Intramolecular Nucleophilic Aromatic Substitution Reaction of 2-Carboxamido-3-arylquinazolin-4-ones and its Application to the Synthesis of Secondary Aryl Amines

Abstract

A novel intramolecular nucleophilic aromatic substitution reaction of 2-carboxamido-3-arylquinazolin-4-one derivatives induced by base treatment and its application to the expeditious ­synthesis of secondary aryl amines, including diaryl amines, are ­described.

heterocycles - nucleophilic aromatic substitutions - amines - tandem reactions - medicinal chemistry

References

1

Visiting scientist from Takeda Pharmaceutical Company Limited (01.2003-03.2004); present address: Medicinal Chemistry Research Laboratories, Takeda Pharmaceutical Company Limited, 10 Wadai, Tsukuba-shi, Ibaraki 300-4293, Japan.

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Premixing MeI and 12 prior to the addition of NaH led to a mixture of the migrated tertiary amide 13 (58%) and N-methylated compound 11 (31%).

13

Representative Procedure for the Intramolecular S _N Ar Reaction: To a solution of 12a (40.5 mg, 0.108 mmol) in DMF (1.5 mL) cooled at 0 °C was added NaH (60% in oil, 5.2 mg, 0.13 mmol) and the reaction mixture was stirred at r.t. for 1 h. The reaction was quenched by the addition of H₂O and solid NH₄Cl (ca 20 mg). The resultant mixture was diluted with EtOAc, washed with H₂O and brine, dried over Na₂SO₄, and concentrated under reduced pressure. Purification of the residue by flash chromatography (silica gel, CHCl₃ then 5% MeOH-CHCl₃) gave 14a (35.6 mg, 88%) as a colorless solid.

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Representative Procedure for the Synthesis of Secondary Aryl Amines: To a solution of 21a (50 mg, 0.15 mmol) in THF (1 mL) cooled at 0 °C were added aniline (21 mg, 0.23 mmol) and NaOMe (41 mg, 0.76 mmol). After being stirred at r.t. for 5 h, the reaction mixture was diluted with EtOAc and neutralized with HOAc. The organic layer was separated, washed with H₂O and brine, dried over MgSO₄, and concentrated under reduced pressure. Purification of the residue by flash chromatography (silica gel, 20% EtOAc-hexane) gave 22a (24 mg, 78%) as a colorless oil.

For recent reviews on diaryl amine synthesis, see:

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