Recent Advances in Hetaryne Chemistry. Efforts Toward the Development of a Single Platform for the Generation of 4,5-, 5,6-, and 6,7-Indole Arynes
In the beginning of 2007, indole arynes and their cycloaddition chemistry were discovered by Buszek laboratories. Since then, indole arynes and their cycloaddition chemistry have demonstrated their value in the construction of biologically active natural products, such as trikentrins and herbindoles. In addition to the tremendous value of indole aryne cycloaddition chemistry in natural products total synthesis, this chemistry has successfully contributed to library development and drug discovery fields. Taking advantage of the relative electronegativity of fluorine atoms, we proposed four polyfluoroindole scaffolds that could potentially generate the all three indole arynes, namely, 4,5 , 5,6-, and 6,7-indole arynes, from a single platform through a combination of dehydrohalogenation and metal halogen exchange chemistry. In these efforts, a practical and efficient synthetic scheme was constructed via the Fischer indole reaction in order to design the four trifluoroindoles from the corresponding trifluoroanilines - a single platform to generate the three indole arynes. This efficient Fischer indole synthetic scheme was used after earlier attempts with a previous and longer synthetic route to produce 4,6,7-trifluoro-1H-indole from 2,4,5-trifluoroaniline was unsuccessful. In spite of the fact that we were not able to obtain the desired compound through this previous synthesis, unexpected results were produced (i.e., diazo-oxides compounds). The four trifluoroindole systems, namely, 4,5,6-trifluoro-3-phenyl-1H-indole, 4,5,7- trifluoro-3-phenyl-1H-indole, 4,6,7-trifluoro-3-phenyl-1H-indole, and 5,6,7- trifluoro-3-phenyl 1H-indole, have now been synthesized via the Fischer indole reaction from the commercially available triflouroanilines in two-step synthesis. Calculated acidities of the four trifluoroindole systems were performed in the gas phase, which indicated the possibility of generation indole arynes from these scaffolds. By comparing proton chemical shifts of trifluoroindole and tribromoindole sets to indole itself, proton chemical shifts of trifluoroindole scaffolds shifted upfield whereas proton chemical shifts of tribromoindole shifted further downfield. Interestingly, this can indicate that in trifluoroindole systems, fluorine atoms shield the protons whereas in tribromoindole systems, bromine atoms deshield the protons. Two systems namely, 4,5,6-trifluoro-1-methyl-3-phenyl-1H-indole and 5,6-difluoro-1-R-3 phenyl-1H-indole were proposed as a potential “universal” indole aryne generating platform.
Table of Contents
Introduction and background -- Efforts toward the generation of 4,6,7-indole via Bartoli reaction -- Synthesis of 3-phenyl-trifluoroindoles via Fischer route -- Conclusion and future directions -- Experimental section