Mild deprotection of the N-tert-butyloxycarbonyl (N-Boc) group using oxalyl chloride.

Nathaniel George,Sean Parkin,Samuel G Awuah,Samuel Ofori

doi:10.1039/d0ra04110f

Abstract

We report a mild method for the selective deprotection of the N-Boc group from a structurally diverse set of compounds, encompassing aliphatic, aromatic, and heterocyclic substrates by using oxalyl chloride in methanol. The reactions take place under room temperature conditions for 1–4 h with yields up to 90%. This mild procedure was applied to a hybrid, medicinally active compound FC1, which is a novel dual inhibitor of IDO1 and DNA Pol gamma. A broader mechanism involving the electrophilic character of oxalyl chloride is postulated for this deprotection strategy.

Highlights

Synthetic organic transformations require the appropriate selection of reagents, catalysts, and most importantly, temporal masking and demasking agents
In our effort to generate an acylchloride from the C-terminus of a N-Boc protected peptidomimetic using oxalyl chloride, we observed the concomitant formation of the deprotected N-Boc to form the peptidomimetic with a free amine
We found that the deprotection reaction proceeds poorly in neat oxalyl chloride

Summary

Introduction

Synthetic organic transformations require the appropriate selection of reagents, catalysts, and most importantly, temporal masking and demasking agents. The amino group is a key functionality that is present in several compounds: natural products, amino acids and peptides.[2] As such, there is an emergent need for its masking and demasking in forward synthesis. Traditional approaches for N-Boc deprotection relies largely on TFA-induced cleavage.[14] Other strategies reported for the deprotection of N-Boc include the use of metal catalysts,[15,16] as well as acetylchloride in methanol,[17] N-Boc removal with HCl in organic solvents: ethylacetate,[18] dioxane,[19] in acetone.[20] Other NBoc deprotection methodologies include aqueous phosphoric acid,[21,22] conc. The reactivity of oxalyl chloride with amides manifests in useful products through a typical imidoyl chloride intermediate when acetamide starting materials are used.[35]

Results and discussion

Conclusion

Experimental procedures