Iodine-promoted amide formation via oxidative cleavage of indoles: novel quinazoline-4(3 H)-one and tryptanthrin syntheses

Abstract

A highly efficient method for the direct construction of amide bonds via a selective cleavage of C-H and C[double bond, length as m-dash]C bonds in indole structures using an iodine-promoted approach was developed. Mechanistic studies indicated the formation of superoxide radicals obtained from molecular oxygen activation as a key intermediate step, which provided a precursor for subsequent oxidative ring-opening and intermolecular cyclization. A broad range of quinazolin-4(3H)-ones and tryptanthrins were synthesized in moderate to good yields under mild and environmentally benign conditions.

Scheme 1. Different routes for the cleavage of C–H to obtain amide bonds. (A) General strategy to constitute the amide bond. (B) This work: using iodine-promotion for the construction of amide bonds in quinazolin-4(3H)-one and tryptanthrin backbone.

Scheme 2. Scope of the synthesis of quinazolin-4(3H)-ones and tryptanthrins. ^aThe reactions synthesis of quinazolin-4(3H)-ones was performed on 0.15 mmol 1 and 1.5 equiv. 2 with I₂ (1.2 equiv.), K₂CO₃ (2 equiv.) in 2 mL ethyl acetate at 80 °C under O₂ atmosphere (1 atm) for 4 h. *3aa was obtained from reactions of 2-phenylindole with NH₄HCO₃, benzamidine-HCl or 2-phenylglycine in 94%, 98% or 86% yields respectively. **4 equiv. of H₂O₂ was added. ^bConditions: indole (0.25 mmol), I₂ (50 mol%), TBHP_aq. (3 equiv.), K₂CO₃ (2 equiv.) in CH₃CN (3 mL), 80 °C, 2 h, under O₂ atmosphere (1 atm).

Scheme 3. Investigation into the iodination at the C-3 position of indoles.

Scheme 4. Determination of intermediates in the transformation of quinazolin-4(3H)-ones.

Scheme 5. Role of oxygen in the reaction and radical trapping tests.

Fig. 1. EPR experiments.

Scheme 6. Possible reaction mechanism.