Organic Letters
Letter
using 4-dimethylaminopyridine (DMAP), N-methylimidazole
(NMI), lutidine, and pyridine (Table 1, entries 1−6). The use
of pyridine as the solvent significantly improved the reaction
time and also permitted a reduction in HFIPS, from 1.5 equiv
to 1.2 equiv (Table 1, entry 7). The sulfamoylation remained
high-yielding when pyridine was used as a cosolvent with
CH2Cl2, tetrahydrofuran (THF), PhMe, acetonitrile (MeCN),
and dimethylformamide (DMF) (Table 1, entries 8−13), and
this versatility is beneficial for substrates with different
solubility requirements. The reaction performed equally well
on gram-scale (Table 1, entry 9).
With a variety of mild reaction conditions established, we
chose the CH2Cl2−pyridine (7:3) solvent mixture to evaluate
the scope of the sulfamoylation reaction with a diverse
collection of substrates (9a−39a) that includes alcohols,
phenols, amines, and anilines (Figure 3). Primary and
secondary alcohols reacted efficiently under the standard
reaction conditions. Upon completion, the reaction mixtures
were simply concentrated under reduced pressure and
subjected to silica gel chromatography, but note that crude
products often showed relatively high purity prior to
chromatography. Alkyl sulfamates 9b−21b were stable under
these conditions, and elimination products were not detected.
Phenols also reacted readily with HFIPS, despite its
diminished reactivity, compared to other reagents such as
sulfamoyl chloride (2) and PCPS (4). Phenols 25a−27a were
slower to react with HFIPS than alcohols, but reaction rates
were improved with additional HFIPS (1.5 equiv), and the aryl
sulfamate products 25b−27b were isolated in good yield. Since
aryl sulfamate esters are known to be sensitive to base-induced
decomposition,14 pyridine was removed with aqueous workups
rather than rotary evaporation.
The sulfamoylation of quinine (19a) was low-yielding under
standard conditions, but sulfamate 19b was isolated in 60%
yield, using 3 equiv HFIPS and an extended reaction time (48
h). Tertiary alcohol 22a was unreactive under the standard
conditions, presumably because of steric hindrance, and
starting material was recovered.
Starting material was also isolated after unsuccessful
attempts to synthesize benzyl sulfamate (23b) from benzyl
alcohol (23a). We identified precipitates formed during the
reaction as benzylpyridinium salts by 1H NMR, supporting our
hypothesis that the benzyl sulfamate product (23b) was
generated in situ, but sensitive to pyridine-catalyzed hydrolysis.
The p-nitrobenzyl derivative is more stable, although the
isolated yield of 24b was moderate (44%).
Figure 2. Common procedures and improved reagents for the
sulfamoylation of alcohols and amines.
HFIPS (also known as Hfs-NH2) has been investigated
previously as a nitrogen-atom donor for intermolecular C−H
aminations,4i−k intermolecular aziridinations,4l,m and as a
carbonic anhydrase inhibitor,12 but has not been investigated
extensively as a sulfamoylation reagent. Among the previous
preparations of HFIPS, we have found the methods of Roizen4j
and Okada13 to be the most reproducible. The two-step, one-
pot procedure involves the addition of formic acid to a solution
of CSI in MeCN,4j rather than neat CSI, to generate sulfamoyl
chloride (2) in situ, followed by the addition of HFIP
(hexafluoro-2-propanol) as a solution in dimethylacetamide
(DMA), without an additional base.13 Following an aqueous
workup, HFIPS was isolated in 74% yield and sufficient purity
(>98%) to be used in sulfamoylations without chromatography
(Scheme 1). We used less CSI (1.3 equiv) than is typically
required (2−4 equiv) and achieved a more atom-economical
procedure.
With the goal of developing mild and general sulfamoylation
conditions with HFIPS, we began our investigation with
secondary alcohol 8a and commonly used soluble amine bases
(see Table 1). Although the sulfamoylation was low-yielding
with triethylamine (Et3N) and 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU), improved yields of sulfamate 8b were obtained
As expected, the reaction conditions optimized for the
sulfamoylation of alcohols were also fully compatible with
more nucleophilic amines. Primary and secondary amines
(28a−34a), anilines (35a, 36a), and phenyl hydrazine 39a all
reacted readily with HFIPS to generate the corresponding
sulfamide products in good to high yields. Heterocyclic amines
37a and 38a reacted more slowly to provide sulfamides 37b
and 38b in moderate yields.
a
Scheme 1. Synthesis of HFIPS
Amino alcohols 33a and 34a reacted predictably with
HFIPS, with sulfamoylation occurring at the amines.
Sulfamides 33b and 34b were isolated cleanly in good yield,
with no detectable sulfamate or aziridine byproducts.
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.9,10 In order to
probe the inherent selectivity of HFIPS toward primary and
secondary alcohols, we designed a competition experiment
a
Thermal ellipsoids are displayed at the 50% probability level.
3374
Org. Lett. 2021, 23, 3373−3378