Solution-phase mixture synthesis has efficiency advantages and favorable reaction kinetics. Applications of this technique, however, have been discouraged by the difficulty in obtaining individual, pure final products by using conventional separation and identification processes. Introduced here is a new strategy for mixture synthesis that addresses the separation and identification problems. Members of a series of organic substrates are paired with a series of fluorous tags of different chain lengths. The tagged starting materials are then mixed and taken through a multistep reaction process. Fluorous chromatography is used to demix the tagged product mixtures on the basis of the fluorine content of the tags to provide the individual pure components of the mixture, which are detagged to release the final products. The utility of fluorous mixture synthesis is demonstrated by the preparation of a 560-membered library of analogues of the natural product mappicine. A seven-component mixture is carried through a four-step mixture synthesis (two one-pot and two parallel steps) to incorporate two additional points of diversity onto the tetracyclic core. Methods for analysis and purification of the intermediates are established for the quality control of the mixture synthesis.
A new strategy to improve the efficiency of Suzuki coupling reactions is introduced by combining fast microwave reaction with easy fluorous separation. Aryl perfluorooctylsulfonates derived from the corresponding phenols are coupled with aryl boronic acids to form biaryls under general microwave conditions. Both intermediates and products are purified by solid-phase extraction over FluoroFlash silica gel. Application of this tagging strategy to multistep synthesis of biaryl substituted hydantoin is also described.The palladium-catalyzed cross-coupling of aryl halides with aryl boronic acids (Suzuki coupling) is a powerful reaction for the construction of biaryls. 1 Its scope has been extended through the use of aryl triflates (ArOSO 2 CF 3 ) or aryl nonaflates (ArOSO 2 (CF 2 ) 3 CF 3 ) as halide equivalents.2 Aryl perfluoroalkylsulfonates prepared from a wide range of commercially available phenols have shown high reactivity, good stability for room temperature storage, chromatography, and resistance towards hydrolysis. 3 Application of Suzuki coupling reactions for parallel and combinatorial synthesis has been explored by conducting the reaction under microwave irradiation 4 or on solid support 5 with a linker such as perfluoroalkylsulfonyl. 6 However, the microwave reaction does not directly address the separation issue, which is usually the bottle-neck of high-throughput synthesis. Microwave-assisted solid-phase reactions have limitations on solvent selection due to resin swelling and thermostability issues. 7 We report here a new strategy which significantly improves the efficiency of Suzuki coupling reactions by combining fast microwave reaction with easy fluorous separation.Fluorous synthesis unites the attractive features of solution-phase chemistry with the convenient workup of solid-phase chemistry. 8 Molecules attached with a perfluoroalkyl "phase tag" can be easily isolated from the reaction mixture by fluorous separation techniques such as fluorous solid-phase extraction (F-SPE). 9 The fluorous Suzuki coupling reaction employs aryl perfluorooctylsulfonates (ArOSO 2 (CF 2 ) 7 CF 3 ) as precursors. The perfluorooctylsulfonyl group has enough fluorines (17) to serve as a fluorous tag for F-SPE. Recently we reported the w.zhang@fluorous.com. Supporting Information Available: 1 H NMR spectra for aryl perfluorooctylsulfonates 1a-d, biaryls 2a-2k, compounds 4, 6, and biarylsubstituted hydantoin 7. This material is available free of charge via the internet at
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