* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With triethylamine In dichloromethane at 0 - 20℃; for 3 h;
EXAMPLE 40A (4-bromopheny)pyrrolidin-1-ylmethanone A solution of 4-bromobenzoyl chloride (3 g, 13.7 mmol)) in dichloromethane (25 mL) was cooled to 0° C. and treated with pyrrolidine (2.5 mL, 30.3 mmol) and triethylamine (2 mL, 14.4 mmol). The mixture was warmed to ambient temperature over 3 hours and concentrated. The residue was purified by flash chromatography on silica gel using 10-60percent hexane/ethyl acetate to provide the title compound (3.1 g, 89percent). MS (ESI) m/e 256 (M+H)+.
86%
With pyridine In dichloromethane for 1 h;
General procedure: To a stirred solution of the amine (2 g) in dichloromethane was added pyridine (1.2 eq.) followed by dropwise addition of the acid chloride(1.2 eq.). After 1 hr, further dichloromethane (10 ml) was added, the solution then washed successively with saturated aqueous sodium hydrogen carbonate, hydrochloric acid (2 M), water, then dried and the solvent removed under reduced pressure to give the amide.
Reference：
[1] Patent: US2007/259937, 2007, A1, . Location in patent: Page/Page column 17
[2] Patent: US6340759, 2002, B1, . Location in patent: Example 274
[3] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2014, vol. 53, # 8, p. 1115 - 1121
[4] Organic Letters, 2015, vol. 17, # 19, p. 4850 - 4853
2
[ 123-75-1 ]
[ 586-76-5 ]
[ 5543-27-1 ]
Yield
Reaction Conditions
Operation in experiment
86.9%
Stage #1: With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 30℃; for 0.25 h; Stage #2: at 30℃; for 16 h;
[0171] To a stirred mixture of 4-bromobenzoic acid (2.00 g,10.0 mol) and Et3N (3.03 g, 30.0 mmol) in DCM (30 mL) wasadded HATU (4.18 g, 11.0 mmol) at 30° C. After 15 mins,pyrrolidine (972 mg, 12.0 mmol) was added into the mixture,which was stirred at 30° C. for 16 hrs. After LCMS and TLC(PE:Et0Ac=2: 1) showed the reaction was complete, the mixturewas concentrated and purified by colunm chromatographyon silica gel (PE:EtOAc=l:0-20:1-10:1-5:1-3:1) to givethe title compound (2.20 g, yield: 86.9percent) as a white solid.
With oxygen; N,N,N,N-tetraethylammonium tetrafluoroborate In N,N-dimethyl-formamide at 25℃; for 12 h; Electrolysis
General procedure: Constant current electrolyses were performed at 25°C, using an Amel Model 552 potentiostat equipped with an Amel Model 731 integrator. All the experiments were carried out in a divided glass cell separated through a porous glass plug filled up with a layer of gel (i.e., methyl cellulose 0.5percent vol dissolved in DMF-Et4NBF4 1.0moldm−3); Pt spirals (apparent area 0.8cm2) were used as both cathode and anode. DMF-Et4NBF4 0.1moldm−3 was used as solvent-supporting electrolyte system (catholyte: 10cm3; anolyte: 5cm3). The current density was 20mAcm−2. In the catholyte 0.5mmol of benzoin (or deoxybenzoin, or benzil) and 1.0mmol of amine were present, with continuous O2 bubbling. The electrolysis was stopped after a prefixed charge (see Tables 1–4), the oxygen bubbling was stopped and the catholyte was kept under stirring at rT for 12hours. Usual workup gave the benzamides reported in Tables 1–4. All the isolated benzamides gave spectral data identical to those reported in the literature. Products spectral characterisation is reported in the Supporting Information.
With triethylamine; In dichloromethane; at 15 - 25℃; for 2h;Inert atmosphere;
General procedure: 4-Brorno2rnethyIbenzoyl chloride (1.24 g, 5.30 mmol) was added to asuspension of (1R,5S8-?oxa-3.-azabicyclo[3.2.1]octane (0.50 g, 4.4 mmol) and triethylamine (2.51 ml, 17.99 mmoi) in DCM (10 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours, then diluted with DCM (30 mL) and washed with brine (x 2). The combined organic layers were concentrated in vacuo and purified by silica chromatography, eluting with 20% EtOAc/hexanes to afford the title compound as a solid,
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;
EXAMPLE 40A (4-bromopheny)pyrrolidin-1-ylmethanone A solution of 4-bromobenzoyl chloride (3 g, 13.7 mmol)) in dichloromethane (25 mL) was cooled to 0 C. and treated with pyrrolidine (2.5 mL, 30.3 mmol) and triethylamine (2 mL, 14.4 mmol). The mixture was warmed to ambient temperature over 3 hours and concentrated. The residue was purified by flash chromatography on silica gel using 10-60% hexane/ethyl acetate to provide the title compound (3.1 g, 89%). MS (ESI) m/e 256 (M+H)+.
86%
With pyridine; In dichloromethane; for 1h;
General procedure: To a stirred solution of the amine (2 g) in dichloromethane was added pyridine (1.2 eq.) followed by dropwise addition of the acid chloride(1.2 eq.). After 1 hr, further dichloromethane (10 ml) was added, the solution then washed successively with saturated aqueous sodium hydrogen carbonate, hydrochloric acid (2 M), water, then dried and the solvent removed under reduced pressure to give the amide.
[0171] To a stirred mixture of 4-bromobenzoic acid (2.00 g,10.0 mol) and Et3N (3.03 g, 30.0 mmol) in DCM (30 mL) wasadded HATU (4.18 g, 11.0 mmol) at 30 C. After 15 mins,pyrrolidine (972 mg, 12.0 mmol) was added into the mixture,which was stirred at 30 C. for 16 hrs. After LCMS and TLC(PE:Et0Ac=2: 1) showed the reaction was complete, the mixturewas concentrated and purified by colunm chromatographyon silica gel (PE:EtOAc=l:0-20:1-10:1-5:1-3:1) to givethe title compound (2.20 g, yield: 86.9%) as a white solid.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 15 - 25℃;Inert atmosphere;
To a suspension of 4-bromobenzoic acid (150 mg, 0.75 mmol) in DCM (7.5 mL) were added pyrrolidine (53 mg, 0.75 mmol), HOBT (110 mg, 0.78 mmol), and Et3N (190 mg, 1.9 mmol) successively at room temperature, then to the mixture was added EDCI (150 mg, 0.78 mmol) in portions. The resulting mixture was stirred overnight, then was poured into water and washed with dilute aq. HC1 (5 mL), sat.aq. NaHC03 (15 mL) and brine (10 mL). The organic layer was dried over Na2S04, filtered then concentrated in vacuo to afford the crude product which was purified by preparative TLC (petroleum ether / EtOAc: 3: 1) to afford the title compound. LRMS (ESI) calc'd. for CnHi3BrNO [M+H]+: 254, found: 254. 1HNMR (400 MHz, CDC13): delta 7.46 (d, / = 8.4 Hz, 2H), 7.33 (d, / = 8.4 Hz, 2H), 3.55 (t, / = 6.8 Hz, 2H), 3.33 (t, J = 6.4 Hz, 2H), 1.92-1.77 (m, 4H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;Inert atmosphere;
To a suspension of 4-bromobenzoic acid (150 mg, 0.75 mmol) in DCM (7.5 mL) were added pyrrolidine (53 mg, 0.75 mmol), HOBT (110 mg, 0.78 mmol), and Et3N (190 mg, 1.9 mmol)successively at room temperature, then to the mixture was added EDCI (150 mg, 0.78 mmol) in portions. The resulting mixture was stirred overnight, then was poured into water and washed with dilute aq. HC1 (5 mL), sat. aq. NaHCO3 (15 mL) and brine (10 mL). The organic layer was dried over Na2504, filtered then concentrated in vacuo to afford the crude product which was purified by preparative TLC (petroleum ether / EtOAc: 3:1) to afford comound 1-37. LRMS ESIcalcd. for C11H13BrNO [M+H]: 254, found: 254. ?HNMR (400 MHz, CDC13): oe 7.46 (d, J = 8.4 Hz, 2 H), 7.33 (d, J= 8.4 Hz, 2 H), 3.55 (t, J=6.8 Hz, 2 H), 3.33 (t, J =6.4 Hz, 2 H), 1.92-1.77 (m, 4H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;
[0173] A mixture of ( 4-bromophenyl)(pyrrolidin-1-yl)methanone (2.20 g, 8.70 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (2.43 g, 9.57 mmol),AcOK (1.17 g, 17.4 mmol) and Pd(dppf)Cl2 (110 mg) indioxane (20 mL) was stirred at 100 C. for 16 hrs under N 2 .After LCMS and TLC (PE:Et0Ac=2: 1) showed the reactionwas complete, the mixture was concentrated and purified bycolunm chromatography on silica gel (PE:EtOAc=l:0-50:1-20:1-10:1-5:1-3:1) to give the title compound (2.15 g,yield: 83.4%) as a white solid.
With oxygen; N,N,N,N-tetraethylammonium tetrafluoroborate; In N,N-dimethyl-formamide; at 25℃; for 12h;Electrolysis;
General procedure: Constant current electrolyses were performed at 25C, using an Amel Model 552 potentiostat equipped with an Amel Model 731 integrator. All the experiments were carried out in a divided glass cell separated through a porous glass plug filled up with a layer of gel (i.e., methyl cellulose 0.5% vol dissolved in DMF-Et4NBF4 1.0moldm-3); Pt spirals (apparent area 0.8cm2) were used as both cathode and anode. DMF-Et4NBF4 0.1moldm-3 was used as solvent-supporting electrolyte system (catholyte: 10cm3; anolyte: 5cm3). The current density was 20mAcm-2. In the catholyte 0.5mmol of benzoin (or deoxybenzoin, or benzil) and 1.0mmol of amine were present, with continuous O2 bubbling. The electrolysis was stopped after a prefixed charge (see Tables 1-4), the oxygen bubbling was stopped and the catholyte was kept under stirring at rT for 12hours. Usual workup gave the benzamides reported in Tables 1-4. All the isolated benzamides gave spectral data identical to those reported in the literature. Products spectral characterisation is reported in the Supporting Information.
(4-bromo-2-fluorophenyl)(pyrrolidin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With silver nitrate; N-fluorobis(benzenesulfon)imide; palladium dichloride; In 1,2-dichloro-ethane; at 110℃; for 24h;Sealed tube;
In a sealed reaction vessel into the 4-bromo-N-substituted benzamide (50.6 mg, 0.2 mmol), palladium chloride (3.6 mg, 0.02 mmol), N-fluorobenzenesulfonimide (126.1 mg, 0.4 mmol), silver nitrate (13.6) Mg, 0.08 mmol), 1,2-dichloroethane (2.0 mL), the reaction mixture was stirred at 110 C,TLC tracking was detected and the reaction was complete at 24 h. The reaction was quenched and the mixture was diluted with ethyl acetate. EtOAc was evaporated. Separation and purification were carried out, and the eluent containing the product was collected, and the solvent was evaporated to give 43.0 mg of pure 2-fluoro-4-bromo-N-substituted benzamide in a yield of 79%.
tert-butyl benzyl(4-bromobenzoyl)carbamate[ No CAS ]
[ 5543-27-1 ]
Yield
Reaction Conditions
Operation in experiment
80%
With air; In toluene; at 100℃; for 24h;Molecular sieve;
Under air conditions, add magnetons to a dry, clean 25mL round bottom flask in sequence.N-Boc amide (194.5 mg, 0.5 mmol) represented by the formula IId,An amine represented by the formula IIIa (53.3 mg, 0.75 mmol),Then, 2.5 mL of toluene dried by molecular sieve was added, and the reaction was performed at 100 C for 24 hours.10 mL of water was added to quench the reaction, and extracted with dichloromethane (25 mL x 3 times),The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.The filtrate was evaporated by rotary evaporation to remove the solvent. After concentration, 200-300 mesh silica gel column chromatography was performed.A mixed solvent of ethyl acetate and petroleum ether (1: 5) was rinsed.102 mg of the compound represented by the formula Id was isolated in a yield of 80%.
General procedure: In a nitrogen-filled glovebox, to a 15 mL reaction tube equipped with a magnetic stirrer, were added Cp2ZrH2 (0.01mmol, 2.2 mg) as the catalyst, and the appropriate amide (0.2mmol); solvent was added when necessary. HBpin (3 equiv. peramide functional group) was then added, and the reaction tube was taken out from the glovebox and stirred at room temperature for 12-48 h. The resultant crude amines were either isolated using silica gel flash chromatography, or acidified by stirring with HCl in Et2O (2 mL, 1N) for 2 h, after which time precipitation was observed. Then, the reaction solution was transferred to a centrifuge tube and centrifuged three times. The supernatant was removed and the resulting solid was dried inan oven at 80 C for several hours to obtain the HCl salt of the amine.
1-(4-bromobenzyl)pyrrolidine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
The bis(cyclopentadiene) zirconium dihydride (denoted as Cp2ZrH2, 0.01mmol, 2.23mg),(4-Bromophenyl)(pyrrolidin-1-yl)methanone(Denoted as 1m, 0.2mmol, 50.8mg) and pinacol borane (denoted as HBpin, 0.6mmol, 87μL), stirred at room temperature under nitrogen (1atm) atmosphere for 12h, treated with hydrogen chloride in ether solution to obtain the structure of formula 2m The hydrochloride compound (white solid, 1-(4-bromobenzyl)pyrrolidine hydrochloride). The isolated yield was 84%.
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