Synthesis of a Tetrafluoro-Substituted Aryl Azide and Its Protio Analogue as Photoaffinity Labeling Reagents for the Estrogen Receptor

Article abstract of DOI:10.1021/jo00009a037

A tetrafluoro-substituted aryl azide 1 and its protio analogue 2, both photoaffinity labeling reagents for the estrogen receptor, have been prepared by direct coupling of the appropriately substituted 4-azidobenzoyl chloride with the electron rich C-3 of 6-methoxy-2-(4-methoxyphenyl)benzothiophene 3.This represents a rare example of aryl azide stability under Friedel-Crafts acylation conditions.Alternatively, the protio analogue 2 can also be prepared with the azide functionality masked as a phthaloyl-protected arylamine, and the tetrafluoro analogue 1, by direct displacement of a pentafluoroaryl derivative 20 with NaN3.Solution photolysis of tetrafluoro-substituted aryl azide (bis-methyl ether) 15 and its protio analogue 16 in toluene at 30 deg C results in relatively high yields of products derived from C-H insertion.Both azides 1 and 2 demonstrate favorable relative binding affinity (RBA) (1 = 10percent, 2 = 66percent, estradiol = 100percent) and photoinactivation efficiency (1 = 43percent, 2 = 55percent at 30 min) for the estrogen receptor (ER).The synthesis of both azides has been modified to accommodate a palladium-catalyzed tritium gas hydrogenolysis of an iodoaryl precursor at a late stage in the synthetic sequence, as will be needed to prepare them in radiolabeled form, and this procedure has been verified dy deuteration.This pair of compounds will allow a detailed evaluation of the role that fluorine substitution plays in the photochemistry and photocovalent attachment behavior of aryl azides in a complex biochemical system, the estrogen receptor.The radiosynthesis and further biochemical results will be presented elsewhere.