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a three-way valve joint. For large scale reactions, depletion of the
sulfuryl fluoride from the balloon was easily observed, and more
SO2F2 gas was introduced with a fresh balloon when required. The
reaction mixture was vigorously stirred at room temperature for 2–
24 h, monitoring by TLC. After completion, the solvent was re-
moved by rotary evaporation. The residue was dissolved in EtOAc,
washed with saturated sodium bicarbonate and brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel to
give heteroaryl fluorosulfates 1.
chemistry would enable a more direct access to Etoricoxib, by
circumventing protecting group chemistry. Beginning with the
same 5-bromo-6-chloropyridin-3-yl fluorosulfate (17) starting
material, the formation of the pyridin-2-yl fluorosulfate (18)
was readily achieved by reaction with sulfuryl fluoride. The syn-
thesis of Etoricoxib was successfully completed by the sequen-
tial installation of the 4-(methylsulfonyl)phenyl and 6-methyl-
pyridin-3-yl substituents into the pyridine core, in an overall
40.3% yield (Scheme 2B). To the best of our knowledge, the
synthetic approach to Etoricoxib described here is the most
concise to date.[22]
General procedures for Pd-catalyzed Suzuki reactions
Conclusions
Method A: General Suzuki procedure associated with (aqueous)
alcohol solution: Het-OSO2F (1.0 mmol, 1.0 equiv), (hetero)arylbor-
onic acid (1.5 mmol, 1.5 equiv), Pd catalyst (1–10 mol%), and base
(3.0 mmol, 3.0 equiv) were successively added to a 50 mL flask
equipped with a stirring bar and a thermometer. The air in the
flask was replaced by nitrogen gas by vacuum, and then (aqueous)
alcohol solution (with different ratios) (1–20 mL) was injected into
the flask through a rubber plug. The reaction mixture was placed
into an oil bath, heated to the corresponding temperature and
stirred for between 1–24 h as determined by TLC or HPLC analysis.
After completion, most of organic solvent was removed by rotary
evaporation. The residue was dissolved in EtOAc, washed with sa-
turated brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography over silica gel to afford the coupling product.
In summary, we have developed an efficient protocol for the
synthesis of functional heteroaryl fluorosulfates. This was made
possible by harnessing the incredible reactivity of the sulfur
connector, SO2F2. The heteroaryl fluorosulfates were demon-
strated as versatile electrophilic cross-coupling partners in the
Pd-catalyzed Suzuki reaction, exhibiting distinct reactivity from
the corresponding halogens and triflates. Harnessing the
unique reactivity of fluorosulfates, enabled the synthesis of
a number of polysubstituted pyridines with exquisite chemose-
lective control.
The privileged nature of the fluorosulfate leaving group was
further demonstrated with the concise synthesis of the drug,
Etoricoxib, in just three steps. The scalability of heteroaryl fluo-
rosulfates to kilogram quantities, coupled with the plethora of
available Pd catalysts, render fluorosulfates ideal substrates for
both process and discovery applications.
Method B: General Suzuki procedure associated with aqueous
NaHCO3 solution in 1,4-dioxane at room temperature: Het-
OSO2F (1.0 mmol, 1.0 equiv), (hetero)arylboronic acid (1.5 mmol,
1.5 equiv), and [Pd(PPh3)4] (10 mol%) were successively added to
a 50 mL flask equipped with a stirring bar and a thermometer. The
air in the flask was replaced by nitrogen gas by vacuum, and then
1,4-dioxane (10 mL) was injected into the flask through a rubber
plug. The reaction mixture was stirred for 10 min and then NaHCO3
(3.0 mmol, 3 equiv) in 10 mL water was injected into the flask. The
reaction mixture was stirred at room temperature for 3–24 h as
monitored by HPLC. After completion, the mixture was diluted
with EtOAc (20 mL), washed with saturated brine, dried over
Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel to
afford the coupling product.
Experimental Section
General procedure for the preparation of heteroaryl fluorosul-
fates 1 with TEA in DCM: A three-neck round-bottom flask
equipped with a thermometer was charged with the correspond-
ing hydroxyheterocycle, DCM (10 mLgÀ1) and TEA (1.5 equiv). The
mixture was stirred at room temperature for 10 min. The reaction
flask was then sealed with a septum. The atmosphere above the
solution was removed under a gentle vacuum, and the SO2F2 gas
(sulfuryl fluoride, Vikane) was introduced from a balloon through
a three-way valve joint. For large scale reactions, the depletion of
the sulfuryl fluoride from the balloon was observed, and additional
SO2F2 gas introduced via a fresh balloon as required. The reaction
mixture was stirred vigorously at room temperature between 2–
24 h, and the reaction progress monitored by TLC. The reaction
mixture was then washed with saturated sodium bicarbonate and
brine, dried over Na2SO4, filtered and concentrated under reduced
pressure. The crude residue was purified by flash column chroma-
tography over silica gel to give the heteroaryl fluorosulfates 1.
Method C: General Suzuki procedure associated with KF in tolu-
ene or 1,4-dioxane at refluxing temperature: Het-OSO2F
(1.0 mmol, 1.0 equiv), arylboronic acid (1.5 mmol, 1.5 equiv),
[Pd(PPh3)4] (10 mol%), and KF (3.0 mmol, 3.0 equiv) were succes-
sively added to a 50 mL flask equipped with a stirring bar and
a thermometer. The air in the flask was replaced by nitrogen gas
by vacuum, and then toluene or 1,4-dioxane (10 mL) was injected
into the flask through a rubber plug. The reaction mixture was
placed into an oil bath, and heated to reflux for between 3–10 h as
determined by HPLC analysis. After completion, the mixture was
diluted with EtOAc (20 mL), washed with saturated brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by flash column chromatography over
silica gel to afford the coupled product.
General procedure for the preparation of heteroaryl fluorosul-
fates 1 with DIPEA in ACN: A three-neck round-bottom flask
equipped with a thermometer was charged with the correspond-
ing hydroxyheterocycle, ACN (10 mLgÀ1) and DIPEA (1.5–3 equiv).
The mixture was stirred at room temperature for 10 min. The reac-
tion flask was then sealed with a septum. The atmosphere above
the solution was removed with gentle vacuum, and SO2F2 gas (sul-
furyl fluoride, Vikane) from a balloon was introduced through
Chem. Eur. J. 2016, 22, 5692 – 5697
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