Synthesis of N-alkoxycarbonyl Pyrroles from O-Substituted Carbamates: A Synthetically Enabling Pyrrole Protection Strategy
Jodie L. Hann, Catherine L. Lyall, Gabriele Kociok-Köhn and Simon E. Lewis*
*Department of Chemistry, University of Bath, Bath BA2 7AY, U.K.,
Email: S.E.Lewis
bath.ac.uk
J. L. Hann, C. L. Lyall, G. Kociok-Köhn, S. E. Lewis, J. Org. Chem., 2023, 88, 13584-13589.
DOI: 10.1021/acs.joc.3c01257
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Abstract
The condensation of readily available O-substituted carbamates with 2,5-dimethoxytetrahydrofuran gives N-alkoxycarbonyl pyrroles in good yield. N-alkoxycarbonyl protection can endow pyrrole with distinct reactivity in comparison with N-sulfonyl protection, for example, in a pyrrole acylation protocol employing carboxylic acids with a sulfonic acid anhydride activator.
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General Procedure for N-alkoxycarbonyl Pyrrole Synthesis
Carbamate (4 mmol, 1.0 equiv) and 1,4-dimethoxytetrahydrofuran (0.63 mL, 4.4 mmol, 1.1 equiv, mixture of cis and trans) were added to a flask and purged with nitrogen. AcOH (2.2 mL) was added, and the reaction was heated to reflux (110 °C) using a heating mantle. The reaction was monitored by TLC, and upon completion was cooled to ambient temperature. (Vanillin TLC stain used for non-UV active substrates). CH2Cl2 (50 mL) was added, then washed with saturated Na2CO3(aq) (50 mL × 2), then brine (50 mL). The organic layer was dried over MgSO4 and filtered, and then the filtrate was concentrated in vacuo. The crude product was purified by passage through a silica plug (elution with CH2Cl2), and any residual 1,4-dimethoxytetrahydrofuran starting material was removed under a vacuum.
General Procedure for Acylation Reactions Using Tf2O
To a nitrogen-purged flask of N-alkoxycarbonyl pyrrole (1 equiv), and carboxylic acid (1 equiv) in dry dichloromethane (c = 0.44 M), trifluoromethanesulfonic anhydride (10 equiv) was added dropwise at 0 °C. The reaction was stirred without further cooling and monitored by TLC, and upon completion, the reaction was diluted with CH2Cl2 and washed with 1 M Na2CO3 (aq). The organic layer was separated, and the aqueous layer extracted with CH2Cl2 (×2). The combined organic solutions were then washed with brine, dried over MgSO4, and filtered, then the filtrate was concentrated in vacuo. The crude product was purified by column chromatography (SiO2, EtOAc-Pet Ether).
General Procedure for N-Troc Deprotection
To zinc dust (1.72 mmol) and the N-Troc-protected product (0.44 mmol), CH2Cl2 (3.2 mL) and AcOH (0.66 mL) were added. The reaction was stirred at ambient temperature and monitored by TLC until consumption of the starting material. The reaction mixture was diluted with acetone (30 mL) and filtered through celite, then concentrated under a vacuum to obtain an analytically pure product.
Key Words
pyrroles, cleavage of carbamates
ID: J42-Y2023
