Abstract
The SNAr arylation of peptides with perfluoroaromatics provides a route by which to install a useful chemical handle that enables both 19F-NMR analysis and further chemical modification. However, chemo-selective arylation in peptides containing multiple nucleophilic side chains currently presents a challenge to the field. Herein, we demonstrate that employing 2,2,2-trifluoroethanol (TFE) as a solvent in peptide SNAr reactions significantly improves nucleophile-selectivity when compared to N,N'-dimethylformamide (DMF).
Highlights
View Article OnlineThe perfluoroaromatic reagent (ArF) pentafluoropyridine (1) is a highly useful synthetic building block that can undergo multiple substitution reactions with a broad range of nucleophiles, owing to its higher reactivity when compared with other heterocycles e.g. pyridine (2) or perfluoroaromatics e.g. hexafluorobenzene (3).[1,2,3]
The SNAr arylation of peptides with perfluoroaromatics provides a route by which to install a useful chemical handle that enables both 19F-NMR analysis and further chemical modification
We demonstrate that employing 2,2,2-trifluoroethanol (TFE) as a solvent in peptide SNAr reactions significantly improves nucleophile-selectivity when compared to N,N’-dimethylformamide (DMF)
Summary
The perfluoroaromatic reagent (ArF) pentafluoropyridine (1) is a highly useful synthetic building block that can undergo multiple substitution reactions with a broad range of nucleophiles, owing to its higher reactivity when compared with other heterocycles e.g. pyridine (2) or perfluoroaromatics e.g. hexafluorobenzene (3).[1,2,3] This arylation reaction to include other amino acids in peptide systems, including lysine and tyrosine (Scheme 1).[8]. In many cases poly-substituted products that arose due to reaction with either tyrosine (OH), lysine (NH2) and cysteine (SH) residues were obtained (Scheme 2 and Table 1).[8] For this reason we were interested to investigate whether replacing DMF with TFE as our reaction solvent would afford improved chemo-selectivity between different peptide side chains and model perfluoro(hetero)aromatic reagents 1 and 3. Scheme 2 Reaction products obtained by treatment of model peptides ( pep1–pep3) with ArF 1 or 3 using DIPEA/Cs2CO3 as base and DMF or TFE as solvent. *Products C and D present as non-equivalent mixture of regioisomers and were not distinguishable
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