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CAS No. : | 1121-07-9 | MDL No. : | MFCD00005517 |
Formula : | C5H7NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KYEACNNYFNZCST-UHFFFAOYSA-N |
M.W : | 113.12 | Pubchem ID : | 70717 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.6 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 31.25 |
TPSA : | 37.38 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.66 cm/s |
Log Po/w (iLOGP) : | 1.16 |
Log Po/w (XLOGP3) : | -0.95 |
Log Po/w (WLOGP) : | -0.62 |
Log Po/w (MLOGP) : | -0.08 |
Log Po/w (SILICOS-IT) : | 0.51 |
Consensus Log Po/w : | 0.01 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 0.06 |
Solubility : | 129.0 mg/ml ; 1.14 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 0.65 |
Solubility : | 505.0 mg/ml ; 4.46 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.43 |
Solubility : | 41.8 mg/ml ; 0.37 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | 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 |
---|---|---|
>= 80% | With ammonia; In water; at 300℃; for 5h; | SUCCINIMIDE is provided to a reactor at 23% by weight in water. Methanol is provided to the reactor at a 1.5 : 1 methanol to succinimide ratio in an absence of added ammonia. The ammonia integrated within the succinimide provides a 1: 1 ammonia to succinate species ratio. The reactor is pressurized with nitrogen and sealed. The reactor is heated to 300C AND is maintained at temperature for 5 hours. Samples are collected at least every hour during the reaction. Product analysis is conducted to determine conversion and product selectivity. Analysis of the 4 hour sample indicates a succinimide conversion of greater than or equal to 96%. The yield of N-methyl succinimide (NMS) is greater than or equal to 80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With potassium carbonate In acetone for 4h; Heating; | |
95% | With potassium carbonate In acetone Sealed tube; Inert atmosphere; Reflux; | |
92% | With potassium carbonate In acetone Heating; |
at 100℃; Ausgangstoff ist Succinimid-silber; unter Ausschluss von Feuchtigkeit; | ||
With potassium carbonate In acetone for 4h; Heating; | ||
With potassium carbonate In acetone | ||
With potassium carbonate In acetone Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | In tetrahydrofuran at -20℃; for 12h; Autoclave; Inert atmosphere; | |
With diethyl ether; benzene |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid; water Bei der elektrochemischen Reduktion an einer Blei-Kathode; | ||
With hydrogen In water at 100℃; for 48h; variation of condition; | ||
With hydrogen at 200℃; for 4h; | 6 Example 6: N-methyl Succinimide Hydrogenation Approximately 5.0 grams (g) of the specified catalyst is charged into a reactor equipped with a magnetic stirrer. Approximately 50.0 g of solid NMS is utilized a feedstock and is provided to the reactor. The reaction is conducted under 1500 psig constant H2 pressure at a stir rate of about 1000 rpm. After 4 hrs, the resulting gas and liquid components are analyzed for determination of NMS conversion and product selectivity. The results of the determinations are indicated in Table 5 for each of the indicated catalysts and reaction temperatures. TABLE 5: Catalyst Based Hydrogenation Selectivities molar% (of Catalyst No. Temp. % of NMS NMP/2-pyrrolidinone theoretical) Yield (from Table 2) (C) Converted (Mole Ratio) of NMP 1 200 <1 0.6 n/d 2 200 7 6. 8 25 3 200 3 3 10 4 200 65 55.9 65 6757-09-1 200 84 69. 3 10 ESCAT-268 200 26 25. 7 >90 ESCAT-340 200 45 41. 8 149 ESCAT-140 200 15 12. 4 48 ESCAT-440 200 96 34. 3 1. 5 ESCAT-440 150 75 42. 2 6. 5 ESCAT-440 120 39 19 n/d ESCAT-340 220 50. 2 50. 2 70 ESCAT-268 220 35. 5 35. 5 n/d Co-0138 E 1/16 3F 200 58. 6 32. 0 18 G106BAN5% Rh 220 95. 8 90. 8 142 * ESCAT-340 200 40.4 38.0 n/d G 106 B/W 5% Rh 220 93. 6 89. 4 134 2Py = 2-pyrrolidinone ; n/d = not detected ; *reaction was conducted at 2000 psig. |
With hydrogen at 200 - 220℃; for 4h; | 6 Example 6: N-methyl Succinimide Hydrogenation Approximately 5.0 grams (g) of the specified catalyst is charged into a reactor equipped with a magnetic stirrer. Approximately 50.0 g of solid NMS is utilized a feedstock and is provided to the reactor. The reaction is conducted under 1500 psig constant H2 pressure at a stir rate of about 1000 rpm. After 4 hrs, the resulting gas and liquid components are analyzed for determination of NMS conversion and product selectivity. The results of the determinations are indicated in Table 5 for each of the indicated catalysts and reaction temperatures. TABLE 5: Catalyst Based Hydrogenation Selectivities molar% (of Catalyst No. Temp. % of NMS NMP/2-pyrrolidinone theoretical) Yield (from Table 2) (C) Converted (Mole Ratio) of NMP 1 200 <1 0.6 n/d 2 200 7 6. 8 25 3 200 3 3 10 4 200 65 55.9 65 6757-09-1 200 84 69. 3 10 ESCAT-268 200 26 25. 7 >90 ESCAT-340 200 45 41. 8 149 ESCAT-140 200 15 12. 4 48 ESCAT-440 200 96 34. 3 1. 5 ESCAT-440 150 75 42. 2 6. 5 ESCAT-440 120 39 19 n/d ESCAT-340 220 50. 2 50. 2 70 ESCAT-268 220 35. 5 35. 5 n/d Co-0138 E 1/16 3F 200 58. 6 32. 0 18 G106BAN5% Rh 220 95. 8 90. 8 142 * ESCAT-340 200 40.4 38.0 n/d G 106 B/W 5% Rh 220 93. 6 89. 4 134 2Py = 2-pyrrolidinone ; n/d = not detected ; *reaction was conducted at 2000 psig. | |
With hydrogen In water at 250℃; for 4h; | 2 Example 2; This example illustrates that N-methyl succinimide may be successfully hydrogenated in the presence of water to produce N-methyl-pyrrolidone. Ruthenium (III) acetylacetonate (0.46mmols, 0. 182g) and 1,1, 1 tris (diphenyl-phosphino- methyl) ethane (6. lmmols, 0. 38g), water (69.7g) N-methyl succinimide (ex Aldrich, 154mmols, 17.45g) were transferred into a 300mol Hastelloy Part autoclave. This was sealed and purged with hydrogen before being pressurised to 600 psig with hydrogen and heated to 250°C. Once 250°C had been achieved, the reactor was topped up with hydrogen to 1000 psig and this pressure was maintained throughout the reaction via a regulator. At the end of the reaction, after 4hrs, the hydrogen supply was isolated and the reactor cooled. At room temperature the headspace gas was vented. The product was removed from the reactor and analysed. The water and organic analysis was determined using an HP gas chromatograph equipped with a micro TCD (wt%): ammonia (0.15) water (86. 93), NMP (12.52) others (0. 392). | |
93 %Chromat. | With palladium 10% on activated carbon; hydrogen In water at 250℃; for 6h; | 10 Hydrogenation of N-methyl Succinimide A 100 cc stainless steel high pressure reactor was charged with N-methyl succinimide (0.5 g; 4.24 mmol), distilled water (15 ml) and 10% Pd on activated charcoal (0.1 g) catalyst. The reactor was pressurized with 40 bar H2 pressure and heated at 250° C. for 6 h. The reactor was being cooled to room temperature and excess H2 released gently. Catalyst was recovered by filtration and the resulting filtrate was concentrated under reduced pressure to give a colorless liquid NMP. The conversion of NMS was found to be 93% and selectivity>99% for NMP, as analyzed by GC analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 2,6-dichloropyridine N-oxide In benzene at 40℃; | |
81% | With pyridine; N-hydroxyphthalimide; sodium perchlorate In acetonitrile controlled potential electrolysis, electrodes: glassy-carbon vs. SCE; | |
81% | With silver tetrafluoroborate; water; Selectfluor In acetone at 40℃; for 1h; Schlenk technique; Inert atmosphere; | 8 Example 8. Experimental Procedures for Silver-Mediated Fluorination: Representative Procedure for the Silver-Mediated Monofluorination of Cyclic Amines General procedure: To a 1-dram vial was added sequentially 1a (18.9 mg, 0.100 mmol), AgBF4 (77.9 mg, 0.400 mmol), Selectfluor (142 mg, 0.400 mmol) and 1 :9 acetone: H20 (0.5 mL) The resulting mixture was heated to 40 °C and held at this temperature. After 1 h, the reaction mixture was partitioned with EtOAc (0.5 mL) and H20 (0.5 mL) and the phases were separated. The aqueous phase was extracted with EtOAc (1.5 mL c 3) and the combined organic layers were concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (50% EtO Ac/hexanes) to provide A-(4-fl uorobutyl )- A'-form yl benzam i de (2a) (18.0 mg, 81%) as a pale yellow oil. NMR (600 MHz, CDCh): d 8.93 (s, 1H), 7.57 (t, J= 7.2 Hz, 1H), 7.53-7.48 (m, 4H), 4.48 (dt, J= 47.6, 5.6 Hz, 2H), 3.92 (t, J= 7.1 Hz, 2H), 1.82-1.72 (m, 4H); 13C NMR (151 MHz, CDCh): 172.5, 164.3, 133.7, 132.3, 129.1, 128.9, 83.6 (d, J = 165.2 Hz), 40.2, 28.0 (d, J= 20.2 Hz), 24.2 (d, J= 5.0 Hz); 19F NMR (376 MHz, CDCh): d -217.5 - -217.9 (m, 1F); HRMS (ESI): Calc’d for Ci2Hi4FN02Na [M+Na]+: 246.0906, found: 246.0906. |
72% | With N-hydroxyphthalimide In pyridine anodic oxidation; | |
34% | With 2-Picolinic acid; manganese(II) perchlorate hexahydrate; dihydrogen peroxide; sodium acetate In acetonitrile at 0 - 20℃; | |
1.0 mmol | With oxygen; titanium(IV) oxide In water for 48h; Irradiation; | |
0.42 mmol | With zirconium triflate; oxygen at 130℃; for 10h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With acetic anhydride; zinc In toluene at 40 - 86℃; for 48h; Inert atmosphere; chemoselective reaction; | |
90% | With Aeroxide (Evonik) P25 TiO2, consisting of a 3:1 anatase/rutile mixture In methanol; acetonitrile for 17h; Inert atmosphere; UV-irradiation; | 3.3. General Procedure for SCPC Hydrogenation of Maleimides General procedure: The maleimide was added to a suspension of P25 in methanol (10%) and acetonitrile (90%). The resulting mixture was then purged with argon for 15 min. The mixture was irradiated with eight 29 cm 15 W Philips Cleo tubes (λ = 350 nm). Following irradiation the P25 powder was removed via filtration through Celite. |
86% | With dichloro(dimethylglyoxime)(dimethylglyoximato)cobalt(III); ethyl 3-([1,1'-biphenyl]-2-yl)-3-oxopropanoate; 9-(2-mesityl)-10-methylacridinium perchlorate In acetonitrile at 20℃; for 24h; Irradiation; Inert atmosphere; |
76% | With 1,2,2,3,4,4-hexamethylphosphetane 1-oxide; phenylsilane; water In toluene at 80℃; for 24h; Schlenk technique; Inert atmosphere; | |
With hydrogen catalytic hydrogenation; | ||
With hydrogen; silver; zinc | ||
With Nicotiana tabacum cultured cells In various solvent(s) at 25℃; for 120h; | ||
97 % Spectr. | With hydrogen In ethanol at 20℃; for 1h; | |
With enoate reductase YqjM from Bacillus subtilis In ethanol Irradiation; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium 1.) Et2O, reflux, 1 h, 2.) Et2O, C6H6, reflux, 4 h; Yield given. Multistep reaction; | ||
With sulfuric acid; sodium carbonate; magnesium In diethyl ether; water; benzene | 1 5-Hydroxy-1-methyl-5-(m-trifluoromethylphenyl)pyrrolidone. EXAMPLE 1 5-Hydroxy-1-methyl-5-(m-trifluoromethylphenyl)pyrrolidone. To a Grignard prepared from 37 g. (0.16 mole) of 3-bromobenzotrifluoride and 3.7 g. (0.16 mole) of magnesium turnings in 100 ml. of dry diethylether, there is added dropwise over a period of about 10 minutes 12.2 g. (0.11 mole) of N-methylsuccinimide in 100 ml. of dry benzene. The resulting mixture is stirred and refluxed for about 4 hours and then allowed to stand overnight at room temperature. Stirring is resumed and 40 ml. of 50% sulfuric acid is added dropwise at such a rate to maintain a gentle reflux. After an additional 0.5 hours, the water layer is separated and washed twice with 50 ml. of benzene. The organic layers are combined and washed with 50 ml. of sodium carbonate and then twice more with 50 ml. of water. The resulting layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting residue is crystallized from methylene chloride/hexane to give 5-hydroxy-1-methyl-5-(m-trifluoromethylphenyl)pyrrolidone; m.p. 137°- 139°C. Following the above procedure and using in place of 3-bromo-benzotrifluoride an equivalent amount of a 2-chloro-5-bromobenzotrifluoride, or b 2-fluoro-5-bromobenzotrifluoride, there is obtained a 5-hydroxy-1-methyl-5-(4-chloro-m-trifluoromethylphenyl) pyrrolidone, or b 5-hydroxy-1-methyl-5-(4-fluoro-m-trifluoromethylphenyl) pyrrolidone. Again following the above procedure and using in place of N-methyl succinimide, an equivalent amount of c N-ethylsuccinimide, d succinimide, e N-methylglutarimide, or f glutarimide, there is obtained c 5-hydroxy-1-ethyl-5-(m-trifluoromethylphenyl)pyrrolidone, d 5-hydroxy-5-(m-trifluoromethylphenyl)pyrrolidone, e 6-hydroxy-1-methyl-6-(m-trifluoromethylphenyl)piperidinone, or f 6-hydroxy-6-(m-trifluoromethylphenyl)piperidinone, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With magnesium 1.) Et2O, reflux, 1 h, 2.) Et2O, C6H6, reflux, 4 h; Yield given. Multistep reaction; | ||
With sulfuric acid; sodium carbonate; magnesium In diethyl ether; water; benzene | 2 5-Hydroxy-1-methyl-5-(m-tolyl)pyrrolidone. EXAMPLE 2 5-Hydroxy-1-methyl-5-(m-tolyl)pyrrolidone. To a Grignard prepared from 27.3g (0.16 mole) of 3-bromotoluene and 3.7 g. (0.16 mole) of magnesium turnings in 100 ml. of dry diethylether, there is added dropwise over a period of about 10 minutes 12.2 g. (0.11 mole) of N-methylsuccinimide in 100 ml. of dry benzene. The resulting mixture is stirred and refluxed for about 4 hours and then allowed to stand overnight at room temperature. Stirring is resumed and 40 ml. of 50% sulfuric acid is added dropwise at such a rate to maintain a gentle reflux. After an additional 0.5 hours, the water layer is separated and washed twice with 50 ml. of benzene. The organic layers are combined and washed with 50 ml. of sodium carbonate and then twice more with 50 ml. of water. The resulting layer is dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting residue is crystallized from methylene chloride/hexane to give 5-hydroxy-1-methyl-5-(m-tolyl) pyrrolidone; m.p. 128°-130°C. Following the above procedure and using in place of 3-bromotoluene an equivalent amount of a 2-chloro-5-bromotoluene, or b 2-fluoro-5-bromotoluene, there is obtained a 5-hydroxy-1-methyl-5-(4-chloro-m-tolyl)pyrrolidone, or b 5-hydroxy-1-methyl-5-(4-fluoro-m-tolyl)pyrrolidone. Again following the above procedure and using in place of N-methylsuccinimide, an equivalent amount of c N-ethylsuccinimide, d N-methylglutarimide, or e N-ethylglutarimide, there is obtained c 5-hydroxy-1-ethyl-5-(m-tolyl)pyrrolidone, d 6-hydroxy-1-methyl-6-(m-tolyl)piperidinone, or e 6-hydroxy-1-ethyl-(m-tolyl)piperidinone, respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With aluminium trichloride In 1,2-dichloro-ethane at 90℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With P-tris(dimethylamino)-C-dimethylphosphonium ylide In tetrahydrofuran at 20℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With lead(II) bromide; zinc In tetrahydrofuran at 20℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With lead(II) bromide; zinc In tetrahydrofuran at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With lead(II) bromide; zinc In tetrahydrofuran at 20℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With nickel(II) iodide; samarium diiodide In tetrahydrofuran at 20℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With samarium diiodide In tetrahydrofuran at 20℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: 1-phenyl-2-bromoethane With magnesium In diethyl ether Heating; Stage #2: N-methylsuccinimide In tetrahydrofuran; diethyl ether at 20℃; | |
Stage #1: 1-phenyl-2-bromoethane With iodine; magnesium In tetrahydrofuran Cooling with ice; Stage #2: N-methylsuccinimide In tetrahydrofuran at 20℃; for 8h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With sodium tetrahydroborate at 0℃; | |
88% | With hydrogenchloride; sodium tetrahydroborate In 1,4-dioxane at 0℃; for 7h; Inert atmosphere; | |
81% | With cobalt(II) tetrafluoroborate hexahydrate; hydrogen; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] at 90℃; for 18h; Sealed tube; Autoclave; Green chemistry; |
75% | With tris(2,4-pentanedionato)ruthenium(III); methanesulfonic acid; hydrogen; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] at 130℃; for 18h; Autoclave; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With methanol; sodium hydride In tetrahydrofuran for 48h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With sodium methylate In tetrahydrofuran for 24h; Reflux; | |
58% | Stage #1: N-methylsuccinimide; C16H14FNO4 With lithium hexamethyldisilazane In tetrahydrofuran at 0 - 20℃; for 2h; Stage #2: With hydrogenchloride; water In tetrahydrofuran at 0℃; | 72 Example 72; Synthesis of Compound 209 To 10 g (33 mmol, 1 equiv) of the dimethyl ester in 100 mL THF, cooled to 0° C., is added 3.7 g (33 mmol, 1 equiv) N-methyl succinimide. Then, 72 mL of a 1M THF solution of LiHMDS (72 mmol, 2.2 equiv) was added dropwise. The reaction was allowed to warm to rt, and an additional 15 mL LiHMDS solution was added. After 2 h of stirring, the reaction was re-cooled to ice-bath temperature and quenched by the addition of 30 mL 6M aq. HCl. The resulting solid was filtered and washed with cold diethyl ether. Oven drying of the precipitate gave 6.7 g of product 203 (58%) as a light yellow solid. 1H NMR (300 MHz, d6-DMSO) shows diagnostic peaks at δ (ppm): 8.95 (s, 1H), 8.44 (s, 1H), 7.38 (m, 2H), 7.18 (m, 2H), 4.24 (s, 2H), and 2.95 (s, 3H). MS=353.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 45% 2: 22% | With ethylaluminum dichloride In hexane; toluene at -78 - 20℃; for 1.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 77% 2: 6.1% 3: 1.7% 4: 5% | With ammonia In water at 280℃; for 10h; | 3 Example 3: N-methyl Succinimide Formation from Succinamic Acid Succinamic acid is provided to a reactor at 30% by weight in water. Methanol is provided to the reactor at a 1.5 : 1 methanol to succinamic acid ratio, and ammonia is added to provide a 0.2 : 1 ammonia to succinamic acid ratio. This represents a 1.2 : 1 ammonia to succinate species ratio due to the ammonia integrated into the succinamic acid. The reactor is filled or pressurized with nitrogen and sealed. The reactor is heated to 280C and maintained at temperature for 10 hours before quench cooling. The product is analyzed to determine conversion and selectivity products. Analysis after 8 hours indicates a succinamic acid conversion of greater than or equal to 96.5%. The yield of N-methyl succinimide (NMS) is greater than or equal to 77% ; with a corresponding production of less than 6. 1% N-METHYL succinamic acid, less than or equal to 5% succinic acid, and less than 1.7% succinimide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen at 200℃; for 4h; | 6 Example 6: N-methyl Succinimide Hydrogenation Approximately 5.0 grams (g) of the specified catalyst is charged into a reactor equipped with a magnetic stirrer. Approximately 50.0 g of solid NMS is utilized a feedstock and is provided to the reactor. The reaction is conducted under 1500 psig constant H2 pressure at a stir rate of about 1000 rpm. After 4 hrs, the resulting gas and liquid components are analyzed for determination of NMS conversion and product selectivity. The results of the determinations are indicated in Table 5 for each of the indicated catalysts and reaction temperatures. TABLE 5: Catalyst Based Hydrogenation Selectivities molar% (of Catalyst No. Temp. % of NMS NMP/2-pyrrolidinone theoretical) Yield (from Table 2) (C) Converted (Mole Ratio) of NMP 1 200 <1 0.6 n/d 2 200 7 6. 8 25 3 200 3 3 10 4 200 65 55.9 65 6757-09-1 200 84 69. 3 10 ESCAT-268 200 26 25. 7 >90 ESCAT-340 200 45 41. 8 149 ESCAT-140 200 15 12. 4 48 ESCAT-440 200 96 34. 3 1. 5 ESCAT-440 150 75 42. 2 6. 5 ESCAT-440 120 39 19 n/d ESCAT-340 220 50. 2 50. 2 70 ESCAT-268 220 35. 5 35. 5 n/d Co-0138 E 1/16 3F 200 58. 6 32. 0 18 G106BAN5% Rh 220 95. 8 90. 8 142 * ESCAT-340 200 40.4 38.0 n/d G 106 B/W 5% Rh 220 93. 6 89. 4 134 2Py = 2-pyrrolidinone ; n/d = not detected ; *reaction was conducted at 2000 psig. | |
With hydrogen at 200℃; for 4h; | 6 Example 6: N-methyl Succinimide Hydrogenation Approximately 5.0 grams (g) of the specified catalyst is charged into a reactor equipped with a magnetic stirrer. Approximately 50.0 g of solid NMS is utilized a feedstock and is provided to the reactor. The reaction is conducted under 1500 psig constant H2 pressure at a stir rate of about 1000 rpm. After 4 hrs, the resulting gas and liquid components are analyzed for determination of NMS conversion and product selectivity. The results of the determinations are indicated in Table 5 for each of the indicated catalysts and reaction temperatures. TABLE 5: Catalyst Based Hydrogenation Selectivities molar% (of Catalyst No. Temp. % of NMS NMP/2-pyrrolidinone theoretical) Yield (from Table 2) (C) Converted (Mole Ratio) of NMP 1 200 <1 0.6 n/d 2 200 7 6. 8 25 3 200 3 3 10 4 200 65 55.9 65 6757-09-1 200 84 69. 3 10 ESCAT-268 200 26 25. 7 >90 ESCAT-340 200 45 41. 8 149 ESCAT-140 200 15 12. 4 48 ESCAT-440 200 96 34. 3 1. 5 ESCAT-440 150 75 42. 2 6. 5 ESCAT-440 120 39 19 n/d ESCAT-340 220 50. 2 50. 2 70 ESCAT-268 220 35. 5 35. 5 n/d Co-0138 E 1/16 3F 200 58. 6 32. 0 18 G106BAN5% Rh 220 95. 8 90. 8 142 * ESCAT-340 200 40.4 38.0 n/d G 106 B/W 5% Rh 220 93. 6 89. 4 134 2Py = 2-pyrrolidinone ; n/d = not detected ; *reaction was conducted at 2000 psig. | |
With hydrogen at 200 - 220℃; for 4h; | 6 Example 6: N-methyl Succinimide Hydrogenation Approximately 5.0 grams (g) of the specified catalyst is charged into a reactor equipped with a magnetic stirrer. Approximately 50.0 g of solid NMS is utilized a feedstock and is provided to the reactor. The reaction is conducted under 1500 psig constant H2 pressure at a stir rate of about 1000 rpm. After 4 hrs, the resulting gas and liquid components are analyzed for determination of NMS conversion and product selectivity. The results of the determinations are indicated in Table 5 for each of the indicated catalysts and reaction temperatures. TABLE 5: Catalyst Based Hydrogenation Selectivities molar% (of Catalyst No. Temp. % of NMS NMP/2-pyrrolidinone theoretical) Yield (from Table 2) (C) Converted (Mole Ratio) of NMP 1 200 <1 0.6 n/d 2 200 7 6. 8 25 3 200 3 3 10 4 200 65 55.9 65 6757-09-1 200 84 69. 3 10 ESCAT-268 200 26 25. 7 >90 ESCAT-340 200 45 41. 8 149 ESCAT-140 200 15 12. 4 48 ESCAT-440 200 96 34. 3 1. 5 ESCAT-440 150 75 42. 2 6. 5 ESCAT-440 120 39 19 n/d ESCAT-340 220 50. 2 50. 2 70 ESCAT-268 220 35. 5 35. 5 n/d Co-0138 E 1/16 3F 200 58. 6 32. 0 18 G106BAN5% Rh 220 95. 8 90. 8 142 * ESCAT-340 200 40.4 38.0 n/d G 106 B/W 5% Rh 220 93. 6 89. 4 134 2Py = 2-pyrrolidinone ; n/d = not detected ; *reaction was conducted at 2000 psig. |
With hydrogen at 200 - 220℃; for 4h; | 6 Example 6: N-methyl Succinimide Hydrogenation Approximately 5.0 grams (g) of the specified catalyst is charged into a reactor equipped with a magnetic stirrer. Approximately 50.0 g of solid NMS is utilized a feedstock and is provided to the reactor. The reaction is conducted under 1500 psig constant H2 pressure at a stir rate of about 1000 rpm. After 4 hrs, the resulting gas and liquid components are analyzed for determination of NMS conversion and product selectivity. The results of the determinations are indicated in Table 5 for each of the indicated catalysts and reaction temperatures. TABLE 5: Catalyst Based Hydrogenation Selectivities molar% (of Catalyst No. Temp. % of NMS NMP/2-pyrrolidinone theoretical) Yield (from Table 2) (C) Converted (Mole Ratio) of NMP 1 200 <1 0.6 n/d 2 200 7 6. 8 25 3 200 3 3 10 4 200 65 55.9 65 6757-09-1 200 84 69. 3 10 ESCAT-268 200 26 25. 7 >90 ESCAT-340 200 45 41. 8 149 ESCAT-140 200 15 12. 4 48 ESCAT-440 200 96 34. 3 1. 5 ESCAT-440 150 75 42. 2 6. 5 ESCAT-440 120 39 19 n/d ESCAT-340 220 50. 2 50. 2 70 ESCAT-268 220 35. 5 35. 5 n/d Co-0138 E 1/16 3F 200 58. 6 32. 0 18 G106BAN5% Rh 220 95. 8 90. 8 142 * ESCAT-340 200 40.4 38.0 n/d G 106 B/W 5% Rh 220 93. 6 89. 4 134 2Py = 2-pyrrolidinone ; n/d = not detected ; *reaction was conducted at 2000 psig. | |
With hydrogen at 220℃; for 4h; | 6 Example 6: N-methyl Succinimide Hydrogenation Approximately 5.0 grams (g) of the specified catalyst is charged into a reactor equipped with a magnetic stirrer. Approximately 50.0 g of solid NMS is utilized a feedstock and is provided to the reactor. The reaction is conducted under 1500 psig constant H2 pressure at a stir rate of about 1000 rpm. After 4 hrs, the resulting gas and liquid components are analyzed for determination of NMS conversion and product selectivity. The results of the determinations are indicated in Table 5 for each of the indicated catalysts and reaction temperatures. TABLE 5: Catalyst Based Hydrogenation Selectivities molar% (of Catalyst No. Temp. % of NMS NMP/2-pyrrolidinone theoretical) Yield (from Table 2) (C) Converted (Mole Ratio) of NMP 1 200 <1 0.6 n/d 2 200 7 6. 8 25 3 200 3 3 10 4 200 65 55.9 65 6757-09-1 200 84 69. 3 10 ESCAT-268 200 26 25. 7 >90 ESCAT-340 200 45 41. 8 149 ESCAT-140 200 15 12. 4 48 ESCAT-440 200 96 34. 3 1. 5 ESCAT-440 150 75 42. 2 6. 5 ESCAT-440 120 39 19 n/d ESCAT-340 220 50. 2 50. 2 70 ESCAT-268 220 35. 5 35. 5 n/d Co-0138 E 1/16 3F 200 58. 6 32. 0 18 G106BAN5% Rh 220 95. 8 90. 8 142 * ESCAT-340 200 40.4 38.0 n/d G 106 B/W 5% Rh 220 93. 6 89. 4 134 2Py = 2-pyrrolidinone ; n/d = not detected ; *reaction was conducted at 2000 psig. | |
With hydrogen at 120 - 200℃; for 4h; | 6 Example 6: N-methyl Succinimide Hydrogenation Approximately 5.0 grams (g) of the specified catalyst is charged into a reactor equipped with a magnetic stirrer. Approximately 50.0 g of solid NMS is utilized a feedstock and is provided to the reactor. The reaction is conducted under 1500 psig constant H2 pressure at a stir rate of about 1000 rpm. After 4 hrs, the resulting gas and liquid components are analyzed for determination of NMS conversion and product selectivity. The results of the determinations are indicated in Table 5 for each of the indicated catalysts and reaction temperatures. TABLE 5: Catalyst Based Hydrogenation Selectivities molar% (of Catalyst No. Temp. % of NMS NMP/2-pyrrolidinone theoretical) Yield (from Table 2) (C) Converted (Mole Ratio) of NMP 1 200 <1 0.6 n/d 2 200 7 6. 8 25 3 200 3 3 10 4 200 65 55.9 65 6757-09-1 200 84 69. 3 10 ESCAT-268 200 26 25. 7 >90 ESCAT-340 200 45 41. 8 149 ESCAT-140 200 15 12. 4 48 ESCAT-440 200 96 34. 3 1. 5 ESCAT-440 150 75 42. 2 6. 5 ESCAT-440 120 39 19 n/d ESCAT-340 220 50. 2 50. 2 70 ESCAT-268 220 35. 5 35. 5 n/d Co-0138 E 1/16 3F 200 58. 6 32. 0 18 G106BAN5% Rh 220 95. 8 90. 8 142 * ESCAT-340 200 40.4 38.0 n/d G 106 B/W 5% Rh 220 93. 6 89. 4 134 2Py = 2-pyrrolidinone ; n/d = not detected ; *reaction was conducted at 2000 psig. | |
With hydrogen at 200℃; for 4h; | 6 Example 6: N-methyl Succinimide Hydrogenation Approximately 5.0 grams (g) of the specified catalyst is charged into a reactor equipped with a magnetic stirrer. Approximately 50.0 g of solid NMS is utilized a feedstock and is provided to the reactor. The reaction is conducted under 1500 psig constant H2 pressure at a stir rate of about 1000 rpm. After 4 hrs, the resulting gas and liquid components are analyzed for determination of NMS conversion and product selectivity. The results of the determinations are indicated in Table 5 for each of the indicated catalysts and reaction temperatures. TABLE 5: Catalyst Based Hydrogenation Selectivities molar% (of Catalyst No. Temp. % of NMS NMP/2-pyrrolidinone theoretical) Yield (from Table 2) (C) Converted (Mole Ratio) of NMP 1 200 <1 0.6 n/d 2 200 7 6. 8 25 3 200 3 3 10 4 200 65 55.9 65 6757-09-1 200 84 69. 3 10 ESCAT-268 200 26 25. 7 >90 ESCAT-340 200 45 41. 8 149 ESCAT-140 200 15 12. 4 48 ESCAT-440 200 96 34. 3 1. 5 ESCAT-440 150 75 42. 2 6. 5 ESCAT-440 120 39 19 n/d ESCAT-340 220 50. 2 50. 2 70 ESCAT-268 220 35. 5 35. 5 n/d Co-0138 E 1/16 3F 200 58. 6 32. 0 18 G106BAN5% Rh 220 95. 8 90. 8 142 * ESCAT-340 200 40.4 38.0 n/d G 106 B/W 5% Rh 220 93. 6 89. 4 134 2Py = 2-pyrrolidinone ; n/d = not detected ; *reaction was conducted at 2000 psig. | |
With hydrogen at 200℃; for 4h; | 6 Example 6: N-methyl Succinimide Hydrogenation Approximately 5.0 grams (g) of the specified catalyst is charged into a reactor equipped with a magnetic stirrer. Approximately 50.0 g of solid NMS is utilized a feedstock and is provided to the reactor. The reaction is conducted under 1500 psig constant H2 pressure at a stir rate of about 1000 rpm. After 4 hrs, the resulting gas and liquid components are analyzed for determination of NMS conversion and product selectivity. The results of the determinations are indicated in Table 5 for each of the indicated catalysts and reaction temperatures. TABLE 5: Catalyst Based Hydrogenation Selectivities molar% (of Catalyst No. Temp. % of NMS NMP/2-pyrrolidinone theoretical) Yield (from Table 2) (C) Converted (Mole Ratio) of NMP 1 200 <1 0.6 n/d 2 200 7 6. 8 25 3 200 3 3 10 4 200 65 55.9 65 6757-09-1 200 84 69. 3 10 ESCAT-268 200 26 25. 7 >90 ESCAT-340 200 45 41. 8 149 ESCAT-140 200 15 12. 4 48 ESCAT-440 200 96 34. 3 1. 5 ESCAT-440 150 75 42. 2 6. 5 ESCAT-440 120 39 19 n/d ESCAT-340 220 50. 2 50. 2 70 ESCAT-268 220 35. 5 35. 5 n/d Co-0138 E 1/16 3F 200 58. 6 32. 0 18 G106BAN5% Rh 220 95. 8 90. 8 142 * ESCAT-340 200 40.4 38.0 n/d G 106 B/W 5% Rh 220 93. 6 89. 4 134 2Py = 2-pyrrolidinone ; n/d = not detected ; *reaction was conducted at 2000 psig. | |
With hydrogen at 200℃; for 4h; | 6 Example 6: N-methyl Succinimide Hydrogenation Approximately 5.0 grams (g) of the specified catalyst is charged into a reactor equipped with a magnetic stirrer. Approximately 50.0 g of solid NMS is utilized a feedstock and is provided to the reactor. The reaction is conducted under 1500 psig constant H2 pressure at a stir rate of about 1000 rpm. After 4 hrs, the resulting gas and liquid components are analyzed for determination of NMS conversion and product selectivity. The results of the determinations are indicated in Table 5 for each of the indicated catalysts and reaction temperatures. TABLE 5: Catalyst Based Hydrogenation Selectivities molar% (of Catalyst No. Temp. % of NMS NMP/2-pyrrolidinone theoretical) Yield (from Table 2) (C) Converted (Mole Ratio) of NMP 1 200 <1 0.6 n/d 2 200 7 6. 8 25 3 200 3 3 10 4 200 65 55.9 65 6757-09-1 200 84 69. 3 10 ESCAT-268 200 26 25. 7 >90 ESCAT-340 200 45 41. 8 149 ESCAT-140 200 15 12. 4 48 ESCAT-440 200 96 34. 3 1. 5 ESCAT-440 150 75 42. 2 6. 5 ESCAT-440 120 39 19 n/d ESCAT-340 220 50. 2 50. 2 70 ESCAT-268 220 35. 5 35. 5 n/d Co-0138 E 1/16 3F 200 58. 6 32. 0 18 G106BAN5% Rh 220 95. 8 90. 8 142 * ESCAT-340 200 40.4 38.0 n/d G 106 B/W 5% Rh 220 93. 6 89. 4 134 2Py = 2-pyrrolidinone ; n/d = not detected ; *reaction was conducted at 2000 psig. | |
With hydrogen at 200℃; for 4h; | 6 Example 6: N-methyl Succinimide Hydrogenation Approximately 5.0 grams (g) of the specified catalyst is charged into a reactor equipped with a magnetic stirrer. Approximately 50.0 g of solid NMS is utilized a feedstock and is provided to the reactor. The reaction is conducted under 1500 psig constant H2 pressure at a stir rate of about 1000 rpm. After 4 hrs, the resulting gas and liquid components are analyzed for determination of NMS conversion and product selectivity. The results of the determinations are indicated in Table 5 for each of the indicated catalysts and reaction temperatures. TABLE 5: Catalyst Based Hydrogenation Selectivities molar% (of Catalyst No. Temp. % of NMS NMP/2-pyrrolidinone theoretical) Yield (from Table 2) (C) Converted (Mole Ratio) of NMP 1 200 <1 0.6 n/d 2 200 7 6. 8 25 3 200 3 3 10 4 200 65 55.9 65 6757-09-1 200 84 69. 3 10 ESCAT-268 200 26 25. 7 >90 ESCAT-340 200 45 41. 8 149 ESCAT-140 200 15 12. 4 48 ESCAT-440 200 96 34. 3 1. 5 ESCAT-440 150 75 42. 2 6. 5 ESCAT-440 120 39 19 n/d ESCAT-340 220 50. 2 50. 2 70 ESCAT-268 220 35. 5 35. 5 n/d Co-0138 E 1/16 3F 200 58. 6 32. 0 18 G106BAN5% Rh 220 95. 8 90. 8 142 * ESCAT-340 200 40.4 38.0 n/d G 106 B/W 5% Rh 220 93. 6 89. 4 134 2Py = 2-pyrrolidinone ; n/d = not detected ; *reaction was conducted at 2000 psig. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In methanol; N-methylphthalimide | 2 Example 2 Example 2 A stainless steel autoclave with a capacity of 250 ml, equipped as described above, is loaded with 11 g of succinimide, 100 g. of dimethylcarbonate, 35.5 g. of methanol and 0.38 g of potassium carbonate. The stirrer is switched on and the autoclave is heated until the temperature inside the reactor reaches 170° C. During the reaction, CO2 is produced and the internal pressure of the reactor builds up to a maximum value of 25 atmospheres. After approximately 50 minutes of reaction at a temperature of 170° C., 99.5% of the phthalimide has been converted and the selectivity in N-methyl phthalimide is 95%. Once the reaction period has finished the autoclave is allowed to cool to environmental temperature, and the methanol and the dimethyl carbonate is taken away for distillation. The residue is taken with 60 ml of dimethylcarbonate and is filtered to eliminate the catalyst. The solvent is eliminated for distillation and 12.5 g of N-methyl succinimide is obtained with a gaschromatography strength of 94% which is purified for recrystallisation by a chloroform-hexane mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With n-butyllithium In tetrahydrofuran; hexane | 10.i Preparation of 3-[2-(3-t-Butylamino-2-hydroxypropoxy)-6-methoxyphenyl]-6-hydrazinopyridazine. i. A solution of 1,3-dimethoxybenzene (89 ml, 0.064 mole) in dry tetrahydrofuran (480 ml) was added during 10 minutes to a stirred solution of n-butyl lithium in hexane (350 ml, 0.6 mole) under an atmosphere of nitrogen. The stirred mixture was heated under reflux for 90 minutes, then a solution of N-methyl succinimide (77 g, 0.68 mole) in dry tetrahydrofuran was added dropwise. The mixture was heated under reflux for an additional hour and then allowed to stand overnight. The supernatant was decanted and the residue was hydrolyzed with 20% aqueous ammonium chloride solution (280 ml) and extracted with chloroform. The washed and dried extract was evaporated and the residue recrystallized from ethyl acetate to give N-methyl 3-(2,6-dimethoxybenzoyl)propionamide (15 g, 10%, m.p. 134°). (Found: C. 62.18; H, 6.73; N, 5.54; C13 H17 NO4 requires C, 62.14; H, 6.82; N, 5.57%). |
10% | With n-butyllithium In tetrahydrofuran; hexane | 7.i Preparation of 6-[2-(3-t-Butylamino-2-hydroxypropoxy)-6-methoxyphenyl]-3(2H)-pyridazinethione (i) A solution of 1,3-dimethoxybenzene (89 ml, 0.064 mole) in dry tetrahydrofuran (480 ml) was added during 10 minutes to a stirred solution of n-butyl lithium in hexane (350 ml, 0.6 mole) under an atmosphere of nitrogen. The stirred mixture was heated under reflux for 90 minutes, then a solution of N-methyl succinimide (77 g, 0.68 mole) in dry tetrahydrofuran was added dropwise. The mixture was heated under reflux for an additional hour and then allowed to stand overnight. The supernatant was decanted and the residue was hydrolyzed with 20% aqueous ammonium chloride solution (280 ml) and extracted with chloroform. The washed and dried extract was evaporated and the residue recrystallized from ethyl acetate to give N-methyl 3-(2,6-dimethoxybenzoyl)-propionamide (15 g, 10%, m.p. 134°). (Found: C, 62.18; H, 6.73; N, 5.54; C13 H17 NO4 requires C, 62.14; H, 6.82; N, 5.57%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium chloride In tetrahydrofuran; benzene | 12.i 3-[3-(3-t-Butylamino-2-hydroxypropoxy)-2-methoxyphenyl]-6-hydrazinopyridazine (i) A solution of 2,3-dimethoxylithiobenzene in tetrahydrofuran was added dropwise to a cold stirred solution of N-methylsuccinimide in benzene. The mixture was stirred overnight at room temperature, then treated with ammonium chloride solution and extracted with chloroform. The washed and dried extract was evaporated to low volume to give a mixture of the tautomers N-methyl 3-(2,3-dimethoxybenzoyl)propionamide and N-methyl 2-(2,3-dimethoxyphenyl)-2-hydroxy-5-pyrrolidinone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With tetrabutyl ammonium fluoride In tetrahydrofuran at -78 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: N-methylsuccinimide With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; Inert atmosphere; Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at -78℃; Inert atmosphere; | |
85% | With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; Inert atmosphere; | |
70% | Stage #1: N-methylsuccinimide With C6H18NSi2(1-)*HNa In tetrahydrofuran at -78℃; for 1.5h; Stage #2: di-<i>tert</i>-butyl dicarbonate With acetyl chloride In tetrahydrofuran at -78℃; for 2h; |
0.63 g | Stage #1: N-methylsuccinimide With sodium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.66667h; Inert atmosphere; Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at -78℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With lithium triethylborohydride In tetrahydrofuran at -78℃; for 1h; | |
With diisobutylaluminium hydride In hexane; dichloromethane at -78℃; for 1h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | Stage #1: N-methylsuccinimide With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 0.166667h; Inert atmosphere; Stage #2: benzyl chloroformate In tetrahydrofuran at -78℃; for 1h; Inert atmosphere; | 3. General Procedure A - Benzylcarboxylation General procedure: Based on the procedure by Bogle.1 To a solution of the amide 11 in THF at - 78 °C was added dropwise a solution of lithium hexamethyldisilazide (1.0 M in THF, 2.1 eq) and the mixture stirred at - 78 °C for 10 min. Benzylchloroformate (1.0 eq) was then added dropwise and the resulting mixture stirred at - 78 °C for 1 h. The reaction was quenched at - 78 °C with aq. NH4Cl (10 mL) and allowed to warm to room temperature. The aqueous layer was extracted with EtOAc (3 x 25 mL), the combined organic extracts washed with brine (10 mL), dried (Na2SO4) and concentrated in vacuo. The crude mixture was loaded onto a silica column and eluted with a PE/ethyl acetate mixture to yield the ester 12. NB. Deviations from this procedure are noted. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With silica gel; pyridinium chlorochromate In dichloromethane at 20℃; for 2h; Sonication; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Stage #1: N-benzyl-N-(1-cyclohexyl)-3-(phenylprop-2-ynyl)-hydroxylamine With silver tetrafluoroborate; copper(l) chloride In dichloromethane at 20℃; for 27h; Inert atmosphere; Stage #2: N-methylsuccinimide In 5,5-dimethyl-1,3-cyclohexadiene at 145℃; for 3h; Inert atmosphere; diastereoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With titanium(IV) oxide In acetonitrile Irradiation; | Photochemistry and photocatalysis: N-methylmaleimide (NMI) and maleimide (MI) Table 2 lists the yields of the various reactants and products of the irradiations of PAA with and without titania for both NMI and also MI. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: N-methylsuccinimide With n-butyllithium; lithium diisopropyl amide In tetrahydrofuran; hexane at -78 - 0℃; Inert atmosphere; Stage #2: 2-chloromethyl-3-chloroprop-1-ene In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; | General procedure: To a cold (-78 °C, acetone/solid CO2) and magnetically stirred solution of diisopropylamine (0.8 mL, 5.7 mmol) in anhydrous THF (15 mL) under an argon atmosphere, a solution of n-BuLi in hexanes (2.3 mL, 2.5 M, 5.7 mmol) was added dropwise.When n-BuLi addition was finished, the solution was allowed to warm to 0 °C for 1 h, it was cooled again to -78 °C, and a solution of 11 (690 mg, 2.38 mmol) in anhydrous THF (8 mL) was added dropwise. Then, the solution was stirred a -78 °C for 15 min and allowed to warm to 0 °C for 1 h. The solution was again cooled to -78 °C and 3-chloro-2-(chloromethyl)-1-propene (0.36mL 96% content, 373 mg, 3.0 mmol) was added dropwise. The reaction mixture was allowed towarm to room temperature and it was stirred for 3 days at this temperature. The mixture was made acidic with aqueous 1N HCl (10 mL) and was extracted with Et2O (3×50 mL). The combined organic extracts were dried (anhydrous Na2SO4) and concentrated in vacuo to give abrown waxy residue (960 mg) that was subjected to column chromatography (silica gel 35-70μm, 30 g, hexane/EtOAc mixtures) to give on elution with hexane/EtOAc 9:1, product 12 (515mg, 63% yield) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: methylmagnesium chloride With bis(cyclopentadienyl)titanium dichloride In tetrahydrofuran; diethyl ether at -10 - 0℃; for 1h; Schlenk technique; Inert atmosphere; Stage #2: N-methylsuccinimide In tetrahydrofuran at 65℃; for 22h; Schlenk technique; Inert atmosphere; | Experimental procedures and spectroscopic characterization: Pyrroles 3a-r General procedure: Dichlorotitanocene [Cp2Ti(Cl)2] (4 mmol with respect to the corresponding succinimide)was introduced in a Schlenk tube and distilled Et2O (5 mL) was added under Argon via asyringe. A solution of CH3MgCl in THF [8.25 mmol with respect to Cp2Ti(Cl)2] wasadded and the mixture stirred for 1 h at -10 0C while slowly warming to 0 0C, affordingan orange solution of the Petasis reagent. The solvent was then removed under vaccumand distilled THF (8 mL) was added. Succinimide (1a-r) (1 mmol) in distilled THF (2mL) was introduced to the mixture via a syringe and the solution was heated at 65 0C tillthe complete disappearance of the starting material (note1). 0.05 mmol PTSA (5%) indistilled THF (1 mL) was added and the solution was allowed to stirr at r.t. for 1 h(complete isomerization).The mixture was then diluted with petroleum ether (100-150 mL) and allowed to standuntil precipitation was complete. Filtration and removal of the solvent in vacuo left aresidue which was purified by flash column chromatography on Et3N pre-treated silicagel using petroleum ether/EtOAc (10:1 to 5:1) as eluent to afford pure pyrrole products.Note1: TLC test: (petroleum ether/EtOAc 90:10); Approximately 10 to 22 hours ofheating at 65 0C, depending on the succinimide used. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: N-methylsuccinimide With thionyl chloride at 10 - 70℃; Stage #2: With water In toluene at 75 - 80℃; for 6h; | 2 COMPARATIVE EXAMPLE 2 COMPARATIVE EXAMPLE 2 243.1 g [2.02 mmol] of thionyl chloride (content: 99%) are initially charged at 10° C., and 150 g [1.14 mol] of N-methylsuccinamide are added in portions. After the reaction has ended, the cooled liquid reaction mixture is metered into a reactor which has been initially charged with 412 g of thionyl chloride (content: 99%; 3.42 mol) at 65-70° C. In the course of metered addition, the temperature is kept within the range of 65-70° C. Evolution of gas sets in, becoming more intense and decreasing again after a while. The reaction mixture is concentrated on a rotary evaporator. The residue (thick dark brown oil) is admixed with 190 ml of toluene, 161 g of water and 9.2 g of Aliquat 336, and heated to 75-80° C. for approx. 6 hours. The mixture is then allowed to cool to room temperature, and the precipitated solids are filtered off with suction and washed with water and ethanol Drying results in 118 g of dark green solids which, according to HPLC analysis, consist to an extent of 98.2 w % of the compound (I-1), corresponding to a yield of 72% of theory. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | at 110℃; for 0.0166667h; Microwave irradiation; Green chemistry; | 4 Succinic anhydride (4.0 mmol) and methylamine hydrochloride (4.5 mmol) were charged into a 25 ml round bottomed flask and placed in a milestone microwave reactor fitted with a condenser. The mixture was irradiated at 110° C. by an energy input of 900 W for 1 minute. The reaction mixture was being cooled to room temperature and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude product was purified by crystallization with n-hexane to yield pure N-methyl succinimide (NMS) in 90% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-methylsuccinimide With lithium hexamethyldisilazane In tetrahydrofuran; toluene at -78℃; for 1h; Stage #2: formic acid ethyl ester In tetrahydrofuran; toluene at -78 - 0℃; | 1 (3E)-3-(hydroxymethylene)-1-methyl-pyrrolidine-2,5-dione II-7 tert-butyl (3Z)-3-(hydroxymethylene)-5-methyl-2-oxo-pyrrolidine-1-carboxylate II-6 [0122] [0123] tert-Butyl (3Z)-3-(hydroxymethylene)-5-methyl-2-oxo-pyrrolidine-1-carboxylate (as prepared in WO 2007098826) (100 mg, 0.50 mmol) in THF (1 mL) was cooled to -78° C. and potassium bis(trimethylsilyl)amide (0.5 M in toluene, 1.51 mL) was added. After 1 h, ethyl formate was added (0.081 mL, 1.0 mmol) The solution was let to warm up to 0° C. and 1N HCl was added. The solution was extracted with ethyl acetate, washed with brine, dried and concentrated to give the desired compound as colourless oil which was used without purification for the next step. LCMS (Method A) 0.73 min; ES-226 (M-H+). [0124] A similar procedure was used to prepare the following compounds: A similar procedure was used to prepare the following compounds: [0125] (3E)-3-(hydroxymethylene)-1-methyl-pyrrolidine-2,5-dione II-7 was prepared from 1-methyl-pyrrolidine-2,5-dione (commercially available) using lithium bis(trimethylsilyl)amide as a base; LCMS (Method D) 0.17 min; ES-140 (M-H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: N-methylsuccinimide With C6H18NSi2(1-)*HNa In tetrahydrofuran at -78℃; for 1.5h; Stage #2: chloroformic acid ethyl ester In tetrahydrofuran at -78℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | In tetrahydrofuran at -20℃; for 12h; Autoclave; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | In tetrahydrofuran at -20℃; for 12h; Autoclave; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | In tetrahydrofuran at -20℃; for 12h; Autoclave; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In tetrahydrofuran at -20℃; for 12h; Autoclave; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In tetrahydrofuran at -20℃; for 12h; Autoclave; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In tetrahydrofuran at -20℃; for 12h; Autoclave; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | In tetrahydrofuran at -20℃; for 12h; Autoclave; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 12h; | 4-(Methoxymethoxy)-2-methyl-3a,4,9,9a-tetrahydro-4,9[1',2']benzeno-1H-benz[f]isoindole-1,3(2H)-dione (17) A solution of 16 (8.20 g, 34.2 mmol) and N-methylmaleimide 1 (3.80 g, 34.2 mmol) in xylene (350 mL)was heated at 140 °C for 12 h. The solution was allowed to cool to room temperature and was concentrated in vacuo to give adduct 17 as yellow solid (11.6 g, 97% yield). An analytical sample of 17(83 mg) was obtained as yellow solid by crystallization of a sample of the above product (200 mg) froma mixture of hexane (3 mL) and EtOAc (1 mL). m.p. 168-169 °C (EtOAc/hexane); 1H-NMR (400 MHz,CDCl3): δ = 2.50 (s, 3H, N-CH3), 3.31 (dd, 3J(H,H) = 8.4 Hz, 3J(H,H) = 3.2 Hz, 1H, 9a-H), 3.44 (d, 3J(H,H)= 8.4 Hz, 1H, 3a-H), 3.82 (s, 3H, OCH3), 4.70 (d, 3J(H,H) = 3.2 Hz, 1H, 9-H), 5.53 (d, 2J(H,H) = 5.4 Hz,1H) and 5.55 (d, 2J(H,H) = 5.4 Hz, 1H) (OCH2O), 7.12 (pseudo dt, 4J(H,H) = 1.2 Hz, 3J(H,H) = 7.4 Hz, 1H,7-H), 7.17 (overlapped pseudo dt, 4J(H,H) = 1.2 Hz, 3J(H,H) = 7.2 Hz, 1H, 6-H), 7.20 (overlapped pseudodt, 4J(H,H) = 1.2 Hz, 3J(H,H) = 7.3 Hz, 1H, 12-H), 7.21-7.26 (complex signal, 2H, 8-H and 13-H), 7.38(dd, 3J(H,H) = 7.4 Hz, 4J(H,H) = 1.4 Hz, 1H, 11-H), 7.65 (dd, 3J(H,H) = 7.2 Hz, 4J(H,H) = 1.2 Hz, 1H, 5-H),7.68 ppm (dd, 3J(H,H) = 7.6 Hz, 4J(H,H) = 1.2 Hz, 1H, 14-H); 13C-NMR (100.6 MHz, CDCl3): δ = 24.3(CH3, N-CH3), 44.6 (CH, C9), 47.4 (CH, C3a), 47.9 (CH, C9a), 57.1 (CH3, OCH3), 81.8 (C, C4), 93.8 (CH2,OCH2O), 121.8 (CH, C5), 122.2 (CH, C14), 124.0 (CH, C11), 124.4 (CH, C8), 126.6 (CH, C13), 126.9 (CH,C12), 127.00 (CH, C7), 127.03 (CH, C6), 136.2 (C, C8a), 139.7 (C, C4a), 140.2 (C, C10), 141.6 (C, C15),174.1 (C, C1), 176.2 ppm (C, C3); IR (ATR): v = 1692 (s), 1457 (m), 1430 (m), 1292 (m), 1276 (m) 1163 (m),1124 (m), 1050 (m), 1013 (m), 963 (m), 771 (m), 738 cm-1 (s); accurate mass measurement: m/z calcd.for C21H19NO4 + Na+: 372.1206; found: 372.1198; elemental analysis calcd. (%) for C21H19NO4: C72.19, H 5.48, N 4.01; found: C 72.08, H 5.42, N 3.79. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 1-Adamantanecarboxylic acid; palladium diacetate; sodium carbonate; p-benzoquinone In 1,1,2-trichloroethane at 100℃; for 24h; Schlenk technique; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
848 mg | Stage #1: 1-bromo-4-butene With magnesium In tetrahydrofuran for 0.5h; Inert atmosphere; Stage #2: N-methylsuccinimide In tetrahydrofuran at -20℃; for 1h; Inert atmosphere; Stage #3: With triethylsilane; boron trifluoride diethyl etherate In dichloromethane at -20 - 0℃; for 0.5h; Inert atmosphere; | Preparation of Lactams 1a-g General procedure: To a solution of magnesium (1.0 M in THF, 22 mL, 23.8 mmmol) was added 4-bromo-1-butene (2.2mL, 22 mmol) under a nitrogen atmosphere. After stirring the mixture for 30 min, the resultingsolution was added to the solution of N-methylphthalimide (1.42 g, 6.38 mmol) in THF (34 mL) at-20 °C and stirred for additional 1 hour at the same temperature. The reaction was quenched byaddition of saturated aqueous NH4Cl (20 mL), and the resulting solution was extracted with EtOAc(30 mL). The organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, andconcentrated in vacuo to give a crude material (1.61 g). To a solution of the crude material (1.61 g) in dichloromethane (68 mL) was added triethylsilane (4.3mL, 27 mmmol) and boron trifluoride diethyl ether complex (3.4 mL, 27 mmol) under a nitrogenatmosphere at -20 °C. The mixture was allowed to warm to 0 °C and stirred for 30 min. The reactionwas quenched by addition of saturated aqueous NaHCO3 (50 mL). The resulting solution wasextracted with EtOAc (60 mL). The organic extracts were washed with brine (50 mL), dried overNa2SO4, filtered, and concentrated in vacuo to give a crude material. This material was purified bycolumn chromatography (silica gel, hexane/EtOAc = 3/1 to 1/1) to give 3a (1.17 g, 5.81 mmol, 85%for 2 steps) as a pale yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: N-methylsuccinimide With bis(cyclopentadienyl)dihydrozirconium; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane at 20℃; Glovebox; Inert atmosphere; Stage #2: With hydrogenchloride In diethyl ether; water for 2h; Glovebox; Inert atmosphere; | 2. Experimental General procedure: In a nitrogen-filled glovebox, to a 15 mL reaction tube equipped with a magnetic stirrer, were added Cp2ZrH2 (0.01mmol, 2.2 mg) as the catalyst, and the appropriate amide (0.2mmol); solvent was added when necessary. HBpin (3 equiv. peramide functional group) was then added, and the reaction tube was taken out from the glovebox and stirred at room temperature for 12-48 h. The resultant crude amines were either isolated using silica gel flash chromatography, or acidified by stirring with HCl in Et2O (2 mL, 1N) for 2 h, after which time precipitation was observed. Then, the reaction solution was transferred to a centrifuge tube and centrifuged three times. The supernatant was removed and the resulting solid was dried inan oven at 80 °C for several hours to obtain the HCl salt of the amine. |
> 99 %Spectr. | With phenylsilane; (bis[(2-diphenylphosphino)phenyl]ether)CoCl2; lithium triethylborohydride In tetrahydrofuran; benzene-d6 at 60℃; for 5h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 18% 2: 13% 3: 20% 4: 32% | Stage #1: N-methylsuccinimide; benzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 25℃; for 0.25h; | Reductive Coupling of 1a with 2a (Workup a). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: N-methylsuccinimide; benzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In benzene for 0.5h; Dean-Stark; Reflux; | Reductive Coupling of 1a with 2a (Workup b). To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. The reductive coupling and following workup with 1 M HCl was carried out as described above. The crude product mixture and p-TsOH (10 mg) were dissolved in benzene (10 mL). The solution was refluxed using Dean-Stark apparatus for 30 min. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexanes-EtOAc) to give 5a in 80% yield. |
80% | Stage #1: N-methylsuccinimide; benzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In benzene for 0.5h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 73% 2: 10% | Stage #1: N-methylsuccinimide; benzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 25℃; for 3h; | Reductive Coupling of 1a with 2a (Workup a). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 12% 2: 54% | Stage #1: N-methylsuccinimide; benzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In benzene for 0.5h; Dean-Stark; Reflux; | Reductive Coupling of 1a with 2a (Workup b). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. The reductive coupling and following workup with 1 M HCl was carried out as described above. The crude product mixture and p-TsOH (10 mg) were dissolved in benzene (10 mL). The solution was refluxed using Dean-Stark apparatus for 30 min. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexanes-EtOAc) to give 5a in 80% yield. |
1: 12% 2: 54% | Stage #1: N-methylsuccinimide; benzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In benzene for 1h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 14% 2: 31% 3: 28% | Stage #1: N-methylsuccinimide; benzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; | Reductive Coupling of 1a with 2a (Workup a). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: N-methylsuccinimide; 4,4'-Difluorobenzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 0 - 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In benzene for 0.5h; Dean-Stark; Reflux; | Reductive Coupling of 1a with 2a (Workup b). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. The reductive coupling and following workup with 1 M HCl was carried out as described above. The crude product mixture and p-TsOH (10 mg) were dissolved in benzene (10 mL). The solution was refluxed using Dean-Stark apparatus for 30 min. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexanes-EtOAc) to give 5a in 80% yield. |
81% | Stage #1: N-methylsuccinimide; 4,4'-Difluorobenzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 0℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In benzene for 0.5h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 10% 2: 61% | Stage #1: N-methylsuccinimide; 4,4'-Difluorobenzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In benzene for 0.5h; Dean-Stark; Reflux; | Reductive Coupling of 1a with 2a (Workup b). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. The reductive coupling and following workup with 1 M HCl was carried out as described above. The crude product mixture and p-TsOH (10 mg) were dissolved in benzene (10 mL). The solution was refluxed using Dean-Stark apparatus for 30 min. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexanes-EtOAc) to give 5a in 80% yield. |
1: 10% 2: 61% | Stage #1: N-methylsuccinimide; 4,4'-Difluorobenzophenone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In benzene for 1h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 17% 2: 58% | Stage #1: N-methylsuccinimide; bis(p-methoxyphenyl)methanone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In benzene for 0.5h; Dean-Stark; Reflux; | Reductive Coupling of 1a with 2a (Workup b). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. The reductive coupling and following workup with 1 M HCl was carried out as described above. The crude product mixture and p-TsOH (10 mg) were dissolved in benzene (10 mL). The solution was refluxed using Dean-Stark apparatus for 30 min. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexanes-EtOAc) to give 5a in 80% yield. |
1: 17% 2: 58% | Stage #1: N-methylsuccinimide; bis(p-methoxyphenyl)methanone With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In benzene for 1h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 73% 2: 8% | Stage #1: N-methylsuccinimide; bis(p-methoxyphenyl)methanone With titanium tetrachloride; zinc In tetrahydrofuran at -10℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at -10 - 25℃; for 0.5h; Stage #3: With toluene-4-sulfonic acid In benzene for 0.5h; Dean-Stark; Reflux; | Reductive Coupling of 1a with 2a (Workup b). General procedure: To a solution of 1a (1 mmol), 2a (2 mmol), and zinc powder (4 mmol) in THF (10 mL) was added TiCl4 (2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1 M HCl (20 mL) at 0 °C and the mixture was stirred for 15 min at 25 °C. The mixture was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed, the residue was purified by column chromatography on silica gel to give 3a-6a. The reductive coupling and following workup with 1 M HCl was carried out as described above. The crude product mixture and p-TsOH (10 mg) were dissolved in benzene (10 mL). The solution was refluxed using Dean-Stark apparatus for 30 min. After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel (hexanes-EtOAc) to give 5a in 80% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: N-methylsuccinimide; bis(p-methoxyphenyl)methanone With titanium tetrachloride; zinc In tetrahydrofuran at -10℃; for 12h; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In benzene for 0.5h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: N-methylsuccinimide; 10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-one With titanium tetrachloride; zinc In tetrahydrofuran at 30℃; Stage #2: With hydrogenchloride In tetrahydrofuran; water at 25℃; for 0.25h; Stage #3: With toluene-4-sulfonic acid In toluene for 2h; Reflux; Dean-Stark; | 4.3. Typical procedure for the reductive coupling of 1a with 2a(Table 1, run 1) General procedure: To a solution of 1a (113 mg, 1 mmol), 2a (384 mg, 2 mmol), and zinc powder (0.26 g, 4 mmol) in THF (10 mL) was added TiCl4 (0.22 mL, 2 mmol) dropwise at 0 °C and then the dark blue suspension was stirred for 12 h at this temperature. To the mixture was added 1M HCl (20 mL) and the mixture was stirred for 15 min at 25 °C. The clear solution was extracted with ethyl acetate three times. The organic layer was washed with aqueous NaCl and dried over MgSO4. After the solvent was removed in vacuo, the residuewas dissolved in benzene (10 mL). The solution was refluxed in the presence of cat. p-TsOH for 30 min using Dean-Stark apparatus.After the solvent was removed in vacuo, the residue was purified by column chromatography on silica gel to give 3a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; sodium acetate In 1,2-dichloro-ethane at 100℃; for 6h; Inert atmosphere; Schlenk technique; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; sodium acetate In 1,2-dichloro-ethane at 100℃; for 6h; Inert atmosphere; Schlenk technique; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; sodium acetate In 1,2-dichloro-ethane at 100℃; for 10h; Inert atmosphere; Schlenk technique; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With silver hexafluoroantimonate; dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer; sodium acetate In 1,2-dichloro-ethane at 100℃; for 8h; Inert atmosphere; Schlenk technique; Sealed tube; | 1 Example 1 Chalcone 1a (0.2 mmol) under nitrogen protection,N-methylmaleimide 2a (0.3 mmol), [Cp*RhCl2]2 (5 mol%), AgSbF6 (20 mol%),Sodium acetate (2 equivalents) and 1,2-dichloroethane (2 mL) were placed in a Schlenk reaction tube and sealed.Heat to 100 ° C and the reaction time was 8 hours.After completion of the reaction, the solvent was removed under reduced pressure, and the title product 3a was obtained by column chromatography, yield 86%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium hydride In tetrahydrofuran at 20 - 85℃; for 12.5h; Inert atmosphere; | 2.1-2.3; 5.1-5.3 Example 2 This embodiment provides a method for preparing a synthetic racemic body (±)-(R, S) -nicotine, which includes the following steps: (1) At room temperature, in a nitrogen atmosphere, first add 1 equivalent of methyl nicotinate and N-methylsuccinimide to the anhydrous tetrahydrofuran solvent, and then add 1.2 equivalent of lithium hydride.The mixture was stirred for 0.5 h to perform a condensation reaction to obtain a first reaction mixture. (2) the first reaction mixture is first stirred at a temperature of 85 ° C. for 12 h;Next, the first reaction mixture is cooled and acidified with 5% hydrochloric acid, and then concentrated hydrochloric acid is added for mixing;Then, the first reaction mixture mixed with concentrated hydrochloric acid was refluxed for 24 h to obtain a second reaction mixture. (3) After the pH of the second reaction mixture is adjusted to 7 with NaOH,Add 3 times the volume of ethyl acetate and separate the layers to obtain an organic extract.Wherein, the layers were separated each time, and the combined organic extracts were dried over sodium sulfate,Filtering and evaporating the solvent to give 4-oxo-4- (3-pyridyl) butanoic acid as a solid material;Next, the solid 4-oxo-4- (3-pyridyl) butyric acid was dissolved in 4 times the equivalent of methanol, and sodium borohydride was added, and the mixture was stirred at room temperature for 12 hours.Concentrated hydrochloric acid was further added for mixing; then, the above mixed solution was refluxed for 12 h to obtain a third reaction mixture. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 3-Bromopyridine With n-butyllithium In diethyl ether at -78℃; for 1h; Inert atmosphere; Stage #2: N-methylsuccinimide In diethyl ether at -78℃; for 1h; Inert atmosphere; | [General Procedure A] 3-(1-Methylpyrrolidin-2-yl)pyridine (7) : At -78 °C, a n-butyllithium solution (4.24 mL,10.6 mmol, 2.5M) was admixed dropwise with a solution of (1.68 g,10.6 mmol) of 3-bromopyridine 5 in absolute diethyl ether (15 mL). The color of the mixture changed to yellow, and a precipitate was formed. After 1 h at -78 °C, a solution of N-Methylsuccinimide 6 (1 g, 8.8 mmol) in 10 mL of absolute tetrahydrofuran was added dropwise to the above mixture. The reaction mixture was stirred for another 1 h at same temperature and then 10 mL THF, followed by the addition of LiAlH4 (836 mg, 22 mmol) at 0 °C was carried and then allowed to stand at room temperature for 2 h. After completion of the reaction it was quenched with brine solution (5 mL) at 0°C and the resulting mixture was filtered. The filtrate was dried over Na2SO4 and evaporated to dryness using a rotary evaporator. The residue was purified using column chromatography on silica gel using a chloroform/methanol gradient (95:5 ratio) to give 0.93 g of 7 (65%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 3-Bromopyridine With n-butyllithium In diethyl ether at -78℃; for 1h; Inert atmosphere; Stage #2: N-methylsuccinimide In diethyl ether at -78℃; for 1h; Inert atmosphere; Stage #3: With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 0 - 20℃; for 2h; Inert atmosphere; | [General Procedure A] 3-(1-Methylpyrrolidin-2-yl)pyridine (7) : At -78 °C, a n-butyllithium solution (4.24 mL,10.6 mmol, 2.5M) was admixed dropwise with a solution of (1.68 g,10.6 mmol) of 3-bromopyridine 5 in absolute diethyl ether (15 mL). The color of the mixture changed to yellow, and a precipitate was formed. After 1 h at -78 °C, a solution of N-Methylsuccinimide 6 (1 g, 8.8 mmol) in 10 mL of absolute tetrahydrofuran was added dropwise to the above mixture. The reaction mixture was stirred for another 1 h at same temperature and then 10 mL THF, followed by the addition of LiAlH4 (836 mg, 22 mmol) at 0 °C was carried and then allowed to stand at room temperature for 2 h. After completion of the reaction it was quenched with brine solution (5 mL) at 0°C and the resulting mixture was filtered. The filtrate was dried over Na2SO4 and evaporated to dryness using a rotary evaporator. The residue was purified using column chromatography on silica gel using a chloroform/methanol gradient (95:5 ratio) to give 0.93 g of 7 (65%): a colorless oil; Rf = 0.4 (CHCl3:MeOH = 20:1); 1H NMR (500 MHz, CDCl3) δ 8.53 (dd, J = 3.4, 2.4 Hz, 1H), 8.49 (ddd, J = 6.4, 4.2, 1.6 Hz, 1H), 7.70 (ddd, J = 7.9, 4.2, 2.0 Hz, 1H), 7.29 - 7.21 (m, 1H), 3.31 - 3.19 (m, 1H), 3.14 - 3.03 (m, 1H), 2.38 - 2.26 (m, 1H), 2.24 - 2.12 (m, 4H), 2.04 - 1.89 (m, 1H), 1.87 - 1.78 (m, 1H), 1.78 - 1.66 (m, 1H); 13C NMR (126 MHz, CDCl3) δ 149.5, 148.6, 138.7, 134.9, 123.6, 68.9, 57.0, 40.4, 35.2, 22.6; IR (neat): υmax 2996, 2861, 2329, 1417, 1196, 1049, 955, 732 cm-1. HRMS (ESI) calcd for C10H14N2 [M+H]+: 163.1235; found: 163.1231. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | Stage #1: 3-Bromopyridine With n-butyllithium In diethyl ether at -78℃; for 1h; Inert atmosphere; Stage #2: N-methylsuccinimide In diethyl ether at -78℃; for 1h; Inert atmosphere; Stage #3: With lithium aluminium deuteride In tetrahydrofuran; diethyl ether at 0 - 20℃; for 2h; Inert atmosphere; | [General Procedure A] 3-(1-Methylpyrrolidin-2-yl)pyridine (7) : General procedure: At -78 °C, a n-butyllithium solution (4.24 mL,10.6 mmol, 2.5M) was admixed dropwise with a solution of (1.68 g,10.6 mmol) of 3-bromopyridine 5 in absolute diethyl ether (15 mL). The color of the mixture changed to yellow, and a precipitate was formed. After 1 h at -78 °C, a solution of N-Methylsuccinimide 6 (1 g, 8.8 mmol) in 10 mL of absolute tetrahydrofuran was added dropwise to the above mixture. The reaction mixture was stirred for another 1 h at same temperature and then 10 mL THF, followed by the addition of LiAlH4 (836 mg, 22 mmol) at 0 °C was carried and then allowed to stand at room temperature for 2 h. After completion of the reaction it was quenched with brine solution (5 mL) at 0°C and the resulting mixture was filtered. The filtrate was dried over Na2SO4 and evaporated to dryness using a rotary evaporator. The residue was purified using column chromatography on silica gel using a chloroform/methanol gradient (95:5 ratio) to give 0.93 g of 7 (65%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With d(4)-methanol; sodium acetate at 80℃; for 24h; Inert atmosphere; | [General Procedure B] 1-Methylpyrrolidine-2,5-dione-3,3,4,4-d4 (6-d4) A screw-cap vial equipped with stirred bar was charged with N-Methylsuccinimide 6 (0.1 g, 0.88 mmol) and anhydrous NaOAc (289 mg, 3.5 mmol) dry CD3OD (8 mL) under nitrogen atmosphere. The reaction mixture was stirred at 80°C for 24 h. Afterwards, it was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silical gel (hexanes/EtOAc: 1/1) to give 91 mg of 6-d4 (88%) with 98% deuterium incorporation, as estimated by 1H NMR spectroscopy: a white solid; Rf = 0.4 (hexanes:EtOAc = 1:1). m.p. : 64-66 oC; 1H NMR (400 MHz, CDCl3) δ 3.00 (d, J = 2.5 Hz, 3H), 2.70 (bs, 0.08H); 13C NMR (101 MHz, CDCl3) δ 177.4, 28.1 - 27.0 (m), 24.8; IR (neat): υmax 1764, 1722, 1685 cm-1; HRMS (ESI) calcd for C5H4D4NO2 [M+H]+: 118.0806; found 118.0811. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: N-methylsuccinimide With tris(bis(trimethylsilyl)amido)lanthanum(III); 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane In benzene at 25℃; for 72h; Inert atmosphere; Glovebox; Stage #2: With hydrogenchloride In methanol at 0℃; | |
91% | Stage #1: N-methylsuccinimide With bis(cyclopentadienyl)dihydrozirconium; 4,4,5,5-tetramethyl-[1,3,2]-dioxaboralane at 20℃; for 12h; Inert atmosphere; Stage #2: With hydrogenchloride In diethyl ether Inert atmosphere; | 42 The bis(cyclopentadiene) zirconium dihydride (denoted as Cp2ZrH2, 0.01mmol, 2.23mg), 1-methylpyrrolidine-2,5-dione (denoted as 1ad, 0.2mmol, 22.6mg) and pinna Alcohol borane (denoted as HBpin, 0.6mmol, 87μL), stirred at room temperature under nitrogen (1atm) atmosphere for 12h, treated with hydrogen chloride in ether solution to obtain the hydrochloride compound of formula 2ad (white solid,1-methylpyrrolidine hydrochloride). The isolated yield was 91%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | In tetrahydrofuran at 15℃; for 12h; Inert atmosphere; | 87 Intermediate 87a: 5-hydroxy-l-methyl-5-octylpyrrolidin-2-one To a solution of l-methylpyrrolidine-2,5-dione (20 g, 1.0 equiv.) in THF (150 mL) was added bromo(octyl)magnesium (1 M, 265 mL, 1.5 equiv.) drop wise at 15 °C under N2. The mixture was stirred at 15 °C for 12 h under N2. The reaction mixture was quenched by addition NH4CI at 0°C. Then it was diluted with H2O and extracted 3x with EtOAc. The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to afford product as a white solid (20 g, 50%). NMR (400 MHz, CDCb) d 3.75 (s, 1H), 2.68 (s, 3H), 2.43 (ddd, J = 16.4, 10.0, 6.4 Hz, 1H), 2.24 (ddd, J = 16.7, 10.0, 4.5 Hz, 1H), 2.13 (ddd, J = 13.6, 10.0, 6.4 Hz, 1H), 1.93 (ddd, J = 14.0, 10.0, 4.7 Hz, 1H), 1.73 (td, J = 13.4, 3.7 Hz, 1H), 1.65 - 1.53 (m, 1H), 1.35 - 1.07 (m, 12H), 0.88 - 0.76 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In dichloromethane at 20℃; for 2h; | General procedure for the domino Michael/O-alkylation reaction General procedure: A solution of maleimide 1 (0.20 mmol , 1equiv ), γ halogenated β ketoester 2 (0.20 mmol , 1 equiv ) in CH2Cl2 (1.0 mL) was stirred at rt and Et3N 0.20mmol 100 mol % was added at the same temperature. The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (eluentP E: EtOAc = 2:1 to afford pure products 3 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76 %Spectr. | With [4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis{3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-κN]phenyl-κC}iridium(III) hexafluorophosphate In dichloromethane; acetonitrile at 20℃; Inert atmosphere; Irradiation; | 1-14 Example 1: Search for an optimal visible light catalyst for the synthesis of cyclobutene derivatives In the reaction vessel, 0.05 mmol of the alkyne compound represented by Formula 1a, 0.1 mmol of the alkene compound represented by Formula 2a, and 65 mol% of Ir[dF(CF3)ppy]2(dtbbpy)PF as a visible photocatalyst were combined with CH2Cl2/MeCN (5: 1, 0.1M) 0.5 mL of a mixed solvent was added, argon gas was injected into the reaction vessel, and then blue light was irradiated using a 12 W blue light LED at room temperature.Then, the above formula (3aa) was obtained as a reaction product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | Stage #1: benzyltriphenylphosphonium bromide With n-butyllithium In 5,5-dimethyl-1,3-cyclohexadiene; hexane at 20℃; for 0.5h; Sealed tube; Inert atmosphere; Stage #2: N-methylsuccinimide In 5,5-dimethyl-1,3-cyclohexadiene; hexane Sealed tube; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | Stage #1: 1-naphthylmethyltriphenylphosphonium chloride With n-butyllithium In 5,5-dimethyl-1,3-cyclohexadiene; hexane at 20℃; for 0.5h; Sealed tube; Inert atmosphere; Stage #2: N-methylsuccinimide In 5,5-dimethyl-1,3-cyclohexadiene; hexane Sealed tube; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | Stage #1: 4-methylbenzyltriphenylphosphonium bromide With n-butyllithium In 5,5-dimethyl-1,3-cyclohexadiene; hexane at 20℃; for 0.5h; Sealed tube; Inert atmosphere; Stage #2: N-methylsuccinimide In 5,5-dimethyl-1,3-cyclohexadiene; hexane Sealed tube; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: (4-tert-butyl-benzyl)-triphenyl-phosphonium bromide With n-butyllithium In 5,5-dimethyl-1,3-cyclohexadiene; hexane at 20℃; for 0.5h; Sealed tube; Inert atmosphere; Stage #2: N-methylsuccinimide In 5,5-dimethyl-1,3-cyclohexadiene; hexane Sealed tube; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: (4-fluorobenzyl)triphenylphosphonium chloride With n-butyllithium In 5,5-dimethyl-1,3-cyclohexadiene; hexane at 20℃; for 0.5h; Sealed tube; Inert atmosphere; Stage #2: N-methylsuccinimide In 5,5-dimethyl-1,3-cyclohexadiene; hexane Sealed tube; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | Stage #1: (4-methoxybenzyl)triphenylphosphonium bromide With n-butyllithium In 5,5-dimethyl-1,3-cyclohexadiene; hexane at 20℃; for 0.5h; Sealed tube; Inert atmosphere; Stage #2: N-methylsuccinimide In 5,5-dimethyl-1,3-cyclohexadiene; hexane Sealed tube; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: 3-fluoro-4-methoxybenzyltriphenylphosphonium chloride With n-butyllithium In 5,5-dimethyl-1,3-cyclohexadiene; hexane at 20℃; for 0.5h; Sealed tube; Inert atmosphere; Stage #2: N-methylsuccinimide In 5,5-dimethyl-1,3-cyclohexadiene; hexane Sealed tube; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | Stage #1: 3-methoxybenzyl-triphenylphosphonium chloride With n-butyllithium In 5,5-dimethyl-1,3-cyclohexadiene; hexane at 20℃; for 0.5h; Sealed tube; Inert atmosphere; Stage #2: N-methylsuccinimide In 5,5-dimethyl-1,3-cyclohexadiene; hexane Sealed tube; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | With nickel(II) iodide; samarium diiodide In tetrahydrofuran at 20℃; Glovebox; Inert atmosphere; |
Tags: 1121-07-9 synthesis path| 1121-07-9 SDS| 1121-07-9 COA| 1121-07-9 purity| 1121-07-9 application| 1121-07-9 NMR| 1121-07-9 COA| 1121-07-9 structure
[ 88661-56-7 ]
1-(3-Bromopropyl)pyrrolidine-2,5-dione
Similarity: 0.88
[ 88661-56-7 ]
1-(3-Bromopropyl)pyrrolidine-2,5-dione
Similarity: 0.88
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H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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