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 °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 = 10%, 2 = 66%, estradiol = 100%) and photoinactivation efficiency (1 = 43%, 2 = 55% 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 by 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.
ASJC Scopus subject areas
- Organic Chemistry