Practice of fluorous biphase chemistry: convenient synthesis of novel fluorophilic ethers via a Mitsunobu reaction Jo ´zsef Ra ´bai a,* , De ´nes Szabo ´ a , Eszter K. Borba ´s a , Istva ´n Ko ¨vesi a , Istva ´n Ko ¨vesdi b , Antal Csa ´mpai c ,A ´ gnes Go ¨mo ¨ry d , Valeriy E. Pashinnik e , Yuriy G. Shermolovich e a Department of Organic Chemistry, Eo ¨tvo ¨s Lora ´nd University, P.O. Box 32, H-1518, Budapest 112, Hungary b EGIS Pharmaceuticals Ltd., P.O. Box 100, H-1475 Budapest, Hungary c Department of General and Inorganic Chemistry, Eo ¨tvo ¨s Lora ´nd University, P.O. Box 32, H-1518, Budapest 112, Hungary d Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, P.O. Box 17, H-1525, Budapest, Hungary e Institute of Organic Chemistry, National Academy of Sciences, Murmanskaya Street 5, 02094 Kiev, Ukraine Received 14 September 2001; accepted 31 October 2001 Dedicated to Professor Andra ´s Messmer on the occasion of his 80th birthday. Abstract The evolution of the term fluorous is addressed first, then a concise terminology is proposed, including fluorous partition coefficient, specific fluorophilicity and fluorousness. Some examples are shown for the design of higher generation fluorophilic molecules, involving Class I to Class III ponytails. Fluorophilic ethers of the structure of ArC(CF 3 ) 2 O(CH 2 ) m (CF 2 ) n F(m ¼ 1, n ¼ 1, 7; m ¼ 3, n ¼ 8) are obtained in high yields, when 2-aryl-1,1,1,3,3,3-hexafluoro-propanols are reacted either with trifluoroethyl- and 1H,1H-perfluorooctyl triflates (NaH/ DMF, Williamson ether synthesis) or with 3-perfluorooctyl-propanol (Ph 3 P/EtO 2 CN=NCO 2 Et/PhCF 3 , Mitsunobu reaction), respectively. Fluorophilic phenol- and perfluoro-tert-butyl ethers can also be prepared effectively by the latter method. In case of higher homologues (n ¼ 7, 8) product isolation can be facilitated using fluorous extraction (C 6 F 14 /CH 3 OH). Specific fluorophilicity values of target molecules are estimated using a 2D method and compared with experimentally determined ones. # 2002 Elsevier Science B.V. All rights reserved. Keywords: Fluorine; Specific fluorophilicity; Mitsunobu reaction; Perfluoroalkylmethyl triflates 1. Introduction The fluorous phase (i.e. the C–F bond rich part of a multiphase system [1,2]) has been involved in several inno- vative catalyst and reagent immobilization protocols, fluor- ous isolation techniques, and seems to alter the way of our thinking about synthetic chemistry [1–15]. In this respect not only chemical reactions, but product separations should also be considered at the design level of a chemical synthesis [1,3,7,12]. The native phasephilicity (e.g. hydrophilic, lipo- philic, fluorophilic, etc.) of the components of a chemical reaction will determine their separation [16]. Thus, fluorous extraction can effectively be used for fluorophilic com- pounds [3,7,16], while chromatography over F-SiO 2 is the method of choice for the sequential isolation of untagged and F-tagged (i.e. perfluoroalkylated) molecules [13]. The popularity of these fluorous techniques is partly due to the unique physical and chemical properties associated with perfluorinated solvents, such as hydrophobicity and lipo- phobicity (amphiphobic [17]), inertness, non-toxicity, and easy separation [1–16]. The concept of fluorous biphase systems noticed by Vogt [18] in 1991, but first drafted by Horva ´th and Ra ´bai [1] in 1994, served as a basis of several novel applications in homogeneous catalytic chemistry utilizing the temperature dependent miscibility of perfluorocarbon fluids with stan- dard organic solvents [1,3,5,7,18]. Soon afterwards, Curran and coworkers introduced a series of synthetic and purifica- tion methods, called fluorous synthesis, in which organic target molecules are rendered selectively soluble in the fluorous phase by the temporary or permanent attachment of adequate fluorous labels [10–13]. Fluorous mixture synth- esis, developed by Curran and coworkers [14] is the most recent application of the power of fluorous-tagging coupled with F-SiO 2 chromatography [13] to allow separation of a mixture of related compounds by their ‘fluorine content’ (or ‘fluorousness’ [16,19]). Journal of Fluorine Chemistry 114 (2002) 199–207 * Corresponding author. Tel.: þ36-1-209-0602; fax: þ36-1-209-0602. E-mail address: rabai@szerves.chem.elte.hu (J. Ra ´bai). 0022-1139/02/$ – see front matter # 2002 Elsevier Science B.V. All rights reserved. PII:S0022-1139(02)00027-1