5-METHYL-1H-PYRROLE-2-CARBALDEHYDE

DMF (8.54 g, 117 mmol) and dichloroethane (120 mL) were added to a 250-mL 3-necked round-bottom flask fitted with a magnetic stir bar. Phosphoryl chloride (17.9 g, 117 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred for 15 min at room temperature and then 2-methyl-1H-pyrrole (10.0 g, 123 mmol) was added dropwise with stirring at 0° C. The resulting solution was stirred at 80° C. for 30 min. A solution of sodium acetate (46 g, 561 mmol) in water (130 mL) was then added at room temperature. The resulting solution was stirred for 20 min at 80° C. then cooled to room temperature and quenched with water (100 mL). The resulting solution was extracted with dichloromethane (3×250 mL) and the organic layers were combined and washed with saturate aqueous sodium bicarbonate solution (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography eluting with ethyl acetate/hexane (1:5 v/v) to afford 5-methyl-1H-pyrrole-2-carbaldehyde (7.50 g, 56percent). LCMS (ESI) m/z 110 [M+H].B. C. 1-Amino-2-cyano-5-methyl-pyrrole A solution of 140 mg (1.28 mmol) of Compound B in 2 ml of methylene chloride, at rt and under argon, was added rapidly dropwise to a solution of 290 mg (1.35 mmol) of MSH(O-mesitylenesulfonyl-hydroxylamine) in 2 ml of methylene chloride. A deep red solution was obtained which was stirred for an additional 0.5 hr. The mixture was washed twice with sat NaHCO3, dried (MgSO4) and the solvent removed to give a deep red oil. A solution of this material in 5 ml of DMF was added a dropwise to a suspension of 102 mg (2.56 mmol) of sodium hydride in 5 ml of DMF, at rt and under argon. The red color was consumed and the reaction became dark yellow. Stirring was continued for an additional 0.5 hr. The mixture was ice cooled and a solution of 385 mg (1.8 mmol) of MSH in 5 ml of DMF was added. Stirring was continued for 1 hr with cooling. The dark solution was diluted with ethyl acetate and washed once with water. The aqueous layer was rextracted once with ethyl acetate. The combined organic layers were dried (MgSO4) and the solvents removed. The resulting dark red oil was subjected to flash chromatography on silica with 20% EtOAc:hexane to afford 100 mg (65%) of Compound C as a yellow solid.5-Methyl-1H-pyrrole-2-carbaldehyde (Step 1, 4.50 g, 41.2 mmol), water (90 mL) and hydroxylamine-O-sulfonic acid (16.34 g, 144 mmol) were added to a 250-mL round-bottom flask fitted with a magnetic stir bar. A solution of potassium hydroxide (46.2 g, 824 mmol) in water (100 mL) was added dropwise with stirring at 0 C. over 1 h. The resulting mixture was allowed to stir for 3.5 h at 0 C. and then for an additional 1 h at room temperature. The mixture was filtered and extracted with dichloromethane (3×250 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:10 v/v) to afford 1-amino-5-methyl-1H-pyrrole-2-carbonitrile (680 mg, 14%). LCMS (ESI) m/z 122 [M+H].Synthesis Example 3 Synthesis of ligand precursor (2) In an atmosphere of nitrogen, 24.8 g (0.26 mol) of pyrrole-2-carboxyaldehyde was introduced into 44.8 g (0.50 mol) of a 50 % aqueous solution of dimethylamine to give a solution. After the solution was stirred at room temperature for 3 hours, water was added to the solution. As a result, a light yellow slurry was obtained. The precipitate was filtered, washed with dichloromethane and water, and then vacuum dried to obtain 29.6 g (yield: 92.0 %) of a purple solid (dimer compound (2a) represented by the following formula). In an atmosphere of nitrogen, 5.0 g (20.5 mmol) of the dimer compound was dissolved in 100 ml of THF. After the solution was cooled to -15 C, 31.9 ml of a hexane solution containing 49.0 mmol of n-BuLi was slowly dropwise added, and the temperature of the resulting solution was raised to room temperature. The solution was then cooled to -78 C, and 3.1 ml (49.0 mmol) of methyl iodide was slowly dropwise added. The temperature of the resulting solution was raised to room temperature, and the solution was stirred for 3 hours. The reaction solution was quenched with a 0.4 mole sodium acetate aqueous solution, and the organic layer was extracted and recrystallized from ethyl acetate to obtain 3.27 g (12.0 mmol, yield: 59 %) of a white solid (alpha-methyl substituted dimer compound represented by the following formula). The alpha-methyl substituted dimer compound was dissolved in 40 ml of THF, and the solution was mixed with 60 ml of a 0.4 mole sodium acetate aqueous solution. The reaction of the mixture was conducted for 6 hours under reflux, whereby hydrolysis proceeded. After the reaction was completed, the organic layer was extracted with diethyl ether, then the solvent was distilled off, and the remainder was vacuum dried to obtain 2.53 g (23.2 mmol, yield: 96.7 %) of 5-methylpyrrole-2-carboxyaldehyde as a reddish purple solid.

Molecular Weight:109.13
XLogP3:0.9
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:109.052763847
Monoisotopic Mass:109.052763847
Topological Polar Surface Area:32.9
Heavy Atom Count:8
Complexity:92.5
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes