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CAS No. : | 1576-37-0 | MDL No. : | |
Formula : | C14H15NO2S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WTHKAJZQYNKTCJ-UHFFFAOYSA-N |
M.W : | 261.34 | Pubchem ID : | 95801 |
Synonyms : |
N-Benzyl-p-toluenesulfonamide;N-Tosylbenzylamine;BnNHTs;NSC 37123
|
Num. heavy atoms : | 18 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 4 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 71.79 |
TPSA : | 54.55 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.94 cm/s |
Log Po/w (iLOGP) : | 2.1 |
Log Po/w (XLOGP3) : | 2.75 |
Log Po/w (WLOGP) : | 3.4 |
Log Po/w (MLOGP) : | 2.46 |
Log Po/w (SILICOS-IT) : | 2.36 |
Consensus Log Po/w : | 2.61 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.42 |
Solubility : | 0.0989 mg/ml ; 0.000378 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.55 |
Solubility : | 0.0736 mg/ml ; 0.000282 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -5.69 |
Solubility : | 0.000539 mg/ml ; 0.00000206 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 2.31 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With acetic acid; NaNO2 In acetic anhydride | 1 N-Nitroso-N-benzyl-p-toluenesulphonamide N-Nitroso-N-benzyl-p-toluenesulphonamide To a solution of N-benzyl-p-toluenesulphonamide (21 g, 80 mmol) and acetic acid (100 ml) in acetic anhydride (400 ml) was added solid sodium nitrite (120 g, 1.7 mol) in portions over a period of 12 hours at 5° C. The temperature was kept below 10° C. all the time. After the addition was finished the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured over an excess of ice water and stirred for 1 hour. The pale yellow precipitate was filtered and washed several times with water. The crude product was recrystallized from ethanol to give the title compound as a tiny yellow needles (19.1 g, 82% yield, m.p. 92°-93° C., (Lit.1 89°-90° C.). δH (CDCl3): 7.80(2H,m); 7.25(7H,m); 4.95(2H,s); 2.40(3H,s)ppm. |
76% | With acetic anhydride; acetic acid; NaNO2 at 0℃; for 15h; | |
76.1% | With NaNO2 In acetic anhydride; acetic acid at 0 - 25℃; |
70% | With acetic anhydride; acetic acid; NaNO2 at 0 - 20℃; | |
With acetic acid; NaNO2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With trichloroisocyanuric acid In dichloromethane at 0℃; for 3h; Schlenk technique; Inert atmosphere; | |
68% | With N-methyl-p-toluenesulfonylamide In water monomer; toluene at 0℃; | N-Benzyl-N-chloro-p-toluenesulfonamide (12). To N-benzyl-p-toluenesulfonamide (2.1 g, 8.0 mmol) was added toluene (8 mL) and the solution cooled to 0 °C. Aqueous NaOCl (0.8 M, 20 mL, 16 mmol) was slowly added. The reaction mixture was stirred until complete consumption of starting material by TLC (silica gel, 1:1 EtOAc/petroleum ether 40-60) and 1H NMR spectroscopy. The organic phase of the reaction solution was separated. The aqueous phase was washed with EtOAc (10 mL). The organic phases were combined, dried over Na2SO4, filtered and the solvent removed by rotary evaporation to leave the pure product as a white solid (1.6 g, 5.4 mmol, 68%). Mp 131-132°C; IR νmax 3267.42, 3066.4, 3030.9, 2967.7, 2919.9, 1594.2, 1166.2, 1084.2, 1010.8, 846.0, 799.5, 787.1, 758.9, 701.6, 625.5, 537.0 cm-1; 1H NMR (CDCl3, 500 MHz) δ ppm 7.89 (d, J = 8.3 Hz, 2H, CHAr), 7.43 (2H, d J = 8.2 Hz, CHAr), 7.35-7.34 (5H, m, CHAr), 4.35 (2H, s, CH2), 2.50 (3H, s, CH3); 13C NMR (CDCl3, 125 MHz) δ ppm 145.63 (CAr), 133.73 (CAr), 129.87 (2 × CHAr), 129.67 (2 × CHAr), 129.09 (2 × CHAr), 128.63 (2 × CHAr), 60.53 (CH2), 21.78 (CH3). Compound is present as amine by mass spectrometry: LRMS: 284.6 (M+ - Cl + H + Na) HRMS m/z (ESI): M+ - Cl + H + Na, 284.0701 C14H15NNaO2S requires M 284.0721. |
67% | With trichloroisocyanuric acid In dichloromethane at 0℃; for 3h; |
With hypochloric acid | ||
With hypochlorous acid tert-butyl ester In dichloromethane at 20℃; for 3h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: N-benzyl-p-toluenesulfonamide With n-butyllithium In tetrahydrofuran at 0℃; Stage #2: With naphthalene; lithium In tetrahydrofuran at -78 - 20℃; | |
99% | Stage #1: N-benzyl-p-toluenesulfonamide With n-butyllithium In tetrahydrofuran at 0℃; for 0.166667h; Inert atmosphere; Stage #2: With naphthalene; lithium In tetrahydrofuran at -78 - 25℃; Stage #3: With water monomer In tetrahydrofuran | 4.5. General procedure for synthesis of amines 17 General procedure: To a solution of the corresponding sulfonamide 16 (1 mmol) in anhydrous THF (10 mL) was added n-buthyl lithium (1 mmol, 0.625 mL) at 0 °C under inert argon atmosphere. After 10 min, the resulting solution was added to a suspension of lithium powder (7.2 mmol, 50 mg) and naphthalene (0.08 mmol, 10 mg) in anhydrous THF (5 mL) at -78 °C. The mixture was stirred during 12 h, reaching temperature to rise to 25 °C, and finally was hydrolyzed with water (10 mL). The mixture was extracted with AcOEt (3×10 mL) and washed with brine (10 mL), after drying with anhydrous MgSO4, ands filtering on Celite, the solvents were removed under low pressure(15-18 Torr). The resulting mixture was purified by column chromatography. |
With naphthalene; water monomer; lithium 1.) THF, -78 deg C, 2 h; Yield given. Multistep reaction; |
With magnesium In methanol at 80℃; for 24h; Inert atmosphere; | ||
With potassium hydroxide; water monomer at 250℃; | ||
56 %Spectr. | With 3,6-di-tert-butyl-9-mesityl-10-phenylacridin-10-ium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In water monomer; acetonitrile for 48h; Irradiation; | |
With naphthalene; natrium |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: N-benzyl-p-toluenesulfonamide With sodium hydride In tetrahydrofuran Stage #2: acetyl chloride In tetrahydrofuran at 0 - 25℃; for 3h; | N-Ts-Activated Secondary Amides; General Procedure General procedure: An oven-dried 100 mL round-bottomed flask was charged with Nbenzyl-4-methylbenzenesulfonamide (1.0 mmol, 1.0 equiv), and NaH (1.5 mmol, 1.5 equiv) in anhyd THF (20 mL). A solution of the respective acyl chloride (1.0 mmol, 1.0 equiv) in anhyd THF (10 mL) was added at 0 °C. The reaction mixture was stirred at r.t. (25 °C) for 3 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with H2O and extracted with CH2Cl2 (3 25 mL). The combined organic layers were washed with brine (20 mL), dried (anhyd Na2SO4), and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (EtOAc/PE) to afford the desired N-tosyl-activated secondary amide. |
With n-butyllithium 1.) THF, hexane, -78 deg C -> 0 deg C, 30 min, 2.) THF, hexane, -78 deg C -> rt, overnight; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In dichloromethane at 4℃; | |
99% | With pyridine; dmap In dichloromethane at 0 - 20℃; for 16h; | |
99% | With triethylamine at 20℃; for 1h; Inert atmosphere; |
98% | In water monomer at 110℃; for 0.0833333h; Microwave irradiation; Green chemistry; chemoselective reaction; | |
98% | With pyridine; dmap In dichloromethane at 0 - 20℃; for 16h; | |
98% | With sulfuryl dichloride; triethylamine In dichloromethane at 0 - 20℃; | |
97% | With pyridine at 20 - 70℃; for 6h; | |
96% | With 1-hydroxybenzotriazole supported on polymer In dichloromethane at 60℃; | |
95% | With (Na1752K0.144Ca0365Mg0.065)(Al2044Si2774O96)*19.16H2O In ethanol at 25 - 30℃; for 0.416667h; Sonication; Green chemistry; | 3.3 General procedure for the N-sulfonylation of amines by Natrolite nanozeolite under ultrasound irradiation General procedure: The reactions were carried out in a round-bottomed flask of 25mL capacity suspended at the center of the cleaning bath, 5cm below the surface of the liquid. To the mixture of amine (1.0mmol) and tosyl chloride (1.0mmol) in 4mL of ethanol, Natrolite nanozeolite (0.08g) was added. The mixture was sonicated at 25-30°C (bath temperature, the temperature inside the reactor was also 25-30°C) for the appropriate time (Table 5) in an US bath having a frequency of 40kHz and an input power of 250W. The addition or removal of water controlled the temperature of the water bath. The water bath was controlled at 25-30°C. The progress of the reaction was monitored by TLC. After completion of the reaction, catalyst was filtrated. The filtrated catalyst, which was washed with ethyl acetate and activated at 100°C for 2h, could be reused in next cycle without considerable activity loss at least five successive runs for the same reaction. The solvent was concentrated under reduced pressure to afford the pure product as solid in good to excellent yields. All compounds were compared with the corresponding compounds prepared by the reported procedure [7,24-28]. All compounds were known and were characterized by spectral analysis. |
95% | With pyridine at 20℃; for 2h; | |
94% | With Sodium hydrogenocarbonate In water monomer; acetone at 25℃; Flow reactor; Combinatorial reaction / High throughput screening (HTS); | |
94% | With Sodium hydrogenocarbonate In water monomer; acetone at 25℃; for 0.25h; | General method for the preparation of sulfonamides under eco-flow conditions General procedure: Sulfonyl chloride (0.20 mmol) was dissolved in acetone (2 mL) and the resulting solution was injected in the reagent loop A. An aqueous NaHCO3 0.4 M (1 mL) was added to a solution of the amine (0.22 mmol) dissolved in PEG-400 (1 mL). The H2O/PEG400 solution (2 mL, 1:1,v/v) was then injected in the reagent loop B. A degassed solution of acetone and water were connected with pump A and B, respectively, and the flow rate was fixed at 0.5 mL min-1 (0.25 mL min-1 + 0.25 mL min-1). After switching the sample loops, the mixtures exited were joined in a T-piece, entered in a 10 mL PTFE coil reactor warmed at 25 °C, fitted with the back pressure regulator (100 psi), directed in UV detector and the output was recovered in a fraction collector. The reaction mixture was drooped in a tube containing Et2O/HCl 3 N (5 mL, 4:1, v/v). The two phases were separated, and the organic one was washed with H2O (2 × 1 mL), dried over Na2SO4, and concentrated under reduced pressure to give the desired pure compound. |
94% | With triethylamine In tetrahydrofuran at 20℃; for 16h; Inert atmosphere; | |
93% | With triethylamine In dichloromethane at 20℃; for 1h; | |
93% | With pyridine In benzene at 20℃; for 12h; Inert atmosphere; | |
93% | With triethylamine In dichloromethane at 0 - 20℃; for 6.5h; Inert atmosphere; | |
92% | With triethylamine In dichloromethane at 0 - 20℃; | Batch formation of N-benzyl-p-toluenesulfonamide (10): (i) To benzylamine (8.0 g, 74.6 mmol), cooled to 0 °C, was added p-toluenensulfonyl chloride (14.3 g, 74.6 mmol) and triethylamine (11.3 g, 112 mmol) in DCM (72 mL). The reaction mixture was stirred and allowed to warm to room temperature until complete conversion was observed by TLC (silica gel, 1:1 EtOAc/petroleum ether 40-60). Then, saturated aqueous NaHCO3 was added to the reaction solution and the product was extracted with DCM (3 × 50 mL). The DCM phases were combined, dried over Na2SO4, filtered and the solvent removed by rotary evaporation to leave the product as a white solid (17.9 g, 68.5 mmol, 92%). 1H NMR (CDCl3, 500 MHz) δH (300 MHz, CDCl3) 7.75 (2H, d J = 8.3 Hz, CHAr), 7.31-7.24 (5H, m, CHAr), 7.20-7.18 (2H, m, CHAr), 4.89 (1H, t J = 6.1 Hz, NH), 4.10 (2H, d J = 6.2 Hz, CH2), 2.43 (3H, s, CH3). |
91% | With triethylamine In dichloromethane at 20℃; for 16h; | |
91% | With pyridine In dichloromethane at 23℃; for 12h; | |
90% | In pyridine | 1 N-Benzyl-p-toluene sulphonamide EXAMPLE 1 N-Benzyl-p-toluene sulphonamide To a solution of benzylamine (5 g, 4.67 mmol) in pyridine (25 ml) was added (cautiously) p-toluenesulphonyl chloride (10 g, 5.25 mmol). The deep red coloured solution was stirred at room temperature for 1 hour before being poured into water (80-100 ml). The oily precipitate which solidified on scratching was filtered and recrystallized from ethanol to give the title compound (10.98 g, 90% yield, m.p. 115°-116° C., (Lit.1 114° C.)). δH (CDCl3): 7.80(2H,m); 7.25(7H,m); 4.95(1H,t); 4.05(2H,d); 2.35(3H,s)ppm. |
90% | With triethylamine In dichloromethane at 0 - 20℃; for 1h; | |
89% | In water monomer; acetone at 20℃; for 0.416667h; | |
89% | In water monomer at 20℃; for 0.416667h; | |
89% | With triethylamine In dichloromethane at 20℃; | |
88% | In dichloromethane; triethylamine at 20℃; for 2h; | |
88% | With triethylamine In dichloromethane at 0 - 20℃; | 4.1.1. General procedure for the preparation of sulfonamides 8a-g, i-l, 9a-h and 10a-h, j General procedure: A solution of appropriate sulfonyl chloride 7a-l (10 mmol) in dichloromethane (15 mL) was slowly added to a cooled (0 °C) solution of amine 4-6 (15 mmol) in dichloromethane (10 mL) and triethylamine (15 mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed at reduced pressure, then the resulting residue was taken up in ethyl acetate and washed with a solution of HCl (1 M, 2 × 25 mL) and brine (2 × 25 mL). The organic phase was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The title compounds were purified by crystallization from ethyl acetate/petroleum ether 40-60 °C. A similar procedure has been employed for the synthesis of 9f-h, 10f-g, while a different synthetic approach has been described for 10a-e, 10h-k; in all cases our 1H NMR spectral data matched those previously reported for these compounds [19b], [19c], [19d], [19e], [19f], [19g], [19h], [19i], [19] and [19a]. |
88% | Stage #1: p-toluenesulfonyl chloride With potassium carbonate at 60℃; for 2.5h; Stage #2: benzylamine at 120℃; | |
87% | With pyridine at 20 - 70℃; | |
87% | In acetonitrile at 20℃; for 8h; | |
87% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; Inert atmosphere; Schlenk technique; | |
85% | With pyridine In dichloromethane at 20℃; | |
85% | With pyridine In dichloromethane at 0 - 20℃; | |
85% | With triethylamine In dichloromethane at 20℃; for 0.5h; Inert atmosphere; | |
84% | With Cs2CO3 In acetonitrile at 25℃; for 0.466667h; | |
84% | With pyridine; dmap at 0 - 20℃; for 12h; Inert atmosphere; | |
83% | With triethylamine In dichloromethane for 12h; | |
80% | With pyridine at 50℃; for 20h; Inert atmosphere; Cooling with ice; | |
79% | With triethylamine In dichloromethane at 0 - 20℃; for 2h; | |
78% | Multistep reaction; | |
77% | With triethylamine In dichloromethane at 0 - 20℃; | |
72.4% | With pyridine at 0 - 25℃; | |
70% | In acetone for 3h; Ambient temperature; | |
63% | In ethanol Reflux; | |
62% | With pyridine; dmap In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere; | |
47% | With triethylamine In dichloromethane at 25℃; | |
45% | With pyridine at 25℃; for 1.5h; | |
32% | In ethyl acetate at 0 - 20℃; for 1h; | |
31% | In tetrahydrofuran at 20℃; | |
With pyridine | ||
With potassium hydroxide | ||
With pyridine | ||
With triethylamine In dichloromethane 1) 0 deg C, 1 h, 2) room temperature; | ||
Yield given. Multistep reaction; | ||
With aminomethylpolystyrene; poly-4-vinylpyridine 1) CH2Cl2, rt, 16 h; 2) CH2Cl2, rt, 3 h; Yield given. Multistep reaction; | ||
With triethylamine In acetonitrile at 0 - 20℃; Yield given; | ||
With indole-3-carboxaldehyde-polystyrene resin; sodium cyanotrihydridoborate; trifluoroacetic acid; tetramethylammonium triacetoxyborohydride Yield given. Multistep reaction; | ||
With triethylamine In dichloromethane at 20℃; for 8h; | ||
With triethylamine In dichloromethane for 2h; | ||
In ethanol at 20℃; for 7h; | ||
With triethylamine In dichloromethane at 20℃; | ||
With triethylamine In dichloromethane at 20℃; Cooling with ice; | ||
With triethylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; | ||
With triethylamine | ||
With triethylamine In acetonitrile at 20℃; for 4h; | ||
Stage #1: benzylamine With sodium hydride In N,N-dimethyl acetamide; mineral oil at 0℃; for 0.166667h; Inert atmosphere; Stage #2: p-toluenesulfonyl chloride In N,N-dimethyl acetamide; mineral oil at 20℃; for 0.5h; Inert atmosphere; | ||
With triethylamine In dichloromethane at 0 - 20℃; | ||
With pyridine In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | ||
With pyridine In dichloromethane at 20℃; | General procedure of preparation of anilines General procedure: Substrates 2a-2l were synthesized by sulfonylationof the corresponding aniline. The aniline (3 mmol) was dissolved in dry CH2Cl2 (6.5 mL), and thesolution was treated with sulfony chloride (687 mg, 3.6 mmol) and pyridine (0.73 mL, 9 mmol).The mixture was stirred at room temperature overnight. Then diluted with H2O (x1) and extracted9with CH2Cl2 (x3). The combined organic layers were washed with 1M HCl, brine(x1), dried overanhydrous Na2SO4, and concentrated in vacuo. The resulting mixture was purified by silica gelcolumn chromatography (EtOAc/Petroleum ether) to afford the sulfonamide 2 | |
With triethylamine In dichloromethane | ||
With pyridine at 20℃; for 2h; | ||
With triethylamine In dichloromethane at 0 - 10℃; | ||
In pyridine at 20℃; for 2h; | ||
With erbium trifluoromethanesulfonate In 2-methyltetrahydrofuran for 2h; Green chemistry; | General Procedure one pot tosylation/azaglycosidation reaction of amine with 3,4,5-tri-O-acetyl-D-glucal. General procedure: To a stirred solution of tosyl chloride (2.2 mmol), in 2-MeTHF (3 mL) was added the N-nucleophile (2.0 mmol) and Er(OTf)3 (0.2 mmol). The reaction was conducted in a two neck round bottom flask using a reflux system. The reaction process was monitored by TLC using ultraviolet illumination at 254 nm allowed for visualization for UV active materials or staining with ninhydrin solution allowed for further visualization. After 2 hours is added 2 mmol of tri-O-acetyl-D-glucal and it is left in the same conditions for another 2 hours. The reaction mixture was extracted with H2O and the organic phase (2-MeTHF as solvent), then dried over Na2SO4. The crude material was dried under vacuum (~1 mmHg) and purified by flash chromatography on silicagel (CHCl3/EtOH 9.5/0.5) to isolate the desired product | |
With triethylamine In dichloromethane at 20℃; Cooling with ice; Inert atmosphere; | Procedure B: Synthetic procedure for the preparation of N-benzyl sulfonamides. General procedure: To a stirred solution of benzylamine (1.0 equivalence) in 10 ml of anhydrous dichloromethane under ice cooling, was added a solution of sulfonylchloride (1.2 equivalence) in dichloromethane (10 ml) dropwise and triethylamine (1.5 equivalence). The reaction mixture was stirred at room temperature under the nitrogen atmosphere for overnight. After completion of the reaction (monitored by TLC), reaction mixture was diluted with chloroform (20 ml) and quenched with water (10 ml), extracted with chloroform (3x50 ml), the organic layer was washed with 1N HCl (50 ml), then with water (50 ml), dried over Na2SO4, concentrated in rota-vap to give desired sulfonamide. | |
With triethylamine In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere; | ||
With triethylamine In dichloromethane at 20℃; for 4h; | ||
With triethylamine In dichloromethane | ||
With pyridine at 20℃; | 2.4. General synthesis process for N-propargylsulfonamides 1 General procedure: To a stirred solution of amine (5 mmol) in 3mL pyridine, aryl sulfonyl chloride (7 mmol) was added and stirred for 3 h at room temperature. After completion of the reaction, the mixture was poured into ice cold water and stirred for 15 min, which resulted inprecipitation of the desired sulfonamide in high yield. To a stirred solution of the synthesized sulfonamide (1 mmol) and K2CO3(1 mmol) in acetonitrile (5 mL), was added dropwise propargyl bromide (1.1 mmol). The reaction mixture was heated at 80 °C for 8 h. After completion of the reaction, as monitoring by TLC, the mixture was evaporated under vacuum. Water was added, and thereaction mixture was extracted by DCM (3 5 mL). The combinedorganic extracts were dried with Na2SO4, filtered, and then evaporated to obtain pure N-propargylsulfonamides 1 in high yields. | |
With pyridine at 20℃; for 2h; | ||
Stage #1: benzylamine With pyridine In dichloromethane for 0.0833333h; Stage #2: p-toluenesulfonyl chloride In dichloromethane at 20℃; | ||
With triethylamine In dichloromethane at 0 - 20℃; | ||
With triethylamine In dichloromethane for 8h; | ||
With triethylamine In dichloromethane at 0 - 20℃; for 0.25h; | ||
In dichloromethane for 0.166667h; | EXPERIMENTALReagents, Preparation of Reaction Mixtures,and Their Preparation for Analysis General procedure: n-Hexylamine hydrochloride was preliminarilytransformed into a free base by adding excess sodiumhydroxide to its aqueous solution. Hexylamine wasextracted (twice) with methylene chloride (“kh.ch.”(reagent grade), Vekton, Russia) from the aqueoussolution and dried over calcium hydroxide. A 2.5-foldexcess of each amine was added to the solution of p-toluenesulfonylchloride in methylene chloride at a concentrationof 0.06 , and the mixture was kept for10 min. Then the reaction mixtures were directly analyzedas the excess amounts of amine and their salts donot hinder UV detection of reaction products, which(except aniline) do not absorb in the near-UV region.The presence of certain amounts of p-toluenesulfonicacid (in the form of anion) is indicated by the appearanceof peaks in the region of the retention time of thenon-sorbing component. As reference compounds for determining the retention indices and comparing themethods for approximation of retention parameters,we used n-alkyl phenyl ketones C6H5COCnH2n+1 with1 ≤ n ≤ 3 (“ch.d.a.” (analytical grade), Sigma-AldrichRus LLC, Russia). | |
With triethylamine In dichloromethane at 0 - 20℃; for 2h; | ||
With triethylamine In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere; | ||
With triethylamine In dichloromethane at 20℃; | 2.1 General procedure A for the synthesis of sulfonamides General procedure: A mixture of sulfonyl chloride (11.0 mmol, 1.1 equiv) and triethylamine (20.0 mmol, 2 equiv)in CH2Cl2 (50 mL, 0.2 M) was stirred at room temperature, then primary amine (10.0 mmol) wasadded dropwise. After completion of the reaction (monitored by TLC), the mixture was pouredinto water (50 mL), then extracted with CH2Cl2, dried over anhydrous Na2SO4, and concentratedin vacuo. The crude product was purified by a flash column chromatography with a 15% EtOAc inpetroleum ether to afford the product sulfonamides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-hydroxyphthalimide; [bis(acetoxy)iodo]benzene In dichloromethane at 20℃; for 0.5h; | |
90% | With N-hydroxyphthalimide; [bis(acetoxy)iodo]benzene In dichloromethane at 20℃; for 0.5h; | |
With bis(p-toluenesulfonyl) sulfur diimide |
16 % Spectr. | With pyridine; MS3 Angstroem; oxygen In toluene at 80℃; for 2h; | |
With [bis(acetoxy)iodo]benzene; iodine In ethyl acetate at 25℃; | ||
Stage #1: N-benzyl-p-toluenesulfonamide With hypochlorous acid tert-butyl ester; Sodium sulfate [anhydrous]; potassium bromide In acetonitrile at 20℃; for 1h; Stage #2: With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In acetonitrile at 20℃; for 0.5h; Stage #3: With anhydrous sodium carbonate In acetonitrile at 20℃; for 20h; | ||
Multi-step reaction with 2 steps 1.1: trichloroisocyanuric acid / dichloromethane / 3 h / 0 °C / Schlenk technique; Inert atmosphere 2.1: 4,4'-Dimethoxy-2,2'-bipyridin; lithium methanolate / acetonitrile / 0.08 h / Schlenk technique; Inert atmosphere 2.2: 18 h / 20 °C / Schlenk technique; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: trichloroisocyanuric acid / dichloromethane / 3 h / 0 °C / Schlenk technique; Inert atmosphere 2: copper(I) thiocyanate; 4,4'-Dimethoxy-2,2'-bipyridin; lithium methanolate / acetonitrile / 18 h / 20 °C / Schlenk technique; Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; Inert atmosphere; Schlenk technique; | |
96% | With dmap; triethylamine In dichloromethane at 0 - 20℃; | |
92% | Stage #1: N-benzyl-p-toluenesulfonamide With sodium hydride In tetrahydrofuran Stage #2: benzoyl chloride In tetrahydrofuran at 0 - 25℃; for 3h; | N-Ts-Activated Secondary Amides; General Procedure General procedure: An oven-dried 100 mL round-bottomed flask was charged with Nbenzyl-4-methylbenzenesulfonamide (1.0 mmol, 1.0 equiv), and NaH (1.5 mmol, 1.5 equiv) in anhyd THF (20 mL). A solution of the respective acyl chloride (1.0 mmol, 1.0 equiv) in anhyd THF (10 mL) was added at 0 °C. The reaction mixture was stirred at r.t. (25 °C) for 3 h. The reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with H2O and extracted with CH2Cl2 (3 25 mL). The combined organic layers were washed with brine (20 mL), dried (anhyd Na2SO4), and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (EtOAc/PE) to afford the desired N-tosyl-activated secondary amide. |
85% | With dmap; triethylamine In dichloromethane | |
Stage #1: N-benzyl-p-toluenesulfonamide With sodium hydride In tetrahydrofuran at 0℃; for 1h; Stage #2: benzoyl chloride In tetrahydrofuran at 0 - 20℃; | ||
With dmap; triethylamine In dichloromethane at 20℃; | ||
With dmap; triethylamine In dichloromethane at 0 - 20℃; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 83% 2: 14% | With boron trifluoride diethyl etherate In chloroform for 2h; Reflux; Green chemistry; | Mono- and Di-N-benzylated Sulfonamides 3 and 4; General Procedure General procedure: In a round-bottom flask, a benzyl alcohol 2 (1.0 mmol), a sulfonamide1 (1.8 mmol) and BF3·OEt2 (151 μL, 1.2 mmol) were dissolved in CHCl3 (2.0 mL). The mixture was stirred for 2 h under reflux in air atmosphere, then the solvent was removed under reduced pressure using a rotary evaporator. The product was isolated by column chromatography of the residue on silica gel (EtOAc-PE, 1:10 to 1:2, v/v) to give the desired mono- and di-N-benzylated products 3 and 4. |
1: 22% 2: 70% | With cyanomethylenetributyl-phosphorane In benzene for 24h; Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: N-benzyl-p-toluenesulfonamide With n-butyllithium In tetrahydrofuran at 0℃; Stage #2: N-formylbenzotriazole In tetrahydrofuran at 0℃; | |
90% | Stage #1: N-benzyl-p-toluenesulfonamide With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.0833333h; Stage #2: N-formylbenzotriazole In tetrahydrofuran; hexane at 20℃; for 2h; | |
90% | With n-butyllithium In tetrahydrofuran; hexane at 20℃; for 2h; |
86% | Stage #1: N-benzyl-p-toluenesulfonamide With n-butyllithium In tetrahydrofuran; hexane at -10℃; for 0.5h; Inert atmosphere; Stage #2: N-formylbenzotriazole In tetrahydrofuran; hexane at -10 - 20℃; for 2.17h; | |
Stage #1: N-benzyl-p-toluenesulfonamide With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.25h; Inert atmosphere; Stage #2: N-formylbenzotriazole In tetrahydrofuran; hexane at 0 - 20℃; for 0.333333h; Inert atmosphere; | ||
Stage #1: N-benzyl-p-toluenesulfonamide With n-butyllithium In tetrahydrofuran at 0℃; Inert atmosphere; Stage #2: N-formylbenzotriazole In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | ||
Stage #1: N-benzyl-p-toluenesulfonamide With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 0.25h; Inert atmosphere; Stage #2: N-formylbenzotriazole In tetrahydrofuran; hexane at 0 - 20℃; for 0.333333h; Inert atmosphere; | N-Benzyl-N-(2,2-dibromovinyl)tosylamide 4 To a nitrogen flushed flask containing a stirrer bar was added N-benzyltosylamide (5.00 g, 19.1 mmol, 1.0 equiv) and anhydrous THF (115 mL). The stirred solution was cooled to 0 °C, then a solution of n-butyllithium (8.42 mL, 19.1 mmol, 1.0 equiv, 2.3 M solution in hexanes) was added dropwise over 5 minutes, and left to stir at 0 °C for 10 minutes. A solution of 1H-benzotriazole-1-carbaldehyde (BtCHO) (3.38 g, 21.1 mmol, 1.1 equiv) in anhydrous THF (69 mL) was added at 0 °C. The reaction was then warmed to room temperature and stirred until completion, as analysed by TLC (~20 min). The reaction was quenched by addition of H2O and Et2O (1:1) and the organic layer was separated. The remaining BtCHO was removed from the organic layer by extraction with 2 M aqueous K2CO3 (2-4 washes, as determined by TLC analysis). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude formamide was used in the next step without purification. To a nitrogen flushed flask containing a stirrer bar was added triphenylphosphine (20.1 g, 76.5 mmol, 4.0 equiv) and anhydrous CH2Cl2 (184 mL), and the solution was cooled to -10 °C whilst stirring. Tetrabromomethane (12.7 g, 38.3 mmol, 2.0 equiv) was added and the mixture stirred at -10 °C for 30 min. The resulting yellow/orangesolution was cooled to -30 °C and a solution of crude formamide in anhydrous CH2Cl2 (66 mL) was added dropwise over 15-20 minutes.The stirred reaction mixture was allowed to warm gradually to room temperature and stirred until completion (~4 h). The resulting darkred mixture was concentrated in vacuo to roughly 50% volume and then filtered through a silica gel column (eluting with 10→30% EtOAc/petrol) to afford the crude dibromoenamide. The resulting solid was then recrystallized from hot EtOH to give the title compound (7.28 g, 16.2 mmol, 85%, mp 110-111 °C) as a white powder. 1H NMR (CDCl3, 400 MHz): δ = 7.72 (2 H, d, J = 8.3 Hz, H3), 7.36-7.24 (7 H, m, H2, H5, H6, H7), 6.62 (1 H, s, H8), 4.54 (2 H, s, H4), 2.45 (3 H, s, H1). 13C NMR (CDCl3, 101 MHz): δ = 144.2, 135.7, 135.0, 131.3, 129.9, 128.6, 128.5, 128.1, 127.4, 97.2, 52.7, 21.6 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetonitrile at 65℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With 1,10-Phenanthroline; potassium carbonate In toluene at 85℃; for 20h; Inert atmosphere; | |
93% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine In toluene at 110℃; | |
93% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine In toluene Heating; |
84% | With potassium phosphate; 1,10-Phenanthroline; copper (II) sulfite In toluene at 60 - 65℃; | |
78% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 11h; Inert atmosphere; | |
76% | With iron(III) chloride hexahydrate; potassium carbonate; N,N`-dimethylethylenediamine In toluene at 90℃; for 12h; | |
70% | With iron(III) chloride hexahydrate; potassium carbonate; N,N`-dimethylethylenediamine In toluene at 90℃; for 12h; | |
64% | With potassium phosphate; 1,10-Phenanthroline; copper(II) sulfate In toluene at 70℃; for 20h; Inert atmosphere; | |
58% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | |
53% | With potassium phosphate | |
42% | Stage #1: N-benzyl-p-toluenesulfonamide With pyridine; copper(l) iodide; potassium hexamethylsilazane In tetrahydrofuran at 20℃; for 2h; Stage #2: 1-bromo-1-octyne In tetrahydrofuran; benzene at 20℃; for 20h; | |
With copper(II) sulfate | ||
With potassium phosphate; 1,10-Phenanthroline; copper(II) sulphate hydrate In toluene at 80℃; for 15h; Inert atmosphere; | Representative procedure for preparation of ynamides, for 1 in Scheme 1 To a solution of bromoethynylbenzene (1.4 g, 8.0 mmol) in 24 mL of anhydrous toluene in a reaction vial were added methyl phenylcarbamate (1.5 g, 9.6 mmol), K3PO4 (3.4 g, 16 mmol), copper sulfate-pentahydrate (400 mg, 16 mmol), and 1,10-phenanthroline (577 mg, 3.2 mmol). The reaction mixtures was capped under an argon atmosphere, and heated in an oil bath at 80 ºC for 15 h. The progress of the reaction was monitored using TLC analysis. Upon completion, the reaction mixture was allowed to cool to room temperature, and diluted with 15 mL of ethyl acetate. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography with eluent of Hexane/ ethyl acetate = 19/1 to give 1.6 g of 1 in 80 % yield as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 1.2, 8.6 Hz, 2H), 7.45-7.40 (m, 4H), 7.33-7.28 (m, 4H), 3.92 (s, 3H). 13C NMR. (100 MHz, CDCl3) δ 154.9, 139.7, 131.5, 129.1, 128.4, 128.0, 127.2, 124.8, 123.0, 83.0, 70.3, 54.5. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine In toluene at 110℃; | |
84% | With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine In toluene Heating; | |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 65℃; for 21h; |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 90℃; for 12h; Inert atmosphere; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 85℃; for 12h; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 14h; Sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium phosphate | |
99% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 72h; Sealed tube; | |
98% | With 1,10-Phenanthroline; copper(II) sulfate heptahydrate; potassium carbonate In water at 50℃; for 26h; |
98% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In water at 50℃; for 26h; | 1 Example 1: To a 4 mL reaction flask previously dried, benzyl-4-methylbenzenesulfonamide (53 mg, 0.2 mmol), copper sulfate pentahydrate (5 mg, 0.02 mmol), 1,10-phenanthroline ( 7.4mg, 0.04mmol), potassium carbonate (56.4mg, 0.4mmol), while adding 2wt.% Surfactant APGS-550-M aqueous phase system (0.4mL), and finally phenylacetylene bromide (44.3mg, 0.24mmol) After heating to 50 ° C, stirring was continued at 900-1000 rpm for 26 hours.After the reaction solution was stirred, it was extracted three times with ethyl acetate. The organic phases extracted several times were combined into a 25 mL eggplant-shaped flask. A Heidolph rotary evaporator was used, the speed was 80-100 rpm, the temperature was 38 ° C, and the degree of vacuum was 0.1 Mpa After treatment for 3 min, column chromatography was performed using 200-mesh column chromatography silica gel. The developing solvent was petroleum ether: ethyl acetate = 20: 1, and the target compound was isolated. (71mg, yield is 98%, purity by HPLC analysis is 98%, and the purity of the product can also be reflected from the NMR profile, signal, noise, etc.). |
97% | With 1,10-Phenanthroline; potassium carbonate In toluene at 110℃; for 24h; Inert atmosphere; | |
96% | With potassium phosphate; 1,10-Phenanthroline; copper (II) sulfite In toluene at 60 - 65℃; | |
96% | With 1,10-Phenanthroline; potassium carbonate; copper(II) sulfate In toluene at 65℃; for 50h; sonication; | |
96% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Schlenk technique; Inert atmosphere; | |
96% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Inert atmosphere; Schlenk technique; | |
95% | With iron(III) chloride hexahydrate; potassium carbonate; N,N`-dimethylethylenediamine In toluene at 90℃; for 12h; | |
94% | With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 65℃; for 18h; | |
92% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | |
90% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 18h; Inert atmosphere; Schlenk technique; | |
88% | With potassium phosphate; 1,10-Phenanthroline; copper(II) sulfate In toluene at 70℃; for 22h; Inert atmosphere; | |
87% | With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 80℃; for 48h; Inert atmosphere; | |
85% | With 1,10-Phenanthroline; potassium carbonate; copper(II) sulfate In toluene at 80℃; for 20h; Inert atmosphere; | |
78% | Stage #1: N-benzyl-p-toluenesulfonamide With pyridine; copper(l) iodide; potassium hexamethylsilazane In tetrahydrofuran at 20℃; for 2h; Stage #2: 1-Bromo-2-phenylacetylene In tetrahydrofuran; benzene at 20℃; for 20h; | |
78% | Stage #1: N-benzyl-p-toluenesulfonamide With pyridine; potassium hexamethylsilazane In tetrahydrofuran at 0 - 20℃; for 0.25h; Stage #2: With copper(l) iodide In tetrahydrofuran at 20℃; for 2h; Stage #3: 1-Bromo-2-phenylacetylene In tetrahydrofuran at 20℃; for 20.75h; Darkness; | |
71% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | |
68% | With iron(III) chloride hexahydrate; potassium carbonate; N,N`-dimethylethylenediamine In toluene at 90℃; for 12h; Inert atmosphere; | 4.3.7 N-Benzyl-4-methyl-N-(2-phenylethynyl)benzene-1-sulfonamide (1g) The reaction was conducted under argon in the presence of K2CO3 (2.0mmol, 276mg, 2 equiv), N-benzyl-4-methylbenzene-1-sulfonamide (1.0mmol, 261mg, 1 equiv) and FeCl3·6H2O (0.1mmol, 27mg, 0.1 equiv) in toluene (5mL). (2-Bromoethynyl)benzene (1.2mmol, 217mg, 1.2 equiv) and DMEDA (0.2mmol, 21μL, 0.2 equiv) were added. The reaction mixture was stirred at 90°C for 12h. The crude product was filtered on a silica pad and washed with diethyl ether. The filtrate was concentrated under vacuum and purified by flash chromatography on silica gel (pentane/diethyl ether (10/0 to 6/4)) to give the tosylynamide 1g (0.68mmol, 246mg, 68% yield) as a colorless oil. 1H NMR (400MHz, CDCl3) δ: 2.45 (s, 3H), 4.59 (s, 2H), 7.24 (br s, 4H), 7.29-7.35 (m, 6H), 7.77-7.83 (m, 2H), 7.82-7.78 (m, 2H). |
59% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Inert atmosphere; | |
43% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | |
With copper(II) sulfate | ||
With potassium phosphate; 1,10-Phenanthroline; copper(II) sulphate hydrate In toluene at 80℃; for 15h; Inert atmosphere; | Representative procedure for preparation of ynamides, for 1 in Scheme 1 To a solution of bromoethynylbenzene (1.4 g, 8.0 mmol) in 24 mL of anhydrous toluene in a reaction vial were added methyl phenylcarbamate (1.5 g, 9.6 mmol), K3PO4 (3.4 g, 16 mmol), copper sulfate-pentahydrate (400 mg, 16 mmol), and 1,10-phenanthroline (577 mg, 3.2 mmol). The reaction mixtures was capped under an argon atmosphere, and heated in an oil bath at 80 ºC for 15 h. The progress of the reaction was monitored using TLC analysis. Upon completion, the reaction mixture was allowed to cool to room temperature, and diluted with 15 mL of ethyl acetate. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography with eluent of Hexane/ ethyl acetate = 19/1 to give 1.6 g of 1 in 80 % yield as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 1.2, 8.6 Hz, 2H), 7.45-7.40 (m, 4H), 7.33-7.28 (m, 4H), 3.92 (s, 3H). 13C NMR. (100 MHz, CDCl3) δ 154.9, 139.7, 131.5, 129.1, 128.4, 128.0, 127.2, 124.8, 123.0, 83.0, 70.3, 54.5. | |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Inert atmosphere; Schlenk technique; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | 16 General procedure 1 for the synthesis of ynamides (1a-1d, 1f-1m, 1o, 1p, 1r)10c and procedure 2 for (1e, 1n, 1q)14 General procedure: Procedure 1: To a solution of alkyne (9.80 mmol, 1.0 equiv) in acetone (10 mL) was added NBS (10.78 mmol, 1.1 equiv) and AgNO3 (0.98 mmol, 0.1 equiv). The resulting solution was stirred under nitrogen at room temperature for 4 h. After removing excess acetone the reaction was quenched with water and extracted with petroleum ether three times, dried over MgSO4, and concentrated under reduced pressure. The residue was eluted through a short silica column (petroleum ether) to obtain the bromoalkyne. To a dried flask was added 2-oxazolidone (4.8 mmol, 1.2 equiv), CuSO4·5H2O (100 mg, 0.4 mmol, 0.1 equiv), 1,10-phenanthroline (144 mg, 0.8 mmol, 0.2 equiv) and K2CO3 (1.38 g, 10.0 mmol, 2.5 equiv), bromoalkyne (4.0 mmol, 1.0 equiv) and this mixture was subsequently treated with anhydrous toluene (10 mL). The flask was charged with nitrogen, and the solution was heated at 80 °C overnight. After completion, the crude reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. Purification of the crude residue using silica gel flash column chromatography yielded the pure ynamides. | |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 70℃; Inert atmosphere; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Schlenk technique; Inert atmosphere; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 70℃; for 24h; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 80℃; Inert atmosphere; Schlenk technique; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | ||
759 mg | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; Sealed tube; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 60℃; Schlenk technique; Inert atmosphere; | General experimental procedure for synthesis of ynamides 2a-l General procedure: A Schlenk flask charged with a stirring bar, sulfonamide (12mmol, 1.2 equiv), K2CO3 (20mmol, 2.0 equiv), CuSO45H2O (1.0mmol, 10mol%), and 1,10-phenanthroline (2.0mmol, 20mol%) was vacuumed and backfilled with N2, repeatedly for 3 times, and then a solution of alkynyl bromide [26] (10mmol, 1.0 equiv) in toluene (10mL, 1M) was added to the mixture by a syringe. The resulting mixture was heated to 60°C for 24-48h. After completion, the mixture was filtered through celite pad, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (PE/EtOAc=20/1-5/1) to give the ynamide product. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Inert atmosphere; Schlenk technique; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | 4.1.1. General Procedure for synthesis of ynamide 7. General procedure: To a mixture of an amide (2 mmol), K3PO4 (4 mmol),CuSO4*5H2O (0.2 mmol) and 1,10-phenanthroline (0.4 mmol) intoluene at N2 atmosphere was added a solution 1-bromoalkyne (2.2 mmol) in toluene. The reaction was stirred at 75 °C for 24 h at N2 atmosphere. The reaction mixture was cooled to room temperature and diluted with EtOAc and filtered through Celite andthe filtrate was concentrated in vacuo. The crude products were purified by silica gel flash chromatography to afford the desired ynamide. | |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | (2) General procedure for the synthesis of ynamides 10a-g and 11a-b. General procedure: To a mixture of an amide (1 eq), K3PO4 (2 eq), CuSO4·5H2O (0.1 eq) and 1,10-phenanthroline (0.2 eq) in toluene was added a solution of 1-bromoalkyne (1.1 eq) intoluene. The reaction was stirred at 75 °C for 24 h at a N2 atmosphere. The reactionmixture was cooled to room temperature, diluted with EtOAc, and filtered throughCelite, and the filtrate was concentrated in vacuo. The crude product is purified bycolumn chromatography to obtain ynamides 10a-g or 11a-b. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | General Procedure for Synthesis of 8.21 General procedure: To a mixture of an amide (2 mmol), K3PO4 (4 mmol), CuSO4·5H2O (0.2 mmol), and 1,10-phenanthroline (0.4 mmol) in toluene under a N2 atmosphere was added a solution 1-bromoalkyne (2.2 mmol) in toluene. The reaction was stirred at 75 °C for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography to afford the desired ynamide. Compounds 8 were obtained in our laboratory. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With tripotassium phosphate tribasic; 1,10-Phenanthroline; copper (II) sulfite In toluene at 60 - 65℃; for 32h; | |
92% | With tripotassium phosphate tribasic; 1,10-Phenanthroline; Cupric sulfate In toluene at 80℃; for 48h; Inert atmosphere; | |
91% | With tripotassium phosphate tribasic; 1,10-Phenanthroline; copper(II) sulphate In toluene at 70℃; for 38h; Inert atmosphere; |
86% | With 1,10-Phenanthroline; Cupric sulfate; potassium carbonate In toluene at 80℃; for 24h; Sealed tube; | |
62% | With 1,10-Phenanthroline; copper(II) sulfate pentahydrate; potassium carbonate In water monomer at 50℃; for 26h; | |
45% | With 1,10-Phenanthroline; Cupric sulfate; potassium carbonate In toluene at 80℃; for 12h; Schlenk technique; Inert atmosphere; | |
45% | With 1,10-Phenanthroline; Cupric sulfate; potassium carbonate In toluene at 80℃; for 12h; Inert atmosphere; Schlenk technique; | |
With tripotassium phosphate tribasic; 1,10-Phenanthroline; Cupric sulfate In toluene at 80℃; for 48h; Inert atmosphere; | ||
With 1,10-Phenanthroline; Cupric sulfate In toluene at 85℃; for 48h; Inert atmosphere; | ||
With 1,10-Phenanthroline; Cupric sulfate; potassium carbonate In toluene at 70℃; Inert atmosphere; Sealed tube; | ||
With 1,10-Phenanthroline; Cupric sulfate In toluene at 80℃; for 24h; Inert atmosphere; Sealed tube; Alkaline conditions; | ||
With tripotassium phosphate tribasic; 1,10-Phenanthroline; Cupric sulfate In toluene at 80℃; for 24h; Inert atmosphere; | ||
With 1,10-Phenanthroline; Cupric sulfate; potassium carbonate In toluene at 85℃; Schlenk technique; Inert atmosphere; | ||
With 1,10-Phenanthroline; Cupric sulfate; potassium carbonate In toluene at 85℃; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1,10-Phenanthroline; copper(II) sulfate heptahydrate; potassium carbonate In water at 50℃; for 26h; | |
96% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In water at 50℃; for 26h; | 6 Example 6: To a 4 mL reaction flask previously dried, benzyl-4-methylbenzenesulfonamide (53 mg, 0.2 mmol), copper sulfate pentahydrate (5 mg, 0.02 mmol), 1,10-phenanthroline ( 7.4mg, 0.04mmol), potassium carbonate (56.4mg, 0.4mmol), while adding 2wt.% Surfactant APGS-550-M aqueous phase system (0.4mL), and finally 2-methoxyphenylacetylene bromide (51.4 mg, 0.24 mmol), after heating to 50 ° C, stirring was continued at 900-1000 rpm for 26 h.After the reaction solution was stirred, it was extracted three times with ethyl acetate. The organic phases extracted several times were combined into a 25 mL eggplant-shaped flask. A Heidolph rotary evaporator was used, the speed was 80-100 rpm, the temperature was 38 ° C, and the degree of vacuum was 0.1 Mpa After treatment for 3 min, column chromatography was performed using 200-mesh column chromatography silica gel. The developing solvent was petroleum ether: ethyl acetate = 15: 1, and the target compound was isolated. (75mg, the yield is 96%, and the purity is 98% by HPLC analysis, which can also reflect the extremely high purity of the product from the shape, signal, and noise of the NMR spectrum). |
93% | With potassium phosphate; 1,10-Phenanthroline; copper (II) sulfite In toluene at 60 - 65℃; |
72% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Schlenk technique; Inert atmosphere; | |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | General Procedure for Synthesis of 8.21 General procedure: To a mixture of an amide (2 mmol), K3PO4 (4 mmol), CuSO4·5H2O (0.2 mmol), and 1,10-phenanthroline (0.4 mmol) in toluene under a N2 atmosphere was added a solution 1-bromoalkyne (2.2 mmol) in toluene. The reaction was stirred at 75 °C for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography to afford the desired ynamide. Compounds 8 were obtained in our laboratory. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium phosphate; 1,10-Phenanthroline In toluene at 65℃; for 17h; | |
99% | With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 65℃; | |
74% | With potassium phosphate; 1,10-Phenanthroline; copper (II) sulfite In toluene at 60 - 65℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With formic acid; C6H15N*C31H37ClN2O2RhS*ClH; triethylamine In ethyl acetate Inert atmosphere; | |
83% | With bis(acetylacetonate)nickel(II); diethylzinc In 1,4-dioxane; toluene at 20℃; | |
80% | With [(η5-pentamethylcyclopentadienyl)Ir(2,2'-biimidazole)(H2O)][OTf]2; caesium carbonate; benzyl alcohol In water at 130℃; for 2h; Microwave irradiation; Inert atmosphere; Sealed tube; |
75% | With methanol; potassium <i>tert</i>-butylate; bis(pinacol)diborane; copper(l) chloride In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; Sealed tube; | 4.5. General procedure of transfer hydrogenation of N-sulfonylimines General procedure: The starting material N-sulfonyl imines 6 (0.2 mmol), CuCl (5 mol %) and bis(pinacolato)diboron (1.2 equiv.), t-BuOK (10 mol %) were placed in oven-dried round bottom flask (10 mL) closed with a septum, the vials were connected to a vacuum/Ar manifold through a needle, evacuated and then back filled with Ar for three times. Regular THF (0.9 mL) was added via a syringe, then MeOH (0.3 mL) was added dropwise and the mixtures were stirred at room temperature for 12 h. The residues obtained were purified by column chromatography on silica gel with EtOAc/Hexane (v/v, 1/3) to provide the desired products 7 as solids. |
73% | With 1,5-dimethylcyclohexa-1,4-diene; tris(pentafluorophenyl)borate In toluene at 125℃; for 18h; Glovebox; Sealed tube; Inert atmosphere; | |
68% | With triethylsilane; iodine In dichloromethane at 20℃; for 0.5h; | N-Benzyl-4-methylbenzenesulfonamide (2a); Typical Procedure A flask was successively charged with HSiEt3 (232.6 mg, 2.0mmol, 2.0 equiv), N-sulfonyl aldimine 1a (259.3 mg, 1.0 mmol,1.0 equiv), DCM (2.0 mL), and I2 (126.9 mg, 0.5 mmol, 0.5 equiv),and the mixture was stirred at rt for 30 min. DCM (20.0 mL) and0.5 M aq Na2S2O3 (10 mL) were added to the flask, and theorganic layer was separated, washed with brine, dried (Na2SO4),filtered, concentrated, and purified by flash column chromatography[silica gel (200-300 mesh), PE-EtOAc (4:1)] to give awhite solid; yield: 178.2 mg (68%); mp 117-118 °C.1H NMR (600 MHz, CDCl3): = 7.75 (d, J = 8.4 Hz, 2 H), 7.30 (d,J = 8.4 Hz, 2 H), 7.28-7.23 (m, 3 H), 7.22-7.16 (m, 2 H), 4.93-4.80 (m, 1 H), 4.11 (d, J = 6.6 Hz, 2 H), 2.44 (s, 3 H). 13C NMR (150MHz, CDCl3): = 143.6, 136.9, 136.4, 129.9, 128.8, 128.0, 127.3,47.4, 21.7. |
65% | With [(η5-C5Me5)Ir(6,6'-dihydroxy-2,2'-bipyridine)(H2O)]OTf2; caesium carbonate; benzyl alcohol In water at 120℃; for 12h; Inert atmosphere; Schlenk technique; | |
Multi-step reaction with 2 steps 1.1: ZnCl2 / tetrahydrofuran / 1 h / 20 °C 1.2: 90 percent / tetrahydrofuran / 2 h / 20 °C 2.1: tetrahydrofuran / 1 h / 20 °C 2.2: 20 percent / tetrahydrofuran / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium hexamethylsilazane In N,N-dimethyl-formamide at 45℃; for 18h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With zinc(II) chloride at 20℃; for 0.0833333h; | |
79% | With 5Cs(1+)*H(1+)*P2W18O62(6-) = Cs5HP2W18O62 In water at 20℃; Inert atmosphere; Green chemistry; | Preparation of N-acyl sulfonamides (2a-j), (3a-m), (5a-f) and cyclic imides (3n-r) General procedure: Under nitrogen atmosphere, a mixture of sulfonamide (1 mmol), acylating agent(2 mmol) and Cs5HP2W18O62 catalyst (5 mmol %) in water (2 mL), was stirred at roomtemperature to obtain compounds (2a-j), (3a-m), (5a-f), and under reflux for (3n-r).The reaction was monitored by TLC. After completion of the reaction, the catalyst wasremoved by filtration. The filtrate was washed by water (10 mL) and extracted withEtOAc (315 mL). The combined organic layers were dried over anhydrous Na2SO4,then the solvent was evaporated in vacuum and the crude compound was purified byflash chromatography (Merck silica gel 60 H, CH2Cl2/MeOH, 9:1) to afford the corresponding products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With palladium diacetate; potassium carbonate In toluene at 150℃; for 8h; | |
99% | With chlorotris(triphenylphosphine) rhodium (I); potassium carbonate at 120℃; for 12h; Sealed tube; | |
98% | With potassium carbonate; iron(II) chloride at 135℃; for 20h; Inert atmosphere; |
98% | With potassium carbonate at 160℃; for 12h; | |
98% | With C44H39IrN2P(1+)*C32H12BF24(1-); Cs2CO3 In toluene at 120℃; for 12h; Inert atmosphere; | |
97% | With Ru/Fe3O4; potassium carbonate at 150℃; for 12h; Inert atmosphere; | |
96% | With air; copper (II) acetate; potassium carbonate at 150℃; for 12h; | |
96% | With copper (II) acetate; potassium carbonate at 150℃; for 12h; | |
95% | With bis[dichlorido(η5-1,2,3,4,5-pentamethyl-cyclopentadienyl)iridium(III)]; potassium-t-butoxide In toluene for 17h; Inert atmosphere; Reflux; | |
94% | With C41H36AsClN3OPRuS; potassium hydroxide In toluene at 100℃; for 12h; | 2.6 Typical procedure for catalytic N-alkylation of amines/sulfonamides with alcohols General procedure: Amine/sulfonamide (1mmol), alcohol (1mmol), catalyst (0.5mol %), KOH (50mol %) and toluene (2mL) were placed in a 25mL round bottomed flask and stirred on a preheated oil bath (100°C) for 12h. Upon completion (as monitored by TLC), the reaction mixture was cooled at ambient temperature, H2O (3mL) was added and the organic layer was extracted with CH2Cl2. The organic extract was separated, dried, and concentrated. The desired product was purified by column chromatography with n-hexane/EtOAc as eluent. |
94% | With trifluoromethylsulfonic anhydride In 1,4-dioxane at 120℃; for 48h; | General procedure for the reaction of sulfonamides with alcohols General procedure: To a mixture of sulfonamide (2 mmol) and alcohol (10 mmol) in 1,4-dioxane (3 mL) was added Tf2O (2 mmol). The mixture was then sealed and stirred at 120 °C until the reaction was completed as judged by TLC. After quenching with satd. aq. NaHCO3, the reaction mixture was extracted three times with EtOAc, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography with PE and EtOAc (3: 1) as the eluent to give the pure product. |
93% | With Cp*Ir(6,6'-dionato-2,2'-bipyridine)(H2O); Cs2CO3 In lithium hydroxide monohydrate at 120℃; for 15h; Inert atmosphere; Schlenk technique; | |
93% | With C20H25IrN2O3; Cs2CO3 In lithium hydroxide monohydrate at 120℃; for 15h; Schlenk technique; | 34 Example 34: N- benzyl-4-methyl-benzenesulfonamide 4-methyl-benzenesulfonamide (171mg, 1mmol), catalyst A (8.3mg, 0.01mmol, 1.0mol%), cesium carbonate (33mg, 0.1mmol, 0.1equiv.), Benzyl alcohol (130mg, 1.2mmol) and water (1ml) were successively added to the reaction flask 25mlSchlenk.After the reaction mixture was reacted at 120 15 hours, cooled to room temperature.A large amount of precipitated, water was removed by filtration, the filter cake was washed with water three times to give the title compound, yield: 92%. Except that catalyst B (5.3 mg, 0. Olmmol, 1 mol%) was used in place of catalyst A, and the other starting materials, conditions and products were the same as in Example 1, yield: 93% |
92% | With potassium-t-butoxide; copper (II) acetate In toluene at 150℃; for 120h; | |
92% | With potassium-t-butoxide; copper (II) acetate In toluene at 150℃; for 120h; Inert atmosphere; | 4.4. General procedure for synthesis of amides 12, 14 and 16 General procedure: To a solution of Cu(OAc)2 (0.05 mmol, 0.0092 g) and potassium tert-butoxide (0.175 g, 2.5 mmol) in anhydrous dioxane (3 mL), the corresponding amide 11, 13 or 15 (2.5 mmol) and the corresponding alcohol 2 (3.25 mmol) were added successively under inert argon atmosphere. After 5 days of reaction at 150 °C, it was hydrolyzed with a saturated solution of ammonium chloride (10 mL). The mixture was extracted with AcOEt (3×10 mL) and washed with brine (10 mL), after drying over anhydrous MgSO4 and filtering on Celite, the solvents were removed under low pressure (15-18 Torr). The resulting mixture was purified by column chromatography (if needed). |
91% | With di-μ-chlorobis-[(η6-p-cymene)chlororuthenium(II)]; bis[2-(diphenylphosphino)phenyl] ether at 165℃; for 2h; Inert atmosphere; Microwave irradiation; Neat (no solvent); | |
91% | With [N,S-(2-(2-(diphenylphosphino)benzylidene)-N-ethylthiosemicarbazone)RuH(CO)(PPh3)2]; potassium hydroxide In toluene at 120℃; for 12h; | |
91% | With [(η5-pentamethylcyclopentadienyl)Ir(2,2'-biimidazole)(H2O)][OTf]2; Cs2CO3 In lithium hydroxide monohydrate at 130℃; for 2h; Microwave irradiation; Inert atmosphere; Sealed tube; | |
91% | With [(η5-pentamethylcyclopentadienyl)Ir(2,2'-biimidazole)(H2O)][OTf]2; Cs2CO3 In lithium hydroxide monohydrate at 130℃; for 2h; | 1 N-benzyl-4-methylbenzenesulfonamide Add 4-methylbenzenesulfonamide (171mg, 1mmol),Catalyst (7.7mg, 0.01mmol, 1.0mol%),Cesium carbonate (33mg, 0.1mmol, 0.1equiv.),Benzyl alcohol (130mg, 1.2mmol)Then add water (1ml) to the microwave tube reaction flask.After the reaction mixture was reacted at 130°C for 2 hours,Cool to room temperature.Rotary evaporation to remove the solvent,Then through column chromatography (developer:Petroleum ether/ethyl acetate) to obtain pure target compound,Yield: 91%. |
91% | With Cs2CO3 In toluene at 40℃; for 48h; Inert atmosphere; | |
89% | With potassium carbonate; benzaldehyde at 135℃; for 18h; Schlenk technique; Green chemistry; | |
89% | With C20H26ClIrN3O(1+)*F6P(1-); anhydrous sodium carbonate In lithium hydroxide monohydrate at 110℃; for 24h; Inert atmosphere; Schlenk technique; Glovebox; | |
86% | With potassium hydroxide In toluene at 130℃; for 48h; Inert atmosphere; | |
86% | With [Cp*Ir(SnCl3)2{SnCl2(H2O)2}] In 1,2-dichloro-ethane at 70℃; Schlenk technique; Inert atmosphere; regioselective reaction; | 4.4. General procedure for the alkylation reaction with pactivatedalcohols catalyzed by 2 General procedure: To a solution of p-activated alcohol (0.5 mmol) in 3 mL of dichloroethaneor dichloromethane were added under an argon atmosphere2 (5 mg, 0.005 mmol) and nucleophile (1.0 mmol). Thereaction mixture was stirred at a specific temperature oil bath.When the reactionwas(monitored by TLC using ethyl acetate/petroleum ether 60e80 C 1:3 v/v), a saturated aqueous solution ofsodium hydrogen carbonate was added. The aqueous layer wasthen extracted two times with dichloromethane (25 mL). Thecombined organic layers were driedsodium sulfate; the solventwas removed under reduced pressure. The resulting productwas purified by column chromatography on silica gel to obtain theexpected coupled products 13, 14, and 15. |
86% | With 2,2,2-trifluoroethanol; chloro[5-methoxy-2-[1-[(4-methoxyphenyl)imino-N]ethyl]phenyl-C][(1,2,3,4,5-η)-1,2,3,4,5-pentamethyl-2,4-cyclopentadien-1-yl]iridium; potassium carbonate at 100℃; for 12h; Inert atmosphere; Sealed tube; | |
86% | With [Mn(HN(C2H4PiPr2)2)(CO)2Br]; potassium carbonate In 5,5-dimethyl-1,3-cyclohexadiene at 150℃; for 24h; Sealed tube; | |
86% | With C21H30N5Ru(1+)*C24H20B(1-); potassium hydroxide In para-xylene at 140℃; for 16h; Inert atmosphere; Schlenk technique; | |
84% | With di-μ-chlorobis-[(η6-p-cymene)chlororuthenium(II)]; potassium carbonate; triphenylphosphine In 5,5-dimethyl-1,3-cyclohexadiene at 150℃; for 24h; Inert atmosphere; | |
84% | With di-μ-chlorobis-[(η6-p-cymene)chlororuthenium(II)]; potassium carbonate; bis[2-(diphenylphosphino)phenyl] ether In 5,5-dimethyl-1,3-cyclohexadiene at 20 - 150℃; for 24.1667h; Inert atmosphere; | |
84% | With C19H37NO3P2Re(1+)*Br(1-); Cs2CO3 In tert-Amyl alcohol at 150℃; for 22h; Inert atmosphere; Sealed tube; | |
79% | With palladium diacetate; potassium carbonate In neat (no solvent) at 135℃; for 24h; Sealed tube; | |
75% | With [Pd(COD)Cl(SnCl3)] In o-dimethylbenzene at 140℃; for 24h; | S-3.Typical Procedure for N-alkylation of amine with alcohols General procedure: A mixture of aniline 1 (23.28 mg, 0.25 mmol), benzyl alcohol 2 (27 mg, 0.25 mmol), [Pd(COD)Cl(SnCl3)] (3.5 mg, 0.007 mmol) in 3mL of o-xylene was stirred at 140 °C for 24h. Then, solvent was removed under reduced pressure, and the mixture was subjected to column chromatography over silica gel (100-200 mesh, eluent: petroleum ether 60-80 °C/ethylacetate 20:1 v/v) to afford a corresponding product 3 as a yellow color oil in 90% (41.5 mg) isolated yield. |
74% | In nitromethane at 100℃; for 8h; | |
74% | In nitromethane at 80℃; for 6h; | |
63% | With potassium carbonate In neat (no solvent) at 175℃; for 60h; Sealed tube; | |
59% | With oxalic acid; 2,3,4,5-tetrafluorophenylboronic acid In nitromethane at 80℃; for 3h; Sealed tube; | |
56% | With trifluorormethanesulfonic acid In 1,4-dioxane at 20℃; for 8h; Inert atmosphere; | |
56% | With bis[dichlorido(η5-1,2,3,4,5-pentamethyl-cyclopentadienyl)iridium(III)]; 2-(2-(diphenylphosphanyl)phenyl)benzo[d]oxazole; potassium hydroxide In toluene at 110℃; for 24h; Schlenk technique; Inert atmosphere; | 4.3. General procedure for alkylation reactions General procedure: [Cp*IrCl2]2 (1 mol %, 0.01 mmol, 8.0 mg), 4a (2 mol %, 0.02 mmol,7.6 mg), KOH (10 mol %, 0.1 mmol, 5.6 mg), and toluene (5 mL) wereadded to a 25mL Schlenk tube with stirring under N2 at roomtemperature. Then ketones/secondary alcohols/amines (1 mmol),primary alcohols (1.1 mmol) were added by syringe. The reactionmixture was heated to 110 °C under reflux in an oil bath for 24 h. Itwas cooled to ambient temperature. Then it was concentrated invacuo, and purified by flash column chromatography with petroleumether/ethyl acetate to afford the corresponding alkylatedproduct. |
53% | With phosphotungstic acid In 1,4-dioxane at 80℃; for 12h; | |
5% | With 4,4′-azobispyridine; triphenylphosphine In acetonitrile for 6h; Reflux; | |
98 %Chromat. | With manganese(IV) oxide; potassium carbonate at 135℃; for 24h; | |
72 %Spectr. | With boron trifluoride diethyl ether complex In chloroform at 60℃; for 2h; Green chemistry; | Mono- and Di-N-benzylated Sulfonamides 3 and 4; General Procedure General procedure: In a round-bottom flask, a benzyl alcohol 2 (1.0 mmol), a sulfonamide1 (1.8 mmol) and BF3·OEt2 (151 μL, 1.2 mmol) were dissolved in CHCl3 (2.0 mL). The mixture was stirred for 2 h under reflux in air atmosphere, then the solvent was removed under reduced pressure using a rotary evaporator. The product was isolated by column chromatography of the residue on silica gel (EtOAc-PE, 1:10 to 1:2, v/v) to give the desired mono- and di-N-benzylated products 3 and 4. |
90 %Spectr. | With potassium hydroxide In mineral oil at 130℃; for 10h; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With phenanthrene; potassium carbonate; copper(II) sulfate In toluene at 70℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With potassium <i>tert</i>-butylate In tetrahydrofuran; toluene at 20℃; Inert atmosphere; | General Procedure A - N-Propargylation of Secondary Sulfonamides General procedure: To a 1.7 M solution of the appropriate secondary sulfonamide in dry THF, exactly one equivalent of tBuOK (dispensed as a 1.0 M solution in THF) was added under an atmosphere of dry Ar. After stirring for the prescribed time (exothermic reaction), propargyl bromide (80% in toluene, approx. 9.2 M, 1.2 equiv) was added and the resulting solution was left overnight at room temperature. Volatiles were evaporated under reduced pressure and the residue was dissolved in toluene (5 mL for each mmol of product) and washed with a NaOH solution (1 M in water, 1 mL per mmol of product, repeated twice), then with brine and exsiccated over Na2SO4. Removal of the solvent in vacuo gave the required N-propargylatedtertiary sulfonamides in sufficient purity for the subsequent transformations. |
97% | With caesium carbonate | |
97% | Stage #1: N-benzyl-p-toluenesulfonamide With sodium hydride In tetrahydrofuran at -20 - 20℃; Inert atmosphere; Stage #2: propargyl bromide In tetrahydrofuran at 0 - 20℃; Inert atmosphere; |
92% | With potassium carbonate In acetone; toluene at 60℃; for 12h; | |
91% | With potassium carbonate In acetonitrile for 8h; Reflux; | |
85% | With potassium carbonate In acetone at 60℃; for 12h; Inert atmosphere; | |
With potassium carbonate In acetonitrile at 80℃; for 8h; | ||
With potassium carbonate In acetone Reflux; Inert atmosphere; | ||
With potassium carbonate In acetonitrile at 80℃; for 8h; | ||
With potassium carbonate In acetone for 12h; Inert atmosphere; Reflux; | ||
With potassium carbonate In acetonitrile at 80℃; for 8h; | 2.4. General synthesis process for N-propargylsulfonamides 1 General procedure: To a stirred solution of amine (5 mmol) in 3mL pyridine, aryl sulfonyl chloride (7 mmol) was added and stirred for 3 h at room temperature. After completion of the reaction, the mixture was poured into ice cold water and stirred for 15 min, which resulted inprecipitation of the desired sulfonamide in high yield. To a stirred solution of the synthesized sulfonamide (1 mmol) and K2CO3(1 mmol) in acetonitrile (5 mL), was added dropwise propargyl bromide (1.1 mmol). The reaction mixture was heated at 80 °C for 8 h. After completion of the reaction, as monitoring by TLC, the mixture was evaporated under vacuum. Water was added, and thereaction mixture was extracted by DCM (3 5 mL). The combinedorganic extracts were dried with Na2SO4, filtered, and then evaporated to obtain pure N-propargylsulfonamides 1 in high yields. | |
With potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium carbonate In acetonitrile at 20℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With pyridine; oxygen; sodium carbonate In toluene at 70℃; for 4h; | |
44% | Stage #1: N-benzyl-p-toluenesulfonamide With pyridine; oxygen; sodium carbonate; copper dichloride In toluene at 70℃; for 0.25h; Stage #2: phenylacetylene In toluene at 70℃; for 8h; | |
44% | Stage #1: N-benzyl-p-toluenesulfonamide With pyridine; oxygen; sodium carbonate; copper dichloride In toluene at 70℃; for 0.25h; Stage #2: phenylacetylene In toluene at 70℃; for 8h; |
43% | Stage #1: N-benzyl-p-toluenesulfonamide With pyridine; oxygen; sodium carbonate; copper dichloride In toluene at 70℃; for 0.25h; Stage #2: phenylacetylene In toluene at 70℃; for 8h; | |
With pyridine; oxygen; sodium carbonate; copper dichloride In toluene at 70℃; for 8h; | ||
With pyridine; oxygen; sodium carbonate; copper dichloride In toluene at 70℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 80℃; for 3h; | |
62% | With iron(III) chloride hexahydrate; potassium carbonate; N,N`-dimethylethylenediamine In toluene at 90℃; for 12h; | |
59% | With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Inert atmosphere; |
52% | With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 80℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With iron(III) chloride hexahydrate; potassium carbonate; N,N`-dimethylethylenediamine In toluene at 90℃; for 12h; | |
88% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 18h; Inert atmosphere; Schlenk technique; | |
82% | With 1,10-Phenanthroline; potassium carbonate In toluene at 70℃; for 20h; Inert atmosphere; |
73% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Schlenk technique; Inert atmosphere; | |
73% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Inert atmosphere; Schlenk technique; | |
72% | With 1,10-Phenanthroline; copper(II) sulfate heptahydrate; potassium carbonate In water at 50℃; for 26h; | |
68% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Inert atmosphere; Schlenk technique; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | (2) General procedure for the synthesis of ynamides 10a-g and 11a-b. General procedure: To a mixture of an amide (1 eq), K3PO4 (2 eq), CuSO4·5H2O (0.1 eq) and 1,10-phenanthroline (0.2 eq) in toluene was added a solution of 1-bromoalkyne (1.1 eq) intoluene. The reaction was stirred at 75 °C for 24 h at a N2 atmosphere. The reactionmixture was cooled to room temperature, diluted with EtOAc, and filtered throughCelite, and the filtrate was concentrated in vacuo. The crude product is purified bycolumn chromatography to obtain ynamides 10a-g or 11a-b. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | General Procedure for Synthesis of 8.21 General procedure: To a mixture of an amide (2 mmol), K3PO4 (4 mmol), CuSO4·5H2O (0.2 mmol), and 1,10-phenanthroline (0.4 mmol) in toluene under a N2 atmosphere was added a solution 1-bromoalkyne (2.2 mmol) in toluene. The reaction was stirred at 75 °C for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography to afford the desired ynamide. Compounds 8 were obtained in our laboratory. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With iron(III) chloride hexahydrate; potassium carbonate; N,N`-dimethylethylenediamine In toluene at 90℃; for 12h; | |
82% | With 1,10-Phenanthroline; potassium carbonate In toluene at 70℃; for 20h; Inert atmosphere; | |
80% | With 1,10-Phenanthroline; copper(II) sulfate heptahydrate; potassium carbonate In water at 50℃; for 26h; |
70% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 18h; Inert atmosphere; Schlenk technique; | |
65% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | |
29% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Schlenk technique; Inert atmosphere; | |
With potassium phosphate; 1,10-Phenanthroline; copper(II) sulphate hydrate In toluene at 80℃; for 15h; Inert atmosphere; | Representative procedure for preparation of ynamides, for 1 in Scheme 1 To a solution of bromoethynylbenzene (1.4 g, 8.0 mmol) in 24 mL of anhydrous toluene in a reaction vial were added methyl phenylcarbamate (1.5 g, 9.6 mmol), K3PO4 (3.4 g, 16 mmol), copper sulfate-pentahydrate (400 mg, 16 mmol), and 1,10-phenanthroline (577 mg, 3.2 mmol). The reaction mixtures was capped under an argon atmosphere, and heated in an oil bath at 80 ºC for 15 h. The progress of the reaction was monitored using TLC analysis. Upon completion, the reaction mixture was allowed to cool to room temperature, and diluted with 15 mL of ethyl acetate. The mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography with eluent of Hexane/ ethyl acetate = 19/1 to give 1.6 g of 1 in 80 % yield as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.55 (dd, J = 1.2, 8.6 Hz, 2H), 7.45-7.40 (m, 4H), 7.33-7.28 (m, 4H), 3.92 (s, 3H). 13C NMR. (100 MHz, CDCl3) δ 154.9, 139.7, 131.5, 129.1, 128.4, 128.0, 127.2, 124.8, 123.0, 83.0, 70.3, 54.5. | |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 80℃; Inert atmosphere; Schlenk technique; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | 4.1.1. General Procedure for synthesis of ynamide 7. General procedure: To a mixture of an amide (2 mmol), K3PO4 (4 mmol),CuSO4*5H2O (0.2 mmol) and 1,10-phenanthroline (0.4 mmol) intoluene at N2 atmosphere was added a solution 1-bromoalkyne (2.2 mmol) in toluene. The reaction was stirred at 75 °C for 24 h at N2 atmosphere. The reaction mixture was cooled to room temperature and diluted with EtOAc and filtered through Celite andthe filtrate was concentrated in vacuo. The crude products were purified by silica gel flash chromatography to afford the desired ynamide. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | General Procedure for Synthesis of 8.21 General procedure: To a mixture of an amide (2 mmol), K3PO4 (4 mmol), CuSO4·5H2O (0.2 mmol), and 1,10-phenanthroline (0.4 mmol) in toluene under a N2 atmosphere was added a solution 1-bromoalkyne (2.2 mmol) in toluene. The reaction was stirred at 75 °C for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography to afford the desired ynamide. Compounds 8 were obtained in our laboratory. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 1,10-Phenanthroline; copper(II) sulfate heptahydrate; potassium carbonate In water at 50℃; for 26h; | |
98% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In water at 50℃; for 26h; | 4 Example 4: To a 4 mL reaction flask previously dried, benzyl-4-methylbenzenesulfonamide (53 mg, 0.2 mmol), copper sulfate pentahydrate (5 mg, 0.02 mmol), 1,10-phenanthroline ( 7.4mg, 0.04mmol), potassium carbonate (56.4mg, 0.4mmol), while adding 2wt.% Surfactant APGS-550-M aqueous phase system (0.4mL), and finally p-chlorophenylacetylene bromide (52.8mg, 0.24 mmol), heated to 50 ° C., and continuously stirred at 900-1000 rpm for 26 h.After the reaction solution was stirred, it was extracted three times with ethyl acetate. The organic phases extracted several times were combined into a 25 mL eggplant-shaped flask. A Heidolph rotary evaporator was used, the speed was 80-100 rpm, the temperature was 38 ° C, and the degree of vacuum was 0.1 Mpa After treatment for 3 min, column chromatography was performed using 200-mesh column chromatography silica gel. The developing solvent was petroleum ether: ethyl acetate = 20: 1, and the target compound was isolated. (77.5mg, the yield is 98%, and the purity is 98% by HPLC analysis. From the shape, signal and noise of the NMR spectrum, it can also reflect the extremely high purity of the product). |
88% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Schlenk technique; Inert atmosphere; |
88% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Inert atmosphere; Schlenk technique; | |
86% | With iron(III) chloride hexahydrate; potassium carbonate; N,N`-dimethylethylenediamine In toluene at 90℃; for 12h; | |
77% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 18h; Inert atmosphere; Schlenk technique; | |
75% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 80℃; Inert atmosphere; Schlenk technique; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Inert atmosphere; Schlenk technique; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | 4.1.1. General Procedure for synthesis of ynamide 7. General procedure: To a mixture of an amide (2 mmol), K3PO4 (4 mmol),CuSO4*5H2O (0.2 mmol) and 1,10-phenanthroline (0.4 mmol) intoluene at N2 atmosphere was added a solution 1-bromoalkyne (2.2 mmol) in toluene. The reaction was stirred at 75 °C for 24 h at N2 atmosphere. The reaction mixture was cooled to room temperature and diluted with EtOAc and filtered through Celite andthe filtrate was concentrated in vacuo. The crude products were purified by silica gel flash chromatography to afford the desired ynamide. | |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | General Procedure for Synthesis of 8.21 General procedure: To a mixture of an amide (2 mmol), K3PO4 (4 mmol), CuSO4·5H2O (0.2 mmol), and 1,10-phenanthroline (0.4 mmol) in toluene under a N2 atmosphere was added a solution 1-bromoalkyne (2.2 mmol) in toluene. The reaction was stirred at 75 °C for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography to afford the desired ynamide. Compounds 8 were obtained in our laboratory. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With iron(III) chloride; potassium carbonate; copper(l) chloride In N,N-dimethyl-formamide at 120℃; for 0.5h; Microwave irradiation; Green chemistry; | 2 N-Benzyl-4-methylbenzenesulfonamide To the reaction vessel was added 1 mmol of 4-methylbenzenesulfonamide, 2 mmol of ferric chloride, 0.1 mmol of cuprous chloride, 0.01 mmol of potassium carbonate, 4 ml of toluene and 3 ml of dimethylformamide (DMF) were added in this order. Placed in a microwave reactor at 150 W power heating to 120°C continuous reaction 30 min. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The product was purified by column chromatography to give a pale yellow solid in a yield of 78% |
70% | With di-tert-butyl peroxide; nickel diacetate In neat (no solvent) at 120℃; for 24h; Schlenk technique; Sealed tube; Inert atmosphere; chemoselective reaction; | |
53% | With di-tert-butyl peroxide; potassium <i>tert</i>-butylate at 110℃; for 10h; | 4.2. General experimental procedure General procedure: In a catalytic reaction, a solution of benzamide (0.0242 g, 0.2 mmol) and diphenyl ether (0.034 mL, 0.2 mmol) in cyclohexane (1.5 mL) was added into a 10-mL screw tube containing the catalyst and di-tert-butyl peroxide (0.147 mL, 0.8 mmol) as an oxidant. The catalyst concentration was determined based on the copper/benzamide molar ratio. The reaction mixture was magnetically stirred at 110 °C for 10 h. Reaction yields were monitored by taking samples and quenching with water (1 mL). The extraction was carried out using ethyl acetate (2 mL), and the organic phase was dried over anhydrous Na2SO4, and analyzed by GC with reference to diphenyl ether as an internal standard. Purification by column chromatography was implemented to afford N-cyclohexyl benzamide. GC-MS, 1H NMR and 13C NMR analyses were also conducted to confirm the structure of the product. To investigate the recyclability of Cu-CPO-27, the catalyst was separated from the reaction mixture by simple centrifugation, washed with DMF and dichloromethane, dried at 150 °C under vacuum on a Shlenk line for 2 h, and reused in further experiments. For the leaching test, after the first run, the catalyst was separated from the reaction mixture. The reaction solution was transferred to a new 10-mL screw tube, and fresh reagents were then added to the solution. The resulting mixture was magnetically stirred for 10 h at 120 °C, and the formation of N-cyclohexyl benzamide was analyzed by GC. |
45% | With [bis(acetoxy)iodo]benzene; iodine at 50℃; Inert atmosphere; | |
37% | With 1,3-Diiodo-5,5-dimethyl-2,4-imidazolidinedione In tetrachloromethane at 60℃; for 24h; Inert atmosphere; | |
30% | With di-tert-butyl peroxide; potassium <i>tert</i>-butylate; copper(l) chloride at 120℃; for 24h; Schlenk technique; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine In N,N-dimethyl-formamide at 70℃; for 48h; Inert atmosphere; regioselective reaction; | |
67% | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine Heating; | |
With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine at 80℃; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine In N,N-dimethyl-formamide at 70℃; for 48h; Inert atmosphere; regioselective reaction; | |
70% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine Heating; | |
60% | With Cupric sulfate; N,N,N,N,-tetramethylethylenediamine; potassium hydroxide In water monomer at 70℃; for 24h; | III General Procedure D for the Synthesis of Ynamides inWater General procedure: To an oven-dried 4 mL vial, N-nucleophile (0.2 mmol, 1 equiv) was added followed byCuSO4•5H2O (0.02 mmol, 10 mol%), KOH (0.8 mmol, 4 equiv), 2 wt.% APGS-2000-M/H2O (0.4mL, 0.5 M), dibromoalkenes (0.3 mmol, 1.5 equiv), and DMEDA (0.04 mmol, 20 mol%). Theresulting mixture was stirred at 60 °C for 8 h. Upon the completion monitored by TLC, thereaction was cooled to room temperature and extracted with ethyl acetate, combined the organic layers then concentrated under reduced pressure. The crude product was further purified by flashcolumn chromatography with a 5% ethyl acetate in petroleum ether to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With Cupric sulfate; N,N,N,N,-tetramethylethylenediamine; potassium hydroxide In water monomer at 70℃; for 8h; | III General Procedure D for the Synthesis of Ynamides inWater General procedure: To an oven-dried 4 mL vial, N-nucleophile (0.2 mmol, 1 equiv) was added followed byCuSO4•5H2O (0.02 mmol, 10 mol%), KOH (0.8 mmol, 4 equiv), 2 wt.% APGS-2000-M/H2O (0.4mL, 0.5 M), dibromoalkenes (0.3 mmol, 1.5 equiv), and DMEDA (0.04 mmol, 20 mol%). Theresulting mixture was stirred at 60 °C for 8 h. Upon the completion monitored by TLC, thereaction was cooled to room temperature and extracted with ethyl acetate, combined the organic layers then concentrated under reduced pressure. The crude product was further purified by flashcolumn chromatography with a 5% ethyl acetate in petroleum ether to afford the desired product. |
86% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine In 1,4-dioxane at 60℃; for 24h; Inert atmosphere; regioselective reaction; | |
86% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With Cupric sulfate; N,N,N,N,-tetramethylethylenediamine; potassium hydroxide In water monomer at 60℃; for 8h; | III General Procedure D for the Synthesis of Ynamides inWater General procedure: To an oven-dried 4 mL vial, N-nucleophile (0.2 mmol, 1 equiv) was added followed byCuSO4•5H2O (0.02 mmol, 10 mol%), KOH (0.8 mmol, 4 equiv), 2 wt.% APGS-2000-M/H2O (0.4mL, 0.5 M), dibromoalkenes (0.3 mmol, 1.5 equiv), and DMEDA (0.04 mmol, 20 mol%). Theresulting mixture was stirred at 60 °C for 8 h. Upon the completion monitored by TLC, thereaction was cooled to room temperature and extracted with ethyl acetate, combined the organic layers then concentrated under reduced pressure. The crude product was further purified by flashcolumn chromatography with a 5% ethyl acetate in petroleum ether to afford the desired product. |
83% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine In 1,4-dioxane at 60℃; for 24h; Inert atmosphere; regioselective reaction; | |
83% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine Heating; |
With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine at 80℃; Inert atmosphere; Sealed tube; | ||
With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine at 60℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine In 1,4-dioxane at 60℃; for 24h; Inert atmosphere; regioselective reaction; | |
94% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine Heating; | |
80.1 mg | With Cupric sulfate; N,N,N,N,-tetramethylethylenediamine; potassium hydroxide In water monomer at 60℃; for 8h; | III General Procedure D for the Synthesis of Ynamides inWater General procedure: To an oven-dried 4 mL vial, N-nucleophile (0.2 mmol, 1 equiv) was added followed byCuSO4•5H2O (0.02 mmol, 10 mol%), KOH (0.8 mmol, 4 equiv), 2 wt.% APGS-2000-M/H2O (0.4mL, 0.5 M), dibromoalkenes (0.3 mmol, 1.5 equiv), and DMEDA (0.04 mmol, 20 mol%). Theresulting mixture was stirred at 60 °C for 8 h. Upon the completion monitored by TLC, thereaction was cooled to room temperature and extracted with ethyl acetate, combined the organic layers then concentrated under reduced pressure. The crude product was further purified by flashcolumn chromatography with a 5% ethyl acetate in petroleum ether to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine In N,N-dimethyl-formamide at 70℃; for 24h; Inert atmosphere; regioselective reaction; | |
84% | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine Heating; | |
68% | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine In N,N-dimethyl-formamide at 70℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With Cupric sulfate; N,N,N,N,-tetramethylethylenediamine; potassium hydroxide In water monomer at 60℃; for 8h; | III General Procedure D for the Synthesis of Ynamides inWater General procedure: To an oven-dried 4 mL vial, N-nucleophile (0.2 mmol, 1 equiv) was added followed byCuSO4•5H2O (0.02 mmol, 10 mol%), KOH (0.8 mmol, 4 equiv), 2 wt.% APGS-2000-M/H2O (0.4mL, 0.5 M), dibromoalkenes (0.3 mmol, 1.5 equiv), and DMEDA (0.04 mmol, 20 mol%). Theresulting mixture was stirred at 60 °C for 8 h. Upon the completion monitored by TLC, thereaction was cooled to room temperature and extracted with ethyl acetate, combined the organic layers then concentrated under reduced pressure. The crude product was further purified by flashcolumn chromatography with a 5% ethyl acetate in petroleum ether to afford the desired product. |
66% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine In 1,4-dioxane at 60℃; for 48h; Inert atmosphere; regioselective reaction; | |
66% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine Heating; |
With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine at 80℃; Inert atmosphere; Sealed tube; | ||
With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine at 60℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With Cupric sulfate; N,N,N,N,-tetramethylethylenediamine; potassium hydroxide In water monomer at 60℃; for 8h; | III General Procedure D for the Synthesis of Ynamides inWater General procedure: To an oven-dried 4 mL vial, N-nucleophile (0.2 mmol, 1 equiv) was added followed byCuSO4•5H2O (0.02 mmol, 10 mol%), KOH (0.8 mmol, 4 equiv), 2 wt.% APGS-2000-M/H2O (0.4mL, 0.5 M), dibromoalkenes (0.3 mmol, 1.5 equiv), and DMEDA (0.04 mmol, 20 mol%). Theresulting mixture was stirred at 60 °C for 8 h. Upon the completion monitored by TLC, thereaction was cooled to room temperature and extracted with ethyl acetate, combined the organic layers then concentrated under reduced pressure. The crude product was further purified by flashcolumn chromatography with a 5% ethyl acetate in petroleum ether to afford the desired product. |
77% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine In 1,4-dioxane at 60℃; for 24h; Inert atmosphere; regioselective reaction; | |
77% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine In N,N-dimethyl-formamide at 70℃; for 48h; Inert atmosphere; regioselective reaction; | |
86% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine Heating; | |
77% | With Cupric sulfate; N,N,N,N,-tetramethylethylenediamine; potassium hydroxide In water monomer at 70℃; for 16h; | III General Procedure D for the Synthesis of Ynamides inWater General procedure: To an oven-dried 4 mL vial, N-nucleophile (0.2 mmol, 1 equiv) was added followed byCuSO4•5H2O (0.02 mmol, 10 mol%), KOH (0.8 mmol, 4 equiv), 2 wt.% APGS-2000-M/H2O (0.4mL, 0.5 M), dibromoalkenes (0.3 mmol, 1.5 equiv), and DMEDA (0.04 mmol, 20 mol%). Theresulting mixture was stirred at 60 °C for 8 h. Upon the completion monitored by TLC, thereaction was cooled to room temperature and extracted with ethyl acetate, combined the organic layers then concentrated under reduced pressure. The crude product was further purified by flashcolumn chromatography with a 5% ethyl acetate in petroleum ether to afford the desired product. |
With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine at 80℃; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With Cupric sulfate; N,N,N,N,-tetramethylethylenediamine; potassium hydroxide In water monomer at 60℃; for 8h; | III General Procedure D for the Synthesis of Ynamides inWater General procedure: To an oven-dried 4 mL vial, N-nucleophile (0.2 mmol, 1 equiv) was added followed byCuSO4•5H2O (0.02 mmol, 10 mol%), KOH (0.8 mmol, 4 equiv), 2 wt.% APGS-2000-M/H2O (0.4mL, 0.5 M), dibromoalkenes (0.3 mmol, 1.5 equiv), and DMEDA (0.04 mmol, 20 mol%). Theresulting mixture was stirred at 60 °C for 8 h. Upon the completion monitored by TLC, thereaction was cooled to room temperature and extracted with ethyl acetate, combined the organic layers then concentrated under reduced pressure. The crude product was further purified by flashcolumn chromatography with a 5% ethyl acetate in petroleum ether to afford the desired product. |
88% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine In 1,4-dioxane at 60℃; for 48h; Inert atmosphere; regioselective reaction; | |
88% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine In N,N-dimethyl-formamide at 90℃; for 48h; Inert atmosphere; regioselective reaction; | |
86% | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine Heating; | |
With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine at 80℃; Inert atmosphere; Sealed tube; |
With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine at 60℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine In 1,4-dioxane at 60℃; for 24h; Inert atmosphere; regioselective reaction; | |
94% | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine Heating; | |
With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine at 80℃; Inert atmosphere; Sealed tube; |
With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine at 60℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine In 1,4-dioxane at 60℃; for 48h; Inert atmosphere; regioselective reaction; | |
92% | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine Heating; | |
With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine at 80℃; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine In N,N-dimethyl-formamide at 70℃; for 48h; Inert atmosphere; regioselective reaction; | |
97% | With copper (I) iodide; Cs2CO3; N,N`-dimethylethylenediamine Heating; | |
76.6 mg | With Cupric sulfate; N,N,N,N,-tetramethylethylenediamine; potassium hydroxide In water monomer at 70℃; for 16h; | III General Procedure D for the Synthesis of Ynamides inWater General procedure: To an oven-dried 4 mL vial, N-nucleophile (0.2 mmol, 1 equiv) was added followed byCuSO4•5H2O (0.02 mmol, 10 mol%), KOH (0.8 mmol, 4 equiv), 2 wt.% APGS-2000-M/H2O (0.4mL, 0.5 M), dibromoalkenes (0.3 mmol, 1.5 equiv), and DMEDA (0.04 mmol, 20 mol%). Theresulting mixture was stirred at 60 °C for 8 h. Upon the completion monitored by TLC, thereaction was cooled to room temperature and extracted with ethyl acetate, combined the organic layers then concentrated under reduced pressure. The crude product was further purified by flashcolumn chromatography with a 5% ethyl acetate in petroleum ether to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1.5h; | The procedure for N-benzyl-4-methylbenzene sulfonamide (refPreviewPlaceHolderTable 1, entry 1) synthesis is described below as a representative procedure for the preparation of sulfonamides from TsOBt and other HOBt sulfonates (see refPreviewPlaceHolderSupplementary data): TsOBt (1 mmol, 1 equiv) is dissolved in a 1 mL DCM in an oven dried 25 mL round bottom flask which is charged with magnetic stir bar. To this, benzyl amine (1 mmol, 1 equiv) was added followed by the addition of DIPEA (1 mmol, 1 equiv) with 0.5 mL of DCM (for amino acid esters DCM and DMF mixture in 1:3). Then stirring was continued at room temperature while being monitored by TLC. After completion of the reaction, the reaction mixture was diluted with 10 mL of DCM and washed with 5% HCl (2 × 10 mL), 5% NaHCO3 (2 × 10 mL), and brine solution (2 × 10 mL). Organic fraction was dried under CaCl2, filtered and evaporated to dryness. Then purified by column chromatography. Rf product 0.58 (EtoAc/Hexane, 1:4) yield 75%, white solid, mp 87-89 °C. IR (KBr, ν/cm-1) 3262, 3027, 1594, 1492, 1450, 1320, 1156.1H NMR (400 MHz, CDCl3) δ ppm 7.38-7.48 (m, 3H, ArH), 7.77-7.75 (d, 2H, J = 8.4 Hz, 2 × ArH), 7.31-7.18 (m, 7H, 7 × ArH), 4.74 (br s, 1H, NH), 4.11(s, 2H, CH2), 2.43 (s, 3H, CH3). LRMS (ESI) m/z 261 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With tin(IV) chloride In dichloromethane at 20℃; Inert atmosphere; stereoselective reaction; | General procedure for the synthesis of β-enamino Ketone derivatives General procedure: Procedure B. Secondary amines (1.0 equiv) and substituted 3-ethoxycyclobutanonesa,b (2.0 equiv) were dissolved in anhydrous dichloromethane in a round bottom flask. Then, SnCl4 (0.1 equiv) was added into the reaction solution. The reaction mixture was kept stirring at room temperature under atmosphere of Argon for 0.5-1.0 h. The reaction was monitored by TLC and LC-MS. After completion of the reaction, Et3N was added to quench the reaction. The reaction mixture was diluted with dichloromethane and washed once with saturated aqueous NaHCO3 and once with water. Then organic layer was dried over MgSO4 and concentrated on rotavapor under reduced pressure. Finally the residue was purified by silical gel column chromatography to give corresponding β-enamino ketone product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With tin(IV) chloride In dichloromethane at 20℃; Inert atmosphere; stereoselective reaction; | General procedure for the synthesis of β-enamino Ketone derivatives General procedure: Procedure B. Secondary amines (1.0 equiv) and substituted 3-ethoxycyclobutanonesa,b (2.0 equiv) were dissolved in anhydrous dichloromethane in a round bottom flask. Then, SnCl4 (0.1 equiv) was added into the reaction solution. The reaction mixture was kept stirring at room temperature under atmosphere of Argon for 0.5-1.0 h. The reaction was monitored by TLC and LC-MS. After completion of the reaction, Et3N was added to quench the reaction. The reaction mixture was diluted with dichloromethane and washed once with saturated aqueous NaHCO3 and once with water. Then organic layer was dried over MgSO4 and concentrated on rotavapor under reduced pressure. Finally the residue was purified by silical gel column chromatography to give corresponding β-enamino ketone product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With iron(III) chloride In 1,2-dichloro-ethane at 90℃; for 1h; Inert atmosphere; | |
40% | With titanium tetrachloride In 1,1,2,2-tetrachloroethane at 120℃; for 48h; sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With titanium tetrachloride In 1,1,2,2-tetrachloroethane at 120℃; for 48h; sealed tube; | |
50% | With trifluorormethanesulfonic acid In toluene at 170℃; for 25h; | In a typical procedure General procedure: To a mixture of tolsulfonamide (0.5mmol) and THF (2mmol) in toluene (1mL), was added TfOH (40mol%). The resulting mixture was than sealed and stirred for 18h at 120°C. After quenching with satdaqNaHCO3, the reaction mixture was extracted three times with EtOAc, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash chromatography with PE and EtOAc (3:1) as the eluent to give the pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | 4.1.2. General procedure for the preparation of compounds 11a-g, i-l, 12a-h, 13a-h, j General procedure: Methyl bromoacetate (15 mmol) and anhydrous K2CO3 (25 mmol) were added to a solution of sulfonamides 8a-g, i-l, 9a-h, 10a-h, j (5 mmol) in N,N-dimethylformamide (5 mL), and the resulting mixture was stirred at room temperature until starting material was not detected by TLC. The solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate, and washed with HCl (1 M, 2 × 25 mL) and brine (2 × 25 mL). The title compounds were obtained after purification by flash chromatography. |
82% | Stage #1: N-benzyl-p-toluenesulfonamide With sodium hydride In N,N-dimethyl-formamide for 0.666667h; Inert atmosphere; Stage #2: bromoacetic acid methyl ester In N,N-dimethyl-formamide for 6h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 1,1,3,3-Tetramethyldisiloxane; (Ace)Ru3(CO)7 In dichloromethane at 20℃; for 20h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate In tetrahydrofuran at 80℃; for 24h; Inert atmosphere; Schlenk technique; | A typical procedure for the preparation of Ynamides: General procedure: Under the protection of nitrogen, 1,2-dibromo-1-alkenes (0.39 mmol), amide (0.3 mmol), CuI (0.03 mmol), 1,10-phenanthroline (0.06 mmol) and Cs2CO3 (1.2 mmol) was added in 2 mL THF. The reaction mixture was stirred at 80 oC for 24 h. After the reaction mixture was filtered by a crude column with ethyl acetate as eluent, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 40:1 petroleum ether/ethyl acetate) to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate In tetrahydrofuran at 80℃; for 24h; Inert atmosphere; Schlenk technique; | A typical procedure for the preparation of Ynamides: General procedure: Under the protection of nitrogen, 1,2-dibromo-1-alkenes (0.39 mmol), amide (0.3 mmol), CuI (0.03 mmol), 1,10-phenanthroline (0.06 mmol) and Cs2CO3 (1.2 mmol) was added in 2 mL THF. The reaction mixture was stirred at 80 oC for 24 h. After the reaction mixture was filtered by a crude column with ethyl acetate as eluent, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 40:1 petroleum ether/ethyl acetate) to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate In tetrahydrofuran at 80℃; for 28h; Inert atmosphere; Schlenk technique; | A typical procedure for the preparation of Ynamides: General procedure: Under the protection of nitrogen, 1,2-dibromo-1-alkenes (0.39 mmol), amide (0.3 mmol), CuI (0.03 mmol), 1,10-phenanthroline (0.06 mmol) and Cs2CO3 (1.2 mmol) was added in 2 mL THF. The reaction mixture was stirred at 80 oC for 24 h. After the reaction mixture was filtered by a crude column with ethyl acetate as eluent, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 40:1 petroleum ether/ethyl acetate) to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate In tetrahydrofuran at 80℃; for 28h; Inert atmosphere; Schlenk technique; | A typical procedure for the preparation of Ynamides: General procedure: Under the protection of nitrogen, 1,2-dibromo-1-alkenes (0.39 mmol), amide (0.3 mmol), CuI (0.03 mmol), 1,10-phenanthroline (0.06 mmol) and Cs2CO3 (1.2 mmol) was added in 2 mL THF. The reaction mixture was stirred at 80 oC for 24 h. After the reaction mixture was filtered by a crude column with ethyl acetate as eluent, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 40:1 petroleum ether/ethyl acetate) to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate In tetrahydrofuran at 80℃; for 24h; Inert atmosphere; Schlenk technique; | A typical procedure for the preparation of Ynamides: General procedure: Under the protection of nitrogen, 1,2-dibromo-1-alkenes (0.39 mmol), amide (0.3 mmol), CuI (0.03 mmol), 1,10-phenanthroline (0.06 mmol) and Cs2CO3 (1.2 mmol) was added in 2 mL THF. The reaction mixture was stirred at 80 oC for 24 h. After the reaction mixture was filtered by a crude column with ethyl acetate as eluent, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 40:1 petroleum ether/ethyl acetate) to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate In tetrahydrofuran at 80℃; for 24h; Inert atmosphere; Schlenk technique; | A typical procedure for the preparation of Ynamides: General procedure: Under the protection of nitrogen, 1,2-dibromo-1-alkenes (0.39 mmol), amide (0.3 mmol), CuI (0.03 mmol), 1,10-phenanthroline (0.06 mmol) and Cs2CO3 (1.2 mmol) was added in 2 mL THF. The reaction mixture was stirred at 80 oC for 24 h. After the reaction mixture was filtered by a crude column with ethyl acetate as eluent, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 40:1 petroleum ether/ethyl acetate) to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With copper(l) iodide; 1,10-Phenanthroline; caesium carbonate In tetrahydrofuran at 80℃; for 26h; Inert atmosphere; Schlenk technique; | A typical procedure for the preparation of Ynamides: General procedure: Under the protection of nitrogen, 1,2-dibromo-1-alkenes (0.39 mmol), amide (0.3 mmol), CuI (0.03 mmol), 1,10-phenanthroline (0.06 mmol) and Cs2CO3 (1.2 mmol) was added in 2 mL THF. The reaction mixture was stirred at 80 oC for 24 h. After the reaction mixture was filtered by a crude column with ethyl acetate as eluent, and evaporated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 40:1 petroleum ether/ethyl acetate) to provide the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With Hexamethylphosphorous triamide In dichloromethane at -78 - 20℃; Inert atmosphere; Schlenk technique; | |
82% | With Hexamethylphosphorous triamide In tetrahydrofuran at -78 - 20℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 47 %Spectr. 2: 18 %Spectr. 3: 26 %Spectr. | Stage #1: carbon dioxide; toluene-4-sulfonamide; ((trimethylsilyl)oxy)(phenyl(CH))tributylstannane With bis(tri-n-butyltin); cesium fluoride Stage #2: diazomethyl-trimethyl-silane In methanol; diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 52 %Spectr. 2: 7 %Spectr. 3: 35 %Spectr. 4: 20 %Spectr. 5: 10 %Spectr. | Stage #1: carbon dioxide; 4-methoxybenzene sulfonamide; N-tosyl-α-(tributylstannyl)benzylamine With bis(tri-n-butyltin); cesium fluoride Stage #2: diazomethyl-trimethyl-silane In methanol; diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 37 %Spectr. 2: 32 %Spectr. 3: 25 %Spectr. | Stage #1: carbon dioxide; benzaldehyde; toluene-4-sulfonamide With trimethylsilyltributyltin; cesium fluoride In N,N-dimethyl-formamide at 100℃; for 3h; Autoclave; Stage #2: diazomethyl-trimethyl-silane In methanol; diethyl ether |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With iodine In water at 20℃; for 3h; Green chemistry; | |
92% | With iodine In 1,2-dichloro-ethane at 25℃; for 24h; | |
91% | With sodium iodide In water at 20℃; for 4h; Electrochemical reaction; |
81% | With tetrabutylammomium bromide; 3-chloro-benzenecarboperoxoic acid In tetrahydrofuran; methanol at 20℃; for 12h; | A Typical Procedure for the Preparation of Sulfonamides General procedure: In mixed solvent THF-MeOH (30:1, 2.0 mL), sodium sulfinates 1(0.45 mmol), amines 2 (0.30 mmol), (n-Bu)4NBr (0.36 mmol),and m-CPBA (0.3 mmol) were added successively. The suspensionmixture was vigorously stirred at r.t. for 12 h. Upon completion,the reaction was quenched by addition of sat. aqNa2S2O3 (2 mL), sat. aq Na2CO3 (8 mL), and H2O (5 mL), respectively.The mixture was extracted with CH2Cl2 (3 × 5 mL) andthe combined organic phase was dried over anhydrous Na2SO4,filtered, and concentrated under reduced pressure. The residuewas then purified on a silica gel plate (PE-EtOAc = 3:1) tofurnish products 3. |
80% | With phenyltrimethylammonium tribromide In tetrahydrofuran at 30℃; for 8h; | General experimental procedure (A) for the synthesis of sulfonamides General procedure: To a well stirred solution of sodium sulfinate(1equiv.) in THF Phenyl Trimethyl ammonium Tribromide (PTAB)(1equiv.) was added and stirred about 5 minutes, The amine (1 equiv.) was then added to the reaction mixture and the reaction mixture was stirred for 6-8 hrs at room temperature. After completion of the reaction which was monitored with TLC, the reaction mixture was quenched with distilled water and extracted with ethyl acetate (3X3ml). The organic fraction was washed with saturated brine solution and dried over oven dried anhydrous sodium sulphate. The solvent was evaporated under reduced pressure. The residual crude mass was then subjected to column chromatography over silica gel, Elution with proper solvent mixture afforded the desired sulfonamide as the pure product. |
75% | With ethylene dibromide; sodium iodide In water at 70℃; for 12h; | 3 Example 3: Synthesis of N-benzyl-4-methylbenzenesulfonamide Sodium p-toluenesulfinate (356 mg, 2.0 mmol),Sodium iodide (300 mg, 2.0 mmol),Benzylamine (107 mg, 1 mmol) was added to a 10 ml reaction tube containing magnetons. 1,2-Dibromoethane (376 mg, 2.0 mmol) dissolved in 2 ml of PEG-400 and 2 ml of distilled water were added to the reaction system by a syringe. It was then stirred at 70 ° C for 12 hours. The heat was removed and quenched with a saturated aqueous solution of NH4Cl. and extracted with dichloromethane (20 ml × 3 times).The organic phase was retained and washed successively with water and saturated brine.Evaporate the solvent under reduced pressure.The product was isolated by flash column chromatography to give 195 mg (yield: 75%). |
75% | With ethylene dibromide; sodium iodide In water at 60℃; for 8h; Schlenk technique; Green chemistry; | |
75% | With 1-iodo-propane; 3-chloro-benzenecarboperoxoic acid In 2,2,2-trifluoroethanol at 20℃; for 4h; | General procedure for the synthesis of sulfonamides General procedure: Sodium sulfinates 1 (1.0 mmol), amines 2 (1.5 mmol), 1-iodopropane (0.2 mmol), and mCPBA (1.5 mmol) were added successively into CF3CH2OH (5.0 mL). The suspension mixture was vigorously stirred at room temperature for 4 h. Upon completion, the reaction mixture was quenched by addition of sat. aq. Na2S2O3 (3 mL), sat. aq. Na2CO3 (8 mL) and H2O (10 mL), respectively. The mixture was extracted with CH2Cl2 (320 mL) and the combined organic phase was dried over anhydrous Na2SO4, filtered,and concentrated under reduced pressure. The residue was then purified on a silica gel plate (3:1 petroleum ether-ethyl acetate) to furnish the products 3. |
72% | With ammonium iodide In methanol at 20℃; Electrolysis; | |
68% | With sodium percarbonate; iodine In cis-1,2-Dichloroethylene; acetonitrile at 40℃; for 24h; | |
61% | With copper(ll) bromide In dimethyl sulfoxide at 100℃; for 24h; Inert atmosphere; chemoselective reaction; | |
60% | With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide In water; acetonitrile at 50℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 65℃; for 36h; Inert atmosphere; | |
92% | With 1,10-Phenanthroline; potassium carbonate In toluene at 65℃; for 20h; Inert atmosphere; | |
86% | With potassium phosphate; copper(ll) sulfate pentahydrate; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane In toluene at 70℃; for 16h; Inert atmosphere; |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 65℃; for 36h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylsilane; trifluoroacetic acid In dichloromethane at 20℃; for 1.5h; | General Procedure for the Cleavage of MePre Group in 1 General procedure: To a stirred solution of protected sulfonamide 1 (0.15 mmol) in CH2Cl2 (0.75 mL) were added triethylsilane (75 μL) and TFA (75μL, 10 vol%). The reaction mixture was stirred at r.t. until full conversion of the starting material was observed (see Table 1).The solvent was removed in vacuo and the residue was diluted with Et2O and the solvent was then evaporated. Dilution and evaporation was repeated twice more to give the deprotected sulfonamide. |
100% | With triethylsilane; trifluoroacetic acid In dichloromethane for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With copper(l) iodide; caesium carbonate; N,N-dimethylethylenediamine In 1,4-dioxane at 70℃; for 17h; Inert atmosphere; | N-benzyl-N-((4-((4-(1,1-dibromoprop-1-en-2-yl)phenyl)(phenyl)amino)phenyl)ethynyl)-4-methylbenzenesulfonamide A solution of bis-dibromoalkene 13 (0.639 g, 1.042 mmol), N-benzyltosylamide (0.246 g, 0.941mmol), CuI (21 mg, 0.110 mmol), N,N'-dimethylethylenediamine (0.020 mL, 0.188mmol) and Cs2CO3 (1.36 g, 4.177 mmol) in dry 1,4-dioxane(5.5 mL) was heated to 70 °C under a nitrogen atmosphere over 17 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL) and filtered through celite. The filtrate was concentrated under reduced pressure and purified by column chromatography (n-pentaneto n-pentane:Et2O 7:3) togive ynamide 14(0.364 g, 0.511 mmol, 54%) as a yellow solid. Rf= 0.58 (n-pentane:Et2O 4:1). 1H NMR (400 MHz, CDCl3) δ 7.83 (2H, d, J = 8.3 Hz), 7.47 (2H, d, J= 8.6 Hz), 7.41 (1H, s), 7.39 - 7.25 (9H, m), 7.19 - 7.08 (5H, m), 7.03 (2H, d,J = 8.6 Hz), 6.98 (2H, d, J =8.7 Hz), 4.60 (2H, s), 2.47 (3H, s). 13C NMR (100MHz, CDCl3) δ 147.6, 147.0, 146.8, 144.7, 136.2, 134.8,134.7, 132.8, 129.8, 129.7, 129.6, 129.3, 129.0, 128.6, 128.4, 127.9, 125.6,124.3, 123.6, 122.8, 116.9, 87.6, 82.3, 71.3, 55.9, 21.8. HRMS (ESI) calculated for C36H29N2O279Br2S[M+H]+ 711.0311, found 711.0311. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: toluene-4-sulfonic acid With N-chlorobenzotriazole; triphenylphosphine In dichloromethane at 0 - 20℃; for 0.25h; Stage #2: benzylamine With triethylamine at 20℃; for 1.33333h; | Typical Procedure for Conversion of Sulfonic Acids to Sulfonamides.N-benzyl-4-methylbenzenesulfonamide (Table 6, Entry 6) General procedure: To a cold solution of PPh3 (0.327 g, 1.25 mmol) in CH2Cl2 (3 mL), freshly preparedNCBT (0.188 g, 1.25 mmol) was added with continuous stirring. p-Toluenesulfonic acid(0.172 g, 1 mmol)was then added and stirringwas continued for 15min at room temperature.Benzylamine (0.267 g, 2.5 mmol) was added. The white suspension was neutralized by triethylamine (0.139 mL). Stirring was continued for 80 min at room temperature. Theprogress of the reaction was followed by TLC. Upon completion of the reaction, theconcentrated residue was passed through a short silica-gel column using n-hexane-ethylacetate (3:1) as eluent. N-Benzyl-4-methylbenzenesulfonamide was obtained with 90%(0.236 g) yield after removing the solvent under reduced pressure |
39.7% | Stage #1: toluene-4-sulfonic acid With (2-bromophenyl)boronic acid In dichloromethane at 15℃; for 2h; Molecular sieve; Stage #2: benzylamine In dichloromethane at 15℃; for 24h; Molecular sieve; | 7 3.444 g (20 mmol) of anhydrous p-toluenesulfonic acid and 0.207 g of 2-bromophenylboronic acid were dissolved in dichloromethane,Add 5g molecular sieve 5A, water bath to the temperature reached 15 °C evenly stirring 2h, then add 2.996g (28mmol) benzylamine. After maintaining the reaction at 15 °C for 24 hours, the molecular sieves were removed by filtration, and the filtrate was washed once with 10 mL of 0.5 mol / L hydrochloric acid solution, 10 mL of 0.5 mol / L sodium hydroxide solution and 10 mL of saturated NaCl solution. The organic phase was dried with anhydrous sodium sulfate to remove the desiccant, and the solvent methylene chloride was recovered by distillation to obtain crude N-benzyl p-toluenesulfonamide. The crude product was washed with 50% aqueous ethanol and dried to give 2.091 g of product, Liquid chromatography, The active ingredient was 99.2%, the yield was 39.7% measured the melting range: 107.7-110.3 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With water; palladium diacetate; caesium carbonate; 1,4-di(diphenylphosphino)-butane In 1,2-dichloro-benzene at 100℃; Inert atmosphere; | Allylic Amines 3a-q; General Procedure General procedure: To an oven-dried 25-mL Schlenk tube equipped with a stir bar wasadded Cs2CO3 (78 mg, 0.24 mmol) in a glovebox. Pd(OAc)2 (4.5 mg,0.02 mmol) was added along with dppb (11 mg, 0.024 mmol) and anamine 2 (0.2 mmol) under a nitrogen atmosphere. To this mixturewas added purified water (10.8 μL, 0.6 mmol), followed by a homoallylicalcohol 1 (0.6 mmol) dissolved in 1,2-dichlorobenzene (ODCB, 2mL). The mixture was stirred at 100 °C until the reaction was completed.The resulting mixture was then cooled to r.t. and directly purifiedby silica gel column chromatography (EtOAc-PE) to afford the allylicamine product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: toluene-4-sulfonic acid hydrazide With N-chloro-succinimide In acetonitrile at 20℃; for 2h; Stage #2: benzylamine With triethylamine at 20℃; for 2h; | 4.4. General Procedure for One-Port Reaction with Nucleophile General procedure: N-Chlorosuccinimide 2a (0.6 mmol, 2.0 equiv) was added to a solution of 4-methylbenzenesulfonhydrazide 1a (0.3 mmol) in CH3CN (2 mL) in one portion. Themixture was stirred at room temperature for 2 h. Then, Et3N (0.6 mmol, 2.0 equiv) andnucleophile (0.6 mmol, 2.0 equiv) were added to the above reaction system, and the mixturewas stirred at room temperature for 2 h. The solvent was removed, and the residuewas purified by flash column chromatography (PE/EA) to provide the correspondingsulfonamides and sulfonate 7. |
56% | With ammonium bromide In water; acetonitrile at 25 - 30℃; Electrolysis; | General procedure General procedure: An undivided cell was equipped with a carbon platea node (7.5 cm2) and a Fe plate cathode (7.5 cm2) and connected to a DC regulated power supply. The solution of corresponding amine 2 (1.5-4.83 mmol) in 30 ml MeCN-H2O (1:1), arenesulfonohydrazide 1 (300 mg, 1.00-1.61 mmol) and supporting electrolyte KBr, NH4Br (0.5-0.8 mmol;molar ratio to 1 was 1:2) were added to the cell. The mixture was electrolyzed with constant current (35-40 mA cm-2) at 25-30 °C under magnetic stirring. Then the solvent was removed under reduced pressure(10-20 Torr). The residue was diluted with EtOAc (50 ml) and washed with brine (2 × 8 ml) and water (2 × 8 ml), dried over Na2SO4, and concentrated under reduced pressure (10-20 Torr). Then it was purified by recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Inert atmosphere; | |
54% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Schlenk technique; Inert atmosphere; | |
54% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Inert atmosphere; Schlenk technique; |
54% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 18h; Inert atmosphere; Schlenk technique; | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Inert atmosphere; Schlenk technique; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | (2) General procedure for the synthesis of ynamides 10a-g and 11a-b. General procedure: To a mixture of an amide (1 eq), K3PO4 (2 eq), CuSO4·5H2O (0.1 eq) and 1,10-phenanthroline (0.2 eq) in toluene was added a solution of 1-bromoalkyne (1.1 eq) intoluene. The reaction was stirred at 75 °C for 24 h at a N2 atmosphere. The reactionmixture was cooled to room temperature, diluted with EtOAc, and filtered throughCelite, and the filtrate was concentrated in vacuo. The crude product is purified bycolumn chromatography to obtain ynamides 10a-g or 11a-b. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | General Procedure for Synthesis of 8.21 General procedure: To a mixture of an amide (2 mmol), K3PO4 (4 mmol), CuSO4·5H2O (0.2 mmol), and 1,10-phenanthroline (0.4 mmol) in toluene under a N2 atmosphere was added a solution 1-bromoalkyne (2.2 mmol) in toluene. The reaction was stirred at 75 °C for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography to afford the desired ynamide. Compounds 8 were obtained in our laboratory. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 12h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Schlenk technique; Inert atmosphere; | |
80% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; for 12h; Inert atmosphere; Schlenk technique; | |
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Schlenk technique; Inert atmosphere; |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 80℃; Inert atmosphere; Schlenk technique; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | ||
With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 80℃; Schlenk technique; Inert atmosphere; | ||
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | (2) General procedure for the synthesis of ynamides 10a-g and 11a-b. General procedure: To a mixture of an amide (1 eq), K3PO4 (2 eq), CuSO4·5H2O (0.1 eq) and 1,10-phenanthroline (0.2 eq) in toluene was added a solution of 1-bromoalkyne (1.1 eq) intoluene. The reaction was stirred at 75 °C for 24 h at a N2 atmosphere. The reactionmixture was cooled to room temperature, diluted with EtOAc, and filtered throughCelite, and the filtrate was concentrated in vacuo. The crude product is purified bycolumn chromatography to obtain ynamides 10a-g or 11a-b. | |
With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 75℃; for 24h; Inert atmosphere; | General Procedure for Synthesis of 8.21 General procedure: To a mixture of an amide (2 mmol), K3PO4 (4 mmol), CuSO4·5H2O (0.2 mmol), and 1,10-phenanthroline (0.4 mmol) in toluene under a N2 atmosphere was added a solution 1-bromoalkyne (2.2 mmol) in toluene. The reaction was stirred at 75 °C for 24 h under a N2 atmosphere. The reaction mixture was cooled to room temperature, diluted with EtOAc, and filtered through Celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel flash chromatography to afford the desired ynamide. Compounds 8 were obtained in our laboratory. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With copper(l) iodide; caesium carbonate; N,N`-dimethylethylenediamine In N,N-dimethyl-formamide at 70℃; Inert atmosphere; | General method XXIV General procedure: (E)-1-Chloro-4-(4,4-dibromobuta-1 ,3-dienyl)benzene (prepared according to Maity, P., et al. Org. Lett. 2014, 764122-4125), the appropriate tosylamine (1.05 eq), and CS2CO3 (4.0 eq) were combined and taken up in DMF (0.33 M) under N2. Next, Λ/,Λ/'-dimethylethylenediamine (0.18 eq) and Cul (0.12 eq) were added and the reaction was heated to 70°C. The reaction was monitored by TLC and/or HPLC (product had UV response only). After 3-5 h, the reaction was cooled to rt, water was added, and the mixture was extracted four times with diethyl ether. The combined organics were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography, eluting with an EtOAc/hexanes gradient, to yield the desired adduct. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With iodine pentoxide; 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 60℃; for 12h; Sealed tube; | |
63% | With iodine pentoxide In acetonitrile at 20 - 60℃; for 12h; | 16 Example 16: At room temperature, p-methylthiophenol (1.24 g, 10 mmol) was added sequentially to a 50 mL round bottom flask,Benzylamine (2.20 ml, 20 mmol), acetonitrile (20 mL) and diiodide pentoxide (10 mmol).Then, the reaction mixture was stirred at 60 ° C for 12 hours (TLC detection reaction).Then, the reaction was stopped and concentrated under reduced pressure to obtain a crude product.And finally rinsed with a mixed eluent of petroleum ether and ethyl acetate,Rapid column chromatography (silica gel column) gave the corresponding product sulfonamide compound(1.64 g of yellow liquid, 63% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With 2-butyl-1,3-diphenyl-1,3,2-diazaphospholidine; 1,1'-azodicarbonyl-dipiperidine In 1,2-dichloro-ethane at 40℃; | |
78.3% | With 1-(tert-butyl)-2-(chlorobenzyl) azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 5h; | General procedure for Mitsunobu reactions General procedure: A solution of azo-reagent (1.2 mmol) in THF or CH2Cl2 (3 mL) was added slowly to the solution of alcohol (1 mmol), acidic pronucleophile (1.2 mmol) and Ph3P (1.2 mmol) in THF or CH2Cl2 (5 mL) at 0-5 °C and the reaction mixture was continued stirring a troom temperature. The reaction was monitored by TLC. The solution was concentrated and the toluene was added. The 1-(tert-butyl)2- (4-chlorobenzyl) hydrazinedicarboxylate (4a) precipitated and was filtered off. Then the filtrate was evaporated under reduced pressure. The product was purified by column chromatography on silica gel to afford the pure products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In dimethyl sulfoxide at 65℃; for 36h; Inert atmosphere; | |
80% | With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 80℃; Inert atmosphere; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 70℃; for 1.5h; Inert atmosphere; | Preparation of Ynamido-Phosphonates from Sulfonamides; General Procedure A General procedure: Sulfonamide (0.67 mmol), CuSO4·5H2O (0.067 mmol), 1,10-phenanthroline (0.134 mmol), and K3PO4 (1.34 mmol) were heated to 70 °C in anhydrous toluene (1.9 mL) under an inert atmosphere. Bromoalkyne 10 (0.84 mmol) in anhydrous toluene (1.9 mL) was then slowly added. After 1.5 h at 70 °C, the mixture was cooled to r.t., filtered through a pad of Celite, and concentrated in vacuo. Purification by flash chromatography on silica gel yielded the N-sulfonyl ynamido-phosphonate 5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With silver hexafluoroantimonate In 1,2-dichloro-ethane at 140℃; for 0.0333333h; Inert atmosphere; Microwave irradiation; | General Procedure for AgI-Catalyzed Deprenylation. General procedure: To a solution of N-prenyl sulfonamide (0.10 mmol) in DCE (0.5 mL) was added a solution ofAgSbF6 (0.005 mmol) in DCE (0.5 mL) under an atmosphere of N2. After stirring for 1-2 min at140 °C under microwave irradiation, the solvent was evaporated off. The residue waschromatographed with hexane-AcOEt to afford sulfonamide. Chemical yields are summarized inScheme 2, 4 and Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 60℃; for 63h; Inert atmosphere; | 3-(Benzyl-p-toluenesulfonylamino)-prop-2-ynyl benzoate (1b) The reaction mixture, which was prepared from 3-Bromo-2-propynyl benzoate (1.52g, 6.36 mmol), N-Benzyl-p-toluenesulfonamide (1.74 g, 6.68 mmol), K2CO3 (1.76 g,12.7 mmol), CuSO4•5H2O (0.16 g, 0.64 mmol) and 1,10-Phenanthroline (0.23 g, 1.27mmol) in Toluene (7 mL), was stirred at 60 °C for 63 h. After cooled to rt, theresulting mixture was filtered on celite, and the volatiles were removed under reducepressure. The residue was separated by column chromatograpy on silicagel (Hexane/EtOAc/CH2Cl2 = 6:1:1) to provide 1b (2.54 g, 95%).IR (KBr) ν 2231, 1721, 1360, 1168 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.37 (s, 3H),4.51 (s, 2H), 4.96 (s, 2H), 7.22 (d, J = 8.8 Hz, 2H), 7.25-7.29 (m, 5H), 7.45 (dd, J =7.3, 8.3 Hz, 2H), 7.59 (tt, J = 1.5, 7.3 Hz, 1H), 7.73 (d, J = 8.8 Hz, 2H), 8.02 (dd, J =1.5, 8.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.5, 53.1, 55.4, 66.8, 80.6, 127.7,128.3, 128.3, 128.5, 128.7, 129.6, 129.7, 129.7, 133.1, 134.3, 134.5, 144.6, 165.8;EI-LRMS m/z 419 (M+), 355, 314, 264, 91; EI-HRMS m/z calcd for C24H21O4NS(M+) 419.1191, found 419.1184. |
37% | With potassium phosphate; 1,10-Phenanthroline; copper(ll) sulfate pentahydrate In toluene at 80℃; for 48h; Inert atmosphere; |
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