2-pyrrolidin-1-ylsulfonylbenzaldehyde

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

Procedure: 2-(2-methyl-4,5-diphenyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid was synthesized according to 2-(2-methyl-4,5-diphenyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid using 2-(pyrrolidin-1-ylsulfonyl)benzaldehyde in the general procedure I (step 1). 1H NMR (CDCl3/400 MHz) δ (ppm) 8.00 (d, 1H), 7.50-7.45 (m, 1H), 7.34-7.24 (m, 5H), 7.19-7.16 (m, 2H), 7.05-7.00 (m, 3H), 6.92-6.88 (m, 2H), 4.65 (s, 2H), 4.21 (s, 2H), 3.15 (t, 4H), 2.10 (s, 3H), 1.69-1.65 (m, 4H). MS m/z: 515.34 (M+1).

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,4-dimethyl-1H-pyrrole (2.0 ml, 19.42 mmol) and 2-(pyrrolidin-1-ylsulfonyl)benzaldehyde (4.65 g, 19.42 mmol) in trifluoroethanol (48.6 ml) and 12.5 sodium hydroxide (1.554 ml, 19.42 mmol) was heated at 50° C. for 1 h. The mixture was poured into ice and the resulting murky solution was decanted. The remaining residue was taken up in benzene and concentrated under vacuum. This residue was diluted in DCM (48.6 ml) and cooled to 0° C. To this solution, were added TFA (7.48 ml, 97 mmol) and triethylsilane (31.0 ml, 194 mmol). This mixture was heated at reflux (50° C.) for 15 min and poured into a mixture of ice and saturated solution of sodium bicarbonate. The mixture was extracted with dichloromethane (100 ml×2). The organic layers were combined, washed with brine (50 ml), dried, filtered, and concentrated to give an oil. Purification of the oil by column chromatography (0 to 20% ethyl acetate in hexanes) gave 2,4-dimethyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrole (380.0 mg, 1.193 mmol, 6.14% yield,) [Rf=0.73 (20% ethyl acetate in hexanes)] and 3,5-dimethyl-2-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrole (1.07 g, 3.36 mmol, 17.30% yield) [Rf=0.63 (20% ethyl acetate in hexanes)]. The mixture was poured into ice the resulting murky solution was decanted concentrated under vacuum This residue was diluted in DCM (48.6 ml) cooled to 0° C This mixture was heated at reflux (50° C.) for 15 min The mixture was extracted with dichloromethane (100 ml×2) washed with brine (50 ml) dried filtered concentrated to give an oil Purification of the oil by column chromatography (0 to 20% ethyl acetate in hexanes)

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

Procedure: was followed using 2-(2-cyclopropyl-5-methyl-1H-pyrrol-1-yl)acetate (1.25 g, 6.03 mmol), triethylsilane (2.89 mL, 18.1 mmol), trimethylsilyl trifluoromethanesulfonate (2.18 mL, 12.1 mmol) and 2-(pyrrolidin-1-ylsulfonyl)benzaldehyde (1.44 g, 6.03 mmol) to afford ethyl 2-(5-cyclopropyl-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (642 mg, 1.49 mmol, 25% yield) as an oil.

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

Procedure: The general procedure was followed using ethyl 2-(2-cyclopentyl-5-methyl-1H-pyrrol-1-yl)acetate (3.49 g, 14.8 mmol), triethylsilane (7.11 mL, 44.5 mmol), trimethylsilyl trifluoromethanesulfonate (5.36 mL, 29.7 mmol), and 2-(pyrrolidin-1-ylsulfonyl)benzaldehyde (3.55 g, 14.8 mmol) in dichloromethane of (total volume: 170 ml). Purification on silica gel (Luknova 330 g, 20 mL/min) using 1 to 7% of a 7:1 acetonitrile/methanol solution in dichloromethane over 70 minutes afforded ethyl 2-(5-cyclopentyl-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (2.54 g, 5.54 mmol, 37% yield) as a viscous gold residue that was approximately 90% pure by 1H-NMR analysis, with the impurity being ethyl 2-(2-cyclopentyl-5-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.96 (dd, 1H), 7.40 (ddd, 1H), 7.22-7.28 (m, 2H, composite of two shifts), 4.56 (s, 2H), 4.23 (s, 2H), 4.18 (q, 2H), 3.28-3.31 (m, 4H), 2.83 (m, 1H), 2.03 (s, 3H), 1.89-1.99 (m, 3H), 1.84-1.88 (m, 4H), 1.49-1.74 (m, 5H, composite of multiple shifts), 1.29 (t, 3H). Purification on silica gel (Luknova 330 g, 20 mL/min) over 70 minutes

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

Procedure: was followed using ethyl 2-(2-cyclohexyl-5-methyl-1H-pyrrol-1-yl)acetate (1.00 g, 4.01 mmol), triethylsilane (1.92 mL, 12.0 mmol), trimethylsilyl trifluoromethanesulfonate (1.45 mL, 8.02 mmol) and 2-(pyrrolidin-1-ylsulfonyl)benzaldehyde (0.960 g, 4.01 mmol) to afford ethyl 2-(5-cyclohexyl-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (642 mg, 1.36 mmol, 34% yield).