One-Pot Synthesis of 6′-Amino-Substituted Spirooxazines

Abstract

A one-pot synthesis of 6¢-amino-substituted spiroindolinonaphth[2,1-b] [1,4]oxazines is developed through the condensation of 2-methylene-1,3,3-trimethylindoline derivatives and 1-amino-2-naphthol in the presence of different secondary amines and oxidizing agents using methanol or toluene as the solvent. The main advantage of the method is its simplicity, and starting from readily accessible reagents, it allows the preparation of amino derivatives of spironaphthoxazine with good yields under mild reaction conditions.Spirooxazines have UV activation properties and thermal bleaching properties that are convenient for practical applications. 1-5 By now, the widely applied procedures for the synthesis of spirooxazines consist in the condensation of nitrogen-containing heterocycles with hydroxynitroso compounds. 3 Unfortunately, this method affords spirooxazines in low yields, even if optimization of experimental conditions allowed to improve it in some cases. 3,6 The spirooxazine molecule can be constructed also by using 1-amino-2-naphthol as the starting material. [7][8][9][10][11][12] Most of the structural modifications of the oxazine fragment in spiro compounds are based on the substitution on the naphthalene ring. The required group is most commonly introduced into this fragment already in the preparation of the starting 1-nitroso-2-naphthol. Rickwood and co-workers used some secondary amines as nucleophiles for the preparation of 6¢-amino-substituted spironaphthoxazines. [13][14][15][16] It was assumed that the reaction involves the nucleophilic addition of secondary amine at position 4 of the quinone oxime tautomer of 1-nitroso-2-naphthol. Subsequent oxidation of intermediate can occur under the action of a second 1-nitroso-2-naphthol molecule, which partially accounts for the low yield.In this paper we describe the synthesis of the 6¢-aminosubsituted spirooxazines by one-pot condensation of 1-amino-2-naphthol with substituted 2-methyleneindolines in the presence of different secondary amines and oxidizing agent using methanol or toluene as the solvent (Scheme 1). To evaluate the general validity of the method and to show its advantages and limitations we varied the substituents in indoline molecules 1a-d and used different secondary cyclic amines 2a-d.Our experiments showed that alicyclic/aliphatic secondary amines did not participate in the condensation reaction. In the presence of diethylamine or bis(2-methoxyethyloxy)amine the condensation of 1a with 1-amino-2-naphthol results in the formation of unsubstituted spiroindolinonaphth[2,1-b][1,4]oxazine. In contrast, the method was successfully applied for the preparation of spirooxazines 3a-c, 4a, 5, and 6 with cyclic amine substitScheme 1 N R 2