* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With triethylamine In dichloromethane at 20℃; for 2 h;
Boc2O (9.8 g, 44.7 mmol) and TEA (6.3 mL, 44.7 mmol) was added to pyrrole (25) (3.0 g, 29.8 mmol) in DCM (15 mL) and the resulting mixture was stirred for 2h at room temperature and then worked up with DCM (2 .x. 400 mL) and water (400 mL). The combined organic layers were dried over MgSO4 and were concentrated to obtain 26 as white solid (7.5 g). Yield: 94percent; 1H NMR (300 MHz, CDCl3) δ (ppm) 7.26 (s, 2H), 7.24 (t, J = 2.4 Hz, 1H), 6.22 (t, J = 2.4 Hz, 1H), 1.60 (d, J = 11.7 Hz, 9H); ESI [M + H] = 169.0.
94%
With triethylamine In dichloromethane at 20℃; for 2 h;
Boc2O (43.65 g, 0.2 mol) and TEA (20.2 g, 0.2 mol)were added to pyrrole (13.42 g, 0.2 mol) in DCM (100 mL)and the resulting mixture was stirred for 2 h at room temperatureand then worked up with DCM (2 x 400 mL) andwater (400 mL). The combined organic layers were driedover MgSO4 and were concentrated to obtain 16 as acolorless oil (31.4 g, yield: 94percent). 1H NMR (600 MHz,CDCl3): 7.27 (s, 2H), 6.25 (s, 2H), 1.62 (s, 9H); 13C NMR(150 MHz, CDCl3): 148.95, 119.98, 111.87, 83.61, 28.01.ESI-MS: m/z 168.4 [M + H]+.
86%
With dmap In acetonitrile at 20℃; for 15 h;
Procedure: 70 g (1.04 mol) of pyrrole, 274 g (1.25 mol) of di-t-butyl dicarbonate, 17.6 g (0.1 mol) of 4-dimethylaminopyridine and 1 liter of acetonitrile were added to a 3000 ml single-necked flask , The mixture was stirred at room temperature for 15 hours, and acetonitrile was concentrated to obtain a crude product.The crude product was purified by column chromatography using petroleum ether and ethyl acetate eluent system to give 150 g of 1-tert-butoxycarbonylpyrrole (yield 86percent).
78.3%
With dmap In acetonitrile at 25℃; for 2 h;
Step A: DMAP (1.00 g, 8.2 mmol, 0.14 eq.) was added to a solution of pyrrole (4.00 g, 59 mmol, 1.00 eq.) and(Boc)2O (15.60 g, 71.5 mmol, 1.20 eq.) dissolved in acetonitrile (200 mL). The mixture was stirred at 25°C for 2hours. The mixture was concentrated and the residue was purified by a silica gel column (the eluent is PE) to givet-butyl pyrryl-1-formate (7.80 g, 46.7 mmol, 78.3percent yield) as colorless liquid.
70%
With dmap; triethylamine In acetonitrile
The starting material was prepared as follows: Triethylamine (13 ml, 93 mmol), 4-(N,N-dimethylamino)pyridine (100 mg), and di-t-butyl dicarbonate (18.1 g, 83 mmol) were added successively to a solution of pyrrole (5 g, 74.6 mmol) in acetonitrile (125 ml). The reaction mixture was then heated at 60° C. for 30 minutes. The reaction was allowed to cool and the solvent was removed by evaporation. The residue was purified by flash column chromatography eluding with isohexanes/ethyl acetate (100/0 and then 95/5) to give 1-t-butoxycarbonylpyrrole (8.74 g, 70percent).
Reference：
[1] European Journal of Organic Chemistry, 2005, # 11, p. 2207 - 2212
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[4] European Journal of Medicinal Chemistry, 2011, vol. 46, # 4, p. 1153 - 1164
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[10] Organic Letters, 2010, vol. 12, # 24, p. 5740 - 5743
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[12] Patent: CN102875535, 2016, B, . Location in patent: Paragraph 0029-0031
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[15] New Journal of Chemistry, 2018, vol. 42, # 13, p. 10472 - 10475
[16] Tetrahedron, 2009, vol. 65, # 34, p. 6877 - 6881
[17] Chemistry - A European Journal, 2017, vol. 23, # 46, p. 10962 - 10968
[18] Patent: EP3248968, 2017, A1, . Location in patent: Paragraph 0077
[19] Journal of Medicinal Chemistry, 1994, vol. 37, # 9, p. 1262 - 1268
[20] Tetrahedron Letters, 2009, vol. 50, # 51, p. 7169 - 7171
[21] Patent: US6265411, 2001, B1,
[22] Angewandte Chemie, 1984, vol. 96, # 4, p. 291 - 292
[23] Patent: US2014/179680, 2014, A1, . Location in patent: Paragraph 0756
2
[ 109-97-7 ]
[ 1538-75-6 ]
[ 5176-27-2 ]
Reference：
[1] Organic and Biomolecular Chemistry, 2013, vol. 11, # 26, p. 4327 - 4332
3
[ 109-97-7 ]
[ 24608-52-4 ]
[ 5176-27-2 ]
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[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 21, p. 3509 - 3513
4
[ 114221-05-5 ]
[ 934-16-7 ]
[ 1006-65-1 ]
[ 5176-27-2 ]
[ 114221-06-6 ]
[ 7710-44-3 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 10, p. 2268 - 2274
With magnesium In tetrahydrofuran for 8h; Heating;
37%
In tetrahydrofuran for 2.5h; Inert atmosphere; Reflux;
1.1 tert-Butyl 11-azatricyclo[6.2.1.02,7]undeca-2,4,6,9-tetraene-11-carboxylate (D3)
To a 1000 mL three neck round bottom flask fitted with condenser, magnetic stir bar and dropping funnel, activated magnesium turning (1.64 g, 68.5 mmol) was added and the flask was flame dried under vacuum. The system was flushed with argon and allowed to cool. N-Boc- pyrrole (9.5 g, 57.1 mmol) in 200 mL of dry THF was introduced into the flask and heated to gentle reflux. 2-Fluorobromobenzene (10 g, 57.1 mmol) dissolved in 200 mL of dry THF was added dropwise under argon atmosphere over a period of 30 min and refluxed for 2 h. The initiation of reaction was indicated by solution turning turbid followed by yellow in colour. The solution was cooled and poured into a flask containing 500 mL aqueous solution of ammonium chloride (300 g) and concentrated ammonium hydroxide (10 mL, 28.0% w/w NH3), The aqueous layer was extracted with petroleum ether (3 X 400 mL), combined organic layer dried over anhydrous sodium sulphate and concentrated, the residue was purified by CC(PE:EA=30:1) to afford D3 (5.1 g, 37%) as a yellow solid. LCMS: BONB-00113-133(ESI) m/z=187.9(M- (CH3)3)+, t=1.330 min (215 nm).
36.3%
With magnesium In tetrahydrofuran at 66℃; for 8h;
4.B
Step B: A mixed solution of t-butyl pyrryl-1-formate (4.60 g, 27.5 mmol, 1.00 eq.) and magnesium powder (720 mg,27.5 mmol, 1.0 eq.) in THF (20 mL) was heated to 66°C in an oil bath. 1-bromo-2-fluoro-benzene (4.88 g, 27.89mmol, 1.0 eq.) was added slowly in 20 min, and after the addition, the mixture was stirred at 66°C for 8 hours. Thesolvent was removed under reduced pressure and 0.5N HCl aqueous solution was added, followed by extractionwith DCM. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The resulting residue was purified by column chromatography (PE/EA = 20/1) to give t-butyl 1,4-dihydro-1,4-epiminonaphthyl-9-formate (2.43 g, 10 mmol, 36.3% yield) as yellow liquid.
With dmap; triethylamine In acetonitrile at 20℃; for 21h;
1-(tert-Butoxycarbonyl)-1H-pyrrole
A solution of pyrrole (38.0 mL, 0.504 mol), di-tert-butylcarbonate (146.45 g, 0.671 mol),and DMAP (9.38 g, 0.077 mol) in a mixture of acetonitrile (375 mL) and triethylamine (200mL) was stirred at r.t. for 21h. Water (125 mL) was added and the resulting mixture wasleft for 30 min with stirring. Then it was concentrated and the residue was partitionedbetween water and hexane. The water layer was washed with hexane and discarded. The combinedorganic layers were washed with brine, dried, and concentrated. The expected product was isolated byvacuum distillation (70-79 °C, 3.4-8.5 mbar) to give 1-(tert-Butoxycarbonyl)-1H-pyrrole (64.46 g,0.386 mol, 77%) as a colourless oil.
[1069] Methyl-3-bromo-propiolate (83.7 g, 0.513 mole) is added to N-t-butyloxy-pyrrole (430 ml, 2.57 mole) under nitrogen. The dark mixture is warmed in a 90 C. bath for 30 h, is cooled, and the bulk of the excess N-t-butyloxy-pyrrole is removed in vacuo using a dry ice/acetone condenser. The dark oily residue is chromatographed over 1 kg silica gel (230-400 mesh) eluting with 0-15% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 97 g (57%) of 7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate as a dark yellow oil. HRMS (FAB) calc'd for C13H16BrNO4+H: 330.0341, found 330.0335 (M+H)+.
57%
at 90℃; for 30h;
Methyl-3-bromo-propiolate (83.7 g, 0.513 mole) is added to N-t-butyloxy-pyrrole (430 ml, 2.57 mole) under nitrogen. The dark mixture is warmed in a 90 C. bath for 30 h, is cooled, and the bulk of the excess N-t-butyloxy-pyrrole is removed in vacuo using a dry ice/acetone condenser. The dark oily residue is chromatographed over 1 kg silica gel (230-400 mesh) eluting with 0-15% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 97 g (57%) of 7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate as a dark yellow oil. HRMS (FAB) calc'd for C13H16BrNO4+H: 330.0341, found 330.0335 (M+H)+.
32.1%
at 90℃; for 16h;Inert atmosphere;
A mixture of S2 (100.0 g, 613.61 mmol) in tert-butyl 1H-pyrrole-1-carboxylate (410.4 g, 2.45 mol) was stirred at 90 C for 16 hrs. After cooled to room temperature, the mixture was purified by silica gel column (eluting with 1% EtOAc in PE to 5% EtOAc in PE) to afford S3 as yellow oil (65.0 g, yield: 32.1%). 1H NMR (400MHz, CHLOROFORM-d): delta 7.20 - 7.02 (m, 2H), 5.57 - 5.45 (m, 1H), 5.23 - 5.08 (m, 1H), 3.82 (s, 3H), 1.44 (s, 9H).
at 95℃; for 30h;
Step 2: Into a 2000-mL 3-necked round-bottom flask was placed <strong>[23680-40-2]methyl 3-bromopropiolate</strong> (120 g, 736.33 mmol, 1.00 equiv) and tert-butyl 1H-pyrrole-1-carboxylate (615.61 g, 3.68 mol, 5.00 equiv). The resulting solution was stirred for 30 hr at 95 C. in an oil bath. The reaction mixture was cooled and distilled under reduced pressure (20 mm Hg). The fraction collected at 55 C. was purified by silica gel chromatography (ethyl acetate/petroleum ether, 1:20) to afford 7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate as a yellow liquid.
In neat (no solvent); at 95℃; for 48h;
Step 2: 3-Bromo-7-aza-bicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylic acid 7-tert-butyl ester 2-methyl ester A mixture of <strong>[23680-40-2]bromo-propynoic acid methyl ester</strong> (81.2 g, 497 mmol) and t-butyl pyrrole-1-carboxylate (216.7 g, 1292 mmol, Combiblock) were combined and heated to 95 C for 2 days. After completion of the reaction, the reaction mixture was concentrated in high vacuum and purified by flash column chromatography (230-400 size mesh silica gel) using gradient elution of ethyl acetate (7.5-8.0%) in n-hexane to afford the pure product as reddish brown gel. 1H NMR (400 MHz, DMSO-d6): delta 7.25-7.22 (m, 2H), 5.30 (s, 1 H), 5.15 (s, 1 H), 3.72 (s, 3H), 1.34 (s, 9H). LCMS: (Method A) 232.0 (M-Boc+H)+, Rt. 4.7 min, 95.6% (Max).
methyl 3-bromo-7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 95℃; for 24h;
The product of Step A (1 1.3g, 69mmol) and f-butyl pyrrole- 1 -carboxylate (30 mL, 1 SOmmol) was combined and heated at 95 and allowed to stir at this temperature for 24 hours. The product was purified using chromatography on silica to provide compound 7OC as a yellow oil.
at 90℃; for 14h;Sealed tube;
A mixture of <strong>[23680-40-2]methyl 3-bromopropiolate</strong> (5.00 g, 28.2 mmol, 1.0 eq) and tert-butyl 1H-pyrrole-1-carboxylate (14.00 g, 84.7 mmol, 3.0 eq) in a sealed tube was heated to 90 C. for 14 hr. After completion of the reaction (monitored by TLC, 5% ethyl acetate-hexane, Rf=0.3), the reaction mixture was purified without work up by flash column chromatography on silica gel (100-200 mesh), eluting with 5% ethyl acetate in hexanes to afford 7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate (2.0 g, 20%) as a brown oil. LCMS m/z=344.2 (M+1); purity=75%.
With isopentyl nitrite In dichloromethane; acetonitrile at 20℃; for 3h; Reflux;
4.3.5. Synthesis of 8
General procedure: Compound 27: To a solution of N-Boc pyrrole (1.50 g, 9.0 mmol) in 60 mL of CH3CN was added a solution of anthranilic acid (1.03 g, 7.5 mmol) in 35 mL of CH2Cl2 and a solution of isoamyl nitrite (1.76 g, 15 mmol) in 30 mL of CH3CN simultaneously at 25 °C over 30 min. The mixture was refluxed for 2 h, then the whole was cooled to rt. The organic solvents were evaporated to give a reddish brown oil, which was column-chromatographed (Et2O/n-hexane = 1:3 to 1:2) to give 27 (924 mg, 41%) as a brown oil.
41%
With isopentyl nitrite In dichloromethane; acetonitrile for 2h; Heating;
41%
With isopentyl nitrite In dichloromethane; acetonitrile for 2h; Heating;
A mixture of m<strong>[41658-03-1]ethyl 3-bromopropiolate</strong> (5.00 g, 28.2 mmol, 1.0 eq) and tert-butyl 1 H-pyrrole-1-carboxylate (14.00 g, 84.7 mmol, 3.0 eq) in a sealed tube was heated to 90 C for 14 h. After completion of the reaction (monitored by TLC, 5% ethyl acetate-hexane, Rf = 0.3), The reaction mixture was purified without work up by flash column chromatography on silica gel (100-200 mesh), eluting with 5% ethyl acetate in hexanes to afford 7-tert-butyl 2-methyl 3- bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate (2.0 g, 20%) as a brown oil. LCMS m/z = 344.2 (M+1); purity = 75%
2 g
at 90℃; for 14h;Sealed tube;
Reaction Step 2 Synthesis of 7-tert-butyl 2-ethyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate A mixture of m<strong>[41658-03-1]ethyl 3-bromopropiolate</strong> (5.00 g, 28.2 mmol, 1.0 eq) and tert-butyl 1H-pyrrole-1-carboxylate (14.0 g, 84.7 mmol, 3.0 eq) in a sealed tube was heated to 90 C. for 14 h. After completion of the reaction (monitored by TLC, 5% ethyl acetate-hexane, Rf=0.3), The reaction mixture was purified without work up by flash column chromatography on silica gel (100-200 mesh), eluting with 5% ethyl acetate in hexanes to afford 7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate (2.0 g, 20%) as a brown oil. LCMS m/z=344.2 (M+1); purity=75%.
(1SR,4RS)-7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30%
at 90℃; for 20h;
Into a 50-mL round-bottom flask, was placed tert-butyl 1H-pyrrole-1-carboxylate (3) (14.4 g, 86.12 mmol, 3.00 equiv), <strong>[23680-40-2]methyl 3-bromoprop-2-ynoate</strong> (2) (4.7 g, 28.84 mmol, 1.00 equiv). The resulting solution was stirred for 20 h at 90 C. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:30?1:15) as eluent to furnish 2.89 g (30%) of 7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate (4) as a yellow oil.
Stage #1: N-tert-butyloxycarbonyl-pyrrole With n-butyllithium; Triisopropyl borate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78 - 20℃;
Stage #2: N-methyliminodiacetic acid In dimethyl sulfoxide at 75℃; for 2h;
29%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - 20℃; for 3.16667h; Inert atmosphere;
Stage #2: N-tert-butyloxycarbonyl-pyrrole In tetrahydrofuran; hexane at -78℃; for 0.5h; Inert atmosphere;
Stage #3: N-methyliminodiacetic acid Inert atmosphere;
3
To a 50 mL Schlenk flask equipped with a stir bar was added THF (15 mL) and diisopropylamine (920 microliters). The solution was cooled to -78 0C and then to the stirred solution was added dropwise n-BuLi (2.5 M in hexanes, 2.75 mL). The solution was maintained at -78 0C for 10 min, and then was allowed to warm to room temperature with stirring for 3 h. The solution was cooled to -78 0C, and to the stirred solution was added dropwise via cannula N-te/t-butoxycarbonylpyrrole (1.016 g, 6.074 mmol) as a solution in THF (15 mL + 10 mL washing). The solution was stirred for 30 min. To the yellow solution was added dropwise triisopropylborate (1.40 mL, 6.07 mmol). The solution was stirred for 10 min at -78 0C and then was allow to warm to room temperature with stirring overnight (1 1 h). To the near-black solution was added DMSO (15 mL). The THF was then removed in vacuo and the resulting DMSO solution was transferred to a 50 mL pressure-equalizing addition funnel. The funnel was fitted onto a 100 mL 3-neck round-bottom flask charged with N-methyliminodiacetic acid (1.407 g, 9.563 mmol) and DMSO (20 mL). To a second neck was fitted a short-path distillation apparatus connected to vacuum. The third neck of the flask was sealed with a septum. The system was placed under vacuum (1 Torr) and the mixture was heated to 75 0C upon which the DMSO began to distill. The DMSO solution of lithium triisopropyl 2-(N-te/t-butoxycarbonyl)pyrrole borate was added to the distilling mixture dropwise over 1 h. The mixture was further distilled to near dryness (1 h). The resulting residue was suspended in acetone and concentrated in vacuo onto Celite (10 g). The resulting powder was lyophilized for one day to remove additional DMSO and then was subjected to flash chromatography on silica gel (Et2O:MeCN, 100:0 -» 80:20) to afford 2e as an off-white crystalline solid (565 mg, 29%). This method is depicted in the scheme below.[00129] TLC (EtOAc) Rf = 0.35, stained with KMnO4. 1H-NMR (500 MHz,CD3CN) δ 7.38 (dd, / = 3.0, 1 .5 Hz, 1 H), 6.61 (dd, / = 3.0, 1.5 Hz, 1 H), 6.20 (t, / = 3.0 Hz, 1 H), 4.09 (d, / = 17 Hz, 2H), 4.05 (d, 17 Hz, 2H), 2.79 (s, 3H), 1.54 (s, 9H). 13C-NMR (125 MHz, CD3CN) δ 169.9, 151.2, 126.2, 124.9, 1 12.1 , 84.9, 65.9, 49.9, 28.0. 11 B-NMR (96 MHz, CD3CN) δ 1 1.1. HRMS (El + ) Calculated for C14H20BN2O6 (M + H) + : 323.1414, Found: 323.1414. IR (KBr, cm -1) 3174, 31 18, 3012, 2982, 2941 , 1743, 1457, 1337, 1304, 1296, 1253, 1235, 1 146, 1027, 1008, 815, 747.
2-ethoxycarbonyl-3-bromo-7-tert-butoxycarbonyl-7-azabicyclo[2.2.1]heptane-2,5-diene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
at 90℃; for 40h;Inert atmosphere;
10.8 g of 1-tert-butoxycarbonylpyrrole (0.065 mol) and 2.30 g (0.013 mole) of <strong>[41658-03-1]ethyl 3-bromopropynanoate</strong> were stirred at 90 C for 40 hours under nitrogen atmosphere. The reaction was treated with petroleum ether And ethyl acetate in an eluent system to give 2.05 g of 2-ethoxycarbonyl-3-bromo-7-tert-butoxycarbonyl-7-azabicyclo [2.2.1] heptane- 2,5-diene (yield 45%).
3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylic acid 7-tert-butyl ester 2-methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 95℃; for 48h;
A mixture of <strong>[23680-40-2]bromo-propynoic acid methyl ester</strong> (81.2 g, 497 mmol) and t-butyl pyrrole-1-carboxylate (216.7 g, 1292 mmol, Combiblock) were combined and heated to 95Cfor2days. After completion of the reaction, the reaction mixture was concentrated in high vacuum and purified by flash column chromatography (230-400 size mesh silica gel)using gradient elution of ethyl acetate (7.5-8.0%) in n-hexane to afford the pure product as reddish brown gel. 1H NMR (400 MHz, DMSO-d6): 6 7.25-7.22 (m, 2H), 5.30 (s, 1 H),5.15 (s, 1H), 3.72 (s, 3H), 1.34 (s, 9H). LCMS: (Method A) 232.0 (M-Boc-f-H), Rt. 4.7 mm, 95.6% (Max).
A mixture of compound S4a (10 g, 56.5 mmol) and tert-butyl 1H-pyrrole-1-carboxylate (50 mE) was stirred at 1100 C. for 12 hours. The reaction mixture was cooled down to room temperature and purified by column chromatography (EtOAc/PE) to give compound 84b (7 g, yield, 37% yield). ?H NMR (400 MHz, CDC13) 7.13 (brs, 2H), 5.48 (brs, 1H), 5.13 (brs, 1H), 4.15-4.37 (m, 2H), 1.41 (s, 9H), 1.32 (t, J=7.15, 3H).
20%
at 90℃; for 14h;Sealed tube;
Reaction Step 2. Synthesis of 7-tert-butyl 2-ethyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylateA mixture of <strong>[23680-40-2]methyl 3-bromopropiolate</strong> (5.00 g, 28.2 mmol, 1.0 eq) and tert-butyl 1H-pyrrole-1-carboxylate (14.00 g, 84.7 mmol, 3.0 eq) in a sealed tube was heated to 90 C. for 14 h. After completion of the reaction (monitored by TLC, 5% ethyl acetate-hexane Rf=0.3), The reaction mixture was purified without work up by flash column chromatography on silica gel (100-200 mesh), eluting with 5% ethyl acetate in hexanes to afford 7-tert-butyl 2-methyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate (2.0 g, 20%) as a brown oil. LCMS m/z=344.2 (M+1); purity=75%.
tert-butyl 4-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-5-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
Stage #1: 5,6-dihydro-<6H>-cyclopenta-<b>-thiophene-4-one With sodium hydride In tetrahydrofuran at 20℃; for 0.333333h;
Stage #2: N-tert-butyloxycarbonyl-pyrrole In tetrahydrofuran Reflux;
diethyl 2-(1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl)-2-methylmalonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
With 2,6-dimethylpyridine; fac-tris(2-phenylpyridinato-N,C2')iridium(III); In acetonitrile; at 20℃; for 24h;Inert atmosphere; Irradiation;
General procedure: To a 7 mL vial equipped with magnetic stir bar was added bromomalonate (1.0 equiv,0.40 mmol), 2,6-lutidine (1.0 equiv, 0.40 mmol), tris[2-phenylpyridinato-C2,N]iridium(III) (1 mol %, 4.0 mumol), and heterocycle (5.0 equiv, 2.0 mmol). Dryacetonitrile or DMA (0.5 mL, 0.8 M) was then added and the reaction was sparged withN2 for 15 min. The reaction was set to stir under nitrogen at room temperature surroundedby a string of 1W or two strings of 4W blue LEDs for 24 h. The reaction mixture wasthen diluted with ethyl acetate and extracted with water. The aqueous layer was extractedwith ethyl acetate (2 x 10 mL). The combined organic layers were washed with brine,dried over Na2SO4, and concentrated in vacuo. The residue was purified bychromatography on silica gel, using the solvent system indicated.
7-tert-butyl 2-ethyl 3-bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 90℃; for 14h;Sealed tube;
Reaction step 2. Synthesis of 7-tert-butyl 2-ethyl 3-bromo-7-azabicyclo[2.2.1]hepta- 2,5-diene-2,7-dicarboxylateA mixture of m<strong>[41658-03-1]ethyl 3-bromopropiolate</strong> (5.00 g, 28.2 mmol, 1.0 eq) and tert-butyl 1H-pyrrole-1-carboxylate (14.00 g, 84.7 mmol, 3.0 eq) in a sealed tube was heated to 90 C for 14 h. After completion of the reaction (monitored by TLC, 5% ethyl acetate-hexane, Rf = 0.3), The reaction mixture was purified without work up by flash column chromatography on silica gel (100-200 mesh), eluting with 5% ethyl acetate in hexanes to afford 7-tert-butyl 2-methyl 3- bromo-7-azabicyclo[2.2.1]hepta-2,5-diene-2,7-dicarboxylate (2.0 g, 20%) as a brown oil. LCMS m/z = 344.2 (M+1); purity = 75%.
A mixture of Compound 180B (4.6 g, 28.4 mmol) and tert-butyl 1H-pyrrole-1- carboxylate (23.7 g, 142 mmol) was stirred at 95 C for 30 hours. The resulting mixture cooled down to room temperature and purified by silica gel column chromatography to afford Compound 180C. ?H-NIVIR (CDC13, 400 IVIHz): (5(ppm) 1.42 (s, 9H), 3.80 (s, 3H), 5.13-5.18 (m, 1H), 5.50 (s, 1H), 7.09-7.14 (m, 2H).
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