3-Bromo-4-fluorobenzonitrile → HCID 21463658, compound

HRID 1348914Notes

Reaction equation

HRID 1348914 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[C:5]#[N:6].[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:10][C:9]1[C:2]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]([F:11])([F:23])[F:24])=[CH:19][CH:18]=2)=[CH:3][C:4]([C:5]#[N:6])=[CH:7][CH:8]=1

Participants

5

Reactant 3

HCID 1235793-Bromo-4-fluorobenzonitrileHCID 516892Sodium BicarbonateHCID 27343864-(Trifluoromethoxy)phenylboronic acid

Product 1

HCID 21463658HCID 21463658, compoundYield 100.4%

Reagents, catalysts & solvents 1

HCID 178418476HCID 178418476, compoundCatalyst

Conditions

Temperature
80 °C

Procedure

A 100 mL 3-necked flask equipped with a stir bar, a condenser, and a nitrogen inlet was flushed with nitrogen and then charged with 3-bromo-4-fluorobenzonitrile (2.507 g, 1.23×10−2 mol), 4-trifluoromethoxyphenyl boronic acid (2.825 g, 1.23×10−2 mol, 1.01 equiv), bis(triphenylphosphine)-palladium(II) chloride (2.0 mg, 2.85×10−6 mol, 0.02 mol %), and sodium bicarbonate (1.577 g, 1.82×10−2 mol, 1.5 equiv). The flask was then evacuated and purged with nitrogen three times, and charged with deoxygenated toluene (6 mL) and deoxygenated water (6 mL). The mixture was heated to 80° C. until HPLC analysis indicated the disappearance of the aryl bromide (less than 16 hours; HPLC conditions: Eclipse XDB-C8 (4.6 mm×150 mm), flow rate: 1.5 mL/min.; mobile phase: 80:20 water(0.1% H3PO4)/CH3CN to 20:80 in 8 minutes, hold to 15 minutes with the column at 35° C. and UV detection: 210 nm. Retention time for the product is 8.88 min, retention time for aryl bromide is 6.47 min, retention time for excess boronic acid is 5.64 min, and retention time for homocoupled product is 10.58 minutes). The reaction was cooled to room temperature and the phases were separated. The organic phase was filtered through a plug of silica (2.5 g) and the silica plug was washed with toluene (25 mL). The filtrate was concentrated to provide the desired product (3.472 g, 92% potency, 93% potency adjusted yield). HRMS (FAB) calcd. for C14H7F4NO (M+H)+; 282.0542, found 282.0536; 1H NMR (CDCl3) δ 7.76 (dd, 1H), 7.68 (ddd, 1H), 7.56 (m, 2H), 7.34 (m, 2H), 7.30 (dd, 1H); 13C (CDCl3) δ 161.9, 149.5, 134.9, 133.5, 131.9, 130.4, 129.5, 121.2 (2), 120.4, 117.8, 117.7, 109.1; IR(KBr) 2230, 1514, 1490, 1265, 1256, 1223, 1210, 1157; Analytical: Pd 6 ppm, B<30 ppm, Na<1 ppm; mp˜63.5-64.2° C.

Workup

  1. customA 100 mL 3-necked flask equipped with a stir bar, a condenser, and a nitrogen inlet
  2. customwas flushed with nitrogen
  3. customThe flask was then evacuated
  4. custompurged with nitrogen three times
  5. additioncharged with deoxygenated toluene (6 mL)
  6. customdeoxygenated water (6 mL)
  7. customless than 16 hours
  8. waithold to 15 minutes with the column at 35° C.
  9. waitRetention time for the product is 8.88 min
  10. waitretention time for aryl bromide is 6.47 min
  11. waitretention time for excess boronic acid is 5.64 min
  12. waitretention time for homocoupled product is 10.58 minutes
  13. temperatureThe reaction was cooled to room temperature
  14. customthe phases were separated
  15. filtrationThe organic phase was filtered through a plug of silica (2.5 g)
  16. washthe silica plug was washed with toluene (25 mL)
  17. concentrationThe filtrate was concentrated

Sources & evidence

ORD record
ord-ffa6a88633db47739a9cbc1f68ca0c58
Source dataset
uspto-grants-2007_05
Patent number
US07211595B2

Reaction notes

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