A joint 2010 J. Org. Chem. ASAP article from groups in Berlin and India describes the three-component synthesis of pyridines with perfluoroalkyl and perfluoroaryl substitution. In actuality the paper is about 95% trifluoromethyl substituted, but they do include an example of a perfluoroheptyl and a pentafluorophenyl substituted pyridine. The paper is interesting to me for it’s lack of the word “fluorous” or use of fluorous purification techniques.
The chemistry as shown above combines a lithiated alkoxyallene, a nitrile, and an acid to form substituted pyridines. The initial heterocycle forming reaction requires an excess of the allene relative to the nitrile and provides the products in 25-50% yield. The resultant 4-hydroxy group can than be converted to a perfluorobutyl(c4F9) sulfonate, commonly known as a nonaflate analogous to triflate. Like other sp2 sulfonates, the nonaflate is a halogen surrogate which can undergo a number of transformations including Suzuki couplings, Buchwald-Hartwig amidations, Stille couplings, etc. The authors used this strategy to prepare a number of different substituted pyridines.
Given the modest yields and the use of excess allene it’s surprising the authors didn’t try to use a fluorous solid phase extraction based purification rather than the flash chromatography employed. Using perfluorooctylsulfonyl instead of the nonaflate would provide an nice fluorous tag for the fluorous solid phase extraction (FSPE) and the subsequent chemistry. The authors were certainly aware of the chemistry considering that two FTI papers using fluorous sulfonates were referenced. If they did try it and it failed, this was not mentioned in the text.
Perhaps, since they used fairly simple allenes and nitriles the separation by flash chromatography was not particularly difficult. If a library were to be made using this chemistry, however, that might not be the case. For example, they already observed that in the case of nitriles with an alpha protein, the major product was not a 4-hydroxy pyridine, but a 4-alkyl pyridine. Upon fluorous sulfonyl tagging, the desired product would be readily separable from the non-fluorous pyridine by FSPE.