Toluene → N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)methanesulfonamide

HRID 391291Notes

Reaction equation

HRID 391291 reaction equation
[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:16]=O)[CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:18][S:19]([NH2:22])(=[O:21])=[O:20].[C:23]1([CH3:29])C=CC=C[CH:24]=1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([CH:16]([CH:29]3[CH2:23][CH2:24]3)[NH:22][S:19]([CH3:18])(=[O:21])=[O:20])[CH:13]=[N:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]

Participants

5

Reactant 3

HCID 1140TolueneHCID 72879MethanesulfonamideHCID 595783972-Chloro-4-(5-formyl-pyridin-3-yl)-benzonitrile

Product 1

HCID 49820122N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)methanesulfonamideYield 49%

Reagents, catalysts & solvents 1

HCID 11026Titanium isopropoxideCatalyst

Conditions

Temperature
-40 °C

Procedure

Titanium isopropoxide (1.16 mL, 3.96 mmol) was added to a mixture of 2-Chloro-4-(5-formyl-pyridin-3-yl)-benzonitrile (480 mg, 1.98 mmol) and methanesulfonamide (188 mg, 1.98 mmol) in toluene (15 mL) at room temperature. The resulting mixture was refluxed for 2 h. After concentration, the residue was dissolved in THF (10 mL) and cooled to −40° C. A solution of c-PrMgBr (0.5 M in THF, 11.9 mL, 5.93 mmol) was added dropwise and the resulting mixture was stirred at −36° C. for 1 h. The reaction was quenched by addition of saturated NH4Cl solution. The resulting mixture was filtered, and the organic layer was separated. After concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-3%) to give N-((5-(3-chloro-4-cyanophenyl)pyridin-3-yl)(cyclopropyl)methyl)methanesulfonamide (351 mg, 49%); ESI-MS m/z: 362 [M+1]+, 1HNMR (MeOD, 400 MHz) δ 8.83 (d, J=2.0 Hz, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.24 (t, J=2.0 Hz, 1H), 7.93 (4H, s), 3.96 (d, J=9.2 Hz, 1H), 3.06-2.93 (m, 2H), 1.35-1.30 (m, 1H), 1.30 (t, J=7.2 Hz, 1H), 0.81-0.76 (m, 1H), 0.67-0.61 (m, 2H), 0.54-0.49 (m, 1H). Enantiomers were separated by chiral HPLC (Chiralpak IA-H column, EtOH/Heptane, v/v, 60/40) to enantiomer 1 (1st peak, t=12.46 min), enantiomer 2 (2nd peak, t=17.09 min).

Workup

  1. temperatureThe resulting mixture was refluxed for 2 h
  2. concentrationAfter concentration
  3. dissolutionthe residue was dissolved in THF (10 mL)
  4. customThe reaction was quenched by addition of saturated NH4Cl solution
  5. filtrationThe resulting mixture was filtered
  6. customthe organic layer was separated
  7. concentrationAfter concentration
  8. customthe residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-3%)

Sources & evidence

ORD record
ord-5c330a697e64458f8076a4a733f68931
Source dataset
uspto-grants-2013_02
Patent number
US08383827B2

Reaction notes

Loading…