* 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 trifluoroacetic acid In dichloromethane at 0 - 20℃; Large scale
To a 250 mL multi-vial was added 1530.0 g (6.5 mol) of benzylmethoxymethyltrimethylsilylmethylamine,31.80 g (3.7 mol)Methyl acrylate and 38 mL of dichloromethane,A solution of 44.0 g (0.4 mol) of trifluoroacetic acid at a mass concentration of 10percent was slowly added dropwise at 0 ° C,After completion of the dropwise addition, the mixture was stirred at room temperature overnight, and the mixture was concentrated under reduced pressure,The residueRespectively, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution,Combined organic phase,The organic phase passes through anhydrous sulfuric acidSodium drying, filtration,The filtrate was concentrated under reduced pressure,To obtain 1420.0 g of crude 1-benzylpyrrolidine-3-carboxylate as a crude product 100percent.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 19, p. 4861 - 4866
[2] Organic Process Research and Development, 2009, vol. 13, # 2, p. 292 - 296
[3] Synthesis, 2006, # 16, p. 2646 - 2648
[4] Synlett, 2015, vol. 26, # 13, p. 1815 - 1818
[5] Chemical & Pharmaceutical Bulletin, 1985, vol. 33, # 7, p. 2762 - 2766
[6] Tetrahedron Letters, 2011, vol. 52, # 26, p. 3266 - 3270
[7] Patent: CN104817549, 2017, B, . Location in patent: Paragraph 0036-0038
2
[ 93102-05-7 ]
[ 140-88-5 ]
[ 5747-92-2 ]
Reference：
[1] Synthesis, 2006, # 16, p. 2646 - 2648
[2] Tetrahedron Letters, 2010, vol. 51, # 7, p. 1026 - 1029
[3] Chemistry Letters, 1984, p. 1117 - 1120
3
[ 50-00-0 ]
[ 53215-95-5 ]
[ 93102-05-7 ]
Yield
Reaction Conditions
Operation in experiment
97.5%
Stage #1: at 0℃; Stage #2: With potassium carbonate In water at 20℃; for 2 h;
To the solution of formaldehyde (37percent, 16.816 g, 207.19 mmol) at 0°C N-benzylo- 1 -(trimethylsilyl)methanamine (Intermediate P15, 28.588 g, 144.89 mmol) was added dropwise. To the mixture solid potassium carbonate (16.182 g, 115.91 mmol) was added and the whole was stirred at room temperature for 2 hours. Water (50 ml) was added and the mixture was extracted with diethyl ether (2 x 50 ml). Organic layer was washed with brine and dried over sodium sulphate. Solvent and drying agent were removed to obtain 33.551 g of the title product in the form of a yellow oil (yield 97.5percent). 1H NMR (300 MHz, CDCl3): δ 7.35 - 7.18 (m, 5H), 3.99 (s, 2H), 3.75 (s, 2H), 3.22 (s, 3H), 2.18 (s, 2H), 0.13 (s, 9H).
Stage #1: at 0 - 15℃; for 4 h; Large scale Stage #2: at 20℃; Large scale
In a 2L multi-bottle, add 1282.0g (6,6mol)Benzyltrimethylsilylmethylamine,800 mL (38 lmol)Formaldehyde and 328 mL (38. lmo 1) methanol,0 ° C under stirring 1 h,And then control the temperature at 10 ° C ~ 15 ° C stirring 3h,To the mixture Was added 413.0 g (2.9 mol) of potassium carbonate,After returning to room temperature and stirring overnight,Filter, filter cake with ether,Collecting filterLiquid, the organic phase is separated, the organic phase is pressurized and concentrated,To give 1530.5 g of benzylmethoxymethyltrimethylsilylmethylamine as a yellow oil,Yield 91percent
82%
With potassium carbonate In methanol at 0 - 15℃; for 5.75 h;
EXAMPLE 2; N-(Benzyl)-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine (Scheme 3, 3-4); To a solution of chloromethyltrimethylsilane (1.34 kg, 10.96 mol) in acetonitrile (17.0 L) is added benzylamine (2.34 kg, 21.92 mol) and the reaction mixture is heated at reflux for 16 h. The reaction mixture is cooled to room temperature and the precipitate of benzylamine hydrochloride is removed by filtration. The filtrate is concentrated under vacuum to about 5 L and then diluted with water (5 L). The reaction mixture is extracted with hexane (2.x.5 L). The organic extracts are combined and washed with brine (5 L) and dried over MgSO4. The filtrate is concentrated under vacuum to give 1.77 kg (83percent) of N-(trimethylsilylmethyl)benzylamine. The above amine (1.77 kg, 9.14 mol) is added to a mixture of 37percent formaldehyde (0.89 kg, 10.96 mol) and methanol (0.35 kg, 10.96 mol) at 0° C. over a period of 30 min. The reaction mixture is further stirred at 0° C. for 1 h and at 10° C. to 15° C. for 3 h. To the reaction mixture is then added anhydrous K2CO3 (1 kg) and stirred for 2 h. The oily layer is decanted onto 100 g of K2CO3 and stirred for 15 min and again decanted. The remaining residual material from the K2CO3 is recovered by washing all the solid K2CO3 with ether. Ether washings are mixed with the decanted oily product and concentrated on rotary evaporator to give 2.10 kg (82percent) of the desired product 3-4, deemed pure enough to be used in the next step.
64%
at 0 - 25℃; for 4 h;
To a mixture containing 6.2 mL of aqueous formaldehyde (37percent) and 3.9mL of methanol at 0°C, the amine iii (12.0 g, 62.1 mmol) was slowly added (30 min).The temperature was then raised to 25°C and the reaction was stirred for 4h. Thereaction was quenched with a saturated solution of K2CO3 and extracted withdichloromethane (4x50 mL). The organic phase was dried with anhydrous Na2SO4,filtered and the solvent removed under vacuum. The residue was distilled under highvacuum at 120°C, and the product 1 was obtained as a colorless liquid in 64percent yield(9.50 g, 39.9 mmol).1H NMR (CDCl3, 400.15 MHz) δ (ppm): 0.05 (br.s, 9H), 2.19 (s, 2H), 3.24 (s, 3H),3.77 (s, 2H ), 4.01 (s, 2H), 7.18-7.35 (m, 5H).13C NMR (CDCl3, 100.4 MHz) δ (ppm): -1.47, 42.8, 55.4, 59.4, 88.4, 126.8, 128.1,139.7.
43.8%
at 0 - 20℃; for 1.83333 h;
Synthesis of benzyl(methoxymethyl)trimethylsilanylmethylamine (Reaction with 1.3 eq. of Paraformaldehyde) 2.00 g (0.014 mol) of potassium carbonate, 24.4 g (0.76 mol) of methanol and 15.6 g (0.52 mol) of paraformaldehyde are initially charged and cooled to 0° C. At this temperature, within 30 min, 77.4 g (0.40 mol) of benzyltrimethylsilanylmethylamine are metered in. The biphasic reaction mixture is stirred at 0° C. for a further 1 h and then warmed to room temperature within 20 min. Within 1 min, 190.9 g of pentane are metered in. The biphasic reaction mixture is separated and the upper organic phase is dried azeotropically for 2 h. The organic phase is concentrated and then fractionally distilled. Yield 74.9 g (79percent) of a colorless liquid. DSC analyses: upper layer of the biphasic reaction mixture after the further reaction time (onset temperature: 154° C., decomposition enthalpy 414 J/g) lower layer of the biphasic reaction mixture after the further reaction time (onset temperature: 72° C., decomposition enthalpy 123 J/g) distillation bottoms (onset temperature: 134° C., decomposition enthalpy 461 J/g). Example 4 Synthesis of benzyl(methoxymethyl)trimethylsilanylmethylamine (Equimolar Reaction)2.50 g (0.018 mol) of potassium carbonate, 30.4 g (0.95 mol) of methanol and 15.0 g (0.50 mol) of paraformaldehyde are initially charged and cooled to 0° C. At this temperature, within 30 min, 96.7 g (0.50 mol) of benzyltrimethylsilanylmethylamine are metered in. The biphasic reaction mixture is stirred at 0° C. for a further 1 h and then warmed to room temperature within 20 min. Within 1 min, 190.9 g of pentane are metered in. The biphasic reaction mixture is separated and the upper, organic phase is dried azeotropically for 2 h. The organic phase is concentrated and then fractionally distilled. Yield 105.9 g (89percent) of a colorless liquid. -b.p. 94° C./1 mbar. -1H NMR(C6D6): δ=0.09 (s, 9H), 2.21 (s, 2H), 3.00 (s, 3H), 3.75 (s, 2H), 3.87 (s, 2H), 7.10-7.45 (m, 5H).DSC analyses: upper layer of the biphasic reaction mixture after the further reaction time (onset temperature: 225° C., decomposition enthalpy 163 J/g) lower layer of the biphasic reaction mixture after the further reaction time (onset temperature: 80° C., decomposition enthalpy 14 J/g) distillation bottoms (onset temperature: 210° C., decomposition enthalpy 646 J/g). Example 5Synthesis of benzyl(methoxymethyl)trimethylsilanylmethylamine (Reactions with Different StoichiometriesThe reactions were carried out analogously to Example 4, with the stoichiometries set forth in Table 1. In the inventive process, the stoichiometry is crucial for yield and onset temperature. The decomposition enthalpies reported are based on the distillation bottoms. TABLE 1 Decompo- Decompo- eq. sition sition Experiment Yield PFA Onset 1 enthalpy 1 Onset 2 enthalpy 2 4(a) 43.8 0.90 260° C. 69 J/g 4(b) 66.0 0.95 256° C. 400 J/g 4(c) 81.3 1.00 245° C. 91 J/g - - 4(d) 81.2 1.05 158° C. 291 J/g 361° C. 12 J/g In the case of substoichiometric use of paraformaldehyde, the yield falls (from 81.3percent at 1.0 equivalent to 43.8percent at 0.90 equivalent). In the case of superstoichiometric use of paraformaldehyde (1.05 eq.), the yield remains virtually unchanged, but the onset temperature falls from approx. 250° C. to 158° C.
1.21 g
at 0 - 15℃; for 5.5 h; Inert atmosphere
To a solution of chloromethyltrimethylsilane(13.4g, 0.11mol) in CH3CN (100mL) was added benzylamine (23.45g, 0.22mol) and the reactionmixture was heated at reflux for 16h. The reaction mixture was cooled to room temperature ,andthe precipitate of benzylamine hydrochloride was removed by filtration. The filtrate wasconcentrated under vacuum and the residue was diluted with water (50mL).The reaction mixturewas extrated with PE (50mL*2 ).The organic extracts were combined and washed with water(50mL*2) and brine (50mL) and dried over Na2SO4. The filtrate was concentrated under vacummto give 18.8g crude product. 88.9percent Yield. The above-mentioned crude product (18.8g0.098mol)was added to a mixture of 37percent formaldehyde (9.49g 0.118mol)and methanol (3.78g, 0.118mol)at 0°C over a period of 60 min. The reaction mixture was further stirred at 0°C for 1.5h and at10-15°C for 3h. To the reaction mixture was then added anhydrous K2CO3 (16.3g, 0.118mol) ,andthis mixture stirred overnight. The oily layer was separated, added K2CO3 (1.63g, 0.012mol) andstirred for 15min and again decanted. The remaining residual material from the K2CO3 wasrecovered by washing all the solid K2CO3 with ether .Ether washings were mixed with thedecanted oily product and concentrated on the rotary evaporator to give crude product ofS2N-Benzyl Substituted Compound 1 21g, 90.8percent Yield.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 21, p. 6038 - 6041
[2] Patent: CN104817549, 2017, B, . Location in patent: Paragraph 0032-0034
[3] Journal of Organic Chemistry, 2016, vol. 81, # 6, p. 2340 - 2354
[4] Patent: US2006/128789, 2006, A1, . Location in patent: Page/Page column 7
[5] Chemistry Letters, 1984, p. 1117 - 1120
[6] European Journal of Medicinal Chemistry, 2010, vol. 45, # 5, p. 1717 - 1723
[7] Tetrahedron Letters, 2014, vol. 55, # 8, p. 1491 - 1495
[8] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 22, p. 3867 - 3872
[9] Patent: US2009/36700, 2009, A1, . Location in patent: Page/Page column 3-4; 4
[10] Journal of Organic Chemistry, 1987, vol. 52, # 2, p. 235 - 244
[11] Journal of Organic Chemistry, 1996, vol. 61, # 10, p. 3362 - 3374
[12] Patent: US2006/63761, 2006, A1, . Location in patent: Page/Page column 6; 13
[13] Journal of the American Chemical Society, 2011, vol. 133, # 26, p. 10184 - 10194
[14] Organic Process Research and Development, 2005, vol. 9, # 2, p. 193 - 197
[15] Patent: WO2013/160273, 2013, A1, . Location in patent: Page/Page column 91
[16] Patent: WO2014/39489, 2014, A1, . Location in patent: Page/Page column 87
[17] Patent: US2015/45408, 2015, A1, . Location in patent: Paragraph 0434-0435
[18] Synlett, 2016, vol. 27, # 2, p. 282 - 286
5
[ 67-56-1 ]
[ 53215-95-5 ]
[ 93102-05-7 ]
Yield
Reaction Conditions
Operation in experiment
69%
Stage #1: at 0℃; for 0.166667 h; Stage #2: at 20℃; for 73 h;
To a 300 mL round bottom flask was charged 57.2 g (698 mmol) of 30 weight percent formaldehyde, which was cooled to O0C. To the cold formaldehyde was added 89.92 g (485 mmol) of Benzyl-methoxymethyl-trimethylsilanylmethyl-amine. After 10 min, 60 mL of methanol were added drop-wise, followed by excessive potassium carbonate (105 g). The reaction mixture was stirred for 1 hour then the liquid phase was separated. More potassium carbonate was added to the liquid phase (20 g) and the reaction mixture was allowed to stir at room temperature for 72 hours. The reaction mixture was filtered and the excess methanol evaporated. The liquid was purified by vacuum distillation to yield 51.3 g (216 mmol) of clear liquid, 69percent. Mass spectrum (APCl) m/e 238 p+1. 1H NMR (CDCI3, 400 MHz)_7.34-7.30(m, 5H), 4.01 (s, 2H), 3.77(s, 2H), 3.19(s, 3H), 2.19(s, 2H), 0.054(s, 9H) ppm.
Part B. Preparation of N-benzyl-N-(trimethylsilylmethyl)aminomethyl methyl ether. To a stirred mixture of methanol (1.25 mL, 31 mmol) and 37percent aqueous formaldehyde (2.56 mL, 31 mmol) at 0° C. was added N-benzyl-N-(trimethylsilylmethyl)amine (5.0 g, 26 mmol) dropwise over 5 minutes. The resulting mixture was stirred for 2 h. Anhydrous potassium carbonate (1.02 g, 7.4 mmol) was added and the mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water and extracted twice with ether. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 5.6 g (92percent) of the title compound. 1 H NMR (CDCl3): δ 7.30-7.15 (m, 5H), 3.95 (s, 2H), 3.71 (s, 2H), 3.19 (s, 3H), 2.14 (s, 2H).
92%
With formaldehyd; potassium carbonate In methanol
Part B. Preparation of N-benzyl-N-(trimethylsilylmethyl)aminomethyl methyl ether. To a stirred mixture of methanol (1.25 mL, 31 mmol) and 37percent aqueous formaldehyde (2.56 mL, 31 mmol) at 0° C. was added N-benzyl-N-(trimethylsilylmethyl)amine (5.0 g, 26 mmol) dropwise over 5 minutes. The resulting mixture was stirred for 2 h. Anhydrous potassium carbonate (1.02 g, 7.4 mmol) was added and the mixture was stirred at 0° C. for 30 min. The reaction mixture was diluted with water and extracted twice with ether. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 5.6 g (92percent) of the title compound. 1 H NMR (CDCl3): δ 7.30-7.15 (m, 5H), 3.95 (s, 2H), 3.71 (s, 2H), 3.19 (s, 3H), 2.14 (s, 2H).
92%
With formaldehyd; potassium carbonate In methanol
Part B. Preparation of N-benzyl-N-(trimethylsilylmethyl)aminomethyl methyl ether. To a stirred mixture of methanol (1.25 mL, 31 mmol) and 37percent aqueous formaldehyde (2.56 mL, 31 mmol) at 0° C was added N-benzyl-N-(trimethylsilylmethyl)amine (5.0 g, 26 mmol) dropwise over 5 minutes. The resulting mixture was stirred for 2 h. Anhydrous potassium carbonate (1.02 g, 7.4 mmol) was added and the mixture was stirred at 0° C for 30 min. The reaction mixture was diluted with water and extracted twice with ether. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 5.6 g (92percent) of the title compound. 1H NMR (CDCl3): δ 7.30-7.15 (m, 5H), 3.95 (s, 2H), 3.71 (s, 2H), 3.19 (s, 3H), 2.14 (s, 2H).
92%
With formaldehyd; potassium carbonate In methanol
Part B. Preparation of N-benzyl-N-(trimethylsilylmethyl)aminomethyl methyl ether. To a stirred mixture of methanol (1.25 mL, 31 mmol) and 37percent aqueous formaldehyde (2.56 mL, 31 mmol) at 0° C was added N-benzyl-N-(trimethylsilylmethyl)amine (5.0 g, 26 mmol) dropwise over 5 minutes. The resulting mixture was stirred for 2 h. Anhydrous potassium carbonate (1.02 g, 7.4 mmol) was added and the mixture was stirred at 0° C for 30 min. The reaction mixture was diluted with water and extracted twice with ether. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 5.6 g (92percent) of the title compound. 1H NMR (CDCl3): δ 7.30-7.15 (m, 5H), 3.95 (s, 2H), 3.71 (s, 2H), 3.19 (s, 3H), 2.14 (s, 2H).
trans-4-(3,4-dichlorophenyl)-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With trifluoroacetic acid; In tetrahydrofuran; at 0 - 20℃;
a) (3RS,4SR)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid To a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (16.87 g, 0.071 mol) and (E)-3-(3,4-Dichloro-phenyl)-acrylic acid (7.71g, 0.036 mol) in THF (50 mL) was added trifluoroacetic acid (0.19 mL, 0.002 mol) at 0 C. The mixture was gradually warmed to room temperature and stirred overnight. It was then diluted with n-heptane (250 mL). The resulted white precipitation was collected and washed with heptane affording 11.6 g (94%) of the title compound as a white solid. ES-MS m/e: 350.2 (M+H+).
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 17h;
A solution of B1_3 (22.06 g,92.7 mmol) and methyl acrylate (C2, 11.54 g, 139.0 mmol) inDCM(100 mL) was cooled to 0 C.Asolutionof trifluoroacetic acid (12.71 g, 111.2 mmol) in DCM (50 mL) was added slowly by drop to the reactionmixture. The solution was warmed to room temperature and stirred for 17 h. NaHCO 3 saturatedsolution (150 mL) was added to the solution and stirred until no gas was produced. The mixture waspartitioned between water and DCM. The organic phase was washed with brine, dried over Na2SO4and concentrated to give the title compound (19.53 g, 96%). 1H-NMR (CDCl3) 7.35-7.23 (m, 5H),3.69 (s, 3H), 3.64 (s, 2H), 3.12-2.99 (m, 1H), 2.98-2.87 (m, 1H), 2.79-2.69 (m, 1H), 2.69-2.57 (m, 1H),2.58±2.48 (m, 1H), 2.17±2.04 (m, 2H). MS (ESI, pos, ion): 219.9 [M+ H]+.
96.8%
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;
A solution of 3 (23.5g, 98.98mmol) and methyl acrylate (12.8g, 148.48mmol) in DCM (100 mL) was treated with TFA (13.5 g, 118.78 mmol) in DCM (50 mL) at 0C. The mixture was stirred at 0C for 0.5h, overnight at room temperature. The saturated aqueous NaHCO3 solution was added in the mixture, and it was stirred for 2h. The organic phase was washed with brine, dried with anhydrous Na2SO4, and concentrated in vacuo to give the compound 4 (21.01g, 96.8%).
1420 g
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;Large scale;
To a 250 mL multi-vial was added 1530.0 g (6.5 mol) of benzylmethoxymethyltrimethylsilylmethylamine,31.80 g (3.7 mol)Methyl acrylate and 38 mL of dichloromethane,A solution of 44.0 g (0.4 mol) of trifluoroacetic acid at a mass concentration of 10% was slowly added dropwise at 0 C,After completion of the dropwise addition, the mixture was stirred at room temperature overnight, and the mixture was concentrated under reduced pressure,The residueRespectively, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution,Combined organic phase,The organic phase passes through anhydrous sulfuric acidSodium drying, filtration,The filtrate was concentrated under reduced pressure,To obtain 1420.0 g of crude 1-benzylpyrrolidine-3-carboxylate as a crude product 100%.
With trifluoroacetic acid; In dichloromethane; for 16h;Inert atmosphere; Reflux;
To a solution of ethyl (E)-4,4,4-trifluorocrotonate (CAS 25597-16-4, 6.0 g, 36 mmol) and TFA (0.55 mL, 7 mmol) in DCM (60 mL) at about 0 C. was added N-(methoxymethyl)-N-[(trimethylsilyl)methyl]-benzenemethanamine (CAS 93102-05-7, 16.85 g, 71 mmol) over a period of about 20 minutes. The reaction mixture was then heated at reflux for 16 h. It was diluted with DCM (100 mL), washed with saturated aqueous NaHCO3 solution (2*100 mL), water (100 mL), and brine (50 mL). The DCM extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography to provide the title compound C164. Yield: 10.5 g (99%). 1H NMR (400 MHz, dmso-d6) delta 7.23-7.34 (m, 5H), 4.07-4.15 (m, 2H), 3.64 (d, 1H), 3.54 (d, 1H), 3.35-3.41 (m, 1H), 3.12 (q, 1H), 2.81 (t, 2H), 2.69-2.73 (m, 1H), 2.55-2.59 (m, 1H), 1.17 (t, 3H).
With dmap; benzoyl fluoride In tetrahydrofuran at 0 - 20℃; for 6.5h; Inert atmosphere;
80%
Stage #1: N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine; phenylpropynoic acid ethyl ester With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16h;
Stage #2: With hydrogenchloride In water
Stage #3: With sodium hydroxide In water
II.9.a a)
a) 1-Benzyl-4-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid ethyl ester A solution of ethyl phenylpropiolate (12.0 g, 68.9 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (26.2 g, 110 mmol) in 180 ml dichloromethane was cooled to 0° C. with an ice-water bath. Trifluoroacetic acid (0.53 ml, 6.9 mmol) was added slowly, keeping the temperature of the reaction mixture below 20° C. After completed addition the mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The residue was dissolved in 2 M aqueous hydrochloric acid solution (150 ml) and extracted with three portions of n-heptane (3*100 ml). The aqueous layer was basified with 32% aqueous sodium hydroxide solution (30 ml) and extracted with three portions of ethyl acetate (3*150 ml). The combined ethyl acetate extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Flash chromatography (n-heptane/ethyl acetate) gave the title compound (17.0 g, 80%) as a slightly yellow oil. MS m/e (%): 308.5 (M+H+, 100).
77%
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 18h; Inert atmosphere;
1.1 Step 1: Ethyl l-benzyl-4-vhenyl-2,5-dihvdro-lH-vwrole-3-carboxylate (1.3)
[00380] A solution of TFA (0.15 mL, 1.98 mmol) in CH2CI2 (3 mL), was added dropwise to a stirred solution of intermediate 1.1 (2.0 g, 11.48 mmol) and intermediate 1.2 (8.1 mL, 31.69 mmol) in CH2CI2 (50 mL) cooled at 0-5 °C. The resulting mixture was stirred at r.t. for 18 h. The reaction was poured into H2O (100 mL), the two phases were separated, and the organic phase was washed with brine (100 mL), aq. NaHCCb ss (100 mL), dried over Na2SC>4, and concentrated under reduced pressure. The crude was purified by flash chromatography (PET/EtOAc from 100% PET to 80:20 v/v PET/EtOAc). The intermediate 1.3 (2.71 g, 8.82 mmol) was obtained in 77% yield. MS-ESI(+) m/z: 308.4 (M+H).
methyl 1-benzyl-3,4-trans-4-p-tolylpyrrolidine-3-carboxylate trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In dichloromethane at 0 - 20℃; for 12h;
1
1 ml of a one molar solution of trifluoroacetic acid in dichloromethane is added dropwise at 0° C. to a solution of 1.36 ml of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine and 850 mg of methyl trans-3-p-tolylacrylate in 10 ml of dichloromethane. Stirring at room temperature for twelve hours is followed by removal of the solvent in vacuo and purification of the residue by RP-HPLC. 1.18 g of methyl 1-benzyl-3,4-trans-4-p-tolylpyrrolidine-3-carboxylate trifluoroacetate are obtained as a colorless oil. C20H23NO2.C2HF3O2 (423.43), LCMS (ESI): 310.4 (M+H+).
Step 1 : i-benzylpyrrolidine-3-carbonitrile To a solution of acrylonitrile (10 g, 188.46 mmol) and TFA (1 mL) in anhydrous DCM (500 mL) was added N-(methoxymethyl)-N-trimethylsilylmethyl)benzylamine (60 g, 0.25 mol) dropwise at 00C. The solution was stirred at room temperature overnight and then saturated aqueous NaHCO3 (200 mL) was added. The organic phase was separated, washed with brine (2 X 200 mL), and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by silica gel chromatography to give 1-benzylpyrrolidine-3- carbonitrile as a yellow oil (25 g, 70%): 1H NMR (400 MHz, CDCI3) delta ppm 7.24-7.34 (m, 5H), 3.64 (s, 2H), 2.89-3.04 (m, 2H), 2.61-2.71 (m, 3H), 2.27-2.29 (m, 2H); ES-LCMS m/z 187 (M+H)+.
Stage #1: maleiimide; N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16.75h;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
5
Example 5 relates to the synthesis of N-(tert-butoxycarbonyl)-3,7- diazabicyclo[3.3.0]octane, which was prepared as described in U.S. applications 2004/0186107 to Schrimpf et al. and 2005/0101602 to Basha et al, according to the following techniques:5-Benzyltetrahydropyrrolo [3,4-c] pyrrole-l,3-dione (or 7-benzyl-3,7- diazabicyclo [3.3.0] octan-2,4-dione); Trifiuoroacetic acid (TFA, 0.50 mL, 6.5 mmol) was added to a cold (O0C) solution of maleimide (6.27 g, 0.0646 mol) in dichloromethane (150 mL) under nitrogen. A solution of N-(methoxymethyl)-N-(trimethylsilyhnethyl)benzylamine (20 g, 0.084 mol) in dichloromethane (100 mL) was added drop- wise over 45 min. After the addition was complete, the mixture was warmed slowly to ambient temperature and stirred for 16 h. The mixture was concentrated and the resulting EPO residue was dissolved in dichloromethane (200 niL) and washed with saturated aqueous sodium bicarbonate (2 x 50 niL). The aqueous layer was separated and extracted with dichloromethane (2 x 75 mL). The combined dichloromethane extracts were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give 12.5 g (83.9% yield) of a light yellow, waxy solid (MS m/z 231 (M+H)).
42%
With trifluoroacetic acid In dichloromethane at -5 - 20℃; for 6h;
11.1 5-benzyltetrahvdropyrrolor3.4-c1pyrrole- 3(2H,3aH)-dione
To a suspension of TFA (1.02 g) andl H-Pyrrole-2,5-dione ( 10.22 g) in CH2C12(250 mL)at -5 °C was addeda solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (29.99 g) in CH2C12(20 mL) dropwise over 1 h. The reaction mixture was stirred at room temperature for another 5 h andevaporated ' i vacuo. The residue was stirred in the mixed solvent (EA : PE = 3:7 ) at -10 °C for 1 h, and the mixture was filtered to afford the title compound as a white solid (10.18 g, 42.00 %).
42%
With trifluoroacetic acid In dichloromethane at -5 - 20℃; for 6h;
11.1 5-benzyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione
To a suspension of TFA (1.02 g) and 1H-Pyrrole-2,5-dione (10.22 g) in CH2Cl2 (250 mL) at -5° C. was added a solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (29.99 g) in CH2Cl2 (20 mL) dropwise over 1 h. The reaction mixture was stirred at room temperature for another 5 h and evaporated in vacuo. The residue was stirred in the mixed solvent (EA: PE=3:7) at -10° C. for 1 h, and the mixture was filtered to afford the title compound as a white solid (10.18 g, 42.00%).
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 19h;
6.A 5-Benzyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione
Example 6A 5-Benzyl-tetrahydro-pyrrolo[3,4-c]pyrrole-1,3-dione To the maleimide (80.4 g, 0.83 mol) in 1.5 L of CH2Cl2 in a 3-neck, 3-L round bottom flask equipped with an addition funnel, internal thermometer, and N2 inlet at 0° C. was added trifluoroacetic acid (TFA) (6.4 mL, 83 mmol). Benzyl(methoxymethyl)trimethylsilylmethylamine (261 g, 1.1 mol) in 500 mL CH2Cl2 was added dropwise via addition funnel over 3 hours with the reaction temperature being maintained below 5° C. After the addition was complete, the mixture was allowed to warm slowly to ambient temperature and then was stirred for 16 h. The mixture was concentrated and the residue was dissolved in 500 mL CH2Cl2 and was washed with 2*50 mL saturated NaHCO3. The layers were separated and the aqueous layer was extracted 2*25 mL CH2Cl2. The combined organics were washed with 25 mL brine, dried over saturated, aqueous Na2SO3, and concentrated under reduced pressure to give the title compound which was carried on to the next step without further purification. MS (DCl/NH3) m/z 231 (M+H)+.
With trifluoroacetic acid In dichloromethane at 0 - 20℃; Inert atmosphere;
5
Trifluoroacetic acid (TFA, 0.50 ml_, 6.5 mmol) was added to a cold (0 0C) solution of maleimide (6.27 g, 0.0646 mol) in dichloromethane (150 mL) under nitrogen. A solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (20 g, 0.084 mol) in dichloromethane (100 mL) was added drop-wise over 45 min. After the addition was complete, the mixture was warmed slowly to ambient temperature and stirred for 16 h. The mixture was concentrated and the resulting residue was dissolved in dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate (2 x 50 mL). The aqueous layer was separated and extracted with dichloromethane (2 x 75 mL). The combined dichbromethane extracts were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give 12.5 g (83.9% yield) of a light yellow, waxy solid (MS m/z 231 (M+H)).
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 3h;
N-(Methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (17.3 mL, 67.6 mmol) and TFA (3.4 mL) were added to a solution of <strong>[72913-59-8]5-methoxy-inden-1-one</strong> (5.4 g, 33.8 mmol) in CH2Cl2 (165 mL) at 0 C. The reaction was stirred for 3 hours at room temperature and quenched with saturated aqueous NaHCO3 (165 mL). The organic layer was separated, washed with brine (100 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C19H19NO2+H: 294, observed: 294.
trans-ethyl-1-benzyl-4-phenylpyrrolidine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
48%
In dichloromethane at 40℃;
1.A
To a mixture of ethyl trans-cinnamate (2 g, 11.4 mmol) and N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine (2.37 mL) in dichloromethane (18 mL) was added 3 drops of trifluoroacetic acid and the mixture was stirred at 40° C. for 45 min. Then another 0.56 mL of N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine and 1 drop of trifluoroacetic acid were added and the mixture was stirred at 40° C. for another 45 min. Then another 0.26 mL of N-(methoxymethyl)(phenyl)-N-((trimethylsilyl)methyl)methanamine and 1 drop of trifluoroacetic acid were added and the mixture was stirred at 40° C. for overnight. After cooling down to room temperature, the mixture was concentrated under vacuum and purified by Flash Chromatography with from 8% ethyl acetate/92% hexane to 10% ethyl acetate/90% hexane over 20 min. to give the title compound as a clear colorless sticky oil (1.69 g, 48% yield). 1H NMR (400 MHz, CDCl3) δ 1.20 (3H, t, J=6.4, 9.6 Hz), 2.86 (1H, m), 3.00 (1H, t, J=9.6 Hz), 3.04-3.07 (2H, m), 3.65-3.68 (3H, m), 4.09-4.13 (2H, m), 7.19-7.37 (10H, m). HPLC purity (retention time): 93% (1.30 min, method C). MS: 310.30 (MH+).
Stage #1: maleiimide; N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine With trifluoroacetic acid In dichloromethane at 0 - 20℃;
Stage #2: With sodium hydrogencarbonate In dichloromethane; water
Stage #3: With hydroxylamine In methanol; water at 20℃; for 20h;
1.1A
Example 1; N-(3,5-dimethylphenyl)-6-((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyrazine-2-carboxamide; Example 1A; (3aR,6aS)-5-benzyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione; A solution of N-benzyl-N-methoxymethyl-N-(trimethylsilylmethyl)amine (76.68 g, 0.29 mol, prepared as in Organic Syntheses (1989), 67, 133-140) in dichloromethane (130 mL) was added to an ice-cooled mixture of maleimide (25.53 g, 0.26 mol) and trifluoroacetic acid (2.2 mL, 0.028 mol) in dichloromethane (350 ml) over 40 min so that the reaction temperature remained between 0-5° C. The resulting bright yellow solution was allowed to warm gradually and stirred at room temperature for 27 h. The mixture was washed with saturated NaHCO3(aq) (80 mL) and the organic phase was dried (MgSO4) and concentrated under vacuum. The residual oil was stirred with 10% EtOAc-heptane (300 mL) for 15 h, and the resulting precipitate was isolated by filtration, washed with 10% EtOAc-heptane (150 mL) and dried under vacuum at 50° C. to provide the crude, title compound as a white solid (54.25 g). This was stirred with methanol (500 mL) and 50% aqueous H2NOH (4.2 mL) at room temperature for 20 h. The mixture was concentrated under vacuum and the residue was taken up in EtOAc (500 mL) and filtered to remove some insoluble material. The filtrate was concentrated under vacuum to leave the pure, title compound as an off-white solid (49.9 g, 83% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.32-2.43 (m, 2H), 3.18 (d, J=9.8 Hz, 2H), 3.20-3.26 (m, 2H), 3.59 (s, 2H), 7.13-7.35 (m, 5H); MS (DCI/NH3) m/z 231 (M+H)+.
39%
With trifluoroacetic acid In dichloromethane at 20℃; for 35h;
5.1
To a solution of 1H-pyrrole-2,5-dione (12.6 g, 130 mmol) in DCM (150 mL) at 0°C was added TFA (1 .1 mL) and a solution of N-benzyl- 1 -methoxy-N-((trimethylsilyl)methyl)5 methanamine (33.9 g, 143 mmol) in DCM (50 mL). The reaction mixture was then stirred atambient temperature for 35 h. The organic layer was washed with sat. NaHCO3 and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was stirred at ethyl acetate / heptane (10 %, 150 mL) overnight. The solid was collected and MeOH1/ NH2OH (aq. 50 %) (2.1 mL) was added. The reaction mixture was stirred at ambient temperatureovernight and then concentrated and the residue was dissolved in ethyl acetate, filtered to remove some insoluble materials. The filtrated was concentrated to provide (3aR,6a5)-5- benzyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione as a light yellow solid (13 g, 39 %).
39%
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 35h;
11.1 Step 1
To a solution of lH-pyrrole-2,5-dione (12.6 g, 130 mmol) in dichloromethane (150 mL) was added TFA (1.1 mL) and a solution of N-benzyl-l-methoxy-N-((trimethylsilyl)methyl)- methanamine (33.9 g, 143 mmol) in dichloromethane (50 mL) at 0 oC dropwise. The mixture was stirred at ambient temperature for 35 h. The organic layer was washed with sat. sodium bicarbonate aqueous solution, washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated under vacuum. The residue was stirred at ethyl acetate / heptane (1 / 9, 150 mL) overnight. The solid was collected and Methanol/ H20H (aq. 50 %) (2.1 mL) was added. The mixture was stirred at ambient temperature overnight.The solvent was removed and the residue was diluted with ethyl acetate and filtered to remove some insoluble materials. The filtrated was concentrated to give the (3aR,6aS)-5-benzyltetrahydropyrrolo[3,4- c]pyrrole-l,3(2H,3aH)-dione as a light yellow solid (13 g, 39 %).
31%
With trifluoroacetic acid In dichloromethane
1.A cis-5-benzyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3H)-dione
EXAMPLE 1A cis-5-benzyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3H)-dione 1H-Pyrrole-2,5-dione (8.0 g, 82 mmol) in dichloromethane (220 mL) at 0° C. was treated with trifluoroacetic acid (0.93 g, 8.2 mmol) and then treated with N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (26 g, 110 mmol) prepared according to (Organic Synthesis (1988), 67, 133-135) in dichloromethane (15 mL) dropwise over 30 minutes. The mixture was allowed to stir at ambient temperature overnight and then concentrated under reduced pressure. The residue was triturated with ethyl acetate:hexane (3:7, 50 mL), cooled to 0° C., and filtered to provide the title compound as a white solid (5.86 g, 31% yield). MS (DCI/NH3) m/z 231 (M+H)+.
49.9 g
Stage #1: maleiimide; N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine With trifluoroacetic acid In dichloromethane at 0 - 20℃;
Stage #2: With hydroxylamine hydrochloride In methanol; water at 20℃; for 20h;
(3aα,9bα)-6-Methoxy-1,2,3,3a,4,9b-hexahydrochromeno[3,4-c]pyrrole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.A (+-)-cis-6-Methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole
EXAMPLE 67A (+-)-cis-6-Methoxy-1,2,3,3a,4,9b-hexahydro-[1]-benzopyrano[3,4-c]pyrrole From 8-methoxy-coumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in an analogous manner as described in Examples 1A-C.
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;
a.) 2-Benzyl-octahydro-isoindol-4-one (Scheme 8); Benzyl-methoxymethyl-trimethylsilanylmethyl-amine (29.6 g, 0.12 mol) was added to a solution of cyclohex-2-enone (10 g, 0.104 mol) in 500 mL of dichloromethane at 0 0C followed by the dropwise addition of 10 mol % TFA dissolved in 2 mL of dichloromethane. The reaction mixture was stirred at room temperature overnight and was quenched with 50 mL of saturated NaHCO3. The organic layer was washed with 500 mL of brine, dried with MgSO4 and solvent was evaporated in vacuo to give the crude product that was purified by column chromatography (SiO2) using a 2-45 % ethylacetate-hexane gradient to afford the subtitle compound. (13.8 g, 60 %). MS calculated for C15H19NO +H: 230, observed: 230.
55%
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;
N-Benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (1.53 mL, 5.98 mmol) was added to a solution of cyclohex-2-enone (0.504 mL, 5.20 mmol) in DCM (25 mL) at 0 oC, followed by dropwise addition of TFA (0.039 mL, 0.520 mmol) in DCM (0.1 mL). The reaction mixture was stirred overnight at rt and then quenched with saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, heptane/EtOAc, 50-100%) to give 63 (659 mg, 55%) as a yellow oil; GC-MS (m/z) 230 [M+H]+; purity (GC-MS) 95.0%.
With trifluoroacetic acid; at 20℃; for 12h;Inert atmosphere;
Step 1 To a solution of cyclohex-2-enone 12a (5.00 g, 52.1 mmol) in 50 mL dichloromethane was added N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine 12b (7.74 g, 34.7 mmol) and 0.5 mL TFA and the resulting mixture was stirred at room temperature for 12 h under N2 atmosphere. The reaction mixture was quenched by adding 20 mL saturated aq. NaHCO3, then extracted with dichloromethane (20 mL*2), washed with 20 mL saturated aq. NaHCO3. The combined organic layers were dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 2-benzylhexahydro-1H-isoindol-4(2H)-one 12c which was used directly without further purification. MS-ESI calc'd. [M+H]+ 230, found 230.
methyl 2-benzyloctahydro-3aH-isoindole-3a-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40%
With trifluoroacetic acid; In 1,2-dichloro-ethane; at 20℃; for 2h;
To a solution of <strong>[18448-47-0]methyl cyclohex-1-ene-1-carboxylate</strong> (19, 25.0 g, 178 mmol) andN-benzyl-N-methoxymethyl-N-trimethylsilylamine (46.6 g, 196 mmol) in 1,2-dichloroethane (178 mL)was added trifluoroacetic acid (0.14 mL, 1.78 mmol) at ambient temperature. After the reaction solutionwas stirred for 2 h, to the mixture were added saturated aqueous NaHCO3 and CHCl3. The organicsolution was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The resultantresidue was purified by silica gel column chromatography, eluting with hexane/EtOAc = 3:1 to yield 20(21.3 g, 40%) as a colorless oil. 1H-NMR (400 MHz, CDCl3) delta: 1.21-1.53 (6H, m), 1.65-1.79 (2H, m),1.90-1.96 (1H, m), 2.68-2.73 (3H, m), 2.92 (1H, d, J = 9.3 Hz), 3.65-3.70 (5H, m), 7.24-7.32 (5H, m).MS (ESI) m/z: 274 (M + H)+.
trifluoroacetic acid; In 1,2-dichloro-ethane; at 20℃; for 2h;
[Reference Example 131]; [ (IR*, 6R*) -delta-Benzyl-S-azabicyclo [4.3.0] nonan-1- yl] carboxylic acid methyl ester; [Formula 227]COOMe (+/-) -cis A catalytic amount of trifluoroacetic acid was added to a solution of 1-cyclohexene-l-carboxylic acid methyl ester(25.0 g, 178 mmol) and N-benzyl-N- (methoxymethyl) -N- trimethylsilylmethylamine (46.6 g, 196 mmol) in 1,2- dichloroethane (178 mL) at room temperature, and the mixture was stirred at room temperature for two hours. A saturated sodium bicarbonate solution (200 mL) was added to the reaction solution, followed by extraction with chloroform (15O mL x I, lOO mL x l). The organic layer was washed with brine (450 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated <n="364"/>under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane : ethyl acetate = 100:0 -> 90:10 -> 85:15 -> 75:25) to give 21.3 g of the title compound. 1H-NMR (400 MHz, CDCl3) delta: 7.32-7.24 (5H, m) , 3.70-3.65 (5H, m) , 2.92 (IH, d, J=9.31 Hz), 2.73-2.68 (3H, m) , 1.93 (IH, td, J=9.01, 4.82 Hz), 1.79-1.65 (2H, m) , 1.53-1.21 (6H, m) . MS (ESI); m/z: 274 (M+H)+.
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 5h;
34 Preparation 34: 1 -benzyl-3-(3,5-dichloro-phenyl)-3-trifluoromethyl-pyrrolidine
Preparation 34: 1 -benzyl-3-(3,5-dichloro-phenyl)-3-trifluoromethyl-pyrrolidine To a stirred solution of 1 ,3-dichloro-5-(1 -trifluoromethyl-vinyl)-benzene (1 Og, 41 .49mmol) in DCM (150ml_) was added benzyl-methoxymethyl- trimethylsilanylmethyl-amine (Preparation 29, 39.33g, 165.97mmol) at room temperature. Resulting reaction mixture was cooled to 0°C and TFA (0.32ml_, 0.41 ) was added slowly and stirred at room temperature for 5 hours. After complete consumption of starting material, reaction mixture was basified by aqueous Na2C03 and extracted with DCM (3x100ml_). Combined organic layer was dried over Na2S04, and concentrated under vacuum to afford brown oil (9.5g, crude). Crude compound was purified by column chromatography using 100-200 mesh silica gel. Desired product was eluted in 2% ethyl acetate in hexane to afford product as brown solid (7.5g, 48.29%). 1H-NMR (400 MHz, CDCI3)8: 2.28-2.35 (m, 1 H), 2.53-2.60 (m, 1 H), 2.69-2.81 (m, 2H), 3.03-3.1 1 (m, 2H), 3.66 (s, 2H), 7.26-7.35 (m, 8H).
0.5 g
With trifluoroacetic acid In dichloromethane at 20℃; for 3h;
7 Preparation of 1-benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine
To a cooled solution of 1,3-dichloro-5-(1-trifluoromethyl)vinyl)benzene (0.5g, 2.0mmol) and N-benzyl-1-methoxy-N-(trimethylsilyl)methyl)methanamine (0.4g, 2.0mmol) in DCM (10 mL) was added dropwisca solution of TFA (0.024g, 0.2mmol) in DCM (1 mL). The reaction mixture was stirred for 3 hrs at rt. The organic layer was washed with water ( 2 x l0 mL) and 10% aq sodium carbonate solution(10 mL).The organic layer was separated, dried with sodium sulphate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to yield 1-benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidine (0.5g). LC-MS (methanol, ESI): m/z = 374 (M+H). 1H-NMR (400 MHz, CDCl3): 7.36 (4H, m), 7.30(2H, m), 7.23 (2H, m), 3.67 (2H, s), 3.08 (2H, dd), 2.69(2H,m), 2.53 (lH, m), 2.27 (1H,m).
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 3h;
2-1
To the solution of l,3-dichloro-5-[l-trifluoromethyl) vinyl]benzene (6.Ig) and N-benzyl-1- methoxy-N-[(trimethylsilyl) methyl]methanamine (5.0g) in dichloromethane was added dropwise the solution of trifluoroacetic acid (0.24g) in dichloromethane while cooling with ice. On completion of the dropwise addition, the mixture was warmed to room temperature and stirred for 3 hours. The solution was concentrated under the reduced pressure, and the residue was then diluted with t-butylmethylether. The solution was washed with saturated sodium bicarbonate water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield l-benzyl-3-(3,5-dichlorophenyl)-3-(trifluoromethyl) pyrrolidine (5.7g). 1H-NMR (CDCl3) δ: 2.27-2.36 (IH, m), 2.53-2.62 (IH, m), 2.69-2.83 (2H, m), 3.08 (2H, dd), 3.67 (2H, s), 7.25-7.36 (8H, m)
(3RS,4SR)-1-benzyl-4-(3,4-difluorophenyl)pyrrolidine-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With trifluoroacetic acid; In tetrahydrofuran; at 0 - 20℃;
a) (3RS,4SR)-1-Benzyl-4-(3,4-difluoro-phenyl)-pyrrolidine-3-carboxylic acid To a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (48.3 g, 204 mmol) and (E)-3-(3,4-difluoro-phenyl)-acrylic acid (15 g, 81.5 mmol) in THF (200 mL) was added trifluoroacetic acid (0.312 mL, 0.0041 mol) at 0 C. The mixture was gradually warmed to room temperature and stirred overnight. It was then concentrated in vaccuo and the residue was diluted with n-heptane (500 mL) followed by vigorous stirring for 1 hour. The resulted white precipitation was collected and washed with heptane affording 26 g (100%) of the title compound as a white solid. MS m/e: 318.1 (M+H+).
To a solution of <strong>[20026-96-4](4-chloro-phenyl)-propynoic acid ethyl ester</strong> (92.65 g, 444.1 mmol) in dichloromethane (425 mL) was added trifluoroacetic acid (3.4, 44.4 mmol). The reaction mixture was cooled with a water bath and a solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (164.7 g, 666.1 mmol) in dichloromethane (325 mL) was added dropwise over a period of 1.5 h. It was stirred for 22 h at ambient temperature. Further N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (27.5 g, 111.0 mmol) in dichloromethane (50 mL) was added and stirring was continued for 2 h at ambient temperature. The solvent was distilled off and the residue was taken up in dioxane (950 mL). After addition of water (475 mL) and sodium hydroxide (32%, 114.3 mL, 1.23 mol), it was stirred for 67 h at ambient temperature. After concentration the residue was diluted with water (400 mL) and extracted with tert-butylmethylether (400 mL). The organic layers were washed with water (400 mL). The aqueous layers were combined, cooled to 5 C. and set to pH=1.5 with aqueous HCl (25%, 172). After stirring for 1 h at 5 C., the solid was filtered off and was washed with water (1400 mL) and ethanol (400 mL). Drying (50 C., 25 mbar) afforded the title compound (109.85 g, 79%) as an off-white solid. MS m/e: 312.2/314.1 [M-H]-.
79%
b) l-Benzyl-4-(4-chloro-phenyl)-2,5-dihydro-lH-pyrrole-3-carboxylic acidTo a solution of <strong>[20026-96-4](4-chloro-phenyl)-propynoic acid ethyl ester</strong> (92.65 g, 444.1 mmol) in dichloromethane (425 mL) was added trifluoro acetic acid (3.4, 44.4 mmol). The reaction mixture was cooled with a water bath and a solution of N-(methoxymethyl)-N- (trimethylsilylmethyl)benzylamine (164.7 g, 666.1 mmol) in dichloromethane (325 mL) was added dropwise over a period of 1.5 h. It was stirred for 22 h at ambient temperature. Further N- (methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (27.5 g, 111.0 mmol) indichloromethane (50 mL) was added and stirring was continued for 2 h at ambient temperature. The solvent was distilled off and the residue was taken up in dioxane (950 mL). After addition of water (475 mL) and sodium hydroxide (32%, 114.3 mL, 1.23 mol), it was stirred for 67 h at ambient temperature. After concentration the residue was dilluted with water (400 mL) and extracted with tert-butylmethylether (400 mL). The organic layers were washed with water (400 mL). The aqueous layers were combined, cooled to 5 C and set to pH=1.5 with aqueous HC1 (25 %, 172). After stirring for 1 h at 5 C, the solid was filtered off and was washed with water (1400 mL) and ethanol (400 mL). Drying (50 C, 25 mbar) afforded the title compound (109.85 g, 79%) as an off-white solid. MS m/e: 312.2/314.1 [M-H]
60%
b) 1-Benzyl-4-(4-chloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (IIa) At r.t., a solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methyl amine (116.8 g, 0.49 mol) in CH2Cl2 (260 ml) was added dropwise over 90 min to a stirred solution of <strong>[20026-96-4](4-chloro-phenyl)-propynoic acid ethyl ester</strong> (72.0 g, 0.34 mol) and trifluoroacetic acid (2.5 ml, 0.03 mol) in CH2Cl2 (350 ml). The reaction mixture was stirred at 25 C. overnight and afterwards evaporated to dryness. The residue was dissolved in dioxane (0.8 l); an aqueous solution of NaOH (91.0 ml, 1.02 mol, 3 eq.) was added, and the resulting emulsion was stirred at r.t. for 48 h. The low boiling organic solvent was removed under vacuum, water (0.9 l) was added, and the aqueous layer was separated and washed with TBME (1 l). The aqueous layer was then acidified to a pH value of 2.5 by addition of 25% HCl. The resulting suspension was stirred overnight; the white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 62.0 g (60%) of IIa as a white solid. ES-MS m/e: 312.4 (M-H+).
(+/-)-trans-methyl 1-benzyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
In dichloromethane at 0 - 20℃;
B
Procedure B: (+/-)-tr cms-Methyl l-benzyl-4-(4-(trifluoromethyl)phenyl)pyrrolidine-3- carboxylate (3); [0174] To a stirred solution of (£)-methyl 3-(4-(trifluoromethyl)phenyl)acrylate (2) (185 g, 0.8 mol) in CH2Cl2 (1 L) was added N- (methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (200 g, 0.8 mol; Aldrich, MO, USA). The resulting mixture was cooled to 0 0C and a solution of TFA (0.5 mL, 0.1 eq) in CH2Cl2 (30 mL) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The solvent was removed by evaporation in vacuo and the resulting oil was purified by flash column chromatography (SiO2; elution with 1 :5 EtOAc/hexanes) to give (+/-)-tr1H NMR (400 MHz, CDCl3) δ 7.41-7.08 (m, 9H), 3.60-3.48 (m, 3H, partial overlap with singlet at 3.52), 3.52 (s, 3H), 3.02-2.89 (m, 2H), 2.85-2.79 (m, IH), 2.73-2.62 (m, 2H).
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16h; stereoselective reaction;
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 2.0h;
Step 2; To a stirred solution of <strong>[3883-39-4]5-methyl-2-vinylpyridine</strong> (600 mg, 1.87 mmol) in dry CH2CI2 (6 mL) was added N-benzyl-1-methoxy-N- ((trimethylsilyl)methyl)methanamine (1.42 g, 6.0 mmol) and TFA (570 mg, 5.0 mmol) at 00C. The mixture was stirred at rt for 2 TLC showed the disappearance of starting material. The mixture was quenched with satd aq NaHCO3 (15 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (40 mL) and brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by chromatography column on silica cartridge eluted with PE/EA=5:1 to afford 2-(1-benzyl-pyrrolidin-3-yl)-5-methyl-pyridine (450 mg, 35%) as a yellow oil
(3,4-trans)-methyl 1-benzyl-4-vinylpyrrolidine-3-carboxylate[ No CAS ]
C24H30N2O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With trifluoroacetic acid In dichloromethane; toluene at 0 - 22℃; for 16h; Inert atmosphere;
(3,4-trans)-methyl 1-benzyl-4-vinylpyrrolidine-3-carboxylate 1a
To a solution of of the commercial (E)-methyl penta-2,4-dienoate (0.965 g, 8.61 mmol) in toluene (5.0 mL) at 0°C in a 25 mL three-neck round bottom flask dried under N2 was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzamine (2.64 mL, 10.3 mmol). The solution was stirred at 0°C for 10 minutes and then treated with trifluoroacetic acid (0.86 mL, 0.86 mmol, 1 M solution of in anhydrous CH2Cl2) dropwise. The reaction mixture was allowed to warm to 22 oC and stir for 15 hours. The mixture was diluted in water (25 mL) and adjusted to a pH of ~8 with saturated aqueous sodium bicarbonate. The product was extracted with dichloromethane (3 x 10 mL) and the combined organics were then washed with brine, and dried over magnesium sulfate. Solvent was removed under reduced pressure, yielding 3.08 g of a yellow oil. The crude product was analyzed by H-NMR and COSY [00701271-0005-002] in deuterated chloroform. A small amount of this NMR sample was then diluted in dichloromethane and analyzed by GC-MS. The desired product 1a (0.77 g, 37% yield) was isolated by column chromatography (silica gel, 20% ethyl acetate in n-heptane). dH (400 MHz; CDCl3) 2.42 (1H, dd, 9.6, 6.8 Hz), 2.76-2.88 (4 H, m), 3.08 (1 H, m), 3.56 (1 H, d, 12.8 Hz) 3.64 (1 H, d, 12.8 Hz), 3.67 (3 H, s), 4.98 (1 H, d, 10 Hz), 5.06 (1 H, d, 17.4 Hz), 5.83 (1 H, m), 7.20-7.32 (5 H, m). dC (100 MHz; CDCl3) 45.80, 48.81, 51.91, 56.56, 59.44, 59.86, 115.01, 126.98, 128.22, 128.65, 139.74, 174.59. HRMS formula C15H19 NO2 m/z 246.1488 [M + H]+calculated; 246.1493 [M + H]+ found.
(4aSR,4bRS,7aSR)-3,6-dibenzyl-7a-nitro-3,4,4a,4b,5,6,7,7a-octahydro-2H-[1,2,5]oxadiazino[2,3-a]pyrrolo[3,4-c]quinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: 4-nitroquinoline-N-oxide; N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine With trifluoroacetic acid In dichloromethane at 20℃; for 23h; Inert atmosphere;
Stage #2: With sodium hydrogencarbonate In dichloromethane Saturated solution; diastereoselective reaction;
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 4h;
N-Benzyl-3-fluoro-β-proline methyl ester (5).
A solution of TFA (0.4 mL) in dry CH2Cl2 (10 mL) was slowly added to a stirred solution of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (2) (12.0 g, 0.050 mol) and methyl 2-fluoroacrylate (4) (5.0 g, 0.048 mol) in dry CH2Cl2 (150 mL) at 0 °C. CAUTION: exothermic reaction. The reaction mixture was stirred for an additional 4 h at room temperature. An excess of aq saturated NaHCO3 solution was added. The organic phase was washed with 100 mL of brine, dried over Na2SO4 and evaporated under vacuum. The residue was purified by flash column chromatography using hexane/EtOAc = 2/1 mixture as eluent to give the pure product 5 (10.5 g, 95% yield) as a colourless oil. Rf = 0.5. 1H NMR (500 MHz; CDCl3; Me4Si), δ: 2.23-2.33 (1H, m, 4-CHH), 2.44-2.54 (1H, m, 4-CHH), 2.69 (1H, q, J = 8.0 Hz, NCHH), 2.95-3.03 (3H, m, NCHH + NCH2), 3.71 (1H, d, J = 13.5 Hz, PhCHH), 3.74 (1H, d, J = 13.5 Hz, PhCHH), 3.83 (3H, s, OCH3), 7.28-7.36 (5H, m, Ph). 13C NMR (125 MHz; CDCl3; Me4Si), δ: 37.11 (d, 2JCF = 23.8 Hz, 4-CH2), 52.77 (s, OCH3), 52.98 (s, PhCH2N), 59.70 (s, 5-CH2), 63.40 (d, 2JCF = 23.8 Hz, 2-CH2), 99.80 (d, 1JCF = 191.3 Hz, 3-CF), 127.21 (s, CH, Ph), 128.37 (s, CH, Ph), 128.70 (s, CH, Ph), 139.53 (s, quat-C, Ph), 171.42 (d, 2JCF = 27.5 Hz, CO2Me). 19F NMR (477 MHz; CDCl3; Me4Si), δ: -149.28 (quint, 3JFH = 28.6 Hz, F). GC-MS: 237 (M+). Anal. calcd for C13H16FNO2: C, 65.81; H, 6.80; N, 5.90. Found: C, 65.51; H, 6.43; N, 5.95.
80%
With trifluoroacetic acid In dichloromethane at 20℃; for 4h; Inert atmosphere;
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere;
2.1
1002421 step 1 : A 0.3 M solution of methyl 2-fluoroacrylate (4.37 g, 41.99 mmol) and DCM (140 mL) was stirred under nitrogen and cooled to 0 °C. The reaction mixture was then treated with N- benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine (10.47 g, 44.09 mmol) followed by TFA (1.56 mL, 20.99 mmol). The reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was then concentrated in vacuo. The crude product was purified by Si02 Biotage chromatography (hexanes/acetone) to afford 4.24 g (42.6%) of methyl l-benzyl-3- fluoropyrrolidine-3-carboxylate (72a): 1H NMR (400 MHz, DMSO-de) δ = 7.35-7.23 (m, 5H), 3.72 (s, 3H), 3.63 (s, 2H), 2.97-2.80 (m, 3H), 2.54-2.48 (m, 1H), 2.43-2.30 (m, 1H), 2.18-2.04 (m, 1H).
With trifluoroacetic acid In dichloromethane at 0℃;
With trifluoroacetic acid In dichloromethane at 20℃; Inert atmosphere;
6_1.1
TFA (4.31 mmol, 0.49 g) was added to a solution of ethyl 2-cyanoacrylate (17.58 mmol, 2.20 g) in DCM (100 mL) under nitrogen atmosphere. Subsequently, a solution of N-benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine (21.49 mmol, 5.10 g) in DCM (50 mL) was added dropwise while cooling with an ice-bath in order to keep the reaction temperature at room temperature (exothermic reaction). The reaction mixture was stirred overnight at room temperature. Then the mixture was washed with saturated aqueous NaHC03 (100 mL). The aqueous phase was extracted with DCM (100 mL). The combined organic phase was dried over MgS04 and evaporated in vacuo. The crude product was purified by flash silicagel chromatography (100 % heptane to 50% EtOAc) yielding 4.27 g of a colorless oil (94 %). 1H-NMR (400 MHz, CDCls, 300K): δ = 1.32 (3H, t, J = 7.1 Hz), 2.44 (1H, m), 2.59 (1H, m), 2.69 (1H, m), 2.89 (1H, m), 2.99 (1H, d, J = 9.8 Hz), 3.17 (1H, d, J = 9.8 Hz), 3.69 (2H, s), 4.27 (2H, q, J = 7.1 Hz), 7.29 (5H, m).
94%
With trifluoroacetic acid In dichloromethane at 0 - 20℃;
2.4 g
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16h;
86.a
To a stirred solution of ethyl 2-cyanoacrylate (2.2 g, 17.6 mmol) in DCM (50 ml) were added TFA (0.48 g, 4.224 mmol) and N-benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine (CAS Number 93102-05-7; 5.0 g, 21.12 mmol) at 0°C. The reaction mixture was stirred at rt for 16 h. The resulting reaction mixture was cooled to 10°C and quenched by saturated NaHC03solution (100 ml). The obtained mixture was extracted with DCM (3 x 50 ml). The combined organic phase was washed with water (50 ml). The obtained organic phase was dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (3% EtOAc in hexane) yielding ethyl l-benzyl-3-cyanopyrrolidine-3-carboxylate (2.4 g, 9.302 mmol). LCMS: Method 1, 1.714 min, MS: ES+ 258.8; 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.25 - 7.36 (m, 5 H), 4.22 (q, J=7.2 Hz, 2 H), 3.67 (dd, J=13.2 Hz, 18.0 Hz, 2 H), 3.14 (d, J=9.6 Hz, 1 H), 2.88 (d, J=10.0 Hz, 1 H), 2.81 - 2.85 (m, 1 H), 2.53 - 2.57 (m, 1 H), 2.44 - 2.47 (m, 1 H), 2.33 - 2.40 (m, 1 H), 1.23 (t, J=7.2 Hz, 3 H)
With trifluoroacetic acid; In dichloromethane; toluene; at 0 - 20℃; for 2h;Inert atmosphere;
General procedure: To a stirred solution of an unsaturated ester (1 equiv) in toluene(0.4 M w.r.t. the ester) was added N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (1.5 equiv) at 0 C underargon. After 10 min, a solution of TFA (0.1 equiv) in CH2Cl2 (1 Mw.r.t. TFA) was added to the mixture, and stirring was continuedfor 2-18 h while allowing the temperature to slowly reach r.t.Subsequently, the volatiles were removed in vacuo, and theresulting crude residue was purified using silica gel chromatographyto provide the desired cycloaddition product 1a-e.
With trifluoroacetic acid; In toluene; for 40h;Inert atmosphere;
Under an argon atmosphere at room temperature, carboxylic acid derivative and N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methaneamine (CAS Registry Number: 93102-05-7; 958 mg) were dissolved in anhydrous toluene (13 mL) and trifluoroacetic acid (12.0 muL) was added, followed by stirring for 40 hours. After the addition of water and stirring, the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain a spiro compound (654 mg).
With trifluoroacetic acid; In 2-methyltetrahydrofuran; at 0 - 20℃; for 2h;
Step 1: Preparation of (3S,4R)-1-benzyl-4-methoxy-pyrrolidine-3-carboxylic acid methyl ester To a solution of (E)-3-methoxy-acrylic acid methyl ester (50 g, 430.6 mmol) in 2-Me-THF (600 mL) and TFA (6.7 mL) at 0 C. was added N-(methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (204 g, 2 eq) dropwise. After addition, reaction was allowed to warm to rt and stirred for 2 hrs. Reaction was transferred to a separatory funnel and washed with sat. NaHCO3, sat. NaCl, then dried over Na2SO4 and the solvent removed to leave the crude racemic product as a yellow oil which was purified on SiO2 (10%-35% EtOAc/heptane) to give the racemic trans product as a yellow oil (82.7 g). Enantiomer separation by chiral-SFC (Chiralpak AD-H 4.6*250 mm column 4% MeOH w/0.1% diethylamine, 140 bar, 3.0 mL/min) gave the desired single isomer product which was verified by comparison with a known standard (34 g, 31.7% yield). Specific rotation [alpha]D27=+23.8 (C=1.3, MeOH). 1H NMR (400 MHz, DMSO-d6) delta ppm 2.55-2.63 (m, 2H) 2.69 (dd, J=9.95, 6.42 Hz, 1H) 2.82-2.88 (m, 1H) 2.90-2.96 (m, 1H) 3.23 (s, 3H) 3.51-3.63 (m, 2H) 3.66 (s, 3H) 4.07-4.12 (m, 1H) 7.22-7.39 (m, 5H). m/z (APCI+) for (C14H19NO3) 250.0 (M+H)+.
trans-ethyl 1-benzyl-4-(trifluoromethyl)pyrrolidine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;
Step 1: Preparation of trans-ethyl 1-benzyl-4-(trifluoromethyl)pyrrolidine-3-carboxylate [1001] [1002] To a solution of (E)-ethyl 4,4,4-trifluorobut-2-enoate (100 g, 0.6 mol) in DCM (1.8 L) was added dropwise TFA (20.52 g, 0.18 mol) at 0 C. and then N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (170.64 g, 0.72 mol) was added and the resulting mixture was stirred at rt overnight. The reaction mixture was washed with sat. aqueous NaHCO3 (two×500 mL), dried over Na2SO4 and concentrated in vacuo and the residue was purified by silica column chromatography eluted with petroleum ether/EtOAc=100:1 to give the title compound (142 g, 79% yield) as a yellow oil.
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 6h;
20.3 2-benzylhexahvdropyranor3.4-clpyrrol-4(2H)-one
To a solution of 5,6-dihydro-2H-pyran-2-one ( 1.00 g, 1 eq) in CH2C12 (150 mL) was added N-(methoxymethyl)-N-(trimethylsilylmethyl) benzylamine (1.2 eq). After the mixture was cooled to 0 °C, a solution of TFA in CH2C12 (0.1 eq, 1 M) was added slowly. The reaction mixture was slowly heated to room temperature and stirred for 6 h. The reaction mixture was washed with water and brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 2: 1 (v/v) ??/??) to give the title compound as colorless oil (1.95 g, 82.87 %).The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 232.3 (M+l ).
82.87%
With trifluoroacetic acid In dichloromethane at 0 - 20℃;
20.3 2-benzylhexahydropyrano[3,4-c]pyrrol-4(2H)-one
To a solution of 5,6-dihydro-2H-pyran-2-one (1.00 g, 1 eq) in CH2Cl2 (150 mL) was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.2 eq). After the mixture was cooled to 0° C., a solution of TFA in CH2Cl2 (0.1 eq, 1M) was added slowly. The reaction mixture was slowly heated to room temperature and stirred for 6 h. The reaction mixture was washed with water and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 2:1 (v/v) PE/EA) to give the title compound as colorless oil (1.95 g, 82.87%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 232.3 (M+1).
75%
With trifluoroacetic acid In dichloromethane at -78 - 25℃; for 4h; Inert atmosphere;
55.1
To a solution of 5,6-dihydro-2H-pyran-2-one 55a (300 mg, 3.06 mmol) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine 55b (1.09 g, 4.59 mmol) in 15 mL dichloromethane was added TFA (520 mg, 4.59 mmol, in 0.6 mL DICHLOROMETHANE) at -78° C. under N2 atmosphere. The resulting mixture was warmed to 25° C. and stirred for 4 h, diluted with 50 mL dichloromethane, washed with saturated aq. K2CO3 (50 mL*2) and brine (50 mL*1) successively. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by prep. TLC (50% EtOAc/PE) to give 2-benzylhexahydropyrano[3,4-c]pyrrol-4(2H)-one 55c (533 mg, colorless oil, yield: 75%). 1H NMR (400 MHz, CDCl3): δ 7.26-7.18 (m, 5H), 4.34-4.33 (m, 2H), 4.18-4.15 (m, 1H), 3.57-3.46 (m, 2H), 2.89-2.85 (m, 2H), 2.77-2.73 (m, 1H), 2.71-2.61 (m, 1H), 2.23-2.19 (m, 1H), 1.94-1.93 (m, 1H), 1.60-1.59 (m, 1H). MS-ESI calc'd. [M+H]+ 232, found 232.
With lithium fluoride; In N,N-dimethyl-formamide; for 5h;Reflux;
General procedure: A mixture of the corresponding aromatic ketone (1.0 mmol), N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (593 mg, 2.5 mmol) and LiF (78 mg, 3 mmol) was refluxed in dry DMF (5 mL) with magneticstirring during 5 h. The resulting mixture was cooled to room temperature and H2O (20 mL) was added. Extraction with Et2O (2×10 mL), drying with Na2SO4 and evaporation gave dark oil of the corresponding 5-aryloxazolidine with admixture of other amines, which were used on the next stage without additional purification.
With lithium fluoride; In N,N-dimethyl-formamide; for 5h;Reflux;
General procedure: A mixture of the corresponding aromatic ketone (1.0 mmol), N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (593 mg, 2.5 mmol) and LiF (78 mg, 3 mmol) was refluxed in dry DMF (5 mL) with magneticstirring during 5 h. The resulting mixture was cooled to room temperature and H2O (20 mL) was added. Extraction with Et2O (2×10 mL), drying with Na2SO4 and evaporation gave dark oil of the corresponding 5-aryloxazolidine with admixture of other amines, which were used on the next stage without additional purification.
ethyl 1-benzyl-3-phenylpyrrolidine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;
Step A. Ethyl 1 -benzyl-3 -phenylpyrrolidine-3 -carboxylateTo a mixture of <strong>[22286-82-4]ethyl 2-phenylacrylate</strong> (0.50 g, 3.1 mmol) and TFA(20 iL, 0.31 mmol) inCH2C12 (18 mL) was added N-benzyl- 1 -methoxy-N-((trimethylsilyl)methyl)methanamine (0.87mL, 3.4 mmol) in CH2C12 (18 mL) at 0 C. The mixture was stirred at RT overnight. The mixturewas concentrated in vacuo and the residue was purified by column chromatography (0-20%EtOAc in heptane) to give the title compound. MS (ESI) mlz = 310 (M+H)
ethyl 1-benzyl-4,4-difluoropyrrolidine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
To a solution of ethyl-<strong>[352-23-8]3,3,3-trifluoropropionate</strong> (2.50 g, 16 mmol) in deuterochloroform(15 mL) was added triethylamine (3.35 mL, 24 mmol) followed by trimethylsiyl triflate(4.45 mL, 24 mmol) dropwise and the reaction was stirred at room temperature for 1hour. The reaction was cooled to 0°C and treated with zirconium tetrachloride (565 mg,2.4 mmol) followed by stirring at room temperature for 1.5 hours. The reaction was cooled to 0°C and quenched by the addition of water (20 mL). The organic layer was collected, dried over magnesium sulphate and the filtrate cooled to 000. To the solution was added N-benzyl-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine (2.50 mL, 9.4 mmol) followed by TFA (0.1 mL) and the reaction was stirred warming to roomtemperature for 18 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution, the organic layer was separated, dried over magnesium sulphate and concentrated in vacuo. The reaction was purified using silica gel column chromatography eluting with 0-40percent EtOAc in heptanes to afford the title compound (468 mg, 27percent).1H NMR (400MHz, CDCI3): O ppm 1.20-1.22 (m, 3H), 2.60-2.70 (m, 1H), 2.80-2.90 (m,1H), 3.00-3.10 (m, 2H), 3.10-3.20 (m, 1H), 3.25-3.35 (m, 1H), 3.60-3.70 (m, 2H), 4.05-4.20 (m, 2H), 7.15-7.30 (m, 5H).
2-benzyl-7-methyl-9-oxo-1,2,3,3a,9,9a-hexahydrochromeno[2,3-c]pyrrole-9a-carbonitrile hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
Stage #1: 6-methyl-4-oxo-4H-1-benzopyran-3-carbonitrile; N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 24.5h;
Stage #2: With acetyl chloride In isopropyl alcohol; toluene diastereoselective reaction;
4.5. General procedure for the synthesis of compounds 9a-c
General procedure: To a cooled to 0 °C solution of 3-cyanochromone 4 (1.5 mmol) and TFA (0.54 mmol) in DCM (5 mL), N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (1.8 mmol) in DCM (10 mL) was added dropwise with stirring during 30 min. Then the resulting solution was allowed to warm to room temperature, and after 4 h the same amount of TFA was added. After 20 h, the mixture was treated with saturated NaHCO3, and the organic layer was separated and dried over Na2SO4. After removing of DCM, the residual oil was washed with hexane, and dissolved in dry toluene (5-7 mL). The hydrochlorides were prepared by addition of isopropanol (1.73 mmol) and acetyl chloride (1.58 mmol) to this solution. The precipitate formed was filtered off, washed with toluene, and dried at 90-95 °C.
2,5-dibenzyl-3-imino-10-methyl-1,2,3,4,5,6,6a,11b-octahydrochromeno[2,3-c:3,4-c']dipyrrol-11b-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
Stage #1: 6-methyl-4-oxo-4H-1-benzopyran-3-carbonitrile; N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine With trifluoroacetic acid In dichloromethane at 0 - 20℃;
Stage #2: With hydrogenchloride In water at 60℃;
Stage #3: With sodium hydroxide In water diastereoselective reaction;
4.6. General procedure for the synthesis of compounds 11a-c
General procedure: To a cooled to 0 °C solution of 3-cyanochromone 4 (1 mmol) and TFA (1.2 mmol) in DCM (5 mL), N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (4 mmol) in DCM (10 mL) was added dropwise with stirring during 30 min. Then the resulting solution was allowed to warm to room temperature and stand overnight. The residual solution was evaporated under reduced pressure to give an oil. The latter was treated with 6 M HCl (6 mmol), the mixture was warmed to 60 °C during 5 min under stirring and was allowed to stand overnight. After that, the 5% aqueous NaOH was added portionwise until the solution became alkaline, accompanied by extraction with DCM (3 mL) at stirring. The layers were separated and the aqueous layer was extracted twice again (DCM, 23 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure. The residue was recrystallized from Et2O/hexane to afford the pure amidines 11.
ethyl 6-benzyl-2-oxa-6-azaspiro[3.4]octane-8-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
With trifluoroacetic acid; In dichloromethane; toluene; at 0 - 20℃; for 12h;Inert atmosphere;
General procedure: To a stirred solution of an unsaturated ester (1 equiv) in toluene(0.4 M w.r.t. the ester) was added N-benzyl-1-methoxy-N-[(trimethylsilyl)methyl]methanamine (1.5 equiv) at 0 C underargon. After 10 min, a solution of TFA (0.1 equiv) in CH2Cl2 (1 Mw.r.t. TFA) was added to the mixture, and stirring was continuedfor 2-18 h while allowing the temperature to slowly reach r.t.Subsequently, the volatiles were removed in vacuo, and theresulting crude residue was purified using silica gel chromatographyto provide the desired cycloaddition product 1a-e.Ethyl 6-Benzyl-2-oxa-6-azaspiro[3.4]octane-8-carboxylate (1a)The general procedure A over 12 h provided 1a (5.3 g, 19.25mmol, 55% yield) as a colorless oil. 1H NMR (600 MHz, CDCl3):delta = 7.33-7.29 (m, 4 H), 7.27-7.24 (m, 1 H), 4.72-4.64 (m, 2 H),4.51-4.43 (m, 2 H), 4.23-4.15 (m, 2 H), 3.66-3.60 (m, 2 H), 3.21(d, J = 9.2 Hz, 1 H), 3.10-3.02 (m, 2 H), 2.74 (dd, J = 9.3, 0.8 Hz, 1H), 2.62-2.59 (m, 1 H), 1.30 (t, J = 7.2 Hz, 3 H). 13C NMR (151MHz, CDCl3): delta = 173.0, 138.5, 128.6, 128.3, 127.1, 84.0, 77.9,64.3, 60.9, 59.6, 56.5, 50.4, 47.9, 14.3. ESI-HRMS: m/z calcd forC16H22NO3 [MH+]: 276.1594; found: 276.1599.
Stage #1: ethyl 3-methylbut-2-enoate; N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine at 0℃; for 0.333333h; Inert atmosphere;
Stage #2: With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 72h; Inert atmosphere;
Ethyl 1-benzyl-4,4-dimethylpyrrolidine-3-carboxylate (S1e)
To a stirred solution of ethyl 3-methylbut-2-enoate (2.465 g, 19.23 mmol) in toluene (33 mL) was added N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (6.02 g, 6.49 mL, 23.08 mmol, 91%) at 0 °C under inert atmosphere. After20 min, a solution of TFA (0.219 g, 0.148 mL, 1.923 mmol) in CH2Cl2 (2 mL) was added slowly at 0 °C. Themixture was stirred for 40 min at 0 °C after which the cooling bath was removed and stirring continued for 72 hat rt. The solvent was removed in vacuo to provide a yellow oil that was purified using silica gel chromatographyto provide S1e (1.72, 6.58 mmol, 34% yield) as a colorless oil
cis-5-benzyl-3a-methyltetrahydro-1H-furo[3,4-c]pyrrole-1,3(3aH)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trifluoroacetic acid In dichloromethane at 25℃; for 3h; Inert atmosphere;
5-Benzyltetrahydro-1H-furo[3,4-c]pyrrole-1,3(3aH)-diones 17a-dand 5-Benzylhexahydro-1H-furo[3,4-c]pyrrol-1-one 17e
General procedure: To a solution of 15 (1.02 mol) in CH2Cl2 (700 mL), N-(methoxymethyl)-N-[(trimethylsilyl)methyl]benzylamine (16, 244 g, 1.03 mol) was added. To the resulting mixture, a solution of TFA (11.6 g, 0.102 mol) in CH2Cl2 (20 mL) was added dropwise at 25 °C under an inert atmosphere. The mixture was stirred for 3 h, washed with H2O (400 mL) and brine (400 mL), dried (Na2SO4), and evaporated under reduced pressure to give adduct 17, which was used in the next step without purification.
With trifluoroacetic acid In dichloromethane at 20℃; for 3h; Inert atmosphere;
61.1 Step 1. Cis-5-benzyl-3a-methyltetrahydro-1H-furo [3, 4-c] pyrrole-1, 3 (3aH) -dione (61b)
To a solution of 3-methylfuran-2,5-dione (5.33 g, 47.6 mmol) and N-benzyl-1-methoxy-N- ((trimethylsilyl) methyl) methanamine (14.8 g, 61.9 mmol) in CH 2Cl 2 (170 mL) was added trifluoroacetic acid (543 mg, 4.76 mmol). The mixture was stirred for 3 h and then concentrated to dryness under vacuum to give the title compound 61b (11.62 g). The crude product was used directly in the next step without further purification MS m/z (ESI) : 246 [M+1]
(3aR,6aS)-5-benzyl-3a,6a-dimethyltetrahydro-1H-furo[3,4-c]pyrrole-1,3(3aH)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
56%
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;
Step 1. Preparation of (3aR,6aS)-5-Benzyl-3a,6a-dimethyltetrahydro-lH-furo[3,4- c]pyrrole-l,3(3aH)-dione 123 To a cooled solution (0C) of 3,4-dimethylfuran-2,5-dione (3 g, 24 mmol) and N-benzyl- l-methoxy-N-((trimethylsilyl)methyl)methanamine (7 g, 29.8 mmol) in dichloromethane (75 mL) was slowly added trifluoroacetic acid (75 mu,). Stir overnight allowing the solution to slowly warm to room temperature as the ice bath melted. The reaction mixture was concentrated to dryness, dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate (2 x l OOmL), dried on magnesium sulfate, filtered and concentrated to dryness. Purification by column chromatography on silica gel (gradient: 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded (3aR,6aS)-5-Benzyl-3a,6a-dimethyltetrahydro-lH-furo[3,4-c]pyrrole-l,3(3aH)- dione as a yellow oil (3.5 g, 56%).
56%
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;
To a cooled solution (0C) of 3,4-dimethylfuran-2,5-dione (3 g, 24 mmol) and N- benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine (7 g, 29.8 mmol) in dichloromethane (75 mL) was slowly added trifluoroacetic acid (75 mu.). Stir overnight allowing the solution to slowly warm to room temperature as the ice bath melted. The reaction mixture was concentrated to dryness, dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate (2 x lOOmL), dried on magnesium sulfate, filtered and concentrated to dryness. Purification by column chromatography on silica gel (gradient: 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded racemic (cis) 5-Benzyl-3a,6a- dimethyltetrahydro-lH-furo[3,4-c]pyrrole-l,3(3aH)-dione as a yellow oil (3.5 g, 56%).
56%
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;Cooling with ice;
To a cooled solution (0C) of 3,4-dimethylfuran-2,5-dione (3 g, 24 mmol) and N-benzyl- l-methoxy-N-((trimethylsilyl)methyl)methanamine (7 g, 29.8 mmol) in dichloromethane (75 mL) was slowly added trifluoroacetic acid (75 mu,). Stir overnight allowing the solution to slowly warm to room temperature as the ice bath melted. The reaction mixture was concentrated to dryness, dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate (2 x lOOmL), dried on magnesium sulfate, filtered and concentrated to dryness. Purification by column chromatography on silica gel (gradient: 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded (3aR,6aS)-5-Benzyl-3a,6a-dimethyltetrahydro-lH-furo[3,4-c]pyrrole- l,3(3aH)-dione as a yellow oil (3.5 g, 56%)
With trifluoroacetic acid; In dichloromethane; at 25℃; for 3h;Inert atmosphere;
General procedure: To a solution of 15 (1.02 mol) in CH2Cl2 (700 mL), N-(methoxymethyl)-N-[(trimethylsilyl)methyl]benzylamine (16, 244 g, 1.03 mol) was added. To the resulting mixture, a solution of TFA (11.6 g, 0.102 mol) in CH2Cl2 (20 mL) was added dropwise at 25 C under an inert atmosphere. The mixture was stirred for 3 h, washed with H2O (400 mL) and brine (400 mL), dried (Na2SO4), and evaporated under reduced pressure to give adduct 17, which was used in the next step without purification.
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 30.25h;
c
To a solution of methyl 2-((tert-butoxycarbonyl)amino)acrylate (10.3 g, 51.24 mmol) in DCM (103 ml) was added TFA (0.26 ml) at 0°C. N-(Methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (13.35 g, 56.37 mmol) was slowly added to the reaction mixture at 0°C. The reaction mixture was stirred at 0°C for 15 min and then stirred at rt for 15 h. After 15 h unreacted starting material was observed so again N-(Methoxymethyl)-N-(trimethylsilylmethyl)-benzylamine (3.64 g, 15.373 mmol) was slowly added to the reaction mixture at 0°C. The reaction mixture was stirred at rt for a further 15 h. The resulting reaction mixture was poured into water (250 ml) and basified using Na2C03. The resulting mixture was extracted with DCM (2 x 150 ml) and the combined organic phase was washed with brine solution (50 ml), dried over Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (20% EtOAc in hexane) yielding methyl 1- benzyl-3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylate (13.80 g, 41.294 mmol). LCMS: Method 3, 4.68 min, MS: ES+ 335.3; 1HNMR (400 MHz, DMSO-d6) δ ppm: 7.59 (s, 1H), 7.21 - 7.33 (m, 5H), 3.57 - 3.62 (m, 5H), 2.99 (d, J=10 Hz, 1 H), 2.67 (d, J=10 Hz, 1 H), 2.50 -2.61 (m, 2H), 2.14 - 2.18 (m, 1H), 1.98 - 1.99 (m, 1H), 1.35 (s, 9H).
1.9 g
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16.08h;
52-0
To a solution of Compound 55-2 (3.7 g, 18.398 mmol) and N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (4.36 g, 18.398 mmol) in DCM (30 mL), TFA (0.1 mL) was added slowly over a period of 5 minutes at 0° C. Then the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with H2O (50 mL) and extracted twice with DCM (50 mL). The combined organic layers were washed with aqueous NaHCO3 and brine (50 mL), the organic layer was dried over Na2SO4 and concentrated in vacuo. The product was purified by normal phase chromatography with a running gradient of 20% EtOAc/n-hexane to afford 1.90 g of Compound 55-3 as a yellow liquid. 1H NMR (400 MHz, CDCl3) δ 7.39-7.27 (m, 5H), 3.73 (s, 3H), 3.64 (q, J=13.0 Hz, 2H), 2.88 (s, 1H), 2.81 (d, J=10.3 Hz, 1H), 2.67-2.52 (m, 2H), 2.08-1.93 (m, 1H), 1.58 (s, 1H), 1.42 (s, 9H). LC-MS=335.2 [M+H]+, retention time=1.04 minutes.
With trifluoroacetic acid In dichloromethane at 0 - 30℃; for 18h;
Intermediate 1 : Methyl (R)-3-((tert-butoxycarbonyl)amino)pyrrolidine-3-carboxylate
To a solution of methyl 2-((tert-butoxycarbonyl)amino)acrylate (430 g, 2.14 mol) and N- benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (533 g, 2.2 mol) in DCM (5.5 L) was added trifluoroacetic acid (24.4 g, 214 mmol) slowly at 0 °C. The reaction mixture was stirred at 30 °C for 18 hrs. The mixture was quenched with aq.NaHCO3 (5 L). The crude product was extracted with DCM (2.5 L). The organic layer was washed with brine (3.0 L), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, PE/EtOAc = 10/1 to 0/1) to afford methyl 1-benzyl-3-((tert- butoxycarbonyl)amino)pyrrolidine-3-carboxylate as a yellow solid (INT-1A). 1H NMR (400 MHz, CDCI3) d 7.35-7.31 (m, 4H), 7.27-7.23 (m, 1 H), 5.12 (s, 1 H), 3.75 (s, 3H), 3.67-3.61 (m, 2H), 2.95-2.87 (m, 2H), 2.82 (d, J = 9.2 Hz, 1 H), 2.67-2.53 (m, 2H), 2.06-1.94 (m, 1 H), 1.43 (s, 9H). LC-MS: [M+H]+ = 335.1 , 336.1.
2-(1-benzyl-2,5-dihydro-1H-imidazol-4-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16.5h; Inert atmosphere; chemoselective reaction;
General procedure for the (3+2) cycloaddition reaction between cyanobenzenes 9 and hemiaminal 1 : Synthesis of imidazolines 10
General procedure: A solution of TFA (0.18 M) in CH2Cl2 (0.18 M) was added dropwise at 0 °C, over 30 minwith a syringe pump, to a solution of hemiaminal 1 (9 equiv) and the requisite cyanoderivative 9 (1 equiv) in dry CH2Cl2 (0.25 M). The resultant mixture was kept under an inert atmosphere at 0 °C for 30 min then warmed to r.t. and stirred for the requisite time. The crude mixture was then concentrated under reduced pressure. The crude material was purified by chromatography to afford the imidazoline derivative.
3-(1-benzyl-2,5-dihydro-1H-imidazol-4-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16.5h; Inert atmosphere; chemoselective reaction;
General procedure for the (3+2) cycloaddition reaction between cyanobenzenes 9 and hemiaminal 1 : Synthesis of imidazolines 10
General procedure: A solution of TFA (0.18 M) in CH2Cl2 (0.18 M) was added dropwise at 0 °C, over 30 minwith a syringe pump, to a solution of hemiaminal 1 (9 equiv) and the requisite cyanoderivative 9 (1 equiv) in dry CH2Cl2 (0.25 M). The resultant mixture was kept under an inert atmosphere at 0 °C for 30 min then warmed to r.t. and stirred for the requisite time. The crude mixture was then concentrated under reduced pressure. The crude material was purified by chromatography to afford the imidazoline derivative.
2-(1-benzyl-2,5-dihydro-1H-imidazol-4-yl)-4,5-dichlorobenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 24.5h;Inert atmosphere;
General procedure: A solution of TFA (0.18 M) in CH2Cl2 (0.18 M) was added dropwise at 0 C, over 30 minwith a syringe pump, to a solution of hemiaminal 1 (9 equiv) and the requisite cyanoderivative 9 (1 equiv) in dry CH2Cl2 (0.25 M). The resultant mixture was kept under an inert atmosphere at 0 C for 30 min then warmed to r.t. and stirred for the requisite time. The crude mixture was then concentrated under reduced pressure. The crude material was purified by chromatography to afford the imidazoline derivative.
1-benzyl-4-(perfluorophenyl)-2,5-dihydro-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16.5h; Inert atmosphere; chemoselective reaction;
General procedure for the (3+2) cycloaddition reaction between cyanobenzenes 9 and hemiaminal 1 : Synthesis of imidazolines 10
General procedure: A solution of TFA (0.18 M) in CH2Cl2 (0.18 M) was added dropwise at 0 °C, over 30 minwith a syringe pump, to a solution of hemiaminal 1 (9 equiv) and the requisite cyanoderivative 9 (1 equiv) in dry CH2Cl2 (0.25 M). The resultant mixture was kept under an inert atmosphere at 0 °C for 30 min then warmed to r.t. and stirred for the requisite time. The crude mixture was then concentrated under reduced pressure. The crude material was purified by chromatography to afford the imidazoline derivative.
1-benzyl-4-(3,5-bis(trifluoromethyl)phenyl)-2,5-dihydro-1H-imidazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
With trifluoroacetic acid; In dichloromethane; at 0 - 20℃; for 16.5h;Inert atmosphere;
General procedure: A solution of TFA (0.18 M) in CH2Cl2 (0.18 M) was added dropwise at 0 C, over 30 minwith a syringe pump, to a solution of hemiaminal 1 (9 equiv) and the requisite cyanoderivative 9 (1 equiv) in dry CH2Cl2 (0.25 M). The resultant mixture was kept under an inert atmosphere at 0 C for 30 min then warmed to r.t. and stirred for the requisite time. The crude mixture was then concentrated under reduced pressure. The crude material was purified by chromatography to afford the imidazoline derivative.
2-benzyl-1,2,3,5,6,10b-hexahydroimidazo[5,1-a]isoquinoline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With trifluoroacetic acid In dichloromethane at 20℃; for 12h;
1 Embodiment 1
In the clean round-bottom flask in turn point pen (2 - 1) is shown in the 3, 4 - ISO-quinoline (1 mmol), formula (3 - 1) shown in - N - N - methoxy methyl (trimethyl silane) aliphatic amine (1 mmol), trifluoroacetic acid (1 mmol) and dichloromethane 10 ml, put into the room temperature stirring reaction for 12 hours, the use of petroleum ether and ethyl acetate mixed solvent (the two mass ratio is 1:3) to column chromatography, separate the product, product yield is 96%.
93%
With trifluoroacetic acid In dichloromethane at 20℃; for 1h;
With trifluoroacetic acid; In dichloromethane; at 20℃; for 1h;
The benzo[b]thiophenesulfone (1 mmol) represented by the formula (2-1) was sequentially added to a clean round bottom flask. N-methoxymethyl-N-(trimethylsilane) fatty amine (1 mmol) represented by formula (3-1), trifluoroacetic acid (1 mmol), and 10 mL of dichloromethane.The reaction was stirred at room temperature for 1 hour to obtain a reaction product.The reaction product was subjected to column chromatography using a mixed solvent of petroleum ether and ethyl acetate (the mass ratio of 1:3).The product was isolated and the product yield was 95%.
ethyl 1-benzyl-4-ethyl-2,5-dihydro-1H-pyrrole-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With trifluoroacetic acid In dichloromethane at 20℃; for 0.833333h;
1; 9.a 1. Synthesis of intermediate 3
10mmol of compound 1 and 1mmol of trifluoroacetic acid was added to 20mL of dichloromethane, the reactor was cooled to 20 ° C, added compound 20 20mmol, stirred for 50min, slowly added water to stop the reaction, the reaction mixture was separated The aqueous layer was extracted twice with dichloromethane, and the combined dichloromethane was dried, and then dichloromethane was evaporated to give a crude product. The crude product was mixed with ethyl acetate petroleum ether (ethyl acetate: petroleum ether = 1:10). Analysis product compound 3: 2.2 g, yield 86%
29.2 g
With trifluoroacetic acid In dichloromethane at -5 - 27℃; for 19h;
12 Example- 12: Preparation of ethyl 1 -benzyl-4-ethyl-2,5-dihydro- 1H-pyrrole-3- carboxylate
A mixture of ethyl-2-pentnoate (25 g), N-benzyl- 1-methoxy-N-trimethylsilyl) methane amine (94.09 g) and dichloromethane (250 mL) was cooled to -5°C and Trifluoro acetic acid (3.05 mL) was added to it slowly. The reaction mixture was stirred for 1 hour at -5°C and for 2 hours at 0°C. The temperature of the reaction mixture was allowed to reach 27°C and stirred at the same temperature for 16 hours. The solvent was removed under reduced pressure after the completion of reaction and purified the crude product by column chromatography using 4% ethyl acetate- hexane mixture as eluent to obtain the title compound as yellow liquid. Yield: 29.2 g
With hydrogenchloride In water; acetonitrile at 20 - 25℃;
1.S1 Example 1
S1, 50.0 g of ethyl pivalate (1.0 eq, 0.396 mol) was added to the reaction flask, and 141.15 g (1.5 eq, 0.594 mol) was added.N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine,Add 750 mL of acetonitrile to the above reaction flask at room temperature.3.8 g/20 ml (0.1 eq, 0.0396 mol) of concentrated hydrochloric acid/water solution was added dropwise.The addition was completed in about 30 minutes. Maintain room temperature at 20~25 °C for 16h.Post-treatment: After completion of the reaction, the acetonitrile was concentrated to remove acetonitrile, and ethyl acetate (700 ml) was added and washed twice with saturated aqueous sodium hydrogen carbonate (250 mL×2).It was washed once more with an aqueous solution of sodium chloride (250 mL × 1); the organic phase was distilled under reduced pressure until no fraction was produced (40 to 50 ° C, -0.1 Mpa), and was applied directly to the next step.
With hydrogenchloride In water; acetonitrile at 20 - 25℃;
1.S1 Embodiment 1
S1, 50.0 g of ethyl pentynoate (1.0 eq, 0.396 mol) was added to the reaction flask, and 141.15 g (1.5 eq, 0.594 mol) of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine was added. 750 mL of acetonitrile was added to the above reaction flask, and 3.8 g/20 ml (0.1 eq, 0.0396 mol) of concentrated hydrochloric acid/water solution was added dropwise at room temperature, and the addition was completed in about 30 minutes. Maintain room temperature at 20~25 °C for 16h. Post-treatment: After completion of the reaction, the acetonitrile was concentrated to remove acetonitrile, and ethyl acetate (700 ml) was added and washed twice with saturated aqueous sodium hydrogen carbonate (250 mL×2).It was washed once more with an aqueous solution of sodium chloride (250 mL × 1); the organic phase was distilled under reduced pressure until no fraction was produced (40 to 50 ° C, -0.1 Mpa), and was applied directly to the next step.
With trifluoroacetic acid In dichloromethane at 5℃; Inert atmosphere;
ethyl 2-benzyl-2-azaspiro[4.4]nonane-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With lithium fluoride In N,N-dimethyl-formamide for 5h; Reflux; Inert atmosphere; Schlenk technique;
Synthesis of azaspiro[4.4]nonanes 5-7 (General method). Method I
General procedure: The corresponding derivative ofcyclopentylideneacetic acid 2-4 (1 mmol) and compound 1(356 mg, 1.50 mmol) were dissolved in DMF (5 ml) underdry argon atmosphere, then anhydrous LiF (52 mg, 2.0 mmol)was added to the mixture. The formed solution was heatedunder reflux for 5 h, then cooled. Then distilled H2O(20 ml) was added, the mixture was stirred and extractedwith AcOEt (3×50 ml). The combined organics werewashed with saturated aqueous K2CO3 (3×20 ml), thensaturated aqueous CuSO4 (3×20 ml) in order to remove theproducts of degradation of compound 1 from the organicphase, then with saturated aqueous NaCl (3×20 ml), thendried over anhydrous Na2SO4. The solvent was removed onthe rotary evaporator, and the product was purified bycolumn chromatography on silica gel (eluent hexane-AcOEt, 10:1)
5-benzylhexahydro-1H-furo[3,4-c]pyrrol-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41.3%
With trifluoroacetic acid In dichloromethane at 0 - 20℃; for 16h;
1 Intermediate V: 3-(3,5-dkhloropienyi)-3~azabicydo[3 ,0]hexane-l-carboxyIic add Step 1 :
A mixture of furan-2(5H)-one (3.0 g, 35.7 mmol) and .Y-benzyl-l -methoxy-N- (itrimethylsilyl)metliyl)meihanamine (10.34 g, 43.5 mmol) in dichloromethane (30 mL) was cooled to 0 °C and was treated with TFA (0.591 mL, 7 67 mmol) drop wise. It was stored for 16 h at rt. The reaction mixture was quenched with saturated NaHCCL and extracted with DCM. The organic extracts were -washed with brine, dried over NaiSCL, filtered and concentrated in vacuo to give the crude material as a yellow oil. The crude material was absorbed onto a plug of silica gel and purified by flash column chromatography eluting with a gradient of 30% to 40% Ethyl acetate in petroleum ether to provide 5-benzylhexahydro-lH-fiiro[3,4-c]pynOl-l-one (3.2 g, 14.73 mmol, 41.3 % yield) as light- yellow oil. i s NMR (400 MHz, DMSO-iA): 5 pm 7.12 - 7.40 (in, 5 H), 4.43 (t, 7 8. " Hz, 1 H), 3.87 - 4.09 (m, 1 H), 3.56 (d, ,7=2.0 Hz, 2 H), 3.12 (ddd, 7=9.5, 7.1, 1.2 Hz, 1 H), 2,90 - 3.06 (m, 2 H), 2.75 - 2.86 (m, 1 H), 2.33 (dt, ,7=9.1, 7.2 Hz, 2 H). m/z (ESI): 218.2 (M+H)+.
With lithium fluoride In N,N-dimethyl-formamide at 20℃; for 72h;
General procedures for the synthesis of 5-alkyloxazolidines 7a-h
General procedure: DMF (6 mL), aldehyde 5 (2.0mmol), N-(methoxymethyl)-N-[(trimethylsilyl)methyl]benzylamine (8) (522 mg, 2.2 mmol) and LiF(57 mg, 2.2 mmol) were sequentially added in 25 mL round-bottom flask equipped with a magneticstirring bar. The resulting mixture was heated in oil bath at 50 °C for 5 h with stirring (procedure A);or heated in oil bath at 50 °C for 3 h and then at 80 °C for 12 h with stirring (procedure B); or stirredat rt for 3 days (procedure C). The resulting mixture was cooled to rt, diluted with water (18 mL), andextracted with toluene (3 × 6 mL). The combined organic layers were extracted with cold solution ofHCl (2.9 mmol) in mixture of H2O (9 mL) and MeOH (3 mL). The aqueous phase was washed withtoluene (2 × 5 mL), basified with NaHCO3 to 8-9, and extracted with toluene (3 × 8 mL). Thecombined organic extracts were washed with water (10 mL), brine (10 mL), dried over Na2SO4 andevaporated in vacuo to give the desired 5-alkyloxazolidines 7a-h, which were purified by columnchromatography.
ethyl (±)-trans-1-benzyl-4-phenylpyrrolidine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54%
With trifluoroacetic acid In toluene at 0 - 20℃; for 48h; Inert atmosphere;
6.1 Step 1: Ethyl () -traps l-benzyl-4-phenylpwrolidine-3-carboxylate (6.2)
[00390] A solution of TFA (0.95 mL, 12.50 mmol) in toluene (10 mL) was added dropwise to a stirred solution of intermediate 6.1 (7.00 mL, 41.67 mmol) and intermediate 1.2 (11.7 mL, 45.84 mmol) in toluene (50 mL) cooled at 0-5 °C. The resulting mixture was stirred at r.t. for 48 h. The reaction was poured into EtOAc (50 mL) and FLO (50 mL), the two phases were separated, and the organic phase was washed with aq. NaHCCh ss (60 mL), brine (60 mL), dried over Na2S04, and concentrated under reduced pressure. The crude was purified by flash chromatography (PET/EtOAc, from 90:10 to 70:30 v/v PET/EtOAc). 7.01 g of intermediate 6.2 were obtained as a colorless oil (yield: 54%). MS-ESI(+) m/z: 310.5 (M+H).
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