Mild Deprotection of Primary N-(p-Toluenesulfonyl) Amides with SmI₂ ­Following Trifluoroacetylation

Abstract

A mild deprotection method for notoriously difficult to unmask primary N-(p-toluenesulfonyl) amides was developed during our total synthesis studies toward the marine toxin, gymnodimine. The deprotection occurs at low temperature (-78 °C) under mild conditions by initial activation of the nitrogen with a trifluoroacetyl group, followed by reductive cleavage of the p-toluenesulfonyl group with samarium diiodide. The substrate scope and functional group tolerance of this useful N-S cleavage process, which builds on related cleavage processes of other nitrogen-heteroatom bonds, is explored.

Key words

sulfonamide - samarium diiodide - reductive cleavage - trifluoroacetylation

References and Notes

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  General Procedure for the Reductive Cleavage of the Tosyl Group of Monosubstituted N -( p -Toluene-sulfonyl) Amides as Described for Preparation of Amide 5: To a stirred solution of sulfonamide 3 (55.1 mg, 0.20 mmol) and Et₃N (60 µL, 0.40 mmol) in CH₂Cl₂ (3.0 mL) was added TFAA (57 µL, 0.40 mmol) dropwise via syringe. After aliquot NMR analysis indicated complete reaction (ca. 10 min), the solvent was concentrated in vacuo and the residue was diluted with THF (1.0 mL), cooled to -78 °C and subsequently treated dropwise with SmI₂ [19] in THF (10.0 mL, 0.098 M, 0.98 mmol). The resulting mixture was stirred for 30 min and then quenched by filtering through a compressed pad of silica gel. The filter pad was washed with EtOAc and the solvent was removed in vacuo. The residue was chromatographed (elution with 10% EtOAc-hexanes) to afford acetamide 5 (37 mg, 85%) as a white solid, followed by the starting material 3 (7.5 mg). The spectral data for the isolated material was in accord with published spectral data. [21]

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20

We were unable to isolate a clean sample of bistrifluoroacetamide 6 as it underwent partial deacetylation to acetamide 5 during chromatography.

23

Et₃N was not suitable for the tosylation of 3′-aminoaceto-phenone (Table [1] , sulfonamide 14) as it resulted in an inseparable mixture of 14 and its bistosylated derivative. However, employing pyridine as a base led to exclusive monotosylation.

24

Substrate 8 (Table [1] , entry 3) required TFAA (3 equiv) and Et₃N for complete acetylation.

25

Reductive cleavage of the tosyl group at 23 °C led to significantly reduced yields of trifluoroacetamide.