ethanesulfonamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromo-pyridine-3-carbaldehyde (0.930 g, 5 mmol), ethanesulfonamide (0.682 g, 6.25 mmol) and titanium(IV) isopropoxide (2.93 ml, 10.00 mmol) in toluene (10 mL) was heated to 100° C. for 4 h. After concentration, the residue was dissolved in THF (12.5 ml), and (4-fluorophenyl)magnesium bromide (1 M in THF, 12.50 mL, 12.50 mmol) was added dropwise at −78° C. The mixture was stirred at −78° C. for 45 min. The mixture was quenched with saturated NH4Cl and extracted with EtOAc two times, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via Biotage (10-40% AcOEt/heptane; SNAP25 column) giving the title compound (986 mg, 53%) as a beige solid. LC-MS (M+1) 375.0. After concentration the residue was dissolved in THF (12.5 ml) The mixture was quenched with saturated NH4Cl extracted with EtOAc two times dried over magnesium sulfate filtered concentrated The residue was purified via Biotage (10-40% AcOEt/heptane; SNAP25 column)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 25 mL flask was charged with 5-(6-Chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-pyridine-3-carbaldehyde (91 mg, 0.335 mmol), ethane sulfonamide (73.1 mg, 0.670 mmol) and toluene (5 mL). Titanium(IV) isopropoxide (0.147 mL, 0.502 mmol) was added dropwise. The mixture was stirred at 120° C. overnight. The mixture was concentrated in vacuo. The residue was taken up in DCM (5 mL) and MeOH (5 mL) and sodium borohydride (50.7 mg, 1.340 mmol) was added at 0° C. The mixture was stirred at 0° C. for 30 min. Water (1 mL) was added and the mixture was stirred for 5 min, then concentrated in vacuo. DMF (5 mL) was added and the suspension was filtered. The filtrate was purified by Xbridge RP 18 eluting with a 5 to 95 ACN-water gradient to afford ethanesulfonic acid [5-(6-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-pyridin-3-ylmethyl]-amide. ESI-MS: m/z 365.2 (M+H)+1H NMR (400 MHz, MeOD) δ ppm 1.38 (t, J=7.3 Hz, 2H), 3.23 (q, J=7.4 Hz, 2H), 4.08-4.17 (m, 2H), 4.59 (dd, J=8.8, 7.3 Hz, 2H), 7.10 (d, J=8.3 Hz, 1H), 7.53 (dd, J=8.6, 2.3 Hz, 1H), 7.63 (d, J=2.3 Hz, 1H), 7.92 (t, J=2.1 Hz, 1H), 8.40 (d, J=2.5 Hz, 1H), 8.56 (d, J=2.0 Hz, 2H) The mixture was concentrated in vacuo The mixture was stirred at 0° C. for 30 min the mixture was stirred for 5 min concentrated in vacuo DMF (5 mL) was added the suspension was filtered The filtrate was purified by Xbridge RP 18 eluting with a 5 to 95 ACN-water gradient