A rationalization for the structure‒activity relationship of α-functionalized β-enamino γ-sultams

Abstract

Herein we describe the reaction of 2-methyl-2-(methylamino)propanenitrile and 1-(methylamino)cyclobutane-1-carbonitrile with α-functionalized sulfonyl chlorides and the reactivity of resulting α-functionalized β-enamino γ-sultams. The nature of the substituent or the functional group in the α-position has a decisive impact on the reactivity of β-enamino γ-sultams. In particular, α-unsubstituted β-enamino γ-sultams and those possessing either electron-donating substituents or phenyl group are prepared through the two-step procedure and are prone to acid-mediated hydrolysis. Contrary to that, a strong electron-withdrawing group in the α-position enables the synthesis of the corresponding β-enamino γ-sultams in a one-pot manner and makes them tolerate the acid-mediated hydrolysis. The analysis of the results of a complex study involving physical methods (NMR and IR spectroscopy, X-ray diffraction study) and DFT calculations (performed at PBE0 QZVP level of theory) allowed us to rationalize and formulate the rules of structure‒activity relationship for the discussed sultams. It turned out, that the simplest way to predict the reactivity of α-functionalized β-enamino γ-sultams is the 1H NMR spectroscopy: if the NH2 group appears in the spectrum as a two-proton singlet the compound is highly likely can be further modified while the appearance of two separated one-proton singlets indicates a low reactivity of β-enamino γ-sultams.