期刊
GREEN CHEMISTRY
卷 23, 期 6, 页码 2336-2351出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d0gc04395h
关键词
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资金
- University of Liege (Welcome Grant) [WG-13/03]
- F.R.S.-FNRS (Incentive grant for scientific research) [MIS F453020F]
- Fonds de la Recherche Scientifique de Belgique (F.R.S.-FNRS) [2.5020.11]
- Walloon Region
- Research Foundation -Flanders (FWO) [AUGE/11/029, G099319N]
A scalable continuous flow process has been developed for the efficient and safe electrophilic alpha-aminohydroxylation of enolizable ketones using alpha-chloronitroso derivatives. The process showcases the economic and efficient nature of alpha-chloronitroso derivatives in transferring electrophilic synthons of hydroxylamine, allowing for the preparation of valuable molecules with high atom economy. The process features sequential modules, in-line extractions, and in-line analytical procedures to improve process control and safety, making it easily transposable to pilot scale and ideal for compound library screening in medicinal chemistry.
The unique reactivity profile of alpha-chloronitroso derivatives is expressed to its fullest potential through the development of an integrated, modular and scalable continuous flow process for the electrophilic alpha-aminohydroxylation of various enolizable ketones. Flow conditions contribute to mitigating the high reactivity and toxicity of alpha-chloronitroso derivatives and provide an efficient, versatile and safe protocol for the alpha-aminohydroxylation of ketones with a minimal footprint. Fundamental aspects of the alpha-aminohydroxylation process were computed by DFT and further supported the experimental observations, hence leading to the unprecedented alpha-chloronitroso-based alpha-aminohydroxylation of primary, secondary and tertiary substrates. Recycling of the carbon backbone of the alpha-chloronitroso derivatives provides a high atom economy for the preparation of value-added molecules. This work showcases alpha-chloronitroso derivatives as economic and efficient vehicles for transferring electrophilic synthons of hydroxylamine toward nucleophilic enolates. A representative range of precursors and analogs of pharmaceutical active ingredients, including WHO essentials and drugs in shortage (such as epinephrine and ketamine), are prepared within minutes according to a fully concatenated process. The process features sequential modules with distinct unit operations including chemical transformations and multiple in-line extractions. The process relies on an upstream chemical Generator that manages the preparation of alpha-chloronitroso derivatives and that feeds downstream a series of alpha-aminohydroxylation modules. The setup is amenable to the addition of libraries of compounds for feeding upstream the process of discovery in medicinal chemistry and is transposable to pilot scale. Several layers of in-line analytical procedures are featured to improve process control and safety.
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