Prof. Wei Zhang, currently located at UMass-Boston, has been using fluorous aryl sulfonates in library synthesis for some time now. The fluorous aryl sulfonate can be used as a fluorous tag to facilitate purification of intermediates by fluorous solid phase extraction (FSPE) and finally as a triflate equivalent that can be used in various organometallic reactions, such as Suzuki couplings. He and his co-workers have used these compounds as building blocks to a number of different heterocyclic libraries. Some examples include tetrahydroquinolines and benzodiazopinediones. In each of these fluorous tagging and separation is used in conjunction with microwave heating and an organometallic coupling reaction to produce a series of compounds easily and quickly.
The latest report from Prof. Zhang’s group using the same strategies and tactics has been published in SynLett and describes the preparation of tetrasubstituted furans. The chemistry is shown below and starts with a fluorous sulfonate tagged benzaldehyde. Microwave assisted aldol reaction with an acetophenone produces the unsaturated ketone 3 which could be purified either by recrystallization or by FSPE. Oxidative cyclization using Mn(OAC)3 and Cu(OAc)2 of 3 with a 1,3-dicarbonyl provided the tetrasubstituted furan 5 which could be further elaborated using Suzuki coupling or a Buchwald-Hartwig amination (not pictured). FSPE was used for the purification of intermediate 5 prior to the coupling reaction. Although not mentioned in this report the authors have previously shown that the fluorous sulfonate can also be reduced to provide the unsubstituted aryl group.
The authors note that no dihydrofuran products were observed compared to other published reports using similar non-fluorous, methods. In addition they report only one regioisomer for each reaction. It’s not exactly clear how the substitution pattern on the furan ring was determined since there is no NOE or 2D NMR data provided in the supplemental data. We’ll have to assume that it was through comparison with analogous compounds made by similar methods. In any event the reaction sequence exhibits high regioselectivity.
This is another example from the Zhang labs demonstrating how fluorous sulfonates can be used in the role of purification handle and functional group synthon.