2-Fluoro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-Dioxide

[124170-23-6]  · C9H10FNO2S  · 2-Fluoro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-Dioxide  · (MW 215.24)

(electrophilic fluorinating agent)

Alternate Name: N-fluoro-2,a-cumenesultam.

Physical Data: mp 115-117 °C.

Solubility: sol various organic solvents including THF, diethyl ether, CH2Cl2, acetonitrile.

Form Supplied in: white or slightly yellow solid, &egt;98% purity; commercially available.

Analysis of Reagent Purity: 1H and 19F NMR.

Preparative Method: pressureless fluorination on a 100 g scale with F2 in N2 (F2/N2 10% v/v) in the presence of powdered NaF in CHCl3/CFCl3 (1/1 v/v) at -40 °C.1,2

Purification: flash chromatography (SiO2, CH2Cl2) and/or crystallization from Et2O/pentane.

Handling, Storage, and Precautions: handle and store at rt or below; protected from light, preferably under nitrogen or argon. Thermally stable up to 200 °C; decomposes exothermally above 200 °C. Reacts with easily oxidized compounds such as iodide or tetramethylphenylenediamine. This reagent should be handled in a fume hood.

Nitrogen-fluorine bond-containing compounds are among the most useful electrophilic fluorinating agents due to their easy access, their inherent stability, and the ease with which they can be handled. 2-Fluoro-3,3-dimethyl-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide (1) is one of the most thoroughly studied reagents, both from a preparative and a mechanistic point of view.1 -8 There is evidence, both preparative and mechanistic, that direct nucleophilic attack at fluorine occurs. Electron transfer is a competing reaction, which leads to nonfluorinated products.5,6,8

Monofluorination of Enolates.

N-Fluorosultam (1) has been successfully used to prepare a-fluorocarbonyl compounds by electrophilic fluorination starting, for example, from disubstituted enolates derived from ketones, esters, and b-dicarbonyl compounds (eqs 1-3).1 The related N-fluorosulfonamide reagents9 give considerably lower yields due to the elimination of HF by proton abstraction from the carbon a to the nitrogen atom.1

Monosubstituted enolates can be selectively monofluorinated using slightly more than 1 equiv of base and N-fluorosultam. The influence of the counterion is crucial and the selectivity decreases in the order Li > Na > K, although Potassium Hexamethyldisilazide often gives higher yields, especially with esters (eqs 4-6).4

See also the related chiral N-fluorosultam reagents derived from camphor which allow for enantioselective fluorination with modest enantiomeric excesses (up to 75%).10,11

Double Fluorination of Enolates.

Double fluorination of monosubstituted enolates is achieved selectively in a one-pot procedure by adding the starting carbonyl compound to 2.4-3.6 equiv of base in THF at -78 °C followed by the addition of 2.6-3.6 equiv of the N-fluorosultam, and warming up to room temperatures. For this process, KHMDS and Potassium Diisopropylamide are the bases of choice (eqs 7-9).4

Fluorination of Organometallic Reagents.

Aryl fluorides can be prepared by reacting the corresponding aryllithium compound with (1) (eq 10). Grignard reagents give significantly lower yields, probably due to competing electron transfer reactions since radical-derived side products have been isolated and characterized (eq 11).6

For a more reactive nitrogen-fluorine bond containing reagent, see N-Fluoro-N-(phenylsulfonyl)benzenesulfonamide.12

1. Differding, E.; Lang, R. W. HCA 1989, 72, 1248.
2. Auer, K.; Hungerbühler, E.; Lang, R. W. C 1990, 44, 120.
3. Differding, E.; Frick, W.; Lang, R. W.; Martin, P.; Schmit, C.; Veenstra, S.; Greuter, H. BSB 1990, 99, 647.
4. Differding, E.; Rüegg, G. M.; Lang, R. W. TL 1991, 32, 1779.
5. Differding, E.; Rüegg, G. M. TL 1991, 32, 3815.
6. Differding, E.; Wehrli, M. TL 1991, 32, 3819.
7. Differding, E.; Bersier, P. M. T 1992, 48, 1595.
8. Andrieux, C. P.; Differding, E.; Robert, M.; Savéant, J.-M. JACS 1993, 115, 6592.
9. Barnette, W. E. JACS 1984, 106, 452.
10. Differding, E.; Lang, R. W. TL 1988, 29, 6087.
11. Davis, F. A.; Zhou, P.; Murphy, C. K. TL 1993, 34, 3971.
12. Differding, E.; Ofner, H. SL 1991, 187.

Edmond Differding

UCB, Braine l'Alleud, Belgium

Robert W. Lang

Ciba-Geigy, Basel, Switzerland

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