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Structure of 1117-71-1 * 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.
With lithium hydroxide monohydrate; water In tetrahydrofuran at 0℃; for 3 h; Inert atmosphere
The (E) -4- bromo crotonate 6g (33.5mmol) was dissolved in THF (60ml) cooled to to 0 ,Under the protection of N2 was added dropwise lithium hydroxide monohydrate 1.83g (43.6mmol) in water(20mL). After the dropping 15min, 0 kept stirred 3h. And then cold water 150ml200ml of petroleum ether was added to the system to continue stirring 10min at 0 . Separating the aqueous phase, at 0 PH adjusted with concentrated hydrochloric acid to 1, with dichloromethane (80mlx3) and extracted. The combined organicPhase was dried over anhydrous sodium sulfate and concentrated to give compound X, a yellow solid 4.5g, 82percent yield.In the E-4- mixed with X-bromo crotonic acid and a drop of DMF in DCM (3ml) was added dropwise a solution of oxalylChlorine (0.025g, 1.96mmol). After the dropwise addition, stirring was raised to room temperature for 1h. Completion of the reaction,The solvent was concentrated to afford the intermediate (E) -4- bromo-2-enoyl chloride III, without further treatment,It was used directly in the next reaction.
82%
With lithium hydroxide monohydrate In tetrahydrofuran; water at 0℃; for 3 h; Inert atmosphere
A solution of methyl (E) -4-bromocrotonate (6 g, 33.5 mmol) in THF (60 mL) was cooled to 0 ° C, an aqueous solution (20 mL) of lithium hydroxide monohydrate (1.83 g, 43.6 mmol) was added dropwise under N2. After 15 min dripping, keep 0 ° C for 3 h. The cold water (150 mL) and petroleum ether (200 mL) were then added to the system and stirring was continued at 0 ° C for 10 min. The aqueous phase was separated, adjusted to pH 1 with concentrated hydrochloric acid at 0 ° C and extracted with dichloromethane (80 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate and concentrated to give E-4-bromocrotonic acid III as a yellow solid (4.5 g, yield 82percent).
64.3%
With lithium hydroxide In tetrahydrofuran; water for 3 h;
A mixture of (E) -4-bromo-2-butenoic acid methyl ester la (10 g, 0.056 mol)Was dissolved in 30 mL of tetrahydrofuran,To the reaction mixture, 30 mL of an aqueous solution of lithium hydroxide (3.05 g, 0.073 m) was slowly added dropwise,After the addition was complete, the reaction was stirred for 3 hours.The reaction solution was extracted with 50 mL of ethyl acetate,The aqueous phase was adjusted to pH <1 with 6M hydrochloric acid,Extraction with dichloromethane (100 mL X2)The organic phases were combined,The organic phase was concentrated under reduced pressure,(E) -4-bromo-2-butenoic acid lb (5.93 g, yellow oil)Yield: 64.3percent
40%
Stage #1: With lithium hydroxide monohydrate; water In tetrahydrofuran at 0℃; for 3.75 h; Inert atmosphere of nitrogen Stage #2: With sulfuric acid In water
To a stirred homogeneous solution of (E)-methyl 4-bromobut-2-enoate (53.7 g, 300 mmol) in THF (100 mL) at 0 °C (bath temperature) under a nitrogen atmosphere, was added a solution of lithium hydroxide monohydrate (16.4 g, 390 mmol) in water (80 mL) dropwise (over 35 min). After addition the mixture was stirred at 0 "C for 3 h. Cold water (300 mL) and petroleum ether (400 mL) were added and the mixture was stirred at 0 °C for 10 min. The organic layer was separated and discarded. Ethyl acetate/petroleum ether (1:10, 300 mL) was then added and-the mixture was again stirred at 0 °C for 10 min before the organic layer was separated and discarded. The aqueous solution was acidified with cone, sulfuric acid at 0 °C to pH <; 1. The product was extracted into dichloromediane (400 mL; 200 mL) and the combined organic extracts were dried (MgSO4) and evaporated under reduced pressure at 35 °C (bath temperature) to give a yellow oil. The oil was stirred with petroleum ether (2x500 mL) at 50 °C (bath temperature). The combined petroleum ether extracts were concentrated under reduced pressure at 20-25 °C (bath) to induce precipitation of the product The suspension was then stood at 5 UC overnight before the solid was collected by filtration, washed with cold petroleum ether and dried to give (E)-4-bromobut-2-enoic acid (9) (19.9g, 40percent).
Reference：
[1] Patent: CN105669521, 2016, A, . Location in patent: Paragraph 0104; 0105; 0106
[2] Patent: CN106946896, 2017, A, . Location in patent: Paragraph 0054
[3] Tetrahedron Letters, 1991, vol. 32, # 34, p. 4239 - 4242
[4] Tetrahedron, 1993, vol. 49, # 18, p. 3691 - 3734
[5] Journal of Organic Chemistry, 1994, vol. 59, # 24, p. 7259 - 7266
[6] Tetrahedron Letters, 1991, vol. 32, # 34, p. 4239 - 4242
[7] Patent: CN103987700, 2016, B, . Location in patent: Paragraph 0164-0166
[8] Patent: WO2010/104406, 2010, A1, . Location in patent: Page/Page column 77
[9] Journal of the Chemical Society, 1949, p. 3104
[10] Justus Liebigs Annalen der Chemie, 1942, vol. 551, p. 115
[11] Journal of Medicinal Chemistry, 2001, vol. 44, # 17, p. 2719 - 2734
[12] Patent: EP1950201, 2008, A1, . Location in patent: Page/Page column 58
[13] Patent: EP1117659, 2003, B1, . Location in patent: Page 54
[14] Patent: EP1171440, 2004, B1, . Location in patent: Page 45
[15] Patent: US2005/250761, 2005, A1, . Location in patent: Page/Page column 13-14
2
[ 1117-71-1 ]
[ 10035-10-6 ]
[ 13991-36-1 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1942, vol. 551, p. 115
3
[ 67-56-1 ]
[ 13991-36-1 ]
[ 1117-71-1 ]
Yield
Reaction Conditions
Operation in experiment
93.1%
at 0℃; for 15 h;
Compound 25 (1.525 g, 9.24 mmol) and anhydrous methanol (10 ml) were added to a 50 ml three-necked flask, stirred at 0° C. until dissolved, and SoCl2 (5.49 g, 46.19 mmol, 5 ml) was slowly added dropwise to generate bubbles. After completion, the temperature was raised to room temperature, stirring was continued for 15 hours, and the reaction was completed by TLC. The solvent was evaporated to dryness, and the mixture was extracted with ethyl acetate/water. The product was in the organic phase, and the liquid was separated. The organic phase was collected and dried over Na 2 SO 4 . The solvent was removed by spin-drying to give a crude product, which was purified by column chromatography. Petroleum ether: ethyl acetate = 8 The elution of: 1 gave a red oily liquid of compound 26, 1.54 g, yield: 93.1percent.
Reference：
[1] Patent: CN107556289, 2018, A, . Location in patent: Paragraph 0112; 0117; 0118; 0119
[2] Tetrahedron Asymmetry, 2009, vol. 20, # 10, p. 1164 - 1167
4
[ 623-43-8 ]
[ 1117-71-1 ]
Yield
Reaction Conditions
Operation in experiment
34 g
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 6 h; Reflux
The compound crotonic acid methyl ester (20 g, 200 mmol) was added to a 500 ml single-necked flask,Treated with carbon tetrachloride (200 ml)A mixture of azobisisobutyronitrile (AIBN) (66 mg, 0.4 mmol)And N-bromosuccinimide (NBS) (39.1 g, 220 mmol)The reaction solution was allowed to react for 6 hours under reflux,cool down,The solid was removed by filtration,The filtrate was washed with water (20 ml x 3), dried over anhydrous Na2SO4,Filtration by spinning gave a yellow oil 4-bromocrotonic acid methyl ester (34 g)The compound was used directly in the next step without purification.
Reference：
[1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 11, p. 1629 - 1632
[2] Tetrahedron, 1988, vol. 44, # 9, p. 2541 - 2548
[3] Phytochemistry (Elsevier), 1983, vol. 22, # 4, p. 1028 - 1030
[4] Angewandte Chemie - International Edition, 2007, vol. 46, # 7, p. 1066 - 1070
[5] Journal of the Indian Chemical Society, 2002, vol. 79, # 11, p. 876 - 883
[6] Australian Journal of Chemistry, 1978, vol. 31, p. 863 - 891
[7] Tetrahedron Letters, 1989, vol. 30, # 52, p. 7399 - 7402
[8] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, # 12, p. 2921 - 2926
[9] Revue Roumaine de Chimie, 2002, vol. 47, # 6, p. 543 - 544
[10] Patent: US4886817, 1989, A,
[11] Patent: CN106146511, 2016, A, . Location in patent: Paragraph 0249; 0250; 0251
5
[ 623-43-8 ]
[ 1117-71-1 ]
Reference：
[1] Journal of Organic Chemistry, 1986, vol. 51, # 26, p. 5243 - 5252
[2] Justus Liebigs Annalen der Chemie, 1942, vol. 551, p. 115
[3] Chemische Berichte, 1948, vol. 81, p. 368,371
[4] Justus Liebigs Annalen der Chemie, 1942, vol. 551, p. 115
[5] Chemische Berichte, 1948, vol. 81, p. 368,371
[6] Journal of the Chemical Society, 1949, p. 3104
[7] Helvetica Chimica Acta, 1946, vol. 29, p. 573,580
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1932, vol. 195, p. 389[2] Bulletin de la Societe Chimique de France, 1934, vol. <5>1, p. 1342
9
[ 56-23-5 ]
[ 623-43-8 ]
[ 1117-71-1 ]
Reference：
[1] Patent: US2790757, 1954, ,
10
[ 56-23-5 ]
[ 3699-18-1 ]
[ 623-43-8 ]
[ 1117-71-1 ]
Reference：
[1] Canadian Journal of Chemistry, 1955, vol. 33, p. 1724,1726[2] Org.Synth.Coll.Vol., 1963, vol. IV, p. 496
11
[ 99848-36-9 ]
[ 71-43-2 ]
[ 1117-71-1 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1935, vol. 200, p. 2089[2] Bulletin de la Societe Chimique de France, 1938, vol. <5> 5, p. 1552,1560
12
[ 67-56-1 ]
[ 60-29-7 ]
[ 99848-36-9 ]
[ 124-41-4 ]
[ 1117-71-1 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1935, vol. 200, p. 2089[2] Bulletin de la Societe Chimique de France, 1938, vol. <5> 5, p. 1552,1560
13
[ 60-29-7 ]
[ 5837-73-0 ]
[ 7789-60-8 ]
[ 1117-71-1 ]
[ 137207-24-0 ]
Reference：
[1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1932, vol. 195, p. 389[2] Bulletin de la Societe Chimique de France, 1934, vol. <5>1, p. 1342
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 2h;
A solution of 4-bromo-2-butenoic acid methyl ester (0.1647 mol) in DMF (50 ml) was added dropwise to a mixture of 2-hydroxy-4, [5-DIMETHOXY-BENZALDEHYDE] (0.0823 mol) and [K2CO3] (0.1647 mol) in DMF (200 ml). The reaction mixture was stirred for 2 hours at room temperature, filtered and the filtrate was evaporated to dryness. The residue was washed in a 10% aqueous [NAOH] solution, then extracted with [CH2C12.] The separated organic layer was dried (Na2SO4), filtered, and the solvent was evaporated. The residue was washed with diethyl ether, then dried. Yielding: 20 g of intermediate compound 1 (87%).
benzyl (2SR)-2-(diphenylmethyleneamino)-2-[(1SR,2SR)-2-methyloxycarbonyl-cyclopropyl]acetate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
Step 2: Benzyl (2SR)-2-(diphenylmethyleneamino-2-[(lSR, 2SR)-2- methyloxycarbonyl-cyclopropyl] acetate hydrochloride:; To a solution of benzyl N- (diphenylmethylene)-glycinate (50.0 g, 151.79 mmol), methyl-4-bromocrotonate (34.0 g, 189.74 mmol) and lithium bromide (19.8 g, 189.74 mmol) in dry THF (900 ml) was added triethylamine (26.4 ml, 189.74 mmol) in dry THF (100 ml) over a period of 45 min. The reaction mixture was stirred for 20 h at room temperature. The mixture was diluted with cold water (500 ml) and then extracted with ethyl acetate (4 x 500 ml). The combined organic extracts were acidified with ION hydrochloric acid (40 ml) and the mixture was stirred for 30 min at room temperature. The amine hydrochloride precipitated out was collected by filtration to give 31 g (68 %) of the product as a white solid; Mp: 208 C, IR (KBr) 3423,2953, 2627,2464, 1756,1717, 1499,1398, 1367, 1297, 1220,1037, 753 cari ;'H NMR (300 MHz, DMSO-d6) 5 1. 11-1. 17 (m, 1H), 1.21-1. 27 (m, 1H), 1.66-1. 71 (m, 1H), 2.00-2. 06 (m, 1H), 3. 61 (s, 3H), 3.74-3. 77 (br d, J= 9.3 Hz, 1H), 5.22-5. 26 (d, J= 12.3 Hz, 1H), 5.27-5. 31 (d, J= 12.3 Hz, 1H), 7.38-7. 41 (m, 5H), 8.78 (br s, 3H).
With triethylamine In toluene at 0 - 20℃; for 48h;
4
Racemic piperazine derivative was obtained starting from dibenzylethylenediamine by addition of methyl-4-bromocrotonate and triethylamine in toluene at 0°C. The solution was agitated for 48 H at room temperature. After evaporation, the medium was hydro lyzed with 10% HCl and extracted with ethyl acetate. The aqueous phase was basified with K2CO3 until pH 7, and extracted with ethyl acetate. The organic phase was evaporated to give oil, followed by hydrogenation catalyzed by palladium on carbon in a mixture methanol-HCl IN, the corresponding product was obtained after filtration on celite and evaporation. A selective protection with EPO 2-chlorobenzyloxysuccinimide was achieved at pH 8,5 regulating pH with K2CO3 (2M) at 0°C. Then the aqueous phase was acidified with KHSO4 5% until pH 2,5 and extracted with ethyl acetate. The organic phase was evaporated to give yellow oil.
Stage #1: methyl 4-bromocrotonate; N,N'-Dibenzylethylenediamine With triethylamine In toluene at 20℃; Cooling with ice;
Stage #2: With hydrogenchloride In water
Stage #3: With potassium carbonate; sodium hydroxide In water
22A
Example 22A methyl (1,4-dibenzylpiperazin-2-yl)acetate Methyl 4-bromocrotonate (Aldrich, 5.53 mL, 40 mmol) was added dropwise with stirring to an ice-cooled solution of triethylamine (11.15 mL, 80 mmol) and N,N'-dibenzylethylenediamine (Aldrich, 9.67 mL, 40 mmol) in toluene (200 mL). The solution was stirred with ice cooling for 1 hour, then allowed to warm gradually to room temperature and stirred 25 hours longer. The mixture was filtered through a pad of diatomaceous earth with an ethyl acetate (20 mL) rinse. The filtrate was concentrated to an oil, which was mixed with 10% aqueous HCl (240 mL). After 5 minutes, the mixture was filtered and the cake was rinsed with water (2*10 mL). The filtrate was washed with ethyl acetate (2*80 mL) and the aqueous phase was made basic (pH~9-10) by portionwise addition of solid K2CO3 (26 g), then 25% aqueous NaOH (10 mL). The turbid mixture was extracted with ethyl acetate (3*120 mL) and the combined extracts were washed with brine (100 mL), dried (MgSO4) and concentrated under vacuum to leave the title compound as an oil (9.78 g): 1H NMR (300 MHz, CDCl3) δ ppm 2.30-2.47 (m, 4H), 2.49-2.73 (m, 4H), 3.06-3.18 (m, 1H), 3.43 (d, J=13.2 Hz, 2H), 3.53 (d, J=13.2 Hz, 1H), 3.60 (s, 3H), 3.76 (d, J=13.6 Hz, 1H), 7.14-7.36 (m, 10H); MS (DCI) m/z 339 (M+H)+.
With potassium carbonate In acetone at 20℃; for 15h;
1a.iv (iv) Preparation of compound 5
4-Bromo methyl crotonate (0.447 gm) was added drop wise at RT to a mixture of dibenzyl diamine (0.6 gm) and K2CO3(0.5 gm) in dry acetone (8 ml). The reaction was allowed to stir at RT for 15 h. Acetone was removed at reduced pressure and the resulting crude compound 5 was purified by column chromatography using silica matrix and 30% ethyl acetate-hexane solution mixture.
5-[4-(tert-butoxycarbonyl)phenyl]-5-hydroxy-2-hexenoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With iodine; In benzene-ether-tetrahydrofuran;
Reference Example 14 Production of 5-[4-(tert-butoxycarbonyl)phenyl]-5-hydroxy-2-hexenoic acid: To a suspension obtained by adding a solution of <strong>[105580-41-4]4-acetylbenzoic acid tert-butyl ester</strong> (7.82 g) in benzene-ether-tetrahydrofuran (3:3:2, 80 ml) to 4.64 g (71 mmol) of zinc, were added gradually under heating and stirring 4-bromocrotonic acid methyl ester (6.36 g) and iodine (20 mg). After reflux under heating in an oil bath at 70 C. for 1 hour, methyl 4-bromocrotonate (2.13 g) and zinc (1.55 g) were added, followed by reflux under heating for 30 minutes. The temperature was cooled down to room temperature, and the reaction mixture was poured into water (300 ml) and adjusted to pH 5 with acetic acid. The organic layer obtained by extraction with ether was washed with 5% aqueous ammonia and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by column chromatography (support; silica gel, 200 g, developing agent; ethyl acetate:hexane=1:4), to obtain the object compound (9.2 g). IR (Neat): 3480, 2975, 1720, 1700, 1650, 1605 cm-1 1 H-NMR (CDCl3) delta: 1.53 (12H,s), 2.64 (2H,d,j=7Hz), 2.67 (1H,brs), 3.63 (3H,s), 5.80 (1H,d,j=15Hz), 6.80 (1H,dt, j=15Hz,7Hz), 7.45 (2H,d,j=8Hz), 7.90 (2H,d,j=8Hz).
With caesium carbonate; In tetrahydrofuran; for 12h;Reflux;
Example XIV (E)-Methyl 4-(cyclododecylamino)but-2-enoate Under an atmosphere of nitrogen (E)-methyl 4-bromobut-2-enoate (5.70 g, 31.8 mmol), <strong>[1502-03-0]cyclododecanamine</strong> (6.41 g, 35.0 mmol) and Cs2CO3 were suspended in absolute tetra-hydrofuran (THF) (150.0 ml). The mixture was heated at reflux for 12 h and NH4Cl (saturated solution, 100 ml) was added. The mixture was extracted with DCM (three times, 50.0 ml). The organic layer was dried with Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using silica and petrol ether/ethyl acetate (4:1) to yield the title compound as yellow solid (5.54 g, 19.7 mmol, 62%). 1H NMR (300 MHz, CD2Cl2) delta=1.07-1.54 (m, 23H, -CH2-, -NH-), 2.67 (m, 1H, -CH-), 3.44 (dd, J=5.4, 2.2 Hz, 2H, -CH2-), 3.75 (s, 3H, -CH3), 6.02 (dd, J=15.7, 2.1 Hz, 1H, =CH-), 7.01 (dq, J=15.7, 5.2 Hz, 1H, =CH-).
62%
With caesium carbonate; In tetrahydrofuran; for 12h;Reflux;
Example XIV (E)-Methyl 4-(cyclododecylamino)but-2-enoate Under an atmosphere of nitrogen (E)-methyl 4-bromobut-2-enoate (5.70 g, 31.8 mmol), <strong>[1502-03-0]cyclododecanamine</strong> (6.41 g, 35.0 mmol) and Cs2CO3 were suspended in absolute tetra-hydrofuran (THF) (150.0 ml). The mixture was heated at reflux for 12 h and NH4Cl (saturated solution, 100 ml) was added. The mixture was extracted with DCM (three times, 50.0 ml). The organic layer was dried with Na2SO4 and the solvent was removed under reduced pressure. The crude product was purified by column chromatography using silica and petrol ether/ethyl acetate (4:1) to yield the title compound as yellow solid (5.54 g, 19.7 mmol, 62%). 1H NMR (300 MHz, CD2Cl2) delta=1.07-1.54 (m, 23H, -CH2-, -NH-), 2.67 (m, 1H, -CH-), 3.44 (dd, J=5.4, 2.2 Hz, 2H, -CH2-), 3.75 (s, 3H, -CH3), 6.02 (dd, J=15.7, 2.1 Hz, 1H, =CH-), 7.01 (dq, J=15.7, 5.2 Hz, 1H, =CH-).
Example 1b Synthesis of (E)-methyl-4-(2,4,5-trifluorophenyl)-but-2-enoate (IIa) Through Grignard Exchange Reaction Followed by Cobalt Catalyzed Cross-Coupling Process A dry and nitrogen-flushed 200 mL two-necked flask, equipped with a magnetic stirrer and a rubber septum was charged with anhydrous THF (20 mL) and cooled to -20C. Afterward 2,4,5-trifluorobenzene (V) (65.2 mmol, 13.7 g, 7.6 mL) was iniciated through a septum following by slow addition of iPrMgCl (2 M in THF, 1.2 equiv. according to (V), 39.6 mL). The reaction temperature was maintained at -10 C and the reaction mixture was stirred for 3 hours, until Br/Mg exchange reaction was completed and (VI) was formed. Into a three-necked dry flask flushed with nitrogen, were placed CoBr2 beads (3.76 mmol, 6 mol% according to (V), 822 mg, 99.99% purity), TMEDA (3.76 mmol, 6 mol%, 564 muL) and anhydrous THF (20 mL). Such reaction system was cooled to 0 C and during intensive stirring methyl-trans-4-bromo-2-butenoate (VIIa) (50 mmol, 8.95 g, 5.98 mL, 90% purity) was iniciated through a rubber septum and reaction mixture was stirred for 30 min. Finally, freshly prepared THF solution of Grignard reagent (VI), previously cooled to -20 C, was slowly added and such reaction mixture was intensively stirred at 0 C for 16 hours. The saturated aqueous NH4Cl solution (150 mL) and extracted with four portions of EtOAc (300 mL). The combined organic phases were washed with brine (200 mL), dried over anhydrous Mg2SO4 and concentrated in vacuo. The crude residue was purified with column chromatography (Isolera; gradient elution n-hexane/EtOAc = 1/10) to obtain pure oily product (IIa) (10.8 g, 93% yield) as determined with 1H NMR and MS analysis.
To a solution of N-<strong>[38256-93-8](2-methoxyethyl)methylamine</strong> (1.1 g; 12.3 mmol) in 25 mL of THF was added 4-trans- bromomethylcrotonate (1 g; 5.6 mmol), and the mixture was stirred at room temperature for overnight. The reaction mixture was diluted by ethyl acetate (25 mL). Then it was washed with brine six times, dried over Na2S04, filtered and concentrated under reduced pressure to give methyl (£)-4-[2-methoxyethyl(methyl)amino]but-2-enoate (895 mg, 86%).
In tetrahydrofuran; at 25℃; for 12h;
Step 1[00382] To a solution of compound 8 (765 mg, 8.6 mmol) in 20 mL of THF was added 4-bromo- methyl-crotonate 1 (700 mg, 3.9 mmol), and the mixture was stirred at 25C for 12h. The reaction was monitored by TLC. After the reaction finished, it was diluted by ethyl acetate (20 mL). Then it was washed with brine several times, dried over MgS04 and concentrated under reduced pressure to give 500 mg of 9 as a crude product, which was used directly in the next step without further purification.
A suspension of bis(2-methoxyethyl)amine (8.1 mL, 56 mmol) and K2CO3 (15.5 g, 112 mmol) in anhydrous MeCN (100 mL) was cooled down to 0 C. with an ice bath. A solution of (E)-methyl 4-bromobut-2-enoate (15.6 mL, 56 mmol) in anhydrous MeCN (20 mL) was added dropwise to the reaction mixture. After addition, the resulting mixture was warmed up to r.t. and stirred for 2 hrs. The reaction mixture was then filtered and the filtrate was concentrated. The residual was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to afford (E)-methyl 4-(bis(2-methoxyethyl)amino) but-2-enoate (77) (10.0 g, 78% yield) as a yellow oil. LC-MS (ESI): m/z (M+1) 232.1.
(2E)‐4‐[4‐(2‐[(tert‐butoxy)carbonyl]amino}ethyl)piperazin‐1‐yl]but‐2‐enoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.05 g
2 g of tert-butyl-(2-(piperazin)-1-yl)ethyl)carbamate was dissolved in 20 ml of DMSO, and 1.35 ml of triethylamine was added thereto. To that solution, (E)-methyl 4-bromobut-2-enoate was added in a total amount of 1.14 ml at room temperature. After the mixture was stirred for 1.5 hours, the solution was added to a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The extract was dried over sodium sulfate, subsequently the solvent was removed, and the residue was purified by silica gel chromatography (eluant: chloroform:methanol). 10 ml of triethylamine and 10 ml of water were added to the product obtained, and the mixture was stirred overnight at 100C. The solvent was removed from the reaction solution, and 2.05 g of the title compound was obtained as an orange-colored amorphous material.
methyl trans-4-(2-bromo-6-methoxyphenoxy)-2-butenoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
91%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 8h;Inert atmosphere;
<strong>[28165-49-3]2-Bromo-6-methoxyphenol</strong> (8.46 g, 41.7 mmol) in DMF (50 mL) was treated with anhydrous K2CO3 (6.91 g, 50.0 mmol) and methyl trans-4-bromo-2-butenoate (5.88 mL, 8.95 g, 50.0 mmol) and the suspension stirred at r.t. for 8 h. The mixture was poured into H2O and extracted with CH2Cl2. The organic layer was washed with sat. aq Na2SO4 and dried over Na2SO4. After filtration and evaporation of the solvent, the residue was chromatographed on silica gel, eluting with hexanes-EtOAc (4:1), to give 54 (11.4 g, 91%) as a yellow oil, used without further purification. 1H NMR (300 MHz, CDCl3): delta = 7.09 (dt, J = 15.6, 4.5 Hz, 1 H), 7.08 (dd,J = 7.8, 1.5 Hz, 1 H), 6.90 (t, J = 8.1 Hz, 1 H), 6.81 (dd, J = 8.4, 1.5 Hz, 1H), 6.27 (dt, J = 15.6, 2.1 Hz, 1 H), 4.63 (dd, J = 4.5, 2.1 Hz, 2 H), 3.81 (s,3 H), 3.73 (s, 3 H).MS (EI, 70 eV): m/z (%) = 302, 300 (1:1, [M+], 25), 203, 201 (1:1, 100),94 (80).
methyl (E)-4-((9-formyl-2,3,6,7-tetrahydro-1H,5H-pyrido-[3,2,1-ij]quinolin-8-yl)oxy)but-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
General procedure: NaH (0.165 g, 6.9 mmol) was slowly added to a solution of 8-hydroxy-2,3,6,7-tetrahydro-1H,5H-pyrido [3,2,1-ij] quinoline-9-carbaldehyde (1 g, 4.6 mmol) in DMF (10 vol) at 0 C. The mixture was stirred at 0 C for 10 min and then added alkyl halide (1.5 eq, 6.9 mmol) at the same temperature. The reaction mixture was stirred at r.t. for 2 h. When the reaction was complete [TLC (EtOAc:hexane, 1:5)], the mixture was extracted with EtOAc and washed with water. The organic layer was separated, dried over anhydrous Na2SO4 and removed under reduced pressure. The residue obtained was purified by flash column chromatography [silica gel (230-400 mesh; Merck), EtOAc-hexane (1:5)].
With potassium carbonate; potassium iodide; In tetrahydrofuran; for 2h;Reflux;
300 mg (0.71 mmol) of <strong>[15291-77-7]ginkgolide B</strong> was dissolved in 30 mL of THF, and 251 mg (1.4 mmol) of methyl 4-bromo-2-butenoate, 232 mg (1.4 mmol) of KI, and 434 mg (3.1 mmol) of potassium carbonate were sequentially added. Stir for 2 hours under heating and reflux. The plate was traced until the substrate was substantially disappeared. After the reaction was completed, potassium carbonate was filtered off, the mother liquor was concentrated, and the residue was subjected to column chromatography to obtain a pale yellow solid. The product was dried by filtration to obtain 192 mg, with a yield of 52.5%. .
(2E,2'E)-dimethyl 4,4'-((2-acetoxyethyl)azanediyl)bis(but-2-enoate)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With potassium tert-butylate; at 50℃; for 16h;
General procedure: KOt-Bu (0.5 mmol, 56 mg), 2-oxazoline (0.5 mmol), benzyl bromide (1.0 mmol) and DMC (2 mL) were introduced in a tube, equipped with magnetic stirring bar and the mixture was stirred at 50 C. After 16 h, the progress of the reaction was analyzed by gas chromatography. The solvent was then evaporated under vacuum and the desired product was purified by silica gel chromatography and a mixture of petroleum ether/ethyl acetate as eluent.
methyl 2-(3-(3-phenylpropyl)-2-thioxothiazolidin-4-yl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: carbon disulfide; 3-Phenylpropan-1-amine With triethylamine In methanol at 20℃; for 0.166667h; Cooling with ice;
Stage #2: methyl 4-bromocrotonate In methanol at 20℃; for 3.5h; Reflux;
General Procedure for one-pot three-component synthesis of alkyl 2-(3-alkyl-2-thioxothiazolidin-4-yl)acetates 3a-q
General procedure: In a 10 mL round bottom flask equipped with a magnetic stirring bar in an ice bath, MeOH or EtOH (5 mL), primary amine (1.2 mmol), CS2 (2 mmol), and Et3N (1 mmol) were added. The mixture was stirred at room temperature for 10 minutes. Then, alkyl -4-bromocrotonate (1 mmol) was added and the mixture was stirred at room temperature for one hour, followed by ref luxing f or 2.5 h. The progress of reaction was monitored by TLC (EtOAc/cyclohexane, 20:80). Water (10 mL) was added and the reaction mixture wa s extracted with EtOAc (3 10 mL), the combined organic phase was dried over MgSO4 and evaporated on rotary evaporator to afford a liquid mixture. Purification was carried out by column chromatography (SiO2; EtOAc/cyclohexane, 20:80 to 30:70).
methyl (±)-2-[(4S,5S)-5-(2-cyanophenyl)-1,1-dioxido-2-phenylisothiazolidin-4-yl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
Stage #1: 1-(2-cyanophenyl)-N-phenylmethanesulfonamide With potassium carbonate In N,N-dimethyl-formamide for 0.166667h;
Stage #2: methyl 4-bromocrotonate In N,N-dimethyl-formamide at 55℃; for 20h; diastereoselective reaction;
Sultams 3; General Procedure
General procedure: To a suspension of K2CO3 (1.2 equiv) in DMF (5 mL) was added th ecorresponding sulfonamide 1 (1-1.2 mmol, 1 equiv). The mixture was stirred for 10 min, and then methyl 4-bromocrotonate (2a; 1.1 equiv) or (E)-1-[(3-bromoallyl)sulfonyl]-4-methylbenzene (2b; 1.1 equiv) was added in one portion. The mixture was stirred at 0, 25, 35 or 55 °C until full consumption of sulfonamide (0.5-20 h, TLC: SiO2, eluent: n-hexane/EtOAc 75:25). After full conversion, DMF was evaporated in vacuo and the residue was partitioned between EtOAc and H2O, and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed sequentially with aq 1 M HCl (2 × 15 mL), H2O (3 × 10 mL) and brine (2 × 20 mL), dried (Na2SO4), filtered, concentrated, and purified by column chromatography on silica gel or by crystallization.
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