Professor Department of Biochemistry, University of Kentucky (7/95-present) Joint appointment Graduate Center for Toxicology, University of Kentucky (7/96-present) Joint appointment Department of Chemistry, University of Kentucky (9/97-present) Director Biological NMR Facility, University of Kentucky (7/95-present)

Facile and Efficient Synthesis of 4-Azidotetrafluoroaniline: A New Photoaffinity Reagent

p-Azidotetrafluoroaniline 1 was synthesized in 65 to 73% yield by two different methods employing a stable carbamate intermediate. The first method trapped the intermediate isocyanate generated via a modified Curtius rearrangement with t-butanol or 2-trimethylsilylethanol to form the stable carbamates 10d and 10e, respectively. Benzoic acid 10c was first converted to its acid chloride with PCl5. Displacement by NaN3 in acetone/water formed the acyl azide. Thermal rearrangement followed by the addition of the appropriate alcohols provided the carbamates. The acid labile carbamate 10d was deprotected with HCl/AcOH to provide 1, while trifluoroacetic acid was required to deprotect 10e and afford 1. In the second path, 1 was synthesized in 5 steps from pentafluoronitrobenzene 2 in 65% overall yield. 2 was converted into 4-azidotetrafluoronitrobenzene 3 with NaN3 in 93% yield and was used without further purification to form 1,4-diaminotetrafluorobenzene 4 by Sn/HCl reduction in 85% yield. The mono-FMOC derivative 5 was formed from 4 with FMOC-Cl and pyridine in EtOAc in 92% yield. Diazotization of 5 under anhydrous conditions with TFA/NaNO2 and NaN3 gave 6 in 87% yield. The aryl azide was formed with concurrent nitration of the 2-position of the fluorenyl system. The protecting group was removed with piperidine to afford 1 in 93% yield. Irradiation of 1 with 254 nm light in cyclohexane gave cyclohexylamine 15, diamine 4, and azobenzene 16 as the primary products. The formation of C-H insertion product 15 indicates that 1 forms a singlet nitrene upon photolysis. Two heterobifunctional photoaffinity reagents iodoacetamide 13 and dansyl derivative 14 were prepared.