Organic Letters
Letter
gas.14d Despite the fact that these methods are powerful, the
utilization of toxic metal might contaminate the final click
reagents, which is a particular concern regarding the
application of click chemistry in biological systems.15
a
Table 1. Selected Optimization Studies
Aromatic amines are ubiquitous and cheap substrates in
research laboratories and industry. Recently, we embarked on a
project to convert the aromatic NH2 group into a SO2F group
in the late stage of the development of novel covalent
inhibitors. We envisaged that this goal might be achieved by
combining several known transformations (Figure 2c), which
b
entry
variation from the standard conditions
yield (%)
c
1
2
3
4
5
6
7
8
none
65 (66)
48
24
trace
N.D.
10
<5
53
N.D.
42
46
15
58
63
32
20
32
Na2S2O4 instead of Na2S2O5
DABSO instead of Na2S2O5
Rongalite instead of Na2S2O5
CF3SO2Na instead of Na2S2O5
Na2SO3 instead of Na2S2O5
K2S2O5 instead of Na2S2O5
NFSI instead of Selectfluor
KF instead of Selectfluor
4.0 equiv of Na2S2O5
9
10
11
12
13
14
15
16
17
2.0 equiv of Na2S2O5
25 °C instead of 70 °C
60 °C instead of 70 °C
2 mL of MeOH
EtOH instead of MeOH
DMF instead of MeOH
under air atmosphere
a
Reaction conditions: 1a (0.2 mmol), Na2S2O5 (0.6 mmol, 3.0 equiv),
Selectfluor (0.4 mmol, 2.0 equiv), MeOH (1 mL), 70 °C, under N2, 9
b
h. 19F NMR yield calculated with PhCF3 as internal standard.
Figure 2. Strategies for the synthesis of arylsulfonyl fluorides.
c
Isolated yield.
involved (1) a Sandmeyer halogenation reaction16 followed by
Willis’s Pd-catalyzed cross-coupling strategy14a or (2) a
Meerwein chlorosulfonylation reaction17 followed by the
fluoride−chloride exchange.7 However, these two-step proce-
dures generally suffer from the use of stoichiometric copper
salts and the tedious separation of intermediates. Thus we
wondered whether the synthesis of sulfonyl fluorides could be
directly achieved from aryldiazonium salts in a single step
under copper-free conditions. Surprisingly, in contrast with its
counterpart sulfonyl chlorides, the synthesis of sulfonyl
fluorides via Sandmeyer-type fluorosulfonylation remains
underexplored,18 which is probably due to the high reactivity
of diazonium salts and the lack of appropriate sulfur dioxide
and fluorine sources. Herein we report a copper-free
Sandmeyer-type fluorosulfonylation reaction of aryldiazonium
salts using readily available sodium metabisulfite and
Selectfluor as the sulfur dioxide surrogate and fluorine source,
respectively.19
Initially, 4-methylbenzenediazonium tetrafluoroborate (1a)
was chosen as the model substrate to optimize the reaction
conditions. Inspired by recent progress20 in the synthesis of
sulfonyl functionalities utilizing sulfur dioxide surrogates
instead of toxic SO2 gas, we first examined a range of solid
sulfur dioxide surrogates (Table 1, entries 1−7), including
sodium metabisulfite (Na2S2O5), sodium dithionite
(Na2S2O4), DABSO, Rongalite,21 Langlois reagent
(CF3SO2Na), sodium sulfite (Na2SO3), and potassium
metabisulfite (K2S2O5). To our delight, utilizing cheap sodium
metabisulfite as the sulfur dioxide surrogate and Selectfluor as
the fluorine source, 4-methylbenzene-1-sulfonyl fluoride (2a)
could be obtained in 66% isolated yield after 9 h at 70 °C
(Table 1, entry 1). When the SO2 source was switched from
sodium metabisulfite to others, the yields decreased (Table 1,
entries 2−7). In addition, using NFSI as the fluorine source
instead of Selectfluor led to a slight decrease in reaction yield
(Table 1, entry 8), whereas no desired product was detected
when replacing Selectfluor with KF (Table 1, entry 9).
Notably, the amount of sodium metabisulfite was found to be
vital because either increasing or reducing the loading provided
less efficient reactions (Table 1, entries 10 and 11). The
examination of temperature, solvents, and concentration
identified 70 °C and MeOH (1 mL) as optimal reaction
parameters (Table 1, entries 12−16). Moreover, the control
experiment indicated that the nitrogen atmosphere is necessary
for this reaction (Table 1, entry 17). For full details of the
Having identified the optimal reaction conditions, we next
investigated the scope of the aryldiazonium salts, and the
results are summarized in Scheme 1. To our delight,
aryldiazonium tetrafluoroborates with electron-donating
groups at the para position on the benzene ring gave the
corresponding sulfonyl fluorides 2a−g in good to excellent
yield (66−85%). However, lower yields were obtained for the
substrates with electron-withdrawing groups under the same
conditions. For example, 4-nitrobenzenediazonium salt gave
the desired product in 34% yield, whereas nitrobenzene was
isolated as the major byproduct in 45% yield. After further
investigation of the reaction condition using the para-nitro
B
Org. Lett. XXXX, XXX, XXX−XXX