α-Tosyloxyketones: Convenient [4+3] Cycloaddition Precursors

Abstract

A concise, simple two-step method for the preparation of [4+3] cycloadducts from ketones using Koser"s reagent and trifluoroethanol-triethylamine has been developed. This sequence affords yields similar to those obtained using the α-halo and α-mesyloxyketones, but with the advantages of simplicity in preparation and stability of the intermediates.

Key words

cycloaddition - ketones - cations - sonication - sulfonyl

References

• For general reviews of [4+3] reactions, see:
• 1a Rigby JH. Pigge FC. Organic Reactions   Vol. 51:  John Wiley & Sons, Inc.; New York: 1997.  p.351-478  
• 1b Cha JK. Oh J. Curr. Org. Chem.  1998,  2:  217 
• 1c Harmata M. Tetrahedron  1997,  53:  6235 
• 2 For a discussion of various methods for the halogenation of ketones, see: House HO. Modern Synthetic Reactions   2nd Ed.:  W. J. Benjamin Inc.; Menlo Park, CA: 1972.  p.459-478  
• 3 This alternative has been most extensively explored by Föhlisch and co-workers. For examples, see: Föhlisch B. Herrscher I. Chem Ber.  1986,  119:  524 ; and further papers from this group
• 4 One similar variation that has been reported is the use of β-keto trifluoromethanesulfones. This option has been used in a number of intramolecular cycloadditions reported by the Harmata and co-workers. For examples, see: Harmata M. Acc. Chem. Res.  2001,  34:  595 
• 5a Tuncay A. Dustman JA. Fisher G. Tuncay CI. Suslick KS. Tetrahedron Lett.  1992,  33:  7647 
• 5b For a review of the use and preparation of α-tosyloxy and mesyloxy ketones, see: Moriarty RM. Prakash O. Organic Reactions   Vol. 54:  John Wiley & Sons, Inc.; New York: 1999.  p.273-418  
• 8 For the first report of these now-standard conditions, see: Föhlisch B. Gehrlach E. Herter R. Angew. Chem. Int. Ed. Engl.  1982,  21:  137 
• 9 Jin S. Choi J.-R. Oh J. Lee D. Cha JK. J. Am. Chem. Soc.  1995,  117:  10914 
• 12 For the first report using these conditions, see: Herter R. Föhlisch B. Synthesis  1982,  976 

6

We have noted that chromatographic purification of the tosyloxyketones is generally unnecessary. Trituration with hexanes is sufficient to remove virtually all of the iodobenzene by-product and afford the products as white, crystalline solids with melting points identical to those reported in the literature. Further, in our studies using a standard sonication cleaning bath, the yield of the reaction is very dependent upon the location in the bath (and thus, the strength of the sonication). Optimization in terms of the location of the flask may be necessary to reproduce the yields reported here and in ref. [5]

7

Representative Procedure: To 0.650 g (1.67 mmol) of [hydroxy(tosyloxy)iodo]benzene in a dry round-bottom flask under argon were added 2 mL of cyclohexanone and 15 mL of acetonitrile. The flask was placed in an ultrasound cleaning bath filled with warm (55 °C) water to a depth of 2 inches. The reaction mixture was sonicated for 15 minutes, during which time the suspension cleared to a yellowish-brown solution. After removal of the volatiles in vacuo, the residue was dissolved in methylene chloride (15 mL) and washed with saturated aqueous NaHCO₃ (3 × 5 mL). The organic layer was dried with magnesium sulfate and concentrated in vacuo. The residue was then triturated with minimal hexane (2 mL) at ice-bath temperatures to afford 0.375 g (89%) of a pale yellow solid.

10

Representative Procedure: To 0.1928 g (0.7194 mmol) of 2-tosyloxycyclohexanone in 0.72 mL of furan was added 0.72 mL of 2,2,-trifluoroethanol at 0 °C under argon. The mixture was stirred and 187 µL (1.35 mmol) of triethylamine was added slowly and the reaction was allowed to warm to room temperature. After 4 hours, TLC indicated complete consumption of starting material. The reaction mixture was diluted with water (10 mL) and extracted with diethyl ether (5 × 5 mL). The combined organics were washed with saturated aqueous NaHCO₃, dried with magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by chromatography (elution with 1:4 ethyl acetate-hexanes) to afford 70.8 mg (60%) of the cycloadduct as a pale yellow solid.

11

All compounds exhibited spectroscopic data consistent with that reported in the literature.