Fluorination, nucleophilic

Creation of a carbon-fluorine bond through reaction of a fluoride anion (nucleophilic fluorination). 

Creation of a C-F bond by means of an F cation (nucleophilic fluorination). 

Creation of a carbon-carbon bond starting from a synthon that already has a C-F bond. 

The main reagents for nucleophilic fluorination are the metal and ammonium fluorides, the DAST reagent and its analogues, and the amine complexes of fluorhydric acid. 

Desilylation with cesium fluoride has been the most common use of cesium compounds in organic synfhesis. HI and tetraalkylammonium fluoride are also commonly used for desilylation but these reagents are difficult to use under anhydrous conditions. The cesium fluoride-induced reaction can be performed easily under anhydrous conditions, so desilylation produces carbanion-equivalent species which can be used for further C-C bond-forming reactions. The reaction seems to 

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Apolymerfi e, AmberliteIRA900)-supportedreagent,f (W/ ) f (K=0-2), where P is the cationic part of the anion-exchange resin, acts as a source of nucleophilic fluorine and yet exhibits linuted basic character, thereby reducing the... 

The different nucleophilicities of 3,5-dimethyl- and 3,5-bis(trifluoromethyl) pyrazoles are shown by their reactions widi lraas-[Rh(CO)Cl(Ph3P)2]. The dimethyl derivative gives die dinuclear species similar to 111. The less nucleophilic fluorine derivative gives 116, where die pyrazole ring is monodentate. The fluoro compound similar to 111 [L2 = (CO)2l may be obtained in the absence... 

Scheme 13.14 Substituent effects in the microwave-enhanced nucleophilic fluorination of a number of pyridine derivatives.

In the solvolysis of secondary alkyl sulfonates, competition between nucleophilic solvation and electron donation by the substituents results in a significantly solvent-dependent p, which varies from — 9 to — 1 on going from the non-nucleophilic hexafluoro-2-propanol to 80% aqueous ethanol (Bentley et al, 1981). In contrast, the p -invariance for alkene bromination in H20, M70, MeOH and AcOH [equations (22)-(25)] seems to imply a perfect balance between the two types of charge stabilization. However, this conclusion is probably risky since the nucleophilicities of the solvents implied in (22)-(25) do not vary markedly. Data in non-nucleophilic fluorinated solvents would therefore help to fill the gap in our knowledge. 

Rate enhancements for these types of reaction have been reported to be as high as 200-fold, and the selectivity of the reaction was found to be very substrate dependent. These reactions must be conducted in dipolar aprotic solvents in the absence of water. Although tetramethylammonium chloride is too polar to find widespread application as a phase transfer agent, it has good thermal stability, and this, combined with its low cost, has resulted in its large scale industrial use in phase transfer catalysed aromatic nucleophilic fluorinations. 

An electrochemical cell [93,94] was used to obtain an efficient anodic deposition of no carrier added F-fluoride solubilized in the target water. The radioisotope is electrochemically adsorbed on the anode (glassy carbon electrode) and can be easily dried. An opposite electrical field releases the radionuclide directly into a solution of a phase transfer catalyst in dipolar aprotic solvents. The nucleophilic fluorination can be performed simultaneously if the electrochemically and thermally induced desorption of radioactivity is done in the presence of the precursor. However, the yields remain poor (3 % in the electrochemical n.c.a [ F]fluorination of anisole). 

One-step synthesis of a radiopharmaceutical involving an aliphatic nucleophilic fluorination... 

The successful use of [ F]FDG in oncology PET imaging has prompted the design of several other radiopharmaceuticals, such as [ F]FLT ([ F]fluorothymi-dine, used as cellular proliferation marker. Scheme 36) [152-154], F-MISO ([ F] fluoromisonidazole, used to assess tissue hypoxia. Scheme 37) [155], c/s-4-[ F] fluoro-L-proline (used as abnormal collagen synthesis marker. Scheme 38) [156] and 0-(2-[ F]fluoroethyl)-L-tyrosine (used as amino acid transport and/or protein synthesis marker. Scheme 39) [157]. All these fluorine-18-labelled molecules have been prepared by aliphatic nucleophilic fluorination followed by a deprotection reaction. 

A.D. Windhorst, R.P. Klok, C.L. Koolen, G.W.M. Visser, J.D.M. Herscheid, Labeling of [ F]flumazenil via instant fluorination, a new nucleophilic fluorination method, J. Label. Compds Radiopharm. 44 (2001) S930-S932. 

A. Katsifis, K. Hamacher, J. Schnitter, G. Stdcklin, Optimization studies concerning the direct nucleophilic fluorination of butyrophenone neuroleptics, Appl. Radiat. Isot. 44 (1993) 1015-1020. 

FI.FI. Coenen, B. Klatte, A. Knochel, M. Schuller, G. Stocklin, Preparation of n.c.a. [i7-i8F]f uoroheptadecanoic acid in high yields via aminopolyether supported, nucleophilic fluorination, J. Label. Compds Radiopharm. 23 (1986) 455-467. 

C. Lemaire, M. Guillaume, R. Cantineau, A. Plevenaux, L. Christiaans, An approach to the asymmetric synthesis of L-6-[ F]fluorodopa via NCA nucleophilic fluorination, Appl. Radiat. Isot. 42 (1991) 629-635. 

K. Hamacher, T. Hirschfelder, H.H. Coenen, Electrochemical cell for separation of [ F]fluoride from irradiated 0-water and subsequent no carrier added nucleophilic fluorination, Appl. Radiat. Isot. 56(3) (2002) 519-523. 

HF—Amine Complexes Complexes of fluorhydric acid (HF) with pyridine or alkyl amines (Et3N, Et2NH) are often utilized as reagents in nucleophilic fluorination reactions such as the opening of oxiranes," the bromofluorination of double bonds in the presence of NBS, or the diazotation/fluorination of amines with sodium nitrite (the Balz-Schiemann-like reaction) (Figure 2.1). ... 

Figure 2.1 Examples of nucleophilic fluorination with fluorides or with HF-amine complexes. ...

Aromatic fluorination involves analogous methods to those used in the aliphatic series. The most utilized methods are electrophihc fluorination (F2, N— F reagents) and nucleophilic fluorination through the Balz-Schiemann reaction (diazotation in the presence of fluoride ion). This latter method is of prime importance in industry. When the aromatic ring is activated by one or several electron-withdrawing groups, the... 

Fluoro-2-deoxynucleosides and 3-fluoro-3-deoxynucleosides are generally prepared either by coupling between the fluorodeoxyfuranose and the base, or by fluorinating the nucleoside (the nucleophilic fluorination reactions are sometimes compatible with the presence of the base). ... 

Nucleophilic fluorination is particularly useful in the synthesis of 2-fluoro-2-deoxypyranoses (e.g., DAST fluorination, displacement of a leaving group by a fluoride ion, oxirane ring opening with HF-amine complexes). Electrophilic fluorination also allows the synthesis of 2-fluoro-2-deoxypyranoses. 

Figure 6.17 Examples of rearrangements during nucleophilic fluorination.

Other sugars labeled with F that are used in PET imaging ([ F] FDGal, 2-[ F]-2-deoxytalose, l-[ F]-l-deoxy-D-fructose) are also prepared by means of nucleophilic fluorination (Figure 6.19).1-[ F]-1 -Deoxy-D-fructose cannot be used as aprobe since it... 

Other nucleophilic fluorination processes in heterocycles have included displacement of bromine with potassium, cesium, or silver fluorides, but these failed to work for 4-bromo-5-nitroimidazole and ethyl 4-bromoimid-azole-5-carboxylate (73JA4619). Xenon hexafluoride was reported to convert 2,4,5-tribromoimidazole into the trifluoro analogue (79JGU1251). 

Nucleophilic fluorine-aryl substitution in iodine pentafluoride with tetrakis(pentafluoro-phcnyl)silane or tris(pentafluorophenyl)bismuthane produces high-purity (pentafluorophen-yl)iodine tetrafluoride in good yield.133,134... 

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