Catalytic Sulfamoylation of Alcohols with Activated Aryl Sulfamates

Abstract

We report a new catalytic method for alcohol sulfamoylation that deploys electron-deficient aryl sulfamates as activated group transfer reagents. The reaction utilizes the simple organic base N-methylimidazole, proceeds under mild conditions, and provides intrinsic selectivity for 1° over 2° alcohols (up to >40:1 for certain nucleosides). The requisite aryl sulfamate donors are stable crystalline solids that can be readily prepared on a large scale. Mechanistic considerations support the intermediacy of HNSO2 “aza-sulfene” in the transfer reaction.

Hexafluoroisopropyl Sulfamate: A Useful Reagent for the Synthesis of Sulfamates and Sulfamides

“…Its high sensitivity to hydrolysis also prevents long-term storage. Boc-protected Burgess-type salts 3a – 3c have been developed as sulfamoylation reagents with improved safety and stability, but Boc removal requires an additional step and strongly acidic conditions. , In 2020, the Miller laboratory disclosed a useful process employing pentachlorophenyl sulfamate (PCPS, 4 ) or pentafluorophenyl sulfamate (PFPS, 5 ) and catalytic NMI for the synthesis of sulfamates, with high selectivity for primary over secondary alcohols (e.g., N 6 -Bz-deoxyadenosine, 6a ) …”

“…The Burgess-type sulfamoylation reagents 3b and 3c and PCPS ( 4 ) are highly selective toward primary alcohols over secondary alcohols in diol or polyol substrates. , In order to probe the inherent selectivity of HFIPS toward primary and secondary alcohols, we designed a competition experiment involving alcohols 9a and 10a , which was followed by 1 H NMR (see Scheme ). Alcohols 9a and 10a were combined with HFIPS in equimolar amounts and stirred in CDCl 3 /pyridine- d 5 (7:3) or neat pyridine- d 5 at 30 °C.…”

“…Several kinetic and computational studies with aryl sulfamates demonstrate that the mechanisms of hydrolysis and aminolysis at neutral or alkaline pH involve E2 or E1cB elimination pathways, rather than direct nucleophilic attack at the S atom. , The elimination generates HNSO 2 ( 42 , which is also known as aza-sulfene) in situ, as a reactive intermediate that is attacked rapidly by nucleophiles.…”

“…In conclusion, we have developed a general and versatile method for the synthesis of sulfamates and sulfamides using hexafluoroisopropyl sulfamate (HFIPS, 7 ) and have demonstrated the utility of this method with a broad scope of alcohol and amine substrates. The HFIPS method is preferable to sulfamoylation using ClSO 2 NH 2 and is complementary to the catalytic method developed by the Miller group . Overall, the HFIPS sulfamoylation method offers substantial improvements in both operational simplicity and time economy.…”

“…Rapp et al have noted safety concerns with PCPS ( 4 ), because of the potential for pentachlorophenol to be contaminated with trace dioxins, and the authors suggest PFPS ( 5 ) as a safer alternative. Hexafluoro-2-propanol (HFIP) is classified as corrosive and an irritant, but its toxicity profile is favorable over pentachlorophenol and pentafluorophenol.…”