SYNTHESIS OF BENZOXAZINE DERIVATIVES USING 2-AMINOPHENOL PRECURSORS

Abstract

The thesis entitled “Synthesis of Benzoxazine Derivatives Using 2-Aminophenol Precursors” is divided into three chapters, viz. (i) Introduction, (ii) Objectives, Results and Discussion, and (iii) Experimental. We have developed a one-pot domino oxidative cyclizationoxidativeacetalizationDiels-Alder reaction for the synthesis of densely substituted (benzoxazol-2’-yl)bicyclo[2.2.2]octen-2-one derivatives using environmentally benign and inexpensive hypervalent iodine reagent diacetoxyiodobenzene (DIB). Further we have developed novel synthetic methodologies for the synthesis of numerous 1,4- benzoxazine and coumarin derivatives from a new class of vinylogous carbamates using Lewis and Brønsted acids. Chapter 1: Introduction The organic compounds containing heteroatoms have engrossed a significant place in the modern organic synthesis as a result of their occurrence in various natural products and drug molecules. The synthesis of these heterocyclic compounds using readily available inexpensive reagents and environmentally benign methodologies has become a challenging task for the chemists. Among the various heterocyclic compounds, the benzoxazole and 1,4- benzoxazine derivatives found to exhibit a wide range of applications in pharma and agrochemical sectors. For example, benzoxazole core containing bicyclic systems calcimycin, cezomycin and routiennocin are isolated from the various strains of Streptomyces. and are found to act as good ionophore antibiotics. Benzoxazole derivatives act as estrogen receptor agonists, melotonin receptor agonists, anti tumor agents, and found to have applications in electronic devices, photoluminescent dyes and as sensors for metals, due to their fluorescent properties. The 1,4-benzoxazine derivatives also exhibit a wide range of biological activities such as antipsychotic agents, vasodilator agents, antibacterial agents, and antagonists, also been used in the treatment of heart disease, and diabetes. Apart from these, synthesis and screening of coumarin derivatives for drug discovery have become a subject of constant interest in pharmaceutical industry. Coumarins exhibit prominent biological activities such as antimicrobial, anticancer, antiallergic, and antiviral properties. The 3-N-substituted coumarins like novobiocin have been shown to bind to the C-terminal domain of heat shock protein 90 (hsp90), and thus become an exciting new target in cancer drug discovery. viii Chapter 2: Objectives, Results and Discussion This chapter deals with objectives, results and discussion which was further divided into six sections. 2.1. Facile one-pot synthesis of (benzoxazol-2’-yl)bicyclo[2.2.2]octen-2-one derivatives In the first instance, we performed one-pot domino oxidative cyclization oxidativeacetalizationDiels-Alder reaction mediated by hypervalent iodine reagent diacetoxyiodobenzene (DIB) in methanol. The process involves the initial oxidation of the aldimine to give the benzoxazole derivative, which was further oxidised in situ to generate the masked o-benzoquinone as intermediate diene that was trapped with various dienophiles to afford the corresponding (benzoxazol-2’-yl)bicyclo[2.2.2]octen-2-one derivatives in good yields. The aldimines which were oxidised in absence of external dienophiles have undergone dimerization via Diels-Alder reaction to afford their respective dimers. The Diels- Alder reaction of benzoxazol-2’-yl MOBs with the various dienophiles was found to be regio- and stereo-selective, which was further confirmed by the 2D-NMR and 1H-1H decoupling experiments (Scheme 1). N OH OH OMe O N OH OMe O N O MeO OMe X PhI(OAc)2 MeOH PhI(OAc)2 MeOH O N O MeO OMe X Y R R Y R R Dimerization O N O MeO OMe O O N MeO MeO R R Z Z Diels-Alder dimer Scheme 1: Domino oxidative cyclizationoxidative acetalizationDiels-Alder reactions. 2.2. Synthesis of pyrrolobenzoxazine derivatives We have developed a rapid and efficient methodology for the synthesis of pyrrolobenzoxazine mediated by trifluoroacetic acid. The initial step in this protocol involves the Michael addition of 1,4-benzoxazinone derivatives to the nitrostyrene ix derivatives and further it undergoes the subsequent cyclization to give the corresponding pyrrolobenzoxazine derivatives in good to excellent yields (Scheme 2). O HN O CO2Me R NO2 Ar TFA O N O R CO2Me Ar CH2Cl2 Scheme 2: Synthesis of pyrrolobenzoxazine derivatives. 2.3. Synthesis of 3-arylamino coumarin derivatives We have explored the reactivity of these novel class of vinylogous carbamates with pbenzoquinone derivatives. The reactions of 1,4-benzoxazinones with p-benzoquinone derivatives in presence of trifluoroacetic acid underwent smoothly and afforded the 3- arylamino coumarin derivatives in excellent yields. The reaction proceeds under mild conditions and obviates the use of column chromatography (Scheme 3). O O O NH MeO O O OH HO R O HN O CO2Me R TFA CH2Cl2 Scheme 3: Synthesis of 3-arylamino coumarin derivatives. 2.4. Synthesis of 3-substituted 1,4-benzoxazinone derivatives We have also developed a novel methodology for the alkylation of 1,4-benzoxazinone derivatives mediated by molecular iodine. These reactions proceeded efficiently with excellent yields and are compatible with various functional groups (Scheme 4). Ar Ar OH OH O N Ar Ar O O N O O OMe O OMe I2, DCE O I2, CH2Cl2 HN O CO2Me R R R Scheme 4: Molecular iodine-mediated alkylation reaction of 1,4-benzoxazinone derivatives. x 2.5. Synthesis of 2-aryl 1,4-benzoxazine derivatives Further to uncover the reactivity of these 1,4-benzoxazinone derivatives, they were transformed to 2-hydroxy-1,4-benzoxazines by reducing with sodium borohydride. These 2- hydroxy-1,4-benzoxazines have undergone the Friedel-Crafts arylation reaction smoothly with various electron-rich arenes in presence BF3.etherate. The current protocol provides an easy access for the synthesis of a series of densely substituted 2-aryl 1,4-benzoxazine derivatives under mild conditions (Scheme 5). O HN CO2Me OH R O HN CO2Me R Rn Rn BF3.Et2O CH2Cl2 Scheme 5: FriedelCrafts arylation reaction of 2-hydroxy-1,4-benzoxazines. 2.6. Synthesis of 2-amino 1,4-benzoxazine derivatives In continuation of our interest to explore their reactivity, the 2-hydroxy-benzoxazine derivatives were reacted with cyclic and acyclic secondary amines to afford 2-aminobenzoxazine derivatives in good yields (Scheme 6). MeOH O HN OH CO2Me R HN R1 R2 HN X O HN N CO2Me R R1 R2 O HN N CO2Me R X MeOH X = O, NBn Scheme 6: Synthesis of 2-amino 1,4-benzoxazine derivatives. [ Chapter 3: Experimental The third chapter provides experimental procedures in detail along with physical constants and spectral data.