p-Cresol as a reversible acylium ion scavenger in solid-phase peptide synthesis

The p-cresol and p-thiocresol adducts produced from acylium ions during HF cleavage after contemporary Boc/benzyl solid-phase peptide synthesis were examined. Findings did not conform with previous reports because both p-cresol and p-thiocresol were observed to predominantly produce aryl esters under the usual cleavage conditions. The p-cresol esters were stable at 0 deg C but rearranged irreversibly at higher temperatures to afford aryl ketones. On the other hand, p-thiocresols did not undergo a Fries rearrangement but readily underwent further additions of p-thiocresol to produce ketenebisthioacetals and trithio ortho esters.