4-Fluorophenylboronic acid → HCID 67497314, compound

HRID 1628280Notes

Reaction equation

HRID 1628280 reaction equation
Cl.Br[C:3]1[CH:4]=[C:5]([N:9]([CH2:21][C:22]2[N:23]=[CH:24][S:25][CH:26]=2)[C:10](=[O:20])[C@H:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH2:12])[CH:6]=[CH:7][CH:8]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>C1COCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([N:9]([CH2:21][C:22]3[N:23]=[CH:24][S:25][CH:26]=3)[C:10](=[O:20])[C@H:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH2:12])[CH:4]=2)=[CH:30][CH:29]=1

Participants

6

Reactant 2

HCID 2856454-Fluorophenylboronic acidHCID 67496753HCID 67496753, compound

Product 1

HCID 67497314HCID 67497314, compoundYield 9.5%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolventHCID 10340Sodium CarbonateSolvent

Conditions

Temperature
135 °C

Procedure

Bromide 44.A (200 mg, 0.44 mmol), 4-fluorophenylboronic acid (68 mg, 0.49 mmol), and Pd(dppf)Cl2 were mixed in THF and Na2CO3 (2 M). The resulting mixture was heated in a sealed tube in a microwave at 135° C. for 10 minutes. The organic layer was concentrated and the residue was partially purified on a silica gel column (12 g, 0-10% MeOH:DCM). The fractions containing desired product were combined, concentrated, and purified again on a prepHPLC (C18, ACN:H2O:0.1% TFA, gradient). The desired fractions were combined and concentrated on a rotavap to remove ACN and then partitioned with NaHCO3 (sat)/EtOAc. The organic layer was dried with sodium sulfate, filtered, and concentrated to yield 44 (18 mg). LC-MS (+esi, M+H+=432.1). 1H NMR (500 MHz, DICHLOROMETHANE-d2) δ ppm 9.63 (br. s., 1H) 8.71 (d, J=1.96 Hz, 1H) 7.86 (t, J=1.96 Hz, 1H) 7.54-7.64 (m, 3H) 7.40 (t, J=7.82 Hz, 1H) 7.28-7.33 (m, 3H) 7.24-7.28 (m, 1H) 7.22 (d, J=6.85 Hz, 2H) 7.12-7.18 (m, 2H) 7.04 (d, J=1.71 Hz, 1H) 3.84-3.94 (m, 2H) 3.54 (dd, J=9.41, 4.28 Hz, 1H) 3.27 (dd, J=13.94, 4.16 Hz, 1H) 2.85 (dd, J=14.06, 9.41 Hz, 1H).

Workup

  1. concentrationThe organic layer was concentrated
  2. customthe residue was partially purified on a silica gel column (12 g, 0-10% MeOH:DCM)
  3. additionThe fractions containing desired product
  4. concentrationconcentrated
  5. custompurified again on a prepHPLC (C18, ACN:H2O:0.1% TFA, gradient)
  6. concentrationconcentrated on a rotavap
  7. customto remove ACN
  8. custompartitioned with NaHCO3 (sat)/EtOAc
  9. dry with materialThe organic layer was dried with sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated

Sources & evidence

ORD record
ord-70f3811f20464662a21861017d223f8d
Source dataset
uspto-grants-2014_07
Patent number
US08785468B2

Reaction notes

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