pyrrolidine-1-carbaldehyde

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,6-dichloro-pyridin-4-yl)-pyrrolidin-1-yl-methanone (2.0 g, 8.2 mmol, prepared from commercially available 2,6-dichloro-isonicotinic acid) in THF (50 mL) is added slowly LDA (4 mL, 2M in heptane/THF/ethylbenzene), maintaining an internal temperature below −65° C. The solution is stirred at −78° C. for 1 hour, then treated dropwise ethyl formate (640 mg, 8.6 mmol), again maintaining an internal temperature below −65° C. The resulting mixture is gradually warmed to room temperature and stirred overnight. The mixture is quenched with saturated NH4Cl, extracted with ether and the combined extracts are washed with brine, dried over sodium sulfate and concentrated to give crude 2,6-dichloro-4-(pyrrolidine-1-carbonyl)-pyridine-3-carbaldehyde, which is used directly for the next step. maintaining an internal temperature below −65° C again maintaining an internal temperature below −65° C The resulting mixture is gradually warmed to room temperature stirred overnight The mixture is quenched with saturated NH4Cl extracted with ether the combined extracts are washed with brine dried over sodium sulfate concentrated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,6-dichloro-pyridin-4-yl)-pyrrolidin-1-yl-methanone (2.0 g, 8.2 mmol, prepared from commercially available 2,6-dichloro-isonicotinic acid) in THF (50 mL) is added slowly LDA (4 mL, 2M in heptane/THF/ethylbenzene), maintaining an internal temperature below −65° C. The solution is stirred at −78° C. for 1 hour, then treated dropwise ethyl formate (640 mg, 8.6 mmol), again maintaining an internal temperature below −65° C. The resulting mixture is gradually warmed to room temperature and stirred overnight. The mixture is quenched with saturated NH4Cl, extracted with ether and the combined extracts are washed with brine, dried over sodium sulfate and concentrated to give crude 2,6-dichloro-4-(pyrrolidine-1-carbonyl)-pyridine-3-carbaldehyde, which is used directly for the next step. maintaining an internal temperature below −65° C again maintaining an internal temperature below −65° C The resulting mixture is gradually warmed to room temperature stirred overnight The mixture is quenched with saturated NH4Cl extracted with ether the combined extracts are washed with brine dried over sodium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: As in Example 14, but using 3,8-diamino-6-diethylaminophenanthridine and N-formylpyrrolidine instead of 3,8-diamino-6-dimethylaminophenanthridine and N,N-diethylformamide. Yield 66%, melting point 149°-150° C. (chloroform/petroleum ether (60°-80° C.)).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 3,8-diamino-6-(5H)-phenanthridone (500 mg) in tetrahydrofuran (5 ml) was added to a mixture of phosphorus oxychloride (0.75 ml) and N-formylpyrrolidine (2.5 ml) and tetrahydrofuran (5 ml), the temperature of the mixture being kept at 5° C. The resulting mixture was stirred for 30 minutes at room temperature, heated at 50° C. for 1 hour and worked as described in Example 8, paragraph 1. Yield 52%, melting point 280° C. (decomposition) (CHCl3 /methanol). being kept at 5° C heated at 50° C. for 1 hour

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2,7-diamino-5,10-dioxo-4,5,9,10-tetrahydro-4,9-dioxapyrene (500 mg) in tetrahyrofuran (4 ml) was added to a mixture of phosphorus oxychloride (0.7 ml) and N-formylpyrrolidine (2 ml) and tetrahydrofuran (4 ml), the temperature of the mixture being kept at 5° C. The resulting mixture was stirred for 30 minutes at room temperature, heated at 80° C. for 1 hour and worked up as described in Example 1, paragraph 1. Yield 68%, melting point 275° C. (decomposition) (CHCl3 /methanol). being kept at 5° C heated at 80° C. for 1 hour

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 2,7-diamino-5,10-dioxo-4,5,9,10-tetrahydro-4,9-dioxapyrene (500 mg) in tetrahyrofuran (4 ml) was added to a mixture of phosphorus oxychloride (0.7 ml) and N-formylpyrrolidine (2 ml) and tetrahydrofuran (4 ml), the temperature of the mixture being kept at 5° C. The resulting mixture was stirred for 30 minutes at room temperature, heated at 80° C. for 1 hour and worked up as described in Example 1, paragraph 1. Yield 68%, melting point 275° C. (decomposition) (CHCl3 /methanol). being kept at 5° C heated at 80° C. for 1 hour

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-formylpyrrolidine (100 g) and dimethylsulfate (126 g) are heated to 80° C. for 4 h. Then a mixture of pyrrolidine (71 g) and toluene (100 ml) are added and the resulting mixture is stirred at reflux for 1 h. The reaction mixture is cooled to room temperature and the phases are separated. The lower layer is concentrated in vacuo and triturated with diethyl ester. The precipitate is collected by filtration and recrystallised using ethyl acetate to give 1-pyrrolidin-1-ylmethylene-pyrrolidinium methylsulfate (18, R6/R7=Pyrrolidinyl). 1H NMR (DMSO-d6), 8.28 (1H), 3.90-3.85 (4H), 3.68-3.62 (4H), 3.38 (3H), 1.99-1.90 (4H), 1.86-1.77 (4H). are added at reflux for 1 h The reaction mixture is cooled to room temperature the phases are separated The lower layer is concentrated in vacuo triturated with diethyl ester The precipitate is collected by filtration recrystallised

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-formylpyrrolidine (100 g) and dimethylsulfate (126 g) are heated to 80° C. for 4 h. Then a mixture of pyrrolidine (71 g) and toluene (100 ml) are added and the resulting mixture is stirred at reflux for 1 h. The reaction mixture is cooled to room temperature and the phases are separated. The lower layer is concentrated in vacuo and triturated with diethyl ester. The precipitate is collected by filtration and recrystallised using ethyl acetate to give 1-pyrrolidin-1-ylmethylene-pyrrolidinium methylsulfate (18, R6/R7=Pyrrolidinyl). 1H NMR (DMSO-d6), 8.28 (1H), 3.90-3.85 (4H), 3.68-3.62 (4H), 3.38 (3H), 1.99-1.90 (4H), 1.86-1.77 (4H). are added at reflux for 1 h The reaction mixture is cooled to room temperature the phases are separated The lower layer is concentrated in vacuo triturated with diethyl ester The precipitate is collected by filtration recrystallised

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2,6-dichloro-pyridin-4-yl)-pyrrolidin-1-yl-methanone (2.0 g, 8.2 mmol, prepared from commercially available 2,6-dichloro-isonicotinic acid) in THF (50 mL) is added slowly LDA (4 mL, 2M in heptane/THF/ethylbenzene), maintaining an internal temperature below −65° C. The solution is stirred at −78° C. for 1 hour, then treated dropwise ethyl formate (640 mg, 8.6 mmol), again maintaining an internal temperature below −65° C. The resulting mixture is gradually warmed to room temperature and stirred overnight. The mixture is quenched with saturated NH4Cl, extracted with ether and the combined extracts are washed with brine, dried over sodium sulfate and concentrated to give crude 2,6-dichloro-4-(pyrrolidine-1-carbonyl)-pyridine-3-carbaldehyde, which is used directly for the next step. maintaining an internal temperature below −65° C again maintaining an internal temperature below −65° C The resulting mixture is gradually warmed to room temperature stirred overnight The mixture is quenched with saturated NH4Cl extracted with ether the combined extracts are washed with brine dried over sodium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In the same manner as indicated in Example 5 there are electrolyzed 17.7 g of N-formylpyrrolidine and 57.2 g of methanol in the presence of 0.29 g of tetramethylammonium tetrafluoroborate as conducting salt. In this case, however, the current is switched off after the throughput of already 2.0 Faraday per mol of N-formylpyrrolidine. The calculated mean cell voltage is 28.8 volts. Work-up of the electrolysis solution gives 20.0 g of 1-formyl-2-methoxypyrrolidine (boiling point 39°-40° C./0.1 mbar; nD25 =1.4700), which corresponds to a product yield of 86.6% and a current efficiency of 86.6%.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In the same manner as indicated in Example 5 there are electrolyzed 17.7 g of N-formylpyrrolidine and 57.2 g of methanol in the presence of 0.29 g of tetramethylammonium tetrafluoroborate as conducting salt. In this case, however, the current is switched off after the throughput of already 2.0 Faraday per mol of N-formylpyrrolidine. The calculated mean cell voltage is 28.8 volts. Work-up of the electrolysis solution gives 20.0 g of 1-formyl-2-methoxypyrrolidine (boiling point 39°-40° C./0.1 mbar; nD25 =1.4700), which corresponds to a product yield of 86.6% and a current efficiency of 86.6%.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The operation was conducted in the same manner as in Example 1 but using an N-phenyl-1-formyl-(S)-prolineamide which was an amide compound having an oxo group on a carbon atom at the β-position of the nitrogen atom, as a formamide compound, instead of using the 1-formylpyrrolidine and conducting the reaction for 15 hours. As a result, there was obtained 0.121 g of a 1-phenyl-1-ethanol (yield, 99%). Further, this compound was measured for its optical purity to be 32.5% ee (R). the reaction for 15 hours