o-Iodoxy Benzoic Acid–Mediated Synthesis of 3,5-Diarylisoxazoles and Isoxazole-3-carboxylic Acids

Abstract A new, convenient, ecofriendly synthesis of 3,5-diarylisoxazoles is reported from α,β-unsaturated ketoximes. Similarly, a novel synthesis of isoxazole carboxylic acids is also reported. Both the methods use efficient, environmentally friendly, and nontoxic iodoxybenzoic acid (IBX) as an oxidative cyclizing reagent. Easy procedure, environmentally benign reaction conditions, and nontoxicity are advantages to the methodology. GRAPHICAL ABSTRACT


INTRODUCTION
In recent years, the organic chemistry of hypervalent iodine compounds [1][2][3][4] such as o-iodoxy benzoic acid (IBX) and iodobenzene diacetate (IBD) has experienced immense development. This growing interest in iodine hypervalent compounds is due to their mild and high chemoselective properties combined with benign environmental character and commercial availability. Hence, numerous new chemical transformations effected by these hypervalent iodine reagents, as powerful reagents, have recently been developed. [5][6][7] Isoxazoles [8][9][10] are an important class of heterocycles owing to their diverse applications. They act as intermediates in the synthesis of natural products and as building blocks for construction of new molecular systems. [11] Activity includes a wide range of applications as herbicides and fungicides. [12,13] There are several routes by which 3,5-diaryl isoxazoles can be synthesized. The [5 þ 0] routes involving oxidative cyclization of a,b-unsaturated ketoximes using oxidizing agents such as 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), [14] MnO 2 , [15] I 2 =KI in NaHCO 3 , [16] tetrakis(pyridine)cobalt dichromate (TPCD), [17] KOH-dioxane, [18] N-bromosuccinimide, [19] and NOBF 4 [20] are some of the few known. Microwave-assisted synthesis of isoxazoles has also been reported. [21][22][23][24] There are few reports of one-pot synthesis of isoxazole. [25][26][27][28][29] However, the mentioned methods involve use of expensive catalyst or high-temperature reaction conditions and have limited applicability to a variety of substrates. Isoxazole-3carboxylic acids also possess various biological activities such as antitubercular, [30,31] protein tyrosine phosphate IB(PT1B) inhibitory, [32] etc. 5-Phenylisoxazole-3carboxylic acid derivatives are found to be potent xanthine oxidase inhibitors. [33] Either it is prepared from previously constructed isoxazole nucleus or by ring-closure methods using appropriate starting compounds containing carboxyl or alkoxy carbonyl groups. In this, ring-construction of isoxazole has been a widely used method. However, few syntheses of isoxazole carboxylic acids have been a reported. [33,34] Despite the various methods of synthesis reported for disubstituted isoxazole and isoxazole-3-carboxylic acid, development of newer ecofriendly and green methodologies remains a challenging task for synthetic organic chemists. In our earlier approaches we have developed novel strategies for synthesis of important heterocycles. [14,15] o-Iodoxy benzoic acid (IBX) is a well-known, nontoxic, environmentally benign reagent which has been extensively used for various organic functional group transformations. [5][6][7]35] In view of this, we thought of trying IBX as a reagent for oxidative cyclization.

RESULTS AND DISCUSSION
Herein, we describe a convenient methodology toward the synthesis of 3,5diaryl isoxazoles from a,b-unsaturated ketoximes. The parent chalcone (1a) prepared by Claisen-Schmidt condensation was first converted into its corresponding oxime by a reported literature procedure [36] via hydroxylamine hydrochloride treatment under weakly basic conditions in good yield. The oxime, after isolation and purification, was then subjected to oxidative cyclization in refluxing chloroform using 1 equivalent of IBX. The reaction mixture was continuously monitored and the thin-layer chromatography (TLC) was checked with the authentic sample for the completion of the reaction. The reaction reached completion in 4 h as indicated by TLC. The crude mixture was then concentrated to remove chloroform, adsorbed over silica gel, and loaded for column chromatographic separation. The product, 3,5-diphenylisoxazole, was obtained as a white solid, which was recrystallized using ethanol to give pure isoxazole (3a) in 78% yield. In its 1 H NMR spectrum, it showed a singlet at d 6.8 ppm, a characteristic signal indicating the presence of C-H at the 4-position of the isoxazole ring. To check the generality of this reaction, various a,b-unsaturated ketoximes were tried for oxidative cyclization using IBX as reagent. Besides the parent 3,5-diphenylisoxazole, 11 more differently substituted 3,5-diaryl isoxazoles were synthesized in moderate to good yields after chromatographic separation (Scheme 1, Table 1). It was observed that the nature and position of the substituent on the aryl ring did not make much difference in reactivity. All the compounds have been well characterized by comparison with authentic sample melting points as well as spectroscopic data (IR, NMR). Having successfully prepared the diarylisoxazoles, we thought of synthesizing isoxazole-3-carboxylic acids starting from benzalacetone oxime and 3 equivalents of IBX. Chromatographic separation and recrystallization gave 5-phenyl isoxazole-3carboxylic acid in 67% yield. Although the actual mechanistic pathway is not known, we thought to propose the following putative mechanism [38,39] (Scheme 2) for the conversion. Intramolecular Michael-type addition, insertion of hypervalent iodine across the double bond, followed by the oxidation of the methyl group to carboxylic acid group with the elimination of iodosobenzoic acid were performed. In its 1 H NMR spectrum, it showed a singlet at d 9.33 ppm, indicating the presence of a proton of carboxylic acid, while in its 13 C NMR spectrum, it showed a singlet at d 171 ppm, indicating the carbonyl carbon of the carboxylic acid. This prompted us to extend this methodology toward synthesizing more isoxazole carboxylic acids. We synthesized in all five such isoxazole-3-carboxylic acids ( Table 2). The melting points obtained for the products compare well with the reported synthesis of isoxazole carboxylic acids (Scheme 3). None of the reactions led to any kind of by product formation.
With the growing need to follow the trend of green chemistry, we also attempted one-pot synthesis of 3,5-disubstitutedisoxazole (Scheme 4). Herein the substituted
Step 1: synthesis of 3-methyl-5-phenyl isoxazole; Step 2: synthesis of 5-phenyl isoxazole-3-carboxylic acid.  [31] a All products were characterized by 1 H NMR, 13 C NMR, and IR data. b Yields after purification by chromatography.   (7) was treated with excess of hydroxylamine under weakly basic conditions in chloroform. After 4 h, TLC indicated the formation of oxime. To this, 3 equivalents of IBX was added and the reaction mixture was further refluxed. After 15 h the reaction reached completion and after purification gave the corresponding isoxazole in 88% yield. Herein, this one-pot methodology involved three reactions: oxime formation, cyclization, and oxidation. The method was tried for only one example. All the products obtained were characterized by comparing melting points with literature and spectroscopic data (IR, 1 H NMR, and 13 C NMR).

CONCLUSION
In conclusion, a convenient and an efficient method for the synthesis of 3,5diarylisoxazoles from a,b-unsaturated ketoximes have been developed for various substrates. The significance of our synthesis of isoxazole carboxylic acid is that it involves three reactions: cyclization, followed by oxidation, leading to isoxazole ring, and then oxidation of side chain methyl group to carboxylic acid group. Also the onepot synthesis of 3,5-diarylisoxazole has been carried out effectively. Use of IBX for oxidative cyclization signifies nontoxicity and ecofriendliness of the methodology. All the reagents are used in stoichiometric amounts in view of the need for environmentally benign synthesis. The sequence exhibits wide scope and is tolerant of various substituted aromatic substrates.