Formic Acid → 4-(Methylamino)benzonitrile

HRID 1876158Notes

Reaction equation

HRID 1876158 reaction equation
C(O)=O.[C:4](OC(=O)C)(=O)C.[NH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>C(Cl)Cl>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([NH:11][CH3:4])=[CH:13][CH:14]=1)#[N:17]

Participants

5

Reactant 3

HCID 284Formic AcidHCID 7918Acetic AnhydrideHCID 133964-Aminobenzonitrile

Product 1

HCID 109645514-(Methylamino)benzonitrile

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a solution of formic acid 30 mL and acetic anhydride 30 mL stirred at room temperature for 1 h was added a solution of 4-aminobenzonitrile 2.36 g (20.0 mmol) in CH2Cl2 150 mL dropwise at 0° C. The reaction mixture was stirred at room temperature for 4 h (EMI-mass: 146 [M]+). After concentration, the crude intermediate was dissolved in THF 50 mL, and was added BH3 in Me2S 15 mL. The reaction mixture was then stirred for 5 h under reflux. The crude product was extracted with EtOAc, washed with water, sat. Na2CO3 aqueous solution and dried on anhydrous MgSO4. After removal of solvents, 4-cyano-N-methylaniline was obtained in 80% purity based on GC/MS (EMI-mass: 132 [M]+). A mixture of crude 4-cyano-N-methylaniline 0.40 g (ca. 2 mmol) and 4-chloro-2-methylquinazoline 0.357 g (2.0 mmol) with NaOAc 0.2 g (2.3 mmol) in THF 20 mL and H2O 12 mL was stirred at 23° C. for 4 days. After removing solvents, the crude product was purified with preparative HPLC to give the titled compound in 1% yield (10 mg). 1H NMR (CD3OD, 400 MHz): δ 7.94 (d, 2H, J=8.8 Hz), 7.91-7.86 (m, 1H), 7.76-7.73 (m, 1H), 7.65 (d, 2H, J=8.8 Hz), 7.34-7.30 (m, 1H), 6.99-6.96 (m, 1H), 3.87 (s, 3H), 2.81 (s, 3H). m/e: 275.1420 (M+1).

Workup

  1. concentrationAfter concentration
  2. dissolutionthe crude intermediate was dissolved in THF 50 mL
  3. additionwas added BH3 in Me2S 15 mL
  4. stirringThe reaction mixture was then stirred for 5 h
  5. temperatureunder reflux
  6. extractionThe crude product was extracted with EtOAc
  7. washwashed with water, sat. Na2CO3 aqueous solution
  8. dry with materialdried on anhydrous MgSO4
  9. customAfter removal of solvents

Sources & evidence

ORD record
ord-616ccad2afe9470dae7203a4215230a8
Source dataset
uspto-grants-2012_11
Patent number
US08309562B2

Reaction notes

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