An Acid-Catalysed Conversion of 2-(4-Quinazolinylamino)benzoic Acid into 2-(2-Aminophenyl)-4(1H)-Quinazolinone

Abstract

An acid-catalysed conversion of N-arylcarboxy-4-quinazolinones into 2-(2-aminoaryl)-4(1H)-quinazolinones has been observed. This reaction allows for a nucleophilic aromatic substitution reaction between aminobenzoic acids and 4-chloroquinazolines to form N-arylcarboxy-4-quinazolinones to be followed in situ by a conversion into 2-(2-aminoaryl)-4(1H)-quinazolinones in a one-pot tandem process.

rearrangement - tandem reaction - nucleophilic aromatic substitution - bicyclic compounds - fused ring systems

References and Notes

1 Gineinah MM. El-Sherbeny MA. Nasr MN. Maarouf AR. Arch. Pharm. (Weinheim, Ger.)  2002,  556 

2

Data courtesy of Scifinder.

3 Parfitt RT. Partridge MW. Vipond HJ. J. Chem. Soc.  1963,  3062 

4a El-Gazzar ABA. Aly AS. Zaki MEA. Hafez HN. Phosphorus, Sulfur Silicon Relat. Elem.  2008,  2119 

4b El-Gazzar ABA. Youssef MM. Youssef AMS. Abu-Hashem AA. Badria FA. Eur. J. Med. Chem.  2009,  609 

5 Shaaban MA. Abou Sier AH. El Ansary AK. Kadry HH. Bull. Fac. Pharm. Cairo Univ.  2002,  15 

6 Mohamed MS. Ibrahim MK. Alafify AM. Abdel-Hamide SG. Mostafa AM. Int. J. Pharmacology  2005,  261 

7

Traces of self-condensation product (12% by LC-MS) also appeared to have been present in the attempted reaction with 2-aminocyclohexylcarboxlic acid (Table  [²] , entry 5).

8

Typical Procedure: A suspension of 2-aminobenzoic acid (83 mg, 0.604 mmol) and 4-chloropyrido[3,2-d]pyrimidine (100 mg, 0.604 mmol) in i-PrOH (4 mL) and 2 M HCl (1 mL) was heated in a sealed vial in a microwave to 140 ˚C for 1 h. The crude reaction mixture was concentrated under reduced pressure, and triturated with Et₂O to yield the product as a pale yellow solid (116 mg, 81%).⁹

9

Lower-yielding reactions and those yielding multiple by-products were purified by reverse-phase flash column chromatography, or by mass-directed HPLC.