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Structure of 17435-72-2 * 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.
With phosphorus tribromide In diethyl ether at 0 - 20℃; for 3 h;
To a stirred solution of ethyl 2-(hydroxyl-methyl)acrylate (2 g, 15.4 mmol) in diethyl ether (15 mL), at0 °C phosphorus tribromide (0.51 mL, 5.4 mmol) wasadded dropwise. The reaction mixture was stirred for3 h from 0 °C to room temperature. Water (5 mL) wasadded and the product was extracted with hexanes (3x 10 mL). The combined organic layers was washed with brine (2 x 10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 2-(bromomethyl)propenoicacid ethyl ester 14 (2.4 g, 12.3 mmol, 82 percent) as a colourless liquid which was used in the next step without further purification. Colourless oil; 1H NMR (400 MHz, CDCI3) O 1.30 (t, J=7.2 Hz, 3H, H6), 4.16 (5, 2H, H4), 4.24 (q, J=7.0 Hz, 2H, H5), 5.92 (5, 1H, Hi’), 6.30 (5, iH, Hi), 13C NMR (101 MHz, CDCI3) O 14.1 (CH3, C6), 29.3 (CH2, C4), 61.2 (CH2, CS), 128.8 (CH2, Ci), 137.6 (C, C2), 164.8 (C, C3), IR (vmaxcm1) 1718 (C=O ester), 1628 (C=Calkene), 1182 (C—C ester), 523 (C—Br), HRMS-El: m/z [M+H] Calcd for C6H10BrO2:Expected: 192.9864. Found: 192.6870.
70%
With phosphorus tribromide In diethyl ether at -10 - 20℃; for 3 h;
To the mixture of ethyl 2-(hydroxymethyl) acrylate (4 g, 0.030 mol) anddry ethyl ether (20 mL), phosphorus tribromide (1.4 mL, 0.015 mol) was added dropwise at –10 oC while stirring. After addition was completed thesolution was stirred at room temperature for 3 h. Water (20 mL) was added at–10 oC and the mixture was extracted with hexane (3X 10 ml) andwashed with a saturated solution of sodium chloride (2X 10 mL). After dryingthe organic layer over magnesium sulfate, the solvent was evaporated underreduced pressure and the crude product 7(4.7 g) was purified using vacuum distillation; Product yield: 4.1 g (70 percent);b.p. 54-58 oC/ 2 torr. Purity was confirmed using 1H NMRanalysis. 1H NMR: (400 MHz, CDCl3), 6.22 (1 H, s), 5.87 (1H, s), 4.22 (2 H, s), 4.24 (2 H, q), 1.31 (3 H, t)
56.6%
With phosphorus tribromide In diethyl ether at -10 - 20℃; for 3 h;
Phosphorus tribromide (17.16 g, 63.41 MMOL) was added to a stirred solution of the compound of example 30 (17.92 g, 138.1 MMOL) in dry ether (132 mL) at-10 °C. The temperature was allowed to rise to 20 °C and stirring was continued for 3h. Water (80 mL) was then added at-10 °C and the mixture was extracted with hexane (3 x 45 mL). The organic extracts were washed with saturated sodium chloride solution (2 x 45 mL) and dried with anhydrous MGS04. Evaporation of solvent under vacuum gave 15.07 g (yield 56.6 percent) of the crude product, which was used directly in the next reaction without any further purification. 1H NMR (CDCI3, 400MHZ) 8 6.25 (s, 1H), 5.88 (s, 1H), 4.2 (q, 2H), 4.11 (s, 2H), 1.25 (t, 3H); 13C NMR (CDCI3, 400 MHz) 5 166. 7,140. 1,125. 3,61. 1, 53.9, 14.4
34%
With sulfuric acid; hydrogen bromide In water at 12 - 26℃; for 24 h;
EXAMPLE 4 Preparation of EBMA EHMA is dissolved in a mixture of 48percent aqueous hydrobromic acid and concentrated sulfuric acid and the mixture is stirred at 25° C. for 24 hours. The reaction mixture is then extracted with a water immiscible solvent (petroleum ether, hexane, heptane), the organic phase is washed with a dilute solution of sodium bicarbonate and the crude product is concentrated under vacuum to afford the compound of Formula II at a purity of >95percent. ; EXAMPLE 5 EHMA (27 kg, 207 moles) was charged to the reactor. HBr (48percent, 3.25 eq, 112 kg, 672 mol) was added and the mixture was then cooled to 12° C. At 12° C., sulfuric acid (2.0 eq, 39 kg, 398 mol) was added at such a rate that the internal temperature did not exceed 15° C. After all the acid was added, the mixture was left to stir at room temperature (22-26° C.) overnight. The reaction mixture was then extracted with hexane (3.x.33 kg). The hexane was pumped into the reactor, stirred for 30 minutes; allowed to settle for 30 minutes and then the phases separated. The hexane extract was washed with an aqueous sodium bicarbonate solution (5percent, 33 kg). The mixture was stirred for 30 minutes, and then the stirrer stopped for 30 minutes to allow the phases to separate. This process was repeated twice. The washed hexane extract was then transferred to the distillation column. The hexane was then distilled at 40° C. under reduced pressure. The temperature was increased to 50° C. to remove any water that might be present. The residue containing EBMA was then distilled under high vacuum pump (80° C./<1 mm Hg) to obtain a 98percent pure product (16.4 kg, 34percent).
Reference：
[1] Journal of Polymer Science, Part A: Polymer Chemistry, 2011, vol. 49, # 6, p. 1513 - 1516
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 5, p. 1872 - 1875[3] Angew. Chem., 2016, vol. 128, # 5, p. 1904 - 1907,4
[4] Angewandte Chemie - International Edition, 2017, vol. 56, # 41, p. 12619 - 12623[5] Angew. Chem., 2017, vol. 129, # 41, p. 12793 - 12797,5
[6] Organic Letters, 2018, vol. 20, # 11, p. 3296 - 3299
[7] Synthesis, 1982, # 11, p. 924 - 926
[8] Tetrahedron Letters, 1994, vol. 35, # 9, p. 1371 - 1374
[9] Tetrahedron Letters, 1994, vol. 35, # 17, p. 2679 - 2682
[10] Journal of Organic Chemistry, 2012, vol. 77, # 22, p. 10010 - 10020
[11] Organic Syntheses, 1988, vol. 66, p. 220 - 220
[12] Patent: WO2017/51326, 2017, A1, . Location in patent: Page/Page column 43
[13] European Journal of Organic Chemistry, 2009, # 12, p. 1944 - 1960
[14] Tetrahedron Letters, 1998, vol. 39, # 24, p. 4163 - 4166
[15] Chemistry - A European Journal, 2018, vol. 24, # 37, p. 9269 - 9273
[16] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 18, p. 4995 - 5010
[17] Tetrahedron Letters, 2014, vol. 55, # 51, p. 7029 - 7033
[18] European Journal of Organic Chemistry, 2014, vol. 2014, # 3, p. 502 - 505
[19] Tetrahedron Asymmetry, 2013, vol. 24, # 7, p. 395 - 401
[20] Journal of the American Chemical Society, 2017, vol. 139, # 43, p. 15308 - 15311
[21] Patent: WO2004/50620, 2004, A2, . Location in patent: Page 47-48
[22] Patent: US2009/88577, 2009, A1, . Location in patent: Page/Page column 7-8; sheet 1; 3
[23] Phosphorus, Sulfur and Silicon and Related Elements, 1999, vol. 144-146, p. 133 - 136
[24] Patent: EP1681283, 2006, A1, . Location in patent: Page/Page column 5
[25] Organic and Biomolecular Chemistry, 2007, vol. 5, # 22, p. 3614 - 3622
[26] Organic Letters, 2009, vol. 11, # 20, p. 4560 - 4563
[27] Organic Process Research and Development, 2011, vol. 15, # 1, p. 249 - 257
[28] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 22, p. 5219 - 5223
[29] Organic Letters, 2017, vol. 19, # 4, p. 914 - 917
[30] Angewandte Chemie - International Edition, 2017, vol. 56, # 14, p. 3987 - 3991[31] Angew. Chem., 2017, vol. 129, # 14, p. 4045 - 4049,5
[32] Patent: US9682019, 2017, B2, . Location in patent: Page/Page column 23; 24
2
[ 64-17-5 ]
[ 72707-66-5 ]
[ 17435-72-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 1987, vol. 30, # 1, p. 165 - 168
[2] Archiv der Pharmazie, 1984, vol. 317, # 2, p. 176 - 183
[3] Organic Syntheses, 1983, vol. 61, p. 56 - 56
3
[ 140-88-5 ]
[ 17435-72-2 ]
Reference：
[1] Journal of Organic Chemistry, 2012, vol. 77, # 22, p. 10010 - 10020
[2] Angewandte Chemie - International Edition, 2016, vol. 55, # 5, p. 1872 - 1875[3] Angew. Chem., 2016, vol. 128, # 5, p. 1904 - 1907,4
[4] Patent: WO2017/51326, 2017, A1,
[5] Angewandte Chemie - International Edition, 2017, vol. 56, # 41, p. 12619 - 12623[6] Angew. Chem., 2017, vol. 129, # 41, p. 12793 - 12797,5
[7] Journal of the American Chemical Society, 2017, vol. 139, # 43, p. 15308 - 15311
[8] Organic Letters, 2018, vol. 20, # 11, p. 3296 - 3299
[9] Chemistry - A European Journal, 2018, vol. 24, # 37, p. 9269 - 9273
4
[ 105-53-3 ]
[ 17435-72-2 ]
Reference：
[1] Patent: EP729449, 2000, B1,
5
[ 7789-60-8 ]
[ 17435-72-2 ]
Reference：
[1] Patent: EP2316407, 2011, A1,
6
[ 58539-11-0 ]
[ 17435-72-2 ]
Reference：
[1] Journal of Organic Chemistry, 1955, vol. 20, p. 780,786
[2] Organic Syntheses, 1983, vol. 61, p. 77 - 77
7
[ 64-17-5 ]
[ 20605-01-0 ]
[ 17435-72-2 ]
Reference：
[1] Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 21, p. 11718 - 11726
8
[ 64-17-5 ]
[ 72707-66-5 ]
[ 17435-77-7 ]
[ 17435-72-2 ]
Reference：
[1] Journal of the Chinese Chemical Society, 2008, vol. 55, # 2, p. 435 - 438
9
[ 50-00-0 ]
[ 140-88-5 ]
[ 17435-72-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 4, p. 776 - 780
With phosphorus tribromide; In diethyl ether; at -10 - 20℃; for 4h;
To a solution of ethyl acrylate (10.91 mL, 100 mmol) in a mixture of dioxane/H2O (80 mL - 1/1) wassuccessively added a 37% aqueous solution of formaldehyde (9.90 mL, 133 mmol) and DABCO(16.25 g, 133 mmol). The resulting mixture was stirred overnight at room temperature then water andEtOAc were added. The layers were separated and the aqueous phase was extracted with EtOAc (2 x50 mL). The combined organic layers were washed with brine, dried over MgSO4 filtered and thesolvents were removed in vacuo. The crude product was purified by flash chromatography (80/20 -cyclohexane/EtOAc) to afford ethyl-2-(hydroxymethyl)acrylate as a colorless liquid (8.00 g, 61%yield). Rf = 0.27 (80/20 - Cyclohexane/EtOAc; KMnO4).1H NMR (400 MHz, CDCl3): delta 6.24 (d, J = 0.9 Hz, 1H, CH2=C), 5.82 (dt, J = 1.6, 0.9 Hz, 1H,CH2=C), 4.31 (dt, J = 6.2, 1.6 Hz, 2H, CH2OH), 4.23 (q, J = 7.2 Hz, 2H, CH2CH3), 2.50 (t, J = 6.2 Hz,1H, OH), 1.30 (t, J = 7.2 Hz, 3H, CH3).13C NMR (100 MHz, CDCl3): delta 166.4 (C=O), 139.6 (C=CH2), 125.6 (CH2=C), 62.5 (CH2OH), 60.9(CH2CH3), 14.2 (CH3). To a solution of the previous hydroxyacrylate (1.20 g, 9.22 mmol) in Et2O (10 mL) was added dropwise phosphorus tribromide (0.30 mL, 3.23 mmol) at -10 C. The resulting mixture was stirred for4 h at room temperature then water was added. The layers were separated and the aqueous phase wasextracted with Et2O (2 x 5 mL). The combined organic layers were washed with brine, dried overMgSO4, filtered and the solvent was removed in vacuo to provide ethyl-2-(bromomethyl) acrylate as apale-yellow liquid (1.68 g, 87% yield).1H NMR (200 MHz, CDCl3): delta 6.32 (d, J = 0.7 Hz, 1H, CH2=C), 5.94 (d, J = 0.7 Hz, 1H, CH2=C),4.27 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.18 (s, 2H, CH2Br), 1.32 (t, J = 7.2 Hz, 3H, CH3).13C NMR (50 MHz, CDCl3): delta 164.8 (C=O), 137.6 (C=CH2), 128.9 (CH2=C), 61.3 (CH3CH2O), 29.4(CH2Br), 14.1 (CH3).
82%
With phosphorus tribromide; In diethyl ether; at 0 - 20℃; for 3h;
To a stirred solution of ethyl 2-(hydroxyl-methyl)acrylate (2 g, 15.4 mmol) in diethyl ether (15 mL), at0 C phosphorus tribromide (0.51 mL, 5.4 mmol) wasadded dropwise. The reaction mixture was stirred for3 h from 0 C to room temperature. Water (5 mL) wasadded and the product was extracted with hexanes (3x 10 mL). The combined organic layers was washed with brine (2 x 10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 2-(bromomethyl)propenoicacid ethyl ester 14 (2.4 g, 12.3 mmol, 82 %) as a colourless liquid which was used in the next step without further purification. Colourless oil; 1H NMR (400 MHz, CDCI3) O 1.30 (t, J=7.2 Hz, 3H, H6), 4.16 (5, 2H, H4), 4.24 (q, J=7.0 Hz, 2H, H5), 5.92 (5, 1H, Hi?), 6.30 (5, iH, Hi), 13C NMR (101 MHz, CDCI3) O 14.1 (CH3, C6), 29.3 (CH2, C4), 61.2 (CH2, CS), 128.8 (CH2, Ci), 137.6 (C, C2), 164.8 (C, C3), IR (vmaxcm1) 1718 (C=O ester), 1628 (C=Calkene), 1182 (C-C ester), 523 (C-Br), HRMS-El: m/z [M+H] Calcd for C6H10BrO2:Expected: 192.9864. Found: 192.6870.
70%
With phosphorus tribromide; In diethyl ether; at -10 - 20℃; for 3h;
To the mixture of ethyl 2-(hydroxymethyl) acrylate (4 g, 0.030 mol) anddry ethyl ether (20 mL), phosphorus tribromide (1.4 mL, 0.015 mol) was added dropwise at -10 oC while stirring. After addition was completed thesolution was stirred at room temperature for 3 h. Water (20 mL) was added at-10 oC and the mixture was extracted with hexane (3X 10 ml) andwashed with a saturated solution of sodium chloride (2X 10 mL). After dryingthe organic layer over magnesium sulfate, the solvent was evaporated underreduced pressure and the crude product 7(4.7 g) was purified using vacuum distillation; Product yield: 4.1 g (70 %);b.p. 54-58 oC/ 2 torr. Purity was confirmed using 1H NMRanalysis. 1H NMR: (400 MHz, CDCl3), 6.22 (1 H, s), 5.87 (1H, s), 4.22 (2 H, s), 4.24 (2 H, q), 1.31 (3 H, t)
56.6%
With phosphorus tribromide; In diethyl ether; at -10 - 20℃; for 3h;
Phosphorus tribromide (17.16 g, 63.41 MMOL) was added to a stirred solution of the compound of example 30 (17.92 g, 138.1 MMOL) in dry ether (132 mL) at-10 C. The temperature was allowed to rise to 20 C and stirring was continued for 3h. Water (80 mL) was then added at-10 C and the mixture was extracted with hexane (3 x 45 mL). The organic extracts were washed with saturated sodium chloride solution (2 x 45 mL) and dried with anhydrous MGS04. Evaporation of solvent under vacuum gave 15.07 g (yield 56.6 %) of the crude product, which was used directly in the next reaction without any further purification. 1H NMR (CDCI3, 400MHZ) 8 6.25 (s, 1H), 5.88 (s, 1H), 4.2 (q, 2H), 4.11 (s, 2H), 1.25 (t, 3H); 13C NMR (CDCI3, 400 MHz) 5 166. 7,140. 1,125. 3,61. 1, 53.9, 14.4
34%
With sulfuric acid; hydrogen bromide; In water; at 12 - 26℃; for 24h;Product distribution / selectivity;
EXAMPLE 4 Preparation of EBMA EHMA is dissolved in a mixture of 48% aqueous hydrobromic acid and concentrated sulfuric acid and the mixture is stirred at 25 C. for 24 hours. The reaction mixture is then extracted with a water immiscible solvent (petroleum ether, hexane, heptane), the organic phase is washed with a dilute solution of sodium bicarbonate and the crude product is concentrated under vacuum to afford the compound of Formula II at a purity of >95%. ; EXAMPLE 5 EHMA (27 kg, 207 moles) was charged to the reactor. HBr (48%, 3.25 eq, 112 kg, 672 mol) was added and the mixture was then cooled to 12 C. At 12 C., sulfuric acid (2.0 eq, 39 kg, 398 mol) was added at such a rate that the internal temperature did not exceed 15 C. After all the acid was added, the mixture was left to stir at room temperature (22-26 C.) overnight. The reaction mixture was then extracted with hexane (3×33 kg). The hexane was pumped into the reactor, stirred for 30 minutes; allowed to settle for 30 minutes and then the phases separated. The hexane extract was washed with an aqueous sodium bicarbonate solution (5%, 33 kg). The mixture was stirred for 30 minutes, and then the stirrer stopped for 30 minutes to allow the phases to separate. This process was repeated twice. The washed hexane extract was then transferred to the distillation column. The hexane was then distilled at 40 C. under reduced pressure. The temperature was increased to 50 C. to remove any water that might be present. The residue containing EBMA was then distilled under high vacuum pump (80 C./<1 mm Hg) to obtain a 98% pure product (16.4 kg, 34%).
With phosphorus tribromide; In diethyl ether; at 0 - 20℃; for 18h;
In a 100 ml flask equipped with a magnetic stirrer, adropping funnel, and a drying tube, 2.3 g (17.7 mmol) 2-hydroxymethacrylic acid ethyl ester are added to 10 mL absolute diethyl ether Under ice cooling, 1.92 g (7.08mmol) phosphorous tribromide in 5 mL absolute diethyl ether are added dropwise. After 18 hours of stirring at room temperature, any excess phosphorous tribromide is hydroplysed by addition of 10 mL of water under ice cooling. The organic layer is washed twice with saturated NaHCO3 solution, dried over Na25O4 and stabilized with a small vacuum amount of hydrochinon. Diethyl ether is removed under vacuum. IR: 2981, 2933, 2901, 2869 (v, -CH3, -CH2), 1718 (v,OOR), 1628 (v, =C), 1463, 1444, 1398 (oe, H3,-CH2), 1182, 1115 (v, -C-O-), 957 (v, RCH=CH2),607 (v, C-Br) cm-1. GC/MS: mlz 192 (M-H+), 164 (C4H613rO2+), 146(C4H413rO+), 118 (C3H4Br+), 113 (C6H902+), 85(C4H502+), 69 (C4H50+), 57 (C3H50+), 41 (C3H5+). 1H-NMR (500 MHz, CDCl3): delta 6.32, 5.93 (s, 2H,RC-CH=CH2), 4.26 (q, 2H, RCOO-CH2-CH3), 4.17(s, 2H, RC-CH2-Br), 1.32 (t, 3H, RC-CH3) ppm.
4-Benzyloxycarbonyl-2,6-bis(ethoxycarbonyl)-4-methoxycarbonyl-1,6-heptadiene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72.4%
In water; acetonitrile;
Example 19 4-Benzyloxycarbonyl-2,6-bis(ethoxycarbonyl)-4-methoxycarbonyl-1,6-heptadiene (20) ›Formula (I); R1 =R2 =COOEt; X=COOCH3; Y=COOCH2 C6 H5! To a suspension of sodium hydride (1.32 g, 0.044 mol, 80% dispersion in oil) in acetonitrile (20 mL) was added a solution of <strong>[52267-39-7]benzyl methyl malonate</strong> (4.16 g, 0.02 mol) in acetonitrile (50 mL) at room temperature with vigorous stirring. The resulting mixture was stirred for 10 minutes before a solution of ethyl 2-(bromomethyl)propenoate (7.72 g, 0.04 mol) in acetonitrile (5 mL) was added and allowed to stir further at room temperature overnight (16 hr). This reaction was initially exothermic. Water (30 mL) was added, and the mixture extracted three times with ethyl acetate (total 200 mL). The organic phase was then washed with brine and dried over anhydrous magnesium sulfate. After removal of solvent under reduced pressure and purification by column chromatography on a silica gel column with ethyl acetate:n-hexane, 1:9 as eluent, the pure product (20) (6.25 g, 72.4%) was obtained as a colourless liquid. 1 H-NMR (CDCl3) δ(ppm): 1.27 (t, 6H, 2*CH2 CH3); 2.96 (s, 4H, 2* allylic-CH2); 3.58 (s, 3H, OCH3); 4.14 (q, 4H, 2*OCH2 CH3); 5.08 (s, 2H, OCH2 Ph); 5.65 (s, 2H, vinylic-H); 6.23 (s, 2H, vinylic-H) and 7.30 (m, 5H, ArH). 13 C-NMR (CDCl3) δ(ppm): 14.1, 35.0, 52.1, 57.5, 60.9, 67.0, 128.0, 128.2, 128.4, 128.8, 135.7, 135.9, 166.9, 170.0 and 170.6.
4-Benzyloxycarbonyl-2-t-butoxycarbonyl-6-ethoxycarbonyl-4-methoxycarbonyl-1,6-heptadiene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
Example 20 4-Benzyloxycarbonyl-2-t-butoxycarbonyl-6-ethoxycarbonyl-4-methoxycarbonyl-1,6-heptadiene (21) ›Formula (I); R1 =COOC(CH3)3; R2 =COOEt; X=COOCH2 C6 H5; Y=COOCH3! The title compound was prepared stepwise. In the first step, <strong>[52267-39-7]benzyl methyl malonate</strong> was reacted with an equimolar amount of ethyl 2-(bromomethyl)propenoate and sodium hydride in acetonitrile to give the product, benzyl 2-methoxycarbonyl-4-ethoxycarbonyl-pent-4-enoate, in 43% yield ›1 H-NMR (CDCl3) δ(ppm): 1.28 (t, 3H); 2.92 (d, 2H); 3.60 (s, 3H); 3.83 (t, 1H); 4.20 (q, 2H); 5.17 (s, 2H); 5.58 (s,1H); 6.18 (s, 1H) and 7.32 (m,[5H)]. In the second step, to a cooled suspension of sodium hydride (0.30 g, 0.01 mol, 80% dispersion in oil) in acetonitrile (20 mL), was added benzyl 2-methoxycarbonyl-4-ethoxycarbonyl-pent-4-enoate (2.68 g, 0.0084 mol). The resulting mixture was allowed to stir for 10 minutes before a solution of t-butyl 2-(bromomethyl)propenoate (1.85 g) in acetonitrile (5 mL) was added and stirring continued at room temperature overnight under nitrogen. After work-up, the title product (21) was obtained in 72% yield as a colourless liquid. 1 H-NMR (CDCl3) δ(ppm): 1.28 (t, 3H); 1.46 (s, 9H); 2.94 (s, 2H); 2.96 (s, 2H); 3.58 (s, 3H); 4.16 (q, 2H); 5.10 (s, 2H); 5.60 (s, 1H); 5.67 (s, 1H); 6.17 (s, 1H) and 7.32 (m, 5H).
Synthesis of ethyl 2-(6-fluoro-3-methoxy-2-nitrobenzyl)acrylate (23): 4-Fluoro-1-methoxy-2-nitrobenzene (21) (171 mg, 1.0 mmol) in THF (2 mL) was added to a solution of TMPZnCl.LiCl (2) (1.3 M in THF, 0.85 mL, 1.1 mmol) at 25 C. and the reaction mixture was then stirred at this temperature for 6 h according to TP 2. After cooling down to -50 C., ethyl 2-(bromomethyl)acrylate (230 mg, 1.2 mmol) and CuCN.2LiCl (1.0 M solution in THF, 5 drops) were added at -40 C. and the resulting mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with a sat. aq. NH4Cl solution (20 mL), extracted with diethyl ether (3×50 mL) and driedanhydrous Na2SO4. After filtration, the solvent was evaporated in vacuo. Purification by flash-chromatography (CH2Cl2/n-pentane, 1:3) furnished compound 23 (189 mg, 67%) as a colourless oil.1H-NMR (300 MHz, CDCl3) delta: 7.15 (m, 1 H), 8.89-8.93 (m, 1 H), 6.24 (s, 1 H), 5.31 (s, 1 H), 4.19 (q, J=7.1 Hz, 2 H), 3.86 (s, 3 H), 3.63 (bs, 2 H), 1.27 (t, J=7.1 Hz, 3 H).13C-NMR (75 MHz, CDCl3) delta: 165.9, 154.3 (d, J=243.6 Hz), 147.1 (d, J=2.8 Hz), 136.2 (d, J=0.8 Hz), 126.3 (d, J=0.8 Hz), 120.0 (d, J=21.9 Hz), 117.6, 117.3, 111.7 (d, J=8.3 Hz), 61.1, 56.7, 26.9 (d, J=2.9 Hz), 14.1.MS (70 eV, El) m/z (%): 283 (1) [M+], 237 (100), 209 (88), 192 (58), 166 (20), 149 (21), 133 (16), 121 (13), 99 (11).IR (ATR) v (cm1): 2969, 2359, 1738, 1503, 1385, 1342, 1294, 1226, 1215, 1084, 1013, 987, 954, 795, 764, 749, 667, 621, 615, 608, 603.HRMS (ESI) for C13H14FNO5 (283.0856): 283.0845.
In N,N-dimethyl-formamide; at 20℃; for 72h;Inert atmosphere;
General procedure: 6-Amino-2-(benzylthio)pyrimidin-4(3H)-one 1 (0.520 g, 2.22 mmol) was dissolved in DMF (10 mL, anhydrous) to which ethyl 2-(bromomethyl)acrylate (310 mul, 2.24 mmol) was added. The reaction mixture was then stirred under nitrogen for 7 days at room temperature prior to the concentration of excess solvent under reduced pressure. The resulting residue was purified by flash column chromatography using hexane/ethyl acetate (2:1) as eluant. The title compound 6a was obtained as a white crystalline solid (0.340 g, 0.998 mmol, 44%).
Stage #1: o-Xylylene dichloride With indium(III) chloride; chloro-trimethyl-silane; aluminium; zinc(II) chloride In tetrahydrofuran at 25℃; for 1.5h; Inert atmosphere;
Stage #2: ethyl 2-bromomethyl-2-propenoate With copper(I) cyanide di(lithium chloride) In tetrahydrofuran at -30℃; for 5h; Inert atmosphere;
With triethylamine; In chloroform; for 1.5h;Reflux;
General procedure: To a solution of alpha-cyanoamine (10 mmol) in chloroform (22.5 mL) was added a solution of bromoacrylate (10 mmol) in chloroform (22.5 mL) followed by freshly distilled triethylamine (0.73 mL, 10 mmol) and the mixture was heated at reflux for 1.5 h. The reaction mixture was allowed to cool to room temperature, washed with saturated aqueous sodium hydrogen carbonate (50 mL), followed by brine (50 mL), dried (Na2SO4), filtered and the solvent removed at reduced pressure to give the product.
With potassium carbonate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere;
General procedure: As a typical experiment, reactionof the heteroarene (1.5 mmol), ethyl 2-bromomethylacrylate (0.193 g,1 mmol), K2CO3 (0.207 g, 1.5 mmol) at 150 C during 16 h in DMA (4 mL)under argon afforded the corresponding products after extraction withdichloromethane, evaporation and filtration on silica gel. All compoundsgave satisfactory 1H, 13C and elementary analysis.
With potassium carbonate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere;
General procedure: As a typical experiment, reactionof the heteroarene (1.5 mmol), ethyl 2-bromomethylacrylate (0.193 g,1 mmol), K2CO3 (0.207 g, 1.5 mmol) at 150 C during 16 h in DMA (4 mL)under argon afforded the corresponding products after extraction withdichloromethane, evaporation and filtration on silica gel. All compoundsgave satisfactory 1H, 13C and elementary analysis.
With potassium carbonate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere;
General procedure: As a typical experiment, reactionof the heteroarene (1.5 mmol), ethyl 2-bromomethylacrylate (0.193 g,1 mmol), K2CO3 (0.207 g, 1.5 mmol) at 150 C during 16 h in DMA (4 mL)under argon afforded the corresponding products after extraction withdichloromethane, evaporation and filtration on silica gel. All compoundsgave satisfactory 1H, 13C and elementary analysis.
With potassium carbonate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere;
General procedure: As a typical experiment, reactionof the heteroarene (1.5 mmol), ethyl 2-bromomethylacrylate (0.193 g,1 mmol), K2CO3 (0.207 g, 1.5 mmol) at 150 C during 16 h in DMA (4 mL)under argon afforded the corresponding products after extraction withdichloromethane, evaporation and filtration on silica gel. All compoundsgave satisfactory 1H, 13C and elementary analysis.
With potassium carbonate; In N,N-dimethyl acetamide; at 150℃; for 16h;Inert atmosphere;
General procedure: As a typical experiment, reactionof the heteroarene (1.5 mmol), ethyl 2-bromomethylacrylate (0.193 g,1 mmol), K2CO3 (0.207 g, 1.5 mmol) at 150 C during 16 h in DMA (4 mL)under argon afforded the corresponding products after extraction withdichloromethane, evaporation and filtration on silica gel. All compoundsgave satisfactory 1H, 13C and elementary analysis.
(R)-3-methylene-5-(3-oxobutyl)dihydrofuran-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: 4-oxopentanal; ethyl 2-bromomethyl-2-propenoate With chromium dichloride; manganese; zirconocene dichloride; tetrabenzoporphyrinatocobalt(II); 1,8-bis((S)-4-isopropyl-4,5-dihydrooxazol-2-yl)-9H-carbazole; N,N,N',N'-tetramethyl-1,8-diaminonaphthalene; lithium chloride In tetrahydrofuran at 20℃; for 8h; Inert atmosphere;
Stage #2: With potassium carbonate In <i>tert</i>-butyl alcohol at 20℃;
ethyl 2-[(2-thioxo-1,3-dithiol-4-yl)methyl]acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
According to GP1, DTT (2; 134 mg, 1.0 mmol) was dissolved in anhydTHF (2 mL). TMPMgCl·LiCl (1; 0.99 mL, 1.1 mmol, 1.11 M in THF) wasadded dropwise at -78 C and the mixture was stirred for 0.5 h. AZnCl2 solution (1.2 mL, 1.2 mmol, 1.0 M in THF) was added at -78 Cand the mixture was stirred for 15 min. A CuCN·2LiCl solution(1.2 mL, 1.2 mmol, 1.0 M in THF) was added at -78 C and the mixturewas stirred at -40 C for 15 min, before ethyl 2-(bromomethyl)acrylate13 (214 mg, 0.17 mL, 1.2 mmol) was added. The mixturewas stirred at -40 C for 4 h, it was then quenched with aq NH4Cl/NH3solution (8:1, 5 mL) and extracted with Et2O (3 × 10 mL), and thecombined extracts were dried (anhyd Na2SO4). After filtration, thesolvents were evaporated in vacuo. The crude product was purified byflash column chromatography (silica gel, isohexane-CH2Cl2, 1:1)yielding 4e as a yellow oil (124 mg, 50%).IR: 2978, 1706, 1630, 1184, 1138, 1101, 1051, 1022 cm-1.1H NMR (300 MHz, CDCl3): delta = 6.76 (s, 1 H), 6.36 (s, 1 H), 5.75 (s, 1 H),4.24 (q, J = 7.2 Hz, 2 H), 3.60 (s, 2 H), 1.32 (t, J = 7.2 Hz, 3 H).13C NMR (75 MHz, CDCl3): delta = 213.5, 165.6, 144.2, 136.5, 128.1, 124.3,61.4, 33.5, 14.1.MS (70 eV, EI): m/z (%) = 246 (100) [M+], 172 (23), 170 (23), 142 (41),141 (40), 127 (19), 97 (15, 97 (76), 85 (22), 85 (12), 83 (17), 71 (31),71 (14), 70 (13), 69 (24), 57 (50), 56 (14), 55 (31), 53 (19), 45 (15), 45(37), 44 (33), 43 (33), 43 (15), 40 (28).HRMS (EI): m/z [M+] calcd for C9H10O2S3: 245.9843; found: 245.9844.
ethyl 8-oxobicyclo[3.2.1]octane-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 1-pyrrolidinocyclopent-1-ene; ethyl 2-bromomethyl-2-propenoate With triethylamine In acetonitrile at 90℃; for 3.5h;
Stage #2: With acetic acid In water; acetonitrile for 0.5h; Reflux;
1 Step 1: ethyl 8-oxobicyclo [3.2.1] octane-3-carboxylate
To a solution of 1- (cyclopent-1-en-1-yl) pyrrolidine (68 g, 496 mmol) and triethylamine (150 g, 1489 mmol) in acetonitrile (1.09 L, dried over calcium hydride) was added a solution ofethyl 2-(bromomethyl) acrylate (96 g, 496 mmol) in dry acetonitrile (1.04 L) dropwise. Heat was generated upon addition and the solution turned reddish brown, asolid was precipitated. The reaction mixture was heated at 90 for 3.5 hours. Hydrolysis of the iminiumion was accomplished by the addition of 150 ml of 5 aqueous acetic acid followed by a 0.5 hour refluxing period. The reaction mixture was cooled and an equal volume of water was added. The aqueous mixture was then extracted several times with ether and the combined organic layers were washed with 5 aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The resulting ethereal solution was dried over anhydrous magnesium sulfate. Filtration and evaporation of the ether gave a pale yellow oil which was purified by column chromatography on silica gel petroleum ether/EtOAc from 15/1 to 9/1 to get the title product.1HNMR (400 MHz, CD3OD) : δ 8.13-8.09 (m, 1H) , 7.32-7.31 (m, 1H) , 3.67 (s, 3H) , 2.50-2.46 (m, 1H) , 2.18-2.13 (m, 2H) , 1.95-1.91 (m, 2H) , 1.86-1.81 (m, 1H) , 1.76-1.68 (m, 1H) , 1.56-1.54 (m, 1H) , 1.21 (s, 3H) ppm.
Stage #1: 1-pyrrolidinocyclopent-1-ene; ethyl 2-bromomethyl-2-propenoate With triethylamine In acetonitrile at 90℃; for 3.5h;
Stage #2: With water; acetic acid In acetonitrile for 0.5h; Reflux;
Step 1: ethyl 8-oxobicyclo[3.2.1]octane-3-carboxylate
To a solution of 1- (cyclopent-1-en-1-yl) pyrrolidine (68 g, 496 mmol) and triethylamine (150 g, 1489 mmol) in acetonitrile (1.09 L, dried over calcium hydride) was added a solution of ethyl 2-(bromomethyl) acrylate (96 g, 496 mmol) in dry acetonitrile (1.04 L) dropwise. Heat was generated upon addition and the solution turned reddish brown, a solid was precipitated. The reaction mixture was heated at 90 for 3.5 hours. Hydrolysis of the iminiumion was accomplished by the addition of 150 ml of 5aqueous acetic acid followed by a 0.5 hour refluxing period. The reaction mixture was cooled and an equal volume of water was added. The aqueous mixture was then extracted several times with ether and the combined organic layers were washed with 5aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. The resulting ethereal solution was dried over anhydrous magnesium sulfate. Filtration and evaporation of the ether gave the crude which was purified by column chromatography on silica gel petroleum ether/EtOAc from 15/1 to 9/1 to get the title product. 1HNMR (400 MHz, CD3OD) : δ 8.13-8.09 (m, 1H) , 7.32-7.31 (m, 1H) , 3.67 (s, 3H) , 2.50-2.46 (m, 1H) , 2.18-2.13 (m, 2H) , 1.95-1.91 (m, 2H) , 1.86-1.81 (m, 1H) , 1.76-1.68 (m, 1H) , 1.56-1.54 (m, 1H) , 1.21 (s, 3H) ppm.
ethyl 2-[[tert-butoxycarbonyl(methyl)amino]methyl]prop-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
30.29%
A mixture of tert- butyl N-methylcarbamate (200.00 mg, 1.52 mmol, 1.00 eq) in THF (5.00 mL) was added NaH (91.20 mg, 2.28 mmol, 60% purity, 1.50 eq) at 0 C for 0.5 hr under N2, then ethyl 2- (bromomethyl)prop-2-enoate (352.10 mg, 1.82 mmol, 1.20 eq) was added to the mixture dropwise at 0 C, and the mixture was stirred at 15 C for 2 hr under N2 atmosphere. TLC (PE/EA=10/1) the starting material was consumed completely and two new spots appeared. The mixture was poured into ice-water (10 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2S04, filtered and concentrated in vacuum. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate= 100/1 to 5/1) to afford the title compound (112.00 mg, 460.34 muiotaetaomicron, 30.29% yield) as colorless oil. MR (1083) (400MHz, CDCh) delta 6.28 (s, 1 H), 5.55 (s, 1 H), 4.23 (q, J= 7.1 Hz, 2 H), 4.07 (br s, 2 H), 2.88 (br s, 3 H), 1.45 (br s, 9 H), 1.31 (br s, 3 H).
N-(2-(furan-2-yl)-4-methylene-5-oxo-2-(trifluoromethyl)pyrrolidin-1-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
42%
General procedure: Trifluoromethyl ketones (1; 0.30 mmol, 1 equiv), acylhydrazines (2; 0.45 mmol, 1.5 equiv) and TsOH (20 mol%) were added to a dried round-bottom flask (50 mL) fitted with a magnetic bar. 1,4-Dioxane 4 mL) was then added and the mixture was stirred and heated to reflux. After the formation of acylhydrazones (monitored by TLC), tin powder (1.35 mmol, 4.5 equiv) and ethyl 2-(bromomethyl)acrylate (3; 1.20 mmol, 4 equiv) were added to the flask. When acylhydrazones had essentially disappeared (monitored by TLC), the reaction mixture was cooled to r.t., then 1,4-dioxane was removed under vacuum. Saturated NH4Cl solution (10 mL) was added and the mixture was stirred for 10 min. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic phases were dried (MgSO4) and concentrated. Purification of the residue by silica gel column chromatography (petroleum ether-EtOAc, 4:1) furnished the pure products 4.
N-(2-(3-chlorophenyl)-4-methylene-5-oxo-2-(trifluoromethyl)pyrrolidin-1-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
General procedure: Trifluoromethyl ketones (1; 0.30 mmol, 1 equiv), acylhydrazines (2; 0.45 mmol, 1.5 equiv) and TsOH (20 mol%) were added to a dried round-bottom flask (50 mL) fitted with a magnetic bar. 1,4-Dioxane 4 mL) was then added and the mixture was stirred and heated to reflux. After the formation of acylhydrazones (monitored by TLC), tin powder (1.35 mmol, 4.5 equiv) and ethyl 2-(bromomethyl)acrylate (3; 1.20 mmol, 4 equiv) were added to the flask. When acylhydrazones had essentially disappeared (monitored by TLC), the reaction mixture was cooled to r.t., then 1,4-dioxane was removed under vacuum. Saturated NH4Cl solution (10 mL) was added and the mixture was stirred for 10 min. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic phases were dried (MgSO4) and concentrated. Purification of the residue by silica gel column chromatography (petroleum ether-EtOAc, 4:1) furnished the pure products 4.
N-(2-(4-chlorophenyl)-4-methylene-5-oxo-2-(trifluoromethyl)pyrrolidin-1-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
General procedure: Trifluoromethyl ketones (1; 0.30 mmol, 1 equiv), acylhydrazines (2; 0.45 mmol, 1.5 equiv) and TsOH (20 mol%) were added to a dried round-bottom flask (50 mL) fitted with a magnetic bar. 1,4-Dioxane 4 mL) was then added and the mixture was stirred and heated to reflux. After the formation of acylhydrazones (monitored by TLC), tin powder (1.35 mmol, 4.5 equiv) and ethyl 2-(bromomethyl)acrylate (3; 1.20 mmol, 4 equiv) were added to the flask. When acylhydrazones had essentially disappeared (monitored by TLC), the reaction mixture was cooled to r.t., then 1,4-dioxane was removed under vacuum. Saturated NH4Cl solution (10 mL) was added and the mixture was stirred for 10 min. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic phases were dried (MgSO4) and concentrated. Purification of the residue by silica gel column chromatography (petroleum ether-EtOAc, 4:1) furnished the pure products 4.
N-(4-methylene-5-oxo-2-(m-tolyl)-2-(trifluoromethyl)pyrrolidin-1-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
General procedure: Trifluoromethyl ketones (1; 0.30 mmol, 1 equiv), acylhydrazines (2; 0.45 mmol, 1.5 equiv) and TsOH (20 mol%) were added to a dried round-bottom flask (50 mL) fitted with a magnetic bar. 1,4-Dioxane 4 mL) was then added and the mixture was stirred and heated to reflux. After the formation of acylhydrazones (monitored by TLC), tin powder (1.35 mmol, 4.5 equiv) and ethyl 2-(bromomethyl)acrylate (3; 1.20 mmol, 4 equiv) were added to the flask. When acylhydrazones had essentially disappeared (monitored by TLC), the reaction mixture was cooled to r.t., then 1,4-dioxane was removed under vacuum. Saturated NH4Cl solution (10 mL) was added and the mixture was stirred for 10 min. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic phases were dried (MgSO4) and concentrated. Purification of the residue by silica gel column chromatography (petroleum ether-EtOAc, 4:1) furnished the pure products 4.
2-chloro-N-(4-methylene-5-oxo-2-phenyl-2-(trifluoromethyl)pyrrolidin-1-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
Stage #1: 2,2,2-Trifluoroacetophenone; 2-chlorobenzoylhydrazide With toluene-4-sulfonic acid In 1,4-dioxane Reflux;
Stage #2: ethyl 2-bromomethyl-2-propenoate With tin In 1,4-dioxane Reflux;
5-Trifluoromethyl-5-aryl-3-methylidenepyrrolidin-2-ones (4); General Procedure
General procedure: Trifluoromethyl ketones (1; 0.30 mmol, 1 equiv), acylhydrazines (2; 0.45 mmol, 1.5 equiv) and TsOH (20 mol%) were added to a dried round-bottom flask (50 mL) fitted with a magnetic bar. 1,4-Dioxane 4 mL) was then added and the mixture was stirred and heated to reflux. After the formation of acylhydrazones (monitored by TLC), tin powder (1.35 mmol, 4.5 equiv) and ethyl 2-(bromomethyl)acrylate (3; 1.20 mmol, 4 equiv) were added to the flask. When acylhydrazones had essentially disappeared (monitored by TLC), the reaction mixture was cooled to r.t., then 1,4-dioxane was removed under vacuum. Saturated NH4Cl solution (10 mL) was added and the mixture was stirred for 10 min. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic phases were dried (MgSO4) and concentrated. Purification of the residue by silica gel column chromatography (petroleum ether-EtOAc, 4:1) furnished the pure products 4.
3-chloro-N-(4-methylene-5-oxo-2-phenyl-2-(trifluoromethyl)pyrrolidin-1-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
Stage #1: 2,2,2-Trifluoroacetophenone; 3-chlorobenzhydrazide With toluene-4-sulfonic acid In 1,4-dioxane Reflux;
Stage #2: ethyl 2-bromomethyl-2-propenoate With tin In 1,4-dioxane Reflux;
5-Trifluoromethyl-5-aryl-3-methylidenepyrrolidin-2-ones (4); General Procedure
General procedure: Trifluoromethyl ketones (1; 0.30 mmol, 1 equiv), acylhydrazines (2; 0.45 mmol, 1.5 equiv) and TsOH (20 mol%) were added to a dried round-bottom flask (50 mL) fitted with a magnetic bar. 1,4-Dioxane 4 mL) was then added and the mixture was stirred and heated to reflux. After the formation of acylhydrazones (monitored by TLC), tin powder (1.35 mmol, 4.5 equiv) and ethyl 2-(bromomethyl)acrylate (3; 1.20 mmol, 4 equiv) were added to the flask. When acylhydrazones had essentially disappeared (monitored by TLC), the reaction mixture was cooled to r.t., then 1,4-dioxane was removed under vacuum. Saturated NH4Cl solution (10 mL) was added and the mixture was stirred for 10 min. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic phases were dried (MgSO4) and concentrated. Purification of the residue by silica gel column chromatography (petroleum ether-EtOAc, 4:1) furnished the pure products 4.
3-bromo-N-(4-methylene-5-oxo-2-phenyl-2-(trifluoromethyl)pyrrolidin-1-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
General procedure: Trifluoromethyl ketones (1; 0.30 mmol, 1 equiv), acylhydrazines (2; 0.45 mmol, 1.5 equiv) and TsOH (20 mol%) were added to a dried round-bottom flask (50 mL) fitted with a magnetic bar. 1,4-Dioxane 4 mL) was then added and the mixture was stirred and heated to reflux. After the formation of acylhydrazones (monitored by TLC), tin powder (1.35 mmol, 4.5 equiv) and ethyl 2-(bromomethyl)acrylate (3; 1.20 mmol, 4 equiv) were added to the flask. When acylhydrazones had essentially disappeared (monitored by TLC), the reaction mixture was cooled to r.t., then 1,4-dioxane was removed under vacuum. Saturated NH4Cl solution (10 mL) was added and the mixture was stirred for 10 min. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic phases were dried (MgSO4) and concentrated. Purification of the residue by silica gel column chromatography (petroleum ether-EtOAc, 4:1) furnished the pure products 4.
2-methyl-N-(4-methylene-5-oxo-2-phenyl-2-(trifluoromethyl)pyrrolidin-1-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
General procedure: Trifluoromethyl ketones (1; 0.30 mmol, 1 equiv), acylhydrazines (2; 0.45 mmol, 1.5 equiv) and TsOH (20 mol%) were added to a dried round-bottom flask (50 mL) fitted with a magnetic bar. 1,4-Dioxane 4 mL) was then added and the mixture was stirred and heated to reflux. After the formation of acylhydrazones (monitored by TLC), tin powder (1.35 mmol, 4.5 equiv) and ethyl 2-(bromomethyl)acrylate (3; 1.20 mmol, 4 equiv) were added to the flask. When acylhydrazones had essentially disappeared (monitored by TLC), the reaction mixture was cooled to r.t., then 1,4-dioxane was removed under vacuum. Saturated NH4Cl solution (10 mL) was added and the mixture was stirred for 10 min. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic phases were dried (MgSO4) and concentrated. Purification of the residue by silica gel column chromatography (petroleum ether-EtOAc, 4:1) furnished the pure products 4.
3-methyl-N-(4-methylene-5-oxo-2-phenyl-2-(trifluoromethyl)pyrrolidin-1-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: 2,2,2-Trifluoroacetophenone; 3-methylbenzoyl hydrazine With toluene-4-sulfonic acid In 1,4-dioxane Reflux;
Stage #2: ethyl 2-bromomethyl-2-propenoate With tin In 1,4-dioxane Reflux;
5-Trifluoromethyl-5-aryl-3-methylidenepyrrolidin-2-ones (4); General Procedure
General procedure: Trifluoromethyl ketones (1; 0.30 mmol, 1 equiv), acylhydrazines (2; 0.45 mmol, 1.5 equiv) and TsOH (20 mol%) were added to a dried round-bottom flask (50 mL) fitted with a magnetic bar. 1,4-Dioxane 4 mL) was then added and the mixture was stirred and heated to reflux. After the formation of acylhydrazones (monitored by TLC), tin powder (1.35 mmol, 4.5 equiv) and ethyl 2-(bromomethyl)acrylate (3; 1.20 mmol, 4 equiv) were added to the flask. When acylhydrazones had essentially disappeared (monitored by TLC), the reaction mixture was cooled to r.t., then 1,4-dioxane was removed under vacuum. Saturated NH4Cl solution (10 mL) was added and the mixture was stirred for 10 min. The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic phases were dried (MgSO4) and concentrated. Purification of the residue by silica gel column chromatography (petroleum ether-EtOAc, 4:1) furnished the pure products 4.
ethyl (E)-6-(4-methoxyphenyl)-2-methylenehex-5-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With ethyloxirane; di-tert-butyl peroxide at 120℃; for 16h; Sealed tube; Inert atmosphere;
Ethyl (E)-2-Methylene-6-phenylhex-5-enoate (3ha); Typical Procedure
General procedure: Allylbenzene (1h) (1181.8 mg, 10.0 mmol), ethyl 2-(bromomethyl)acrylate (2a) (193.0 mg, 1.0 mmol), 1,2-epoxybutane (144.2 mg, 1.5 mmol), and di-tert-butyl peroxide (DTBPO) (29.2 mg, 0.2 mmol) were added to a 5 mL screw-capped test tube; this test tube was then purged with argon and sealed. The mixture was stirred at 120 °C for 16 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (hexane/EtOAc, 100:1) and by preparative HPLC (chloroform) to give product 3ha. Yield: 126.7 mg (55%)
ethyl 2-(((3-methyloxetan-3-yl)oxy)methyl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a stirred solution of Compound 2q (10.5 g, 119.16 mmol) in DMF (120 mL) was added portion wise NaH (5.72 g, 238.33 mmol) at 0 C. The reaction mixture was stirred at 0 C. for 30 min followed by addition of Compound 3q (23 g, 119.16 mmol) at 0 C. and stirring at room temperature for 2 h. The progress of the reaction was monitored by TLC (10% EtOAc in hexane, Rf: 0.5, UV and PMA active). The reaction mixture was quenched using ice cold water (120 ml) and extracted using diethyl ether (100 ml×3). The combined organic layers were washed with cold water (100 ml×3). The organic layer was separated and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure, and the residue was purified by silica column using 10% ethyl acetate in hexane as an eluent. The pure fractions were collected and evaporated under reduced pressure to obtain Compound 4q (7 g, 29%) as a colorless oil. 1H NMR (400 MHz, chloroform-d) delta ppm 1.29-1.34 (t, 3H), 1.58-1.60(s,3H), 4.13 (s, J=1.67 Hz, 2H), 4.20-4.27 (q, 2H), 4.37-4.40 (d, 2H), 4.73 (d, J=6.32 Hz, 2H), 5.93 (s, 1H) 6.32 (s, J=1.55 Hz, 1H); LCMS: 71.79% (201.23, M+H), RT=1.57 min.
ethyl 2-(2-bromo-4,6-difluorobenzyl)acrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
> 95%
To a cooled solution of l-<strong>[175278-11-2]bromo-3,5-difluoro-2-iodobenzene</strong> (10.0 g, 31.4 mmol) in THF (25 mL, 1.3 M) at -20 C was added a solution of iPrMgCl (2M in THF, 20.4 mL, 40.8 mmol) dropwise. The mixture was stirred for 10 min and then warmed to 0 C and stirred an additional 50 min. Copper iodide (1.49 g, 7.84 mmol) was added, and the mixture was stirred for 10 min. Ethyl 2-(bromomethyl)acrylate (6.36 g, 4.55 mL, 32.9 mmol) was added, and the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with sat. aq. NH4C1 (25 mL), diluted with EtOAc (25 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine (4 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel column to give the desired product l-bromo- 3,5-difluoro-2-(2-methylallyl)benzene as a colorless and clear oil (10 g). Yield >95%.
diethyl 2,2’-((3-oxo-3,4-dihydroquinoxaline-2(1H)-diyl)bis(methylene))diacrylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With tin In tetrahydrofuran at 75℃; for 18h;
4.1. General experimental procedure for the synthesis of compounds 3
General procedure: A mixture of quinoxalin-2(1H)-ones 1 (0.2 mmol, 1 equiv), tin powder (0.3 mmol, 1.5 equiv) and allyl bromides 2 (0.7 mmol, 3.5equiv) in THF (3 mL) was stirred at 75 C in the metal bath for 18 h.The mixture was cooled to room temperature and THF was removed under vacuum. The saturated NH4Cl solution (5 mL) was poured into the mixture and stirred for 10 min. The mixture was extracted with ethyl acetate (3 10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum. Purification of the residue by silica gel column chromatography using ethyl acetate/petroleum ether (1/31/2) as the eluent furnished the pure products.
diethyl 2-hydroxy-2-isopropyl-4-methylenepentanedioate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With acetic acid; zinc In acetonitrile at 20℃;
2.1.2. General synthesis method for the Barbier reaction
General procedure: To a suspension of activated zinc powder (1.5 mol equiv.) in 50 mLdry acetonitrile was added acetic acid (1.5 mol equiv.). Ethyl 2-bromoacrylate(1 mol equiv.) was added to the reaction mixture followed by thedrop wise addition of aldehyde or ketone (1.1 mol equiv.). The reactionmixture was stirred at 20 C for 6-12 h. The reaction was monitored byTLC for completion (Potassium permanganate staining). The mixturewas filtered through celite and the filtrate evaporated under reducedpressure. The residue was dissolved in 100 mL ethyl acetate and theorganic layer washed with 50 mL of saturated aqueous ammoniumchloride solution followed by brine, separated, and dried over sodiumsulfate. Filtration and evaporation under reduced pressure provided thecrude products as oils. Flash silica gel column chromatography elutingwith 7-12% ethyl acetate: hexanes provided desired products in 45-95%yields in > 95% purity. All new compounds were fully characterized by1H, 13C NMR, and HRMS.
Stage #1: 3-iodobenzonitrile With di-sec-butylmagnesium In toluene at -78℃; for 0.166667h; Schlenk technique;
Stage #2: ethyl 2-bromomethyl-2-propenoate With copper (I) cyanide di(lithium chloride)complex In tetrahydrofuran; toluene at 20℃;
Typical Procedure 1: Preparation of Diorganomagnesium Species by Halide/Magnesium Exchange Followed by Electrophilic Functionalization
General procedure: A dry and argon-flushed Schlenk-flask equipped with a magnetic stirring bar and a septum was charged with the corresponding (hetero)aryl or alkenyl halide (1.00 equiv) and dissolved in dry toluene at the indicated concentration. When necessary, DMPU was added (detailed for each compound thereafter). Then, the exchange reagent R2Mg (R=sBu, 1c; R=Mes, 1d 0.60-0.70 equiv) was added dropwise at the indicated temperature and the reaction stirred for the indicated time. Subsequent reactions with electrophiles were carried out under the indicated conditions. The mixture was then quenched with a sat. aq. NH 4 Cl solution (10 mL), diluted with water (10 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were dried over Na 2 SO 4 , filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using the appropriate eluent.
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