Kacey G. Ortiz, Andrew T. Brusoe, Jason An, Eugene Chong, Lifen Wu
{"title":"Green Synthesis of Morpholines via Selective Monoalkylation of Amines","authors":"Kacey G. Ortiz, Andrew T. Brusoe, Jason An, Eugene Chong, Lifen Wu","doi":"10.1021/jacs.4c11708","DOIUrl":null,"url":null,"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 <i>t</i>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<sub>N</sub>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.","PeriodicalId":49,"journal":{"name":"Journal of the American Chemical Society","volume":null,"pages":null},"PeriodicalIF":14.4000,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of the American Chemical Society","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1021/jacs.4c11708","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
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 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 SN2 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.
期刊介绍:
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