Complementary Site-Selective Sulfonylation of Aromatic Amines by Superacid Activation

Article abstract of DOI:10.1021/acs.orglett.1c00994

Under superacidic conditions, aniline and indole derivatives are sulfonylated at low temperature with easy-to-access arenesulfonic acids or arenesulfonyl hydrazides. By modification of the functional-group directing effect through protonation, this method allows nonclassical site functionalization by overcoming the innate regioselectivity of electrophilic aromatic substitution. This superacid-mediated sulfonylation of arenes is complementary to existing methods and can be applied, through protection by protonation, to the late-stage site-selective functionalization of natural alkaloids and active pharmaceutical ingredients.

Full text of DOI:10.1021/acs.orglett.1c00994

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Letter
Complementary Site-Selective Sulfonylation of Aromatic Amines by
Superacid Activation
̀
Paul Bourbon, Emeline Appert, Agnes Martin-Mingot, Bastien Michelet,* and Sébastien Thibaudeau*
Cite This: Org. Lett. 2021, 23, 4115−4120
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ABSTRACT: Under superacidic conditions, aniline and indole
derivatives are sulfonylated at low temperature with easy-to-access
arenesulfonic acids or arenesulfonyl hydrazides. By modification of
the functional-group directing effect through protonation, this
method allows nonclassical site functionalization by overcoming
the innate regioselectivity of electrophilic aromatic substitution.
This superacid-mediated sulfonylation of arenes is complementary
to existing methods and can be applied, through protection by
protonation, to the late-stage site-selective functionalization of
natural alkaloids and active pharmaceutical ingredients.
romatic sulfones are important scaffolds in organic
Scheme 2. (a, b) Reported Methods for Direct C−H
Sulfonylation of Arenes and (c) Our Strategy Using
Superacid Activation
A
synthesis and have found many applications in the
medicinal, agrochemical, and materials fields (Scheme 1).1
Scheme 1. Selected Examples of Sulfone Derivatives and
Their Applications
Over the past decades, numerous methods have been
developed for their synthesis.1,2 The most classical approaches
rely on oxidation of the corresponding sulfides or sulfoxides,
addition of sulfinates to unsaturated bonds, or metal-catalyzed
cross-coupling reactions from sulfinates or sulfonyl halides.1
Although these methods proved their efficiency to generate a
wide variety of aromatic sulfones, they are still strongly limited
by the necessity of prefunctionalizing the aromatic starting
material. In this context, great efforts have recently been made
to develop new methods for direct C(sp2)−H sulfonylatio-
n,2a−c mainly through metal-catalyzed C−H activation
(Scheme 2a)3 or oxidative C−H functionalization of quino-
lines,4 anilines,5 indoles,6 or phenol derivatives.7 However,
these strategies necessitate the preinstallation of a directing
group and/or are limited to specific substrates, narrowing their
Received: March 23, 2021
Published: May 17, 2021
https://doi.org/10.1021/acs.orglett.1c00994
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4115−4120
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scope of application. Moreover, although it is highly site-
specific, directed C−H sulfonylation of arenes occurs mostly at
the position ortho to the directing group.2c,8 On the other
hand, one of the simplest and oldest strategies to substitute an
aromatic hydrogen atom by a sulfonyl group is probably
aromatic electrophilic substitution, akin to Friedel−Crafts
acylation (Scheme 2b).9 This strategy benefits from ease of
setup, a large variety of accessible catalysts, and a wide range of
commercially available reagents. Nevertheless, in most cases
Friedel−Crafts-type sulfonylation is applicable only to low-
weight benzene derivatives and suffers from poor regioselec-
tivity dictated by the innate orientation effect of the
substituents.
Table 1. Optimization of the Superacid-Promoted
Benzenesulfonylation of p-Methylacetanilide
b
We previously demonstrated10 that under superacid
conditions,11 aromatic amines (or amides)despite being
fully protonatedcan react with an electrophile provided that
the latter is further activated by the superacidic medium
(superelectrophilic activation).12 In particular, under these
conditions the orientation effect of the amine substituent is no
longer effective, and the site selectivity of the reaction is
dictated by the secondary substituent, leading to nonclassical
regioselectivity. Motivated by these previous results and by the
absence of general procedures for direct electrophilic
sulfonylation of aromatic amines,9 we aimed at developing a
complementary site-selective method that would allow the
direct functionalization of aniline and indole derivatives from
readily available sulfone precursors by taking advantage of
superelectrophilic activation (Scheme 2c).
We started our investigations with p-methylacetanilide as
model substrate and benzenesulfonic acid Aa as a cheap and
readily available sulfonyl source (Table 1). With neat HF/SbF5
(7/1) superacid, the desired product 1a was obtained after 2 h
at −20 °C in an encouraging 30% yield (Table 1, entry 1).
Delightfully, the substrate was selectively functionalized at the
meta position (with respect to the acetamido group),
confirming our initial hypothesis. The peculiar regioselectivity
of this transformation was also confirmed by X-ray analysis of
collected crystals of 1a (see the Supporting Information (SI)).
We next evaluated the impact of the acidity on the reactivity by
modulating the concentration of SbF5 (Table 1, entries 1−4)
and found that the optimal conditions were reached with a 2/1
HF/SbF5 mixture (73% yield; Table 1, entry 3). Increasing the
amount of benzenesulfonic acid to 2 equiv did not improve the
yield (Table 1, entry 5). While decreasing the temperature to
−40 °C completely inhibited the reaction (Table 1, entry 6),
performing the reaction at higher temperature led to a poor
yield and to the formation of the undesired regioisomer 1a′
(Table 1, entry 7). The formation of 1a′ can be explained by
an initial intramolecular rearrangement within the arenium ion
generated by the protonation of p-methylacetanilide to the
more stable m-methylacetanilide, which then reacts with
benzenesulfonic acid.13,14 No reaction occurred using the
weaker superacid TfOH (Table 1, entry 8), a result that
supports our initial hypothesis and the necessity to use
superelectrophilic activation to perform this transformation. As
expected, the use of excess of Lewis acids in dichloromethane
did not afford the desired product even at room temperature
with a prolonged reaction time (Table 1, entries 9−14). We
next evaluated the reactivity of p-methylacetanilide with other
sulfonyl precursors (Table 1, entries 15−23). Methyl sulfonate
Ba was found to be totally unreactive under these conditions
(Table 1, entry 15). Although good conversion of the starting
material was obtained with sulfonyl chloride Ca, 1a was
Yield [%]
a
entry
acid (v/v)
PhSO2Y (n)
T [°C]
1a
1a′
1
2
3
4
5
6
7
8
HF/SbF5 (7/1)
HF/SbF5 (3/1)
HF/SbF5 (2/1)
HF/SbF5 (1/1)
HF/SbF5 (2/1)
HF/SbF5 (2/1)
HF/SbF5 (2/1)
TfOH
Aa (1.2)
Aa (1.2)
Aa (1.2)
Aa (1.2)
Aa (2.0)
Aa (1.2)
Aa (1.2)
Aa (1.2)
Aa (1.2)
Aa (1.2)
Aa (1.2)
Aa (1.2)
Aa (1.2)
Aa (1.2)
Ba (1.2)
Ca (1.2)
Da (1.2)
Ea (1.2)
Fa (1.2)
Ga (1.2)
Ha (1.2)
Ia (1.2)
Ja (1.2)
−20
−20
−20
−20
−20
−40
0
−20
20
20
20
20
20
20
−20
−20
−20
−20
−20
−20
−20
−20
30
58
73
49
72
0
15
0
0
0
0
0
0
0
0
10
12
0
0
68
3
86
72
0
0
0
0
0
0
45
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
c
d
e
9
SbF5
AlCl3
FeCl3
d
e
10
11
12
13
d
e
d
e
Cu(OTf)2
d
e
Bi(OTf)3
d
e
14
P2O5
15
16
17
18
19
20
21
22
23
HF/SbF5 (2/1)
HF/SbF5 (2/1)
HF/SbF5 (2/1)
HF/SbF5 (2/1)
HF/SbF5 (2/1)
HF/SbF5 (2/1)
HF/SbF5 (2/1)
HF/SbF5 (2/1)
HF/SbF5 (2/1)
f
−20
a
b
Used as the solvent unless stated otherwise. Yields of isolated
c
d
products. 58% yield after 1 h. The reaction time was extended to 20
e
f
h. 2 equiv in CH2Cl2. Concomitant formation of 3-chloro-4-
methylacetanilide in 50% yield.
obtained in a low 10% yield accompanied by the formation of
3-chloro-4-methylacetanilide in 50% yield (Table 1, entry 16).
In this case, reagent C is a source of chloride ions, which can
be oxidized in situ by SbV. The generated halenium ions then
react with the aromatic nucleophile to furnish the chlorinated
product, as previously observed.10b In order to avoid this
competitive process, sulfonyl fluoride Da was evaluated as the
reaction partner (Table 1, entry 17).15 However, the reaction
was very slow in this case, and 1a was isolated in only 12%
yield. We next turned our attention to sulfonyl reagents
derived from sulfonamide. While N,N-dimethylsulfonamide Ea
and N-acetylsulfonamide Fa were found to be unreactive
(Table 1, entries 18 and 19), using the symmetrical
sulfonimide Ga afforded 1a in a good 68% yield (Table 1,
entry 20). On the other hand, only traces of 1a were obtained
when the reaction was performed with imidazole derivative Ha
(Table 1, entry 21). Sulfonyl azide Ia and sulfonyl hydrazide Ja
were revealed to be also very efficient in this transformation,
broadening the panel of reagents with the ability to sulfonate
aromatic amines in superacid. Under these conditions, 1a was
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obtained in 86% and 72% yield from Ia and Ja, respectively
(Table 1, entries 22 and 23).
With these optimized conditions in hand, we next moved to
the study of the scope and limitations of this transformation,
starting with the screening of various arenesulfonyl precursors
(Scheme 3). At this stage, we decided to evaluate the reactivity
and alkanesulfonyl reagents were found to be unreactive under
these conditions.
We next evaluated the scope of the superacid-mediated
sulfonylation on various aromatic amines (Scheme 4). With p-
Scheme 4. Scope of the Superacid-Promoted Sulfonylation
of Arenes Using Reagent Jh
Scheme 3. Scope and Limitations of the Superacid-
Promoted Sulfonylation of p-Methylacetanilide Using
Various Sulfonylation Reagents
a
The reaction time was extended to 4 h, and 2.4 equiv of Jh was used.
fluorobenzenesulfonyl hydrazide Jh, unsubstituted acetanilide
reacted as expected at the para position, affording sulfone 2 in
65% yield. The meta-sulfonylation was again observed starting
from 2-chloroacetanilide to afford compound 3, the chloro
substituent orientating the substitution in this case despite its
innate deactivating nature. The reaction could also be
performed on unprotected 4-methylaniline to afford product
4, albeit with moderate efficiency. On the other hand, the
sulfonylation was found very efficient on unprotected indoline,
tetrahydroquinoline, and tetrahydrocarbazole, affording the
corresponding compounds 5−7 in very good yields. In all three
cases, the reaction occurred meta to the nitrogen atom and
para to the alkyl chain. The unnatural regioselectivity of this
reaction is even more striking with 2-methylindole as the
starting material. Indoles are known to be excellent
nucleophiles, usually reacting at C3.16 In our case, the C6-
sulfonylated compound 8 was exclusively obtained and
represents, to the best of our knowledge, the first example of
non-directed C−H sulfonylation at C6 from a C3-unsub-
stituted indole.3b This unusual selectivity for an electrophilic
substitution on indole derivatives can be attributed to the
formation of an iminium ion after protonation of the pyrrole
ring in superacid. Oxindoles tend to react at C5, as exemplified
by the preparation of sulfones 9 and 10 in good to very good
yields. This superacid-mediated sulfonylation could also be
applied to the late-stage functionalization of more complex and
valuable substrates. The local anesthetic lidocaine was
efficiently sulfonylated at C3 to furnish compound 11. The
vinca alkaloid vinburnine was functionalized at C6 of its indole
core to give 12 in good yield. Protected phenylalanine was also
of both sulfonic acids and sulfonyl hydrazides. We chose to
discard G-type sulfonimides (as they would be less accessible
once functionalized) and sulfonyl azides (for safety reasons). It
appeared that sulfonic acids, despite their apparent simplicity,
are not ideal reagents: they are surprisingly less commercially
available than the sulfonyl chloride analogues (from which they
were prepared in some cases), sometimes difficult to
synthesize, and most of all highly hygroscopic, leading to
poorly reproducible results. On the contrary, sulfonyl
hydrazides2d are easy-to-handle, are readily prepared from
the corresponding sulfonyl chlorides and hydrazine hydrate,
and gave better results than their sulfonic acid counterparts in
most of the cases. Thus, diaryl sulfones 1a−d were synthesized
from alkyl-substituted arenesulfonyl precursors in good yields
with, again, full meta selectivity. The reaction proceeded
equally well with an electron-rich methoxy-substituted
arenesulfonyl hydrazide, affording compound 1e in 61%
yield. Naphthalene derivatives 1f and 1g could also be
generated, although in low yields due to the extensive
formation of degradation byproducts. Halo-substituted arene-
sulfonyl hydrazides were also compatible with these conditions,
affording fluoro-, chloro-, bromo-, and iodo-substituted diaryl
sulfones 1h−k. This method also afforded diaryl sulfone 1l
from an electron-poor trifluoromethyl-substituted arenesulfon-
yl hydrazide. However, strongly deactivated arenesulfonyl
precursors, such as nosyl or 3-pyridinesulfonyl derivatives,
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Letter
found to be compatible with our conditions and was
transformed into optically pure sulfone 13 in very good yield.17
To gain better insight into the mechanism of this
transformation and explore the transient formation of an
activated sulfonyl intermediate, we next decided to evaluate the
behavior of benzenesulfonic acid Aa in HF/SbF5 1 by low-
temperature in situ NMR analysis (see the SI). The H NMR
spectrum of this mixture displayed two sets of signals
corresponding to two different species in a 4.6 to 1 ratio.
Interestingly, in the 19F NMR spectrum, a new signal appeared
at 58.0 ppm that was attributed to the formation of a sulfonyl
fluoride derivative, as previously observed by Olah under
similar conditions.18 This was confirmed by the NMR analysis
of a solution of benzenesulfonyl fluoride Da in HF/SbF5, which
have developed a direct and regioselective C−H sulfonylation
of arenes at low temperature. These conditions allow the
electrophilic sulfonylation of functionalized arenes with
excellent regioselectivity. Furthermore, aniline and indole
derivatives are functionalized with nonclassical regioselectivity
due to deactivation of their nitrogen substituent by
protonation. In a context where new approaches are required
to address unmet selectivity challenges in the field of late-stage
C−H functionalization,22 this new method provides access to
diaryl sulfones with site selectivity complementary to that of
existing methods.
ASSOCIATED CONTENT
■
sı
* Supporting Information
1
provided the same set of H NMR signals as for the major
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00994.
species observed from benzenesulfonic acid Aa. The formation
of the sulfonyl fluoride was also confirmed by 19F and 13C
NMR analyses. We also submitted reagent Aa to the softer
superacid TfOH and obtained a very clean 1H NMR spectrum
displaying the same signals as for the minor species observed in
HF/SbF5. More importantly, no evidence for the eventual
addition of triflate to benzenesulfonic acid was obtained,
despite the stronger nucleophilicity of triflate anion compared
with fluoroantimonates.19 This observation suggests that under
HF/SbF5 conditions, benzenesulfonic acid is transformed into
a highly activated electrophilic species. Although this species
could not be directly observed because of its rapid trans-
formation into sulfonyl fluoride, we can postulate the
formation of a benzenesulfonylium ion, as has been previously
suggested.18 In the presence of an aromatic nucleophile, the
transient generation of this key intermediate would trigger the
electrophilic aromatic substitution (Scheme 5, path a), while in
General experimental procedures, reaction setup, char-
acterization data, low-temperature NMR spectra, and
spectra for all key compounds (PDF)
Accession Codes
CCDC 2081182 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Sébastien Thibaudeau − Université de Poitiers, UMR-CNRS
7285, IC2MP, Superacid Lab - Organic Synthesis Team,
86073 Poitiers, France; orcid.org/0000-0002-6246-
5829; Email: sebastien.thibaudeau@univ-poitiers.fr
Bastien Michelet − Université de Poitiers, UMR-CNRS 7285,
IC2MP, Superacid Lab - Organic Synthesis Team, 86073
Poitiers, France; Email: bastien.michelet@univ-poitiers.fr
Scheme 5. Postulated Mechanism of the Superacid-
Promoted C−H Sulfonylation of Arenes from Sulfonic
Acids and Hydrazides
Authors
Paul Bourbon − Université de Poitiers, UMR-CNRS 7285,
IC2MP, Superacid Lab - Organic Synthesis Team, 86073
Poitiers, France
Emeline Appert − Université de Poitiers, UMR-CNRS 7285,
IC2MP, Superacid Lab - Organic Synthesis Team, 86073
Poitiers, France; @rtMolecule, 86000 Poitiers, France
the absence of a sufficiently nucleophilic partner, the latter
sulfonylium ion would collapse to the more stable sulfonyl
fluoride,20,21 which would react very slowly because of its very
high stability in superacidic media21 (Scheme 5, path b).
To confirm the generality of this mechanistic hypothesis, we
evaluated the reactivity of the benzenesulfonyl sources listed in
Table 1 by in situ NMR analysis in HF/SbF5 without
nucleophilic partners (see the SI). As expected, the effective
reagents Ca, Ga, Ia, and Ja were almost instantaneously
transformed into sulfonyl fluoride similarly to Aa, while the
ineffective sulfonyl derivatives remained stable or were
transformed very slowly. Likewise, the low reactivity of
alkanesulfonic acids under these conditions could be explained
by the very high stability of their protonated forms in
superacid.18
̀
Agnes Martin-Mingot − Université de Poitiers, UMR-CNRS
7285, IC2MP, Superacid Lab - Organic Synthesis Team,
86073 Poitiers, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00994
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Région Nouvelle-Aquitaine
(Ph.D. grant to P.B.), ANRT and the @rtMolecule Society
(Ph.D. grant to E.A. and financial support through the
ISOTOP Project). We also acknowledge the University of
Poitiers, the Centre National de la Recherche Scientifique
To conclude, taking advantage of the superelectrophilic
activation of simple arenesulfonic acids and hydrazides, we
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Letter
(8) For rare examples of meta-sulfonylation, see: (a) Saidi, O.;
Marafie, J.; Ledger, A. E. W.; Liu, P. M.; Mahon, M. F.; Kociok-Köhn,
G.; Whittlesey, M. K.; Frost, C. G. Ruthenium-Catalyzed Meta
Sulfonation of 2-Phenylpyridines. J. Am. Chem. Soc. 2011, 133,
19298−19301. (b) Li, G.; Lv, X.; Guo, K.; Wang, Y.; Yang, S.; Yu, L.;
Yu, Y.; Wang, J. Ruthenium-catalyzed meta-selective C−H sulfonation
of azoarenes with arylsulfonyl chlorides. Org. Chem. Front. 2017, 4,
1145−1148. (c) Li, G.; Zhu, B.; Ma, X.; Jia, C.; Lv, X.; Wang, J.;
Zhao, F.; Lv, Y.; Yang, S. Ruthenium-Catalyzed ortho/meta-Selective
Dual C−H Bonds Functionalizations of Arenes. Org. Lett. 2017, 19,
5166−5169.
(CNRS), the European Union (ERDF), and the French
Fluorine Network (GIS-FLUOR).
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