Chemo- and regio-selective functionalization of Morita-Baylis-Hillman bromides with anthranilic acid.

Introduction

The Morita-Baylis-Hillman reaction (1-4) (MBH), a powerful C-C bond forming reaction, has earned overwhelming popularity in recent years. The MBH adduct comprise of a contiguous assembly of three different functionalities and a chiral center. The versatility of the functionality of MBH adducts have made them valuable synthetic intermediates. Efforts of various research groups contributing to the widening of the substrate scope (1) of the MBH reaction have further diversified the functionality of MBH adducts (Fig. 1).

Functionalization of MBH adducts and their derivatives is an active area of research, as it provides valuable synthetic intermediates, which have been successfully translated into various useful synthetic targets, including substituted alkenes, (5) carbocycles, (6) heterocycles, (7) and several biologically relevant molecules. (1e,1g) The repertoire of nucleophiles added to MBH adducts includes carbon, (8) hydrogen, (9) heteroatomic nucleophiles, (10) aromatics, (11) and heteroaromatics. (12) In addition to newer nucleophiles (13) being added to MBH acetates/bromides, the synthetic potential of previously reported nucleophilic substitution products is illustrated by newer applications. (14)

Nucleophilic substitution of MBH adducts and their derivatives with monofunctional aromatics and their further elaboration to several synthetic targets have been extensively studied. (15) Basavaiah et al. (16) synthesized chromones from phenol (16b-16d) substitution products and successfully applied the same strategy to the synthesis of antifungal agents.

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Aniline substitution products have been elaborated to synthesize indenoquinolinones, (17a) polysubstituted quinolines, (17b) quinolones, quinolinols, indanones and indenoindenones, (17C) and [beta]-lactam. (17d,17e) The fascinating post modifications of nucleophilic substitution products of monofunctional aromatics made the nucleophilic substitution of bifunctional aromatics intriguing. However, literature scanning reveals only a few reports of nucleophilic substitution of MBH derivatives with bifunctional aromatics. (18) Kim et al. (18a) added o-phenylenediamine on Baylis-Hillman acetates and subsequently converted to benzodiazepinones and benzoimidazoles. Basavaiah and Satyanarayana (18b) reported one-pot transformation of the Baylis-Hillman acetates to fused pyrimidones via a reaction with 2-aminopyridine in aqueous media. The synthetic utility of dinaphthol substitution products were illustrated in the synthesis of bis-chromones. (18c) In this context, we were prompted to explore this avenue of MBH chemistry, and herein, we wish to report the results of our investigation of the chemo- and regio-selectivity of nucleophilic substitution of MBH bromides with anthranilic acid.

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Results and discussion

Recently, we have reported the functionalization of MBH bromides with symmetric and asymmetric bifunctional aromatics, (19) and in continuation of our interest in this avenue of MBH chemistry, we intended to study the functionalization of MBH bromides with anthranilic acid. Accordingly, a solution of MBH bromide (1a) in DMF was treated with anthranilic acid in the presence of potassium carbonate to furnish 2a in 61% isolated yield (Scheme 1).

The presence of two stretching absorptions in the IR spectrum of 2a (3266 and 3468 [cm.sup.-1]) indicated that the N-terminal of the anthranilic acid moiety is free. Moreover, the downfield appearance of the allylic protons ([delta] 5.15 ppm) confirmed the formation of O-linked products. The reaction was then extended to other MBH bromides (1b-1i), and the results are assembled in Table 1.

The stereochemistry of the products 2a-2i was settled on the basis of difference nuclear Overhauser effect (NOE) experiments on 2f. Irradiation of the methylene protons at [delta] 5.0 ppm led to the enhancement of the aromatic signal at [delta] 7.33 by 5.25%. However, there was comparatively less enhancement in the olefinic signal (0.69%) implying they are spatially far, and thus confirming E stereochemistry (Fig. 2). Further irradiation of the ester methyl proton resulted in the enhancement of the olefinic peak, confirming their spatial proximity.

To study the regio- and chemo-selective outcome of the reaction, we further treated MBH bromide with anthranilic acid in the presence of [K.sub.2]C[O.sub.3] in DMF at 80[degrees]C. TLC monitoring revealed the formation of a new minor product in addition to O-linked product. Prolonging the heating did not improve the yield of the minor product. The new product was characterized by IR, NMR, and Mass studies. The IR spectrum of the product exhibited only one stretching absorption, suggesting secondary amine functionality. The allylic protons were observed at [delta] 4.26 ppm (as compared with the O-linked allylic protons at [delta] 4.92-5.15 ppm), confirming the formation of N-linked product 3a. Small coupling was observed in the allylic proton signal due to the NH proton further confirming the formation of N-linked products. However, the carboxyl proton was not detected in the [sup.1]H NMR spectrum, and the presence of the carboxyl group in the product was confirmed through IR and [sup.13]C spectral analysis.

Interestingly, on heating O-linked anthranilic acid, substitution products 2a in DMF with [K.sub.2]C[O.sub.3] at 80[degrees]C, N-linked [S.sub.N]2 products 3a was obtained in comparatively good yields (Scheme 1). (20) The generality of the reaction was demonstrated by the successful conversion of O-linked products 2b, 2c, and 2h to 3b, 3c, and 3d, respectively (Table 2).

With the O-linked anthranilic acid products in our hands, we intended to further derivatize these substitution products by treatment with trifluoroacetic anhydride (Scheme 2). Consequently, 2a was stirred in trifluoroacetic anhydride at ice temperature under nitrogen atmosphere, and we observed solidification of the reaction mixture immediately. TLC profile of the reaction mixture showed two new spots. The major product was assigned the structure 4a and the minor product was found to be 5a. (20)

The formation of 5a can be explained as the …