Site-Selective C-H Functionalization-Sulfination Sequence to Access Aryl Sulfonamides

Article abstract of DOI:10.1021/acs.orglett.0c00982

Aryl sulfinates are precursors to a diverse number of sulfonyl-derived arenes, which are common motifs in pharmaceuticals and agrochemicals. Here, we report a site-selective two-step C-H sulfination sequence via aryl sulfonium salts to access aryl sulfonamides. Combined with site-selective aromatic thianthrenation, an operationally simple one-pot palladium-catalyzed protocol introduces the sulfonyl group using sodium hydroxymethylsulfinate (Rongalite) as a source of SO₂^2-. The hydroxymethyl sulfone intermediate generated from the catalytic process can be employed as a synthetic handle to deliver a variety of sulfonyl-containing compounds.

Full text of DOI:10.1021/acs.orglett.0c00982

pubs.acs.org/OrgLett
Letter
Site-Selective C−H Functionalization−Sulfination Sequence to
Access Aryl Sulfonamides
Eva Maria Alvarez, Matthew B. Plutschack, Florian Berger, and Tobias Ritter*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00982
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ABSTRACT: Aryl sulfinates are precursors to a diverse number of
sulfonyl-derived arenes, which are common motifs in pharmaceut-
icals and agrochemicals. Here, we report a site-selective two-step
C−H sulfination sequence via aryl sulfonium salts to access aryl
sulfonamides. Combined with site-selective aromatic thianthrena-
tion, an operationally simple one-pot palladium-catalyzed protocol
introduces the sulfonyl group using sodium hydroxymethylsulfinate
(Rongalite) as a source of SO22−. The hydroxymethyl sulfone
intermediate generated from the catalytic process can be employed as a synthetic handle to deliver a variety of sulfonyl-containing
compounds.
Scheme 1. Synthetic Approaches to Aryl Sulfonyl Groups
ulfur occurs in several different oxidation states; the most
stable hexavalent organosulfur compounds such as
S
sulfonamides, sulfones, and sulfonyl fluorides are abundant
motifs in pharmaceuticals and agrochemicals.1 Commonly,
sulfonyl functionality is introduced into arenes by electrophilic
aromatic substitution with reagents such as chlorosulfuric
acid.2 The limitations of such transformations are the
formation of constitutional isomers and the low functional
group tolerance.3 Synthetically valuable sulfonyl-containing
molecules can be obtained by using aryl sulfinates as versatile
intermediates, which can be formed from prefunctionalized
arenes such as aryl halides,4 aryl boronic acids,5,6 aryl Grignard
reagents,7,8 or aryl iodonium salts9 in the presence of sulfur
dioxide surrogates.10 Additionally, primary11,12 and secon-
dary13 sulfonamides can generate sulfinates in situ acting as
terminal functional groups. However, the site selectivity of the
synthesis of the starting materials remains a challenge for many
of those substrates.14−16 Here, we present a two-step C−H
sulfination sequence of site-selectively formed aryl thianthre-
nium salts under the action of a palladium catalyst and the
inexpensive industrial reagent sodium hydroxymethanesulfi-
nate (Rongalite) to synthetically access the sulfinate salt
precursor, hydroxymethylsulfone. Subsequent electrophilic
trapping of the sulfinate can be useful for functional group
diversification (Scheme 1).
Scheme 2. Formation of Phenyl Hydroxymethyl Sulfone en
a
Route to a Sulfonamide
a
Two-step yield of the sulfonylation. Reaction conditions: (i)
sulfonium salt (0.2 mmol), Pd(dppf)Cl2 (5 mol %), Rongalite (1.5
equiv), i-PrOH (0.2 M), 60 °C, 12 h; (ii) Et3N (2.0 equiv),
morpholine (2.0 equiv), NCS (2.0 equiv), 25 °C, 1 h.
and arylboronic acids,5,6 all of which react well with DABSO.
Given that sulfinates can often be difficult to purify,
strategies for accessing sulfonamides among other valuable
sulfonyl-containing groups entail a two-step one-pot procedure
by using the aryl sulfinate in a subsequent transformation.17−23
Aryl sulfinates can be obtained from the reaction of aryl
nucleophiles with SO2, which is a toxic gas and is therefore
frequently replaced with solid SO2 surrogates such as the
adduct of SO2 with DABCO, called DABSO.24 Suitable aryl
nucleophiles are Grignard reagents,7 aryl-zinc compounds,8
The generation of arylsulfinates from aryl electrophiles such as
Received: March 17, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00982
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
Scheme 3. Evaluation of Thianthrenium Salts for the Palladium-Catalyzed Coupling with Rongalite toward the Synthesis of
a
Sulfonamides
a
Reaction conditions: (1) sulfonium salt (0.1−0.2 mmol), Pd(dppf)Cl2 (5 mol %), Rongalite (1.5 equiv), i-PrOH (0.2 M), 60 °C, 12 h; (2) Et3N
b
c
d
(2.0 equiv), R1R2NH (2.0 equiv), NCS (2.0 equiv), 25 °C, 1 h. Yield of thianthrenation. Two-step yield of sulfonylation. Yield of the
e
f
g
thianthrenation from ref 28. Yield of the thianthrenation from ref 27. Yield of the thianthrenation from ref 29. MeCN was used as a co-solvent.
h
Two-step yield of the sulfonylation with (2) hydroxylamine-O-sulfonic acid (4.0 equiv) and sodium acetate (7.0 equiv), at 25 °C for 1 h, instead
of Et3N and NCS.
aryl halides4 and SO2 (surrogates) is also possible when using
an additional reducing agent.19 An alternative route for
generating sulfinates from aryl electrophiles, without the
need for an exogenous reducing reagent, would be the reaction
with a source of SO22−, such as Rongalite (sodium
hydroxymethylsulfinate), an industrial bleaching and reducing
reagent.25 While alkyl halides have been converted to alkyl
sulfinates by reaction with Rongalite,26 methods for achieving
aromatic sulfinylation with Rongalite remain unexplored.
Although previous methods for making aryl sulfinates are
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Letter
the reactivity of sulfonium salts exceeds the reactivity of
standard palladium cross-coupling partners, bromo and triflate
groups, and compounds 12 and 13 were obtained in 74% and
60% yields, respectively. As a further demonstration of the
utility of this methodology, late-stage functionalization of
several active pharmaceuticals and agrochemicals was
performed. For these more complex sulfonium salts (15−
20), the solubility in isopropanol was low and proved to be an
obstacle to achieving full conversion. However, when using the
polar aprotic acetonitrile as a co-solvent, conversion improved
and the morpholino sulfonyl compounds were obtained in 20−
67% yields.
Scheme 4. Functional Group Diversification via an Aryl
Hydroxymethyl Sulfone
a
We tested our two-step one-pot procedure with a set of
primary (22−25), benzylic (26 and 27), and secondary (28−
37) amines (Scheme 3B), resulting in 45−91% yields. In
addition, the ammonia-derived sulfonamide 21 could be
obtained in 62% yield with hydroxylamine-O-sulfonic acid in
the presence of sodium acetate.
Finally, we evaluated several common electrophiles in the
synthesis of sulfone derivatives via the hydroxymethyl sulfone
intermediate (Scheme 4). The reaction with alkyl electrophiles,
such as alkyl bromides or epoxides, afforded the alkylaryl
sulfones (38−40) in 55−70% yields. Trapping with a
heteroaryl electrophile in a nucleophilic aromatic substitution
reaction yielded an aryl-heteroaryl sulfone (41) in 60% yield.
Sulfonyl fluoride (42) can be obtained in 72% yield by reaction
with the electrophilic fluorinating reagent N-fluorobenzene-
sulfonimide.33
a
For detailed experimental procedures, see the Supporting Informa-
tion. The corresponding electrophiles were reacted: (a) α-bromo tert-
butyl acetate, (b) benzyl bromide, (c) cyclohexene oxide, (d) 2-
chloro-5-(trifluoromethyl)pyridine, and (e) N-fluorobenzenesulfoni-
mide.
practical when synthetic handles already exist, selective
installation of halo or boryl substituents at a late stage can
be challenging.14−16 The combination of site-selective
thianthrenation and the first example of a palladium-catalyzed
C−S bond forming reaction using Rongalite grants access to
aryl hydroxymethyl sulfones, masked sulfinates that undergo a
base-mediated fragmentation to release aryl sulfinates.
In conclusion, we have identified the readily available and
2−
In our previous work,27 we capitalized on the exquisite
selectivity of aromatic C−H thianthrenation for subsequent
site-selective functionalization in a two-step process to access
various functional groups via palladium or photoredox
catalysis.28−31 In this study, we envisioned a synthetic strategy
for installing a masked sulfinate via a cross-coupling between
aryl sulfonium salts and Rongalite. In contrast to our previous
sulfone synthesis,27 the sulfinate precursor can be used in situ
for further derivatization.32
inexpensive SO2 source, Rongalite, as a coupling partner in
the palladium-catalyzed sulfination of aryl sulfonium salts.
Besides a highly selective C−H functionalization, the two-step
sequence grants access to valuable sulfinate precursors that can
subsequently be unmasked and afford sulfonamides, which are
important functional motifs in pharmaceuticals and agro-
chemicals among sulfones and sulfonyl fluorides.
ASSOCIATED CONTENT
■
We developed reaction conditions to synthesize aryl
hydroxymethyl sulfones [1 (Scheme 2)] from aryl thianthre-
nium salts via a palladium-catalyzed C−S bond formation by
employing Pd(dppf)Cl2 as the catalyst and Rongalite as the
coupling partner in iPrOH at 60 °C. The structure of 1 was
confirmed by NMR spectroscopy and high-resolution mass
spectrometry (see the Supporting Information). In the
presence of a base, intermediate 1 loses formaldehyde, and
the aryl sulfinate is generated in situ. The oxidative amination
of the resulting aryl sulfinate with Et3N (2.0 equiv),
morpholine (2.0 equiv), and N-chlorosuccinimide (NCS)
(2.0 equiv) at 25 °C for 1 h resulted in sulfonamide 2 in 73%
yield from the corresponding aryl sulfonium salt TT-1
(Scheme 2).
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00982.
Detailed experimental procedures and spectroscopic
characterization (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Tobias Ritter − Max-Planck-Institut fu
45470 Mulheim an der Ruhr, Germany; orcid.org/0000-
0002-6957-450X; Email: ritter@mpi-muelheim.mpg.de
̈
r Kohlenforschung, D-
̈
The optimal reaction conditions proved to be effective for
generating a variety of structurally diverse sulfonamides with
respect to the sulfonium salts, using morpholine as a
representative amine component (Scheme 3A). Alkyl-sub-
stituted aryl sulfonamides (3−5) were obtained in 45−64%
yields. A range of electron-rich arenes reacted under our
conditions, providing aryl sulfonamides (6−9) in 51−65%
yields. ortho-Substituted sulfonamides 10 and 11 were
obtained in 50% and 77% yields, respectively. The hydro-
defunctionalized compound was identified as the major side
product for these substrates. Under our coupling conditions,
Authors
Eva Maria Alvarez − Max-Planck-Institut fu
D-45470 Mulheim an der Ruhr, Germany
Matthew B. Plutschack − Max-Planck-Institut fu
Kohlenforschung, D-45470 Mulheim an der Ruhr, Germany;
orcid.org/0000-0002-5665-7445
Florian Berger − Max-Planck-Institut fu
45470 Mulheim an der Ruhr, Germany
̈
r Kohlenforschung,
̈
̈
r
̈
̈
r Kohlenforschung, D-
̈
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00982
C
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Letter
Turnover Numbers, Room Temperature Reactions, and Isolation of a
Potential Intermediate. J. Am. Chem. Soc. 2002, 124, 390−391.
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Derivatives by a Bulky Iridium Catalysts. J. Am. Chem. Soc. 2015, 137,
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Author Contributions
E.M.A. and M.B.P. developed the sulfination reaction. E.M.A.
optimized follow-up transformations. All authors wrote the
manuscript. T.R. directed the project.
(16) Tang, R.-J.; Milcent, T.; Crousse, B. Regioselective Halogen-
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Notes
The authors declare the following competing financial
interest(s): A patent application (EP18204755.5, Germany)
dealing with the use of thianthrene and its derivatives for CH
functionalization has been filed, and F.B. and T.R. may benefit
from royalty payments.
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ACKNOWLEDGMENTS
■
The authors thank the MPI fu
̈
r Kohlenforschung for funding.
́
The authors thank C. Fares and M. Kochius (MPI KOFO) for
assistance with NMR structural assignments and S. Marcus and
D. Kampen (MPI KOFO) for mass spectroscopy analysis. The
̈
authors thank P. S. Engl, A. Haring, and F. Ye (MPI KOFO)
for providing aryl sulfonium salts.
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