Organic Letters
Letter
SbF6. The reactivity profile of the putative sulfonyl hypoiodites
is adaptable through the appropriate choice of the silver salt
and enlarges the currently available scope for (hetero)aromatic
iodination chemistry.
hypoiodite and arene as we observed in the related
mesyloxylation reaction34 was prevented by in situ formation
of the reactive intermediate. Scale-up to the gram scale was
established for iodination of coumarin1 with silver methanesu-
fonate to afford product 19 in 91% yield. Electron-withdrawing
arenes gave low yields for the corresponding iodinated
products.
Based on our reaction chemistry developed with 1,34 we
have discovered a productive, high-yielding iodination reaction
in the presence of iodide and 1 (Table 1). Because 1 is
explosive, we attempted to reproduce the observed reactivity
with reagents that are more convenient and safer. We assumed
the formation of methanesulfonylhypoiodite as the reactive
electrophilic iodinating reagent that formed in situ upon
mixing 1 and iodide and attempted to intercept it
independently through the reaction of molecular iodine with
silver mesylate. We successfully observed a similar reactivity,
which is superior when compared to conventional iodination
reagents and reactions (Table 1). Because the putative sulfonyl
hypoiodites are prepared in situ in solution, this reaction setup
does not share the same safety concerns associated with the
explosiveness of bis(methansulfonyl) peroxide that was used as
an isolated solid.
We observed chemoselective iodination for sp2 C−H
functionalization with no benzylic or α-carbonyl oxidation
observed, an advantage when compared to the combination of
iodine and other oxidants.36 The reaction is insensitive to
oxygen or traces of water and thus can be carried out under an
ambient atmosphere. For most substrates, clean conversion of
the starting material to the product was observed, which
renders purification straightforward. When compared to
conventional iodinating reagents such as NIS, the reaction
conditions shown here typically afforded substantially higher
yields, higher selectivity, and no overiodination (see Table S1
in the Supporting Information for a comparison).
In summary, we have presented a simple C−H iodination of
various carboarenes and heteroarenes via putative sulfonyl
hypoiodites that has not been appreciated before and extends
the substrate scope of iodination chemistry. The operational
ease, scalability, broad functional group tolerance, and
substrate scope make this protocol suitable for both academic
and industrial settings.
Although NIS is a practical and convenient reagent for the
iodination of simple, electron-rich (hetero)arenes, its utility is
severely limited for less electron-rich substrates. While NIS can
furnish the same iodinated product 2 (Table 1), albeit in a
substantially lower yield, for more complex, functionalized, or
electron-poor substrates, it often fails, as shown in Table 2, and
for a selection of a dozen compounds in the Supporting
ASSOCIATED CONTENT
■
The simple reaction setup of mixing a silver salt that could
form a putative iodine−oxygen bond potentially enables the in
situ generation of a variety of hypoiodites that could, in the
best case, be adapted to the required reactivity for efficient
iodination of a given arene. In other words, tuning the
reactivity of the presumed hypoiodite would allow for an
appropriate electrophilicity for any given (hetero)arene.
After a brief evaluation of simple arenes (Table 3), we
focused our attention on the C−H iodination of various
heteroarenes because N-containing heterocycles represent an
sı
* Supporting Information
The Supporting Information is available free of charge at
Detailed experimental procedures and spectroscopic
AUTHOR INFORMATION
■
Corresponding Author
important class of compounds in medicinal chemistry.35
A
Tobias Ritter − Max-Planck-Institut fu
̈
r Kohlenforschung,
variety of functional groups such as electron-rich pyridines,
carboxylic acids, esters, amines, sulfonamides, and phthali-
mides are well tolerated. If acid-sensitive functional groups are
present, the addition of Li2CO3 as a base to neutralize the in
situ formed acid byproduct results in productive iodination.
The iodination reaction reported here could be extended to
electron-rich heteroarenes such as N-methylpyrrole (10) and
2,6−dimethoxypyridine (11), with the best results obtained
when using silver acetate. Compounds containing ketones are
generally challenging for iodination; however, ketone 2 was
obtained in 80% isolated yield with less than 5% α-iodination
byproduct. Other 5-membered heteroarenes such as thiazole
(14) and pyrroles (17) afforded the highest yields with silver
tosylate.
As can be seen in Table 4, the scope of the new iodination
reaction includes a range of small-molecule pharmaceutical
carboarenes. The reaction condition proved to be compatible
with structurally complex arenes, such as nimesulide (3),
procymidone (20), boscalid (21), and strychnine (25).
Notably, no competing addition of iodine to double bonds
was observed for arenes 18, 19, and 25. The method often
affords a high yield and high positional selectivity. A detailed
study of the hypothesis that the magnitude of the selectivity
can be rationalized by a charge transfer complex between
45470 Mulheim an der Ruhr, Germany; Institute of Organic
̈
Chemistry, RWTH Aachen University, 52074 Aachen,
Authors
Lalita Tanwar − Max-Planck-Institut fu
45470 Mulheim an der Ruhr, Germany; Institute of Organic
̈
r Kohlenforschung,
̈
Chemistry, RWTH Aachen University, 52074 Aachen,
Germany
Jonas Börgel − Max-Planck-Institut fu
Johannes Lehmann − Max-Planck-Institut fu
Kohlenforschung, 45470 Mulheim an der Ruhr, Germany
̈
r Kohlenforschung,
̈
̈
r
̈
Complete contact information is available at:
Author Contributions
L.T. developed the C−H iodination reaction protocol. J.B. and
J.L. helped in the synthesis of the peroxide and the mechanism
study. L.T. and T.R. wrote the manuscript. T.R. directed the
project.
5026
Org. Lett. 2021, 23, 5024−5027