Organic Letters
Letter
clearly demonstrates the challenge of the nucleophilic attack of
fluorine ion at arenediazonium salt being much easier than at
sulfur dioxide, which makes the desired fluorosulfonylation of
arenediazonium salts via Balz−Schiemann-type nucleophilic
reaction unlikely. To our delight, subsequent extensive
screening of reaction conditions revealed that the combination
of 1.0 equiv of DABSO and 5.0 equiv of KHF2 in MeCN in the
presence of catalytic amounts of CuCl2 and 6,6′-dimethyl-2,2′-
dipyridyl at room temperature provided suitable reaction
conditions to generate the desired fluorosulfonylation product
in good yield. Notably, both the copper catalyst and the halide
in the catalyst played a very important role in the desired
fluorosulfonylation reaction (also vide infra). A detailed
screening of reaction conditions with regard to catalyst, ligand,
solvent, and fluoride source is provided in the Supporting
With the optimal reaction conditions successfully estab-
lished, we next turned our attention to the generality of this
copper-catalyzed fluorosulfonylation of various arenediazo-
nium salts. As shown in Figure 2, a wide variety of
arenediazonium salts with electron-donating, neutral, and
electron-withdrawing substituents were effectively subjected
to the optimal reaction conditions, affording the corresponding
fluorosulfonylation products in good yields. Some polar and
complicated byproducts were observed via TLC analysis and
might be Sandmyer-type or azo byproducts. To the best of our
knowledge, no fluorinated byproducts were observed in these
reactions as expected. Most likely due to the mild reaction
conditions employed, various functional groups were well
tolerated, including ether (2a−g), halogen (2n−r), ketone
(2s−u), ester (2v−x), amide (2y−aa), cyano (2bb), nitro
(2cc), and heterocyclic (2dd) groups. In particular, substrates
1y and 1aa bearing an active N−H group provided the
corresponding products in good yields. Additionally, the
robustness of this transformation can be demonstrated by
the successful application of this protocol to various
heteroarenediazonium salts, thus affording the corresponding
desired products in acceptable yields (2ee−hh). Next, several
complex molecules, including aminoglutethimide (1ii),
cabozantinib intermediate (1jj), menthol derivative (1kk),
and sulfamethazine (1ll), were selected as suitable reaction
partners for the current transformation, and all proceeded well
to generate the corresponding products in satisfactory yields.
Furthermore, gram-scale synthesis of 2a was performed to
illustrate the good viability of the transformation for scale-up.
We also decided to investigate derivatization reactions of the
arenesulfonyl fluorides acquired to further expand the scope
and utility of this protocol. As shown in Scheme 2, benefiting
from the thermodynamic stability and relative stability toward
nucleophilic substitution, bromo- and iodo-containing arene-
sulfonyl fluorides can undergo several orthogonal functional-
izations at bromo or iodo sites, including trifluoromethylation
with Chen’s reagent,16 Heck and Suzuki cross-coupling
reactions, affording the corresponding products 3−5, respec-
tively, with the SO2F group intact. Moreover, arenesulfonyl
units frequently exist in many pharmaceuticals and herbicides,
and the sulfonylation reaction of alcohol and amine is one of
the top five widely applied reactions during pharmaceutical
research.17 Various arenesulfonyl fluorides obtained by this
transformation may serve as good sulfonylation reagents. Facile
reactions of arenesulfonyl fluoride 2a with various oxygen- or
nitrogen-containing nucleophiles give the corresponding
sulfonate 6, sulfonylamide 7, and sulfonylazide 8 in excellent
Figure 1. Representative arenesulfonyl fluorides with significant
biological values and established synthetic methods for arenesulfonyl
fluorides.
The very mild practical reaction conditions and the wide
availability of the starting arenediazonium salts from various
anilines allow for quick access to a broad range of highly
valuable arenesulfonyl fluorides and will significantly promote
their application in different research fields.
We commenced our study of the desired fluorosulfonylation
of arenediazonium salts by using p-bromobenzenediazonium
salt as the model substrate, SO2 gas as received, and KHF2 as
an inexpensive and atom-efficient fluoride source (KHF2 at
∼$10/mol vs Selectfluor at ∼$400/mol and NFSI at ∼$110/
mol)14 in toluene at 110 °C for 1 h according to the novel
concept presented in Figure 1c. No formation of the desired
fluorosulfonylation product (II) was observed, but the
competitive Balz−Schiemann fluorination byproduct (I) was
produced in 46% 19F NMR yield (Scheme 1). This result
Scheme 1. Initial Fluorosulfonylation Attempt with p-
Bromobenzenediazonium Salt via Balz-Schiemann-Type
Nucleophilic Reaction
B
Org. Lett. XXXX, XXX, XXX−XXX