Acetic Acid → HCID 68312682, compound

HRID 1472926Notes

Reaction equation

HRID 1472926 reaction equation
[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=O)[N:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:18][C@@H:19]([CH2:23][OH:24])[CH:20]([CH3:22])[CH3:21].C(O)(=O)C.C([BH3-])#N>CO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:18][C@H:19]([CH:20]([CH3:22])[CH3:21])[CH2:23][OH:24])[N:11]=2)=[CH:6][C:3]=1[C:4]#[N:5]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 498716Cyano-borohydrideHCID 6950587D-ValinolHCID 86671317HCID 86671317, compound

Product 1

HCID 68312682HCID 68312682, compoundYield 52.5%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 3-cyano-4-fluorophenylboronic acid (0.887 g, 5.38 mmol), 2M cesium carbonate (8.1 mL, 16.2 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. The mixture was cooled, concentrated and partitioned between water and CH2Cl2. The organic layer was concentrated and purified by chromatography (30% ethyl acetate:hexanes) to provide 2-fluoro-5-(6-formylpyridin-2-yl)benzonitrile. To a solution of 2-fluoro-5-(6-formylpyridin-2-yl)benzonitrile (0.500 g, 2.21 mmol) in methanol (20 mL) at ambient temperature was added D-valinol (0.25 mL, 2.2 mmol), acetic acid (0.50 mL, 8.8 mmol) followed by MP-cyanoborohydride (2.49 mmol/g; 1.0 g). After 2 hours, the mixture was filtered, concentrated, and the residue partitioned between ether and 1M NaOH. The organic layer was concentrated and purified by chromatography to provide 362 mg (52%) of the title compound. MS (DCI+) m/z 314 (M+H); 1H NMR (400 MHz, DMSO-d6) δ 8.62 (dd, J=6.3, 2.3 Hz, 1H), 8.52 (ddd, J=8.9, 5.3, 2.4 Hz, 1H), 7.97-7.84 (m, 2H), 7.66 (t, J=9.0 Hz, 1H), 7.49 (dd, J=7.4, 1.1 Hz, 1H), 3.92 (d, J=3.6 Hz, 2H), 3.52-3.43 (m, 1H), 2.40-2.22 (m, 2H), 1.93-1.76 (m, 1H), 0.89 (dd, J=9.5, 6.9 Hz, 6H).

Workup

  1. filtrationthe mixture was filtered
  2. concentrationconcentrated
  3. customthe residue partitioned between ether and 1M NaOH
  4. concentrationThe organic layer was concentrated
  5. custompurified by chromatography

Sources & evidence

ORD record
ord-e8675230bcf54a1bbd5f714d4ef1a2c8
Source dataset
uspto-grants-2015_04
Patent number
US09012651B2

Reaction notes

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