A Practical Synthesis of 3-Diethoxyphosphoryl-1,2-pyridazine Derivatives

Under microwave (MW) heating, 1-diethoxyphosphorylbuta- 1,3-diene cycloadds to diethyl, diisopropyl and di-tert-butyl azodicarboxylates leading to the corresponding hetero Diels-Alder (HD-A) cycloadducts in excellent yields. Cycloaddition to the ditert-butyl derivative is conveniently scaled up using a six-entry parallel synthesis rotor (>10 g scale). B3LYP/6-31G** calculations confirmed the concerted, but highly asynchronous character of this reaction. The di-tert-butyloxycarbonyl cycloadduct is compatible with orthogonal deprotection (i.e., selective N-deprotection without degradation of the phosphonate ester). Thus, reduction and dihydroxylation of the C=C bond of this cycloadduct, followed by TFA deprotection, gave 3-diethoxyphosphorylhexahydro-1,2-pyridazine and 3-diethoxyphosphoryl-4,5-dihydroxyhexahydro-1,2-pyridazine, respectively. This H D-A strategy offers a convenient entry towards phosphonate bioisosters of cyclic alpha-hydrazino acid and azafagomine derivatives in racemic series.