Sulfur-Phenolate Exchange As a Fluorine-Free Approach to S(VI) Exchange Chemistry on Sulfonyl Moieties

Abstract

SuFEx chemistry has recently evolved as next-generation click chemistry. However, in most SuFEx syntheses, additional reagents/catalysts and carefully controlled conditions are still needed. Here, we aim to further generalize S(VI) exchange chemistry, using 4-nitrophenyl phenylmethanesulfonate as example, in which the nitrophenolate group is exchanged for a wide range of (substituted) phenols and alkyl alcohols. Quantitative yields were reached within 10 min under ambient conditions and required only filtering through silica as workup.

Sulfur-Phenolate Exchange as a Mild, Fast, and High-Yielding Method toward the Synthesis of Sulfonamides

“…1 H NMR analysis of the crude reaction mixture after degradation also indicated side reactions on the amine itself, though the exact products were not analyzed in detail. As the corresponding reaction with phenols showed no such dependence on the presence of water, we postulate that a reaction occurs between the deprotonated amine and water. As a result of this, the amount of amine available for reaction with 1 is decreased, causing a lower yield and eventual base-catalyzed hydrolysis of 1 .…”

“… 31 , 32 Specifically, 4-nitrophenyl benzylsulfonate ( 1 ) was shown to be a good alternative to benzylsulfonyl chloride or fluoride as a starting material, by the creation of a large library of sulfonates in a near-quantitative fashion using a simple and fast SuPhenEx reaction at room temperature. 32 Now, we demonstrate that the same class of starting materials can also be used to create a large array of sulfonamides in good yields via the reaction with a wide range of alkylamines and N -alkylated anilines ( Figure 1 ).…”

“…To demonstrate its scope, we thus used several amino acids to attach to 1 . Since previous studies in our lab showed an incompatibility of carboxylic acid groups with the SuPhenEx reaction, 32 a benzyl protecting group was used on the C-terminus of the amino acids. With this precaution, it was possible to obtain all three products 3m – o in good yield, i.e ., comparable to but minimally slightly faster than previously reported coupling reactions of benzylsulfonyl chloride to (benzyl-protected) amino acids.…”

“…Previously, we have shown that the p -nitrophenolate moiety can function as an excellent leaving group in S­(VI) exchange chemistry, making the corresponding sulfur-phenolate exchange (SuPhenEx) an efficient, fluorine-free alternative for the SuFEx reaction. , Specifically, 4-nitrophenyl benzylsulfonate ( 1 ) was shown to be a good alternative to benzylsulfonyl chloride or fluoride as a starting material, by the creation of a large library of sulfonates in a near-quantitative fashion using a simple and fast SuPhenEx reaction at room temperature . Now, we demonstrate that the same class of starting materials can also be used to create a large array of sulfonamides in good yields via the reaction with a wide range of alkylamines and N -alkylated anilines (Figure ).…”

“…The previously demonstrated stability of 1 in aqueous solutions is, of course, especially effective in the SuPhenEx reactivity for use in many biological applications, specifically those involving polar natural amines (Table ). To demonstrate its scope, we thus used several amino acids to attach to 1 .…”