[151556-58-0]  · C10H14Cl2FNO2S  · (302.19)

(neutral, aprotic, electrophilic fluorinating agent for the asymmetric a-fluorination of enolates1)

Physical Data: mp 161-162 °C, [a]20D +16.4 (c 1.3, CHCl3).

Solubility: soluble in THF, CH2Cl2, CHCl3; insoluble in hexane, pentane, H2O.

Form Supplied in: white solid.

Preparative Methods: the title reagent 1 can be prepared by fluorination of the corresponding (+)-2,10-(3,3-dichlorocamphorsultam)2 using 10% F2/N2 in dry chloroform in the presence of sodium fluoride.3,4

Purification: purified by silica gel chromatography using a mixture of CH2Cl2/n-pentane (70:30) as eluent.

Handling, Storage, and Precautions: can be stored in a bottle in the refrigerator for months without noticeable decomposition.

Fluorination of Ketone Enolates

(+)-N-Fluoro-2,10-(3,3-dichlorocamphorsultam) (1) reacts with ketone enolates to give a-fluoro ketones. For example, reaction of the sodium enolate of propiophenone 2 gives a-fluoropropiophenone 3 in 41% isolated yield (1). No enantioselectivity, however, is observed due to racemization of the product under the reaction conditions.4 When a tertiary substituted ketone such as a-methyltetralone (4) is employed, the desired a-fluorinated product (S)-(-)-5 is obtained in 76% ee and 53% isolated yield (2).4 In this reaction, (+)-1 was found to be more reactive, affording higher yields and better enantioselectivities than its parent (-)-N-fluoro-2,10-camphorsultam; i.e., 35% ee, <5% yield.5

Fluorination of Ester Enolates

(+)-N-Fluoro-2,10-(3,3-dichlorocamphorsultam) (1) also reacts with the enolates generated from esters. For example, treatment of methyl 2-phenylpropionate 6 with NaHMDS in THF followed by addition of (+)-1 affords the corresponding a-fluoro ester 7 in 54% yield and 33% ee (3). The absolute configuration was not determined. The enantioselectivity observed with (+)-1 is better than (-)-N-fluoro-2,10-camphorsultam; i.e., < 10% ee (30% yield).5

Fluorination of b-Ketoester Enolates

(+)-N-Fluoro-2,10-(3,3-dichlorocamphorsultam) (1) is reactive towards the enolates generated from b-ketoesters. Thus, treatment of the sodium enolate of 8 with (+)-1 afforded the desired product 9 in 95% isolated yield and 46% ee with undetermined stereochemistry (4). Reduced yields and enantioselectivities were noted under similar conditions for (-)-N-fluoro-2,10-camphorsultam (28% yield, 25% ee).4

Related Reagents.

(+)-N-fluoro-2,10-camphorsultam;4,5 (-)-N-fluoro-2,10-(3,3-dimethoxycamphorsultam);4 (3S)-(−)-N-fluoro-3-cyclohexyl-3-methyl-2,3-dihydrobenzo[1,2-d]isothiazole 1,1-dioxide;6 N-fluoro-o-benzenesulfonimide;7 N-fluorobenzenesulfonimide.8

1. (a) Davis, F. A.; Qi, H.; Sundarababu, G. In Enantiocontrolled Synthesis of Fluoro-Organic Compounds: Stereochemical Challenges and biomedical Targets; Soloshonok, V. A., Ed.; John Wiley & Sons Ltd: Chichester, 1999, pp 1-32. (b) Davis, F. A.; Kasu, P. V. N., Org. Prep. Proc. Int. 1999, 31, 125.
2. (a) Davis, F. A.; Zhou, P.; Chen, B.-C., Phosphorus Sulfur Silicon 1996, 115, 85. (b) Chen, B.-C.; Murphy, C. K.; Kumar, A.; ThimmaReddy, R.; Zhou, P.; Lewis, B. M.; Gala, D.; Mergelsberg, L.; Scherer, D.; Buckley, J.; Dibenedetto, D.; Davis, F. A., Org. Synth. 1995, 73, 159.
3. Davis, F. A.; Zhou, P.; Murphy, C. K., Tetrahedron Lett. 1993, 34, 3971.
4. Davis, F. A.; Zhou, P.; Murphy, C. K.; Sundarababu, G.; Qi, H.; Han, W.; Przeslawski, R. M.; Chen, B.-C.; Carroll, P. J., J. Org. Chem. 1998, 63, 2273.
5. Differding, E.; Lang, R. W., Tetrahedron Lett. 1988, 29, 6087.
6. Takeuchi, Y.; Suzuki, T.; Satoh, A.; Shiragami, T.; Shibata, N., J. Org. Chem. 1999, 64, 5708.
7. Davis, F. A.; Han, W., Tetrahedron Lett. 1991, 32, 1651.
8. Differding, E.; Ofner, H., Synlett 1991, 187.

Franklin A. Davis & Bang-Chi Chen

Temple University, Philadelphia, USA

Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA

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