Abstract: We developed an electrochemical carboamidation sequence that affords either cyclic β-amidoamine products via direct functionalization or linear hydroxybisamide products via a ring opening pathway. The reaction pathway was dependent on the nature of the N-acyl activating group, with carbamate groups favoring direct isocyanide addition to the N-acyliminium ion intermediate and the benzoyl activating group favoring the ring opening–functionalization pathway. Both protocols are one-pot reaction sequences, have general applicability, and lead to peptide-like products of greatly increased molecular complexity.
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 8, p. 2127 - 2131[2] Angew. Chem., 2017, vol. 129, p. 2159 - 2163,5
2
[ 123-75-1 ]
[ 24424-99-5 ]
[ 86953-79-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
With triethylamine In dichloromethane at 0 - 20℃; for 1 h;
Racemic 2-benzyl pyrrolidine was synthesized using a modified literature procedure (the Sparteine chiral ligand was omitted), see: J. Am. Chem. Soc. 1994, 116, 3231 as follows: A) Procedure for the preparation of Boc-protected pyrrolidine To a stirred mixture of pyrrolidine (10.0 g, 0.14 mol) in DCM (150 mL) at 0°C was added TEA (15.6 g, 0.15 mol) followed by (Boc)20 (30.6 g, 0.14 mol) and the mixture was stirred at RT for 1 h, TLC showed that pyrrolidine had disappeared. The mixture was washed with a 1 M aqueous HC1 solution (100 mL), brine, dried over Na2S04, filtered and concentrated in vacuo to give the product (24.0 g, 100percent) as a colorless oil, which was used in the next step directly.
97%
at 20℃; for 0.0333333 h; Green chemistry
General procedure: To (Boc)2O (1.0 mmol), was added an amine (1.0 mmol)and the mixture was stirred at room temperature for the time indicated in Table 1. The progress of the reaction was monitored by TLC. In most cases, the BOC protected product was found to be sufficiently pure and did not require any further purification. In some cases the product was purified by silica gel column chromatography (1:2; EtOAc/ Petrolium ether).All products were characterized by IR, 1H NMR and their physical properties.
97%
With phenylsulfonic acid supported on mesoporous silica SBA-15 In neat (no solvent) at 20℃; for 0.05 h; Green chemistry
General procedure: An amine (1 mmol) was added to a magnetically stirred mixture of SBA-15-Ph-SO3H (1 mol percent, 4 mg) and (Boc)2O (1.1 mmol) at room temperature. The progressof the reaction was monitored by thin-layer chromatography (TLC). After completion of the reaction, the reaction mixture was diluted with EtOH (5 mL)and centrifuged. Then the clear liquid was separated, and the residue containing the catalyst was kept for recovery. EtOH was distilled off under vacuum to yield the highly pure N-Boc derivative.
96%
at 100℃; for 0.0333333 h; Microwave irradiation; Green chemistry
General procedure: Amine (1 mmol) and di-tert-butyl dicarbonate [(Boc)2O] (1.1 mmol) were placed in a microwave reaction vial. The LG microwave oven MG 555f was programmed to 300 W at 100 °C. The reaction was monitored using TLC. After the reaction, ice water was added to the reaction mixture which resulted in the precipitation of the product. The solid product was merely filtered off and washed with excess cold water. The product was pure enough for all practical purposes. For characterization purpose, it was further purified by column chromatography (Neutral Alumina as adsorbent, solvent system: Hexane: Ethyl acetate (7.5:2.5)).#10;
87%
at -10 - 20℃;
Synthesis of N-BOC pyrrolidine: In a reaction flask, pyrrolidine (11.3 mL, 133 mmol) and dichloromethane (120 mL) were added, and cooled to -10 to 0 ° C, followed by dropwise addition of BOC2O (24.6 g, 112 mmol) dissolved in 35 mL Dichloromethane solution. After the addition, the mixture was stirred at room temperature for 3-5 hours. The solvent was evaporated to dryness, and then evaporated to dryness to afforded 16.6 g of colorless oily liquid, yield: 87 percent
Reference：
[1] Tetrahedron Letters, 2008, vol. 49, # 16, p. 2527 - 2532
[2] Patent: WO2013/102242, 2013, A1, . Location in patent: Page/Page column 94; 95
[3] Tetrahedron Letters, 2007, vol. 48, # 47, p. 8318 - 8322
[4] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8267 - 8276
[5] Synthesis, 2001, # 4, p. 550 - 552
[6] Tetrahedron Letters, 2009, vol. 50, # 46, p. 6244 - 6246
[7] Journal of the American Chemical Society, 2010, vol. 132, # 43, p. 15445 - 15450
[8] Organic Process Research and Development, 2002, vol. 6, # 6, p. 814 - 816
[9] Organic Letters, 2013, vol. 15, # 21, p. 5424 - 5427
[10] Tetrahedron Letters, 2010, vol. 51, # 29, p. 3855 - 3858
[11] Letters in Organic Chemistry, 2013, vol. 10, # 2, p. 121 - 125
[12] Research on Chemical Intermediates, 2016, vol. 42, # 2, p. 1451 - 1461
[13] Journal of Organic Chemistry, 1997, vol. 62, # 22, p. 7726 - 7735
[14] Organic Letters, 2010, vol. 12, # 18, p. 4176 - 4179
[15] Tetrahedron Letters, 2012, vol. 53, # 43, p. 5803 - 5806
[16] Organic Letters, 2006, vol. 8, # 15, p. 3259 - 3262
[17] Journal of the American Chemical Society, 2011, vol. 133, # 48, p. 19483 - 19497
[18] Tetrahedron Letters, 2008, vol. 49, # 49, p. 6962 - 6964
[19] Journal of Organic Chemistry, 2013, vol. 78, # 21, p. 11066 - 11070
[20] Tetrahedron Letters, 2010, vol. 51, # 49, p. 6388 - 6391
[21] Organic Syntheses, 1997, vol. 74, p. 23 - 23
[22] Patent: CN108047257, 2018, A, . Location in patent: Paragraph 0017
[23] Tetrahedron, 2005, vol. 61, # 9, p. 2365 - 2372
[24] Angewandte Chemie - International Edition, 2007, vol. 46, # 11, p. 1893 - 1896
[25] Tetrahedron Letters, 2017, vol. 58, # 7, p. 629 - 633
[26] Organic Letters, 2018, vol. 20, # 18, p. 5661 - 5665
Reference：
[1] Chemical Communications, 2007, # 48, p. 5244 - 5246
5
[ 109-96-6 ]
[ 24424-99-5 ]
[ 73286-70-1 ]
[ 86953-79-9 ]
Yield
Reaction Conditions
Operation in experiment
37%
at 0 - 20℃;
The tetrahydro-3aH-[1, 3] dioxolo [4,5-c] pyrrole hydrochloride was made as follows: A mixture of 3-pyrroline (2, 5-DIHYDRO-LH-PYRROLE) (25g; 0.36mole ; 65percent pure containing pyrrolidine) and ethyl acetate (125mL) was cooled to 0°C and a solution of BOC2O (78.95g ; 0. 36MOL) in ethyl acetate (125mL) was added dropwise while keeping the temperature between 5 and 10°C. The reaction mixture was then left to rise to ambient temperature overnight. The organic phase was washed successively with water, HC1 0. 1N, water, saturated sodium hydrogen carbonate, brine and dried over magnesium sulphate. Filtration and evaporation of the solvent gave a colourless oil (62g) containing 37percent of pyrrolidine-Boc in addition to the desired tert-butyl 2, 5-dihydro-lH-pyrrole-l- carboxylate (62g, 100percent based on conversion of both pyrroline and pyrrolidine). IH NE SPECTRUM : (CDC13) 1.45 (s, 9H), 4.1 (d, 4H), 6.75 (M, 2H) Pyrrolidone-Boc: 1.50 (s, 9H), 1.80 (br s, 4H), 3.3 (br s, 4H)
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1996, vol. 35, # 2, p. 91 - 98
[2] Journal of the Chemical Society - Perkin Transactions 1, 1996, # 2, p. 219 - 224
[3] Tetrahedron, 2002, vol. 58, # 18, p. 3525 - 3534
11
[ 109-97-7 ]
[ 24424-99-5 ]
[ 86953-79-9 ]
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8283 - 8286
12
[ 123-75-1 ]
[ 24424-99-5 ]
[ 86953-79-9 ]
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 20, p. 6368 - 6380
13
[ 85909-08-6 ]
[ 86953-79-9 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2014, vol. 62, # 6, p. 1233 - 1239
Reference：
[1] Journal of the American Chemical Society, 1994, vol. 116, # 8, p. 3231 - 3239
34
[ 86953-79-9 ]
[ 137496-71-0 ]
Reference：
[1] Patent: WO2008/73825, 2008, A1,
35
[ 61676-62-8 ]
[ 86953-79-9 ]
[ 149682-82-6 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 16, p. 6276 - 6279
[2] Journal of the American Chemical Society, 2016, vol. 138, # 30, p. 9521 - 9532
36
[ 121-43-7 ]
[ 86953-79-9 ]
[ 149682-75-7 ]
Yield
Reaction Conditions
Operation in experiment
9%
With sec.-butyllithium In tetrahydrofuran; cyclohexane at -78℃; for 3 h; Inert atmosphere
A flame dried round bottom flask equipped with a magnetic stir bar was charged with N-Boc-pyrrolidine (10g, 58mmol, 1eq) and dry THF (40mL) under a nitrogen atmosphere. The clear colorless solution was cooled to −78°C and a solution of s-BuLi (64mL of a 1.0M solution in cyclohexane, 64mmol) was added slowly over a 30min period. The light orange colored solution was stirred at −78°C for 3h followed by treatment with B(OMe)3 (15mL, 175mmol) after which the cooling bath was removed and the clear colorless solution slowly warmed to 0°C. Upon reaching 0°C, the reaction was quenched with a small amount of water (∼2mL), allowed to warm to room temp then extracted into 2N NaOH (100mL) and backwashed with additional EtOAc (60mL). The aqueous phase was acidified to pH 3 by the addition of 2N HCl and then extracted with EtOAc (3×60mL). The organic extracts were combined and dried over Na2SO4 and concentrated to produce the free boronic acid 9g as a sticky white solid. Without further purification the boronic acid was dissolved in EtOAc (60mL) and with constant stirring (+)-pinanediol (7.0g, 41mmol) was added at room temperature. After 18h the ester was removed and the (+)-pinanediol boronic ester was purified by column chromatography (silica gel, 6:1 hexanes/EtOAc) to give a clear thick oil (12.1g, 34.8mmol) 60percent yield in two steps. 1H NMR (400MHz, CDCl3) δ 4.50–4.15 (m, 1H), 3.38 (dt, J=13.8, 6.1Hz, 2H), 3.12 (ddd, J=25.1, 15.8, 8.4Hz, 1H), 2.33 (dd, J=12.3, 10.3Hz, 1H), 2.20 (s, 1H), 2.10–1.69 (m, 7H), 1.45 (d, J=7.3Hz, 9H), 1.41 (s, 3H), 1.28 (s, 3H), 0.84 (s, 3H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 15, p. 4031 - 4044
37
[ 86953-79-9 ]
[ 149682-75-7 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 16, p. 6276 - 6279
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (-)-sparteine In diethyl ether at -78℃;
Stage #2: In tetrahydrofuran at -55℃; for 0.75h;
Stage #3: prop-2-yn-1-ol methanesulfonate
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (-)-sparteine In diethyl ether at -78℃;
Stage #2: In tetrahydrofuran at -55℃; for 0.75h;
Stage #3: propargyl p-toluenesulfonate
83%
Stage #1: tert-butyl pyrrolidine-1-carboxylate With N,N,N,N,-tetramethylethylenediamine; sec.-butyllithium In tetrahydrofuran at -78℃; for 1h;
Stage #2: In tetrahydrofuran at -78℃; for 0.75h;
Stage #3: propargyl p-toluenesulfonate In tetrahydrofuran at -78 - 20℃; for 3h;
Stage #1: tert-butyl pyrrolidine-1-carboxylate With N,N,N,N,-tetramethylethylenediamine; sec.-butyllithium In diethyl ether; cyclohexane at -78℃; for 2h;
Stage #2: Di-t-butyl ketone In diethyl ether; cyclohexane at -78 - 25℃; Further stages.;
N-(tert-butoxycarbonyl)-2-(2-acetoxy-1-oxopropyl)pyrrolidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (-)-sparteine In tetrahydrofuran at -78℃; for 1h;
Stage #2: With lithium chloride In tetrahydrofuran at -78℃; for 0.666667h;
Stage #3: (S)-2-acetoxypropanoyl chloride In tetrahydrofuran at -78 - 20℃;
N-[(1,1-dimethylethoxy)carbonyl]-2-[1-(trimethylsilyl)ethenyl]pyrrolidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (-)-sparteine In tetrahydrofuran at -78℃; for 1h;
Stage #2: With lithium chloride In tetrahydrofuran at -78℃; for 1h;
Stage #3: 1-bromo-1-(trimethylsilyl)ethene In tetrahydrofuran at -78 - 25℃; for 12h;
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (-)-sparteine In cyclohexane at -78 - -68℃; for 3h;
Stage #2: With zinc(II) chloride In diethyl ether; cyclohexane at -74 - 20℃;
Stage #3: bromobenzene With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate In diethyl ether; cyclohexane at 20℃; Title compound not separated from byproducts;
84 % ee
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (1R,5S,11aS)-3-methyldecahydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocine In diethyl ether; hexane at -30℃; for 0.0333333h; Inert atmosphere;
Stage #2: With zinc(II) chloride In diethyl ether; hexane at -30 - 20℃; for 1h;
Stage #3: bromobenzene With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate In diethyl ether; hexane at 20℃; for 16h; Overall yield = 58 %; Overall yield = 142 mg; enantioselective reaction;
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (-)-sparteine In cyclohexane at -78 - -68℃; for 3h;
Stage #2: With zinc(II) chloride In diethyl ether; cyclohexane at -74 - 20℃;
Stage #3: chlorobenzene With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate In diethyl ether; cyclohexane at 20℃; Title compound not separated from byproducts;
Step 1. To a solution of 1-boc-pyrrolidine (976 mg, 5.70 mmol, 1.0 eq) and (-)-sparteine (1.34 g, 5.70 mmol, 1.0 eq) in 12 mL anhydrous MTBE at -78C in acetone/dry ice bath was added sec-butyl lithium (4.07 mL, 5.70 mmol, 1.0 eq, 1.4 M in cyclohexane) dropwise, keeping the temperature below -680C. The resulting reaction solution was stirred for 3 hours at -78C (light yellow clear solution).A solution of zinc chloride (6.84 mL, 3.42 mmol, 0.6 eq, 1 M in ether) was added to the above reaction dropwise with rapid stirring, keeping the temperature below -68C. A light suspension was formed, and was stirred for 30 minutes at -78C, and then warmed up to 2O0C (yellow color faded, suspension). Methyl 4-bromo-3-fluorobenzoate (1.13 g, 4.84 mmol, 0.85 eq), palladium acetate(51 mg, 0.228 mmol, 0.04 eq), and tri-tert-butylphosphine tetrafluoroborate (83 mg, 0.285 mmol, 0.05 eq) were added sequentially to the reaction. The resulting reaction mixture was stirred at room temperature overnight (after stirring for 20 minutes, the suspension solution turned from yellow to greenish). The reaction was checked by LC/MS. To facilitate the filtration, NH4OH (0.35 mL) was added, and the mixture was stirred for 1 hour. The resulting slurry was filtered through Celite and washed with 60 mL MTBE. The resulting filtrate was washed with 1 M HCI (50 mL), water (2 x 5OmL), dried over sodium sulfate, and concentrated to obtain a rose-red oil. Biotage was then used to purify the desired product. Fractions containing the desired product were then combined and evaporated to obtain a light brown oil (compound 6 in General Procedure G20c, 830 mg, 53% yield).
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (-)-sparteine In diethyl ether; cyclohexane at -78℃; for 3h; Inert atmosphere;
Stage #2: With zinc(II) chloride In tetrahydrofuran; diethyl ether; cyclohexane at -78 - 20℃; for 1.08333h; Inert atmosphere;
Stage #3: bromobenzene With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate In tetrahydrofuran; diethyl ether; cyclohexane at 20℃; for 16h; Inert atmosphere; optical yield given as %ee; enantioselective reaction;
81%
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (-)-sparteine In tert-butyl methyl ether; cyclohexane at -78℃; for 3.25h; Inert atmosphere;
Stage #2: With zinc(II) chloride In diethyl ether; tert-butyl methyl ether; cyclohexane at -78 - 23℃; Inert atmosphere;
Stage #3: bromobenzene With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate In diethyl ether; tert-butyl methyl ether; cyclohexane at 23℃; Inert atmosphere; optical yield given as %ee;
92 % ee
Stage #1: tert-butyl pyrrolidine-1-carboxylate With C13H26N2; (-)-sparteine In diethyl ether at -80℃; for 4h; Inert atmosphere;
Stage #2: With zinc(II) chloride In diethyl ether at -80 - 20℃; for 1h; Inert atmosphere;
Stage #3: bromobenzene With palladium diacetate; tri tert-butylphosphoniumtetrafluoroborate In diethyl ether at 20 - 40℃; for 16 - 36h; Inert atmosphere; enantioselective reaction;
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (-)-sparteine
Stage #2: With zinc(II) chloride
Stage #3: bromobenzene Further stages;
Step 1: sec-Butyl lithium (25.3 mL, 35.4 mmol) was added into a solution of tert-butyl 1-pyrrolidinecarboxylate (6.2 mL, 35.4 mmol) and (-)-spartiene (8.29 g, 35.4 mmol) in MTBE (100 mL) at -78C. The mixture was stirred for 1 hour at -78C. Zinc chloride solution (35.4 mL, 35.4 mmol) was added, and the reaction was stirred for 15 minutes at -78C. The reaction was allowed to warm up to room temperature. 4- Bromoindolin-2-one (5.00 g, 23.6 mmol), palladium (II) acetate (0.53 g, 2.4 mmol) and tri- tert-butylphosphine tetrafluoroborate (0.68 g, 2.4 mmol) was added into the reaction mixture. The reaction was stirred for 12 hours at room temperature. The reaction mixture was poured into EtOAc (200 mL), and the suspension was filtered with a pad of celite. The filtrate was concentrated, and the residue was purified by flash chromatography (silica gel eluted with 4:1 hexanes : ethyl acetate) to give (R)-tert-butyl 2-(2-oxoindolin-4-yl)pyrrolidine-l-carboxylate (1.9 g, 27%) as a solid. 1H NMR (CDCl3, 400 MHz) delta 7.80 (s, IH), 7.10-7.20 (m, IH), 6.75- 6.82 (m, IH), 6.62-6.78 (m, IH), 4.65-4.93 (m, IH), 3.34-3.73 (m, 4H), 2.20-2.40 (m, IH), 1.84-2.00 (m, 2H), 1.68-1.83 (m, IH), 1.45 (2, 4H), 1.14 (s, 5H). MS (APCI+) [M+H]+ 303.
A solution of tert-butyl pyrrolidine- 1-carboxylate (20 g, 116.8 mmol) and (- )sparteine (32.9, 140 mmol) in MTBE (360 mL) was cooled to -78 0C, and sec-BuLi (10OmL, 140 mmol, 1.4 M in cyclohexane) was introduced drop-wise via cannula, keeping the internal temperature under -70 0C. The resulting solution was stirred for 3 hours at -78 0C, followed by addition of a solution of ZnCl2 (93.4 mL, 93.4 mmol, IM in Et2O) drop-wise with rapid stirring, keeping the internal temperature below -65 0C. The resulting light suspension was stirred at -78 0C for 30 minutes and then warmed to ambient temperature. The resulting mixture was charged with 2-bromo-l,4-difluorobenzene (14.5 mL, 128 mmol), followed by Pd(OAc)2 (1.31 g, 5.8mmol) and ^-Bu3P-HBF4 (2.03 g, 7.0 mmol) in one portion. After stirring overnight at ambient temperature, 10.5 mL Of NH4OH solution was added and the reaction was stirred for another hour. The resulting slurry was filtered through CELITE and washed with Et2O (1 L). The filtrate was washed with HCl (0.5 L, IM aq.) and brine. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5-10% EtO Ac/hex anes to give product (R)-tert-butyl 2- (2,5-difluorophenyl)pyrrolidine- 1-carboxylate as yellow oil (23.9 g, 72% yield).
72%
Preparation A; Preparation of (R)-2-(2,5-difluorophenyl)pyrrolidine; [00378] Step A: Preparation of (PQ-tert-butyl 2-(2.5-difluorophenv0pyrrolidine-l- carboxylate; A solution of tert-butylpyrrolidine-1-carboxylate (20 g, 116.8 mmol) and (-)sparteine (32.9, 140 mmol) in MTBE (360 mL) was cooled to -78 0C, and sec-BuU (100 mL, 140 mmol, 1.4 M in cyclohexane) was introduced dropwise via cannula, keeping the internal temperature under -70 0C. The resulting solution was stirred for 3 hours at -78 0C, followed by addition of a solution of ZnCl2 (93.4 mL, 93.4 mmol, IM in Et2O) drop-wise with rapid stirring, keeping the internal temperature below -65 0C. The resulting light suspension was stirred at -78 0C for 30 minutes and then warmed to ambient temperature. The resulting mixture was charged with 2-bromo-l,4-difluorobenzene (14.5 mL, 128 mmol), followed by Pd(OAc)2 (1.31 g, 5.8 mmol) and J-Bu3P-HBF4 (2.03 g, 7.0 mmol) in one portion. After stirring overnight at ambient temperature, 10.5 mL Of NH4OH solution was added and the reaction was stirred for another hour. The resulting slurry was filtered through CELITE and washed with Et2O (1 L). The filtrate was washed with HCl (0.5 L, IM aq.) and brine. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5-10% EtOAc/hexanes to give product (R)-tert- butyl 2-(2,5-difluorophenyl)pyrrolidine-l-carboxylate as yellow oil (23.9 g, 72% yield).
72%
Preparation A; (R)-2-(2,5-difluorophenyl)pyrrolidine; Step A: Preparation of (RVtert-butyl 2-(2.5-difluorophenyl)pyrrolidine-l- carboxylate.; A solution of tert-butyl pyrrolidine- 1-carboxylate (20 g, 116.8 mmol) and (-)- sparteine (32.9, 140 mmol) in MTBE (360 mL) was cooled to -78 0C and sec-BuU (100 mL, 140 mmol, 1.4 M in cyclohexane) was introduced drop-wise via cannula, keeping the internal temperature under -70 0C. The resulting solution was stirred for 3 hours at -78 0C, followed by addition of a solution of ZnCl2 (93.4 mL, 93.4 mmol, IM in Et2O) drop-wise with rapid stirring, keeping the internal temperature below -65 0C. The resulting light suspension was stirred at -78 0C for 30 minutes and then warmed to ambient temperature. The resulting mixture was sequentially charged with 2-bromo-l,4-difluorobenzene (14.5 mL, 128 mmol), Pd(OAc)2 (1.31 g, 5.8 mmol) and J-Bu3P-HBF4 (2.03 g, 7.0 mmol) in one portion. After stirring overnight at ambient temperature, concentrated NH4OH (10.5 mL) was added and the reaction was stirred for 1 hour. The resulting slurry was filtered through Celite and the filter cake washed with Et2O (1 L). The filtrate was washed with a IM aqueous HCl solution (0.5 L) and brine. The organic layer was filtered and concentrated, and the crude product was purified by silica column chromatography, eluting with 5-10% EtOAc/hexanes to give product (R)-tert-butyl 2-(2, 5 -difluorophenyl)pyrrolidine- 1-carboxylate as yellow oil (23.9 g, 72% yield).
Example 222alpyrimidine-3-carboxamido)propylcarbamate; Step A: Preparation of (RVtert-butyl 2-(2-chloro-5-fluoropyridin-3- yDpyrrolidine- 1 -carboxylate:; A solution of tert-butyl pyrrolidine- 1-carboxylate (1 mL 5.70 mmol) and (-)-sparteine (1.31 mL, 5.70 mmol) in anhydrous MTBE (30 mL) was first cooled to -78 0C under nitrogen, followed by addition of sec-butyl lithium (4.07 mL, 1.4M, 5.70 mmol) drop-wise over 15 minutes with a syringe, maintaining the temperature below -75 0C. The pale yellowish solution was stirred at -78 0C for 3 hours before being treated with zinc chloride (3.80 mL, 1.0 M, 3.80 mmol) dropwise over 15 minutes while maintaining the temperature below -73 0C. The mixture was stirred at -78 0C for 30 minutes, then placed into an ambient temperature water bath and stirred for another hour. At this point a large amount of white precipitate was present. The mixture was treated with 3-bromo-2-chloro-5- fluoropyridine (1.00 g, 4.75 mmol) in MTBE (5 mL), followed by addition of palladium acetate (53 mg, 0.24 mmol) and tri-t-butylphosphine tetrafluoroborate (83 mg, 0.28 mmol). The mixture was allowed to stir at ambient temperature overnight to reach completion. The mixture was treated with NH4OH (1 mL), stirred for 30 minutes and filtered through GF/F paper, washing with MTBE. The filtrate was washed with 10% citric acid (30 mL) and the aqueous layer was back-washed with MTBE (2 x 30 mL). The combined organic phases were washed with brine (20 mL), dried (MgSO4), and concentrated to afford the crude product as dark yellowish oil. This crude material was purified on a silica 5O g Biotage SNAP cartridge eluting with 10% EtOAc in hexanes to afford the desired product as colorless oil (0.5 g, 35%). MS (apci pos) m/z = 201.1 (M+H-Boc).
(R)-tert-butyl 2-(3-(methylsulfonyl)phenyl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.5%
Example 31 A: (R)-tert-Butyl 2-(3-(methylsulfonyl)phenyl)pyrrolidine-1-carboxylateTo a solution of tert-butyl pyrrolidine- 1-carboxylate (1 mL, 5.71 mmol) and (-)- sparteine (1.310 mL, 5.70 mmol) in MTBE (12 mL) at -78 C was added sec-BuLi (1.4 M in cyclohexane, 4.07 mL, 5.7 mmol) dropwise. The resulting solution was aged for 3 h at -78 C. A solution of ZnCl2 (1 M in Et2O, 3.4 mL, 3.40 mmol) was added to the reaction dropwise. The resulting light suspension was aged at -78 C for 30 min, and then was warmed to 20 C. The resulting homogeneous solution was stirred for 30 min at 20 C, and then was added <strong>[34896-80-5]1-bromo-3-(methylsulfonyl)benzene</strong> (1.117 g, 4.75 mmol), followed by the additions of Pd(OAc)2 (0.053 g, 0.238 mmol) and tri-tert-butylphosphonium tetrafluoroborate (0.083 g, 0.285 mmol). The mixture was stirred overnight in a water bath at 20 C. To facilitate the filtration, 0.35 mL of NH4OH was added, and the mixture was aged for 1 h. The resulting slurry was filtered through a pad of CELITE, and was washed with 60 mL MTBE. The filtrate was washed with 50 mL of 1 M HCl, and then twice with 50 mL of water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by normal phase chromatography to provide Example 31A (0.95 g, 61.5%) as a white crystalline solid. LC-MS (ESI) m/z: 348.0 [M+Na]+; 1H NMR (400MHz, CDCl3) delta 7.90 - 7.68 (m, 2H), 7.57 - 7.40 (m, 2H), 5.16 - 4.68 (m, 1H), 3.75 - 3.43 (m, 2H), 3.01 (s, 3H), 2.36 (br. s., 1H), 1.99 - 1.73 (m, 3H), 1.44 (br. s., 4H), 1.26 - 1.07 (m, 5H).
Multi-step reaction with 2 steps
1.1: sec.-butyllithium; N,N,N,N,-tetramethylethylenediamine / diethyl ether; hexane / 3 h / -78 °C
1.2: 1 h / -78 °C
2.1: n-butyllithium / hexane / 0.5 h / 20 °C / Inert atmosphere
2.2: 0.83 h / -78 - -42 °C
With sec.-butyllithium; In tetrahydrofuran; cyclohexane; at -78℃; for 3.0h;Inert atmosphere;
A flame dried round bottom flask equipped with a magnetic stir bar was charged with N-Boc-pyrrolidine (10g, 58mmol, 1eq) and dry THF (40mL) under a nitrogen atmosphere. The clear colorless solution was cooled to -78C and a solution of s-BuLi (64mL of a 1.0M solution in cyclohexane, 64mmol) was added slowly over a 30min period. The light orange colored solution was stirred at -78C for 3h followed by treatment with B(OMe)3 (15mL, 175mmol) after which the cooling bath was removed and the clear colorless solution slowly warmed to 0C. Upon reaching 0C, the reaction was quenched with a small amount of water (?2mL), allowed to warm to room temp then extracted into 2N NaOH (100mL) and backwashed with additional EtOAc (60mL). The aqueous phase was acidified to pH 3 by the addition of 2N HCl and then extracted with EtOAc (3×60mL). The organic extracts were combined and dried over Na2SO4 and concentrated to produce the free boronic acid 9g as a sticky white solid. Without further purification the boronic acid was dissolved in EtOAc (60mL) and with constant stirring (+)-pinanediol (7.0g, 41mmol) was added at room temperature. After 18h the ester was removed and the (+)-pinanediol boronic ester was purified by column chromatography (silica gel, 6:1 hexanes/EtOAc) to give a clear thick oil (12.1g, 34.8mmol) 60% yield in two steps. 1H NMR (400MHz, CDCl3) delta 4.50-4.15 (m, 1H), 3.38 (dt, J=13.8, 6.1Hz, 2H), 3.12 (ddd, J=25.1, 15.8, 8.4Hz, 1H), 2.33 (dd, J=12.3, 10.3Hz, 1H), 2.20 (s, 1H), 2.10-1.69 (m, 7H), 1.45 (d, J=7.3Hz, 9H), 1.41 (s, 3H), 1.28 (s, 3H), 0.84 (s, 3H).
With tert-butyl peroxyacetate; [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate; trifluoroacetic acid In acetone at 20℃; for 24h; Irradiation; Sealed tube; Green chemistry;
N-Boc-pyrrolidine (2g, 11.7mmol) under nitrogenDissolved in 30 mL of re-distilled anhydrous THF, the solution was cooled to -78 C,A solution of s-BuLi in hexane (14 mmol) was slowly added over 30 min.Then, stirring was continued at -78 C for 3 h;Treated with B(OMe)3 (3.9 mL, 35 mmol),After that, the temperature was slowly raised to about 0 C, and the reaction was quenched with a small amount of water (about 0.5 mL).After warming to room temperature, extract with 2N NaOH (25 mL) solution.The aqueous phase was adjusted to pH=3 by adding 2N hydrochloric acid to the aqueous phase.Extract with ethyl acetate (3 x 20 mL) and combine the organic phases.Drying over anhydrous sodium sulfate and evaporating the solvent gave a white viscous solid.The yield was 84%.The crude product was used in the next reaction without purification.
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (-)-sparteine In hexane; cyclohexane at -78℃; for 0.5h; Inert atmosphere;
Stage #2: N-methoxy-N-methyl-2-phenylacetamide In hexane; cyclohexane at -78℃; for 3h; Inert atmosphere; enantioselective reaction;
benzyl 4-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
A flask was charged with t-butyl pyrrolidine-1-carboxylate (744 mg, 4.34 mmol, 1.50 equiv), N,N,N',N'-tetramethylethylenediamine (505 mg, 4.35 mmol, 1.50 equiv), and ether (10 mL) under nitrogen. s-Butyllithium (3.57 mL, 4.64 mmol, 1.60 equiv, 1.3M in n-hexane) was added dropwise at -78 C. The resulting solution was stirred for 3.5 h at -78 C. Zinc diiodide (693 mg, 2.17 mmol, 0.75 equiv) in THF was added. The resulting solution was stirred for 0.5 h at -78 C. and stirred for 1 h at room temperature. A solution of <strong>[885275-00-3]benzyl 4-iodopiperidine-1-carboxylate</strong> in THF (1.00 g, 2.90 mmol, 1.00 equiv) was added to a solution of nickel chloride ethylene glycol dimethyl ether complex (94.8 mg, 0.430 mmol, 0.15 equiv) and N,N'-dimethylethylenediamine (43.4 mg, 0.490 mmol, 0.17 equiv). The organozinc solution was added to the catalyst/electrophile mixture. The resulting solution was stirred for 60 h at room temperature and quenched with water (20 mL). The resulting solution was extracted with DCM (3*20 mL) and the organic layers were combined, washed with brine (2*20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to provide 212 mg (19% yield) of benzyl 4-(1-(t-butoxycarbonyl)pyrrolidin-2-yl)piperidine-1-carboxylate as a yellow oil. LCMS (ESI, m/z): 389 [M+H]+.
tert-butyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
40.7 mg
With nickel(II) bromide dimethoxyethane; dipotassium hydrogenphosphate; benzaldehyde; 4,4'-di-tert-butyl-2,2'-bipyridine In acetonitrile at -78 - 20℃; for 72h; Inert atmosphere; UV-irradiation;
Stage #1: tert-butyl pyrrolidine-1-carboxylate With N,N,N,N,-tetramethylethylenediamine; sec.-butyllithium In diethyl ether; cyclohexane at -78℃; for 4.5h; Inert atmosphere;
Stage #2: tricyclohexyltin(IV) chloride In diethyl ether; cyclohexane; toluene at -78 - 20℃; Inert atmosphere;
tert-Butyl 2-(tricyclohexylstannyl)pyrrolidine-1-carboxylate (2c).
To an ovendriedround bottom flask under an atmosphere of argon, tetramethylethlenediamine(TMEDA) (1.3 mmol, 1.3 equiv) was added via syringe. Diethyl ether (6 mL) wasthen added, and the resulting solution was cooled to -78 C. To the cooled solution, s-BuLi (in cyclohexane) (1.3 mmol, 1.3 equiv) was added dropwise, and the resultingmixture was then allowed to stir at -78 C for 30 min. Next, N-Boc-pyrrolidine (1mmol, 1.0 equiv) was added dropwise to the cooled solution. The resulting mixturewas stirred at -78 C for 4 h. A solution of tricyclohexyltin chloride (1.5 mmol, 1.5equiv) in toluene (1 mL) was added. The mixture was allowed to slowly warm to rt,and stirred overnight at rt. The reaction mixture was poured into a separatory funnelcontaining a mixture of water and diethyl ether. The organic layer was separated,washed with brine, dried over Na2SO4, and filtered. Solvent was removed under reducedpressure, and tert-butyl 2-(tricyclohexylstannyl)pyrrolidine-1-carboxylate (2c)was isolated by flash column chromatography (10% K2CO3/Silica gel, 3:97 ethyl acetate:hexane) as a white solid (479 mg, 88%). 1H NMR (300 MHz, CDCl3): δ 3.93 (m,0.3H), 3.41 (m, 1.7H), 3.17 (m, 1H), 2.17 (m, 1H), 1.88 (m, 10H), 1.55 (m, 25H),1.29 (m, 10H) ppm. 13C NMR (75 MHz, CDCl3): δ 153.9, 78.3, 46.2, 46.1, 33.8, 32.5,32.2, 31.2, 30.9, 29.6, 28.9, 28.7, 28.6, 27.4, 26.9 ppm. HRMS (ES+): Calcd (M-H)+540.2869; Found 540.2885.
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; sparteine In diethyl ether; cyclohexane at -78℃; for 4.5h; Inert atmosphere;
Stage #2: tricyclohexyltin(IV) chloride In diethyl ether; cyclohexane; toluene at -78 - 20℃; Inert atmosphere;
(R)-tert-Butyl-2-(tricyclohexylstannyl)pyrrolidine-1-carboxylate ((R)-2c).
General procedure: To anoven-dried round bottom flask under an atmosphere of argon, (+)-sparteine (2.6 mmol,1.3 equiv) was added via syringe. Diethyl ether (12 mL) was then added, and the resultingsolution was cooled to -78 C. To the cooled solution, s-BuLi (in cyclohexane)(2.6 mmol, 1.3 equiv) was added dropwise, and the resulting mixture was then allowedto stir at -78 C for 30 min. Next, N-boc-pyrrolidine (1 mmol, 1.0 equiv) wasadded dropwise to the cooled solution. The resulting mixture was stirred at -78 C for4 h. A solution of tricyclohexyltin chloride (3 mmol, 1.5 equiv) in toluene (2 mL) wasadded. The mixture was allowed to slowly warm to rt, and stirred overnight at rt. Thereaction mixture was poured into a separatory funnel containing a mixture of waterand diethyl ether. The organic layer was separated, washed with brine, dried overNa2SO4, and filtered. Solvent was removed under reduced pressure, and (R)-2c wasisolated by flash column chromatography (10% K2CO3/Silica gel, 3:97 ethyl acetate:hexane) as a white solid (915.2 mg, 85%). (S)-tert-butyl 2-(tricyclohexylstannyl)pyrrolidine-1-carboxylate ((S)-2c) was prepared through ananalogous route using (-)-sparteine (452 mg, 84%).
Stage #1: tert-butyl pyrrolidine-1-carboxylate With sec.-butyllithium; (-)-sparteine In diethyl ether; cyclohexane at -78℃; for 4.5h; Inert atmosphere;
Stage #2: tricyclohexyltin(IV) chloride In diethyl ether; cyclohexane; toluene at -78 - 20℃; Inert atmosphere;
(R)-tert-Butyl-2-(tricyclohexylstannyl)pyrrolidine-1-carboxylate ((R)-2c).
General procedure: To anoven-dried round bottom flask under an atmosphere of argon, (+)-sparteine (2.6 mmol,1.3 equiv) was added via syringe. Diethyl ether (12 mL) was then added, and the resultingsolution was cooled to -78 C. To the cooled solution, s-BuLi (in cyclohexane)(2.6 mmol, 1.3 equiv) was added dropwise, and the resulting mixture was then allowedto stir at -78 C for 30 min. Next, N-boc-pyrrolidine (1 mmol, 1.0 equiv) wasadded dropwise to the cooled solution. The resulting mixture was stirred at -78 C for4 h. A solution of tricyclohexyltin chloride (3 mmol, 1.5 equiv) in toluene (2 mL) wasadded. The mixture was allowed to slowly warm to rt, and stirred overnight at rt. Thereaction mixture was poured into a separatory funnel containing a mixture of waterand diethyl ether. The organic layer was separated, washed with brine, dried overNa2SO4, and filtered. Solvent was removed under reduced pressure, and (R)-2c wasisolated by flash column chromatography (10% K2CO3/Silica gel, 3:97 ethyl acetate:hexane) as a white solid (915.2 mg, 85%). (S)-tert-butyl 2-(tricyclohexylstannyl)pyrrolidine-1-carboxylate ((S)-2c) was prepared through ananalogous route using (-)-sparteine (452 mg, 84%).
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