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A novel use of catalytic zinc-hydroxyapatite columns for the selective deprotection of N-tert-butyloxycarbonyl (BOC) protecting group using flow chemistry

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Abstract

The development of a single step flow process for the deprotection of the common protecting group tert-butyloxycarbonyl (BOC) is presented. Conventional BOC deprotection methods can require up to 24 h to fully deprotect compounds and may require cleanup due to undesired side products [1]. Long reaction times, high temperature, and undesired destruction of other protecting groups or the compound itself, have been reported in alternative methods presented recently in the literature [2]. The process presented herein allows for near quantitative and selective deprotection of the BOC protecting group in 30 min at 150 °C in flow using a zinc-hydroxyapatite (Zn-HAP) column. A selection of nineteen examples with diverse functionalities were used to demonstrate the application of this catalyst in flow. The products of the reactions were analyzed by HPLC, LC-MS and CE to determine the yield and purity. In comparison to the standard deprotection methods our process yields a clean, fast and selective method to deprotect N-Boc products and yields the desired corresponding free amine products. Of the nineteen compounds, nine transformations resulted in clean products (≥90 % ). One of these products was tested for racemization and the product remained enantiopure.

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Acknowledgements

We thank Jason Crema, Laurent Vinet, Ali Azizi and Réjean Fortin for their contribution to this project. This research was funded by Natural Sciences and Engineering Research Council of Canada (NSERC) and the Atlantic Canada Opportunities Agency (ACOA) Atlantic Innovation Fund (AIF), both to CB.

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Authors and Affiliations

  1. Department of Chemistry, Bishop’s University, 2600 College Street, Sherbrooke, QC, J1M 1Z7, Canada

    Evan Langille & Alexandre Drouin

  2. Department of Chemistry, Memorial University of Newfoundland, 283 Prince Philip Drive, St. John’s, NL, A1B 3X7, Canada

    Evan Langille & Christina S. Bottaro

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  1. Evan Langille
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  2. Christina S. Bottaro
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  3. Alexandre Drouin
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Correspondence to Evan Langille.

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Article Highlights

• A method of catalytic BOC deprotection in flow has been reported using a zinc-hydroxyapatite column

• The method tolerates a wide variety of functional groups and yields selective deprotection when other protecting groups are present

• The method utilizes low temperature (150°C) allowing for this methodology to be more accessible for larger scale production processes

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Langille, E., Bottaro, C.S. & Drouin, A. A novel use of catalytic zinc-hydroxyapatite columns for the selective deprotection of N-tert-butyloxycarbonyl (BOC) protecting group using flow chemistry. J Flow Chem 10, 377–387 (2020). https://doi.org/10.1007/s41981-019-00052-x

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