Throughout the last decade, novel Mannich bases have served as important sources of new drug candidates.These have been evaluated as potential treatments for a multitude of diseases and medical conditions as prodrugs, or as molecules eliciting responses from specific biological targets. Nabumetone (Figure 1) is an inexpensive readily-available non-steroidal anti-inflammatory drug (NSAID) with well-defined activity and toxicity profiles. Since it is a methyl ketone, we felt that it would be a useful starting material for Mannich reactions aimed at preparing a new category of sulfonamide anti-bacterials. The present work is a pilot study directed toward the building of novel Mannich bases derived from nabumetone and the well-documented sulfa drug sulfamethoxazole (Figure 2). In the event, compounds 1-4 were prepared by reaction of nabumetone with aromatic aldehydes and sulfamethoxazole in a straightforward procedure (Scheme 1;; see Experimental section), leading to the desired Mannich bases. Sulfonamides in general have reduced nucleophilicity due to the electron-withdrawing capability of the sulfonyl moiety, and sometimes they do not undergo reactions typical of primary amines. We were thus pleased to note that our procedure led to the desired bases in moderate to good yields (mean 70), typical for the Mannich process. The products were obtained in pure form. The novel Mannich bases could be readily identified on the basis of their characteristic spectra. Thus, the FTIR data of compounds 1-4 showed the appearance of absorption bands near 3400-3344 cm~(-1) for NH, 3080 cm~(-1) for C-H (aromatic), 1710 cm~(-1) for C = 0, 1340 and 1160 cm~(-1) for SO2. In addition, we observed the disappearance of the two bands near 3300 cm~(-1) for NH2. The spectrometric data are more extensively listed in Table 1 and microanalysis data are listed in Table 2.
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