Green Synthesis of Morpholines via Selective Monoalkylation of Amines
Kacey G. Ortiz, Andrew T. Brusoe, Jason An, Eugene Chong, Lifen Wu
Abstract
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 t BuOK) 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 N 2 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.