* 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.
To a solution of pyrrole-2-carboxylic acid (1) (16.65 g, 0.15 mol)in 10 mL of MeOH was added 50 mL of SOCl2 dropwise within30 min at 0 C. Subsequently, the reaction mixture was stirred at35 C for 24 h. Then, the solvent was evaporated in vacuo, andthe residue was purified by column chromatography using ethylacetate/petroleum ether as eluent, giving intermediate 2 as a whitesolid, yield 85percent, mp: 72–73 C.
79%
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide) at 20 - 60℃; for 72 h;
Example 36-1 Preparation for methyl 1H-pyrrole-2-carboxlate A suspension of 1H-pyrrole-2-carboxylic acid (5.5g, 49.5mmol), WSCI*HCl (12.2g, 63.6mmol), HOBt (8.4g, 62.2mmol), methanol (7.0g, 218mmol) and 4-dimethylaminopyridine (3.0g, 24.5mmol) in dimethylformamide (60ml) was stirred for 70 hours at room temperature and for 2 hours at 60°C. To the reaction mixture was added an aqueous 5percent potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate/toluene (1/1).. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, and an aqueous saturated sodium chloride solution, and dried over magnesium sulfate.. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=5:13:1) to give the subject compound (4.88g, 79percent).1H NMR (CDCl3, 400 MHz) δ 9. 08 (brs, 1 H), 6. 90 - 6. 98 (m, 2 H), 6.25 - 6.29 (m, 1 H), 3.86 (s, 3 H).
65%
With chloro-trimethyl-silane In methanol at 20℃;
Method I Synthesis of 5-tert-Butyl-3-(3-p-tolyl-ureido)-1H-pyrrole-2-carboxylic acid methyl ester. (Example 24) [Show Image] Step 1; Chlorotrimethylsilane (17.9 mL, 141 mmol, 2.5 equiv) is added in one portion to a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in dry methanol (100 mL) under N2 at rt. After stirring overnight, the reaction mixture is concentrated in vacuo, redissolved in dichloromethane, washed with water, dried (Na2SO4) and concentrated to give 4.62 g of methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (65percent), which was used without further purification. 1H NMR (CDCl3) d 9.3 (br s, 1H), 6.96 (br m, 1H), 6.92 (br m, 1H), 6.29 (br q, 1H), 3.86 (s, 3H).
65%
at 20℃;
To a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in anh. MeOH (100 mL) under N2 at room temp. was added TMSCl (17.9 mL, 141 mmol, 2.5 equiv) in one portion. After stirring overnight, the reaction mixture was concentrated under reduced pressure, redissolved in CH2Cl2, washed with water, dried (Na2SO4) and concentrated to give methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (4.62 g, 65percent): 1H NMR (CDCl3) δ 3.86 (s, 3H), 6.29 (br q, 1H), 6.92 (br m, 1H), 6.96 (br m, 1H), 9.30 (br s, 1H). This material was used in the next step without further purification.
Reference：
[1] Canadian Journal of Chemistry, 2002, vol. 80, # 12, p. 1662 - 1667
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 22, p. 7091 - 7100
[3] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 20, p. 2997 - 3003
[4] Patent: EP1386913, 2004, A1, . Location in patent: Page 88
[5] Patent: EP986382, 2008, B1, . Location in patent: Page/Page column 23
[6] Patent: EP1019040, 2004, B1, . Location in patent: Page/Page column 31
[7] Journal of Natural Products, 2012, vol. 75, # 10, p. 1765 - 1776
[8] Patent: WO2006/23844, 2006, A2, . Location in patent: Page/Page column 92
3
[ 67-56-1 ]
[ 35302-72-8 ]
[ 1193-62-0 ]
Yield
Reaction Conditions
Operation in experiment
87%
Stage #2: at 20℃; for 2.5 h;
In dry methanol (40 mL), sodium (0.14 g, 6.20mmol) was dissolved and trichloroacetyl-1H-pyrrole (8) (9.440 g, 44.43 mmol) was added insmall quantities over 30 min. Then the reaction mixture was stirred for additional 2 hours atroom temperature, and then the solvent was removed and resulting crystals were dissolved indiethyl ether (50 mL). Ether solution was washed with HCl (4 mL, 3 N) and then NaHCO3(10 mL) solution. Then the organic phase was dried over Na2SO4. After the filtration andevaporation of the solvent, the crude product was purified via column chromatography (SiO2,ethyl acetate/hexane, 2:3) and concentrated in vacuum to obtain methyl 1H-pyrrole-2-carboxylate 9 (4.83 g, 87percent) which was crystallized from ethyl acetate/hexane as colorlesspellets
Reference：
[1] Green Chemistry, 2011, vol. 13, # 1, p. 102 - 108
[2] Beilstein Journal of Organic Chemistry, 2017, vol. 13, p. 825 - 834
[3] Chemical Communications, 1999, # 9, p. 843 - 844
[4] Chemistry - A European Journal, 2000, vol. 6, # 4, p. 709 - 718
[5] Tetrahedron Letters, 2005, vol. 46, # 12, p. 2041 - 2044
4
[ 35302-72-8 ]
[ 124-41-4 ]
[ 1193-62-0 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 23℃; for 0.666667 h; Inert atmosphere
To a freshly prepared solution of NaOCH3 from sodium (0.25 g, 10.9 mmol) and anhydrous CH3OH (20 mL) was added in batches 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-ethanone9 (4.70 g, 22.0 mmol) over a period of 10 min in an atmosphere of N2. After stirring for 30 min at 23 °C the solvent was removed under reduced pressure (11 mbar, 40 °C). The dark residue was partitioned between Et2O (50 mL) and 2 m aq. HCl (15 mL). The organic layer was separated and kept. The aqueous layer was extracted with Et2O (2 .x. 10 mL). Combined organic layer and extracts were washed with satd. aq. NaHCO3 (15 mL) and dried (MgSO4). The solvent was removed under reduced pressure (10 mbar, 40 °C) to afford a purple solid which was purified by column chromatography (Et2O). Yield: 2.56 g (20.0 mmol, 92 percent), colourless solid, mp 74-77 °C. IR (KBr) (cm-1) 3290, 3122, 2953, 1685, 1559, 1446, 1406, 1128. 1H NMR (CDCl3, 600MHz) d 3.86 (s, 3 H), 6.26-6.28 (m, 1 H), 6.91-6.93 (m, 1 H), 6.95-6.96 (m, 1 H), 9.22 (br.s, 1 H, NH). 13C NMR (CDCl3, 150MHz) d 51.6, 110.6, 115.4, 122.8, 123.0, 161.7. MS (EI) m/z 125 (66), 94 (100), 66 (36).
88%
at 0℃; for 3 h;
To a stirred solution of 11 (31.87 g, 0.150 mol) in methanol (50 mL) was added a solution of NaOMe solution in methanol (50 mL), prepared by dissolving of Na (3.46 g, 0.150 mol) in methanol, dropwise at 0 °C for 3 h. The solvent was evaporated and diluted HCl (50 mL) was added to residue. The mixture was extracted with ethyl acetate (3 × 150 mL) and dried over MgSO4. Evaporation of solvent gave the ester 12 as a brown solid (16.5 g, 88percent).
Reference：
[1] Tetrahedron, 2011, vol. 67, # 22, p. 4048 - 4054
[2] Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 897 - 905
[3] European Journal of Organic Chemistry, 1999, # 9, p. 2397 - 2403
[4] Journal of Organic Chemistry, 2005, vol. 70, # 20, p. 8231 - 8234
[5] Synthesis, 2004, # 14, p. 2367 - 2375
[6] Chinese Chemical Letters, 2013, vol. 24, # 7, p. 619 - 621
[7] Tetrahedron Letters, 2016, vol. 57, # 32, p. 3629 - 3634
5
[ 2133-40-6 ]
[ 1193-62-0 ]
Yield
Reaction Conditions
Operation in experiment
89%
With β-cyclodextrin; 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione In water at 20℃; for 4 h;
General procedure: To an aqueous solution of βcyclodextrin (1.0 mmol of β-CD in 5mL of water), IBX (2.0 mmol), N-benzylpyrrolidine (1.0 mmol) was added while stirring, and stirring was continued for the stipulated reaction time as shown in the table at room temperature. After completion of reaction as indicated by TLC, the reaction mixture was extracted with ethylacetate (3 X 5mL), the combined organic layers were washed with saturated brine solution, dried and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate (9:1) as an eluent.
With sodium In methanol for 12 h; Heating / reflux
Sodium metal (6.9 g, 0.30 mol) was dissolved in anhydrous methanol (1.5 L) and then 2-(trichloroacetyl)pyrrole (223 g, 1.5 mol) dissolved in anhydrous methanol (500 mL) was added. The mixture was heated at reflux for 12 hour. The methanol was removed under reduced pressure and the product crystallized by pouring the residue into a 3:1 ice-water/methanol mixture (2 L). The light brown solid was collected by vacuum filtration and dried to afford 97.2 g (0.78 mol, 74percent) of the title compound. 1H-NMR (CDCl3): ? 7.00 (m, 1H), 6.79 (d, 1H), 6.15 (dd, 1H), 3.74 (s, 1H).
Reference：
[1] European Journal of Organic Chemistry, 2008, # 2, p. 324 - 329
[2] Patent: US6696575, 2004, B2, . Location in patent: Page column 3;4;17;18;11
[3] Patent: US2012/114696, 2012, A1,
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 8, p. 1833 - 1836
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 8, p. 1833 - 1836
41
[ 186581-53-3 ]
[ 18276-53-4 ]
[ 124-38-9 ]
[ 1193-62-0 ]
[ 2703-17-5 ]
[ 4277-63-8 ]
[ 1757-29-5 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 8, p. 1833 - 1836
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1982, # 8, p. 1833 - 1836
42
[ 1193-62-0 ]
[ 74-88-4 ]
[ 37619-24-2 ]
Yield
Reaction Conditions
Operation in experiment
89%
Stage #1: With sodium hydride In tetrahydrofuran at 0 - 20℃; for 0.5 h; Stage #2: at 20℃; for 17 h;
To a mixture of methyl- lH-pyrrole-2-carboxylate (10 g, 79.9 mmol) in anhydrous THF (200 mL) was added NaH (3.52 g, 60percent w.t., 87.9 mmol) at 0°C. The resulting mixture was stirred at 20°C for 30 min, then CH3I (13.62 g, 95.9 mmol) was added. The reaction mixture was stirred at 20°C for 17 hrs. The mixture was then poured into an aqueous solution of NH4CI (200 mL). The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (150 mL), dried (Na2S04), filtered, and concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc/PE = 1/20) to afford methyl 1 -methyl- lH-pyrrole-2- carboxylate (9.88 g, 71 mmol, 89 percent) as a yellow oil. MS (EI+, m/z): 140.1 [M+H]+.
Reference：
[1] Organic Letters, 2015, vol. 17, # 11, p. 2652 - 2655
[2] Patent: WO2018/89493, 2018, A1, . Location in patent: Paragraph 00214
[3] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 11, p. 3219 - 3223
43
[ 1193-62-0 ]
[ 616-38-6 ]
[ 37619-24-2 ]
Reference：
[1] Organic Process Research and Development, 2009, vol. 13, # 6, p. 1199 - 1201
44
[ 1193-62-0 ]
[ 37619-24-2 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 4458,4462
45
[ 1193-62-0 ]
[ 43041-12-9 ]
Reference：
[1] Canadian Journal of Chemistry, 2002, vol. 80, # 12, p. 1662 - 1667
46
[ 1193-62-0 ]
[ 934-05-4 ]
[ 934-07-6 ]
Reference：
[1] Green Chemistry, 2011, vol. 13, # 1, p. 102 - 108
[2] Journal of Organic Chemistry, 2018, vol. 83, # 16, p. 9250 - 9255
[3] Tetrahedron, 2011, vol. 67, # 22, p. 4048 - 4054
[4] Bioorganic Chemistry, 2012, vol. 44, p. 25 - 34
47
[ 1193-62-0 ]
[ 934-05-4 ]
[ 934-07-6 ]
[ 937-16-6 ]
Reference：
[1] Dalton Transactions, 2013, vol. 42, # 33, p. 11926 - 11940
[2] Green Chemistry, 2011, vol. 13, # 1, p. 102 - 108
[3] Tetrahedron, 2011, vol. 67, # 22, p. 4048 - 4054
48
[ 1193-62-0 ]
[ 934-05-4 ]
Reference：
[1] Tetrahedron, 2011, vol. 67, # 22, p. 4048 - 4054
[2] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 205 - 222
With N-Bromosuccinimide In tetrahydrofuran; methanol at 0℃; for 3.5 h;
Synthesis of methyl 5 -bromo- 1H-pyrrole-2-carboxylate (53): Methyl 1H-pyrrole-2-carboxylate (52; lOg, 80 mmol) was dissolved in 800 mL of THF and 400 mL of MeOH. The mixture was cooled to 0 °C. NBS (15 g, 8 4 mmol) was added in 5 portions in 1.5 h. After the addition, the mixture was stirred at 0 °C for 2 h. The reaction mixture was concentrated and purified by silica gel chromatography (2percent EtOAc/petroleum ether) to give 4.3 g of methyl 5-bromo-1H-pyrrole-2-carboxylate 53 as white solid (26percent yield). LCMS:m/z 206.0 [M+H], , tR= 1.50 min
27%
With bromine; iodine In tetrachloromethane; water
A solution of pyrrole-2-carboxylic acid methyl ester (79.9 mmol, 10.0 g) in carbon tetrachloride (300 ml) was heated to 70° C., then treated dropwise with a solution of bromine (99.9 mmol, 126.0 ml) in carbon tetrachloride (200 ml). The reaction was initiated by the addition of iodine (40 mg). After the addition was complete, the reaction was held at 70° C. for 10 min, then cooled to room temperature using an ice bath. The mixture was washed with 10percent aqueous sodium carbonate (100 ml), followed by water (100 ml). The organics were concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 4.5 g (27percent) of 5-bromo-1H-pyrrole-2-carboxylic acid methyl ester. 1H NMR (CDCl3) δ9.29 (1H, s), 6.80 (1H, dd, J=3.9, 2.7), 6.23 (1H, dd, J=3.8, 2.6), 3.88 (3H, s).
Reference：
[1] Journal of the American Chemical Society, 2006, vol. 128, # 18, p. 6054 - 6055
[2] Chemistry - A European Journal, 2009, vol. 15, # 28, p. 6910 - 6919
[3] Organic and Biomolecular Chemistry, 2013, vol. 11, # 16, p. 2574 - 2577
[4] Patent: WO2017/31213, 2017, A1, . Location in patent: Paragraph 00361
[5] Patent: US2002/6943, 2002, A1,
51
[ 1193-62-0 ]
[ 934-05-4 ]
[ 934-07-6 ]
Reference：
[1] Green Chemistry, 2011, vol. 13, # 1, p. 102 - 108
[2] Journal of Organic Chemistry, 2018, vol. 83, # 16, p. 9250 - 9255
[3] Tetrahedron, 2011, vol. 67, # 22, p. 4048 - 4054
[4] Bioorganic Chemistry, 2012, vol. 44, p. 25 - 34
52
[ 1193-62-0 ]
[ 934-05-4 ]
[ 934-07-6 ]
[ 937-16-6 ]
Reference：
[1] Dalton Transactions, 2013, vol. 42, # 33, p. 11926 - 11940
[2] Green Chemistry, 2011, vol. 13, # 1, p. 102 - 108
[3] Tetrahedron, 2011, vol. 67, # 22, p. 4048 - 4054
53
[ 1193-62-0 ]
[ 68-12-2 ]
[ 1197-13-3 ]
Yield
Reaction Conditions
Operation in experiment
66%
With trichlorophosphate In 1,2-dichloro-ethane at 0 - 20℃; for 0.25 h; Heating / reflux
Anhydrous DMF (7.0 mL, 90.4 mmol) was cooled to 5-10 degrees Centigrade under nitrogen. POCl3 (7.8 mL, 83.7 mmol) was added dropwise to the cooled DMF over a couple of minutes. Dry 1,2-dichloroethane (25 mL) was then added and the solution was cooled to 0-5 degrees Centigrade during the addition of 2 (9.46 g, 75.6 mmol) in dry 1,2-dichloroethane (25 mL). The mixture was then heated to reflux for 15 minutes. The reaction was cooled to room temperature, treated with a mixture of ethyl acetate (60 mL) and water (75 mL), poured into saturated NaHCO3 (350 mL), and separated. The aqueous layer was washed three times with ether, and the combined organic extracts were washed twice with aqueous saturated Na2CO3, dried over Na2SO4, and evaporated under vacuum. The resulting solid was sublimed under reduced pressure (20?10?3 torr) at 60 degrees Centigrade in 3-hour intervals to yield compound 3 (7.79 g, 50.1 mmol, 66percent). 1H-NMR (CDCl3): ? 10.57 (br s, 1H), 9.70 (s, 1H), 6.95 (m, 2H), 3.94 (s, 3H).
63%
With trichlorophosphate In dichloromethane; N,N-dimethyl-formamide at 0℃; for 4 h; Inert atmosphere; Reflux
Phosphorylchloride (4.39 mmol, 0.4 mL) was added dropwise to 0.34 mLDMF at 0 C. The reaction was allowed to reach room temperatureand 2.2 mL of dry CH2Cl2 were subsequently added. The mixturewas cooled again to 0 C and a solution of 6 (500 mg, 4 mmol)was added dropwise within 1 h. The reaction mixture was thenrefluxed for 4 h, cooled to 0 C and hydrolysed with a solution ofsodium acetate (1.8 g, 22 mmol) in water (5.5 mL). The phaseswere separated and the aqueous phase was extracted with ethylacetate. The combined organic extracts were dried with Na2SO4and concentrated. The residue was purified by flash chromatography(eluent; hexane/ethyl acetate = 5/1) to afford 387 mg of compound7 (yield = 63percent). Characterization was in agreement withliterature data.17 1H NMR (500 MHz, DMSO-d6) d 13.07 (s, 1H),9.70 (s, 1H), 6.97 (d, J = 3.9 Hz, 1H), 6.90 (d, J = 3.9 Hz, 1H), 3.83(s, 3H).
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 20, p. 2997 - 3003
[2] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9350 - 9359
[3] Patent: US6696575, 2004, B2, . Location in patent: Page column 3;4;17;18;11-12
[4] Chemical Communications, 1999, # 9, p. 843 - 844
[5] European Journal of Organic Chemistry, 1999, # 9, p. 2397 - 2403
[6] Chemistry - A European Journal, 2000, vol. 6, # 4, p. 709 - 718
[7] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 5, p. 1622 - 1629
[8] Patent: US2012/184521, 2012, A1, . Location in patent: Page/Page column 27
[9] Tetrahedron Letters, 2016, vol. 57, # 32, p. 3629 - 3634
54
[ 1193-62-0 ]
[ 68-12-2 ]
[ 40611-79-8 ]
[ 1197-13-3 ]
Yield
Reaction Conditions
Operation in experiment
48.18%
at 0 - 20℃;
To the stirred solution of methyl 1H-pyrrole-2-carboxylate (0.9 g, 7.19 mmol) in DMF (4.2 g, 57.52 mmol) at 0 00, POOl3 (5.5 g, 35.96 mmol) was added. The reaction mixture was stirred at 10 00 for 30 mm at room temperature over night. The reaction mixture was quenched with sodium hydroxide solution and extracted using ethyl acetate dried over anhydrous Na2SO4. The crude mixture of products was purified by column chromatography to yield the title compound polar spot (0.53 g, 48.18percent) as a pale yellow solid. LCMS: (M-H) = 152.1; 1H NMR: (DMSO-d6, 300MHz) 6 12.73 (5, 1H), 7.76 (5, 1H), 7.82-7.83 (d, 1H), 7.14 (5, 2H), 3.81 (5, 3H). Intermediate 12a: Methyl 5-formyl-1H-pyrrole-2-carboxylate was formed along with11 a. Upon separation of 11 a and 1 2a, intermediate 1 2a obtained (0.5 g, 45.45percent) asa pale yellow solid. LOMS: (M-H) = 152.1
Reference：
[1] Tetrahedron, 1992, vol. 48, # 8, p. 1457 - 1464
[2] Tetrahedron, 2001, vol. 57, # 15, p. 3063 - 3067
[3] European Journal of Organic Chemistry, 2008, # 2, p. 324 - 329
[4] Patent: WO2014/202580, 2014, A1, . Location in patent: Page/Page column 84; 85
[5] Tetrahedron Letters, 2006, vol. 47, # 27, p. 4631 - 4634
[6] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 11, p. 2935 - 2937
[7] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 19, p. 5763 - 5773
Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; Inert atmosphere Stage #2: With O-(2,4-dinitrophenyl)hydroxylamine In N,N-dimethyl-formamide; mineral oil at 0℃;
(Step 1) methy 1-amino-1H-pyrrolo-2-carboxylate; To a mixture of NaH (60percent, 4.1 g, 102.2 mmol) suspended in dimethylformamide (120 mL) at 0° C. under nitrogen atmosphere, methyl pyrrolo-1-H-2-carboxylate (8.0 g, 63.9 mmol) was slowly added over minutes. After stirring for 1 hour, a solution of 2,4-dinitrophenolamine (19.1 g, 95.9 mmol) in dimethylformamide (30 mL) was added dropwise for 30 minutes. The resulting reaction mixture was stirred at 0° C. for 2.5 hours. The reaction was completed by slowly adding saturated sodium thiosulfate aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with 10percent lithium chloride aqueous solution, dried with sodium sulfate, and then filtered. The filtrate was concentrated. The resulting brown residue was purified by silica gel chromatography (10percent ethyl acetate in hexane) to give the target compound as an oil (7.5 g, 53.5 mmol, 84percent yield).1H NMR (400 MHz, CDCl3): 6.96 (t, J=2.4 Hz, 1H), 6.83 (dd, J=4.4 Hz, 2.0 Hz, 1H), 6.02 (dd, J=4.4 Hz, 2.8 Hz, 1H) 5.54 (br s, 2H), 3.83 (s, 3H).
81.1%
Stage #1: With sodium hydride In hexanes; N,N-dimethyl-formamide at -5℃; Inert atmosphere Stage #2: With diphenyl aminooxyphosphonate In hexanes; N,N-dimethyl-formamide at 20℃; for 4 h; Stage #3: With sodium thiosulfate In hexanes; water; N,N-dimethyl-formamide at 80℃; for 1 h;
a) Methyl 1 -amino-1 W-pyrrole-2-carboxylateSodium hydride (4.40 g, 0.1 1 mol, 60percent in hexanes) was suspended in DMF (550 ml) under nitrogen atmosphere. Once cooled at - 5°C, methyl 1 H-pyrrole-2-carboxylate (1 1 .0 g, 0.09 mol) dissolved in DMF (182 ml) was dropwise added and vigorously stirred for 30. 277ml more of DMF was added and then O- (diphenylphosphoryl)hydroxylamine (32.8g, 0.14 mol) was introduced into the reaction mixture. The reaction mixture was stirred at room temperature for 4h. Once the reaction is over, 11 of saturated sodium thiosulfate solution (x5H20) was added and the mixture was warmed to 80°C for 1 h. Once at room temperature, 11 of ethyl ether was added and the phases separated. The aqueous phase was twice extracted with ethyl ether. The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 10.41 g (81 .1 percent yield) of the final compound were obtained.LRMS (m/z): 141 (M+1 )+
With hydrogen bromide; dimethyl sulfoxide; at 50℃; for 2h;
General procedure: In a round-bottomed flask, the substrate (1 mmol) and aqueous HBr(48%) (1 mL) were mixed in DMSO (1 mL). The mixture was stirredat corresponding temperature for 1-4 h. After cooling to roomtemperature, the reaction was adjusted to pH 7-8 with aqueous NaOHsolution (4 M). Then the mixture was washed twice with EtOAc, andthe combined organic extracts were dried, filtered and concentratedunder reduced pressure to give bromination products.
With Ascophyllum nodosum vanadate(V)-dependent bromoperoxidase I; dihydrogen peroxide; sodium bromide; In water; tert-butyl alcohol; at 23℃; for 24h;pH 6.2;aq. buffer; Enzymatic reaction;
A solution of H2O2 (2.0 mL, 0.825 M) and NaBr (169.8 mg, 1.65 mmol) in MES-buffer (500 mM, pH 6.2) was added with a syringe pump (20 h, 1.67 muL/min) to a solution of substrate 1a (0.75 mmol) and VBrPO(AnI) (125.6 muL, 34.6 UT, 0.063 mmol%) in MES-buffer (500 mM, pH 6.2, 10.0 ml) and tBuOH (3.3 mL). The reaction mixture was stirred at 23 C for 1 day. The aqueous layer was extracted with Et2O (3×20 mL). Combined organic extracts were dried (MgSO4). The solvent was removed under reduced pressure (14 mbar, 40 C) to afford a product mixture, which was analyzed by 1H NMR and GC, using pentachlorobenzene (1H NMR) as an internal standard in comparison to spectral data from authentic references. For spectral data see Section 4.2.1. 611 U0T, 279 inlMMLBox, pHfinal 6.9.
With aluminum (III) chloride In dichloromethane at 0℃;
With aluminum (III) chloride; nitromethane In DCE
In CH2Cl2:CH3NO2
6 Synthesis of E6
Methyl 4-formyl-1H-pyrrole-2-carboxylate (3). To a solution of 2 (4.50 g, 36.0 mmol) in CH2Cl2:CH3NO2 (1:1, 40 mL) at -40° C., was added AlCl3 (12.48 g, 93.6 mmol) followed by α,α-dichloromethyl methyl ether (4.15 mL, 46.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was slowly poured onto ice (10.00 g) and allowed to warm to room temperature. The aqueous phase was extracted with CH2Cl2 (3*50 mL). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 3 as a dark brown solid (3.40 g, 62%). 1H NMR (400 MHz, CDCl3) δ 10.32 (bs, 1H), 9.83 (s, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.30 (s, 1H), and 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.07, 161.71, 129.15, 127.71, 124.99, 114.56, and 52.34.
In CH2Cl2:CH3NO2
8 Synthesis of E6b
Methyl 4-formyl-1H-pyrrole-2-carboxylate (3). To a solution of 2 (4.50 g, 36.0 mmol) in CH2Cl2:CH3NO2 (1:1, 40 mL) at -40° C., was added AlCl3 (12.48 g, 93.6 mmol) followed by ∝,∝-dichloromethyl methyl ether (4.15 mL, 46.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was slowly poured onto ice (10.00 g) and allowed to warm to room temperature. The aqueous phase was extracted with CH2Cl2 (3*50 mL). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 3 as a dark brown solid (3.40 g, 62%). 1H NMR (CDCl3) δ 10.32 (bs, 1H), 9.83 (s, 1H), 7.59 (d, J=1.6 Hz, 1H), 7.30 (s, 1H), and 3.88 (s, 3H); 13C NMR (CDCl3) δ 186.07, 161.71, 129.15, 127.71, 124.99, 114.56, and 52.34.
11a Intermediate 11a: Methyl 4-formyl-1 H-pyrrole-2-carboxylate
To the stirred solution of methyl 1H-pyrrole-2-carboxylate (0.9 g, 7.19 mmol) in DMF(4.2 g, 57.52 mmol) at 000, POOl3 (5.5 g, 35.96 mmol) was added. The reaction mixture was stirred at 10 00 for 30 mm and at room temperature over night. The reaction mixture was quenched with sodium hydroxide solution and extracted usingethyl acetate dried over anhydrous Na2SO4. The crude product was purified by column chromatography to yield the title compound polar spot (0.53 g, 48.18%) as a pale yellow solid. LCMS: (M-H) = 152.1; 1H NMR: (DMSO-d6, 300MHz) 6 12.73 (5, 1H), 7.76 (5, 1H), 7.82-7.83 (d, 1H), 7.14 (5, 2H), 3.81 (5, 3H).
With trichlorophosphate Multistep reaction;
With trichlorophosphate at 20℃; for 16h; Inert atmosphere;
To the stirred solution of methyl 1H-pyrrole-2-carboxylate (0.9 g, 7.19 mmol) in DMF (4.2 g, 57.52 mmol) at 0 00, POOl3 (5.5 g, 35.96 mmol) was added. The reaction mixture was stirred at 10 00 for 30 mm at room temperature over night. The reaction mixture was quenched with sodium hydroxide solution and extracted using ethyl acetate dried over anhydrous Na2SO4. The crude mixture of products was purified by column chromatography to yield the title compound polar spot (0.53 g, 48.18%) as a pale yellow solid. LCMS: (M-H) = 152.1; 1H NMR: (DMSO-d6, 300MHz) 6 12.73 (5, 1H), 7.76 (5, 1H), 7.82-7.83 (d, 1H), 7.14 (5, 2H), 3.81 (5, 3H). Intermediate 12a: Methyl 5-formyl-1H-pyrrole-2-carboxylate was formed along with11 a. Upon separation of 11 a and 1 2a, intermediate 1 2a obtained (0.5 g, 45.45%) asa pale yellow solid. LOMS: (M-H) = 152.1
Example 36-2 Preparation for methyl 1-allyl-1H-pyrrole-2-caboxylate To a solution of methyl 1H-pyrrole-2-caboxylate (4.48g, 35.8mmol) in tetrahydrofuran (100ml) were added potassium t-butoxide (4.2g, 37.4mmol) and dimethylformamide (20ml), and the mixture was stirred for 10 minutes at room temperature.. To the mixture was added allyl bromide (5.4g, 44.6mmol), and the mixture was stirred for 4 hours at room temperature.. Thereto was added an aqueous 5% potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate.. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate.. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=5:13:1) to give the subject compound (5.46g, 92%).1H NMR (CDCl3, 400 MHz) delta 6.97 (dd, 1 H, J = 3.9, 1.8 Hz), 6.86 (dd, 1 H, J = 2.6, 1.8 Hz), 6.16 (dd, 1 H, J = 3.9, 2.6 Hz), 5.96 - 6.06 (m, 1 H), 5.12 - 5.17 (m, 1 H), 4.94-5.01 (m, 3 H), 3.80 (s, 3 H).
Phosphoryl chloride (4.93 mL, 53.0 mmol) was added dropwise to a stirred solution of dry DMF (4.07 mL, 53.0 mmol) cooled to 15 oC under a nitrogen atmosphere over 15 min. DCE (12 mL) and a solution of Methly 2-pyrrolecarboxylate (6.00 g, 48.0 mmol) in DCE (12 mL) were added sequentially to the solution over 1 h. The resulting solution was heated at reflux for 15 min, cooled to ambient temperature, treated with a solution of sodium acetate tetrahydrate (35.9 g, 264 mmol) in water (70 mL) and heated at reflux for an additional 15 min. The mixture was extracted with CH2Cl2 (3x 30 mL), the combined organics were washed with sat. aq. NaHCO3 (3x 30 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography on silica (2% MeOH / CH2Cl2) to afford methyl 5-formyl-1H-pyrrole-2-carboxylate as a yellow solid (5.00 g, 68%). Rf = 0.37 (2% MeOH / CH2Cl2). Experimental data as per literature. ADDIN EN.CITE Ranganath2016171117117125Ranganath, M. J. R.Madhavan, G. R.Shanmugam, P.Spiro-Substituted Oxindole Derivatives Having AMPK ActivityUnited States Patent ApplicationUnited States Patent Application2016United States1 1H NMR (500 MHz, CDCl3) delta 3.93 (s, 3H), 6.95 (s, 1H), 6.95 (s, 1H), 9.68 (s, 1H), 9.80 (br s, 1H). 13C NMR (125 MHz, CDCl3) delta 52.2, 114.3, 124.9, 127.8, 128.5, 161.4, 185.8.
66%
With trichlorophosphate; In 1,2-dichloro-ethane; at 0 - 20℃; for 0.25h;Heating / reflux;
Anhydrous DMF (7.0 mL, 90.4 mmol) was cooled to 5-10 degrees Centigrade under nitrogen. POCl3 (7.8 mL, 83.7 mmol) was added dropwise to the cooled DMF over a couple of minutes. Dry 1,2-dichloroethane (25 mL) was then added and the solution was cooled to 0-5 degrees Centigrade during the addition of 2 (9.46 g, 75.6 mmol) in dry 1,2-dichloroethane (25 mL). The mixture was then heated to reflux for 15 minutes. The reaction was cooled to room temperature, treated with a mixture of ethyl acetate (60 mL) and water (75 mL), poured into saturated NaHCO3 (350 mL), and separated. The aqueous layer was washed three times with ether, and the combined organic extracts were washed twice with aqueous saturated Na2CO3, dried over Na2SO4, and evaporated under vacuum. The resulting solid was sublimed under reduced pressure (20?10?3 torr) at 60 degrees Centigrade in 3-hour intervals to yield compound 3 (7.79 g, 50.1 mmol, 66%). 1H-NMR (CDCl3): ? 10.57 (br s, 1H), 9.70 (s, 1H), 6.95 (m, 2H), 3.94 (s, 3H).
63%
With trichlorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 0℃; for 4h;Inert atmosphere; Reflux;
Phosphorylchloride (4.39 mmol, 0.4 mL) was added dropwise to 0.34 mLDMF at 0 C. The reaction was allowed to reach room temperatureand 2.2 mL of dry CH2Cl2 were subsequently added. The mixturewas cooled again to 0 C and a solution of 6 (500 mg, 4 mmol)was added dropwise within 1 h. The reaction mixture was thenrefluxed for 4 h, cooled to 0 C and hydrolysed with a solution ofsodium acetate (1.8 g, 22 mmol) in water (5.5 mL). The phaseswere separated and the aqueous phase was extracted with ethylacetate. The combined organic extracts were dried with Na2SO4and concentrated. The residue was purified by flash chromatography(eluent; hexane/ethyl acetate = 5/1) to afford 387 mg of compound7 (yield = 63%). Characterization was in agreement withliterature data.17 1H NMR (500 MHz, DMSO-d6) d 13.07 (s, 1H),9.70 (s, 1H), 6.97 (d, J = 3.9 Hz, 1H), 6.90 (d, J = 3.9 Hz, 1H), 3.83(s, 3H).
Preparation Example 51; Under ice-cooling, to DMF (31 mL) was slowly added dropwise phosphorous oxychloride (4.47 mL), followed by stirring at the same temperature for about 15 minutes. To the reaction mixture was added methyl 1H-pyrrole-2-carboxylate (5.0 g), followed by slowly warming to 60 C. and stirring for about 5 hours. The reaction mixture was neutralized by the addition of a 8 M aqueous sodium hydroxide solution under ice-cooling, followed by extraction with ethyl acetate several times. The organic layer was washed with brine and dried over MgSO4, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to prepare methyl 5-formyl-1H-pyrrole-2-carboxylate (2.53 g).Subsequently, methyl 5-[(3-phenylpropyl)amino]methyl}-1H-pyrrole-2-carboxylate (1.28 g) was prepared from methyl 5-formyl-1H-pyrrole-2-carboxylate (1.0 g) in the same manner as the method of Preparation Example 52.
To a solution of pyrrole-2-carboxylic acid (1) (16.65 g, 0.15 mol)in 10 mL of MeOH was added 50 mL of SOCl2 dropwise within30 min at 0 C. Subsequently, the reaction mixture was stirred at35 C for 24 h. Then, the solvent was evaporated in vacuo, andthe residue was purified by column chromatography using ethylacetate/petroleum ether as eluent, giving intermediate 2 as a whitesolid, yield 85%, mp: 72-73 C.
79%
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20 - 60℃; for 72h;
Example 36-1 Preparation for methyl 1H-pyrrole-2-carboxlate A suspension of 1H-pyrrole-2-carboxylic acid (5.5g, 49.5mmol), WSCI·HCl (12.2g, 63.6mmol), HOBt (8.4g, 62.2mmol), methanol (7.0g, 218mmol) and 4-dimethylaminopyridine (3.0g, 24.5mmol) in dimethylformamide (60ml) was stirred for 70 hours at room temperature and for 2 hours at 60C. To the reaction mixture was added an aqueous 5% potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate/toluene (1/1).. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution, and an aqueous saturated sodium chloride solution, and dried over magnesium sulfate.. The solvent was removed and the residue was purified with silica gel chromatography (hexane:ethyl acetate=5:13:1) to give the subject compound (4.88g, 79%).1H NMR (CDCl3, 400 MHz) delta 9. 08 (brs, 1 H), 6. 90 - 6. 98 (m, 2 H), 6.25 - 6.29 (m, 1 H), 3.86 (s, 3 H).
65%
With chloro-trimethyl-silane; In methanol; at 20℃;
Method I Synthesis of 5-tert-Butyl-3-(3-p-tolyl-ureido)-1H-pyrrole-2-carboxylic acid methyl ester. (Example 24) [Show Image] Step 1; Chlorotrimethylsilane (17.9 mL, 141 mmol, 2.5 equiv) is added in one portion to a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in dry methanol (100 mL) under N2 at rt. After stirring overnight, the reaction mixture is concentrated in vacuo, redissolved in dichloromethane, washed with water, dried (Na2SO4) and concentrated to give 4.62 g of methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (65%), which was used without further purification. 1H NMR (CDCl3) d 9.3 (br s, 1H), 6.96 (br m, 1H), 6.92 (br m, 1H), 6.29 (br q, 1H), 3.86 (s, 3H).
65%
With chloro-trimethyl-silane; at 20℃;
To a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in anh. MeOH (100 mL) under N2 at room temp. was added TMSCl (17.9 mL, 141 mmol, 2.5 equiv) in one portion. After stirring overnight, the reaction mixture was concentrated under reduced pressure, redissolved in CH2Cl2, washed with water, dried (Na2SO4) and concentrated to give methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (4.62 g, 65%): 1H NMR (CDCl3) delta 3.86 (s, 3H), 6.29 (br q, 1H), 6.92 (br m, 1H), 6.96 (br m, 1H), 9.30 (br s, 1H). This material was used in the next step without further purification.
With hydrogenchloride;
General scheme for synthesis of pyrroles.; Commercially available 2-carboxypyrrole was esterified under acidic conditions to yield a methyl ester. The pyrrole was alkylated using potassium carbonate, followed by ester hydrolysis to give the acid. The acid was converted to an amide using oxalyl chloride and the appropriate amine.; Synthesis of ENMD-1537: N-(6-aminohexyl)-l-(2-methylpropyl)-2-pyrrolecarboxamide.; Target was prepared by converting 2-carboxyacid pyrrole to the methyl ester, and alkylating the N with isobutyl bromide. The ester was hydrolyzed and the resulting acid was converted to an amide using oxalyl chloride and N-Boc-l,6-diaminohexane. Boc deprotection yielded the target.
Sodium metal (2g, 84.7mmol) was dissolved in anhydrous methanol (50mL), added 1 (6g, 28.2mmol), r.t reaction 2h,Evaporate the solvent, add 30ml of EtOAc, and wash with saturated aqueous NaCl solution.The organic phase was dried over anhydrous Na2SO4 and the solvent was evaporated to give 2a. The yield was 89%.
87%
In dry methanol (40 mL), sodium (0.14 g, 6.20mmol) was dissolved and trichloroacetyl-1H-pyrrole (8) (9.440 g, 44.43 mmol) was added insmall quantities over 30 min. Then the reaction mixture was stirred for additional 2 hours atroom temperature, and then the solvent was removed and resulting crystals were dissolved indiethyl ether (50 mL). Ether solution was washed with HCl (4 mL, 3 N) and then NaHCO3(10 mL) solution. Then the organic phase was dried over Na2SO4. After the filtration andevaporation of the solvent, the crude product was purified via column chromatography (SiO2,ethyl acetate/hexane, 2:3) and concentrated in vacuum to obtain methyl 1H-pyrrole-2-carboxylate 9 (4.83 g, 87%) which was crystallized from ethyl acetate/hexane as colorlesspellets
Sodium(0.223 g, 9.7 mmol) was dissolved in dry MeOH(64 mL) at room temperature. To the resulting solution,(2-trichloroacetyl)-1H-pyrrole (14.700 g, 69.2 mmol)was added in six portions under stirring for 30 min.The reaction mixture was stirred for 2 h at room temperature(control by TLC). The solvent was evaporated,and the residue was diluted with Et2O (80 mL). To the solution, 3 M HCl (5 mL) was added, theorganic phase was separated, and the aqueous phasewas extracted with Et2O (3 × 15 mL). The combinedorganic phase was successively washed with a saturatedaqueous NaHCO3 solution and a saturatedaqueous NaCl solution and dried over Na2SO4. Thedrying agent was filtered off, and the solvent was evaporatedunder low pressure. At the next stage, the productwas used without additional purification. Ether (5)was obtained as white crystals. Yield 8.215 g (95%); Rf0.31 (PE-EtOAc 5 : 1); mp 73.0C. The spectral characteristicscoincided with those reported in the literature[6]. 1H NMR (CDCl3): 3.86 (s, 3H), 6.26-6.28(m, 1H), 6.91-6.93 (m, 1H), 6.95-6.97 (m, 1H), 9.27(m, 1 H).
92%
With methanol; at 23℃; for 0.666667h;Inert atmosphere;
To a freshly prepared solution of NaOCH3 from sodium (0.25 g, 10.9 mmol) and anhydrous CH3OH (20 mL) was added in batches 2,2,2-trichloro-1-(1H-pyrrol-2-yl)-ethanone9 (4.70 g, 22.0 mmol) over a period of 10 min in an atmosphere of N2. After stirring for 30 min at 23 C the solvent was removed under reduced pressure (11 mbar, 40 C). The dark residue was partitioned between Et2O (50 mL) and 2 m aq. HCl (15 mL). The organic layer was separated and kept. The aqueous layer was extracted with Et2O (2 × 10 mL). Combined organic layer and extracts were washed with satd. aq. NaHCO3 (15 mL) and dried (MgSO4). The solvent was removed under reduced pressure (10 mbar, 40 C) to afford a purple solid which was purified by column chromatography (Et2O). Yield: 2.56 g (20.0 mmol, 92 %), colourless solid, mp 74-77 C. IR (KBr) (cm-1) 3290, 3122, 2953, 1685, 1559, 1446, 1406, 1128. 1H NMR (CDCl3, 600 MHz) d 3.86 (s, 3 H), 6.26-6.28 (m, 1 H), 6.91-6.93 (m, 1 H), 6.95-6.96 (m, 1 H), 9.22 (br.s, 1 H, NH). 13C NMR (CDCl3, 150 MHz) d 51.6, 110.6, 115.4, 122.8, 123.0, 161.7. MS (EI) m/z 125 (66), 94 (100), 66 (36).
88%
In methanol; at 0℃; for 3h;
To a stirred solution of 11 (31.87 g, 0.150 mol) in methanol (50 mL) was added a solution of NaOMe solution in methanol (50 mL), prepared by dissolving of Na (3.46 g, 0.150 mol) in methanol, dropwise at 0 C for 3 h. The solvent was evaporated and diluted HCl (50 mL) was added to residue. The mixture was extracted with ethyl acetate (3 × 150 mL) and dried over MgSO4. Evaporation of solvent gave the ester 12 as a brown solid (16.5 g, 88%).
With potassium hydroxide In methanol; water at 20℃; for 6h; Inert atmosphere; Schlenk technique;
With potassium hydroxide In methanol at 50℃;
With potassium hydroxide In methanol; water at 20℃; for 6h;
1
An aqueous KOH solution (2.24 g, 40 mmol) was added to a solution of lH-pyrrole-2-carboxylic acid methyl ester (1.25 g, 10 mmol) in MeOH.The mixture was stirred at room temperature for 6 hours. After completion of the reaction, the system was neutralized with 0.5 M HCl to pH = 8 and then extracted with ether (200 mL * 3).The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated to give methyl-lH-pyrrole-2-carboxylic acid.Methyl-1H-pyrrole-2-carboxylic acid was dissolved in SOCl2 (20 mL) and the mixture was refluxed for 3 hours.The solvent was then removed in vacuo to give a solid yellow product.Pyrazole (0.68 g, 10 mmol), yellow solid and Et3N (1.5 g) were stirred at 0 C for 2 h in Et2O.The mixture was then concentrated in vacuo and the residue was purified by silica gel column chromatography.Eluting with n-hexane / ethyl acetate (6: 1) to give L as a pale yellow solid (1.29 g, total yield 81%)
With potassium hydroxide In methanol; water at 20℃; for 7h;
1 Example 1:Synthesis of Ligand L
At room temperature,Methyl 1H-pyrrole-2-carboxylate (1.25 g, 10 mmol) in MeOHAqueous KOH (2.24 g, 40 mmol) was added to the solution and stirred for 7 h.After the reaction is completed, add 0.5M HCl to the solution pH=8 and extract it.After filtration and concentration in vacuo, 1H-pyrrole-2-carboxylic acid was obtained.Dissolve 1H-pyrrole-2-carboxylic acid in SOCl 2 (20 mL) and reflux for 2 h.The solvent was removed in vacuo to give 1H-pyrrole-2-acid chloride.Pyrazole (0.68 g, 10 mmol), 1H-pyrrole-2-acid chloride, at 0°C,Et3N (1.5 g) was stirred in Et20 for 2 h. The resulting mixture is concentrated,Column chromatography on silica gel (hexane:Ethyl acetate 6:1) gave pale yellow solid ligand L (1.35 g, overall yield 85%).
methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4'-di-tert-butyl-2,2'-bipyridine; In tetrahydrofuran; for 2h;Reflux; Inert atmosphere;
To a solution of B2Pin2 (6.82 g, 26.9 mmol) , dtbpy (2.12 g, 7.90 mmol) and [Ir(cod)(ome)j2 (882 mg, 1.33 mmol) in THF (60 mL) was added methyl 1H-pyrrole-2-carboxylate (2.88 g, 23.0 mmol) at room temperature under N2. The resulting solution was refluxed for 2 h. Then the reaction was cooled to rt, poured into H20 (50 mL), and extracted with EtOAc (150 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 0-5% EtOAc in hexane to afford the title compound (3.74 g, 14.9 mmol, 65% yield) as awhite solid. LC-MS [M+Hfb = 252.
methyl 1-[2-(4-hydroxyphenyl)-2-oxoethyl]pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
Step 1: To a chilled solution of methyl 1 H-pyrrole-2-carboxylate (1.0 g, 8.0 mmol) in dry DMF (20 ml.) was added sodium hydride (60% in mineral oil, 320 mg, 8.0 mmol)portionwise. The mixture was stirred at 0 C for 1 hour before a solution of 2-bromo-1-(4- hydroxyphenyl)ethanone (780 mg, 3.6 mmol) in DMF (5 ml.) was added. The resulting yellow solution was allowed to warm to room temperature. After 2.5 hours the reaction was complete (monitored by LCMS). A saturated aqueous solution of NH4CI (40 ml.) was added and the mixture was extracted with EtOAc (1 x 20 ml_). The organic layer was concentrated in vacuo to yield a residue that was purified by flash chromatography using the (Biotage SP4, 40 g cartridge, 0 to 100% EtOAc gradient in hexane) to give methyl 1-[2-(4- hydroxyphenyl)-2-oxoethyl]-1 H-pyrrole-2-carboxylate as a white solid (810 mg, yield 87%). 1H-NMR (400 MHz, d6-acetone): delta 3.66 (s, 3H), 5.86 (s, 2H), 6.16 (dd, 1 H, J 3.9, 2.6 Hz), 6.92 (dd, 1 H, J 4.0, 1 .8 Hz), 6.96-7.00 (m, 2H), 7.04-7.06 (m, 1 H), 7.95-8.00 (m, 2H, 9.23 (br s, 1 H).
Potassium hydroxide (11.2 g, 200 mmol) was added in one portion to asolution of methyl 1H-pyrrole-2-carboxylate (5.0 g, 40 mmol) in dimethyl sulfoxide (40 mL), and the mixture was stirred for 1.25 hours, at which point approximately half of the potassium hydroxide had dissolved. The reaction mixture was cooled to 0 C and 1 2-dibromoethane (37.5 g, 200 mmol) was added via syringe over 3 - 5minutes. The cooling bath was removed, and the reaction mixture was allowed to warm to room temperature and stir for 18 hours. It was then partitioned between diethyl ether (150 mL) and water (100 mL); the organic layer was washed twice with half-saturated aqueous sodium chloride solution, washed once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, andconcentrated in vacuo. Silica gel chromatography (Gradient: 0% to 60% ethylacetate in heptane) afforded the product as a colorless oil. Yield: 7.05 g, 30.4 mmol,76%. 1H NMR (400 MHz, CDCI3) oe 7.00 (dd, J=4.0, 1.8 Hz, 1H), 6.93 (brdd, J=2.6,1.8 Hz, 1H), 6.16 (dd, J=4.0, 2.6 Hz, 1H), 4.67 (t, J=6.4 Hz, 2H), 3.83 (5, 3H), 3.69 (t,J=6.4 Hz, 2H).
With N-Bromosuccinimide; In tetrahydrofuran; methanol; at 0℃; for 3.5h;
Synthesis of methyl 5 -bromo- 1H-pyrrole-2-carboxylate (53): Methyl 1H-pyrrole-2-carboxylate (52; lOg, 80 mmol) was dissolved in 800 mL of THF and 400 mL of MeOH. The mixture was cooled to 0 C. NBS (15 g, 8 4 mmol) was added in 5 portions in 1.5 h. After the addition, the mixture was stirred at 0 C for 2 h. The reaction mixture was concentrated and purified by silica gel chromatography (2% EtOAc/petroleum ether) to give 4.3 g of methyl 5-bromo-1H-pyrrole-2-carboxylate 53 as white solid (26% yield). LCMS:m/z 206.0 [M+H], , tR= 1.50 min
4.5 g (27%)
With bromine; iodine; In tetrachloromethane; water;
A solution of pyrrole-2-carboxylic acid methyl ester (79.9 mmol, 10.0 g) in carbon tetrachloride (300 ml) was heated to 70 C., then treated dropwise with a solution of bromine (99.9 mmol, 126.0 ml) in carbon tetrachloride (200 ml). The reaction was initiated by the addition of iodine (40 mg). After the addition was complete, the reaction was held at 70 C. for 10 min, then cooled to room temperature using an ice bath. The mixture was washed with 10% aqueous sodium carbonate (100 ml), followed by water (100 ml). The organics were concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 4.5 g (27%) of 5-bromo-1H-pyrrole-2-carboxylic acid methyl ester. 1H NMR (CDCl3) delta9.29 (1H, s), 6.80 (1H, dd, J=3.9, 2.7), 6.23 (1H, dd, J=3.8, 2.6), 3.88 (3H, s).
With sodium hydroxide In dichloromethane; water at 18℃; for 16h;
40%
With sodium hydroxide In dichloromethane; water at 0 - 18℃; for 16h;
Stage #1: methyl Pyrrole-2-carboxylate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere;
Stage #2: p-methoxybenzyl chloride In N,N-dimethyl-formamide at 0 - 20℃; for 4h; Inert atmosphere;
4-Cyano-lH-pyrrole-2-carboxylic acid methyl ester was prepared as described in Can. J. Chem., 59, 2673-76 (1981). lH-Pyrrole-2-carboxylic acid methyl ester (2.00 g, 16.00 mmol) was dissolved in acetonitrile (5 mL) and the solution was cooled to -20 0C. Chlorosulfonylisocyanate (3.40 g, 24.00 mmol) was dissolved in acetonitrile (5 mL) and added dropwise via syringe over a period of 5 min to the above solution. The solution was allowed to warm to 25 0C and was stirred for 20 h. The solution was cooled back to 0 0C, NN-dimethylformamide (2 mL) was added and the solution was heated to 50 0C for 15 min. The reaction mixture was poured into ice and was extracted with chloroform, washed with saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 40% ethyl acetate in hexanes) afforded the desired product, 4-cyano-lH-pyrrole-2- carboxylic acid methyl ester (1.09 g, 7.265 mmol, 45.4% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ: 3.91 (3H, s), 7.12 (IH, t, J= 2.0 Hz), 7.40 - 7.41 (IH, m), 9.60 (IH, bs). FT-IR (ATR) vmax (neat): 2228, 1691 cm"1.
methyl 1-[4-(methoxycarbonyl)-2-nitrophenyl]-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 4h;
EXAMPLE 1: N-(^-Morpholin-4-ylethyl)-4-oxo-4,5-dihydropyrrolo[l.,2-fllquinoxaline-7- carboxamide; Step 1: Methyl l-r4-(methoxycarbonyl)-2-nitrophenyll-lH-pyrrole-2-carboxylate; A solution (0.3 M) of methyl 4-fluoro-3-nitrobenzoate in DMF was treated with methyl IH- pyrrole-2-carboxylate (1.0 eq.) and Cs2CO3 (1.2 eq.). The reaction mixture was heated at 600C for 4 h. After cooling down, the reaction mixture was filtered, and the filtrate was diluted with water and extracted with EtOAc. The combined organic phase was dried and solvent was evaporated giving a residue that was purified by flash chromatography on silica gel (petroleum ether/EtOAc 10:1) to afford (77%) the title compound as a yellow solid. 1R NMR (300 MHz, CDCl3, 300K) delta 3.67 (s, 3H), 4.01 (s, 3H), 6.41 (dd, J= 4.0, 2.9 Hz, IH), 6.92 (dd, J= 2.9, 1.8 Hz, IH), 7.13 (dd, J= 3.8, 1.8 Hz, IH), 7.51 (d, J= 8.2 Hz, IH), 8.34 (dd, J = 8.2, 2.0 Hz, IH), 8.73 (d, J= 2.0 Hz, IH). MS (ES+) Ci4Hi2N2O6 requires: 304, found: 305 (M+H)+.
With N-chloro-succinimide In tetrahydrofuran at 70℃; for 24h;
14.1
EXAMPLE 14: 4-(2-U(l.,2-dichloro-4-oxo-4.,5-dihydropyrrolo[l.,2-fllquinoxalin-7- yDcarbonyll amino} ethyl)morpholin-4-ium trifluoroacetate and 4-(2-U(l.,3-dichloro-4-oxo- 4,5-dihydropyrrolo [ 1 ,2-a] q uinoxalin-7-yl)carbonyll amino} ethyl)morpholin-4-ium trifluoroacetate; Step 1: Methyl 4,5-dichloro-pyrrole-2-carboxylate (DIa) and methyl 3,5-dichloro-pyrrole-2- carboxylate (DIb); A solution (1.0 M) of methyl pyrrole-2-carboxylate in THF was treated with N-chloro succinimide (3.0 eq.). The reaction mixture was heated at 700C for 24 h. After cooling down, the reaction mixture was diluted with DCM and washed with brine. The organic phase was dried and solvents were evaporated giving a residue that was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 100:1 to 10:1) to afford (30 %) the title compounds as a mixture of the two isomers (ratio DIa /DIb = 7:3).DIa: 1U NMR (400 MHz, CDCl3, 300K) δ 6.52 (d, J = 3.0 Hz, IH), 3.57 (s, 3H). MS (ES+)C6H5Cl2NO2 requires: 194, found: 194, 196, 198 (M+H)+.DIb: 1U NMR (400 MHz, CDCl3, 300K) δ 5.84 (d, J = 3.05 Hz, IH), 3.61 (s, 3H). MS (ES+)C6H5Cl2NO2 requires: 194, found: 194, 196, 198 (M+H)+.
Multi-step reaction with 2 steps
1: chloroform; phosphorus pentachloride
In methanol; dichloromethane
1.1 Step 1
Step 1 To a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in anh. MeOH (100 mL) under N2 at room temp. was added TMSCl (17.9 mL, 141 mmol, 2.5 equiv) in one portion. After stirring overnight, the reaction mixture was concentrated under reduced pressure, redissolved in CH2Cl2, washed with water, dried (Na2SO4) and concentrated to give methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (4.62 g, 65%): 1H NMR (CDCl3) δ3.86 (s, 3H), 6.29 (br q, 1H), 6.92 (br m, 1H), 6.96 (br m, 1H), 9.30 (br s, 1H). This material was used in the next step without further purification.
With thionyl chloride In methanol; dichloromethane
107 Methyl Pyrrole-2-Carboxylate
EXAMPLE 107 Methyl Pyrrole-2-Carboxylate Pyrrole-2-carboxylic acid (5 g.) was combined with 200 ml. of methylene chloride and 20 ml. of thionyl chloride and refluxed for 2 hours. The solution was evaporated to dryness in vacuo and the resulting acid chloride converted to ester by addition of 30 ml. of methanol and 20 minutes stirring at room temperature. Ether (50 ml.) was added and the mixture extracted with 50 ml. of water. The ether phase was dried over anhydrous sodium sulfate, filtered and evaporated to yield methyl pyrrole-2-carboxylate (5 g., m.p. 69°-71° C.).
With chloro-trimethyl-silane In methanol; dichloromethane
24.1 Step 1
Step 1 Chlorotrimethylsilane (17.9 mL, 141 mmol, 2.5 equiv) is added in one portion to a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in dry methanol (100 mL) under N2 at rt. After stirring overnight, the reaction mixture is concentrated in vacuo, redissolved in dichloromethane, washed with water, dried (Na2SO4) and concentrated to give 4.62 g of methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (65%), which was used without further purification. 1H NMR (CDCl3) d 9.3 (br s, 1H), 6.96 (br m, 1H), 6.92 (br m, 1H), 6.29 (br q, 1H), 3.86 (s, 3H).
With aluminum (III) chloride; In 1,2-dichloro-ethane; at 20℃; for 2h;
To a solution of methyl pyrrole-2-carboxylate (0.30 g, 2.42 mmol) in anh. 1,2-dichloroethane (12 mL) under N2 at room temp. was added AlCl3 (0.710 g, 5.33 mmol, 2.2 equiv) in one portion. 2-Chloro-2-methylpropane (0.26 mL, 2.42 mmol, 1.0 equiv) was added in one portion via syringe. After 2 h, the reaction was quenched by slowly pouring it into a saturated NaHCO3 solution. The resulting white suspension was extracted with Et2O (2x). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to give an off-white solid (0.40 g), which was purified by flash chromatography (60% CH2Cl2/hexane) to give methyl 5-tert-butylpyrrole-2-carboxylate as a white amorphous solid (0.36 g, 81%): 1H NMR (CDCl3) delta 1.31 (s, 9H), 3.83 (s, 3H), 6.00 (t, J = 3.3 Hz, 1 H), 6.81 (t, J = 3.3 Hz, 1H), 8.82 (br s, 1H).
aluminium trichloride; In 1,1-dichloroethane;
Step 2 Aluminum chloride (0.710 g, 5.33 mmol, 2.2 equiv) is added in one portion to a solution of methyl pyrrole-2-carboxylate (0.30 g, 2.42 mmol) in dry dichloroethane (12 mL) under N2 at rt. Subsequently, 2-chloro-2-methylpropane (0.26 mL, 2.42 mmol, 1.0 equiv) is added in one portion via syringe. After 2 h, the orange solution is quenched by slowly pouring into a saturated sodium bicarbonate solution. The resulting white suspension is extracted with diethyl ether (2*). The combined organic layers are dried (Na2SO4) and concentrated in vacuo to give 0.40 g of methyl 5-t-butylpyrrole-2-carboxylate as an off-white solid. Flash chromatography (40% hexane in dichloromethane) gives 0.3 6 g of the desired material as a white amorphous solid (81%). 1H NMR (CDCl3) d 8.82 (br s, 1H), 6.81 (t, 1H, J=3.3 Hz), 6.00 (t, 1H, J=3.3 Hz), 3.83 (s, 3H), 1.31 (s, 9H).
Step 2; Aluminum chloride (0.710 g, 5.33 mmol, 2.2 equiv) is added in one portion to a solution of methyl pyrrole-2-carboxylate (0.30 g, 2.42 mmol) in dry dichloroethane (12 mL) under N2 at rt. Subsequently, 2-chloro-2-methylpropane (0.26 mL, 2.42 mmol, 1.0 equiv) is added in one portion via syringe. After 2 h, the orange solution is quenched by slowly pouring into a saturated sodium bicarbonate solution. The resulting white suspension is extracted with diethyl ether (2 x). The combined organic layers are dried (Na2SO4) and concentrated in vacuo to give 0.40 g of methyl 5-t-butylpyrrole-2-carboxylate as an off-white solid. Flash chromatography (40% hexane in dichloromethane) gives 0.3 6 g of the desired material as a white amorphous solid (81%). 1H NMR (CDCl3) d 8.82 (br s, 1H), 6.81 (t, 1H, J = 3.3 Hz), 6.00 (t, 1H, J = 3.3 Hz), 3.83 (s, 3H), 1.31 (s, 9H).
EXAMPLE 2371 -(5-tert-Butyl-2-(2,2-dimethyl-3-oxopiperazine- 1 -carbonyl)- l?/-pyrrol-3-yl)- 3 -(2 , 3 -dichloro-4-fluorophenyl)urea [0965] The compound of this example was prepared according to the following procedure: [0966] A) Methyl 5 -tert-butyl- lH-pyrrole-2-carboxylate.Q ,HNL - C4-l N [0967] A mixture of the methyl pyrrole-2-carboxylate (1.0 g, 7.99 mmol) and aluminum trichloride (2.13 g, 16.0 mmol) was dissolved in carbon disulfide (20 mL) and stirred at 50 0C for 1 hour. Tert-butyl chloride (0.740 g, 7.99 mmol) in carbon disulfide (5 mL) was added in one portion and the mixture stirred at room temperature for an additional 20 hours. The reaction mixture was quenched with ice and extracted with dichloromethane. The solvent was removed under vacuum and the resulting solid was washed with cold hexane to afford 0.85Og of the expected methyl 5-tert-butyl-lH-pyrrole-2-carboxylate as a tan solid.
With N,N-dimethyl-formamide; trichlorophosphate; In dichloromethane; at 0 - 20℃; for 0.5h;Heating / reflux;
Example 5 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(perhydro-1,4-oxazepine-4-carbonyl)-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide (i) 4-Formyl-1H-pyrrole-2-carboxylic acid methyl ester and 5-formyl-1H-pyrrole-2-carboxylic acid methyl ester: Both formyl-pyrrole derivatives were prepared adopting a procedure described by C. Schmuck,Tetrahedron2001, 57, 3063: To DMF (1.61 g) was added POCl3 (3.37 g) dropwise under Ar at 0C. The mixture was allowed to warm to RT after which it was diluted with DCM (11 mL). A solution of 1H-pyrrole-2-carboxylic acid methyl ester (2.51 g) in DCM (11 mL) was added dropwise. The mixture was refluxed for 30 min whereupon it was cooled to 10 C and quenched with a solution of potassium acetate (10.8 g) in water (28 mL). The phases were separated and the aqueous layer was extracted with MTBE. The combined organic phases were washed with saturated aqueous K2CO3 solution and concentrated in vacuo. The residue was purified by flash column chromatography on silica (ethyl acetate / heptane 1:5) to yield 4-formyl-1H-pyrrole-2-carboxylic acid methyl ester (589 mg) and 5-formyl-1H-pyrrole-2-carboxylic acid methyl ester (1.60 g) as solids.
With N,N-dimethyl-formamide; trichlorophosphate; In 1,2-dichloro-ethane; at 0℃; for 1.33333h;Heating / reflux;
2.1.) Synthesis of Methyl 4-oxo-l,4,5,6-tetrahydrocyclopenta[6]pyrrole-2-carboxylate2.1. a) Synthesis of 5-formyl-l H-pyrrole-2-carboxylic acid methyl ester [0300] To 1,2-dichloroethane (40 mL) was added DMF (13.6 mL, 176 mmol). The mixture was cooled to 0 0C and phosphorus oxychloride (16.4 mL, 176 mmol) was added dropwise over 5 min. The resulting solution was stirred for 15 min. To the solution at 0 0C was added dropwise methyl lH-pyrrole-2-carboxylate (20 g, 160 mmol) in dichloroethane (80 mL) (about 1 h). The cooling bath was removed, and the reaction mixture was heated to reflux for about Ih and was then cooled to rt. EtOAc (250 mL) in ice water (400 mL) was added and the organic layer was separated. The aqueous layer was neutralized with NaHCO3 solution, and then extracted with EtOAc (4 x 100 mL). The organic layer and the combined organic extracts were washed with dilute NaHCO3 solution, brine, dried (Na2SO4) and filtered. Silica gel was added, the solvent removed and the silica gel-imbedded material was purified by flash chromatography (0-50% EtO Ac/Heptane) to afford a major product, methyl 5-formyl- lH-pyrrole-2-carboxylate (16.3 g) and a minor product, methyl 4-formyl-lH-pyrrole-2- carboxylate (6.94 g). Combined yield: 23.3 g (95 %).[0301] Methyl 5-formyl-l/f-pyrrole-2-carboxylate: 1H NMR (400 MHz, CDCl3) delta ppm: 3.93 (s, 3 H), 6.95 (d, J= 2.39 Hz, 2 H), 9.68 (s, 1 H), 9.82 (br s, 1 H); LCMS- MS (ESI+) 153.9 (M+H). <n="96"/>[0302] Methyl 4-formyl-lH-pyrrole-2-carboxylate: 1H NMR (400 MHz, CHLOROFORM-J) delta ppm: 3.91 (s, 3 H), 7.32 (dd, J= 2.29, 1.61 Hz, 1 H), 7.57 (dd, J= 3.32, 1.51 Hz, 1 H), 9.55 (br s, 1 H), 9.86 (s, 1 H); LCMS- MS (ESI+) 153.8 (M+H).
methyl 4-tridecanoylpyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With thionyl chloride;aluminium trichloride; In ice-water; dichloromethane; N,N-dimethyl-formamide;
SYNTHESIS EXAMPLE 1 Synthesis of methyl 4-tridecanoylpyrrole-2-carboxylate In 480 ml of methylene chloride, were dissolved 102.9 g (0.48 mol) of <strong>[638-53-9]<strong>[638-53-9]tridecanoic</strong> acid</strong>, to which 52.6 ml (0.72 mol) of thionyl chloride and 0.2 ml of N,N-dimethylformamide were added to obtain a solution. The solution was allowed to stand over night and was evaporated under a reduced pressure. The remaining oil was added to 400 ml of methylene chloride containing 106.6 g (0.8 mol) of anhydrous aluminum chloride, to which 200 ml of methylene chloride solution containing 50.05 g (0.4 mol) of methyl pyrrole-2-carboxylate was added dropwise in 40 minutes at a temperature of 3 to 9 C. After the addition, the temperature of the mixture was elevated slowly up to room temperature and the mixture was stirred for 2 hours. Then, the mixture was poured into 800 ml of ice-water, and 1000 ml of methylene chloride was added thereto to dissolve all the crystals precipitated, followed by liquid separation. The organic layer was washed with water three times, dried over anhydrous magnesium sulfate and condensed under a reduced pressure. The residue was recrystallized from 400 ml of ethyl acetate and 400 ml of hexane to obtain 107.2 g of methyl 4-tridecanoylpyrrole-2-carboxylate as white crystals. The yield was 83% and the melting point was 92 to 93 C. IR (KBr) cm-1: 3270, 2920, 2855, 1690, 1660, 1565, 1455, 1385, 1290, 1215. NMR (CDCl3) delta: 0.88 (t, 3H), 1.15, 1.38 (each m, 18H), 1.65, 1.75 (each m, 2H), 2.75 (t, 2H), 3.89 (s, 3H), 7.28, 7.30 (each m, 1H), 7.53, 7.55 (each m, 1H), 9.52 (broad s, 1H).
83%
With thionyl chloride;aluminium chloride; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane; N,N-dimethyl-formamide;
SYNTHETIC EXAMPLE 7 Preparation of methyl 4-tridecanoylpyrrole-2-carboxylate <strong>[638-53-9]Tridecanoic acid</strong> (102.8 g, 0.48 mol) was dissolved into 480 ml of methylene chloride, and 52.6 ml (0.72 mol) of thionyl chloride and 0.2 ml of N,N-dimethylformamide were added thereto. The mixture was allowed to stand overnight followed by concentration under reduced pressure, and the remaining oil was added to 400 ml of methylene chloride containing 106.6 g (0.8 mol) of anhydrous aluminium chloride. A solution of 50.05 g (0.4 mol) of methyl pyrrole-2-carboxylate in 200 ml of methylene chloride was added dropwise to the mixture for ca. 40 minutes at 3 to 9 C. After the addition was finished, the temperature was raised gradually to room temperature, and the mixture was stirred for 2 hours followed by pouring it into 800 ml of ice water. To this mixture was added 1000 ml of methylene chloride to completely dissolve the crystals. The organic layer was separated, washed with water three times and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was recrystallized from 400 ml of ethyl acetate and 400 ml of hexane to give 107.2 g (83% yield) of methyl 4-tridecanoylpyrrole-2-carboxylate as white crystals, m.p. 92-93 C. IR (KBr) cm-1: 3270, 2920, 2855, 1690, 1660, 1565, 1455, 1385, 1290, 1215. 1 H NMR (CDCl3, 250 MHz) delta: 0.88 (3H, t, J=6.6 Hz), 1.15-1.38 (18H, m), 1.65-1.75 (2H, m), 2.75 (2H, t, J=7.5 Hz), 3.89 (3H, s), 7.28-7.30 (1H, m), 7.53-7.55 (1H, m), 9.52 (1H, broad s).
methyl 1-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
General procedure: To a stirred solution of substituted methyl 1H-pyrrole-2-carboxylate (5 mmol) in DMF (10 mL) was added solid NaH (8 mmol) portionwise at 0 C over 30 min. The reaction mixture was stirred at room temperature for 30 min. followed by dropwise addition of propargyl bromide or 1-bromobut-2-yne (6 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 2 d. Water (30 mL) was added, and the mixture was extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (4 × 25 mL) and dried over MgSO4. Evaporation of solvent gave propargyl esters.
In tetrahydrofuran; vaseline oil; hexane; ethyl acetate;
STEP B: methyl 1-(2-propynyl)-1H-pyrrol-2-carboxylate 3.302 g of methyl 1H-pyrrole-2-carboxylate were dissolved in 40 ml of tetrahydrofuran and then, at 0 C., 1.422 g of sodium hydride in suspension at 50% in vaseline oil were added. The mixture stirred for 1 hour at 20 C. and a solution of 2 ml of propargyl bromide in 10 ml of tetrahydrofuran was introduced dropwise. The mixture was stirred for 1 hour at 50 C. and after having added 5 ml of propargyl bromide, the reaction mixture was poured into water. The mixture was extracted with methylene chloride and the extracts were concentrated to dryness by distilling under reduced pressure. The residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (9-1) to obtain 2.993 g of methyl 1-(2-propynyl)-1H-pyrrol-2-carboxylate.
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 48.0h;
EXAMPLE 8B; Methyl 1H-pyrrole-2-carboxylate (0.716 g), EXAMPLE 8A (1.18 g) and cesium carbonate (3.28 g) were stirred in 20 mL DMF at room temperature for 48 hours. The reaction mixture was partitioned between ethyl acetate and H20. The aqueous phase was extracted with ethyl acetate. The extract were dried over MgSO4, filtered and concentrated. The crude product was purified on silica gel (40 g) eluting with 1:1 ethyl acetate:hexane to provide This example. 1H NMR (300 MHz, DMSO-d6) delta 8.21 (d, 1H), 7.90 (dd, 1H), 7.73 (d, 1H), 7.33 (d, 1H), 7.07 (m, 1H), 6.40 (m, 1H), 3.59 (s, 3H), 3.50 (s, 3H), 3.29 (s3H).
a) 1-(1-tert-Butoxycarbonyl-ethyl)-1H-pyrrole-2-carboxylic Acid Methyl Ester A 60percent suspension of sodium hydride in mineral oil (0.704 g, 17.6 mmol) was added to anhydrous N,N-dimethylformamide (40 mL). 1H-Pyrrole-2-carboxylic acid methyl ester (2.0 g, 16 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL) and added dropwise to the solution containing the sodium hydride over a period of 2 min. Effervescence was observed and the mixture was stirred for 30 min. 2-Bromo-propionic acid tert-butyl ester (4.0 g, 19.2 mmol) was added and the mixture was stirred at 80° C. for 45 min. Upon cooling to 25° C., the mixture was poured into 1.0 M aqueous hydrochloric acid solution (200 mL) and the product was extracted into ethyl acetate (200 mL). The organic phase was washed with saturated aqueous brine solution (50 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by flash column chromatography (Merck silica gel 60, 40-63 muM, 10percent ethyl acetate in hexanes) afforded the desired product, 1-(1-tert-butoxycarbonyl-ethyl)-1H-pyrrole-2-carboxylic acid methyl ester (3.8 g, 15 mmol, 94percent yield) as clear oil. 1H NMR (400 MHz, CDCl3) delta: 1.45 (9H, s), 1.72 (3H, d, J=6.9 Hz), 3.79 (3H, s), 5.77 (1H, quartet, J=7.4 Hz), 6.18-6.20 (1H, m), 6.98-7.04 (2H, m).
With tert-butylhypochlorite In tetrachloromethane at 20℃; for 48h;
6.d
Cyano- and halo-substituted pyrrole derivatives were prepared according to the procedure outlined in Scheme 3. 1 -Alkylpyrroles 101 were allowed to react with chlorosulfonyl isocyanate to give two readily separable regioisomeric cyanopyrrole derivatives 106 and 107 (1 :4). Each was converted the corresponding acid and then coupled with 2-chloro-6-fluorobenzylamine to give 108 and 109, respectively. Methyl 2-pyrrolecarboxylate, 100, was also regioselectively chlorinated with t-butyl hypochlorite to give 110. N-alkylation gave 111 and subsequent ester hydrolysis yielded 112, which was coupled with 2-chloro-6-fluorobenzylamine to give compound (78).
With tetrachloromethane; tert-butylhypochlorite at 20℃; for 48h; regioselective reaction;
To a mixture of methyl- lH-pyrrole-2-carboxylate (10 g, 79.9 mmol) in anhydrous THF (200 mL) was added NaH (3.52 g, 60% w.t., 87.9 mmol) at 0C. The resulting mixture was stirred at 20C for 30 min, then CH3I (13.62 g, 95.9 mmol) was added. The reaction mixture was stirred at 20C for 17 hrs. The mixture was then poured into an aqueous solution of NH4CI (200 mL). The aqueous layer was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (150 mL), dried (Na2S04), filtered, and concentrated in vacuo. The residue was purified by chromatography (silica, EtOAc/PE = 1/20) to afford methyl 1 -methyl- lH-pyrrole-2- carboxylate (9.88 g, 71 mmol, 89 %) as a yellow oil. MS (EI+, m/z): 140.1 [M+H]+.
88%
Step 1: methyl-1-methyl-1H-pyrrole-2-carboxylate To a solution of methyl-1H-pyrrole-2-carboxylate (25.0 g, 199.79 mmol) in DMF (100 ml) at 0 C. was added NaH (11.18 g, 279.21 mmol). The reaction mixture was stirred at 0 C. for 1 hr, then MeI (36.88 g, 259.73 mmol) was added. The reaction mixture was stirred for 16 hrs and allowed to warm from 0 C. to rt, then the mixture was diluted with H2O (500 mL) and extracted with EtOAc (150 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and purified by chromatography (silica, EtOAc/PE=1/10) to afford methyl-1-methyl-1H-pyrrole-2-carboxylate (24.7 g, 177.51 mmol, 88%) as an oil. ESI-MS (EI+, m/z): 140.2 [M+H]+.
Stage #1: methyl Pyrrole-2-carboxylate; Vilsmeier reagent In N,N-dimethyl-formamide at 20℃; for 16h;
Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide at 0℃;
29
To a solution of methyl 1 H-pyrrole-2-carboxylate (35 g) in DMF (80 ml_) a solution of Vilsmeier reagent (synthesized as follow: phosphorus (III) oxychloride (85.12g) adding drop wise at 0 0C to DMF (40.88 g), then the solution was warmed to rt and stirred for 30 min) in DMF (20 ml_) was added at rt and the reaction mixture was stirred for 16h. NaOH 4N solution was added slowly at 0 0C under stirring to the reaction mixture until pH=7, filtrated and washed several times with EA. The filtrate was extracted with EA for three times and the collected organic phase was washed with water, brine, dried over Na2SO4 and concentrated under vacuum. The crude product was combined with one other batch of crude product obtained with the same procedure starting from methyl 1 H-pyrrole-2- carboxylate (15 g). The collected crude was purified by FC on silica gel to give the title compound (32 g) as yellow solid.1H NMR (400 MHz, DMSO-d6) δ:3.77 (3H, s), 7.09 (1 H, s), 7.77 (1 H, s), 9.71 (1 H, s), 12.6- 12.7 (1 H,b).
(Step 1) methy 1-amino-1H-pyrrolo-2-carboxylate; To a mixture of NaH (60%, 4.1 g, 102.2 mmol) suspended in dimethylformamide (120 mL) at 0 C. under nitrogen atmosphere, methyl pyrrolo-1-H-2-carboxylate (8.0 g, 63.9 mmol) was slowly added over minutes. After stirring for 1 hour, a solution of 2,4-dinitrophenolamine (19.1 g, 95.9 mmol) in dimethylformamide (30 mL) was added dropwise for 30 minutes. The resulting reaction mixture was stirred at 0 C. for 2.5 hours. The reaction was completed by slowly adding saturated sodium thiosulfate aqueous solution. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with 10% lithium chloride aqueous solution, dried with sodium sulfate, and then filtered. The filtrate was concentrated. The resulting brown residue was purified by silica gel chromatography (10% ethyl acetate in hexane) to give the target compound as an oil (7.5 g, 53.5 mmol, 84% yield).1H NMR (400 MHz, CDCl3): 6.96 (t, J=2.4 Hz, 1H), 6.83 (dd, J=4.4 Hz, 2.0 Hz, 1H), 6.02 (dd, J=4.4 Hz, 2.8 Hz, 1H) 5.54 (br s, 2H), 3.83 (s, 3H).
81.1%
a) Methyl 1 -amino-1 W-pyrrole-2-carboxylateSodium hydride (4.40 g, 0.1 1 mol, 60% in hexanes) was suspended in DMF (550 ml) under nitrogen atmosphere. Once cooled at - 5C, methyl 1 H-pyrrole-2-carboxylate (1 1 .0 g, 0.09 mol) dissolved in DMF (182 ml) was dropwise added and vigorously stirred for 30. 277ml more of DMF was added and then O- (diphenylphosphoryl)hydroxylamine (32.8g, 0.14 mol) was introduced into the reaction mixture. The reaction mixture was stirred at room temperature for 4h. Once the reaction is over, 11 of saturated sodium thiosulfate solution (x5H20) was added and the mixture was warmed to 80C for 1 h. Once at room temperature, 11 of ethyl ether was added and the phases separated. The aqueous phase was twice extracted with ethyl ether. The organic phase was washed with water and brine, dried over magnesium sulphate, filtered and the solvent evaporated under reduced pressure. 10.41 g (81 .1 % yield) of the final compound were obtained.LRMS (m/z): 141 (M+1 )+
a) 1-Amino-1H-pyrrole-2-carboxylic acid methyl ester To a stirred, ice/water cooled mixture of 1H-pyrrole-2-carboxylic acid methyl ester (425 mg, 3.40 mmol) in NMP (10 mL) was added a solution of potassium tert-pentoxide in toluene (2.30 mL, 3.90 mmol, 25 wt % solution); then the solid of O-4-chlorobenzoyl hydroxyamine (670 mg, prepared according to the literature: Parlanti, L Discordia, R. P.; Hynes, J. Jr.; Miller, M. M.; O'Grady, H. R.; Shi, Z. Org. Lett. 2007, 9(19) 3821-3824) was added in one portion; the cold bath was removed after addition completed, and the slurry was stirred at rt for 30 min. Subsequently, the reaction was quenched by addition of saturate sodium bicarbonate solution, then extracted with EtOAc, washed with brine; organic layers was dried over anhydrous sodium sulfate, filtered, concentrated and the residue was column purified to give the desired product (309 mg). 1H NMR (CDCl3, delta in ppm): 6.94 (t, 1H, J=2.3 Hz), 6.81 (dd, 1H, J=2.0 Hz, 4.0 Hz), 6.00 (dd, J=2.7 Hz, 4.3 Hz), 5.53 (br, s, 2H), 3.82 (s, 3H).
Chloramine was made according to J. Org. Chem., VoI 69 (4), 1368-1371. Into 4L Erlenmyer flask, lH-Pyrrole-2-carboxylic acid methyl ester (25.00 g, 0.1938 mol) and Tetrahydrofuran (1000 mL, 10 mol) were added and stirred at room temperature for 20 minutes under an atmosphere of Nitrogen . 1.00 M of Potassium tert-Butoxide in Tetrahydrofuran(500.0 mL, 0.5000 mol) was added and stirred for 30 minutes at room temperature. 0.15 M of Chloramine in Ether(2100 mL, 0.31 mol) was added to the reaction mixture at 10 0C over 20 minutes with nitrogen bubbling into the reaction mixture. The reaction was stirred at room temperature for 2 hours. HPLC suggested 72% conversion (18% SM remained). Saturated Na2S2O3 (500 mL) was added at 10 0C over 30 minutes. The mixture was stired for one hour. The organic was separated, washed with water, then subsequently with Brine, and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was concentrated to approximately 500 mL. Benzoyl isothiocyanate (22.75 g, 0.1394 mol) in Tetrahydrofuran (100 mL, 1 mol) was added dropwise to the residual organic. The reaction mixture was stired at room temperature overnight. The solvent was removed under vacuum. The solid was partitioned with Et2O (200 mL) and stirred for 30 minutes. The solid was filtered and washed with hexane/Et2O (9 to 1) to give l-(3-Benzoyl-thioureido)-lH-pyrrole-2-carboxylic acid ethyl ester (38.2Og) as an off white solid. NMR 1H (DSMO-d6) 12.89 (s, IH), 11.92 (s, IH), 7.99 (d, 2H, J= 7.46Hz), 7.68 (t, IH, J=7.37Hz), 7.55 (t, IH, J=7.81Hz ), 7.19 (dd, IH, JJ=2.04, 1.64 Hz), 6.89 (dd, IH, JJ=I.76, 1.60 Hz), 6.20 (dd, IH, J=3.00, 1.04 Hz),3.68 (s, 3H).
Step 1: Into a 5 L round bottom flask containing a solution of 1H-pyrrole-2-carboxylic acidmethyl ester (15.0 g, 120 mmol) in tetrahydrofuran (500 mL) was added a solution of potassiumtert-butoxide (35 g, 310 mmol) in tetrahydrofuran (500 mL) and the reaction mixture was stirred at room temperature for 30 mm. A solution of monochloramine (0.15 M in diethyl ether, 2.1 L) was added at 10 C over 20 mm, while bubbling nitrogen into the reaction mixture and stirred at room temperature for 2 h. Aqueous Na25203 (500 mL) was added dropwise at 10 C over 30 mmand the reaction was stirred for 1 h. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford methyl 1 -amino- 1H-pyrrole-2-carboxylate.
4L flask, 25.0 g of starting material 1-a-1 (0.19mol) was dissolved in 1L of tetrahydrofuran was stirred at room temperature under nitrogen for 20 minutes, the tetrahydrofuran solution of 1M potassium tert-butoxide (500.0ml, 0.50mol ) was added to this solution, stirred for 1 hour. Then 0.15M solution of chloramine in ether (2.1L, 0.31mol) in 20 minutes at 10 deg. C was added to the reaction mixture, while introducing nitrogen, after two hours, the saturated aqueous sodium thiosulfate solution (500ml) to the reaction solution was added dropwise, stirring was continued for one hour. The organic phase was separated, washed with water, saturated brine, dried over anhydrous sodium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure to give the oily compound 1-a-2.
To a solution of methyl 1H-pyrrole-2-carboxylate (100 g, 799 mmol) indimethylformamide (DMF; 1.2 L) was added NaH (51.1 g, 1.28 mol, 60% purity) at 0 C. The mixture was stirred at 0 C for 1 hour, then O-(2,4-dinitrophenyl)hydroxylamine (238.71 g, 1.20 mol) in DMF (300 mL) was added dropwise. The mixture was stirred at 0 C for 3 hours. The reaction mixture of two batches was combined and poured into aqueous (aq.) sat. sodium thiosulfate solution (10 L). The resulting mixture was extracted with EtOAc (4 L x 3). The combined organic layers were washed with brine (2 L x 3), dried over Na2SO4, and then filtered. The filtrate was concentrated, then purified by silica gel chromatography to afford methyl 1- amino-1H-pyrrole-2-carboxylate (190 g, crude) as a yellow oil.
With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine; In toluene; at 110℃; for 17h;Inert atmosphere;
Methyl 1-phenyl-1H-pyrrole-2-carboxylate (EV-AW1367-001)- Step 1 Methyl 1H-pyrrole-2-carboxylate (CAS 1193-62-0, 100 mg, 0.80 mmol) and iodobenzene (CAS 591-50-4, 107 mul, 0.96 mmol) were dissolved in toluene (2 ml) and N,N'- dimethylethane-1,2-diamine (35 mul, 0.32 mmol) and potassium phosphate (356 mg, 1.68 mmol) were added. The reaction was purged with nitrogen for 5 minutes then copper(I) iodide (30 mg, 0.16 mmol) was added. The mixture was stirred at 110C for 17h. The reaction was allowed to cool to room temperature, diluted with ethyl acetate (20 ml) and washed with water (5x10 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash column chromatography (0- 100% ethyl acetate/heptane) to obtain 127 mg (79%) of methyl 1-phenyl-1H-pyrrole-2-carboxylate (EV-AW1367-001) as a white powder. LCMS (method D): retention time 1.15min, M/z = 202 (M + 1).
Methyl 1H-pyrrole-2-carboxylate (5.78 g, 46.2 mmol) was dissolved in DMSO and cooled to 10° C. NaH was added in two portions over 5 min. The reaction mixture was stirred at 10° C. for 10 min and <strong>[59237-53-5]methyl 6-chloro-5-nitronicotinate</strong> (5 g, 23.09 mmol) in DMSO (10 mL) was added slowly over 3 min. The red reaction mixture was allowed to warm to room temperature and stirred overnight. It was cooled to 0° C. and quenched with water (12 mL) and diluted with brine (50 mL). The mixture was washed with EtOAc (2.x.25 mL) and the aqueous layer was acidified to pH=2 with 4.5 N HCl. It was extracted with EtOAc (1.x.100 mL) and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford a yellow solid, which was dissolved in MeOH (100 mL) and cooled to 0° C. Thionyl chloride (45 mL, 617 mmol) was added slowly over 5 min. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature overnight. It was concentrated in vacuo and the resulting solid was triturated with ethyl acetate (300 mL). The solid was filtered off and the filtrate was concentrated in vacuo. then washed with ethyl ether to afford methyl 6-(2-(methoxycarbonyl)-1H-pyrrol-1-yl)-5-nitronicotinate (5.04 g, 16.51 mmol, 92percent yield) as a yellow solid, [M+H] calc'd for C13H11N3O6, 306; found, 306.
With Ascophyllum nodosum vanadate(V)-dependent bromoperoxidase I; dihydrogen peroxide; sodium bromide; In water; tert-butyl alcohol; at 23℃; for 24h;pH 6.2;aq. buffer; Enzymatic reaction;
General procedure: A solution of H2O2 (3×2.0 mL, 0.825 M) and NaBr (3×154.4 mg, 1.50 mmol) in MES-buffer (500 mM, pH 6.2) was added every day with a syringe pump (8 h, 0.004 mL/min) to a solution of substrate 1 (1.50 mmol) and VBrPO(AnI) (34.6 UT, 0.032 mmol%) in MES-buffer (500 mM, pH 6.2, 20.0 ml) and tBuOH (6.6 mL) [for: 1f 3× H2O2 (2.0 mL, 0.511 M) and NaBr (95.7 mg, 0.93 mmol) in MES-buffer 500 mM to a solution of 1f (0.93 mmol) and VBrPO(AnI) (21.5 UT, 0.032 mmol%) in MES-buffer (500 mM, pH 6.2, 10.1 ml) and tBuOH (4.1 mL)]. The reaction mixture was stirred at 23 C for 3 days. The aqueous layer was extracted with Et2O (3×20 mL). Combined organic extracts were dried (MgSO4). The solvent was removed under reduced pressure (14 mbar, 40 C) to afford a product mixture, which was analyzed by 1H NMR and GC, using pentachlorobenzene (1H NMR) as an internal standard in comparison to spectral data from authentic references. New compounds were purified via column chromatography and fully characterized. pH and bromoperoxidase activity (triiodide assay) were determined from the aqueous layer.
With vanadate-dependent bromoperoxidase II from Ascophyllum nodosum; dihydrogen peroxide; sodium bromide; In tert-butyl alcohol; at 23℃; for 44h;pH 6.2;Enzymatic reaction;
A solution of H2O2 (2.0 mL, 0.825 M) and NaBr (170 mg, 1.65 mmol) in MES-buffer (500 mM, pH 6.2) was added with a syringe pump (20 h, 1.67 muL/min) to a solution of substrate 4 (0.75 mmol) and VBrPO(AnII) (546 muL, 34.6 UT, 63 mumol%) in MES-buffer (500 mM, pH 6.2, 10.0 mL) and tBuOH (3.3 mL). The reaction mixture was stirred at 23 C for 24 h. The aqueous layer was extracted with Et2O (4 × 10 mL). Combined organic extracts were dried (MgSO4). The solvent was removed under reduced pressure (40 mbar, 40 C) to afford a product mixture which was analyzed by 1H NMR (pentachlorobenzene as internal standard) and GC (Supplementary Material). Final pH and bromoperoxidase activity (triiodide assay) were determined from the aqueous layer.
With Ascophyllum nodosum vanadate(V)-dependent bromoperoxidase I; dihydrogen peroxide; sodium bromide; In water; tert-butyl alcohol; at 23℃; for 24h;pH 6.2;aq. buffer; Enzymatic reaction;
General procedure: A solution of H2O2 (3×2.0 mL, 0.825 M) and NaBr (3×154.4 mg, 1.50 mmol) in MES-buffer (500 mM, pH 6.2) was added every day with a syringe pump (8 h, 0.004 mL/min) to a solution of substrate 1 (1.50 mmol) and VBrPO(AnI) (34.6 UT, 0.032 mmol%) in MES-buffer (500 mM, pH 6.2, 20.0 ml) and tBuOH (6.6 mL) [for: 1f 3× H2O2 (2.0 mL, 0.511 M) and NaBr (95.7 mg, 0.93 mmol) in MES-buffer 500 mM to a solution of 1f (0.93 mmol) and VBrPO(AnI) (21.5 UT, 0.032 mmol%) in MES-buffer (500 mM, pH 6.2, 10.1 ml) and tBuOH (4.1 mL)]. The reaction mixture was stirred at 23 C for 3 days. The aqueous layer was extracted with Et2O (3×20 mL). Combined organic extracts were dried (MgSO4). The solvent was removed under reduced pressure (14 mbar, 40 C) to afford a product mixture, which was analyzed by 1H NMR and GC, using pentachlorobenzene (1H NMR) as an internal standard in comparison to spectral data from authentic references. New compounds were purified via column chromatography and fully characterized. pH and bromoperoxidase activity (triiodide assay) were determined from the aqueous layer.
With beta?cyclodextrin; 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione; In water; at 20℃; for 4h;
General procedure: To an aqueous solution of betacyclodextrin (1.0 mmol of beta-CD in 5mL of water), IBX (2.0 mmol), N-benzylpyrrolidine (1.0 mmol) was added while stirring, and stirring was continued for the stipulated reaction time as shown in the table at room temperature. After completion of reaction as indicated by TLC, the reaction mixture was extracted with ethylacetate (3 X 5mL), the combined organic layers were washed with saturated brine solution, dried and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using hexane/ethyl acetate (9:1) as an eluent.
With tris(bipyridine)ruthenium(II) dichloride hexahydrate; N,N,N,N,-tetramethylethylenediamine; In acetonitrile; at 20℃;Inert atmosphere;
General experimental procedure An oven-dried resealable test tube equipped with a magnetic stir bar was charged with a heterocycle (0.3 mmol) and Ru(bpy)3Cl2·6H2O (1 mol%, 0.003 mmol), and sealed with a screw-cap. Acetonitrile (1.2 mL, 0.25 M) and N,N,N,N-tetramethylethylenediamine (0.6 mmol) were added to it under argon. CF3I (0.9 mmol-1.2 mmol) was then bubbled into the reaction mixture by using a gastight syringe. The test tube was placed under 24 W household light bulb or blue LEDs at room temperature. The reaction was allowed to proceed for 10-24 h while its progress was checked by TLC. The reaction mixture was then diluted with diethylether, filtered through a plug of silica gel to remove all solids, concentrated in vacuo, and purified by flash column chromatography to give the trifluoromethylated compound. An oven-dried resealable test tube equipped with a magnetic stir bar was charged with a heterocycle (0.3 mmol) and Ru(bpy)3Cl2·6H2O (1 mol%, 0.003 mmol), and sealed with a screw-cap. Acetonitrile (1.2 mL, 0.25 M) and N,N,N,N-tetramethylethylenediamine (0.6 mmol) were added to it under argon. CF3I (0.9 mmol-1.2 mmol) was then bubbled into the reaction mixture by using a gastight syringe. The test tube was placed under 24 W household light bulb or blue LEDs at room temperature. The reaction was allowed to proceed for 10-24 h while its progress was checked by TLC. The reaction mixture was then diluted with diethylether, filtered through a plug of silica gel to remove all solids, concentrated in vacuo, and purified by flash column chromatography to give the trifluoromethylated compound.
4 Synthesis of E4
Methyl 4-formyl-1H-pyrrole-2-carboxylate (3). To a solution of 2 (4.50 g, 36.0 mmol) in CH2Cl2:CH3NO2 (1:1, 40 mL) at -40° C., was added AlCl3 (12.48 g, 93.6 mmol) followed by α,α'-dichloromethyl methyl ether (4.15 mL, 46.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was slowly poured onto ice (10.00 g) and allowed to warm to room temperature. The aqueous phase was extracted with CH2Cl2 (3*50 mL). The combined organic layer was dried over anhydrous MgSO4, filtered and concentrated to give 3 as a dark brown solid (3.40 g, 62%). 1H NMR (400 MHz, CDCl3) δ 10.32 (brs, 1H), 9.83 (s, 1H), 7.59 (m, 1H), 7.30 (s, 1H), and 3.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.07, 161.71, 129.15, 127.71, 124.99, 114.56, and 52.34.
With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 16h;
General procedure: To a suspension of AlCl3 (2.5 eq.) in DCM (1mL/mmol AlCl3) at 0C was added the relevant acid chloride (2 eq.) followed by methyl 1H-pyrrole-2-carboxylate (1 eq.). The resulting mixture was allowed to reach RT and stirred for 16h. The reaction was quenched at 0C with a 1M aqueous solution of HCl (20mL). The product was extracted with DCM (3×100mL), washed with an aqueous saturated solution ofNaHCO3 (2×100mL) and brine (100mL). Combined organic layers were dried over Na2SO4 and concentrated in vacuo.
General procedure: To a solution of methyl pyrrole-2-carboxylate (24.6 mmol) in 85 mL of DMF was added cesium carbonate (29.5 mmol). The mixture was stirred at room temperature for 10 min, then <strong>[367-80-6]ethyl 4-fluoro-3-nitrobenzoate</strong> or ethyl 3-fluoro-4-nitrobenzoate (7.25 mmol) was added. The reaction mixture was refluxed for 1 h 30 min or 4 h (in case of 6b), then was diluted in AcOEt (100 mL).The organic layer was washed with water (2 60 mL), then brine (70 mL) and dried over sodium sulfate. The organic layer was concentrated under vacuo to give a brown oil. After triturating in Et2O a solid was obtained and filtered off, washed with Et2O and dried to give the desired product 6.
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 18h;
A suspension of 200 mg (1.60 mmol) 1 H-pyrrole-2-carboxylic acid methyl ester and 1.56 g (4.79 mmol) cesium carbonate in 3 ml DMF is heated to 50 C under stirring. Then a solution of 488 mg (1.60 mmol) 1-(4-benzyloxy- phenyl)-2-bromo-ethanone in 1 ml DMF is added within 3 minutes. The reaction mixture is stirred for 18 hours at 50 C. The reaction mixture is filtered with suction and the filtrate is evaporated. The residue is crystallized from diethyl ether to give 1-[2-(4-benzyloxy-phenyl)-2-oxo-ethyl]-1H-pyrrole-2- carboxylic acid methyl ester as beige crystals; HPLC/MS 2.51 min (A), [M+H] 350.
methyl 1-but-2-ynyl-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
Stage #1: methyl Pyrrole-2-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h;
Stage #2: 1-Bromo-2-butyne In N,N-dimethyl-formamide; mineral oil at 20℃; for 48h;
General procedure for propargylation of pyrrole and indole derivatives.
General procedure: To a stirred solution of substituted methyl 1H-pyrrole-2-carboxylate (5 mmol) in DMF (10 mL) was added solid NaH (8 mmol) portionwise at 0 °C over 30 min. The reaction mixture was stirred at room temperature for 30 min. followed by dropwise addition of propargyl bromide or 1-bromobut-2-yne (6 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 2 d. Water (30 mL) was added, and the mixture was extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (4 × 25 mL) and dried over MgSO4. Evaporation of solvent gave propargyl esters.
methyl 4-(2-chloro-6-fluorobenzoyl)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
methyl 4-(2-chloro-6-fluorobenzoyl)-1H-pyrrole-2-carboxylate To a suspension of AICI3 (2.23 g, 16.8 mmol, 2.5 eq.) in DCM (17 mL) at 0 C was added 2- chloro-6-fluorobenzoyl chloride (1 .8 mL, 13.3 mmol, 2 eq.). The mixture was stirred at 0 C for 10 minutes, and then methyl-i H-pyrrole-2-carboxylate (847 mg, 6.7 mmol, 1 eq.) was added. The mixture was stirred at r.t. for 18 h, cooled to 0 C and aqueous HCI (1 M) added until gas evolution ceased. Rochelle?s salt (sat?d aq., 50 mL) was added and the mixture stirred at r.t. for 45 mm. The mixture was then extracted with DCM (3 x 100 mL), the organic layers combined, washed with 10% NaHCO3(aq) (100 mL) and brine (100 mL), dried over MgSO4, and solvent removed in vacuo. The residue was purified by MPLC on SiC2 with a gradient elution from 0% to 100% EtOAc/petrol to give a white solid (1.74 g, 92%); H NMR (500 MHz;DMSO-d6) 3h 3.83 (3H, s, OMe), 7.02-7.05 (1H, m, H-3), 7.42 (1H, apptd, J= 8.2 and 0.8 Hz,H-5?), 7.49 (1H, d, J= 8.2 Hz, H-3?), 7.57 (1H, dd, J= 1.7 and 3.3 Hz, H-5), 7.61 (1H, td, J=6.3 Hz and 8.2 Hz, H-4?), 12.94 (1H, br s, NH); MS (ES+) m/z 282.3 [M+H] MS (ES-) m/z280.2 [M-H]; HRMS calcd for C13H1035C11F103N1 [M+H] 282.0328, found 282.0333.
63%
With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 16h;
General procedure: To a suspension of AlCl3 (2.5 eq.) in DCM (1mL/mmol AlCl3) at 0C was added the relevant acid chloride (2 eq.) followed by methyl 1H-pyrrole-2-carboxylate (1 eq.). The resulting mixture was allowed to reach RT and stirred for 16h. The reaction was quenched at 0C with a 1M aqueous solution of HCl (20mL). The product was extracted with DCM (3×100mL), washed with an aqueous saturated solution ofNaHCO3 (2×100mL) and brine (100mL). Combined organic layers were dried over Na2SO4 and concentrated in vacuo.
methyl 4-(2,6-difluorobenzoyl)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 20.5h;
To a suspension of aluminium trichloride (277 mg, 2.08 mmol) in DCM (2.1 mL), cooled at 0C, was added 2,6-difluorobenzoyl chloride (209 pL, 1.66 mmol) followed by methyl IHpyrrole-2-carboxylate (104 mg, 0.83 mmol). The resulting solution was stirred at 0 C for 30 mm and allowed to warm to room temperature. After 20 h, the reaction mixture was cooled too C and quenched by cautious addition of I M aq. HCI (1 mL). The resulting solution was stirred at room temperature for 2 h. The reaction was then diluted with water (20 mL) and extracted with DCM (3 x 50 mL). The pooled organic extracts were washed with sat. aq. NaHCO3 and brine (50 mL, respectively), dried over MgSO4 and concentrated in vacuo. The crude product was purified by MPLC on Si02 with gradient elution from 0-40% EtOAc in petroleum ether to give methyl 4-(2,6-difluorobenzoyl)-1 H-pyrrole-2-carboxylate as an orange oil (201 mg, 91%); OH NMR (500 MHz; DMSO-d6) 1H 3.80 (3H, s, OCH3), 7.05 (1H, s, Hpyrrole), 7.26 (2H, appt, J = 8.8 Hz, H-Ar), 7.58 (1H, m, H-pyrrole), 7.59-7.64 (1H, m, H-Ar), 12.90 (IH, brs, NH); MS(ES) mlz 264.3 [M-H].
22%
With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 16h;
General procedure: To a suspension of AlCl3 (2.5 eq.) in DCM (1mL/mmol AlCl3) at 0C was added the relevant acid chloride (2 eq.) followed by methyl 1H-pyrrole-2-carboxylate (1 eq.). The resulting mixture was allowed to reach RT and stirred for 16h. The reaction was quenched at 0C with a 1M aqueous solution of HCl (20mL). The product was extracted with DCM (3×100mL), washed with an aqueous saturated solution ofNaHCO3 (2×100mL) and brine (100mL). Combined organic layers were dried over Na2SO4 and concentrated in vacuo.
methyl 1-(2-(1-acetyl-2-oxocyclohexyl)allyl)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 120℃; for 2h;Inert atmosphere; Sealed tube;
General procedure: Carbonate 14 (0.24 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), Xantphos(13.9 mg, 0.024 mmol) and the N-heterocyclic nucleophile (0.24mmol) were added to a dried tube under argon. The tube was fittedwith a septum and purged further with argon. Toluene (1.5 mL) was added and the sealed tube was placed in an oil bath preheated to120 C. The mixture was stirred at 120 C for 2 h, then cooled to roomtemperature, concentrated in vacuo and purified by flash columnchromatography.
(4S)-4-methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
Stage #1: tert-butyl (5R)-5-methyl-2,2-dioxo-1,2λ6,3-oxathiazolidine-3-carboxylate; methyl Pyrrole-2-carboxylate With potassium <i>tert</i>-butylate In acetonitrile at 20℃; for 1h; Inert atmosphere;
Stage #2: With hydrogenchloride In 1,4-dioxane; methanol at 20℃; for 0.5h;
Stage #3: With triethylamine In methanol at 50℃;
methyl 1-(3-phenylpropyl)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
Stage #1: methyl Pyrrole-2-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5h;
Stage #2: 1-Bromo-3-phenylpropane In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 4h;
64%
Stage #1: methyl Pyrrole-2-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h;
Stage #2: 1-Bromo-3-phenylpropane In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 4h;
1.1 Step 1: Preparation of methyl 1- (3-phenylpropyl) -1H-pyrrole-2-carboxylate (Compound 6a)
NaH (60% w / w mineral oil, 102 mg, 2.55 mmol) was added to a DMF (20 mL) solution containing 1H-pyrrole-2-carboxylate (5) . After stirring at room temperature for 30 minutes, 3-phenylpropyl bromide (324 mg, 1.63 mmol) was slowly added at 0 ° C. The temperature was slowly raised to room temperature and stirred for 4 hours. The reaction mixture was treated with a saturated aqueous solution of NH4Cl (10 mL) and extracted with ethyl acetate (30 mL). The organic extracts were washed with water and brine, and dried over Na2SO4. The crude product was purified by silica gel column chromatography (Hexane-Ethyl acetate, 20: 1) to give compound 6a as a colorless oil (248 mg, 64%).
Stage #1: methyl Pyrrole-2-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h;
Stage #2: 1-Bromo-3-phenylpropane In N,N-dimethyl-formamide; mineral oil at 20℃;
1 Procedure 2 -intermediate for A64
roundbottom flask with stir bar was charged with NaH (210 mg, 60 wt%,5.13 mmol,1.2 equiv) and DMF (20 ml_). Methyl 1H-pyrrole-2-carboxylate (535 mg, 4.27 mmol,1.0 equiv) was slowly added to the reaction mixture, and the solution was stirred at room temperature for 30 min. After 30 min, (3-bromopropyl)benzene (936 mg, 4.70 mmol,1.1 equiv) was added, and the reaction mixture was allowed to stir at room temperature overnight. The next morning, the reaction mixture was diluted with DCM (200 ml_) and washed with water (3 x 200 ml_). The organic layer was dried over Na2SC>4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel (0387) chromatography (0-15% EtOAc in hexanes) to yleld the desired product.
methyl 1-(2-(3-acetyl-2-oxotetrahydrofuran-3-yl)allyl)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 120℃; for 2h;Inert atmosphere; Sealed tube;
General procedure: Carbonate 14 (0.24 mmol), Pd2(dba)3 (11 mg, 0.012 mmol), Xantphos(13.9 mg, 0.024 mmol) and the N-heterocyclic nucleophile (0.24mmol) were added to a dried tube under argon. The tube was fittedwith a septum and purged further with argon. Toluene (1.5 mL) was added and the sealed tube was placed in an oil bath preheated to120 C. The mixture was stirred at 120 C for 2 h, then cooled to roomtemperature, concentrated in vacuo and purified by flash columnchromatography.
Stage #1: methyl Pyrrole-2-carboxylate; dichloromethyl propyl ether With aluminum (III) chloride In nitromethane; dichloromethane at -15℃; for 2.16667h;
Stage #2: With water In nitromethane; dichloromethane chemoselective reaction;
1-(5-bromo-2-cyanopyridin-3-yl)-1H-pyrrole-2-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With caesium carbonate; at 130℃; for 0.166667h;Microwave irradiation;
General procedure: Under inert atmosphere, a mixture of nitrile A (1.0 equiv.), methyl ester B (tO equiv.) and cesium carbonate (2.5 equiv.) in DMF or DMA (0.20 moLL1) was submitted to microwave irradiation at 130CC for 10 minutes. The reaction mixture was neutralized with aqueous HCI(IN) and extracted twice with EtOAc, The organic layers were combined, washed with brine, dried over MgSO4, concentrated and purified by flash column chromatography on silica gel (using a gradient of EtOAc in cyclohexane as eluent) to afford the product. nj: I Hpyrrole2carboxylic acid methyl esterCompound 1 was obtained according to general procedure 1(u), starting from 5bromo3 fluoropyridine2carbonitrile and pyrrole2carboxylic acid methyl ester. It was isolated as a yellow sohd in 53% yield. M/Z (M[79Br]+H) 306.
1-(2-chloro-5-cyanopyridin-4-yl)-1H-pyrrole-2-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22%
At 0 C, to a suspension of sodium hydride (60% dispersion in oil, I 5 equiv) in DMF or DMA(080 moLL1), a solution of methyl ester B (tO equiv.) in DMF or DMA (0.65 moLL1) wasslowly added, foHowed after 15 minutes by a solution of nitrile A (11 equiv.) in DMF or DMA(0.65 moLL1). The reaction mixture was stirred at 70 C (oil bath) for 3 hours, before beingpoured into an ice cold saturated aqueous solution of NH4CI and extracted twice with CH2CI2.The organic layers were combined, washed with brine, dried over MgSO4, concentrated under vacuum and purified by flash column chromatography on silica gel (using a gradient of EtOAc in cyclohexane as eluent) to afford the product.
1-(3,6-dichloro-pyridazin-4-yl)-1H-pyrrole-2-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
With caesium carbonate; In N,N-dimethyl acetamide; at 80℃; for 2h;Sealed tube;
Under dry atmosphere, in a sealed vial, a mixture of <strong>[6082-66-2]<strong>[6082-66-2]3,4,6-trichloropyridazin</strong>e</strong> (1.2 equiv.), methyl 2-pyrrole carboxyiate (1.0 equiv.) and cesium carbonate (1.7 equiv.) in anhydrous DMA (0.10 mol.L"1) was heated at 80 C for 2 hours. After cooling to room temprerature, the reaction mixture was neutralized with aqueous NH4CI and extracted twice with EtOAc. The combined organic layers were washed with water, dried with brine and over MgS04, filtered off and concentrated under vacuum. Purification by flash column chromatography on silica gel (using 0% to 15% EtOAc in cyclohexane as eluent) afforded the product as a white solid in 43% yield. 1H-NMR (400 MHz, DMSO-D6): 8.46 (s, 1 H, Ar); 7.39 (dd, J 2.7, 1 .8 Hz, 1 H, Ar); 7.16 (dd, J 3.8, 1.8 Hz, 1 H, Ar); 6.50 (dd, J 3.8, 2.7 Hz, 1 H, Ar); 3.68 (s, 3H, CH3). M/Z (M[35CI][35CI]+H)+ = 272.4.
methyl 4-(2,3-difluorobenzoyl)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
With aluminum (III) chloride In dichloromethane at 0 - 20℃; for 16h; regioselective reaction;
General procedure A:
General procedure: To a suspension of AlCl3 (2.5 eq.) in DCM (1mL/mmol AlCl3) at 0°C was added the relevant acid chloride (2 eq.) followed by methyl 1H-pyrrole-2-carboxylate (1 eq.). The resulting mixture was allowed to reach RT and stirred for 16h. The reaction was quenched at 0°C with a 1M aqueous solution of HCl (20mL). The product was extracted with DCM (3×100mL), washed with an aqueous saturated solution ofNaHCO3 (2×100mL) and brine (100mL). Combined organic layers were dried over Na2SO4 and concentrated in vacuo.
methyl 4-(2-bromo-6-fluorobenzoyl)-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 16h;
General procedure: To a suspension of AlCl3 (2.5 eq.) in DCM (1mL/mmol AlCl3) at 0C was added the relevant acid chloride (2 eq.) followed by methyl 1H-pyrrole-2-carboxylate (1 eq.). The resulting mixture was allowed to reach RT and stirred for 16h. The reaction was quenched at 0C with a 1M aqueous solution of HCl (20mL). The product was extracted with DCM (3×100mL), washed with an aqueous saturated solution ofNaHCO3 (2×100mL) and brine (100mL). Combined organic layers were dried over Na2SO4 and concentrated in vacuo.
With aluminum (III) chloride; In dichloromethane; at 0 - 20℃; for 12h;
Anhydrous AlCl3 (2.35g, 18mmol) was suspended in anhydrous CH2Cl2 (30mL),Cool to 0C, add 2-fluoronitrostyrene (6mmol), 2a (6mmol), r.t for 12h,The organic phase was washed with a saturated NaCl aqueous solution, dried, and the solvent was distilled off to obtain 3c, which was directly used in the next reaction.NiCl2·6H2O (6 mmol) was added to methanol (25 mL) in which compound 3c was dissolved, and stirred under ice bath conditions for 5 min, NaBH4 (24 mmol) was added, and the ice bath was reacted for 1 h.At the end of the reaction, add saturated NH4Cl solution (25mL), filter, evaporate the solvent, add HCl (1M) solution to adjust the pH to 4-5, add CH2Cl2 solution to extract twice, retain the aqueous phase, add NaOH (1M) solution to adjust the pH to Alkaline, the organic phase was extracted twice with CH2Cl2, the organic phase was retained, dried over anhydrous Na2SO4 overnight, and the solvent was evaporated to obtain the product, with a total yield of 77% in two steps.
With dichloro bis(acetonitrile) palladium(II); norbornene; potassium hydrogencarbonate In N,N-dimethyl acetamide at 120℃; for 37.5h; Sealed tube; Inert atmosphere;
5
0.25g (2mmol) α-pyrrole methyl ester (V), 0.93mL (4.06mmol) tetradecyl chloride (IV1) and 0.6g (6mmol) KHCO3, 0.38g (4mmol) were respectively added to a 20mL microwave reaction tube Norbornene, 0.05 g (0.2 mmol) PdCl 2 (MeCN) 2 , and 10 mL anhydrous dimethylacetamide (DMA) were used as solvents; the seal was sealed after being protected by argon. Set microwave synthesis parameters: temperature 120°C, reaction time: 37h, microwave power: medium; pre-stir for 30min, after the reaction is over, wait for natural cooling, the reaction system is extracted twice with petroleum ether 1:3, and washed twice with saturated sodium chloride water. The crude product was obtained by adding anhydrous sodium sulfate to remove water, and then rotary evaporation under reduced pressure to remove the solvent. Cyclohexane:ethyl acetate=70:160:1 as eluent gradient elution, and the product was separated by column chromatography to obtain 0.57 g of yellow oily product as shown in Figure 8, with a yield of 71.2%.
methyl 5-dodecyl-1H-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With dichloro bis(acetonitrile) palladium(II); norbornene; potassium hydrogencarbonate In N,N-dimethyl acetamide at 90℃; for 22.5h; Microwave irradiation; Inert atmosphere;
1
Into a 20mL microwave reaction tube were added0.25g (2mmol) α-Methyl pyrrolate (V), 0.831mL (4.06mmol)Dodecyl chloride (IV1) and 0.6g (6mmol)KHCO3,0.38g (4mmol) norbornene,0.05g (0.2mmol) PdCl2(MeCN)2,And 10 mL of anhydrous dimethylacetamide (DMA) as a solvent; sealed with argon protection. Set microwave synthesis parameters: temperature at 90°C, reaction time: 22h, microwave power: medium; pre-stir for 30min, after the reaction is over, wait for natural cooling, the reaction system is extracted twice with petroleum ether 1:3, washed twice with saturated sodium chloride water , adding anhydrous sodium sulfate to remove water and then rotary evaporation under reduced pressure to remove the solvent to obtain the crude product. Cyclohexane:ethyl acetate=70:160:1 as eluent gradient elution, and the product was separated by column chromatography to obtain 0.47 g of yellow oily product as shown in Figure 1, with a yield of 81.0.%.
With tripotassium phosphate tribasic; copper(I) tetrakis(acetonitrile) hexafluorophosphate In acetonitrile at 25℃; for 12h; Sealed tube;
Route 5
A 100 mL vial with stir bar was charged with methyl pyrrole-2-carboxylate (100.00 mg, 0.80 mmol, 1.00 equiv.), isoquinolin-5-ylboronic acid (414.73 mg, 2.40 mmol, 3.00 equiv.), K3PO4 (508.92 mg, 2.40 mmol, 3.00 equiv.), Cu(MeCN)4PFe (148.65 mg, 0.40 mmol, 0.50 equiv.) and ACN (15 mL, 0.05 M). The vial was capped and placed in a 25°C bath. The reaction mixture was stirred at 25°C for 12 h. The reaction mixture was poured into EtOAc (80 mL) and washed with H2O (1 x 40 mL) and brine (1 x 40 mL). The organic layer was dried over Na2SC>4, filtered and concentrated in vacuo. The resulting crude material was purified via silica gel chromatography to yield the desired product.
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