Reaction of N-t-Boc, Z or Fmoc protected 4-iodo-L-phenylalanine with t-BuSH was explored as a direct approach to the preparation of the corresponding novel 4-thiophenylalanine derivatives. It was found that Pd (0), additive, and Et3N are all essential to bring about the desired coupling reaction. Of the two sources of Pd (0) employed, Pd2dba3. CHCl3 was found to be more satisfactory and of the six additives screened DPPF was the most efficient reagent to bring about a clean coupling reaction in 3 h at 70-75 °C. While the t-Boc and Z protected 4-iodophenylalanines provided the corresponding thiophenylalanine derivatives in good yields the Fmoc protected derivative underwent base promoted cleavage of the Fmoc group. However, the desired N-Fmoc protected 4-S-t-butyl thiophenylalanine was obtained from the corresponding Boc-protected thiophenylalanine derivative via a sequential deprotection- reprotection approach. Finally, stability of the S-t-butyl group in these N-protected thiophenylalanine derivatives to the conditions of peptide synthesis was evaluated.
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