Synthesis of 4 H-Benzo[ e][ 1,3]oxazin-4-ones by a Carbonylation-Cyclization Domino Reaction of ortho-Halophenols and Cyanamide

Abstract

A mild and convenient one-step preparation of 4H-1,3-benzoxazin-4-ones by a domino carbonylation-cyclization process is developed. Readily available ortho-iodophenols are subjected to palladium-catalyzed carbonylative coupling with Mo(CO)₆ and cyanamide, followed by a spontaneous, intramolecular cyclization to afford 4H-1,3-benzoxazin-4-ones in moderate to excellent yields. Furthermore, the scope of the reaction is extended to include challenging ortho-bromophenols. Finally, to highlight the versatility of the developed method, Mo(CO)₆ is successfully replaced with a wide array of CO-releasing reagents, such as oxalyl chloride, phenyl formate, 9-methylfluorene-9-carbonyl chloride, and formic acid, making this an appealing strategy for the synthesis of 4H-benzo[e][1,3]oxazin-4-ones.

Keywords: 4H-benzo[e][1,3]oxazin-4-ones; carbonylation; domino reactions; halophenols; heterocycles.

Scheme 1

Synthetic procedures for the preparation of benzoxazinones, carbonylation–cyclization domino reactions used in the synthesis of 2‐aminoquinazolinones, and the work presented herein.

Scheme 2

Synthesis of 2‐amino‐4H‐benzo[e][1,3]oxazin‐4‐ones 2 a–l from ortho‐iodophenols 1 a–l (isolated yields).

Scheme 3

Synthesis of 2‐amino‐4H‐benzo[e][1,3]oxazin‐4‐ones 2 a, 2 d, and 2  m ‐q from ortho‐bromophenols 3 a–g (isolated yields).

Scheme 4

Mechanistic studies for the formation of 2 a from 1 a. Reaction conditions: a) 4‐methoxybenzylbromide, K₂CO₃, DMF, 50 °C, 5 h; b) NH₂CN, Pd(PPh₃)₄, Et₃N, Mo(CO)₆, DBU, 1,4‐dioxane, 65 °C, 20 h; c) TFA, CH₂Cl₂, 0 °C to RT, 1 h.