Aprotic solvents are usually preferred for the SN2 reactions, because nucleophilicity and hence SN2 reactivity are severely retarded by the influence of the partial positive charge of protic solvents. In this work, we introduce a remarkable effect of using tertiary alcohols as a reaction medium for nucleophilic fluorination with alkali metal fluorides. In this novel synthetic method, the nonpolar protic tert-alcohol enhances the nucleophilicity of the fluoride ion dramatically in the absence of any kind of catalyst, greatly increasing the rate of the nucleophilic fluorination and reducing formation of byproducts (such as alkenes, alcohols, or ethers) compared with conventional methods using dipolar aprotic solvents. The great efficacy of this method is a particular advantage in labeling radiopharmaceuticals with [18F]fluorine (t1/2 = 110 min) for positron emission tomographic (PET) imaging, and it is illustrated by the synthesis of four [18F]fluoride-radiolabeled molecular imaging probes-[18F]FDG, [18F]FLT, [18F]FP-CIT, and [18F]FMISO-in high yield and purity and in shorter times compared to conventional syntheses.

Although nucleophilic substitutions that use metal salts as nucleophiles are crucial synthetic transformations, these reactions, especially fluorinations, [1] often proceed sluggishly because of the limited solubility and low nucleophilicity of metal salts in organic solvents.[2] Phase-transfer catalysts such as crown ethers [3] and quaternary ammonium or phosphonium salts [4] have been used to enhance the solubility and nucleophilicity of the metal salt in organic solvent systems, consequently accelerating the reaction rate. [3,4] However, phase-transfer catalysts are ineffective when the metal and nuclelophile form a tight ion pair, and some quaternary ammonium salt catalysts are thermally unstable.[5] There are many reports in which catalysts of this nature are immobilized (so-called triphase catalysts) to facilitate product isolation and enable catalyst recovery by simple filtration. [5,6] However, nucleophilic displacements using such solid-supported phasetransfer catalysts generally proceed at slower rates than those using the corresponding nonimmobilized catalysts. [5] Due to their unique physical and chemical properties, ionic liquids containing imidazolium cations and their counteranions have currently received much attention as alternative reaction media for conducting various chemical processes.[7] Recently, we reported highly efficient nucleophilic fluorination and other substitution reactions [8] using alkali-metal salts in the presence of ionic liquids. In these transformations, the ionic liquid not only significantly enhanced the reactivity of the alkali-metal salts, but they also reduced by-product formation compared to the use of conventional protocols.[1, 8a] However, we encountered problems when the product was polar and contained many heteroatoms, because it became difficult to extract it from the ionic liquid.To overcome this drawback of ionic liquids, we have designed a polymer-supported ionic liquid (Figure 1) that can be used for nucleophilic displacements. There have been some recent efforts to prepare immobilized ionic liquids. Mehnert et al. reported an ionic liquid supported on the surface of silica gel.[9] However, they used a nonimmobilized ionic liquid to carry out their reaction, and the silica framework is also unstable against fluoride ions, water, and acids. In this report, we introduce a new polystyrene-based polymer-supported ionic-liquid system, which we term a "polymer-supported imidazolium salt" (PSIS), as a highly efficient catalyst for nucleophilic fluorination and for other nucleophilic substitution reactions. These PSISs have the advantage of significantly enhancing the nucleophilicity of the metal salts compared with conventional methods. Furthermore, PSISs can be reused many times without decomposition and loss of activity. The PSISs PS [hmim][X] (PS = polymer support; hmim = 1-n-hexyl-3-methylimidazolium cation; X = BF 4 , OTf) were prepared by the procedure shown in Scheme 1. We have prepared many PSISs with different linkers. The physical and chemical propertie...

We have found the new nucleophilic fluorination reaction of some halo- and mesylalkanes to the corresponding fluoroalkanes with KF in the presence of [bmim][BF4] under various reaction conditions. 2-(3-Methanesulfonyloxypropoxy)naphthalene (1) was used as a model compound to optimize this fluorination reaction. Whereas the fluorination of the mesylate 1 with KF in an organic solvent such as CH3CN at 100 degrees C occurred hardly even after 24 h, the same reaction in ionic liquids, [bmim][BF4], as a reaction solvent was completed within 1.5 h, affording the wanted product 2-(3-fluoropropoxy)naphthalene 2a (85%) together with the alkene byproduct 2c (10%). Very interestingly, however, the addition of water (5 equiv) completely eliminated the formation of the undesired alkene 2c and thus gave higher yield of 2a (92%, entry 2). The use of acetonitrile as a cosolvent did not affect the reactivity of the fluorination. The presence of a proper amount of cosolvent was rather desirable (94% yield of 2a). We performed fluorination reactions with other ionic liquids ([bmim][PF6], [bmim][SbF6], [bmim][OTf], and [bmim][N(Tf)2], and two other cosolvents, to find the optimal ionic liquid and cosolvent. Nine different compounds were examined, including the 10 g-synthesis of 2-(fluoromethyl)naphthalene in 93% of isolated yield.

Due to the tremendous interest in carbon-fluorine bond-forming reactions, research efforts in this area have been dedicated to the development of facile processes to synthesize small fluorine-containing organic molecules. Among others, PET (Positron Emission Tomography) is one of the most important applications of fluorine chemistry. Recognizing the specific requirements of PET processes, some groups have focused on fluorination reactions using alkali metal fluorides, particularly through SN2-type reactions. However, a common "misconception" about the role of protic solvents and hydrogen bonding interactions in this class of reactions has hampered the employment of these excellent promoters. Herein, we would like to review recent discoveries in this context, showing straightforward nucleophilic fluorination reactions using alkali metal fluorides promoted by protic solvents. Simultaneous dual activation of reacting partners by intermolecular hydrogen bonding and the enhancement of the "effective fluoride nucleophilicity", which is Nature's biocatalytic approach with the fluorinase enzyme, are the key to this unprecedentedly successful nucleophilic fluorination.