Rapid Access to N-Protected Sulfonimidoyl Fluorides: Divergent Synthesis of Sulfonamides and Sulfonimidamides

Article abstract of DOI:10.1021/acs.orglett.1c01118

Herein we report a practical and efficient copper-catalyzed approach for the conversion of various arenediazonium salts to the corresponding N-protected sulfonimidoyl fluorides. This operationally simple protocol tolerates a wide range of functional groups and can be applied to the late-stage modification of complex bioactive molecules. Furthermore, pharmaceutically important primary sulfonamides and sulfonimidamides derived from these valuable N-protected sulfonimidoyl fluoride units were prepared in minimal synthetic steps.

Full text of DOI:10.1021/acs.orglett.1c01118

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Letter
Rapid Access to N‑Protected Sulfonimidoyl Fluorides: Divergent
Synthesis of Sulfonamides and Sulfonimidamides
Yongan Liu, Qijun Pan, Xiaojun Hu,* Yong Guo, Qing-Yun Chen,* and Chao Liu*
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ABSTRACT: Herein we report a practical and efficient copper-
catalyzed approach for the conversion of various arenediazonium
salts to the corresponding N-protected sulfonimidoyl fluorides.
This operationally simple protocol tolerates a wide range of
functional groups and can be applied to the late-stage modification
of complex bioactive molecules. Furthermore, pharmaceutically
important primary sulfonamides and sulfonimidamides derived
from these valuable N-protected sulfonimidoyl fluoride units were
prepared in minimal synthetic steps.
ulfonamide moieties are ubiquitous in medicinal and
agricultural chemistry due to their high metabolic stability,
S
enhanced crystallinity, hydrophilic properties, and high level of
biological activity.1 Developed as a result of the reliance of
pharmaceutical chemistry on sulfonamides, these moieties have
become very popular in synthetic chemistry, and a myriad of
traditional2 or recently developed3 approaches make these
valuable structural motifs easily achievable. In contrast,
sulfonimidamides, the monoaza analogues of sulfonamides
that were first prepared in the 1960s,4 have been far less
explored for use in drug design. However, recently, this long-
forgotten functional group has experienced impressive
reinvigoration. The increased interest in sulfonimidamide-
containing compounds and the potential of such compounds
as biologically active molecules have been highlighted in recent
publications.4 However, few methods for the construction of
this intriguing pharmacophore have been reported.
Figure 1. Early reports and current work toward sulfonimidoyl
halides.
chlorosuccinimide, as reported by Bolm11b in 2007. Although
the deoxychlorination of N-silylated sulfonamides affords the
corresponding chlorides,12 the employment of phosphorus
chlorides limits its applicability in the context of the late-stage
functionalization of complex molecules. More recently, Willis
and coworkers unveiled an elegant one-pot synthesis of
sulfonimidamides from Grignard reagents via sulfonimidoyl
chloride intermediates.13 This synthetic strategy uses the stable
and readily available N-sulfinyltritylamine (TrNSO) as a key
linchpin and makes sulfonimidamide synthesis more conven-
ient and efficient.
Given the growing importance of sulfonimidamides in
medicinal chemistry, methods that can be used to construct
this moiety will attract significant attention. Recently, elegant
work by Bolm,5 Luisi and Bull,6 Stockman and Lucking,7 and
̈
others8 presented several examples of important contributions
to the preparation of sulfonimidamides. In addition to these
methods, the classical and main approach to prepare this
moiety is the nucleophilic amination of sulfonimidoyl
chloride.9 However, unlike widely available sulfonyl chlorides,
sulfonimidoyl chlorides are not commercially available and are
usually prepared and used in situ in organic synthesis due to
their inherent instability. Sulfonimidoyl chlorides were first
successfully prepared by imination of arylsulfinyl chlorides with
positive N-halogen compounds (Figure 1).10 Johnson and
coworkers11 developed an alternative method via oxidative
chlorination of sulfinamides with chlorine, N-chlorobenzo-
triazole, or tert-butyl hypochlorite, later replaced with N-
Received: April 7, 2021
Published: May 10, 2021
https://doi.org/10.1021/acs.orglett.1c01118
© 2021 American Chemical Society
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As analogues of sulfonimidoyl chlorides, sulfonimidoyl
fluorides have been recognized as thermodynamically and
redox-stable reaction intermediates and can be conveniently
isolated and utilized.14 They have displayed unique and
promising properties and have been applied in organic
synthesis as valuable reagents.14 A variety of sulfoximines,
sulfonimidates, and sulfonimidamides can be prepared
efficiently through nucleophilic reactions of the corresponding
sulfonimidoyl fluorides with diverse nucleophiles.15 However, a
shortage of practical and efficient synthetic methods seriously
hinders their further application. Traditional approaches
toward sulfonimidoyl fluorides consist of reacting their
chloride counterparts with diverse nucleophilic fluorine
sources (NaF, KF, KHF2, TBAF) by fast and reliable halide
exchange.16 In 2018, Sharpless and coworkers demonstrated
thionyl tetrafluoride (SOF4) as the new connective hub to
enable the synthesis of sulfonimidoyl fluorides in two steps.15
Despite its modularity and versatility, to avoid the use of toxic
and corrosive SOF4 gas, highly basic and nucleophilic
organolithium reagents are desired. More recently, Cornella
disclosed the oxyfluorination reaction of N-(arylsulfenyl)
phthalimides (Ar−S−Phth) with large amounts of oxidative
chlorination reagent and potassium fluoride for the synthesis of
less-explored sulfinyl trifluorides (ArSOF3).17 This highly
electrophilic ArSOF3 poses good reactivity with various
primary amines to forge sulfonimidoyl fluorides. Additionally,
a recent example also disclosed the possibility of accessing
highly enantioenriched sulfonimidoyl fluorides by oxidative
fluorination of the corresponding sulfinamide salts with an
electrophilic fluorination reagent for the first time.18 Given the
promising applications of sulfonimidoyl fluoride in organic
synthesis and the limitations of the current synthetic methods,
we were interested in exploring a straightforward and practical
synthetic method toward these compounds.
In 1957, Meerwein and coworkers described a copper-
catalyzed Sandmeyer chlorosulfonylation reaction of arenedia-
zonium salts under acidic conditions.19 The reaction proceeds
via the radical sulfur dioxide insertion of aryl radicals formed
from arenediazonium salts and the subsequent capture of
chlorine. Notably, Bolm and coworkers have reported an
elegant method for the preparation of O-benzotriazolyl
sulfonimidates from arenediazonium salts and TrNSO via a
novel radical N-sulfinylamine insertion reaction.5c Although
transition-metal-catalyzed sulfonimidoyl halide synthesis re-
mains underexplored, our recent fluorosulfonylation reaction
of arenediazonium salts20 and related reports5c,13 prompted us
to investigate the possibility of a copper-catalyzed multi-
component cascade reaction for the synthesis of sulfonimidoyl
fluorides. We speculated that if N-protected sulfinylamine
(PGNSO) can serve as a radical trap as well as an
efficient coupling partner in relative transition-metal catalysis,
an efficient synthesis of sulfonimidoyl fluorides from
arenediazonium salts derived from widely available anilines
might be expected and might provide an opportunity to rapidly
access a broad range of valuable sulfonimidoyl fluorides, greatly
expand the toolkit of sulfonimidoyl fluorides, and significantly
promote their application in different research fields. Thus, as
shown in Figure 2, we envisioned that CuCl(L) undergoes a
single-electron transfer (SET) with arenediazonium salt 1 to
generate a key aryl radical A and CuCl2(L) species. If the
radical PGNSO insertion of aryl radical A could
proceed to produce sulfonimidoyl radical B, then this nascent
radical abstract chlorine from the CuCl2(L) species might
Figure 2. Proposed reaction mechanism for the synthesis of
sulfonimidoyl fluorides.
deliver the corresponding sulfonimidoyl chloride C and
regenerate the Cu(I) species. The relatively unstable
sulfonimidoyl chloride C undergoes fast Cl−F exchange to
form the final products. To test the feasibility of our
hypothesis, we selected p-methoxybenzenediazonium salt 1a
as the pilot substrate, readily available sulfinylamine TrNSO as
the NSO linchpin, and KHF2 as fluorine source. Detailed
screening of the reaction conditions regarding the solvent,
reaction temperature, catalyst, ligand, fluoride source, base, and
reaction time is provided in the Supporting Information. The
extensive screening of the reaction conditions showed that the
combination of 1.0 equiv of arenediazonium salt 1, 1.1 equiv of
PGNSO, 5.0 equiv of KHF2, and 1.0 equiv of 2,6-
lutidine in the presence of CuCl2 (5 mol %) and neocuproine
(5 mol %) in MeCN at room temperature for 12 h provided
the optimal reaction conditions.
Under the optimized reaction conditions, the substrate
scope was investigated. A wide range of arenediazonium salts
was successfully converted into the corresponding sulfonimi-
doyl fluorides in moderate to excellent yields, as summarized in
Figure 3. In general, arenediazonium salts bearing both
electron-donating and electron-withdrawing substituents can
be subjected to the copper-catalyzed fluorosulfonimidoylation
reaction, leading to high yields of the target products. Most
likely due to the mild reaction conditions employed, a variety
of functional groups, such as chloro, bromo, iodo, nitro, cyano,
amide, ketone, ester, and sulfonamide, were all accommodated
in this transformation. Notably, halogen-substituted arenedia-
zonium salts gave the corresponding products (2e, 2f, 2o)
while leaving the C−X bond intact, which could serve as ideal
handles for further functionalization through well-established
cross-coupling reactions (vide infra). Sterically hindered ortho
substitution had only a minor impact, and ortho-substituted
arenesulfonimidoyl fluorides (2l, 2m) were obtained in 78 and
64% yield, respectively. Moreover, several heterocycles,
including the most widely used frameworks in drug design,
such as pyridine, oxazole, pyrazole, quinoline, benzothiazole,
and thiophene, were all compatible in this transformation
(2q−2w). Additionally, to showcase the utility of our method
in the late-stage diversification of natural compounds or drug
molecules, we successfully extended this method to several
complex molecules, including menthol derivative 1x, amino-
glutethimide 1y, lapatinib intermediate 1z, cabozantinib
intermediate 1aa, sulfamethazine 1bb, and sulfamethoxazole
1cc. It is worth noting that the desired products 2dd and 2ee
were successfully isolated in good yields with the utilization of
t-OctNSO featuring electron-rich and less hindered N-
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Figure 3. Substrate scope for the synthesis of sulfonimidoyl fluorides.
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), PGNSO (1.1
equiv), KHF2 (5.0 equiv), 2,6-lutidine (1.0 equiv), CuCl2 (5 mol %),
and neocuproine (5 mol %) in MeCN (1 mL) at room temperature
for 12 h. Yields of isolated products are given. Thermal ellipsoids of
the X-ray crystal structure of 2f are shown at 50% probability.
aReaction performed on a 6 mmol scale and 2.3 g of 2f was obtained.
t-Oct, tert-octyl. bYields were determined by 19F NMR. See the
Supporting Information for details.
Figure 4. Derivatization reactions of sulfonimidoyl fluorides.
spectrometry-based analysis of pharmacokinetics and pharma-
codynamics.23
Encouraged by this success, we further explored the
reactivity of N-trityl-protected sulfonimidoyl fluorides with
suitable Lewis acids. To our delight, the treatment of
compound 2a with AlCl3 as the defluoridation reagent and
amine as the nucleophile afforded the corresponding
sulfonimidamides in moderate to good yields (Figure 5).
substituents as sulfinylamine reagents. Finally, the gram-scale
synthesis of 2f was performed to demonstrate the scalability of
this method, and its structure was unambiguously confirmed
by X-ray crystallography.
The synthetic utility of the method was demonstrated in a
number of transformations of sulfonimidoyl fluorides synthe-
sized. Iodo-containing sulfonimidoyl fluoride compounds
underwent several metal-mediated orthogonal functionaliza-
tions, including Heck, Suzuki, and Sonogashira cross-coupling
reactions and trifluoromethylation modification,21 which
proceeded selectively at the iodo site, leaving the sulfonimidoyl
fluoride fully untouched (Figure 4a). These examples, along
with others (see the Supporting Information for details),
demonstrated the unusual thermodynamic stability, base
stability, and resistance to nucleophilic substitution of N-
trityl-protected sulfonimidoyl fluorides. This remarkable
stability can tentatively be ascribed to the strong S−F bond
and the steric hindrance of the trityl group. Interestingly, as
shown in Figure 4b, the N-trityl-protected sulfonimidoyl
fluoride underwent quick deprotection and hydrolysis to afford
a valuable primary sulfonamide under acidic conditions.22
Specifically, using the eco-friendly reagent H218O, a series of
single labeled isotopologues of sulfonamides (7a−7h) were
obtained with good 18O enrichment (Figure 4c). This isotope
labeling method might be highly useful for the mass-
Figure 5. Synthesis of various sulfonimidamides from sulfonimidoyl
fluoride 2a. Reaction conditions: (i) 2a (0.2 mmol, 1.0 equiv), AlCl3
(0.6 equiv), MeCN (2 mL), 0 °C, 30 min, (ii) Et3N (2.5 equiv),
amine (2.5 equiv), 0 °C to rt, 16 h. Yields of isolated products are
a
given. MsOH was added at the end of reaction.
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Accession Codes
Furthermore, the trityl group could be removed by simple
treatment with methanesulfonic acid, efficiently providing N−
H sulfonimidamides (8e, 8f). Importantly, modification of the
drug molecules amoxapine, deacetyl linezolid, and deslorata-
dine through this protocol was achieved (8g−8i), thus
demonstrating the good functional group tolerance of this
method. The surprising stability and unique reactivity under
suitable reaction conditions of N-protected sulfonimidoyl
fluorides might provide additional flexibility in organic
synthesis.
CCDC 2008749 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, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Finally, to underscore the versatility of this method, the anti-
inflammatory drug celecoxib and a monoaza analogue were
prepared. As depicted in Figure 6, aniline 11 was synthesized
Chao Liu − School of Chemical and Environmental
Engineering, Shanghai Institute of Technology, Shanghai
201418, China; Key Laboratory of Organofluorine
Chemistry, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy
of Sciences, Shanghai 200032, China; orcid.org/0000-
0003-1968-031X; Email: chaoliu@sit.edu.cn
Qing-Yun Chen − Key Laboratory of Organofluorine
Chemistry, Shanghai Institute of Organic Chemistry,
University of Chinese Academy of Sciences, Chinese Academy
of Sciences, Shanghai 200032, China; Email: chenqy@
sioc.ac.cn
Xiaojun Hu − School of Chemical and Environmental
Engineering, Shanghai Institute of Technology, Shanghai
201418, China; Email: hu-xj@mail.tsinghua.edu.cn
Authors
Yongan Liu − Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China
Figure 6. Divergent synthesis of celecoxib and a monoaza analogue
via a sulfonimidoyl fluoride intermediate.
Qijun Pan − School of Chemical and Environmental
Engineering, Shanghai Institute of Technology, Shanghai
201418, China
Yong Guo − Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, University of
Chinese Academy of Sciences, Chinese Academy of Sciences,
Shanghai 200032, China; orcid.org/0000-0002-5534-
0091
from commercially available compounds 9 and 10 in 65% yield
in two steps. Diazotization of 11 and treatment of the
diazonium salt with TrNSO and KHF2 under optimized
conditions afforded the key sulfonimidoyl fluoride intermediate
12. Celecoxib and sulfonimidamide were quickly obtained in
good yields under the aforementioned reaction conditions.24
In conclusion, we have developed a practical and efficient
copper-catalyzed multicomponent cascade reaction for the
rapid preparation of much less explored sulfonimidoyl fluoride.
This transformation features abundant and readily available
starting materials, mild reaction conditions, no basic organo-
metallic reagents or oxidants, and good functional group
tolerance. It provides access to a great variety of primary
sulfonamides and sulfonimidamides, which have convention-
ally been prepared through lengthy de novo synthesis. The
versatility of this strategy is clearly emphasized by the
preparation of celecoxib and a monoaza analogue with minimal
effort. We envision this method to be highly useful for the
possible applications of S(VI)-containing compounds in drug
discovery. Further studies and synthetic applications of these
transformations are under way in our laboratory.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01118
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (nos.
21421002, 21871283, 21737004, 21672239) and the Chinese
Academy of Science (KF-STS-QYZX-068). We thank Prof.
Qilong Shen from Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences for helpful discussions.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01118.
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