Green Synthesis of Morpholines via Selective Monoalkylation of Amines

Morpholines are common heterocycles in pharmaceutical and agricultural products, yet methods to synthesize them from 1,2-amino alcohols are inefficient. We report the simple, high yielding, one or two-step, redox neutral protocol using inexpensive reagents (ethylene sulfate and tBuOK) for the conversion of 1,2-amino alcohols to morpholines. Key to this methodology is the identification of general conditions that allow for the clean isolation of monoalkylation products derived from a simple S_N2 reaction between an amine and ethylene sulfate. Experiments suggest that the degree of selectivity is dependent upon the structure of reacting 1,2-amino alcohol as well as the unique properties of ethylene sulfate. This method can be used for the synthesis of a variety of morpholines containing substituents at various positions, including 28 examples derived from primary amines and multiple examples contained in known active pharmaceutical ingredients. We have conducted multiple examples on >50 g scale. We have also demonstrated the formal synthesis of a morpholine from a simple primary amine using ethylene sulfate. Overall, while this new methodology has many environmental and safety benefits relative to the traditional methods used to prepare morpholines from 1,2-amino alcohols, the most striking feature is the facile selective monoalkylation of a variety of primary amines. We have also explored various reactions beyond those related to the synthesis of morpholines, including obtaining proof-of-principle that ethylene sulfate can be used for the synthesis of piperazines and as a 2-carbon electrophile for fragment couplings.