Chemistry
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Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions
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Summary July 28th, 2022
Contiguous bisaziridines containing non-activated and activated aziridines were synthesized by asymmetric organocatalytic aziridinations and then subjected to chemoselective ring-opening reactions under acidic or basic conditions. The non-activated aziridine ring opens with less reactive nucleophiles under acidic conditions, whereas the activated aziridine ring opens with more reactive nucleophiles under basic conditions.
Transcript
The significance of our protocol is rational design of contiguous bisaziridine containing both activated and non-activated aziridines, and subject it to regioselective ring-opening reactions with diverse nucleophiles. The advantage of this technique is that it allows the synthesis of nitrogen-rich molecules using predictive modeling tools for selective ring openings. The current protocol can be used to develop practical methods for the synthesis of nitrogen-enriched bioactive compounds and natural products.
To begin, flame dry a 50-milliliter round-bottomed flask with a stirrer bar and a septum under vacuum conditions. After cooling it to room temperature, fill it with argon gas. Then add anhydrous methanol and aldehyde to the flask, and stir the solution for a minute.
Next, add sodium borohydride to the stirred solution, and stir the reaction mixture at zero degrees Celsius for one hour. Monitor the reaction progress by TLC, using ethyl acetate and hexanes as an eluent. After one hour, quench the reaction mixture with distilled water, and extract with ethyl acetate in a separatory funnel.
Dry the combined organic layer over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify the crude residue by silica gel flash chromatography with ethyl acetate and hexanes as the eluent, to isolate pure products as a yellow liquid. Afterward, confirm the product by NMR and polarimeter measurements.
First, flame-dry a five-milliliter round-bottomed flask with a stirrer bar and a septum under vacuum conditions. Then cool it to room temperature while filling it with argon gas. Next, add the previously synthesized bisaziridine and acetic acid to the flask.
Stir the mixture at room temperature for five hours, and monitor the reaction progress by TLC, using ethyl acetate and hexanes as an eluent. After five hours, remove the acetic acid in vacuo, and purify the crude residue by silica gel flash chromatography with ethyl acetate and hexanes as the eluent, to isolate the pure product as a yellow liquid. Confirm the product by NMR and polarimeter measurements.
The proton NMR spectrum revealed a peak at 1.42 ppm, corresponding to the alcohol hydrogen in the ethyl alcohol adjacent to the aziridine, indicating the reduction of an aldehyde into ethyl alcohol. Moreover, the peaks at 4.00 and 3.54 ppm represent the methylene hydrogens in ethyl alcohol. The peak observed at 2.13 ppm corresponds to the methyl hydrogens of acetate, whereas peaks at 4.43 and 4.15 ppm correspond to the methylene hydrogens adjacent to acetate formed after the aziridine ring-opening reaction.
Reduction involving NaBH4 have found to be exothermic, and thus, maintain the reaction temperature at zero degrees Celsius. Also, care is required during the quenching of NaBH4 by H2O. We believe that this technique will stimulate further research toward the development of practical methods for the construction of nitrogen-enriched complex molecules having biological activities.
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