Experimental and Theoretical Studies on the Reactions of Aliphatic Imines with Isocyanates

In the context of a project aiming at the replacement of the 3-substituted β-lactam ring in classical β-lactam antibiotics by an N(3)-acyl-1,3-diazetidinone moiety, we have investigated the reaction of isocyanates with imines derived from allyl glycinate and differently substituted propionaldehydes. Imines of aromatic aldehydes with anilines have been reported to react with acyl isocyanates to give 1,3-azetidinones or 2,3-dihydro-4H-1,3,5-oxadiazin-4-ones, via [2+2] or [4+2] cycloaddition, respectively. However, neither of these products was formed with imines from allyl glycinate and 2-(mono)methyl propionaldehydes. α,α-Dimethylation of the imine enabled the [4+2] cycloaddition pathway, but the desired 1,3-diazetidinone products were not observed. Surprisingly, the imines obtained from thioesters of 2,2-dimethyl 3-oxo propionic acid reacted with aryl isocyanates or with benzyl isocyanate to give 2,2-dimethyl-2,4-dioxo-6-(aryl/akylthio)tetrahydropyrimidines, via thiol displacement and re-addition to a putative six-membered iminium intermediate. Such compounds have not been described in the literature so far. For aryl isocyanates, the reaction was insensitive to the nature of a para-substituent on the aromatic ring. The experimental results obtained for the reactions of acyl isocyanates with imines could be rationalized by DFT calculations. In addition, we have also shown that N(3)-acyl-1,3-azetidinone and 2,3-dihydro-4H-1,3,5-oxadiazin-4-one products can be distinguished based on experimental IR data in combination with theoretical reference spectra employing the IR spectra alignment (IRSA) algorithm. This discrimination was not possible by means of 1H, 13C, or 15N NMR spectroscopy.