Treatment of CH‐diazomethane sulfonamides with tert‐butyl nitrite produces novel sulfamoyl cyanide N‐oxides which dimerize to form furoxanes. When the reaction is performed in the presence of a dipolarophile, an olefin or an alkyne, dipolar cycloaddition takes place to deliver isoxazolines or isoxazoles, respectively.
A newly introduced diazo reagent, 1‐diazo‐N,N‐bis(4‐methoxybenzyl)methanesulfonamide, enables access to a range of azole‐based primary sulfonamides via [3+2] cycloaddition followed by protecting group removal. Such compounds are representative of the sulfonamide chemical space highly relevant but hitherto not investigated in the context of inhibition of therapeutically relevant isoforms of carbonic anhydrase enzyme. Using this reagent, three sets of primary sulfonamides based on pyrazole, 1,2,3‐triazole and tetrazole cores were synthesized and profiled for inhibition of tumor‐associated hCA IX and XII isoforms as well as abundant cytosolic hCA I and II isoforms. Using virtual library design and docking prioritization tool of the Schrödinger suite, one of the promising leads was evolved into a dual hCA IX/XII inhibitor with excellent selectivity over off‐target hCA I and II. The new synthetic strategy to access azole‐based primary sulfonamides will support the discovery of novel, isoform‐selective inhibitors of carbonic anhydrase within the poorly explored azole chemical space.
The previously described α-acetyl-α-diazomethanesulfonamide was employed in a three-component reaction with azide-containing benzaldehydes and propargylamines. Besides the initial formation of the triazole core, the reaction proceeded further, in uncatalyzed fashion at room temperature and yielded, after intramolecular azide–alkyne click reaction novel, structurally intriguing bistriazoles.
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