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Structure of 1631-26-1 * Storage: {[proInfo.prStorage]}
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Chemical Research - Part S, 1999, # 7, p. 420 - 421
[2] Asian Journal of Chemistry, 2013, vol. 25, # 13, p. 7451 - 7456
2
[ 108-31-6 ]
[ 100-46-9 ]
[ 1631-26-1 ]
Yield
Reaction Conditions
Operation in experiment
38%
at 20℃; Reflux
General Procedure: Benzylamine (17 mmol) was added dropwise into a solution of maleic anhydride (20 mmol) in AcOH (10 mL) at room temperature and the resulting suspension was stirred at reflux (overnight). Solvent was removed under reduced pressure and the residue was partitioned between CHCl3 (100 mL) and H2O (30 mL). The aqueous phase was extracted (CHCl3; 3 x 50 mL) and the combined organic phase was washed (saturated aqueous sodium bicarbonate (30 mL) and brine (30 mL)) and the organic phase was dried (Na2SO4), taken to dryness and the residue was purified by silica gel column chromatography.
33%
at 5 - 25℃; for 16 h;
To a stirred solution of furan-2,5-dione (20.0 g, 204.0 mmol) in EtO (500.0 ml) was added dropwise phenylmethanamine (32.8 g, 306.0 mmol) in Et20 (50 ml) at 5—lO °C. The reaction mixture was stirred at room temperature for 16 h. The crystallized acid was filtered and washed with Et20, then added to a mixture of acetic anhydride (40 ml) and CH3COOK (4.0 g). The suspension was heated on a steam bath (70 °C ) for 16 h, dissolved in CH2CI2 (400ml), washed with aq.NaHCO3 (2 x 500 ml) and concentrated. The residue was purified by column chromatography (PE/EtOAc =10/1) to give the desired product as a white solid (12.6 g, yield: 33percent).1H NMR (400 MHz, CDCI3) 7.35—7.28 (m, 5H), 6.70 (s, 2H), 4.67 (s, 2H),
30%
With acetic acid In dichloromethane at 120℃; for 4 h;
Maleic anhydride (0.98 g, 10 mmol) dissolved in glacial acetic acid (15 ml) in, side electromagnetic stirring and slowly instillment animal pen amine (0.83 g, 6 . 67 mmol), the reaction liquid is heated to 120 °C stirring reflux 4 h. TLC detection reaction has been substantially completely, stop stirring, cooled to the room temperature, for a dilute sodium hydroxide solution prepared (8g/100 ml) diluted in and the reaction solution, ethyl acetate (30 ml × 3) extraction three times, the collection of organic phase, the organic phase dried with anhydrous sodium sulfate 12 h. Filtering, environment friendly with silica gel column chromatography, eluting agent is ethyl acetate: petroleum ether=1:10, to obtain white solid 0.41 g, yield 30.0percent.
29%
for 5 h; Reflux
To a suspension of cis-butenedioic anhydride (1b) (49 g, 0.5 mol)in 600mL AcOH was added benzylamine (54 g, 0.5 mmol). The reactionwas then heated to reflux for 5 h. The reaction mixture wasconcentrated and the residue was dissolved in 300 mL EtOAc. TheEtOAc layerwaswashed with saturated aqueous NaHCO3 and brine.The organic layer was dried over anhydrous Na2SO4, concentratedin vacuum, purified by flash chromatography (petroleum ether:-EtOAc 8:1) to afford 1-benzyl-1H-pyrrole-2,5-dione as a whitesolid (26.9 g, 29percent). M.p.: 58-60 °C. 1H NMR (400 MHz, CDCl3) d 4.65(s, 2H), 6.68 (s, 2H), 7.24-7.30 (m, 5H); 13C NMR (100 MHz, CDCl3)d 41.4, 127.8, 128.3, 128.7, 134.2, 136.1, 170.4; HRMS (ESI) m/z calcdfor C11H9NO2[MH] 188.0706, found 188.0709.
Reference：
[1] Journal of Chemical Research - Part S, 1998, # 5, p. 272 - 273
[2] Journal of the Chinese Chemical Society, 2009, vol. 56, # 4, p. 839 - 842
[3] Synthesis, 2004, # 7, p. 995 - 998
[4] Tetrahedron Letters, 1997, vol. 38, # 46, p. 8089 - 8092
[5] Tetrahedron Asymmetry, 2008, vol. 19, # 18, p. 2115 - 2118
[6] Tetrahedron, 1999, vol. 55, # 37, p. 11365 - 11384
[7] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2005, vol. 44, # 7, p. 1476 - 1480
[8] Synlett, 2009, # 2, p. 297 - 301
[9] Organic and Biomolecular Chemistry, 2013, vol. 11, # 3, p. 407 - 411
[10] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 6, p. 1154 - 1176
[11] Analytical Biochemistry, 2011, vol. 418, # 2, p. 184 - 196
[12] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 10, p. 2986 - 2990
[13] Patent: WO2018/137593, 2018, A1, . Location in patent: Page/Page column 189
[14] Patent: CN108929260, 2018, A, . Location in patent: Paragraph 0109-0111
[15] European Journal of Medicinal Chemistry, 2019, p. 408 - 422
[16] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 9, p. 2876 - 2879
[17] Synthesis, 2011, # 10, p. 1595 - 1598
[18] Beilstein Journal of Organic Chemistry, 2012, vol. 8, p. 192 - 200
[19] Angewandte Chemie - International Edition, 2013, vol. 52, # 8, p. 2203 - 2206[20] Angew. Chem., 2013, vol. 125, p. 2259 - 2262,4
[21] Chemical Communications, 2014, vol. 50, # 88, p. 13506 - 13509
[22] Chemical Communications, 2016, vol. 52, # 12, p. 2493 - 2496
[23] Organic Letters, 2018, vol. 20, # 10, p. 2835 - 2838
3
[ 134575-94-3 ]
[ 1631-26-1 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2010, vol. 49, # 4, p. 487 - 488
[2] Journal of Enzyme Inhibition and Medicinal Chemistry, 2012, vol. 27, # 1, p. 117 - 124
[3] Patent: WO2008/92168, 2008, A2, . Location in patent: Page/Page column 19-20
[4] Organic Preparations and Procedures International, 2013, vol. 45, # 4, p. 314 - 320
[5] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2724 - 2732
[6] Journal of Agricultural and Food Chemistry, 2016, vol. 64, # 24, p. 4876 - 4881
[7] Chemistry - An Asian Journal, 2017, vol. 12, # 18, p. 2393 - 2398
[8] New Journal of Chemistry, 2018, vol. 42, # 9, p. 6880 - 6888
[9] Advanced Synthesis and Catalysis, 2018, vol. 360, # 18, p. 3553 - 3562
4
[ 15329-69-8 ]
[ 1631-26-1 ]
Reference：
[1] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2009, vol. 48, # 4, p. 569 - 573
[2] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1983, vol. 22, # 10, p. 1070 - 1071
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1986, vol. 25, p. 342 - 344
[4] Farmaco, 1994, vol. 49, # 10, p. 675 - 677
[5] Tetrahedron Asymmetry, 1997, vol. 8, # 1, p. 101 - 107
[6] Journal of Organic Chemistry, 1997, vol. 62, # 8, p. 2652 - 2654
[7] Pharmaceutical Sciences, 1997, vol. 3, # 2, p. 67 - 71
[8] Farmaco, 2002, vol. 57, # 5, p. 421 - 426
[9] Synthesis, 2003, # 10, p. 1549 - 1552
[10] Arzneimittel-Forschung/Drug Research, 2005, vol. 55, # 2, p. 123 - 132
[11] Journal of the Chemical Society. Perkin Transactions 2, 2002, # 9, p. 1611 - 1619
[12] Journal of Organic Chemistry, 1991, vol. 56, # 20, p. 5893 - 5903
[13] Australian Journal of Chemistry, 1991, vol. 44, # 2, p. 323 - 330
[14] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 1, p. 560 - 568
[15] Journal of Medicinal Chemistry, 2009, vol. 52, # 23, p. 7410 - 7420
[16] Organic and Biomolecular Chemistry, 2010, vol. 8, # 19, p. 4444 - 4450
[17] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 9, p. 2823 - 2834
[18] Journal of Chemical Sciences, 2013, vol. 125, # 6, p. 1529 - 1534
[19] Macromolecules, 2016, vol. 49, # 17, p. 6193 - 6202
5
[ 541-59-3 ]
[ 100-51-6 ]
[ 1631-26-1 ]
Reference：
[1] Organic Preparations and Procedures International, 2008, vol. 40, # 6, p. 574 - 574
[2] Tetrahedron Letters, 2006, vol. 47, # 15, p. 2619 - 2622
[3] Tetrahedron Letters, 1994, vol. 35, # 5, p. 665 - 668
[4] Journal of Organic Chemistry, 1995, vol. 60, # 16, p. 5352 - 5355
6
[ 100-46-9 ]
[ 1631-26-1 ]
Reference：
[1] Tetrahedron Letters, 1988, vol. 29, # 29, p. 3525 - 3528
[2] Journal of Organic Chemistry, 1991, vol. 56, # 20, p. 5893 - 5903
[3] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1983, vol. 22, # 10, p. 1070 - 1071
[4] Gazzetta Chimica Italiana, 1896, vol. 26 I, p. 438
[5] Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 9, p. 2823 - 2834
[6] Journal of Enzyme Inhibition and Medicinal Chemistry, 2012, vol. 27, # 1, p. 117 - 124
[7] Organic Preparations and Procedures International, 2013, vol. 45, # 4, p. 314 - 320
[8] Journal of Chemical Sciences, 2013, vol. 125, # 6, p. 1529 - 1534
[9] Journal of Organic Chemistry, 2015, vol. 80, # 5, p. 2724 - 2732
[10] Journal of Agricultural and Food Chemistry, 2016, vol. 64, # 24, p. 4876 - 4881
[11] Chemistry - An Asian Journal, 2017, vol. 12, # 18, p. 2393 - 2398
[12] New Journal of Chemistry, 2018, vol. 42, # 9, p. 6880 - 6888
[13] Journal of Organic Chemistry, 2018, vol. 83, # 8, p. 4427 - 4440
[14] Advanced Synthesis and Catalysis, 2018, vol. 360, # 18, p. 3553 - 3562
7
[ 133341-92-1 ]
[ 1631-26-1 ]
Reference：
[1] Australian Journal of Chemistry, 1991, vol. 44, # 2, p. 323 - 330
With potassium carbonate;silica gel; In water; acetone;
Example 1 1alpha, 5alpha, 6alpha-3-Benzyl-6-nitro-2,4-dioxo-3-azabicyclo[3.1.0]hexane. To a stirred slurry of potassium carbonate (7.5g;0.054 mole) in acetone (40 ml) and water (1 ml) at ambient temperature was added dropwise, over a period of about 2 hours, a solution of <strong>[563-70-2]bromonitromethane</strong> (5 g - 4.48gA, 0.032 mole) and N-benzylmaleimide (5 g; 0.026 mole) in acetone (40 ml). When reaction was complete (in situ yield 61%), powdered molecular sieves (10 g) were added and the solvent exchanged with toluene by constant volume distillation. The resulting slurry was filtered to remove unreacted potassium carbonate/sieves/tar and the filter cake washed with toluene. The combined toluene filtrates were washed with dilute hydrochloric acid (2M), then concentrated under reduced pressure to approximately 20 ml then cooled to 0-5C. The desired product was subsequently isolated by filtration and dried in vacuo to yield the title compound (3.03gA, 46%) as a white to pale yellow crystalline solid, m.p. 115C. NMR (CDCl3): delta 3.34 (s,2H), 4.46 (s,1H), 4.53 (s, 2H), 7.3 (s, 5H).
With potassium carbonate; acetic acid; In N-methyl-acetamide; water;
Example 2 1alpha, 5alpha, 6alpha-3-Benzyl-6-nitro-2,4-dioxo-3-azabicyclo [3.1.0]hexane. To a stirred slurry of potassium carbonate (7.5 g, 0.054 mole) in dimethylformamide (40 ml) and water (1 ml) at ambient temperature was added dropwise, over a period of about 2 hours, a solution of <strong>[563-70-2]bromonitromethane</strong> (5 g - 4.48gA, 0.032 mole) and N-benzylmaleimide (5 g; 0.026 mole) in dimethylformamide (40 ml). When the reaction was complete (in situ 72%), the excess potassium carbonate was neutralised by the addition of acetic acid (4.68 g, 0.078 mole) and then water (160 ml) was added. The resulting precipitate was isolated by filtration and dried in vacuo to yield the title compound (4.2 gA, 66%) as an off-white/light brown solid, m.p. 114C. NMR (CDCl3):delta 3.34 (s, 2H), 4.46 (s, 1 H), 4.53 (s, 2H), 7.3 (s, 5H).
With potassium carbonate; In N-methyl-acetamide; water;
Example 3 1alpha, 5alpha, 6alpha-3-Benzyl-6-nitro-2.4-dioxo-3-azabicyclo [3.1.0] hexane. To a stirred slurry of potassium carbonate (7.5 g, 0.054 mole) in dimethylformamide (40 ml) and water (1 ml) at ambient temperature was added dropwise, over a period of about 2 hours, a solution of <strong>[563-70-2]bromonitromethane</strong> (5 g - 4.48gA, 0.032 mole) and N-benzylmaleimide (5 g; 0.026 mole) in dimethylformamide (40 ml). When the reaction was complete, the excess potassium carbonate was removed by filtration and then water (160 ml) was added.. The resulting precipitate was isolated by filtration and dried in vacuo to yield the title compound (3.5gA, 54%) as a light brown solid, m.p. 116-117C. NMR (CDCl3): delta 3.34 (s, 2H), 4.46 (s, 1 H), 4.53 (s, 2H), 7.3 (s, 5H).
With D-glucose 6-phosphate; glucose-6-phosphate dehydrogenease; Shewanella yellow enzyme 4; NADP; In ethanol; water; at 28℃; for 1h;pH 8.0;Tris-HCl buffer; Enzymatic reaction;
General procedure: Biotransformations were performed with SYE-4 protein (25 mg/mL) in sterile multi-well plates (500 muL each well) in the presence of Tris-HCl (50 mM, pH 8), NADP+ (200 muM), glucose-6-phosphate (4 mM), glucose-6-phosphate dehydrogenease (1 unit), and substrate 2 mM, 0.8 muL (stock solution in EtOH/H2O (2:1)) at 28 C for 6 h. Samples were collected after 1 h, 3 h and 6 h. The reaction mixture was extracted with ethyl acetate containing the internal standard methyl benzoate and samples were analyzed by chiral GC and GC-MS (Table 1).
4-(1-Benzyl-2,5-dioxo-pyrrolidin-3-ylsulfanyl)-N-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-butyramidine; hydrochloride[ No CAS ]
4-(1-Benzyl-2,5-dioxo-pyrrolidin-3-ylsulfanyl)-N-((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-butyramidine; hydrochloride[ No CAS ]
A mixture of paraformaldehyde (3.37 g), N-benzyhnaleimide (2. 80 g) and N benzylglycine hydrochloride (3.02 g) in toluene (100 mL) was heated to reflux with azeotropic removal of water for 16 hours. The mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexane) to afford the title compound 1 as a low melting white solid (3.60 g, 75%). LCMS: Rf: 2.616 min, M+H+ : 321.
With potassium carbonate; In acetonitrile; at 20℃; for 48h;
To a solution of N-benzylmaleimide (5.Og, 26.7mmol) in MeCN (334ml) was added <strong>[563-70-2]bromonitromethane</strong> (1.87ml, 26.7mmol). K2CO3 (3.69g, 26.7mmol) was added and the reaction mixture vigorously stirred at r.t. After 4 h an additional portion of <strong>[563-70-2]bromonitromethane</strong> (0.2ml) was added. Further addition of <strong>[563-70-2]bromonitromethane</strong> (0.2ml) was added at further 4 h intervals (x4). After 48 h, TLC (50% DCM / heptane) indicated reaction completion. The reaction mixture was evaporated to dryness. The brown residue was purified by column chromatography (100% DCM), giving the title EPO <DP n="30"/>compound as a white solid (3.Og, 42%). 1H NMR (300 MHz, CDCI3) delta: 3.35 (2H, s),4.50 (1H, s), 4.55 (2H, s), 7.2-7.4 (5H, m).
40%
With potassium carbonate; In acetonitrile; at 20℃; for 24h;
To a mixture of N-benzylmaleimide (7.40 g) and K2CO3 (5.50 g) in 500 mL of CH3CN was added <strong>[563-70-2]bromonitromethane</strong> (5.60 g) dropwise. The reaction mixture was stirred for 24 h at room temperature and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 4:1 (v/v) PE/EA) to give the title compound as a pale yellow solid (3.90 g, 40.00%), HPLC: 93.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 247.1 (M+1); 1H NMR (400 MHz, CDCl3) delta: 3.34 (d, J=1.8 Hz, 2H), 4.51 (t, J=1.6 Hz, 1H), 4.53 (s, 2H), 7.22-7.42 (m, 5H) ppm.
17%
With potassium carbonate; In acetonitrile; at 25℃; for 48h;
to a mixture ofN-benzylmaleimide (75.00 g, 401.07 mmol, 1 eq) [32] and BrCH2NO2(45.00 g, 320.09 mmol, 0.8 eq), K2CO3 (44.00 g, 320.09 mmol, 0.8 eq) and ACN (0.40 L) were slowlyadded and then stirred at 25 C for 48 h. The reaction mixture was extracted with DCM (0.30 L*3) andbrine (0.30 L). The combined organic layers were dried with anhydrous Na2SO4 and concentrated togive compound 19 (17.00 g, 17%) as a yellow oil. 1H-NMR (400 MHz, CDCl3)delta 7.36-7.27 (m, 5H), 4.54(s, 2H), 4.50±4.46 (m, 1H), 3.35 (s, 2H). ESI-MS (m/z): 246.9 [M + H]+.
With potassium carbonate; In N,N-dimethyl-formamide; at -30 - -25℃;Molecular sieve;
Example 35; Preparation of l-(5-nitropyridin-2-yl)-3-{(lalpha,5alpha,6alpha)-3-[3-(trifluoromethyl)pyridin-2-yl]-3- azabicyclo[3.1.0]hex-6-yl } urea: <n="59"/>Step 1: 1 a,5a,6a-6-amino-3-azabicyclo [3.1.0] hexane hydrochlorideStep a: 2-Benzyl-4-nitrohexahydrocyclopropa[c] azole-1 ,3-dione:To a well-stirred suspension of N-benzyl maleimide (5.0 g, 26.7 mmol), <strong>[563-70-2]bromonitromethane</strong> (7.48 g, 52.4 mmol), celite (5.0 g), and molecular sieve 4A (5.0 g) in dimethyl formamide (50.0 mL), anhydrous potassium carbonate (7.4 g, 53.4 mmol) is added in portions at -30 to -250C and stirred for 3-4 hrs. Water (500 mL) is added to the reaction mixture and acidified to pH 5-6 with 10% aq. HCl solution. Ethyl acetate (100 mL) is added and the mixture is filtered through celite bed. The layers are separated and the organic layer is washed with water (2 x 25 mL), dried over anhydrous sodium sulfate, and concentrated to give crude product (4.5 g). The crude product is then purified through silica gel column using ethyl acetate: pet. ether (2:8), to give 2.1 gm of product as light yellow product. IR (KBr):- 3086, 1789, 1707, 1560, 1433, 1405, 1360, 1 173, 1017, 883 cm-1. IH NMR (300 MHz, DMSO-d6): delta 3.74 (s, 2H), 4.40 (s, 2H), 5.57 (s, IH), 7.23-7.35 (m, 5H).
With potassium carbonate; In acetonitrile; at 20℃; for 24h;
To a mixture of N-benzylmaleimide (7.40 g) and K2C03 (5.50 g) in 500 mL of CH3CN was added <strong>[563-70-2]bromonitromethane</strong> (5.60 g) dropwise. The reaction mixture was stirred for 24 h at room temperature and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 4: 1 (v/v) PE/EA) to give the title compound as a pale yellow solid (3.90 g, 40.00 %), HPLC: 93.00 %. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 247.1 (M+l ); 'H NMR (400 MHz, CDC13) ?: 3.34 (d, J = 1.8 Hz, 2H), 4.51 (t, J = 1.6 Hz, 1 H), 4.53 (s, 2H), 7.22-7.42 (m, 5H) ppm.
With potassium carbonate; In acetonitrile; at 25℃; for 28h;
Step B: To a solution of 1-benzyl-1H-pyrrole-2,5-dione (15.08 g, 81 mmol) in CH3CN (810 mL) was added <strong>[563-70-2]bromo(nitro)methane</strong> (11.33 g, 81 mmol), followed by added K2CO3 (11.19 g, 81 mmol). The mixture was stirred at 25 C for 4 hours. Then <strong>[563-70-2]bromo(nitro)methane</strong> (1.13 g, 8 mmol) was added every 4 hours x 5 times to the reaction mixture at 25 C and the total number of times is five. The resulting mixture was stirred at 25 C for 4 hours. The mixture was concentrated in vacuo to give crude. The crude was purified by silica gel column chromatography (EA : PE = 1:10 to 1:5) to give 3-benzyl-6-nitro-3-azabicyclo[3.1.0]hexane-2,4-dione (8.00 g, crude) as a yellow solid which was used directly in the next step. LCMS (ESI) m/z: 247(M+1).
With triethylamine; In 1,4-dioxane; ice-water; chloroform; ethyl acetate; Petroleum ether;
(a) 1-Benzyl-3-(2-chloroethyl-methyl-amino)-pyrrolidine-2,5-dione 74.8 g (0.4 mol) of N-benzylmaleimide [Arch. Pharm. 308, 489 (1975)] and 52.0 g (0.4 mol) of 2-chloroethyl-methylamine hydrochloride are initially introduced into 400 ml of dioxane and 40.4 g (0.4 mol) of triethylamine are added dropwise at 20 C. The mixture is then boiled under reflux for 5 hours. The batch is subsequently poured into 2 l of ice-water and extracted with 3 portions of 400 ml of chloroform and the extract is washed with water, dried over sodium sulphate and concentrated on a rotary evaporator. Chromatography of the residue (101.1 g) on silica gel using ethyl acetate:petroleum ether (1:2) gives 56.8 g (51% of theory) of an oil. RF value: 0.33 (silica gel, ethyl acetate/petroleum ether=1:2)
In accordance with the general Scheme 2C, the following is the preparation of a compound of Structure 4C, wherein each of p, q, r and s=1; and Y is benzyl. triethylamine (16.2 g, 0.16 mol) was added to a suspension of N-benzylmaleimide (25.0 g, 0.13 mol), <strong>[7689-50-1]N-benzylglycine hydrochloride</strong> (32.3 g, 0.16 mol) and paraformaldehyde (25.2 g, 0.84 mol) in benzene (1 L) in a mechanically stirred flask, under a nitrogen atmosphere.. The resulting solution was refluxed (3.5 h), cooled to room temperature, dried over anhydrous magnesium sulfate, treated with decolorizing charcoal, filtered through Celite and evaporated under reduced pressure.. The residue (52.9 g) was dissolved in 1,2-dichloroethane, and under a nitrogen atmosphere, sodium bicarbonate (22.4 g, 0.26 mol) was added followed by dropwise addition of 1-chloroethylchloroformate (38.18 g, 0.26 mol).. The resulting mixture was refluxed overnight before cooling to room temperature.. The solution was dried over anhydrous magnesium sulfate, treated with decolorizing charcoal, filtered through Celite and evaporated under reduced pressure.. The residue was dissolved in anhydrous methanol (500 ML) and heated at 50 C. for 3 h.. On cooling to room temperature the solution was concentrated to approximately half its volume yielding a precipitate.. The solid was collected by filtration, washed on the filter with diethyl ether and dried under vacuum yielding a white crystalline solid (26.0 g). A solution of the above mentioned solid (25.9 g) in tetrahydrofuran (250 ML) was added dropwise under a nitrogen atmosphere (over 1 h) to a solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 300 ML, 300 mmol) in tetrahydrofuran (200 ML) cooled to 0 C. The resulting slurry was warmed slowly, refluxed for 15 min, cooled and stirred overnight at room temperature.. water (11.3 ML) was added very carefully with stirring followed by 15% aqueous NaOH (11.3 ML).. Additional water (34.1 ML) was added followed by anhydrous magnesium sulfate, and the mixture was stirred at room temperature, filtered through Celite and evaporated under reduced pressure to yield the desired product as a yellow oil 198 (18.7 g).. 1H NMR: (CDCl3) delta7.36-7.19 (m, 5H), 3.51 (s, 2H), 2.89-2.57 (m, 8H), 2.35-2.27 (m, 2H), 2.01 (br. s,1H, exch. D2O).
With (S,S)-2,2'-methylenebis(4-tert-butyl-2-oxazoline) In dichloromethane at 20℃; for 24h; optical yield given as %ee; enantioselective reaction;
With 1-{3,5-bis(trifluoromethyl)phenyl}-3-{(1R,2R)-2-(dimethylamino)cyclohexyl}thiourea In toluene at 20℃; for 14h; optical yield given as %ee; enantioselective reaction;
4.5. General experimental procedure for the addition of anthrones to maleimides
General procedure: To a stirred solution of catalyst (R,R)-V (10 mg, 0.025 mmol) in toluene (1 mL) were added the maleimide (0.30 mmol) and the anthrone (1a or 1b, 0.25 mmol). The reaction mixture was vigorously stirred at room temperature during 14 h, and the crude product was directly purified by column chromatography on silica gel (hexane/ethyl acetate mixtures) to afford the Diels-Alder or the Michael adduct. Racemic products were obtained from the corresponding substrates by catalysis with DABCO in toluene at room temperature.
70 % ee
With (1R,2R)-N,N-dimethyl-N'-phthaloyl-1,2-diaminocyclohexane In 1,2-dichloro-ethane at -10℃; for 12h; Overall yield = 70 %; enantioselective reaction;
Representative experimental procedure for D-A reaction
General procedure: A mixture of maleimide 3 (0.24 mmol), anthrone 2 (0.2 mmol), and the catalyst (20 mol %) in 1,2-dichloroethane (0.6 mL) at -10 °C was stirred for 12 h (monitored by TLC). After evaporation under reduced pressure, the residue was purified through column chromatography on silica gel (petroleum ether/ethyl acetate=3/1) to yield pure products.
46 % ee
With (S)-2-amino-1,1-diphenyl-3-(triethylsilyloxy)propanol In dichloromethane at 20℃; for 48h; Inert atmosphere; Overall yield = 93 %; enantioselective reaction;
4.7. General procedure for the asymmetric Diels-Alder reactionof anthrones 6,9a,b, with maleimides 7,10a-f
General procedure: Anthrones 6,9a,b (0.10 mmol), maleimides 7,10a-f (0.12 mmol)and amino alcohol catalysts 2e (0.02 mmol) were stirred in CH2Cl2(1 mL) at room temperature for 48 h. The reaction mixture wasdirectly purified by preparative TLC on silica gel (CHCl3) to affordDiels-Alder adducts 11a-h. The enantiomeric excess (ee) wasdetermined by HPLC (DAICEL CHIRALPAK AD-H, 1.0 mL/min, nhexane/2-propanol = 80:20). Compounds 11a-h were known compoundsand were identified by spectroscopic data, which were ingood agreement with those reported.2-9
24 % ee
With (S)-(-)-N-(methyl-1'-benzotriazolyl)-2-(α-hydroxyethyl)benzimidazole In chloroform at 20℃; for 12h; Overall yield = 86 %; Overall yield = 163.7 mg; enantioselective reaction;
3 For chiral Tweezer Btz-HEB 2d
General procedure: To a 50mL RBF containing Btz-HEB 2d (10mol%) and a stirring bar, anhydrous Chloroform at room temperature, anthrone 3 (97mg, 0.5mmol) and N-substituted maleimide 4a-g (0.5mmol) were added in this sequence. The reaction was carried out under dry condition and monitored with TLC. After stirring at room temperature for 12h, on completion, the reaction mixture was acidified with dilute hydrochloric acid and extracted with chloroform. The organic extracts were washed with brine, dried over sodium sulfate, and filtered. The solvent was removed in vacuum, purified by using silica column chromatography (gradient elution with chloroform/pet. ether mixtures; 80:20).
78 % ee
With (S)-(-)-N-(methyl-2'-pyridyl)-2-(α-hydroxyethyl)benzimidazole In 1,2-dichloro-ethane at -10℃; Overall yield = 75 %; Overall yield = 142.8 mg; enantioselective reaction;
7 Asymmetric Diels-Alder reaction of anthrone 3 and various N-substituted maleimides 4a-g 4.3.1 Representative experimental procedure for the Diels-Alder reaction
General procedure: For chiral Tweezer Pyr-HEB 2a (0026) To a 50mL round bottom flask (RBF) containing Pyr-HEB 2a (10mol%) and a stirring bar, anhydrous 1,2-dichloroethane at -10°C, anthrone 3 (97mg, 0.5mmol) and N-substituted maleimide 4a-g (0.5mmol) were added in this sequence. The reaction was carried out under dry condition and monitored with TLC. After stirring at -10°C for 8-12h, on completion, the reaction mixture was acidified with dilute hydrochloric acid and extracted with chloroform. The organic extracts were washed with brine, dried over sodium sulfate and filtered. The solvent was removed in vacuum, purified by using Silica column chromatography (gradient elution with chloroform/pet. ether mixtures; 80:20).
Stage #1: 1-benzyl-1H-pyrrole-2,5-dione; N-benzylglycine In toluene at 105℃; Large scale reaction;
Stage #2: With formaldehyd; water In toluene at 105℃; Large scale reaction;
(3aRS,9bSR)-2-benzyl-5,8-dimethyl-3a,4,5,9b-tetrahydro-1H-pyrrolo[3,4-c]quinoline-1,3(2H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With surface-modified titanium dioxide by 10.6 wt. percent NiO particles (1 molpercent) In N,N-dimethyl-formamide for 12h; Irradiation;
76%
With tris(1,10-phenanthroline)iron(III) tris(hexafluorophosphate) In dimethyl sulfoxide at 50℃; for 12h;
73%
With tert.-butylhydroperoxide; cobalt(II) chloride In decane; acetonitrile at 60℃; for 5h; Inert atmosphere; Sealed tube;
General procedure for the cobalt-catalyzed oxidative annulation of aromatic tertiary amines with N-substituted maleimides
General procedure: To a screw-capped tube (5 mL) containing freshly distilled MeCN (2.0-3.0 mL) was successively added CoCl2 (0.10 equiv for N-substituted maleimide), an aromatic tertiary amine (2.0 equiv for N-substituted maleimide), an N-substituted maleimide (0.50-1.0 mmol), and 5.5 M TBHP in decane solution (1.5 equiv for N-substituted maleimide) under N2 atmosphere. After the tube was sealed with a cap that contained a PTFE septum, the resultant mixture was stirred at 60 °C (bath temperature). After cooling to room temperature, the mixture was passed through a silica gel-packed short column (EtOAc as the eluent), and the filtrate was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane : EtOAc =5 : 1) to give the corresponding tetrahydroquinoline derivative. If necessary, the isolated product was further purified by a preparative HPLC equipped with a GPC column (chloroform as the eluent).
68%
With Ru(bpy)<SUB>3</SUB>Cl<SUB>2</SUB> In N,N-dimethyl-formamide at 20℃; Irradiation; regioselective reaction;
66%
With iridium complex immobilized on vinylpyridine and divinylbenzene copolymer In 1-methyl-pyrrolidin-2-one for 6h; Irradiation;
52%
With copper dichloride In acetonitrile at 20℃; for 24h;
85 %Spectr.
With [Ru(2,2'-bipyridine)3]2+-encapsulating zeolite-like metal-organic framework with sodalite-like cages In N,N-dimethyl-formamide for 36h; Irradiation;
General procedure: In a typical experiment, a,a-disubstituted aldehyde(0.40 mmol), maleimides (0.20 mmol), and catalyst (0.03 mmol,15 mol%) in CH2Cl2 (0.5 mL) were stirred magnetically at room temperatureuntil the maleimide was consumed (monitored by TLC).The corresponding product was obtained after column chromatography(silica gel, eluent n-hexane/EtOAc). The enantiomeric excessof the products was determined by chiral HPLC analysis using chiralcolumns. All products were identified by spectroscopic data. Racemicsamples of the Michael adducts were prepared using racemiccatalyst. Compounds 6a'-6i' , 6m' and 6r' are known. The analyticaland spectroscopic data are in accordance with those reported.
ethyl (1S*,3R*,3aS*,6aR*)-1,5-dibenzyl-3-(dimethoxymethyl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With silver(I) acetate; triethylamine; In water; toluene; at 25℃; for 24h;Darkness;
General procedure: Ethyl glyoxylate (100 muL, 0.5 mmol, 50% in toluene) or 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> (75 muL, 0.5 mmol, 50% in water), or phenylglyoxal monohydrate (58 muL, 0.5 mmol); diethyl aminomalonate hydrochloride or the amino acid ethyl ester hydrochloride (0.5 mmol), the corresponding dipolarophile (0.5 mmol), AgOAc (4.1 mg, 0.025 mmol) and triethylamine (90 muL, 0.55 mmol) were dissolved in toluene (4 mL). The reaction vessel was covered with an aluminium foil in order to prevent the light exposure. Once the reaction was judged complete after a TLC test the solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate, washed with brine and dried over MgSO4. After evaporation the residue was purified by flash chromatography (silica gel) to afford the corresponding product. The reaction involving ethyl glyoxylate and 2,2-<strong>[51673-84-8]dimethoxyacetaldehyde</strong> were scaled up 10 times to afford endo-cis-3a and endo-cis-5a in 80% and 75%, respectively.
(±)-tert-butyl (3R,3a'R,3b'S,9a'S)-2’-benzyl-5-methoxy-1',2,3'-trioxo-2',3',3a',3b',4',6',7',9a'-octahydrospiro[indoline-3,9'-pyrrolo[3',4':3,4]pyrrolo[1,2-a]pyrazine]-5'(1'H)-carboxylate[ No CAS ]
(±)-tert-butyl (3R,3a'R,3b'S,9a'S)-1,2’-dibenzyl-1',2,3'-trioxo-2',3',3a',3b',4',6',7',9a'-octahydrospiro[indoline-3,9'-pyrrolo[3',4':3,4]pyrrolo[1,2-a]pyrazine]-5'(1'H)-carboxylate[ No CAS ]
(±)-tert-butyl (3R,3a'R,3b'S,9a'S)-2’-benzyl-1',2,3'-trioxo-2',3',3a',3b',4',6',7',9a'-octahydrospiro[indoline-3,9'-pyrrolo[3',4':3,4]pyrrolo[1,2-a]pyrazine]-5'(1'H)-carboxylate[ No CAS ]
1-benzyl-3-(4-oxo-4H-chromen-5-yl)pyrrolidine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; benzoic acid; silver(I) triflimide In neat (no solvent) at 80℃; for 6.5h;
25 Example 25
At room temperature, chromone (0.2 mmol), N-ethylmaleimide (0.5 mmol), [Ru (p-cymene) Cl2] 2 (2.5mol%), AgNTf2 ( 10mol%), benzoic acid (0.8equiv.). Warm to 80 ° C and stir. TLC tracking detection reaction. After 6.5 hours, the reaction was stopped. Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate. Combine all organic layers, dry over anhydrous sodium sulfate, concentrate, and separate by column chromatography (30% ethyl acetate in petroleum ether) to obtain 59.9 mg of product with a 90% yield
81%
With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; Trimethylacetic acid In 1,2-dichloro-ethane at 80℃; for 20h; Sealed tube;
With acetic acid In ethanol at 110℃; for 12h; Sealed tube; Green chemistry; Overall yield = 65 %;
4.2. General procedure for synthesis of α-trifluoromethyl-substituted pyrrolidines 1
General procedure: To a solution of an amino acid 2 (1.5 mmol), trifluoroacetophenones 3 (1.3 mmol), and maleimide 4 (1.0 mmol) in a sealed tube (3.0 mL of ethanol) was added acetic acid (0.3 mmol). After stirred at 110 °C for 12 h. The concentrated reaction mixture was isolated on a semi prepHPLC with C18 column to afford purified product 1.
methyl (1R*,3S*,3aR*,6aS*)-5-benzyl-3-(3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With silver(I) acetate; triethylamine; In ethanol; at 70℃;
General procedure: To a stirred solution of ester hydrochloride as amine (1.1 equiv, 0.5 mmol) in EtOH (3 mL) was added pyridoxal hydroclorhide (1 equiv, 0.5 mmol). After, Et3N (2 equiv, 140 muL), dipolarophile (1 equiv, 0.5 mmol) and AgOAc (5 mol%). The reaction mixture was stirred overnight at 70 C. The solvent was removed under reduced pressure. The crude mixture was extracted with ethyl acetate and was washed with brine. The organic phase was dried (MgSO4) and after filtration and evaporation, the corresponding pyrrolidines were obtained without purification.
ethyl (1S*,3R*,3aR*,6aS*)-1,5-dibenzyl-3-(3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With silver(I) acetate; triethylamine; In ethanol; at 70℃;
General procedure: To a stirred solution of ester hydrochloride as amine (1.1 equiv, 0.5 mmol) in EtOH (3 mL) was added pyridoxal hydroclorhide (1 equiv, 0.5 mmol). After, Et3N (2 equiv, 140 muL), dipolarophile (1 equiv, 0.5 mmol) and AgOAc (5 mol%). The reaction mixture was stirred overnight at 70 C. The solvent was removed under reduced pressure. The crude mixture was extracted with ethyl acetate and was washed with brine. The organic phase was dried (MgSO4) and after filtration and evaporation, the corresponding pyrrolidines were obtained without purification.
methyl (1S*,3R*,3aS*,6aR*)-5-benzyl-3-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With silver(I) acetate; triethylamine; In toluene; at 20℃; for 10h;
General procedure: To a stirred solution of ester hydrochloride as amine (1.1 equiv, 0.6 mmol) in toluene (2 mL) was added <strong>[1195-08-0]5-formyluracil</strong>e (1 equiv, 0.5 mmol) and Et3N (1.1 equiv). After that, dipolarophile (1.0 equiv) and AgOAc (5 mol%). The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. The crude mixture was filtrated through Celite with warm EtOH to furnish the corresponding product. To remove the ammonium salt, it was washed with DCM.
ethyl (1S*,3R*,3aS*,6aR*)-1,5-dibenzyl-3-(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With silver(I) acetate; In toluene; at 20℃; for 10h;
General procedure: To a stirred solution of free amine ester (1 equiv was previously isolated: 1 equiv of the corresponding hydrochloride with 1.3 equiv K2CO3, in a mixture of AcOEt/H2O during 1h. It was washed with water and the organic fase evaporated), in toluene (2 mL) was added <strong>[1195-08-0]5-formyluracil</strong>e (1 equiv, 0.5 mmol). After that, dipolarophile (1.0 equiv, 0.5 mmol) and AgOAc (5 mol%). The solvent was removed under reduced pressure. The crude mixture was filtrated through Celite with warm EtOH to furnish the corresponding product.
With pepsin In water at 50℃; for 60h; Green chemistry; Enzymatic reaction; diastereoselective reaction;
4. General procedure for the pepsin-catalyzed vinylogous Michael addition
General procedure: A round bottom flask was charged with γ-substituted butenolide (0.2 mmol), maleimide (0.4 mmol), pepsin (19.5 kU) and deionized water (1.0 mL). The resulting mixture was stirred at 50 °C and was monitored by TLC. Upon completion of the reaction, the enzyme was filtered out, and ethyl acetate was added to wash the filter cake and tomake the product dissolved in the filtrate. The organic layer was separated with a separatory funnel, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography with petroleum ether/ethyl acetate (2:1-1:1) as eluent to afford the product.
With acetic acid In ethanol at 110℃; for 12h; Sealed tube; Green chemistry; Overall yield = 55 %;
4.2. General procedure for synthesis of α-trifluoromethyl-substituted pyrrolidines 1
General procedure: To a solution of an amino acid 2 (1.5 mmol), trifluoroacetophenones 3 (1.3 mmol), and maleimide 4 (1.0 mmol) in a sealed tube (3.0 mL of ethanol) was added acetic acid (0.3 mmol). After stirred at 110 °C for 12 h. The concentrated reaction mixture was isolated on a semi prepHPLC with C18 column to afford purified product 1.
With acetic acid In ethanol at 110℃; for 12h; Sealed tube; Green chemistry; Overall yield = 50 %;
4.2. General procedure for synthesis of α-trifluoromethyl-substituted pyrrolidines 1
General procedure: To a solution of an amino acid 2 (1.5 mmol), trifluoroacetophenones 3 (1.3 mmol), and maleimide 4 (1.0 mmol) in a sealed tube (3.0 mL of ethanol) was added acetic acid (0.3 mmol). After stirred at 110 °C for 12 h. The concentrated reaction mixture was isolated on a semi prepHPLC with C18 column to afford purified product 1.
(R)-1-benzyl-3-((3-methylbenzyl)amino)pyrrolidine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With calcium 2,6-di(phenanthren-9-yl)dinaphtho[2,1-d:1?,2?-f][1,3,2]dioxaphosphepin-4-olate 4-oxide; In toluene; at -20℃; for 18h;Inert atmosphere; Molecular sieve;
General procedure: In a nitrogen-filled dry box, a screw-cap reaction tube equipped with a magnetic stirbar was charged with the corresponding maleimide 2 (0.2 mmol, 1.0 equiv), calcium phosphate complex catalyst Ca[B]2 (14.0 mg, 0.01 mmol, 0.05 equiv), and 4 MS (100 mg). The tube was capped with a septum cap, removed from the drybox and put under positive N2 pressure. Dry toluene (3.0 mL) was then added and the heterogeneous mixture was cooled to -20 C. A solution of the corresponding amine (0.20 mmol, 1.0 equiv) in toluene (0.9 mL) was added dropwise, and the reaction was stirred for 14 h at spectrum C. At this point an additional bolus of amine (0.02 mmol, 0.1 equiv) in toluene (0.1 mL) was added. After 18 h, the entire crude reaction mixture at -20 C. was directly transferred onto a SiO2 column pre-equilibrated with 3:1 Hex:EtOAc. Flash chromatography (gradient 3:1 Hex:EtOAc?1:1 Hex:EtOAc) afforded the aminosuccinimide product, followed by elution with 10:1 EtOAc:MeOH to recover Ca[B]2.
ethyl 2-(1-benzyl-2,5-dioxopyrrolidin-3-yl)-4-methylbenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
With silver hexafluoroantimonate; Cp*Co(CO)I2; sodium acetate In 2,2,2-trifluoroethanol at 120℃; for 24h; Schlenk technique; Inert atmosphere; regioselective reaction;
With silver hexafluoroantimonate; Cp*Co(CO)I2; sodium acetate In 1,2-dichloro-ethane at 120℃; for 24h; Schlenk technique; Inert atmosphere; regioselective reaction;
With triethylamine; In acetonitrile; at 125℃; for 0.416667h;Microwave irradiation;
General procedure: To a solution of 2-azidebenzenaldehyde (0.1 mmol), maleimide (0.1 mmol) and amino acid ester (0.12 mmol) in MeCN (3 mL) was added Et3N (0.12 mmol). The reaction mixture was heated by microwave at 125 C for 25 min. Upon the completion of the reaction monitored by LC-MS, CS2 (0.5 mmol), PPh3 (0.15 mmol), and K2CO3 (0.2 mmol) was added to the reaction system and heated under 90 C for 6 hrs. Upon the completion of the reaction monitored by LC-MS, the reaction mixture was concentrated and purified by column chromatography to afford products 4.
With triethylamine; In acetonitrile; at 125℃; for 0.416667h;Microwave irradiation;
General procedure: To a solution of 2-azidebenzenaldehyde (0.1 mmol), maleimide (0.1 mmol) and amino acid ester (0.12 mmol) in MeCN (3 mL) was added Et3N (0.12 mmol). The reaction mixture was heated by microwave at 125 C for 25 min. Upon the completion of the reaction monitored by LC-MS, CS2 (0.5 mmol), PPh3 (0.15 mmol), and K2CO3 (0.2 mmol) was added to the reaction system and heated under 90 C for 6 hrs. Upon the completion of the reaction monitored by LC-MS, the reaction mixture was concentrated and purified by column chromatography to afford products 4.
2,5-dibenzyl-4,4-dimethyltetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
In toluene at 130℃; for 18h;
1.1 Step 1. 2, 5-dibenzyl-4,4-dimethyltetrahydropyrrolo [3, 4-c] pyrrole-1, 3 (2H, 3aH) -dione
The solution of 1-benzyl-1H-pyrrole-2,5-dione (23.4 g, 0.125 mol), 2- (benzylamino) acetic acid (31 g, 0.188 mol) and acetone (22 g, 0.375 mol) in touluene was stirred at 130 °C for 18 h. The precipicate after cooling to room temperature was filtered off and the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated in vacuo and the crude product was purified by silica gel flash column chromatography (PE/EtOAc =5/1-3/2) to give the title compound (32.2 g, 74% yield).
In toluene at 140℃; for 48h;
The first step
Benzyl glycine 4a (7.06 g, 42.74 mmol), acetone (6.21 g, 106.85 mmol), 1-benzyl-2,5-dihydropyrrole-2,5-dione 4b (4.00 g, 21.37 mmol) and toluene (40 mL) were added into a 200 mL pot. The reaction mixture obtained was stirred at 140 °C for 48hrs. After completion of the reaction, the reaction mixture was concentrated, the crude product was purified by silica gel chromatography (PE/EtOAc = 100-0%) to give the compound 4c. 1H NMR (400 MHz, CDCl3) δ 7.40-7.32 (m, 10H), 4.77-4.72 (t, J = 5.2, 2H), 3.96-3.74 (m, 3H), 2.90-2.66 (m, 3H), 2.31 (s, 3H), 1.60 (s, 3H).
5-benzyl-3-methyl-3aH-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%
With copper(II) nitrate trihydrate In 1,4-dioxane at 75℃; for 8h;
3 Example 3: 5-benzyl-3-methyl-3aH-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione
5-Benzyl-3-methyl-3aH-pyrrolo[34-d]isoxazole-4,6(5H6aH)-dione was prepared using the following procedure: 1 In a 1000 ml reaction three-necked flask, 15.3 g of 2 was added. - ketobutyric acid (150 mol), 56.2 g of N-benzylmaleimide (300 mol), 72.5 g of copper nitrate trihydrate (300 mol), 750 ml of 1,4-dioxane, heated to 75 ° C. The reaction was followed by thin layer chromatography, and the reaction was completed until the disappearance of the starting material (8 h); 2 the crude product obtained by removing the solvent in the reaction system was directly subjected to column chromatography (petroleum ether (V): ethyl acetate (V) = 2: 1) Separation and purification were carried out to obtain 25.7 g of 5-benzyl-3-methyl-3aH-pyrrolo[3,4-d]isoxazole-4,6(5H,6aH)-dione (96 mol). For: 'The yield is 64%.
methyl 5-benzyl-3-ferrocenyl-1-methyl-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With triethylamine; In acetonitrile; at 125℃; for 4h;Sealed tube;
General procedure: Maleimide 3 (1.5 mmol) and Et3N (152 mg, 1.5 mmol) were added to a stirred solution of ferrocenecarboxaldehyde (1) (214 mg, 1 mmol) and 2-aminopropionic acid ester 2 (1 mmol) in MeCN (3 ml) in a tube at room temperature. Then the tube was sealed, and the reaction mixture was stirred at 125C for 4 h. After the completion of the reaction (TLC control, EtOAc - petroleum ether, 1:3), the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (15 ml), washed with brine (15 ml) and H2O (2×15 ml), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (EtOAc - petroleum ether, 1:3.5) to afford product 4.
ethyl 5-benzyl-3-ferrocenyl-1-methyl-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With triethylamine; In acetonitrile; at 125℃; for 4h;Sealed tube;
General procedure: Maleimide 3 (1.5 mmol) and Et3N (152 mg, 1.5 mmol) were added to a stirred solution of ferrocenecarboxaldehyde (1) (214 mg, 1 mmol) and 2-aminopropionic acid ester 2 (1 mmol) in MeCN (3 ml) in a tube at room temperature. Then the tube was sealed, and the reaction mixture was stirred at 125C for 4 h. After the completion of the reaction (TLC control, EtOAc - petroleum ether, 1:3), the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (15 ml), washed with brine (15 ml) and H2O (2×15 ml), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (EtOAc - petroleum ether, 1:3.5) to afford product 4. Ethyl 5-benzyl-3-ferrocenyl-1-methyl-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (4a). Yield 445 mg (89%), brown solid, mp 179-180C. Rf 0.45. IR spectrum, nu, cm-1: 1747 (C=O), 1699 (C=O), 1428,1396, 1172, 701. 1H NMR spectrum, delta, ppm (J, Hz): 1.22(3H, t, J = 7.2, CO2CH2CH3); 1.51 (3H, s, CH3); 2.69 (1H,d, J = 7.2, NH); 3.35-3.44 (2H, m, FcCHCHCH); 3.72(1H, t, J = 1.2, H Fc); 3.91 (1H, d, J = 1.2, H Fc); 4.08 (1H,dd, J = 3.4, J = 2.2, H Fc); 4.11-4.15 (7H, m, H Fc,CO2CH2CH3); 4.26-4.32 (3H, m, H Fc, NCH2Ar); 4.47(1H, t, J = 8.0, FcCHCHCH); 7.14-7.16 (2H, m, H Ar);7.25-7.30 (3H, m, H Ar). 13C NMR spectrum, delta, ppm:14.4; 23.8; 41.8; 49.9; 56.6; 58.1; 61.1; 65.1; 66.6; 67.3; 67.8; 68.8; 68.9 (5C); 85.9; 127.8; 128.1 (2C); 128.7 (2C); 136.3; 172.6; 175.1; 176.3. Found, m/z: 500.1387 [M]+. C27H28FeN2O4. Calculated, m/z: 500.1393.
1-benzyl-3-(4-oxo-4H-chromen-5-yl)-1H-pyrrole-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; silver(I) acetate; silver(I) triflimide In 1,2-dichloro-ethane at 120℃; for 0.5h;
15 Example 15
At room temperature, chromone (0.2mmol),N-benzylmaleimide (0.5mmol), [Ru (p-cymene) Cl2] 2 (5mol%),AgNTf2 (20 mol%), silver acetate (3equiv.), And DCE (2.0 mL).The temperature was raised to 120 ° C and stirred. TLC tracks the reaction. After 0.5 hours, the reaction was stopped.Water and ethyl acetate were added to the reaction system, the organic layer was separated, and the aqueous layer was washed three times with ethyl acetate.Combine all organic layers, dry over anhydrous sodium sulfate, concentrate, and isolate by column chromatography (40% ethyl acetate in petroleum ether),57.6 mg of product was obtained with a yield of 87%,
87%
With [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2; silver(I) acetate; silver(I) triflimide In 1,2-dichloro-ethane at 20 - 120℃; for 0.5h; Sealed tube;
diethyl [(3aSR,4RS,7aSR)-2-benzyl-1,3-dioxo-2,3,3a,4,7,7ahexahydro-1H-isoindol-4-yl]phosphoramidate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With acetic anhydride; toluene-4-sulfonic acid In toluene at 110℃; diastereoselective reaction;
4.2. General procedure for the synthesis of products 6
General procedure: To a stirred solution of diethyl phosphoramidate (154 mg,1 mmol), TsOH (8.6 mg, 0.05 mmol), acetic anhydride (4.8 mL,0.05 mmol) in 3 mL of toluene was added the aldehyde (1 mmol), the maleimide (1 mmol). The solution was stirred under reflux for24 h, and then the solvent was removed under vacuum. The crude of the reaction was purified with flash chromatography to give the desired compound.
(E)-3-(1-benzyl-2,5-dioxopyrrolidin-3-ylidene)-N-butyl-2-methylpropanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With silver hexafluoroantimonate; carbonyl(pentamethylcyclopentadienyl)cobalt diiodide; Trimethylacetic acid; In 2,2,2-trifluoroethanol; at 120℃; for 16h;Schlenk technique; Inert atmosphere;
General procedure: A 15 mL Schlenk tube with septum containing Cp*Co(CO)I2 (10 mol%),acrylamide 1 (50 mg, 1 equiv), maleimide 2 (1.2 equiv) and AgSbF6(20 mol%) was evacuated and purged with nitrogen gas three times(AgSbF6 was transferred inside a glovebox). To the tube were thenadded PivOH (30 mol%) and TFE (3.0 mL) via syringe; after that, thereaction mixture was evacuated and purged with nitrogen gas threetimes. Then, the septum was taken out immediately and a screw capwas used to cover the tube under the nitrogen atmosphere, and thereaction mixture was stirred at room temperature for 5 min. Then,the mixture was stirred at 120 C for 16 h. After cooling to ambienttemperature, the mixture was diluted with CH2Cl2 and filteredthrough Celite, and the filtrate was concentrated. The crude residuewas purified through a silica gel column (40% ethyl acetate in hexanesas eluent) to give pure product 3.
2-benzyl-1H-benzo[e]pyrido[1',2':1,2]imidazo[4,5-g]isoindole-1,3(2H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; copper diacetate In 1,2-dichloro-ethane at 100℃; for 20h; Sealed tube;
20 Example 20
Into a 15mL pressure tube, add 1a (146mg, 0.75mmol), 2f (94mg, 0.5mmol), 1,2-dichloroethane (3mL), Dichloro(pentamethylcyclopentadienyl) rhodium(III) dimer (15mg, 0.025mmol) and copper acetate (228mg, 1.25mmol), Then the pressure tube was sealed and placed in an oil bath at 100°C for reaction for 20 hours. After the reaction is over, cool to room temperature, filter with diatomaceous earth and spin-dry the organic phase, and separate the crude product through a silica gel column (petroleum ether/ethyl acetate = 5/1, v/v) to obtain a yellow solid product 3f( 174mg, 92%)
67%
With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; copper diacetate; toluene-4-sulfonic acid In toluene at 120℃; for 8h;
1-benzyl-3-(5-fluoro-1H-indole-3-yl)pyrrolidine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With boron trifluoride diethyl etherate In ethyl acetate at 60℃; for 6h;
Appendix A.2. General Procedure for the Synthesis of Compounds (3a-3x)
General procedure: A mixture of 117 mg (1 mmol) indole, 97 mg (1 mmol) maleimide andapproximately adrop of BF3OEt2 (0.5 mmol) in 5 mL of ethyl acetate solvent was stirred at 60 °C for 6 h.Completion of reaction was monitor by TLC. After completion, the mixture was cooledto room temperature. In some cases where the product succinimide appeared as a solidfrom the reaction mixture filtered and recrystallized. Otherwise, H2O (20 mL) was addedto the solution and extracted with EtOAc (2 x25 mL). The combined organic layer wasdried over anhydrous Na2SO4 and concentrated by rotary evaporation to afford crudeproduct which was further purified by column chromatography using EtOAc and hexaneas solvent system.
1-benzyl-3-(5-nitro-1H-indole-3-yl)pyrrolidine-2,5-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
With boron trifluoride diethyl etherate In ethyl acetate at 60℃; for 6h;
Appendix A.2. General Procedure for the Synthesis of Compounds (3a-3x)
General procedure: A mixture of 117 mg (1 mmol) indole, 97 mg (1 mmol) maleimide andapproximately adrop of BF3OEt2 (0.5 mmol) in 5 mL of ethyl acetate solvent was stirred at 60 °C for 6 h.Completion of reaction was monitor by TLC. After completion, the mixture was cooledto room temperature. In some cases where the product succinimide appeared as a solidfrom the reaction mixture filtered and recrystallized. Otherwise, H2O (20 mL) was addedto the solution and extracted with EtOAc (2 x25 mL). The combined organic layer wasdried over anhydrous Na2SO4 and concentrated by rotary evaporation to afford crudeproduct which was further purified by column chromatography using EtOAc and hexaneas solvent system.
2-benzyl-4-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With manganese(II) acetate In N,N-dimethyl-formamide; chlorobenzene at 120℃; for 24h;
17 Preparation of 2-benzyl-4-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-dione:
Weigh N-(1-phenylvinyl)acetamide (48.4mg, 0.3mmol), N-benzylmaleimide (171.9mg, 0.9mmol), and accelerator manganese acetate (26.5mg, 0.15mmol) , Then add 2mL of mixed solvent (DMF/PhCl=1:1), and react in an oil bath at 120°C for 24 hours. After the reaction is complete, extract with 20.0mL×3 ethyl acetate, combine the organic phases, and anhydrous sulfuric acid. The sodium was dried and separated by column chromatography (eluent: petroleum ether/ethyl acetate = 50:1) to obtain the target product 2-benzyl-4-methyl-1H-pyrrolo[3,4-c]pyridine- 1,3(2H)-dione 79.9mg, white solid, the yield was 81%.
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