylamine (2 ml),and THF (2 ml) were added under nitrogen atmosphere and then the mixture was stirred at 60 C for 5 h. The reaction mixture was allowed to cool, and the solvents were removed under vacuum followed by addition of hexane. The mixture was filtered and washed with 2 Chi 5 ml of hexane. The concentration ofthe filtrate under reduced pressure afforded the title compound in good to excellent yield.
With bromotris(triphenylphosphine)copper(I); triethylamine; In tetrahydrofuran; at 60℃; for 5h;Inert atmosphere;
To a 50.0 ml two-necked round bottom flask with alkyne function (2 mmol), azide function (2 mmol/alkyne function), [CuBr(PPh3)3] (0.01 mmol/alkyne function), triethylamine (2.0 ml), and THF (2.0 ml) under nitrogen atmosphere and then the mixture was stirred at 60 C for 5 h. The reaction mixture was allowed to cool, and the solvents were removed under vacuum followed by addition of hexane. The mixture was filtered and washed with 2 x 5.0 ml of hexane. The concentration of the filtrate under reduced pressure afforded the title compound in good to excellent yield.
With copper(ll) sulfate pentahydrate; sodium L-ascorbate; In tetrahydrofuran; water; at 20℃;
General procedure: To a vigorously stirred solution of 9b (3.32mmol) in THF/H2O (3:1) (10mL), 5a (3.32mmol) was added. The reaction was initiated by the addition of CuSO4·5H2O (0.33mmol) and sodium ascorbate (1.32mmol). The coloured suspension that formed was stirred at room temperature for 12-16h. Progress of the reaction was monitored on TLC. After completion of the reaction, ice-cold water was added and the aqueous layer was extracted twice with CH2Cl2. The combined organic extracts were dried, evaporated under reduced pressure and purified by using a very short column of silica gel to afford pure 10a as yellow oil;
With copper(ll) sulfate pentahydrate; sodium L-ascorbate; In tetrahydrofuran; water; at 20℃;
General procedure: To a vigorously stirred solution of 9b (3.32mmol) in THF/H2O (3:1) (10mL), 5a (3.32mmol) was added. The reaction was initiated by the addition of CuSO4·5H2O (0.33mmol) and sodium ascorbate (1.32mmol). The coloured suspension that formed was stirred at room temperature for 12-16h. Progress of the reaction was monitored on TLC. After completion of the reaction, ice-cold water was added and the aqueous layer was extracted twice with CH2Cl2. The combined organic extracts were dried, evaporated under reduced pressure and purified by using a very short column of silica gel to afford pure 10a as yellow oil;
With copper(ll) sulfate pentahydrate; sodium L-ascorbate; tert-butyl alcohol; In water; at 20℃; for 10h;
General procedure: A mixture of azide [8 (0.50 equiv), 9 (0.33 equiv),10 (0.25 equiv) or 11 (0.50 equiv)], alkyne 7 or 13 (1.0equiv), CuSO4·5H2O (5 mol%), and sodium ascorbate (10mol%) in a mixture of t-BuOH-H2O (1:1, 20 mL) was stirredfor 10 h at r.t. The residue obtained after evaporation of thesolvent was washed thoroughly with H2O and dissolved inCHCl3 (150 mL). The organic layer was separated, washedwith brine (150 mL), dried (anhyd Na2SO4), filtered andevaporated to give the crude triazole, which was purified bycolumn chromatography (SiO2) using the eluent asmentioned under each compound.
With copper(ll) sulfate pentahydrate; sodium L-ascorbate; tert-butyl alcohol; In water; at 20℃; for 10h;
General procedure: A mixture of azide [8 (0.50 equiv), 9 (0.33 equiv),10 (0.25 equiv) or 11 (0.50 equiv)], alkyne 7 or 13 (1.0equiv), CuSO4·5H2O (5 mol%), and sodium ascorbate (10mol%) in a mixture of t-BuOH-H2O (1:1, 20 mL) was stirredfor 10 h at r.t. The residue obtained after evaporation of thesolvent was washed thoroughly with H2O and dissolved inCHCl3 (150 mL). The organic layer was separated, washedwith brine (150 mL), dried (anhyd Na2SO4), filtered andevaporated to give the crude triazole, which was purified bycolumn chromatography (SiO2) using the eluent asmentioned under each compound.
With copper(ll) sulfate pentahydrate; sodium L-ascorbate; tert-butyl alcohol; In water; at 20℃; for 10h;
General procedure: A mixture of azide [8 (0.50 equiv), 9 (0.33 equiv),10 (0.25 equiv) or 11 (0.50 equiv)], alkyne 7 or 13 (1.0equiv), CuSO4·5H2O (5 mol%), and sodium ascorbate (10mol%) in a mixture of t-BuOH-H2O (1:1, 20 mL) was stirredfor 10 h at r.t. The residue obtained after evaporation of thesolvent was washed thoroughly with H2O and dissolved inCHCl3 (150 mL). The organic layer was separated, washedwith brine (150 mL), dried (anhyd Na2SO4), filtered andevaporated to give the crude triazole, which was purified bycolumn chromatography (SiO2) using the eluent asmentioned under each compound.
With copper(ll) sulfate pentahydrate; sodium L-ascorbate; tert-butyl alcohol; In water; at 20℃; for 10h;
General procedure: A mixture of azide [8 (0.50 equiv), 9 (0.33 equiv),10 (0.25 equiv) or 11 (0.50 equiv)], alkyne 7 or 13 (1.0equiv), CuSO4·5H2O (5 mol%), and sodium ascorbate (10mol%) in a mixture of t-BuOH-H2O (1:1, 20 mL) was stirredfor 10 h at r.t. The residue obtained after evaporation of thesolvent was washed thoroughly with H2O and dissolved inCHCl3 (150 mL). The organic layer was separated, washedwith brine (150 mL), dried (anhyd Na2SO4), filtered andevaporated to give the crude triazole, which was purified bycolumn chromatography (SiO2) using the eluent asmentioned under each compound.
2-((trifluoromethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide[ No CAS ]
2-{3-[(trifluoromethyl)sulfanyl]prop-2-yn-1-yl}-2,3-dihydro-1H-isoindole-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With pyridine; copper(l) iodide; In tetrahydrofuran; at 60℃; for 4.5h;Inert atmosphere; Sealed tube;
Under argon atmosphere,<strong>[7223-50-9]N-propargylphthalimide</strong> (110 mg, 0.60 mmol),Trifluoromethylthio reagent(85 mg, 0.3 mmol), cuprous iodide (60 mg, 0.60 mmol),Pyridine (72 [mu] l, 0.90 mmol) was placed in a 25 ml sealed tube,Then, 2 ml of a tetrahydrofuran solution was added, and the mixture was reacted at 60C for 4.5 hours.After completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was removed by rotary evaporation under reduced pressure. The residue was purified by flash silica gel column to give the corresponding product e2 (65 mg, 76%). The purity was more than 95% by 1H-NMR.
With copper(l) iodide; potassium carbonate; 1,8-diazabicyclo[5.4.0]undec-7-ene; potassium iodide; sodium sulfite; In N,N-dimethyl-formamide; at 0 - 22℃; for 17h;Inert atmosphere;
To a cooled (0 C) solution of 12 (500 mg, 2.700 mmol, 1 equiv) in DMF (27 mL, 0.1M) was added sodium sulfite (170.2 mg, 1.350 mmol, 0.5 equiv), potassium carbonate (373.2mg, 2.700 mmol, 1 equiv), copper (I) iodide (102.8 mg, 0.540 mmol, 0.2 equiv), potassiumiodide (672.3 mg, 4.050 mmol, 1.5 equiv), 1,8-diazabicycloundec-7-ene (205.5 mg, 1.350 mmol, 0.5 equiv), and 13 (366.7 mg, 4.050 mmol, 1.5 equiv)4. The reaction was allowed to warm up toambient temperature (22 C) in the melting ice bath. After 17 h, the solution was cooled (0 C),diluted with water (100 mL), ammonium hydroxide (50 mL), and ethyl acetate (30 mL), thelayers were separated, and the aqueous layer was extracted with ethyl acetate (4 x 50 mL). Thecombined organic layers were washed with brine and dried over magnesium sulfate. Thesolvent was removed under reduced pressure and the crude was purified by columnchromatography eluted with 30% ethyl acetate/hexanes to afford 14 as a white solid (620.7 mg,96% yield)
General Procedure for Hydration of Terminal Alkynes inPEG-400
General procedure: To a solution of alkyne (1.0 mmol) in PEG-400/H2O(4:1) was added [Ru(p-cymene)Cl2]2 (0.01 mmol), and themixture stirred at room temperature. Upon completion of thereaction (monitoring by TLC), the reaction mixture was dilutedwith Et2O (10 mL), stirred for 10 min, and allowed to stand in anice-salt bath to solidify the PEG-400. The organic layer wasdecanted, dried over anhydrous Na2SO4, filtered, and concentratedunder reduced pressure. The residue obtained was purifiedby silica gel flash column chromatography (ethyl acetate-petroleum ether) to give the pure product.
2-((1-((7-methyl-2-oxo-2H-chromen-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
General procedure: To a solution of compound 2 (1.0 mmol) in THF/H2O, 1: 1(v/v), CuSO4. 5H2O (0.15 mmol), sodium carbonate (0.15 mmol), ascorbic acid (0.3 mmol) were added. The mixture was stirred at room temperature for 15 min. Then, 6-methyl-4-azidomethyl coumarin 5a (1.0 mmol) was added, and the resulting reaction mixture was refluxed on water bath until the starting material was consumed as judged by thin layer chromatography (TLC). Then, the reaction mixture was cooled, separated solid was filtered, washed with water, and recrystallized from DMF.
2-((1-((5,7-dimethyl-2-oxo-2H-chromen-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
General procedure: To a solution of compound 2 (1.0 mmol) in THF/H2O, 1: 1(v/v), CuSO4. 5H2O (0.15 mmol), sodium carbonate (0.15 mmol), ascorbic acid (0.3 mmol) were added. The mixture was stirred at room temperature for 15 min. Then, 6-methyl-4-azidomethyl coumarin 5a (1.0 mmol) was added, and the resulting reaction mixture was refluxed on water bath until the starting material was consumed as judged by thin layer chromatography (TLC). Then, the reaction mixture was cooled, separated solid was filtered, washed with water, and recrystallized from DMF.
2-((1-((6-bromo-2-oxo-2H-chromen-4-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)isoindoline-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
General procedure: To a solution of compound 2 (1.0 mmol) in THF/H2O, 1: 1(v/v), CuSO4. 5H2O (0.15 mmol), sodium carbonate (0.15 mmol), ascorbic acid (0.3 mmol) were added. The mixture was stirred at room temperature for 15 min. Then, 6-methyl-4-azidomethyl coumarin 5a (1.0 mmol) was added, and the resulting reaction mixture was refluxed on water bath until the starting material was consumed as judged by thin layer chromatography (TLC). Then, the reaction mixture was cooled, separated solid was filtered, washed with water, and recrystallized from DMF.
(5R)-5-(3-azidoprop-1-en-2-yl)-2-methylcyclohex-2-en-1-one[ No CAS ]
2-[(1-{2-[(1R)-4-methyl-5-oxocyclohex-3-en-1-yl]prop-2-en-1-yl}-1H-1,2,3-triazol-4-yl)methyl]-1H-isoindole-1,3(2H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
With copper(l) iodide; triethylamine; In acetonitrile; at 60℃; for 10h;
General procedure: 369 mg (2 mmol) of (5R)-5-(3-chloroprop-1-en-2-yl)-2-methylcyclohex-2-en-1-one, 2 mL ofacetonitrile, 156 mg (2.4 mmol) of sodium azide are placed in a round-bottomed 5 mL flask andheated with stirring for 10 h (60 C). After cooling, 242 mg (2.4 mmol) of triethylamine, 19 mg(0.1 mmol) of CuI and 2.4 mmol of the corresponding propargyl derivative are added to the resultingmixture. The whole is heated then for 10 h at 60 C and the solvent is distilled off. The cooled mixtureis dissolved in benzene, filtered and hexane is added to the filtrate. The precipitated crystals are filteredoff, washed with hexane and dried.
With hydrogen; In toluene; at 110℃; under 760.051 Torr; for 4h;Schlenk technique;
General procedure: The starting alkyne 1 (0.5 mmol) and dodecane as internal standard(0.22 mmol, 50 muL) were added to a suspension of the Cu-Pd-NPs/MCM-48 catalyst (10 mg) in toluene (5 mL). All reactions werecarried out in a Schlenk-type flask, fitted with a reflux condenser andsealed with a rubber septum. The reaction flask was purged and filledwith H2 (1 atm) through a balloon connected to the flask by a needle,and then heated at 110 C. Then, the reaction mixture was centrifugedand the supernatant removed. The solvent was evaporated invacuo, and the crude product was purified by flash column chromatography(silica gel, hexane/EtOAc). The recovered solid catalyst waswashed with toluene (3 × 2 mL), dried in an oven, calcined at 150 C(4 h), and reduced in H2 atmosphere at 200 C before its reuse. The following known compounds included in Table 2 were characterizedby comparison of their chromatographic and spectroscopic data (FTIR,1H NMR, 13C NMR, and MS) with those described in the literature.Styrene (2a)18Yield: 46 mg (0.44 mmol, 89%); colorless liquid.IR (film): 3082, 3060, 3027, 1630, 1496, 1449, 992, 909, 777, 698 cm-1.1H NMR (300 MHz, CDCl3): delta = 7.35 (m, 2 H), 7.25 (m, 3 H), 6.7 (dd, J =10.8, 17.1 Hz, 1 H), 5.71 (d, J = 17.1 Hz, 1 H), 5.20 (d, J = 10.8 Hz, 1 H).13C NMR (75 MHz, CDCl3): delta = 137.5, 128.5, 127.7, 126.1, 136.9, 113.7.MS: m/z (%) = 104 (100, [M+]), 103 (40), 78 (35), 77 (17), 51 (17).
N-[3-(1,3-dioxoisoindolin-2-yl)-1-morpholinopropylidene]-4-methylbenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With heterogeneous nanocatalyst based on chelated copper iodide supported on salicylaldehyde functionalized magnetic chitosan; In N,N-dimethyl-formamide; at 20℃; for 0.0166667h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and amines (1.2mmol) in DMF (1mL), triethylamine (1.2mmol) was slowly added (in the case of secondary amines, NEt3 was not used) and the mixture was stirred at room temperature. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1: 3), the catalyst was separated by an external magnet. Upon addition of H2O (5mL), the mixture was extracted with ethyl acetate (3×10mL). The organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under vacuum. The resulting residue was recrystallized from ethanol to give 4a-p.
N-[3-(1,3-dioxoisoindolin-2-yl)-1-(piperidin-1-yl)propylidene]-4-methylbenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With heterogeneous nanocatalyst based on chelated copper iodide supported on salicylaldehyde functionalized magnetic chitosan; In N,N-dimethyl-formamide; at 20℃; for 0.0166667h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and amines (1.2mmol) in DMF (1mL), triethylamine (1.2mmol) was slowly added (in the case of secondary amines, NEt3 was not used) and the mixture was stirred at room temperature. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1: 3), the catalyst was separated by an external magnet. Upon addition of H2O (5mL), the mixture was extracted with ethyl acetate (3×10mL). The organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under vacuum. The resulting residue was recrystallized from ethanol to give 4a-p.
N-[3-(1,3-dioxoisoindolin-2-yl)-1-(pyrrolidin-1-yl)propylidene]-4-methylbenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With heterogeneous nanocatalyst based on chelated copper iodide supported on salicylaldehyde functionalized magnetic chitosan; In N,N-dimethyl-formamide; at 20℃; for 0.0166667h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and amines (1.2mmol) in DMF (1mL), triethylamine (1.2mmol) was slowly added (in the case of secondary amines, NEt3 was not used) and the mixture was stirred at room temperature. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1: 3), the catalyst was separated by an external magnet. Upon addition of H2O (5mL), the mixture was extracted with ethyl acetate (3×10mL). The organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under vacuum. The resulting residue was recrystallized from ethanol to give 4a-p.
3-(1,3-dioxoisoindolin-2-yl)-N,N-diethyl-N'-tosylpropanimidamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With heterogeneous nanocatalyst based on chelated copper iodide supported on salicylaldehyde functionalized magnetic chitosan; In N,N-dimethyl-formamide; at 20℃; for 0.0166667h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and amines (1.2mmol) in DMF (1mL), triethylamine (1.2mmol) was slowly added (in the case of secondary amines, NEt3 was not used) and the mixture was stirred at room temperature. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1: 3), the catalyst was separated by an external magnet. Upon addition of H2O (5mL), the mixture was extracted with ethyl acetate (3×10mL). The organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under vacuum. The resulting residue was recrystallized from ethanol to give 4a-p.
3-(1,3-dioxoisoindolin-2-yl)-N,N-dipropyl-N'-tosylpropanimidamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With heterogeneous nanocatalyst based on chelated copper iodide supported on salicylaldehyde functionalized magnetic chitosan; In N,N-dimethyl-formamide; at 20℃; for 0.0333333h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and amines (1.2mmol) in DMF (1mL), triethylamine (1.2mmol) was slowly added (in the case of secondary amines, NEt3 was not used) and the mixture was stirred at room temperature. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1: 3), the catalyst was separated by an external magnet. Upon addition of H2O (5mL), the mixture was extracted with ethyl acetate (3×10mL). The organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under vacuum. The resulting residue was recrystallized from ethanol to give 4a-p.
N,N-dibutyl-3-(1,3-dioxoisoindolin-2-yl)-N'-tosylpropanimidamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With heterogeneous nanocatalyst based on chelated copper iodide supported on salicylaldehyde functionalized magnetic chitosan; In N,N-dimethyl-formamide; at 20℃; for 0.0333333h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and amines (1.2mmol) in DMF (1mL), triethylamine (1.2mmol) was slowly added (in the case of secondary amines, NEt3 was not used) and the mixture was stirred at room temperature. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1: 3), the catalyst was separated by an external magnet. Upon addition of H2O (5mL), the mixture was extracted with ethyl acetate (3×10mL). The organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under vacuum. The resulting residue was recrystallized from ethanol to give 4a-p.
3-(1,3-dioxoisoindolin-2-yl)-N-(4-nitrophenyl)-N'-tosylpropanimidamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 0.0666667h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and amines (1.2mmol) in DMF (1mL), triethylamine (1.2mmol) was slowly added (in the case of secondary amines, NEt3 was not used) and the mixture was stirred at room temperature. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1: 3), the catalyst was separated by an external magnet. Upon addition of H2O (5mL), the mixture was extracted with ethyl acetate (3×10mL). The organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under vacuum. The resulting residue was recrystallized from ethanol to give 4a-p.
3-(1,3-dioxoisoindolin-2-yl)-N-(pyridin-2-yl)-N'-tosylpropanimidamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 0.0833333h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl)isoindoline-1,3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and amines (1.2mmol) in DMF (1mL), triethylamine (1.2mmol) was slowly added (in the case of secondary amines, NEt3 was not used) and the mixture was stirred at room temperature. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1: 3), the catalyst was separated by an external magnet. Upon addition of H2O (5mL), the mixture was extracted with ethyl acetate (3×10mL). The organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under vacuum. The resulting residue was recrystallized from ethanol to give 4a-p.
methyl 3-(1,3-dioxoisoindolin-2-yl)-N-tosylpropanimidate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With triethylamine; In chloroform; at 20℃; for 0.0333333h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl) isoindoline-1, 3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and alcohols or phenols (1.2mmol) in chloroform (1mL), triethylamine (1.2mmol) was slowly added. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1:3), the catalyst was separated by an external magnet. Evaporation of the solvent under vacuum gave the crude product which was recrystallized from ethanol to give 4q-y.
ethyl 3-(1,3-dioxoisoindolin-2-yl)-N-tosylpropanimidate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With triethylamine; In chloroform; at 20℃; for 0.0333333h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl) isoindoline-1, 3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and alcohols or phenols (1.2mmol) in chloroform (1mL), triethylamine (1.2mmol) was slowly added. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1:3), the catalyst was separated by an external magnet. Evaporation of the solvent under vacuum gave the crude product which was recrystallized from ethanol to give 4q-y.
propyl 3-(1,3-dioxoisoindolin-2-yl)-N-tosylpropanimidate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With triethylamine; In chloroform; at 20℃; for 0.0666667h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl) isoindoline-1, 3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and alcohols or phenols (1.2mmol) in chloroform (1mL), triethylamine (1.2mmol) was slowly added. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1:3), the catalyst was separated by an external magnet. Evaporation of the solvent under vacuum gave the crude product which was recrystallized from ethanol to give 4q-y.
phenyl 3-(1,3-dioxoisoindolin-2-yl)-N-tosylpropanimidate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With triethylamine; In chloroform; at 20℃; for 0.0833333h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl) isoindoline-1, 3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and alcohols or phenols (1.2mmol) in chloroform (1mL), triethylamine (1.2mmol) was slowly added. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1:3), the catalyst was separated by an external magnet. Evaporation of the solvent under vacuum gave the crude product which was recrystallized from ethanol to give 4q-y.
p-tolyl 3-(1,3-dioxoisoindolin-2-yl)-N-tosylpropanimidate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With triethylamine; In chloroform; at 20℃; for 0.0666667h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl) isoindoline-1, 3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and alcohols or phenols (1.2mmol) in chloroform (1mL), triethylamine (1.2mmol) was slowly added. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1:3), the catalyst was separated by an external magnet. Evaporation of the solvent under vacuum gave the crude product which was recrystallized from ethanol to give 4q-y.
o-tolyl 3-(1,3-dioxoisoindolin-2-yl)-N-tosylpropanimidate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With triethylamine; In chloroform; at 20℃; for 0.0833333h;
General procedure: To a mixture of 2-(prop-2-yn-1-yl) isoindoline-1, 3-dione (1mmol), sulfonylazide (1mmol), CuI/Fe3O4NPsCS-SB (0.05g, 1.4mol% CuI) and alcohols or phenols (1.2mmol) in chloroform (1mL), triethylamine (1.2mmol) was slowly added. After completion of the reaction, as monitored by TLC (silica gel, EtOAc: n-hexane, 1:3), the catalyst was separated by an external magnet. Evaporation of the solvent under vacuum gave the crude product which was recrystallized from ethanol to give 4q-y.
Stage #1: N-propargylphthalimide With copper(l) iodide; trimethylsilylazide In water; N,N-dimethyl-formamide at 100℃;
Stage #2: With hydrazine hydrate In ethanol for 3h; Reflux;
Stage #3: With hydrogenchloride In ethanol; water
2-[3-(quinolin-3-yl)prop-2-yn-1-yl]isoindolin-1,3-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62.2%
With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In acetonitrile; at 80℃; for 4h;Inert atmosphere;
General procedure: To a solution of compound 2 or 3 (1.2 eq) in acetonitrile in a high pressure vessel, CuI (0.1 eq), bis(triphenylphosphine)palladium(II) dichloride (0.05 eq), the corresponding halogenated aryl (1 eq) and triethylamine (1.5 eq) were added. The reaction mixture was stirred at 80C for 4h under Ar. Water was added and the resulting mixture was extracted with EtOAc. The organic layer was washed with water and brine, and concentrated by evaporation. The residue was dissolved with EtOAc and treated with petroleum ether. The product was precipitated and filtered to yield the compounds 6a, 7a, 7b and 7d-7i.
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