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Sulfonyl Fluorides and Pentafluorophenyl Sulfonates as Stable Substitutes for Sulfonyl Chlorides

Sulfonyl chlorides are widely used in medicinal chemistry as precursors to pharmacologically relevant sulfonamides. Although the majority of aromatic sulfonyl chlorides are considerably stable and, therefore, commercially available compounds capable of reacting with amines under mild conditions there are many aliphatic and heteroaromatic sulfonyl chlorides that encounter following synthetic problems.

First, many aliphatic sulfonyl chlorides are considerably poor sulfonylating reagents because they undergo dehydrochlorination under mild basic conditions. Second, some sulfonyl chlorides (mainly heteroaromatic ones) are unstable under ambient conditions and, consequently, cannot be commercialized. They are usually prepared under specific conditions and used immediately in a next synthetic step. A good alternative to the highly reactive and often unstable sulfonyl chlorides are sulfonyl fluorides and pentafluorophenyl esters of sulfonic acids. In contrast to the chlorides, the fluorides and pentafluorophenyl esters are stable to a variety of conditions including column chromatography and even basic workup procedures.

For example, freshly prepared 2-pyrimidinyl sulfonyl chloride 1 (Scheme 1) undergoes a fast decomposition resulting in 2-pyrimidinyl chloride 2. At the same time 2-pyrimidinyl sulfonyl fluoride 3 is a stable substance that smoothly reacts with amines to give sulfonamides 4.


Scheme 1

The pentafluorophenyl esters become irreplaceable sulfonylating reagents when the corresponding sulfonyl chlorides or fluorides cannot be prepared. Scheme 2 shows such a case in which pentafloroethyl ester 6 was prepared from alkyl iodide 4 and easily accessible pentafluorophenyl vinylsulfonate 5. The action of different amines on ester 6 gave rise to a number of sulfonamides 7 that were isolated in high yields.


Scheme 2

Because of the vast potential that is displayed by sulfonamides and their relative difficulty in preparation, Enamine Ltd has generated a collection of pentafluorophenyl alkyl- and arylsulfonates and sulfonyl fluorides. The example structures of the in-stock available sulfonylating reagents are given below.
Full lists of the title compounds available from Enamine can be found in our downloadable catalogue or our on-line searchable EnamineStore.

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