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CAS No. : | 623-91-6 | MDL No. : | MFCD00064455 |
Formula : | C8H12O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IEPRKVQEAMIZSS-AATRIKPKSA-N |
M.W : | 172.18 | Pubchem ID : | 638144 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.5 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 42.67 |
TPSA : | 52.6 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.68 cm/s |
Log Po/w (iLOGP) : | 2.42 |
Log Po/w (XLOGP3) : | 0.94 |
Log Po/w (WLOGP) : | 0.67 |
Log Po/w (MLOGP) : | 0.84 |
Log Po/w (SILICOS-IT) : | 0.99 |
Consensus Log Po/w : | 1.17 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.1 |
Solubility : | 13.6 mg/ml ; 0.0788 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.63 |
Solubility : | 4.02 mg/ml ; 0.0234 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.93 |
Solubility : | 20.3 mg/ml ; 0.118 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.34 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P210-P264-P270-P273-P280-P301+P312+P330-P370+P378-P403+P235-P501 | UN#: | N/A |
Hazard Statements: | H227-H302-H401 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.6% | at 25℃; for 12 h; | To a solution of diethyl (E)-but-2- enedioate (30.2 g, 175 mmol, 28.8 mL) in i-PrOH (300 mL) was added ethane-1,2-diamine (11.0 g, 183 mmol, 12.2 mL). After stiring at 25 °C for 12 hours, the reaction mixture was concentrated under reduced pressure to dryness. The crude white solid was washed with MTBE (500 mL) and dried under vacuum to give ethyl 2-(3-oxopiperazin-2-yl)acetate (26.0 g, 140 mmol, 79.6 percent yield, 100 percent purity) as a white solid.’H NMR (400 MFIz, Chloroform-d) = 6.55 (br s, 1H), 4.15 (q,J= 6.8 Hz, 2H), 3.80-3.72 (m, 1H), 3.47 (dt,J=4.8, 11.2 Hz, 1H), 3.36- 3.22 (m, 1H), 3.18 - 3.08 (m, 1H), 3.07 - 2.95 (m, 2H), 2.76 - 2.70 (m, 1H), 1.25 (t, J= 7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | at 50℃; for 24h; heating the mixture in a bomb; | |
40% | In benzene at 0℃; for 24h; | 3.1 Diethyl fumarate (53 g, 0.31 mol) was dissolved in anhydrous benzene (200 mL), and 1,3-butadiene (29 g) was added thereto, maintaining at 0 °C. The reaction was carried out for 24 h in a pressurized vessel, maintaining at 50 °C, and a residue was obtained by removing the solvent. The residue was distilled under vacuo (80-83 °C /0.5 mmHg) to give the the title compound (28 g, Yield 40%) as a white liquid. [529] 1H NMR (CDCl3): δ 1.34 (t, 6H), 2.19 (m, 2H), 2.22 (m, 2H), 2.84 (m, 2H), 4.10 (q, 4H), 5.69 (d, 2H). |
With toluene at 150 - 160℃; |
With hydroquinone In toluene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With diisobutylaluminium hydride In toluene at 20℃; for 12h; | |
60% | With diisobutylaluminium hydride In toluene at 20℃; Inert atmosphere; | |
With diethylaluminium hydride; benzene |
With diisobutylaluminium hydride; benzene | ||
With diisobutylaluminium hydride In hexane; benzene at 5 - 20℃; for 3h; | 1 REFERENCE EXAMPLE 1; trans-2-Buten-1,4-diol REFERENCE EXAMPLE 1 trans-2-Buten-1,4-diol fumaric acid diethyl ester (1.72 g) was dissolved into benzene (50 ml).. Thereto, diisobutylalminium hydride (53 ml, 0.94 M in hexane) was added at 5-10° C. The mixture was stirred at room temperature for 3 hours.. To the readction mixture, methanol (6 ml) and water (20 ml) were added.. The mixture was stirred at room temperature for 1 hour.. The precipitated solid was filtered by Celite. The filtrate was washed by methanol.. The methanol solution and filtrate were concentrated to obtain the title compound (0.68 g) having the following physical data. TLC: Rf 0.15 (ether); NMR (CDCl3): δ 5.68 (t, J=2.5 Hz, 2H), 4.64 (t, J=5.5 Hz, 2H), 3.92 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With ruthenium trichloride; sodium periodate; sulfuric acid In ethyl acetate; acetonitrile at 0℃; for 0.0333333h; | |
95% | With tert.-butylhydroperoxide; tetraethylammonium hydroxide In <i>tert</i>-butyl alcohol for 60h; Ambient temperature; | |
95% | With 2-Picolinic acid; manganese(II) perchlorate hexahydrate; dihydrogen peroxide; sodium acetate In water; butanone at 0 - 20℃; |
91% | With dihydrogen peroxide; sodium acetate In water; acetone at 0 - 20℃; | 1.1 EXAMPLESExample 1 :; Alkene oxidation catalyzed by the Mn/picolinic acid system in acetoneThe following table provides examples that demonstrate the usefulness of the Mn/picolinic acid catalyst system for the oxidation of alkenes with H202 in acetone as the solvent, providing epoxides or (cis-)diols as the major products: Added at 0°C, then bath allowed to warm to room temperature overnight General procedure (amounts as specified per substrate in Table 1 ): Aqueous NaOAc was added to a mixture of substrate, 1 ,2-dichlorobenzene (internal standard), Mn(CI04).6H20, and picolinic acid in acetone. At 0°C, 50 wt% H202 was subsequently added gradually. The mixture was stirred additionally overnight, with gradual warming to room temperature. Workup typically consisted of adding solid NaHS03 to reduce residual peroxide, removal of solids by filtration, evaporation, and extraction with CDCI3. Analysis was done by NMR, Raman spectroscopy, and/or GC. |
90% | With 4-methylmorpholine N-oxide; citric acid In water; <i>tert</i>-butyl alcohol | |
With dihydrogen peroxide; vanadia; <i>tert</i>-butyl alcohol | ||
With osmium(VIII) oxide; dihydrogen peroxide; <i>tert</i>-butyl alcohol | ||
With manganese(II) perchlorate hexahydrate; 2,2'-(2-(pyridin-2-yl)imidazolidine-1,3-diyl)bis(methylene)dipyridine; dihydrogen peroxide; sodium acetate In [(2)H6]acetone; water at 0 - 20℃; for 16h; | ||
With osmium(VIII) oxide; dihydrogen peroxide; <i>tert</i>-butyl alcohol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With hydrogenchloride; sodium ethanolate In acetone | III Preparation of Triethyl Acetotricarballylate EXAMPLE III Preparation of Triethyl Acetotricarballylate Into a 500 ml, one neck Erlenmeyer flask equipped with stirrer and drying tube is placed 103.2 grams (0.6 mole) of diethyl fumarate and 78 grams (0.6 mole) of ethyl acetoacetate. Six grams (0.088 mole) of freshly prepared sodium ethoxide is added slowly and the yellow solution is heated to 40°-45° C. for 15 minutes. The solution is then cooled to 10° C. and 9 grams conc. hydrochloric acid is dropped slowly into the solution followed by the addition of 400 ml of acetone. The acetone solution is filtered and evaporated down under vacuum. 174.8 grams (96% yield) of product is obtained. STR7 |
With potassium fluoride |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-benzyl-1,4-dihydronicotinamide In acetonitrile at 49.9℃; for 2h; | |
92% | With 1-methyl-3-pentyl-1H-imidazolium tetrafluoroborate at 130 - 135℃; for 0.05h; microwave irradiation; | |
80% | With indium(III) chloride; sodium tetrahydroborate In acetonitrile at -10℃; for 2.75h; |
78% | With bis(cyclopentadienyl)titanium dichloride; zinc In tetrahydrofuran for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With diisobutylaluminum chloride; N-ethyl-N,N-diisopropylamine In toluene at -40℃; | |
54% | In <i>tert</i>-butyl alcohol at 84℃; for 72h; | |
53% | In <i>tert</i>-butyl alcohol at 84℃; for 72h; |
42.3% | Stage #1: ketene diethyl acetal With diethylaluminium chloride In toluene at -45℃; for 0.166667h; Inert atmosphere; Stage #2: With N-ethyl-N,N-diisopropylamine In toluene at -45℃; for 0.166667h; Inert atmosphere; Stage #3: diethyl Fumarate In toluene at -45℃; for 3h; Inert atmosphere; | B Step B P R.2S)-Diethyl 3.3-diethoxycvclobutane- 1.2-dicarboxylate. A mixture of toluene (100 mL) and 1 , 1 -di ethoxy ethene (6.50 g, 37.75 mmol) was cooled to - 45°C under N2 atmosphere. Diethylaluminum chloride (1 M, 113.25 mL) was added slowly by syringe. The reaction mixture was stirred for 10 min, then N,N-diisopropylethylamine (DIPEA) (1.95 g, 15.10 mmol) was added. After stirring at -45 °C for 10 min, diethyl fumarate (8.77 g, 75.50 mmol) was added by syringe, and the mixture was stirred at -45 °C for 3 h. The mixture was quenched with saturated aqueous sodium bicarbonate (200 mL), extracted with hexane (200 mL x2). The combined organic layer was washed with brine, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford (lR,2S)-diethyl 3, 3-diethoxycyclobutane-l, 2-dicarboxylate. Purification (LCC, S1O2, PE:EA=80: 1) afforded the title compound (3.41 g, 42.3% yield) as a yellow oil. XH NMR (400 MHz, CDCb) d 4.31 - 4.18 (m, 4H), 4.18 - 4.11 (m, 4H), 3.75 - 3.69 (m, 1H), 3.34 (m, 7 = 10.2, 8.5 Hz, 1H), 2.59 (m, 1H), 2.31 - 2.21 (m, 1H), 1.33 (m, 6H), 1.20 - 1.07 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In 1,3,5-trimethyl-benzene at 160 - 170℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With potassium-t-butoxide In tetrahydrofuran at 0 - 25℃; for 2.33h; Inert atmosphere; | 2.2 Synthesis of pyrrole-3,4-dicarboxylic acid diethyl ester (2) Potassium tert-butoxide (7.09 g, 60.0 mmol) was suspended in anhydrous THF (90.0 mL) under N2 atmosphere and stirred at 0 °C. A solution of diethyl fumarate (5.00 mL, 5.26 g, 30.0 mmol) and p-toluenesulfonylmethylisocyanide (TosMIC) (5.98 g, 30.0 mmol), in anhydrous THF (60 mL), was added dropwise for 20 min. After the addition, the mixture was stirred for 2 h at 25 °C. An aqueous solution of HCl (pH = 5-6, 100 mL) was added and the mixture was extracted with EtOAc (2 × 100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated almost to dryness. The mixture was gently heated with a heat gun until the entire solid became soluble. The solution was allowed to cool to 25 °C and then taken to 0 °C for about 30 min. The solid obtained was collected by removing the EtOAc with a Pasteur pipette and the organic phase (EtOAc with remaining compound 2) was saved. The solid was crystallized twice yielding pyrrole 2 as white crystals (3.14 g). The EtOAc layers were concentrated and purified by silica-flash column chromatography using toluene/EtOAc (7:3) as eluent, obtaining a further 1.35 g of 2. The product 2 was obtained in 71% yield (4.49 g, 21.3 mmol). 1H NMR (CDCl3, 400.15 MHz): δ (ppm): 1.34 (t, J = 7.1 Hz, 6H, H-33, H-43); 4.30 (q, J = 7.1 Hz, 4H/H-32, H-42); 7.36 (d, J = 2.9 Hz, 2H, H-2, H-5); 9.39 (brs, 1H, H-1). 13C NMR (CDCl3, 100.62 MHz): δ(ppm): 14.3 (C-33, C43); 60.3 (C-32, C-42); 115.9 (C-3, C-4); 125.7 (C-2, C-5); 164.1 (C-31, C-41). HRMS (ESI-TOF): calc. for [M+H]+,C10H14NO4+, 212.0917; found: 212.0921. |
63% | With 18-crown-6 ether; potassium-t-butoxide In tetrahydrofuran | |
57% | With potassium-t-butoxide In tetrahydrofuran at 0 - 20℃; for 5h; Schlenk technique; Inert atmosphere; Cooling with ice; |
53% | With sodium hydride In diethyl ether; dimethyl sulfoxide; mineral oil at 20℃; for 5h; Inert atmosphere; | |
44% | With potassium-t-butoxide In tetrahydrofuran for 2h; | |
With potassium-t-butoxide In tetrahydrofuran | ||
4.6 g (44%) | With sodium chloride In tetrahydrofuran | 39 Diethyl pyrrole-3,4-dicarboxylate EXAMPLE 39 Diethyl pyrrole-3,4-dicarboxylate Tosylmethyl isocyanide (9.8 g, 50 mmol), diethyl fumarate (8.2 mL, 50 mmol) and dry THF (1000 mL) were added dropwise to a stirred suspension of potassium t-butoxide (11.2 g, 100 mmol) and THF (150 mL). The mixture was stirred for 2 hours, saturated NaCl (500 mL) was added, and the mixture was extracted with THF (2*250 mL). The organic layers were dried (Na2 SO4), filtered and concentrated in vacuo to give a solid. The solid was recrystallized from MeOH to give the title compound 4.6 g (44%) (mp 148-149° C.). 1 H NMR (DMSO) δ 1.22 (t, 3H, CH3), 4.18 (q, 2H, CH2), 7.39 (s, 2H, ArH), 11.8 (bs, 1H, NH). |
With 18-crown-6 ether; potassium-t-butoxide In tetrahydrofuran | ||
With potassium-t-butoxide Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With fluoride In acetonitrile at 0℃; Yield given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 82 % Chromat. 2: 18 % Chromat. 3: 93 % Chromat. 4: 7 % Chromat. | With 2,9-bis(2,6-bis(1,4,7-trioxaoctyl)phenyl)-1,10-phenanthroline In dichloromethane; 1,2-dichloro-ethane at 20℃; for 24h; var. of reagent, temp.; | |
at 100℃; for 4h; other olefins, other temperature and reaction time; competition with cyclooctene, other catalyst: Rh2(OAc)4; | ||
In dichloromethane; 1,2-dichloro-ethane at 20℃; for 24h; Yield given. Yields of byproduct given; |
In dichloromethane; 1,2-dichloro-ethane at 20℃; for 24h; Yield given. Yields of byproduct given. Title compound not separated from byproducts; | ||
With copper trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; | ||
With bimacrocyclic concave 1,10-phenanthroline ligand; copper trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; Title compound not separated from byproducts; | ||
With 1,10-phenanthroline-bridged calix[6]arene; copper trifluoromethanesulfonate In 1,2-dichloro-ethane at 20℃; Title compound not separated from byproducts; | ||
In dichloromethane at 20℃; for 2.75h; | ||
In dichloromethane | ||
In dichloromethane at 25℃; | ||
In benzene at 50℃; for 16h; | ||
With gold In 1,2-dichloro-ethane at 80℃; for 24h; Inert atmosphere; optical yield given as %de; | ||
With (tetra-n-butylammonium)4-[γ-H2SiW10O36Cu(II)2(μ-1,1-N3)2] In 1,2-dichloro-ethane at 59.84℃; for 8.5h; Inert atmosphere; optical yield given as %de; chemoselective reaction; | ||
With Cu2(4,4'-bpy)2SO4*6H2O In n-undecan; dichloromethane at 20℃; for 24h; | ||
1: 59.8 % de 2: 23 % de | With C38H36ClN3OPRu(1+)*Cl(1-) In dichloromethane at 20℃; for 4h; Inert atmosphere; Schlenk technique; diastereoselective reaction; | |
1.47 % de | With C63H68Cl2N2P2Ru In toluene at 0 - 60℃; for 4h; chemoselective reaction; | General procedure: In a typical GC experiment the following operations were undertaken: from a preliminary prepared solution of catalyst in freshly distilled toluene, with known concentration, 2.5 μmol of catalyst were transferred under Ar-flow to an empty 15 ml vessel. The solvent was evaporated in vacuo affording a small amount of solid catalyst. Styrene (10 mmol) was next added. EDA (1 mmol) was dissolved in styrene (10 mmol), cooled to 0 °C and the solution added very slowly, at 0 °C (over 4 h, using a peristaltic pump) to the above reaction mixture. After addition of a few drops of the EDA solution, the mixture was heated to the reaction temperature and kept at this temperature overnight. Before GC-analysis, the reaction mixture was passed through a celite filter in order to remove the catalyst. Celite was washed with 20 ml toluene/EtOAc (1/1). The composition of the reaction mixture was determined by GC using authentic samples and diethyl adipate as internal standard. |
1: 30 % de 2: 60 % de | With [(tris(3,5-dimethylpyrazolylmethyl)amine)Cu]PF6 In dichloromethane at 20℃; for 3h; Inert atmosphere; diastereoselective reaction; | |
1: 38 % de 2: 78 % de | With μ-carbido-bis[2,3,9,10,16,17,23,24-octa-n-butoxyphthalocyaninatoruthenium(IV)] In dichloromethane; toluene at 90℃; for 6h; Inert atmosphere; | |
With HKUST-1 In chloroform-d1; dichloromethane at 150℃; for 3h; | ||
16.667 % de | With AuNPs functionalized with IPrpyr immobilized on graphene oxide In dichloromethane at 80℃; for 24h; Inert atmosphere; Darkness; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With Corey's chiral ligand In dichloromethane at -35℃; optical yield given as %ee; | |
99% | With triflimide activated chiral oxazaborolidine In toluene at -60℃; for 2h; | |
99% | With trifluorormethanesulfonic acid; 1,2-oxaborolane In dichloromethane at -35℃; for 1.5h; |
95% | at -78℃; for 6h; | |
95% | With (3aS)-1,3,3-triphenyltetrahydro-1H,3H-thieno[1,2-c][1,3,2]oxathiaborol-7-ium pentachlorostannate In dichloromethane Schlenk technique; Inert atmosphere; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triflimide activated chiral oxazaborolidine In toluene at 20℃; for 40h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triflimide activated chiral oxazaborolidine In toluene at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.3% | In toluene at 105℃; for 18h; Heating / reflux; | 1.1 Fumaric acid diethylester (21.6 g; 0.126 mol) is dissolved in toluene (900 ml) and heated at 105 °C. A mixture of N-benzylglycine (25 g; 0.151 mol) and paraformaldehyde (25.36 g; 0.844 mol) is added in 4 g portions to the refluxing solution. After completion of the addition the mixture is heated for 18 h at 105°C. The mixture is then evaporated to dryness and suspended in n-hexane. The insoluble material is filtered off and the remaining solution is evaporated to dryness. The crude product is used for the next step without further purification. Yield: 32.5 g (70.3 %), ESI-MS : m/z = 306 [M+H]+ |
In toluene Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium bromide; 1,8-diazabicyclo[5.4.0]undec-7-ene; isopropyl alcohol In tetrahydrofuran at 70℃; | |
65% | With 3-ethyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazolium bromide; 1,8-diazabicyclo[5.4.0]undec-7-ene; isopropyl alcohol In tetrahydrofuran at 70℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In tetrahydrofuran at 35℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 99 % ee 2: 96% | With aluminum oxide; potassium carbonate In chloroform at 0 - 20℃; for 24 - 25h; | 2.1. Cyclopropanation and Purification of Compound 3; An improved Evans cyclopropanation protocol was used for this synthesis using the Cu catalyst prepared from copper (I) triflate and chiral ligand 10. Other ligands and Rh catalysts were tried but all afforded lower diastereoselectivity. The major by-products from the reaction were the cis-isomer, 11 and 12 from the dimerization of ethyl diazoacetate. Solvent plays a significant role in enantioselectivity, diastereoselectivity, and formation of the dimer impurities. As shown in Table 1, a variety of solvents, including coordinating and non-coordinating ones, gave good to excellent conversions (74-98%), except for THF (45%). The diastereoselectivity varied from 80:20 (trans:cis, 1,2-dichloroethane) to 93:7 (trans:cis, MTBE), and ee varied from 85% (1,2-dichloroethane) to 99% (many solvents including MTBE). MTBE gave the best results and was used as the solvent for our first GMP campaign. A significant amount of precipitate was formed when the catalyst was prepared in MTBE. In early studies, this precipitate was removed by filtration prior to the cyclopropanation. However, conversions and ethyl diazoacetate accumulation varied from batch to batch. The situation was greatly improved by generation of the catalyst in situ without filtration. The solid catalyst was completely dissolved after the addition of styrene, giving a clear solution before addition of ethyl diazoacetate. Similar diastereoselectivity and enantioselectivity were obtained. In the prep lab, the cyclopropanation reaction was run in two batches. The first batch used the procedure with the solid catalyst removed and 2.4 kg (assayed, 85% yield after NaBH4 treatment, see below) of 3 was obtained with a trans/cis ratio of 92:8 and 98.8% ee for the trans. The conversion for the reaction was only 95% with 2.0 equiv of ethyl diazoacetate used. The second batch used the procedure with in situ generated catalyst without solid removal. Complete conversion was observed with the use of 1.5 equiv of ethyl diazoacetate. Again, 2.4 kg (assayed, 85% yield after NaBH4 treatment) of 3 was obtained with a trans/cis ratio of 88:12 and 98.9% ee for the trans. |
1: 99 % ee 2: 97 % ee | In ethyl acetate at 0 - 20℃; for 24 - 25h; | 2.1. Cyclopropanation and Purification of Compound 3; An improved Evans cyclopropanation protocol was used for this synthesis using the Cu catalyst prepared from copper (I) triflate and chiral ligand 10. Other ligands and Rh catalysts were tried but all afforded lower diastereoselectivity. The major by-products from the reaction were the cis-isomer, 11 and 12 from the dimerization of ethyl diazoacetate. Solvent plays a significant role in enantioselectivity, diastereoselectivity, and formation of the dimer impurities. As shown in Table 1, a variety of solvents, including coordinating and non-coordinating ones, gave good to excellent conversions (74-98%), except for THF (45%). The diastereoselectivity varied from 80:20 (trans:cis, 1,2-dichloroethane) to 93:7 (trans:cis, MTBE), and ee varied from 85% (1,2-dichloroethane) to 99% (many solvents including MTBE). MTBE gave the best results and was used as the solvent for our first GMP campaign. A significant amount of precipitate was formed when the catalyst was prepared in MTBE. In early studies, this precipitate was removed by filtration prior to the cyclopropanation. However, conversions and ethyl diazoacetate accumulation varied from batch to batch. The situation was greatly improved by generation of the catalyst in situ without filtration. The solid catalyst was completely dissolved after the addition of styrene, giving a clear solution before addition of ethyl diazoacetate. Similar diastereoselectivity and enantioselectivity were obtained. In the prep lab, the cyclopropanation reaction was run in two batches. The first batch used the procedure with the solid catalyst removed and 2.4 kg (assayed, 85% yield after NaBH4 treatment, see below) of 3 was obtained with a trans/cis ratio of 92:8 and 98.8% ee for the trans. The conversion for the reaction was only 95% with 2.0 equiv of ethyl diazoacetate used. The second batch used the procedure with in situ generated catalyst without solid removal. Complete conversion was observed with the use of 1.5 equiv of ethyl diazoacetate. Again, 2.4 kg (assayed, 85% yield after NaBH4 treatment) of 3 was obtained with a trans/cis ratio of 88:12 and 98.9% ee for the trans. |
1: 99 % ee 2: 97 % ee | In toluene at 0 - 20℃; for 24 - 25h; Molecular sieve; | 2.1. Cyclopropanation and Purification of Compound 3; An improved Evans cyclopropanation protocol was used for this synthesis using the Cu catalyst prepared from copper (I) triflate and chiral ligand 10. Other ligands and Rh catalysts were tried but all afforded lower diastereoselectivity. The major by-products from the reaction were the cis-isomer, 11 and 12 from the dimerization of ethyl diazoacetate. Solvent plays a significant role in enantioselectivity, diastereoselectivity, and formation of the dimer impurities. As shown in Table 1, a variety of solvents, including coordinating and non-coordinating ones, gave good to excellent conversions (74-98%), except for THF (45%). The diastereoselectivity varied from 80:20 (trans:cis, 1,2-dichloroethane) to 93:7 (trans:cis, MTBE), and ee varied from 85% (1,2-dichloroethane) to 99% (many solvents including MTBE). MTBE gave the best results and was used as the solvent for our first GMP campaign. A significant amount of precipitate was formed when the catalyst was prepared in MTBE. In early studies, this precipitate was removed by filtration prior to the cyclopropanation. However, conversions and ethyl diazoacetate accumulation varied from batch to batch. The situation was greatly improved by generation of the catalyst in situ without filtration. The solid catalyst was completely dissolved after the addition of styrene, giving a clear solution before addition of ethyl diazoacetate. Similar diastereoselectivity and enantioselectivity were obtained. In the prep lab, the cyclopropanation reaction was run in two batches. The first batch used the procedure with the solid catalyst removed and 2.4 kg (assayed, 85% yield after NaBH4 treatment, see below) of 3 was obtained with a trans/cis ratio of 92:8 and 98.8% ee for the trans. The conversion for the reaction was only 95% with 2.0 equiv of ethyl diazoacetate used. The second batch used the procedure with in situ generated catalyst without solid removal. Complete conversion was observed with the use of 1.5 equiv of ethyl diazoacetate. Again, 2.4 kg (assayed, 85% yield after NaBH4 treatment) of 3 was obtained with a trans/cis ratio of 88:12 and 98.9% ee for the trans. |
1: 85 % ee 2: 94 % ee | In 1,2-dichloro-ethane at 0 - 20℃; for 24 - 25h; Molecular sieve; | 2.1. Cyclopropanation and Purification of Compound 3; An improved Evans cyclopropanation protocol was used for this synthesis using the Cu catalyst prepared from copper (I) triflate and chiral ligand 10. Other ligands and Rh catalysts were tried but all afforded lower diastereoselectivity. The major by-products from the reaction were the cis-isomer, 11 and 12 from the dimerization of ethyl diazoacetate. Solvent plays a significant role in enantioselectivity, diastereoselectivity, and formation of the dimer impurities. As shown in Table 1, a variety of solvents, including coordinating and non-coordinating ones, gave good to excellent conversions (74-98%), except for THF (45%). The diastereoselectivity varied from 80:20 (trans:cis, 1,2-dichloroethane) to 93:7 (trans:cis, MTBE), and ee varied from 85% (1,2-dichloroethane) to 99% (many solvents including MTBE). MTBE gave the best results and was used as the solvent for our first GMP campaign. A significant amount of precipitate was formed when the catalyst was prepared in MTBE. In early studies, this precipitate was removed by filtration prior to the cyclopropanation. However, conversions and ethyl diazoacetate accumulation varied from batch to batch. The situation was greatly improved by generation of the catalyst in situ without filtration. The solid catalyst was completely dissolved after the addition of styrene, giving a clear solution before addition of ethyl diazoacetate. Similar diastereoselectivity and enantioselectivity were obtained. In the prep lab, the cyclopropanation reaction was run in two batches. The first batch used the procedure with the solid catalyst removed and 2.4 kg (assayed, 85% yield after NaBH4 treatment, see below) of 3 was obtained with a trans/cis ratio of 92:8 and 98.8% ee for the trans. The conversion for the reaction was only 95% with 2.0 equiv of ethyl diazoacetate used. The second batch used the procedure with in situ generated catalyst without solid removal. Complete conversion was observed with the use of 1.5 equiv of ethyl diazoacetate. Again, 2.4 kg (assayed, 85% yield after NaBH4 treatment) of 3 was obtained with a trans/cis ratio of 88:12 and 98.9% ee for the trans. |
1: 99 % ee 2: 97 % ee | In tert-butyl methyl ether at 0 - 20℃; for 24 - 25h; Molecular sieve; | 2.1. Cyclopropanation and Purification of Compound 3; An improved Evans cyclopropanation protocol was used for this synthesis using the Cu catalyst prepared from copper (I) triflate and chiral ligand 10. Other ligands and Rh catalysts were tried but all afforded lower diastereoselectivity. The major by-products from the reaction were the cis-isomer, 11 and 12 from the dimerization of ethyl diazoacetate. Solvent plays a significant role in enantioselectivity, diastereoselectivity, and formation of the dimer impurities. As shown in Table 1, a variety of solvents, including coordinating and non-coordinating ones, gave good to excellent conversions (74-98%), except for THF (45%). The diastereoselectivity varied from 80:20 (trans:cis, 1,2-dichloroethane) to 93:7 (trans:cis, MTBE), and ee varied from 85% (1,2-dichloroethane) to 99% (many solvents including MTBE). MTBE gave the best results and was used as the solvent for our first GMP campaign. A significant amount of precipitate was formed when the catalyst was prepared in MTBE. In early studies, this precipitate was removed by filtration prior to the cyclopropanation. However, conversions and ethyl diazoacetate accumulation varied from batch to batch. The situation was greatly improved by generation of the catalyst in situ without filtration. The solid catalyst was completely dissolved after the addition of styrene, giving a clear solution before addition of ethyl diazoacetate. Similar diastereoselectivity and enantioselectivity were obtained. In the prep lab, the cyclopropanation reaction was run in two batches. The first batch used the procedure with the solid catalyst removed and 2.4 kg (assayed, 85% yield after NaBH4 treatment, see below) of 3 was obtained with a trans/cis ratio of 92:8 and 98.8% ee for the trans. The conversion for the reaction was only 95% with 2.0 equiv of ethyl diazoacetate used. The second batch used the procedure with in situ generated catalyst without solid removal. Complete conversion was observed with the use of 1.5 equiv of ethyl diazoacetate. Again, 2.4 kg (assayed, 85% yield after NaBH4 treatment) of 3 was obtained with a trans/cis ratio of 88:12 and 98.9% ee for the trans. |
In Isopropyl acetate at 0 - 20℃; for 24 - 25h; Molecular sieve; | 2.1. Cyclopropanation and Purification of Compound 3; An improved Evans cyclopropanation protocol was used for this synthesis using the Cu catalyst prepared from copper (I) triflate and chiral ligand 10. Other ligands and Rh catalysts were tried but all afforded lower diastereoselectivity. The major by-products from the reaction were the cis-isomer, 11 and 12 from the dimerization of ethyl diazoacetate. Solvent plays a significant role in enantioselectivity, diastereoselectivity, and formation of the dimer impurities. As shown in Table 1, a variety of solvents, including coordinating and non-coordinating ones, gave good to excellent conversions (74-98%), except for THF (45%). The diastereoselectivity varied from 80:20 (trans:cis, 1,2-dichloroethane) to 93:7 (trans:cis, MTBE), and ee varied from 85% (1,2-dichloroethane) to 99% (many solvents including MTBE). MTBE gave the best results and was used as the solvent for our first GMP campaign. A significant amount of precipitate was formed when the catalyst was prepared in MTBE. In early studies, this precipitate was removed by filtration prior to the cyclopropanation. However, conversions and ethyl diazoacetate accumulation varied from batch to batch. The situation was greatly improved by generation of the catalyst in situ without filtration. The solid catalyst was completely dissolved after the addition of styrene, giving a clear solution before addition of ethyl diazoacetate. Similar diastereoselectivity and enantioselectivity were obtained. In the prep lab, the cyclopropanation reaction was run in two batches. The first batch used the procedure with the solid catalyst removed and 2.4 kg (assayed, 85% yield after NaBH4 treatment, see below) of 3 was obtained with a trans/cis ratio of 92:8 and 98.8% ee for the trans. The conversion for the reaction was only 95% with 2.0 equiv of ethyl diazoacetate used. The second batch used the procedure with in situ generated catalyst without solid removal. Complete conversion was observed with the use of 1.5 equiv of ethyl diazoacetate. Again, 2.4 kg (assayed, 85% yield after NaBH4 treatment) of 3 was obtained with a trans/cis ratio of 88:12 and 98.9% ee for the trans. | |
In α,α,α-trifluorotoluene at 0 - 20℃; for 24 - 25h; | 2.1. Cyclopropanation and Purification of Compound 3; An improved Evans cyclopropanation protocol was used for this synthesis using the Cu catalyst prepared from copper (I) triflate and chiral ligand 10. Other ligands and Rh catalysts were tried but all afforded lower diastereoselectivity. The major by-products from the reaction were the cis-isomer, 11 and 12 from the dimerization of ethyl diazoacetate. Solvent plays a significant role in enantioselectivity, diastereoselectivity, and formation of the dimer impurities. As shown in Table 1, a variety of solvents, including coordinating and non-coordinating ones, gave good to excellent conversions (74-98%), except for THF (45%). The diastereoselectivity varied from 80:20 (trans:cis, 1,2-dichloroethane) to 93:7 (trans:cis, MTBE), and ee varied from 85% (1,2-dichloroethane) to 99% (many solvents including MTBE). MTBE gave the best results and was used as the solvent for our first GMP campaign. A significant amount of precipitate was formed when the catalyst was prepared in MTBE. In early studies, this precipitate was removed by filtration prior to the cyclopropanation. However, conversions and ethyl diazoacetate accumulation varied from batch to batch. The situation was greatly improved by generation of the catalyst in situ without filtration. The solid catalyst was completely dissolved after the addition of styrene, giving a clear solution before addition of ethyl diazoacetate. Similar diastereoselectivity and enantioselectivity were obtained. In the prep lab, the cyclopropanation reaction was run in two batches. The first batch used the procedure with the solid catalyst removed and 2.4 kg (assayed, 85% yield after NaBH4 treatment, see below) of 3 was obtained with a trans/cis ratio of 92:8 and 98.8% ee for the trans. The conversion for the reaction was only 95% with 2.0 equiv of ethyl diazoacetate used. The second batch used the procedure with in situ generated catalyst without solid removal. Complete conversion was observed with the use of 1.5 equiv of ethyl diazoacetate. Again, 2.4 kg (assayed, 85% yield after NaBH4 treatment) of 3 was obtained with a trans/cis ratio of 88:12 and 98.9% ee for the trans. |
Yield | Reaction Conditions | Operation in experiment |
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74% | In toluene at 105℃; for 17h; Heating / reflux; | 5.16.16 To a mixture of diethyl fumarate (8 68g, 50 4mmol, Sigma-Aldϖch) and toluene (80OmL) at 1050C was added dropwise over Ih a mixture of formaldehyde, in the form of paraformaldehyde, (10 2g, 339mmol (based on formaldehyde monomer molecular weight), Sigma-Aldϖch) and 2-(benzylamino)acetic acid (12 2g, 60 5mmol, Sigma-Aldϖch) The resulting reaction mixture was refluxed for 16h in an apparatus comprising a Dean-Stark trap After concentration under reduced pressure, the residue was dissolved in hexanes, filtered, and concentrated under reduced pressure to provide a brown oil. Flash chromatography of the oil with a silica gel column eluting with 1 :5 EtOAc:hexanes provided 13 8g of the compound of formula FU as a colorless oil (yield 74%). The identity of the compound of formula FU, (3S,4S)-di ethyl l-benzylpyrrohdine-3,4- dicarboxylate, was confirmed using TLC and LC/MS.Compound FU: TLC (SiO2) 1 :1 EtOAc:hexanes: Rf=O 8 with UV detection, Dragendorff s reagent; LC/MS: /n/z=306 [M+H]+ (CaIc: 305). |
Yield | Reaction Conditions | Operation in experiment |
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90% | With 4,4,6,6-tetramethyl-1,3,2-dioxaborinane; copper (I) acetate; triphenylphosphine In tetrahydrofuran at 20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
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55% | Stage #1: (3-chloro-2-pyridyl)hydrazine With sodium ethanolate In ethanol at 83℃; Heating / reflux; Stage #2: diethyl Fumarate In ethanol for 0.25h; Heating / reflux; Stage #3: With acetic acid In ethanol at 65℃; | 1.A A 2-L four-necked flask equipped with a mechanical stirrer, thermometer, addition funnel, reflux condenser, and nitrogen inlet was charged with absolute ethanol (250 mL) and an ethanolic solution of sodium ethoxide (21%, 190 mL, 0.504 mol). The mixture was heated to reflux at about 83 °C. It was then charged with 3-chloro-2-hydrazinopyridine (68.0 g, 0.474 mol). The mixture was re-heated to reflux over a period of 5 minutes. The yellow slurry was then treated dropwise with diethyl maleate (88.0 mL, 0.544 mol) over a period of 5 minutes. The reflux rate increased markedly during the addition. By the end of the addition all of the starting material had dissolved. The resulting orange-red solution was held at reflux for 10 minutes. After being cooled to 65 °C, the reaction mixture was treated with glacial acetic acid (50.0 mL, 0.873 mol). A precipitate formed. The mixture was diluted with water (650 mL), causing the precipitate to dissolve. The orange solution was cooled in an ice bath. Product began to precipitate at 28 °C. The slurry was held at about2 °C for 2 hours. The product was isolated by filtration, washed with aqueous ethanol (40%,3 x 50 mL), then air-dried on the filter for about 1 hour. The title product compound was obtained as a highly crystalline, light orange solid (70.3 g, 55% yield). No significant impurities were observed by ^H NMR..H NMR (Me2SO-d6) 8 10.18 (s, 1H), 8.27 (d, 1H), 7.92 (d, 1H), 7.20 (dd, 1H), 4.84 (d,1H), 4.20 (q, 2H), 2.91 (dd, 1H), 2.35 (d, 1H), 1.22 (t, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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48% | With bis[dichlorido(η5-1,2,3,4,5-pentamethyl-cyclopentadienyl)iridium(III)]; Cu(OAc)2*H2O In acetonitrile at 120℃; for 12h; Inert atmosphere; Schlenk technique; | General Procedure for the Iridium-Catalyzed Preparation of 3, 5 General procedure: A mixture of substituted isoquinolones (1, 4) (0.2 mmol, 1.0 equiv), olefins (2) (0.4 mmol, 2.0 equiv), [Cp*IrCl2]2 (8.0 mg, 0.01 mmol, 5 mol%) and Cu(OAc)2·H2O (0.44 mmol, 2.2 equiv) were weighted in a Schlenk tube equipped with a stir bar. Dry CH3CN (1.5 mL) was added and the mixture was stirred at 120 oC in a pre-heated oil bath for 12 h under N2 atmosphere. Then, the mixture was cooled to room temperature and concentrated in vacuo and the resulting residue was purified by column chromatography on silica gel with EtOAc/petroleum ether. |
41% | With bis[dichlorido(η5-1,2,3,4,5-pentamethyl-cyclopentadienyl)rhodium (III)]; copper (II) acetate In acetonitrile at 115℃; for 16h; sealed tube; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
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42% | With (tetra-n-butylammonium)4-[γ-H2SiW10O36Cu(II)2(μ-1,1-N3)2] at 59.84℃; Inert atmosphere; optical yield given as %de; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With ammonium perrhenate; zinc In benzene at 150℃; for 24h; Inert atmosphere; Sealed tube; | |
85% | With ammonium perrhenate; benzyl alcohol In benzene at 150℃; for 24h; Sealed tube; regioselective reaction; | |
42% | With ammonium perrhenate; 2,4-dimethyl-3-pentanol In toluene for 24h; Sealed tube; Heating; stereoselective reaction; | Isolation NH4ReO4 (28 mg, 0.1 mmol,), (+)-diethyl tartrate (198 mg,1 mmol), 2,4-dimethyl-3-pentanol (388lL), and anhydrous toluene (6 mL) were added to a thick-walled Ace glass reactor tube.The reactor was placed in a heating mantle bath in the range of 165°C for 24 h while stirring magnetically. The reaction mixture was cooled and filtered over silica gel. Solvents were removed using a rotary evaporator under reduced pressure. The product was separated by column chromatography using ethyl acetate/hexane eluent. Product yield was 73 mg, 42%. |
35% | With methyltrioxorhenium(VII); sodium sulfite at 150 - 160℃; for 84h; regiospecific reaction; | |
> 95 %Spectr. | With hydrogen In benzene at 150℃; for 48h; Autoclave; stereoselective reaction; | |
20 %Spectr. | With ammonium molybdate; sodium sulfite In toluene at 190℃; Sealed tube; | 4.2 Representative procedure for deoxydehydration reactions General procedure: A flame dried thick-wall Chemglass high-pressure tube was charged with the styrene glycol (0.140g, 1.01mmol), AHM (0.061g, 0.05mmol), reductant (1.5mmol) and toluene (ca. 5mL) followed by a Teflon-coated stir bar. The pressure tube was sealed with a Teflon screw cap and then placed in a pre-heated oil bath or aluminum heating block which are both equipped with a digital temperature controller. The pressure tube was heated at 170°C or 190°C for 18-24h with stirring. The resulting reaction flask is then pulled out of the oil bath and allowed to cool to room temperature. At this point, 1,3,5-trimethoxybenzene (0.010g) was introduced into the flask and the mixture stirred at room temperature to get a uniform solution. An aliquot was taken by pipette and analyzed by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. |
Yield | Reaction Conditions | Operation in experiment |
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82% | With dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; copper(II) acetate monohydrate; In toluene; at 130℃; for 24h;Inert atmosphere; | General procedure: N-Benzoylsulfonamide 1a (27.5 mg, 0.1 mmol), [RhCl2Cp*]2 (1.2 mg, 0.002 mmol), and Cu(OAc)2·H2O (40.0 mg, 0.20 mmol) were loaded in a dry vial, which was subjected to evacuation/flushing with dry argon three times. Anhydrous toluene (1.0 mL) solution of tert-butyl acrylate 2a (17.4 muL, 0.12 mmol) was syringed into the mixture, which was then stirred at 130 C for 24 h or until the starting material had been consumed as determined by TLC. Upon cooling to room temperature, all volatiles were evaporated and the residue was purified by preparative TLC (ethyl acetate/hexane 1:2) to give isoindolinone 3a in 88% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: diethyl Fumarate With N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine; trifluoroacetic acid In dichloromethane at 0 - 20℃; for 1.16667h; Stage #2: di-<i>tert</i>-butyl dicarbonate With hydrogen In ethyl acetate for 18h; | 6 Example 6(+/-) rans-{4-[5-(4-Benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-1-methyl-pyrrolidin-3-yl}-methand dihydrochlorideTo a stirred solution of (E)-but-2-enedioic acid diethyl ester (23.23 mmol, 4 g) in DCM (50 ml_) at 0°C was added benzyl-methoxymethyl-trimethylsilanylmethyl-amine (21.06 mmol, 5 g) followed by drop wise addition of a solution of TFA in DCM (0.1 mL of TFA in 1 mL of DCM) over 10 min. After completion of addition, the cold bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM, washed with a saturated solution of sodium bicarbonate, the organic layer was dried and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and added di-ferf-butyl dicarbonate (36.66 mmol, 8 g) followed by 10% palladium on carbon (1 g, wet). The resultant reaction mixture was subjected to catalytic hydrogenation using hydrogen gas at 55 psi for 18 h with stirring. The catalyst was filtered through a pad of celite, the celite pad was washed with ethyl acetate (200 mL), and the combined filtrate was concentrated. The residue was purified by flash silica gel column chromatography by eluting with 20% ethyl acetate in hexanes to provide (+/-)-trans-pyrrol i di ne- 1 , 3,4-tri carboxyl ic acid 1-tert- butyl ester 3,4-diethyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | Stage #1: diethyl Fumarate With triethylphosphine In tetrahydrofuran; dichloromethane at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 9,10-anthraquinone-1,5-dicarbaldehyde In tetrahydrofuran; dichloromethane at 0 - 20℃; for 2h; Inert atmosphere; Stage #3: 1,2-Dicyanoethylene Further stages; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In neat (no solvent) at 53℃; for 0.666667h; Sonication; Green chemistry; | 1 General procedure under sonochemical conditions (method B) General procedure: To a well ground mixture of p-toluenesulfonamide (1.5 mmol) and K2CO3 (1.5 mmol) was added fumaric esters (1.5 mmol) and mixed thoroughly with a glass rod. The mixture was irradiated in the water bath of an ultrasonic cleaner at 53 °C. In order to control the temperature of the water bath, addition or removal water technique was used. After completion of reaction the mixture was suspended in chloroform (30 mL), filtered and the filtrate was washed with water (3 × 15 ml) and dried with MgSO4. The solvent was removed under reduced pressure and the resulting crude material was purified on short silica-gel column with ethyl acetate/n-hexane (1:9) as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium hydroxide In neat (no solvent) at 53℃; for 1h; Sonication; | 1 General procedure under sonochemical conditions (method B) General procedure: To a well ground mixture of p-toluenesulfonamide (1.5 mmol) and K2CO3 (1.5 mmol) was added fumaric esters (1.5 mmol) and mixed thoroughly with a glass rod. The mixture was irradiated in the water bath of an ultrasonic cleaner at 53 °C. In order to control the temperature of the water bath, addition or removal water technique was used. After completion of reaction the mixture was suspended in chloroform (30 mL), filtered and the filtrate was washed with water (3 × 15 ml) and dried with MgSO4. The solvent was removed under reduced pressure and the resulting crude material was purified on short silica-gel column with ethyl acetate/n-hexane (1:9) as the eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: 1-tert-butoxycarbonyl-4-dimethylamino-2-phenyl-1,3-diaza-1,3-butadiene; diethyl Fumarate With lithium carbonate at 100℃; for 40h; Inert atmosphere; Stage #2: With methyl iodide In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere; | General procedure for synthesis of dihydropyrimidines 9a-c by cyclization-elimination reactions of 1,3-diaza-1,3-butadiene 7 with 1,2-disubstituted ethylene 8a-c (Table 1, entries 1-4) General procedure: Under an atmosphere of argon, a mixture of 7a (82.5 mg, 0.300 mmol), 8a (1.45 mL, 9.00 mmol), and Li2CO3 (22.0mg, 0.300 mmol) was heated at 100 C for 40 h. After cooled to room temperature, the reaction mixture was filtratedand concentrated under reduced pressure. To the crude mixture was added CH2Cl2 (2.0 mL) and MeI (0.950 mL, 15.3mmol) at 0 C and the mixture was stirred at room temperature for 4 h. After removal of excess MeI under reducedpressure, to the reaction mixture was added EtOAc (15 mL) followed by saturated NaHCO3 aqueous solution (5 mL),and the organic layer was separated. The aqueous layer was extracted with EtOAc (15 mL), and the combinedorganic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, and concentrated under reducedpressure. The residue was purified by flash column chromatography [hexane-EtOAc-(i-Pr)2NEt (40:5:1)] to give 9a(73.2 mg, 0.182 mmol, 61%) as colorless crystals. Mp 97-98 C (hexane). IR (KBr) cm-1: 2980, 1745, 1726, 1534,1369, 1285, 1223, 1151. 1H NMR (CDCl3) d: 1.13 (9H, s), 1.23 (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.2 Hz), 4.14 (1H,dq, J = 10.8, 7.2 Hz), 4.20 (1H, dq, J = 10.8, 7.2 Hz), 4.29 (1H, dq, J = 10.8, 7.2 Hz), 4.37 (1H, dq, J = 10.8, 7.2 Hz),5.99 (1H, s), 7.43 (2H, t, J = 7.8 Hz), 7.49 (1H, t, J = 7.8 Hz), 7.73 (1H, s), 7.84 (2H, d, J = 7.8 Hz). 13C NMR(CDCl3) d: 13.9, 14.3, 27.3, 51.2, 60.9, 62.0, 83.8, 114.9, 128.1, 128.6, 131.0, 136.7, 142.3, 151.5, 156.9, 164.6,169.0. HRMS-FAB m/z: 403.1863 (Calcd for C21H27N2O6: 403.1869). MS (FAB) m/z: 403 [(M+H)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.81 % de | With tris(triphenylphosphine)ruthenium(II) chloride In toluene at 0 - 60℃; for 4h; chemoselective reaction; | General procedure: In a typical GC experiment the following operations were undertaken: from a preliminary prepared solution of catalyst in freshly distilled toluene, with known concentration, 2.5 μmol of catalyst were transferred under Ar-flow to an empty 15 ml vessel. The solvent was evaporated in vacuo affording a small amount of solid catalyst. Styrene (10 mmol) was next added. EDA (1 mmol) was dissolved in styrene (10 mmol), cooled to 0 °C and the solution added very slowly, at 0 °C (over 4 h, using a peristaltic pump) to the above reaction mixture. After addition of a few drops of the EDA solution, the mixture was heated to the reaction temperature and kept at this temperature overnight. Before GC-analysis, the reaction mixture was passed through a celite filter in order to remove the catalyst. Celite was washed with 20 ml toluene/EtOAc (1/1). The composition of the reaction mixture was determined by GC using authentic samples and diethyl adipate as internal standard. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | In ethanol; at 80℃; | To the solution of diethyl fumarate 3 (260mg, 1.5 mmol) in EtOH (25 mL) was added <strong>[17672-28-5](4-phenoxyphenyl)hydrazine</strong> 2 (254 mg, 1.3 mmol), and the resulting solution was stirred overnight at 80C. The solvent was evaporated under vacuum and the crude residue was diluted with water (30 mL). The solution was extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 20: 1 DCM/MeOH to afford the title compound (174 mg, 42%) as a yellow solid. MS (ESI): m/z = 325.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With K10 supported ecological catalyst (0.1equiv. Zn) In toluene at 5℃; for 1h; | 2 A 1M solution of catalyst derived from Thiaspi (Ganges Ecotype), purified on Amberlyte resin Reference Example 1.2.1) and dehydrated (150°C., 2 hours) is prepared in anhydrous toluene. This solution is added to a solution diethyl fumarate (2.5 mmol) in 15 mL of toluene. Afier stirring for 30 minutes, freshly distilled cyclopentadienemmol) is added. The reaction mixture is stirred for 15 minutes, then the solution is hydrolyzed by a saturated aqueous solution of sodium hydrogen carbonate.The aqueous phase is extracted with ether (3x20 mL). The organic phases are combined, dried over sodium sulphate and concentrated under vacuum.The adduct is characterized by GC-MS, ‘H and ‘3C NMR. The reaction is quantitative and perfectly diastereoselective: no isomerization is observed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With tert.-butylhydroperoxide; tetra-(n-butyl)ammonium iodide In water; 1,2-dichloro-ethane at 70℃; for 12h; diastereoselective reaction; | 20 General procedure for product synthesis: General procedure: To a screw cap reaction vial, maleimide (0.1 mmol, 1 equiv), tertiary aniline[1] (0.2 mmol, 2 equiv), tetrabutyl ammonium iodide 3.69 mg (TBAI, 10 mol%), TBHP 55 µL (70% in H2O, 0.4 mmol, 4 equiv) and DCE (1.0 mL) were added. The reaction mixture was heated to 70 °C. The reaction progress was monitored by thin layer chromatography (ethyl acetate/petroleum ether mixture) and GC-MS. Upon completion, the crude reaction mixture was concentrated under reduced pressure and subsequently purified by flash column chromatography over silica gel using petroleum ether/ethyl acetate as eluent system. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With 1,4-diaza-bicyclo[2.2.2]octane; tetrabutylammomium bromide In neat (no solvent) at 70℃; for 1.66667h; | 4.2. General procedure for the Michael addition of 4-phenylurazole to fumaric esters General procedure: A well ground mixture of 4-phenylurazole (1.0 mmol), DABCO (1.0 mmol), and TBAB (0.5 mmol) was placed in a flask. Fumaric ester (1.2 mmol) was added to this mixture and the flask was heated in the oil bath. When the oil bath temperature reached 70 °C, a brown solution was formed. After keeping the reaction flask at this temperature for stipulated time (Table 2), the reaction was completed as monitored by TLC. The flask was allowed to cool down to room temperature and chloroform (30 mL) was added. The solution was stirred to dissolve all the solids. TBAB was recovered by the addition of water (15 mL) to this solution, then collected and dried under vacuum. The chloroform layer was washed with water (315 mL). After dried with sodium sulfate and removal of the organic solvent, the residue was purified on short silica-gel columnwith n-hexane/ethyl acetate (9:1) as the eluent. 4.2.1. (Z)-Ethyl 2-(2,5-dioxo-1-phenylimidazolidin-4-ylidene)acetate (3a). White crystal, mp 186-187 °C(191°C);24Rf (20% ethyl acetate/hexane) 0.30;1H NMR (400 MHz, CDCl3): δ ppm 1.34 (t, 3H, J=7.1 Hz), 4.29 (q, 2H,J=7.1 Hz), 6.02 (s, 1H), 7.39-7.51 (m, 5H), 9.18(s, 1H); 13C NMR (100 MHz, CDCl3): 13.1, 60.4, 96.0, 124.8, 127.6,128.2, 129.5, 137.7, 151.3, 160.3, 165.7; IR (KBr, cm-1): 3297, 2933,1782, 1733, 1698, 1413, 1262, 772, 691; Anal. Calcd for C13H12N2O4:C, 60.00; H, 4.65; N, 10.76. Found: C, 60.56; H, 4.16; N, 10.23. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(acetonitrile)copper(I) perchlorate; siloxane-FOXAP; potassium carbonate; In dichloromethane; at 20℃;Inert atmosphere; Schlenk technique; Molecular sieve; | General procedure: Cu(OAc)2·H2O (0.04 mmol) and the ferrocenyl-oxazoline ligand L1(0.04 mmol) were added under argon to a 10 mL Schlenk tube, containing activated 4Å MS. The freshly distilled anhydrous DCM (2 mL) was added into the tube. After being stirred for 60 min at room temperature, the solution was cooled to 0 oC before the glycine imino ester 1 (0.8 mmol), maleate ester 2b-c (1.2 mmol) and Et3N (0.08 mmol) were added subsequently. The reaction mixture was stirred at -5 oC for overnight. When the reaction was complete as monitored by TLC, the pure adducts was purified by column chromatography on silica gel (200- 300 mesh). Enantiomeric excess was determined by chiral HPLC: racemate of all products for HPLC analyses were prepared by using Cu(OAc)2·H2O/PPh3. | |
With tetrakis(acetonitrile)copper(I) perchlorate; siloxane-FOXAP; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;Inert atmosphere; Schlenk technique; Molecular sieve; | General procedure: Cu(OAc)2·H2O (0.04 mmol) and the ferrocenyl-oxazoline ligand L1(0.04 mmol) were added under argon to a 10 mL Schlenk tube, containing activated 4Å MS. The freshly distilled anhydrous DCM (2 mL) was added into the tube. After being stirred for 60 min at room temperature, the solution was cooled to 0 oC before the glycine imino ester 1 (0.8 mmol), maleate ester 2b-c (1.2 mmol) and Et3N (0.08 mmol) were added subsequently. The reaction mixture was stirred at -5 oC for overnight. When the reaction was complete as monitored by TLC, the pure adducts was purified by column chromatography on silica gel (200- 300 mesh). Enantiomeric excess was determined by chiral HPLC: racemate of all products for HPLC analyses were prepared by using Cu(OAc)2·H2O/PPh3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(acetonitrile)copper(I) perchlorate; siloxane-FOXAP; caesium carbonate; In dichloromethane; at -5℃;Inert atmosphere; Schlenk technique; Molecular sieve; | General procedure: Cu(OAc)2·H2O (0.04 mmol) and the ferrocenyl-oxazoline ligand L1(0.04 mmol) were added under argon to a 10 mL Schlenk tube, containing activated 4Å MS. The freshly distilled anhydrous DCM (2 mL) was added into the tube. After being stirred for 60 min at room temperature, the solution was cooled to 0 oC before the glycine imino ester 1 (0.8 mmol), maleate ester 2b-c (1.2 mmol) and Et3N (0.08 mmol) were added subsequently. The reaction mixture was stirred at -5 oC for overnight. When the reaction was complete as monitored by TLC, the pure adducts was purified by column chromatography on silica gel (200- 300 mesh). Enantiomeric excess was determined by chiral HPLC: racemate of all products for HPLC analyses were prepared by using Cu(OAc)2·H2O/PPh3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With siloxane-FOXAP; copper(II) acetate monohydrate; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;Inert atmosphere; Schlenk technique; Molecular sieve; | General procedure: Cu(OAc)2·H2O (0.04 mmol) and the ferrocenyl-oxazoline ligand L1(0.04 mmol) were added under argon to a 10 mL Schlenk tube, containing activated 4Å MS. The freshly distilled anhydrous DCM (2 mL) was added into the tube. After being stirred for 60 min at room temperature, the solution was cooled to 0 oC before the glycine imino ester 1 (0.8 mmol), maleate ester 2b-c (1.2 mmol) and Et3N (0.08 mmol) were added subsequently. The reaction mixture was stirred at -5 oC for overnight. When the reaction was complete as monitored by TLC, the pure adducts was purified by column chromatography on silica gel (200- 300 mesh). Enantiomeric excess was determined by chiral HPLC: racemate of all products for HPLC analyses were prepared by using Cu(OAc)2·H2O/PPh3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With [Yb(bis(trimethylsilyl)amido)3(μ-Cl)Li(tetrahydrofuran)3]; phosphonic acid diethyl ester In acetonitrile at 20℃; for 5h; Inert atmosphere; | 29 Example 29: N-allyl isatin, diethyl phosphite and diethyl fumarate were reacted to prepare spiro [cyclopropane-1,3'-indole] compound In the reaction bottle subjected to dewatering and deoxygenation, [(Me3Si) 2N] 3Yb (μ-(0.5 mmol), diethyl phosphite (0.6 mmol), N-allyl isatin (0.0936 g, 0.5 mmol), acetonitrile (0.20 mmol) 0.5 mL), diethyl fumarate (1.5 mmol), after mixing Stirring at room temperature for 5 hours, adding water to stop the reaction, ethyl acetate extraction three times, the extract with anhydrous sodium sulfate drying, filtration, The solvent was removed by depressurization and finally subjected to flash column chromatography on silica gel (eluent: ethyl acetate: petroleum ether = 1: 7) to give a white solid The yield was 85%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | To a stirred solution of ethyl fumarate (CAS Number 2459-05-4; 5.0 g, 34.7 mmol) in THF (50 ml) were added EDC.HCl (7.3 g, 38.2 mmol) and HOBt (2.6 g, 17.4 mmol) at rt. The reaction mixture was stirred at rt for 30 min. 2-Amino-5-phenylthiazole (CAS Number 39136-63-5; 6.1 g, 34.7 mmol) was added portion wise to the reaction mixture. The reaction mixture was stirred at rt for 1.5 h. The resulting reaction mixture was poured into water (600 ml). The obtained precipitates were filtered under vacuum and dried yielding ethyl (E)-4-oxo-4-((5-phenylthiazol-2-yl)amino)but-2-enoate (12.35 g, quantitative). This material was used for the next step without further purification. LCMS: Method C, 2.16 min, MS: ES+ 303.23; NMR (400 MHz, DMSO-d6) delta ppm 12.82 (br s, 1 H), 7.98 (s, 1 H), 7.64 (d, J=7.2 Hz, 2 H), 7.44 (t, J=7.6 Hz, 2 H), 7.31- 7.35 (m, 1 H), 7.28 (d, J=15.6 Hz, 1 H), 6.84 (d, J=15.6 Hz, 1 H), 4.23 (q, J=7.2 Hz, 2 H), 1.26 (t, J=7.6 Hz, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.6% | In isopropyl alcohol; at 25℃; for 12h; | To a solution of diethyl (E)-but-2- enedioate (30.2 g, 175 mmol, 28.8 mL) in i-PrOH (300 mL) was added ethane-1,2-diamine (11.0 g, 183 mmol, 12.2 mL). After stiring at 25 C for 12 hours, the reaction mixture was concentrated under reduced pressure to dryness. The crude white solid was washed with MTBE (500 mL) and dried under vacuum to give ethyl 2-(3-oxopiperazin-2-yl)acetate (26.0 g, 140 mmol, 79.6 % yield, 100 % purity) as a white solid.?H NMR (400 MFIz, Chloroform-d) = 6.55 (br s, 1H), 4.15 (q,J= 6.8 Hz, 2H), 3.80-3.72 (m, 1H), 3.47 (dt,J=4.8, 11.2 Hz, 1H), 3.36- 3.22 (m, 1H), 3.18 - 3.08 (m, 1H), 3.07 - 2.95 (m, 2H), 2.76 - 2.70 (m, 1H), 1.25 (t, J= 7.2 Hz, 3H). |
79.6% | In isopropyl alcohol; for 12h;Heating; | To a solution of diethyl (E)-but-2-enedioate (30.2 g, 175 mmol, 28.8 mL) in i-PrOH (300 mL) was added ethane-1,2-diamine (11.0 g, 183 mmol, 12.2 mL). After stirring at 25° C. for 12 hours, the reaction mixture was concentrated under reduced pressure to dryness. The crude white solid was washed with MTBE (500 mL) and dried under vacuum to give ethyl 2-(3-oxopiperazin-2-yl)acetate (26.0 g, 140 mmol, 79.6% yield, 100% purity) as a white solid. 1H NMR (400 MHz, Chloroform-d) delta=6.55 (br s, 1H), 4.15 (q, J=6.8 Hz, 2H), 3.80-3.72 (m, 1H), 3.47 (dt, J=4.8, 11.2 Hz, 1H), 3.36-3.22 (m, 1H), 3.18-3.08 (m, 1H), 3.07-2.95 (m, 2H), 2.76-2.70 (m, 1H), 1.25 (t, J=7.2 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 72% 2: 7 %Spectr. | With dirhodium tetraacetate In dichloromethane at 20℃; for 1.58333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With methyltrioxorhenium(VII) In toluene at 190℃; for 70h; regioselective reaction; | 2.2. Representative procedure for DODH reactions General procedure: 1-Phenyl-2-ethanediol (0.32 mmol, 44 mg), MTO (0.032 mmol,8 mg), indoline (0.36 mmol, 34 lL), toluene (1 mL), and dodecane(5 lL) were added to a thick-walled Ace glass tube reactor. Thereactor was placed in a heating mantle bath at 190 °C for 2.5 h while stirring magnetically. After cooling to room temperature,the reaction mixture was filtered and analyzed by GC-MS. ForNMR of Diprophylline (7-(2,3-Dihydroxypropyl)-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione), mucic acid (tetrahydroxyadipicacid), and inositol, a 100 μL aliquot of reaction mixture was withdrawn.To this mixture CDCl3 and 2 μL DMSO as internal standardfor NMR analysis was added. The product was identified and quantifiedby 1H NMR spectroscopy and by comparison with an authenticsample. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With toluene-4-sulfonic acid In chlorobenzene at 180℃; for 0.166667h; Microwave irradiation; | Cycloaddition of 23 with diethyl fumarate p-Toluenesulfonic acid monohydrate (5.0% equiv, 12.5 μmol, 2.4 mg) was added to a solution of methyl 2-(((1R*,5S*,6r*)-6-(methoxymethyl)bicyclo[3.1.0]hexan-6-yl)amino)acetate 23 (1.00 equiv, 250 μmol, 53.3 mg) and diethyl fumarate (1.00 equiv, 250 μmol, 43.0 mg) in PhCl (0.25 mL). The mixture was heated using a CEM Discover microwave apparatus (power: 300 W, temperature: 180 °C, ramp time: 2 min, hold time: 10 min, max. pressure: 10 bars). After cooling, the reaction mixture was diluted with CH2Cl2 (10 mL), washed with 1 M NaOH aqueous solution (2.0 mL) and H2O (5.0 mL), then dried over Na2SO4, filtered and concentrated to afford the crude product (162 mg). Analysis by 1H NMR spectroscopy revealed the presence of the expected adduct, 3,4-diethyl 2-methyl 5-cyclopentyl-5-(methoxymethyl)pyrrolidine-2,3,4-tricarboxylate, produced in 61% yield as estimated by setting a value of 4.00 for the integral of the signals in the 4.10-4.40 ppm range, corresponding to all the OCH2CH3 protons, and measuring the integral of the signals at 3.29 and 3.82 ppm. The amount of unreacted diethyl fumarate was estimated to be 17% by measuring the integral of the two olefinic protons, at 6.85 ppm. Purification by flash column chromatography on silica gel (EtOAc/heptane 20%) afforded pure O3,O4-diethyl O2- methyl (2R*,3R*,4R*,5S*)-5-cyclopentyl-5-(methoxymethyl)pyrrolidine-2,3,4-tricarboxylate 24 (63.0 mg, 163 μmol, 65%). O3,O4-Diethyl O2- methyl (2R*,3R*,4R*,5S*)-5-cyclopentyl-5-(methoxymethyl)pyrrolidine-2,3,4-tricarboxylate 24Thick pale yellow oil. Rf 0.55 (EtOAc/heptane 50%, PMA). 1H NMR (CDCl3, 300 MHz): δ 1.24 (3H, t, J 7.0, H17 or H19), 1.25 (3 H, t, J 7.0, H17 or H19), 1.28-1.88 (8 H, m, H5-H8), 2.26 (1 H, m,H4), 2.39 (1 H, br s, NH), 3.19 (3 H, s, H1), 3.30 (1 H, d, J 11.0, H13), 3.32 (2 H, AB system, δA3.23, δB 3.41, JAB 9.5, H2), 3.50 (1 H, dd, J 11.0, 10.0, H14), 3.74 (3 H, s, H11), 3.83 (1 H, d, J10.0, H9), 4.12 (2 H, q, J 7.0, H16 or H18), 4.17 (2 H, AB part of an ABX3 system, δA 4.13, δB4.21, JAB 18.0, JAX 7.0, JBX 7.0, H16 or H18). 13C NMR (CDCl3, 75.5 MHz): δ 14.1, 14.2 (C17,C19), 24.7, 25.5 (C6, C7), 26.8, 27.5 (C5, C8), 46.5 (C4), 52.0, 52.3 (C11, C13), 54.3 (C14), 58.6(C1), 60.6, 60.9 (C16, C18), 62.6 (C9), 69.1 (C3), 76.0 (C2), 170.8, 172.2, 172.8 (C10, C12, C15). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Stage #1: (1S,R<SUB>S</SUB>)-N-tert-butanesulfinyl-3-methyl-1-phenylbut-3-en-1-amine; diethyl Fumarate With iron(III)-acetylacetonate; phenylsilane In ethanol at 60℃; for 15h; Stage #2: With formic acid In toluene at 110℃; for 15h; | Method A for Synthesis of 2-Piperidinone. General procedure: Phenylsilane (2 eq.) was added to a solution of Michael Acceptor (1 to 3 eq.), allylic amine (1 to 3 eq.),Fe(acac)3 (0.3 eq.) in EtOH (2 to 4 mL ~ 0.2 M). The reaction was heated at 60 °C for 15 hours, then a solution of HCl in 1,4-dioxane (4M, 0.5 ml) was added and the reaction mixture was stirred at room temperature for 2h then concentrated. The mixture was then dissolved in Toluene (2 mL) and Formic Acid (0.5 ml) and heated at 110°Cfor 15 hours. The reaction mixture was then concentrated and purified by flash chromatography (0-100% EtOAcin hexanes) or Prep HPLC (0-95% Acetonitrile in Water) to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In N,N-dimethyl-formamide at 40℃; for 24h; diastereoselective reaction; | 1-(tert-Butyl) 2,3-Diethyl (2S*,3S*)-Cyclopropane-1,2,3-tricarboxylate (7) (Table 1, run 1) To a stirred suspensionof potassium carbonate (35.0 mg, 0.255mmol) and benzyltriethylammonium chloride (0.264 mg, 0.00116mmol) in DMF(0.066 mL) at 40 °C were added a solution of diethyl fumarate(1, 20.0 mg, 0.116mmol) and tert-butyl chloroacetate (6,23.6 mg, 0.157mmol) in DMF (0.050 mL). After stirring at40 °C for 24 h, H2O (1 mL) was added and the mixture extractedwith EtOAc/hexane (1:1, 3 1 mL). Combined extractswere dried over Na2SO4 and concentrated under reduced pressure.The residue was purified by column chromatography onsilica gel (1 g, EtOAc/hexane = 1:9) to give cyclopropanetert-butyl diethyl ester 7 (28.2 mg, 0.0985mmol, 85%) as acolorless oil: IR (neat) 2981, 1727, 1639, 1370, 1308, 1150cm1; 1HNMR (400 MHz, CDCl3) δ 4.16 (dd, J = 7.0, 7.0 Hz,2 H), 4.13 (dd, J = 7.0, 7.0 Hz, 2 H), 2.69 (t, J = 8.0 Hz, 1 H),2.48 (dd, J = 10.0, 10.0 Hz, 1 H), 2.43 (dd, J = 10.0, 10.0 Hz,1 H), 1.41 (s, 9 H), 1.24 (t, J = 7.0 Hz, 3 H), 1.24 (t, J = 7.0 Hz,3 H); 13CNMR (100 MHz, CDCl3) δ 170.3, 167.5, 166.6, 82.0, 61.5, 61.4, 29.5, 28.7, 28.0 (3), 25.4, 14.1, 14.1; HRMS (ESI,positive) calcd for C14H22O6Na [(M + Na)+] 309.1314, found309.1311 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With [methyl-3-(butyl-4-sulfonate) imidazolium]CuPW12O40; oxygen; at 159.84℃; under 6000.6 Torr; for 5h; | General procedure: In a typical process, 0.25 g lignin, 0.9 mmol POM-IL catalyst and 20 mL 100% ethanol werecharged into a 100 mL stainless autoclave (Andorra MED1220, Premex Co. Ltd.). After airpurging with pure oxygen five times and pressurizing to 0.8 MPa, the reactor was heated to thedesignated temperature and maintained for the desired time. Once the latter elapsed, the autoclavewas cooled rapidly to room temperature in an ice water bath. The reaction mixture was removedand the reactor was washed with anhydrous ethanol (3 5.0 mL). The IL catalyst was precipitatedat room temperature and used for the next run after drying (extra fresh catalyst was added tooffset transfer losses). The liquid mixture was then diluted by ethanol to 50 mL for qualitative andquantitative analysis, while dimethyl phthalate was used as the internal standard. When aqueoussolutions of ethanol were used, the spent mixture was rotary evaporated under reduced pressurefor solvent recovery. The concentrated liquor was esterified with 10 mL anhydrous ethanol at 373K for 2 h and then diluted to 50 mL with ethanol. Volatile products were qualitatively andquantitatively analyzed via gas chromatography-mass spectrometry (GC-MS) and gaschromatography-flame ionization detection (GC-FID). Residual lignin can be obtained throughsimple precipitation processes. Organosolv lignin was recovered as follows: 60 mL deionized water was added into 20 mL of the above reaction mixture causing precipitation. The mixture wasthen separated using centrifugation and was dried until a constant weight was obtained. For therecovery of dealkaline lignin the mixture obtained after reaction was acidified to pH=2 with 1.0mol L-1 HCl solution and the same procedure described for organosolv lignin was conducted.In the atmosphere investigation, a mixture of nitrogen and oxygen with various molar ratioswas used, while depolymerization of lignin was conducted at 433 K for 5.0 h in the single stageexperiments. For a typical two-stage process, the lignin was first depolymerized employing theaforementioned conditions. When the mixture was cooled to room temperature, an extra 0.8 MPanitrogen or oxygen was purged into the reactor and the reaction was heated to 433 K for 1.0 or 2.0h. The product separation and analysis procedure remained unchanged to that describedpreviously. In comparative and control experiments, a series of model compounds (monolignolsand potential intermediate products) were tested under the same procedures as that for lignin (i.e.,0.25 g model compound, 0.9 mmol POM-IL catalyst and 20 mL 100% ethanol solvent). Triplicateexperiments were conducted and the data shown in this study is the average. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With [methyl-3-(butyl-4-sulfonate) imidazolium]CuPW12O40; oxygen at 159.84℃; for 5h; | General procedure for catalytic oxidation of lignin and model compound. General procedure: In a typical process, 0.25 g lignin, 0.9 mmol POM-IL catalyst and 20 mL 100% ethanol werecharged into a 100 mL stainless autoclave (Andorra MED1220, Premex Co. Ltd.). After airpurging with pure oxygen five times and pressurizing to 0.8 MPa, the reactor was heated to thedesignated temperature and maintained for the desired time. Once the latter elapsed, the autoclavewas cooled rapidly to room temperature in an ice water bath. The reaction mixture was removedand the reactor was washed with anhydrous ethanol (3 5.0 mL). The IL catalyst was precipitatedat room temperature and used for the next run after drying (extra fresh catalyst was added tooffset transfer losses). The liquid mixture was then diluted by ethanol to 50 mL for qualitative andquantitative analysis, while dimethyl phthalate was used as the internal standard. When aqueoussolutions of ethanol were used, the spent mixture was rotary evaporated under reduced pressurefor solvent recovery. The concentrated liquor was esterified with 10 mL anhydrous ethanol at 373K for 2 h and then diluted to 50 mL with ethanol. Volatile products were qualitatively andquantitatively analyzed via gas chromatography-mass spectrometry (GC-MS) and gaschromatography-flame ionization detection (GC-FID). Residual lignin can be obtained throughsimple precipitation processes. Organosolv lignin was recovered as follows: 60 mL deionized water was added into 20 mL of the above reaction mixture causing precipitation. The mixture wasthen separated using centrifugation and was dried until a constant weight was obtained. For therecovery of dealkaline lignin the mixture obtained after reaction was acidified to pH=2 with 1.0mol L-1 HCl solution and the same procedure described for organosolv lignin was conducted.In the atmosphere investigation, a mixture of nitrogen and oxygen with various molar ratioswas used, while depolymerization of lignin was conducted at 433 K for 5.0 h in the single stageexperiments. For a typical two-stage process, the lignin was first depolymerized employing theaforementioned conditions. When the mixture was cooled to room temperature, an extra 0.8 MPanitrogen or oxygen was purged into the reactor and the reaction was heated to 433 K for 1.0 or 2.0h. The product separation and analysis procedure remained unchanged to that describedpreviously. In comparative and control experiments, a series of model compounds (monolignolsand potential intermediate products) were tested under the same procedures as that for lignin (i.e.,0.25 g model compound, 0.9 mmol POM-IL catalyst and 20 mL 100% ethanol solvent). Triplicateexperiments were conducted and the data shown in this study is the average. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With [methyl-3-(butyl-4-sulfonate) imidazolium]CuPW12O40; oxygen at 159.84℃; for 5h; | General procedure for catalytic oxidation of lignin and model compound. General procedure: In a typical process, 0.25 g lignin, 0.9 mmol POM-IL catalyst and 20 mL 100% ethanol werecharged into a 100 mL stainless autoclave (Andorra MED1220, Premex Co. Ltd.). After airpurging with pure oxygen five times and pressurizing to 0.8 MPa, the reactor was heated to thedesignated temperature and maintained for the desired time. Once the latter elapsed, the autoclavewas cooled rapidly to room temperature in an ice water bath. The reaction mixture was removedand the reactor was washed with anhydrous ethanol (3 5.0 mL). The IL catalyst was precipitatedat room temperature and used for the next run after drying (extra fresh catalyst was added tooffset transfer losses). The liquid mixture was then diluted by ethanol to 50 mL for qualitative andquantitative analysis, while dimethyl phthalate was used as the internal standard. When aqueoussolutions of ethanol were used, the spent mixture was rotary evaporated under reduced pressurefor solvent recovery. The concentrated liquor was esterified with 10 mL anhydrous ethanol at 373K for 2 h and then diluted to 50 mL with ethanol. Volatile products were qualitatively andquantitatively analyzed via gas chromatography-mass spectrometry (GC-MS) and gaschromatography-flame ionization detection (GC-FID). Residual lignin can be obtained throughsimple precipitation processes. Organosolv lignin was recovered as follows: 60 mL deionized water was added into 20 mL of the above reaction mixture causing precipitation. The mixture wasthen separated using centrifugation and was dried until a constant weight was obtained. For therecovery of dealkaline lignin the mixture obtained after reaction was acidified to pH=2 with 1.0mol L-1 HCl solution and the same procedure described for organosolv lignin was conducted.In the atmosphere investigation, a mixture of nitrogen and oxygen with various molar ratioswas used, while depolymerization of lignin was conducted at 433 K for 5.0 h in the single stageexperiments. For a typical two-stage process, the lignin was first depolymerized employing theaforementioned conditions. When the mixture was cooled to room temperature, an extra 0.8 MPanitrogen or oxygen was purged into the reactor and the reaction was heated to 433 K for 1.0 or 2.0h. The product separation and analysis procedure remained unchanged to that describedpreviously. In comparative and control experiments, a series of model compounds (monolignolsand potential intermediate products) were tested under the same procedures as that for lignin (i.e.,0.25 g model compound, 0.9 mmol POM-IL catalyst and 20 mL 100% ethanol solvent). Triplicateexperiments were conducted and the data shown in this study is the average. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With [methyl-3-(butyl-4-sulfonate) imidazolium]CuPW12O40; oxygen; at 159.84℃; under 6000.6 Torr; for 5h; | General procedure: In a typical process, 0.25 g lignin, 0.9 mmol POM-IL catalyst and 20 mL 100% ethanol werecharged into a 100 mL stainless autoclave (Andorra MED1220, Premex Co. Ltd.). After airpurging with pure oxygen five times and pressurizing to 0.8 MPa, the reactor was heated to thedesignated temperature and maintained for the desired time. Once the latter elapsed, the autoclavewas cooled rapidly to room temperature in an ice water bath. The reaction mixture was removedand the reactor was washed with anhydrous ethanol (3 5.0 mL). The IL catalyst was precipitatedat room temperature and used for the next run after drying (extra fresh catalyst was added tooffset transfer losses). The liquid mixture was then diluted by ethanol to 50 mL for qualitative andquantitative analysis, while dimethyl phthalate was used as the internal standard. When aqueoussolutions of ethanol were used, the spent mixture was rotary evaporated under reduced pressurefor solvent recovery. The concentrated liquor was esterified with 10 mL anhydrous ethanol at 373K for 2 h and then diluted to 50 mL with ethanol. Volatile products were qualitatively andquantitatively analyzed via gas chromatography-mass spectrometry (GC-MS) and gaschromatography-flame ionization detection (GC-FID). Residual lignin can be obtained throughsimple precipitation processes. Organosolv lignin was recovered as follows: 60 mL deionized water was added into 20 mL of the above reaction mixture causing precipitation. The mixture wasthen separated using centrifugation and was dried until a constant weight was obtained. For therecovery of dealkaline lignin the mixture obtained after reaction was acidified to pH=2 with 1.0mol L-1 HCl solution and the same procedure described for organosolv lignin was conducted.In the atmosphere investigation, a mixture of nitrogen and oxygen with various molar ratioswas used, while depolymerization of lignin was conducted at 433 K for 5.0 h in the single stageexperiments. For a typical two-stage process, the lignin was first depolymerized employing theaforementioned conditions. When the mixture was cooled to room temperature, an extra 0.8 MPanitrogen or oxygen was purged into the reactor and the reaction was heated to 433 K for 1.0 or 2.0h. The product separation and analysis procedure remained unchanged to that describedpreviously. In comparative and control experiments, a series of model compounds (monolignolsand potential intermediate products) were tested under the same procedures as that for lignin (i.e.,0.25 g model compound, 0.9 mmol POM-IL catalyst and 20 mL 100% ethanol solvent). Triplicateexperiments were conducted and the data shown in this study is the average. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 4h; Inert atmosphere; | 3.2.6. Diethyl (1R,3S,10bS)- and (1S,3R,10bR)-10b-hydroxy-6-oxo-1,2,3,4,6,10b-hexahydropyrido[2,1-a]isoindole-1,3-dicarboxylate, (rac-6a) General procedure: A solution of 2 (300 mg, 1.21 mmol) and ethyl acrylate (0.2 mL, 1.84 mmol) in dry THF (25 mL) was cooled to -78 °C under nitrogen atmosphere. Subsequently, lithium bis(trimethylsilyl)amide (LHMDS, 1.3 mL of 1M solution in THF, 1.3 mmol) was added dropwise and the reaction mixture was stirred for 4 h at -78 °C. The resulting mixture was warmed to room temperature and aq. NH4Cl (10 mL) was added, before extraction with EtOAc (3 x 20 mL). The combined organic extracts were washed with aq. NaHCO3 (10 mL) and brine (10 mL) and dried over anhydr. Na2SO4. The solvent was evaporated under vacuum and the residue was purified by column chromatography (hexane-EtOAc 7:3 v/v). TLC (hexane/EtOAc 7:3, eluted four times) of the reaction crude showed three components with Rf 0.30, 0.24, and 0.20. The fraction with Rf 0.30 (major diastereoisomer) was isolated and recrystallized from hexane-EtOAc (2:1 v/v) to afford 185 mg (44% yield) of rac-6a as colorless crystals with mp 154-155 °C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; lithium acetate In 1,2-dichloro-ethane at 80℃; for 16h; | 3 General procedure: More specifically, in Example 1, the cationIn the presence of a Rh (III) catalystN-sulfonyl aldimine (1a)And through the reaction of N- methyl maleimide (2a), it was intended to derive the optimization conditions for the synthesis of 1-aminoindane derivatives (1-Aminoindanes). The result was formed in 79% yield in DCE for 16 hours at 80 ° C., as shown in Table 1 below (item 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: ethyl β-alaninate hydrochloride; chloroformic acid ethyl ester With triethylamine In dichloromethane at 20℃; for 2h; Cooling with ice; Stage #2: diethyl Fumarate With sodium In toluene at 110℃; for 4h; | 1.1; 2.1 Step 1 Dissolve 40 g of ethyl 3-aminopropanoate hydrochloride and 52.6 g of Et3N in anhydrous dichloromethane, add28.3 g of ethyl chloroformateunder ice bath, stir at room temperature for 2 h, and quench with water. The organic layer was dried and concentrated; the concentrate was dissolved in 680 mL of anhydrous toluene, and 44.8 g of diethyl fumarate and 5.99 g of sodium metal were added. The mixture was heated to 100 ° C and stirred for 6 hours. After cooling, it was quenched with a large amount of ice water. The aqueous phase was washed with methyl tert-butyl ether, acidified to pH = 1-2, and extracted with methyl tert-butyl ether.The organic layer was dried and concentrated, and then dissolved in 450 mL of 12N hydrochloric acid, stirred for 36 hours and concentrated to dryness, dissolved in 450 mL of 4N hydrogen chloride ethanol and refluxed for 12 hours, concentrated to remove the solvent, and distilled under reduced pressure to obtain 2- (ethoxycarbonyl) methyl-3. -51 g of ethyl oxopyrrolidine-1-carboxylate, yield 79%, purity 99.6% (HPLC); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With lithium perchlorate at 20℃; for 3h; Sonication; | General procedure for Aza-Michael addition to trans diethyl fumarate. General procedure: To a mixture of (S)-α-methylbenzylamine (1.32 mL, 10.31 mmol) and trans diethyl fumarate(2.03 mL, 12.38 mmol), lithium perchlorate (0.54 g, 5.16 mmol) was added. The reaction mixture was sonicated at room temperature for 3h, and then underwent extraction withDCM (3x20 mL). The combined organic extract was dried over anhydrous Na2SO4 and thesolvent was removed under reduced pressure. The residue was purified by column chromatography on silica (AcOEt:Petroleum ether). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: (E)-N-(1-(5-chlorothiophen-2-yl)ethylidene)-P,P-diphenylphosphinic amide With copper diacetate In tetrahydrofuran at 20℃; for 0.25h; Inert atmosphere; Stage #2: diethyl Fumarate With 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In tetrahydrofuran at 20℃; for 16h; | 151.3 Step-3: To a stirred solution of compound (E)-N-(1-(5-chlorothiophen-2-yl)ethylidene)-P,P-diphenylphosphinic amide (15 g, 41.71 mmol, 1.0 eq) in THF (200 mL) at RT were under nitrogen atmosphere added Cu(OAc)2 (0.377 g, 2.85 mmol, 0.05 eq), TPP (1.0 g, 4.16 mmol, 0.1 eq). The mixture was stirred for 15 min prior to the addition of diethyl fumarate (18 mL, 104 mmol, 2.5 eq), and pinacolborane (14.8 mL, 116 mmol, 2.8 eq). Stirring was continued for 16 h at RT. The reaction progress was monitored by TLC. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried (Na2SO4) and evaporated. The crude compound was purified by flash chromatography (silica 40-60% EtOAc in petroleum ether as an eluent) to get compound ethyl 2-(5-chlorothiophen-2-yl)-1-(diphenylphosphoryl)-2-methyl-5-oxopyrrolidine-3-carboxylate (15 g, ~75%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: N-[(1E)-1-phenylethylidene]-P,P-diphenylphosphinic amide; diethyl Fumarate With triphenylphosphine In tetrahydrofuran at 20℃; for 0.333333h; Stage #2: With 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In tetrahydrofuran at 20℃; for 48h; | 3 Step 3: To a stirred solution of (E)-P,P-diphenyl-N-(1-phenylethylidene)phosphinic amide (5 g, 15.657 mmol, 1 eq) in THF (75 mL), 1,4-diethyl (2E)-but-2-enedioate (6.75g, 39.143 mmol, 2.5eq), Cu(OAc) (285 mg, 1.5657 mmol, 0.1eq), PPh3 (410 mg, 1.5657 mmol, 0.1eq) were added at RT and the mixture was stirred at RT for 20 min. Then pinacolborane (5.62 g, 43.839 mmol, 2.8eq) was added at RT and the reaction mixture was stirred at RT for 48 h. After completion of reaction (monitored by TLC, 50% EtOAc in hexane, Rf=0.4), reaction mixture was diluted with EtOAc, washed with water (100 mL) and brine (100 mL),dried over Na2SO4 and concentrated to get the crude product which was purified by column chromatography using 230-400 silica gel and 20-40 % EtOAc in hexane to afford pure desired ethyl 1-(diphenylphosphoryl)-2-methyl-5-oxo-2-phenylpyrrolidine-3-carboxylate (4 g, 57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 12h; Inert atmosphere; | 1 Add 100ml of anhydrous tetrahydrofuran (THF) into a three-necked round-bottom flask, add potassium tert-butoxide (11.5g, 102.6mmol) under nitrogen atmosphere, and then add p-toluenesulfonyl methyl isocyanide (10.0g, 51.2mmol) dropwise ), a mixed solution of diethyl fumarate (8.8g, 51.2mmol) and 50ml THF, followed by stirring at room temperature for 12h. After the reaction, saturated brine was added, and the organic layer was extracted with 50ml of THF, and the water was removed After filtering and removing the solvent, dissolve in methanol; add water to the methanol solution until a precipitate is formed. After cooling and filtering, a solid is obtained, which is washed and dried with excess water to obtain a milky white compound a (6.4g, yield 59%) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: N-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)ethylidene)-P,P-diphenylphosphinic amide With copper diacetate In tetrahydrofuran at 20℃; for 0.25h; Inert atmosphere; Stage #2: diethyl Fumarate With 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In tetrahydrofuran at 20℃; for 2h; | 33.5 Step 5: To a stirred solution of N-(1-(1-(4-fluorophenyl)-1H-indazol-5-yl)ethylidene)-P,P-diphenylphosphinic amide (6.5 g, 14.34 mmol, 1.0 eq) in THF (60 mL) at RT under nitrogen atmosphere were added Cu(OAc)2 (0.13 g, 0.717 mmol, 0.05 eq), and TPP (0.37 g, 1.43 mmol, 0.1 eq) and the reaction mixture was stirred for 15 min, prior to the addition of diethyl fumarate (3.7 mL, 21.52 mmol, 1.5 eq) and pinacol borane (2.93 g, 22.94 mmol, 1.6 eq), and stirring was continued for 2 h at RT. Upon reaction completion, the reaction mixture was diluted with water (50 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2S04 and evaporated under reduced pressure. The crude compound was purified by column chromatograpy (120 g silica gel; 30-60% EtOAc in petroleum ether) to afford ethyl 1-(diphenylphosphoryl)-2-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-5-oxopyrrolidine-3-carboxylate (3.9 g, ~46%) as a yellow gum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With sodium carbonate In tetrahydrofuran at 100℃; for 48h; Inert atmosphere; Sealed tube; regioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With triethylamine In acetonitrile at 40℃; for 24h; Inert atmosphere; |
Tags: 623-91-6 synthesis path| 623-91-6 SDS| 623-91-6 COA| 623-91-6 purity| 623-91-6 application| 623-91-6 NMR| 623-91-6 COA| 623-91-6 structure
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