Photocatalytic decarboxylative amidosulfonation enables direct transformation of carboxylic acids to sulfonamides

Article abstract of DOI:10.1039/d1sc01389k

Sulfonamides feature prominently in organic synthesis, materials science and medicinal chemistry, where they play important roles as bioisosteric replacements of carboxylic acids and other carbonyls. Yet, a general synthetic platform for the direct conversion of carboxylic acids to a range of functionalized sulfonamides has remained elusive. Herein, we present a visible light-induced, dual catalytic platform that for the first time allows for a one-step access to sulfonamides and sulfonyl azides directly from carboxylic acids. The broad scope of the direct decarboxylative amidosulfonation (DDAS) platform is enabled by the efficient direct conversion of carboxylic acids to sulfinic acids that is catalyzed by acridine photocatalysts and interfaced with copper-catalyzed sulfur-nitrogen bond-forming cross-couplings with both electrophilic and nucleophilic reagents. This journal is

Full text of DOI:10.1039/d1sc01389k

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Photocatalytic decarboxylative amidosulfonation
enables direct transformation of carboxylic acids to
sulfonamides†
Cite this: Chem. Sci., 2021, 12, 6429
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Vu T. Nguyen, ‡ Graham C. Haug,‡ Viet D. Nguyen,
Ngan T. H. Vuong,
*
Hadi D. Arman and Oleg V. Larionov
Sulfonamides feature prominently in organic synthesis, materials science and medicinal chemistry, where
they play important roles as bioisosteric replacements of carboxylic acids and other carbonyls. Yet,
a general synthetic platform for the direct conversion of carboxylic acids to a range of functionalized
sulfonamides has remained elusive. Herein, we present a visible light-induced, dual catalytic platform
that for the first time allows for a one-step access to sulfonamides and sulfonyl azides directly from
carboxylic acids. The broad scope of the direct decarboxylative amidosulfonation (DDAS) platform is
enabled by the efficient direct conversion of carboxylic acids to sulfinic acids that is catalyzed by acridine
photocatalysts and interfaced with copper-catalyzed sulfur–nitrogen bond-forming cross-couplings with
both electrophilic and nucleophilic reagents.
Received 9th March 2021
Accepted 6th April 2021
DOI: 10.1039/d1sc01389k
rsc.li/chemical-science
New reactions that produce aliphatic sulfonamides from a previ-
ously inaccessible precursor chemical space in an operationally
Introduction
uninterrupted manner will increase the structural diversity and
facilitate synthetic access to C(sp3)–sulfonamide bonds.
The sulfonamide group is one the most centrally important
functionalities.1 In drug discovery, the sulfonamide group
occupies a preeminent position, due to the favorable properties
that include a pronounced electron withdrawing character,
hydrolytic stability, polarity, hydrogen bonding ability, and
resistance to reduction and oxidation. The combination of the
favorable properties has made sulfonamide-containing groups
some of the most widely used bioisosteric replacements for
a broad range of more reactive and labile functionalities, e.g.,
ketone, ether, and especially carboxylic acid moieties, as, for
example, the distance between the two oxygen atoms in
In addition, aliphatic carboxylic acids are abundant feed-
stock materials that are readily available from natural sources
and industrial precursors, while their central position in drug
discovery, agroscience, and materials chemistry5 warrants the
development of a reaction that enables direct conversion of
carboxylic acids to diverse bioisosteric and structurally analo-
gous sulfonamides to streamline library synthesis, lead
2
˚
carboxylate and sulfonamide is virtually identical (2.1–2.3 A).
Remarkably, although the sulfonamide group has been used as
a bioisosteric replacement for the carboxylic acid moiety since
1930s, predating Friedman's denition of bioisosterism,2a,3 the
direct decarboxylative conversion of carboxylic acids to sulfon-
amides has remained elusive (Fig. 1).
The one-step decarboxylative amidosulfonation will be partic-
ularly important for the construction of C(sp3)–sulfonamide
bonds, since they cannot be accessed by one-step methods devel-
oped for the C(sp2)–sulfonamide bond formation, e.g., Sandmeyer-
type reactions and transition metal-catalyzed cross-couplings.4
Department of Chemistry, The University of Texas at San Antonio, One UTSA Circle,
San Antonio, TX 78249, USA. E-mail: oleg.larionov@utsa.edu
† Electronic supplementary information (ESI) available. CCDC 2042738–2042746.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/d1sc01389k
Fig. 1 Decarboxylative amidosulfonation as an enabling synthetic tool
‡ These authors contributed equally.
for the direct conversion of carboxylic acids to sulfonamides.
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optimization, and process chemistry, and improve access to prohibitively high oxidation potentials (Fig. 2).8 Direct decar-
new functionalized materials.6 A broad-scope decarboxylative boxylation of carboxylic acids can enable a decarboxylative
amidosulfonation will also facilitate direct access to other SO2– radical generation in one step and without prior derivatization.
N functionalities, e.g., sulfonyl azides that are versatile reagents However, direct decarboxylation of unactivated carboxylic acids
with applications in materials synthesis and chemical biology.7 that do not bear stabilizing a-heteroatoms or aromatic groups
Photocatalytic decarboxylative functionalizations are typically remains challenging, because of the high oxidation potentials of
accomplished in a stepwise manner by rst converting carboxylic carboxylic acids and carboxylates, requiring strong photo-
acids to redox-active derivatives, e.g., N-hydroxyphthalimide or oxidants that are unsuitable for easily oxidizable functionalities,
hypervalent iodine esters, because they provide a workaround for e.g., sulnates, anilines, alcohols, and electron-rich heterocycles.
the challenging direct oxidation of carboxylic acids that occurs at Additionally, photocatalytic direct decarboxylation may be more
difficult to interface with transition metal-catalyzed processes,
due to the reactivity of the carboxylic group. Consequently, the
scope of transformations that can be accomplished by photo-
catalytic direct decarboxylation of diverse carboxylic acids has
remained narrow.8 Photocatalytic systems that selectively induce
direct decarboxylation of carboxylic acids without affecting other
oxidizable functionalities and are compatible with a wide range
of uncatalyzed and catalytic functionalizations of the nascent
radical intermediate have the potential to provide broadly
applicable synthetic platforms for construction of carbon–carbon
and carbon–heteroatom bonds. Accordingly, further work is
needed to develop such photocatalytic systems and expand the
scope, both with respect to substrates and the diversity of
transformations. In particular, mechanistically novel photo-
catalytic systems that are based on hydrogen bonding can
provide the directional character that is necessary for improving
chemoselectivity and facilitating new transformations. We
recently described a photocatalytic system based on the 9-aryla-
cridine structure (A1–A3), enabling visible light-induced direct
decarboxylative dehydrodecarboxylation, amination and conju-
gate addition reactions of unactivated primary, secondary and
tertiary alkylcarboxylic acids (Fig. 2).9
Table 1 Reaction conditions for the photocatalytic direct decarbox-
ylative amidosulfonationa
Entry
Change from optimal conditions
Yield, %
1
2
3
4
5
6
7
8
9
None
92 (89b)
95
0
420 nm instead of 400 nm LED
No light
No A1
0
A2 instead of A1
A3 instead of A2
81
59
0
88
87
[Acr-Mes]+(ClO4)ꢀ instead of A1
Cu(OAc)2 instead of CuF2
CuOAc instead of CuF2
a
Reaction conditions: carboxylic acid (0.3 mmol), DABSO (0.33 mmol),
A1 (10 mol%), CuF2 (10 mol%) O-benzoylhydroxylamine (0.6 mmol),
CH2Cl2 (6 mL), LED light (400 nm), 12 h. Yield was determined by 1H
NMR spectroscopy with 1,4-dimethoxybenzene as an internal
b
Fig. 2 Tricomponent synthesis of sulfonamides and sulfonyl azides by
the dual catalytic direct decarboxylative amidosulfonation.
standard. Isolated yield. DABSO ¼ O2S–N(CH2CH2)3N–SO2. [Acr-
Mes]+(ClO4)ꢀ ¼ N-methyl 9-mesitylacridinium perchlorate.
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The role of the photocatalytic system is particularly critical and in a multicomponent fashion, i.e., with concomitant
for the development of the direct decarboxylative amidosulfo- formation of the C–SO2 and O2S–N bonds by directly combining
nation, as it involves sulnate intermediates. Since sulnates carboxylic acids with a sulfur dioxide source and corresponding
are more readily oxidizable than carboxylates (e.g., Eox ¼ 0.3 V nucleophilic and electrophilic N-centered coupling partners in
vs. SCE for CH3SO2NBu4 and 1.28 V for CH3CO2NBu4 in MeCN), the presence of acridine photocatalysts A1–A3 that proved to be
photocatalytic systems operating by a single electron oxidation uniquely active in enabling this new reaction. This study
of carboxylate anions are expected to be unsuitable for the provides the rst example of an adaptive decarboxylative ami-
development of the DDAS platform.
dosulfonation platform that can be readily adjusted to produce
Recent examples of construction of sulfones from redox- a divergent array of SO2–N functionalities from a common
active N-hydroxyphthalimide esters by Wang and Jiang,10 and carboxylic precursor and offers a mechanistic rationale for the
Liu and Li11 have highlighted the synthetic potential of the observed dual catalytic activity.
decarboxylative approach to installation of sulfonyl-containing
functionalities (Fig. 2).
Results and discussion
We report herein the development of a simple dual catalytic
system for the rst direct decarboxylative amidosulfonation
We rst focused on the direct conversion of carboxylic acids to
(DDAS) of carboxylic acids that can be adapted to access N-alkyl
N-alkyl sulfonamides, hypothesizing that O-benzoylhydroxyl-
and N-aryl sulfonamides, as well as sulfonyl azides in one step
amines could serve as readily available N-centered coupling
Scheme 1 Scope of the direct decarboxylative amidosulfonation with O-benzylhydoxylamines. Reaction conditions: carboxylic acid (0.15–0.3
mmol), DABSO (0.33 mmol), A1 (10 mol%), CuF2 (10 mol%) O-benzoylhydroxylamine (0.6 mmol), CH2Cl2 (6 mL), LED light (400 nm).
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partners. Aer initial optimization studies, we found that pal-
mitic acid can be efficiently converted to the corresponding
sulfonamide 1a in a tricomponent reaction with N-BzO-
morpholine and DABSO (DABCO–bis(sulfur dioxide) adduct)12
in the presence of acridine catalyst A1 with 400 or 420 nm LED
irradiation (Table 1, entries 1 and 2), providing the rst example
of direct decarboxylative amidosulfonation and catalytic S–N
bond formation with O-benzoylhydroxylamines. The reaction
did not proceed without light and the acridine catalyst (entries 3
and 4). Other acridine catalysts A2 and A3 provided lower
catalytic performance (entries 5 and 6). Importantly, other
classes of photocatalysts (e.g., N-methyl 9-mesitylacridinium
catalyst [Acr-Mes]+(ClO4)ꢀ, Ir- and Ru-based photocatalysts, and
4CzIPN) failed to deliver the sulfonamide product (entry 7 and
Table S1†). While copper(II) uoride emerged as the most effi-
cient pre-catalyst, other CuI and CuII salts (entries 8 and 9) also
promoted amidosulfonation, pointing to a common in situ-
formed catalytically active Cu species.
The simplicity of the direct decarboxylative amidosulfona-
tion provided an opportunity to carry out an initial evaluation of
the substrate scope with morpholine as a common amine unit
that revealed broad compatibility and efficiency with a wide
array of functionalized carboxylic acids (sulfonamides 1b–1p,
Scheme 1). An assortment of diverse functional groups were
well tolerated, including electron rich aryl and boryl groups (1c,
1i and 1d). The reaction can be used for a simultaneous
installation of two sulfonamide groups (1g) and performs well
with a variety of cyclic acids (1i–1p), proceeding highly stereo-
selectively in the norbornane and cyclohexane series (1m, 1n).
Sulfonamides derived from other secondary and primary
amines can also be readily accessed, including piperidine (2a–
2f), tert-butyl (3a–3f), benzyl (4a–4d), 2-arylethyl (5a–5e), 1-phe-
nylethyl (6a, 6b), and dibenzyl (7a–7c) amines.
Tertiary acids can be efficiently converted to corresponding
sulfonamides, (e.g., 1o, 1p, 2e, 2f) including sterically encum-
bered sulfonamides 3d and 3e that feature tertiary alkyl groups
both on the S and N atoms.
Scheme 2 Scope of the direct decarboxylative amidosulfonation of
anilines. Reaction conditions: aniline (0.3 mmol), carboxylic acid (0.6–
0.75 mmol), CuOTf$21PhMe (10 mol%), A2 (7 mol%), DABSO (0.45
mmol), tBuO2Bz (0.36–0.45 mmol), CH2Cl2 (3 mL), LED light (400 nm).
aA1 (7 mol%). bA3 (10 mol%), Cu(acac)2 (10 mol%).
The results demonstrate that the direct decarboxylative
amidosulfonation with O-benzoylhydroxylamines allows for
a facile construction of N-alkylsulfonamides. However, it would
not be as practical for the synthesis of aromatic sulfonamides
because the corresponding N-aryl-substituted O-benzoylhy-
droxylamines are not readily available. We therefore questioned
if aromatic sulfonamides could instead be accessed by a direct
decarboxylative amidosulfonation with anilines. Indeed, simple
modication of the reaction conditions (i.e., with copper(I) tri-
ate as a catalyst and tert-butyl perbenzoate as an oxidant)
resulted in an efficient amidosulfonation of anilines (Scheme
2). The scope of anilines was investigated with cyclo-
hexanecarboxylic acid, and a range of substituted aromatic
sulfonamides were readily accessed in one step (8a–8k). The
reaction performs well with para-, meta-, and ortho-substituted
anilines (8a, 8b, 8e, 8j). Acyclic and cyclic N-substituted anilines
were also suitable substrates (8i, 8k). Other combinations of
carboxylic acids and anilines were further tested (8l–8y), and
comparable performance was observed in all cases with
a diverse set of anilines bearing electron-withdrawing, electron-
donating, and heterocyclic substituents (8n, 8r, 8w). These
results indicate that the acridine/copper dual catalytic, decar-
boxylative amidosulfonation can be readily accomplished
directly with carboxylic acids and anilines, providing
a straightforward access to N-aryl sulfonamides.
Sulfonyl azides have emerged as versatile synthetic inter-
mediates,7 yet their accessibility is limited and subject to the
availability of their typical precursors – sulfonyl chlorides and
sulfonamides.13 We, therefore, tested if the dual catalytic direct
decarboxylative procedure could be extended to a coupling
reaction with azides, resulting in a one-step conversion of
carboxylic acids to sulfonyl azides. Gratifyingly, the direct
decarboxylative azidosulfonation could indeed be readily
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Scheme
3 Scope of the direct decarboxylative azidosulfonation.
Reaction conditions: carboxylic acid (0.3 mmol), copper 2-thio-
phenecarboxylate (CuTC) (10 mol%), A1 (10 mol%), DABSO (0.45
mmol), tBuO2Bz (0.75 mmol), NaN3 (0.9 mmol), PhCF3/MeCN (3 : 1, 3
mL), LED light (400 nm), 12 h.
accomplished with sodium azide as the nitrogen nucleophile
with minor adjustments of the reaction conditions (Table S4†
and Scheme 3). The method can be used to prepare an assort-
ment of functionalized sulfonyl azides (9a–9k), bearing ketone
(9b, 9d), ester (9c), amide (9e, 9f), boronate (9e), and other
functional groups. Importantly, the facile adaptability of the
DDAS reaction to an inorganic nucleophile demonstrates the
synthetic potential of the method. Taken together, the devel-
oped dual catalytic methods provide the rst examples of direct
tricomponent conversion of carboxylic acids to sulfonamides
and sulfonyl azides. The synthetic utility of the developed DDAS
approach to the diverse classes of sulfonamides was further
tested in several gram scale syntheses, and the corresponding
products 1a, 3a, 8b, 8m, 9d were readily obtained in good yields.
The synthetic potential of the acridine-photocatalyzed direct
decarboxylative amidosulfonation in the drug discovery context
is also evident from the facility of the generation of libraries of
sulfonamide bioisosteres and synthetic sulfa-analogues of the
anticonvulsant drug valproic acid (1h, 2c, 5b, 8q, 9k, Schemes
1–3) and the lipid regulator gembrozil (3f, 5e, Scheme 1).
Sulfonamide and sulfonyl azide analogues of other drugs and
natural products, e.g., bile acids (10a, 10i), aleuritic acid (10b,
10j), plant growth regulator gibberellic acid (10c, 10g), breast
and prostate drug aminoglutethimide (10d), amino acid and
carbohydrate derivatives (10e, 10f), as well as pinonic acid (10h)
are also readily produced (Fig. 3).
Fig. 3 Direct decarboxylative amidosulfonation and azidosulfonation
of natural products and active pharmaceutical ingredients.
+
low basicity of acridine (e.g., pKBH ¼ 12.7 in the ground state
and 15.5 in the lowest singlet excited state for acridine versus
pKa ¼ 21.6 for AcOH in MeCN).9a Consistent with this conclu-
sion, N-methylacridinium carboxylates do not undergo photo-
induced decarboxylation, acridines do not catalyze
photoinduced decarboxylation of carboxylate salts, and an
addition of excess organic bases leads to suppression of the
acridine-catalyzed decarboxylation.9 In agreement with the
prior observations, no decarboxylative amidosulfonation reac-
tion was observed with the N-methyl 9-mesitylacridinium cata-
lyst (Table S1†), and the involvement of alkyl and alkylsulfonyl
radicals was supported by radical trapping and EPR spectro-
scopic experiments (Figures S1 and S2†). The experimental
studies show that acridines A1–A3 are capable of catalyzing the
direct amidosulfonation of carboxylic acids, while no reaction is
observed with other common types of photocatalysts (Table
S1†).
A DFT computational study was therefore carried out to
clarify the mechanistic details that underpin the efficiency and
facility of the acridine turnover and the dual catalytic processes
(Fig. 4). The studies showed that alkylsulfonyl radical 11 that is
formed in an exergonic reaction of the alkyl radical with SO2 can
Previous experimental and computational studies of the
acridine photocatalysis established that the photoinduced
decarboxylation takes place aer a proton-coupled electron
transfer in the singlet excited acridine–carboxylic acid complex
B (Fig. 4A). Acridinium carboxylates are not formed due to the
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Fig. 4 Computed energy profiles of the acridine catalyst turnover in the sulfinic acid formation and the Cu-catalyzed N-alkyl and N-aryl
amidosulfonation and azidosulfonation, DG, kcal molꢀ1
.
abstract a hydrogen atom from acridinyl radical HA2 in a highly undergo an exergonic proton-coupled electron transfer,9b
thermodynamically favorable process, enabling a facile turn- producing amido complex 17, along with benzoic acid and the
over of the acridine catalyst. The Cu-catalyzed amidosulfona- tert-butoxy radical that generates sulfonyl radical 11 in a reac-
tion with O-benzoylhydroxylamines was studied next. CuF2 can tion with the sulnic acid. Subsequent reaction of amido
be readily reduced by acridinyl radical HA2 (0.7 V vs. SCE and complex 17 with sulfonyl radical 11 produces Cu sulnate
ꢀ0.6 V vs. SCE, respectively), producing CuI intermediate 12 intermediate 18. The ensuing S–N bond-forming coupling
upon complexation with the O-benzoylhydroxylamine reagent. proceeds exergonically over a small barrier of 3 kcal molꢀ1 (TS4,
The subsequent displacement of the uoride with sulnate in 7.4 kcal molꢀ1 from 17), affording Cu-ligated sulfonamide 19
hydroxylamine-ligated complex 12 affords S-bound sulnate that subsequently releases the sulfonamide product in a reac-
complex 13 that can further undergo the exergonic and readily tion with aniline.
kinetically accessible (via TS1) N–O bond cleavage-induced
Finally, we investigated the mechanism of the azidosulfo-
formation of Cu amido intermediate 14 (Fig. 4B). The subse- nation reaction (Fig. 4D). Azide complex 20 that is readily
quent S–N bond-forming step proceeds highly exergonically and formed from CuTC can reduce the oxidant, affording azide
over a small barrier (TS2) en route to sulfonamide-ligated complex 21 and the tert-butoxy radical in an exergonic step. The
species 15. The ensuing ligand exchange with the hydroxyl- latter engages the sulnic acid in a HAT, producing sulfonyl
amine reagent liberates the sulfonamide product. An alternative radical 11. The addition of sulfonyl radical 11 to azide complex
pathway that involves concerted displacement of the benzoate 21 results in intermediate 22 that undergoes a facile S–N bond-
by the sulnate on the nitrogen atom in CuI complex 13 forming reaction with an accessible overall barrier of
proceeds over a substantially higher barrier (cf., TS1 vs. TS3), 9.2 kcal molꢀ1 (TS5) from 21.14,15 Collectively, the efficiency of
pointing to the stepwise pathway as the major amidosulfona- the dual catalytic decarboxylative amidosulfonation and azido-
tion route.
sulfonation reactions is enabled by the thermodynamically
In the amidosulfonation with anilines (Fig. 4C), complex 16 favorable acridine catalyst turnover in the reaction of the acri-
can be readily formed in an exergonic reaction of copper(I) tri- dinyl radical with the sulfonyl radical and the kinetic and
ate with a carboxylic acid (e.g., benzoic acid formed from the thermodynamic facility of the Cu-catalyzed S–N bond-forming
oxidant) and aniline (Figure S3†). Aniline complex 16 can processes.
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and C. M. Crudden, Chem. Sci., 2021, DOI: 10.1039/
D1SC00133G.
Conclusions
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In conclusion, we have developed a visible light-induced pho-
tocatalytic amidosulfonation platform that enables the rst
direct conversion of a wide range of carboxylic acids to aliphatic
and aromatic sulfonamides, as well as sulfonyl azides in an
adaptive tricomponent process with electrophilic and nucleo-
philic N-centered coupling partners. The scope and functional
group tolerance of the method were further demonstrated on
representative functionalized substrates, as well as natural
products and medicinally relevant compounds. The develop-
ment of the dual catalytic process for concomitant formation of
C–S and C–N bonds with electrophilic and nucleophilic
nitrogen coupling partners points to a potential adaptability of
the photocatalytic platform to a wide range of sulfonyl products.
4 For
examples
of
non-decarboxylative
one-step
intermolecular tricomponent approaches to aromatic
sulfonamides, see: (a) B. Nguyen, E. J. Emmett and
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Author contributions
OVL conceived the project. VTN, VDN, and NTHV carried out
the experiments and GCH performed the computational
studies, in consultation with OVL. HDA performed the X-ray
crystallography studies. OVL, wrote the manuscript, and VTN,
VDN, NTHV, and GCH contributed to writing the manuscript.
´
(f) X. Marset, J. Torregrosa-Crespo, R. M. Martınez-
´
Espinosa, G. Guillena and D. J. Ramon, Green Chem., 2019,
Conflicts of interest
21, 4127–4132; (g) X. Wang, M. Yang, Y. Kuang, J.-B. Liu,
X. Fan and J. Wu, Chem. Commun., 2020, 56, 3437–3440; (h)
S. P. Blum, T. Karakaya, D. Schollmeyer, A. Klapars and
S. R. Waldvogel, Angew. Chem., Int. Ed., 2021, 60, 5056–
5062For examples of stepwise and one-pot approaches, see:
(i) A. Shavnya, S. B. Coffey, K. D. Hesp, S. C. Ross and
A. S. Tsai, Org. Lett., 2016, 18, 5848–5851; (j) Y.-Y. Jiang,
Q.-Q. Wang, S. Liang, L.-M. Hu, R. D. Little and C.-C. Zeng,
J. Org. Chem., 2016, 81, 4713–4719; (k) D.-K. Kim, H.-S. Um,
H. Park, S. Kim, J. Choi and C. Lee, Chem. Sci., 2020, 11,
13071–13078For examples of other C–S bond forming
approaches to sulfonamides, see: (l) S. M. Hell,
There are no conicts to declare.
Acknowledgements
Financial support by NIGMS (GM134371) is gratefully
acknowledged. The UTSA NMR and X-ray crystallography facil-
ities were supported by NSF (CHE-1625963 and CHE-1920057).
The authors acknowledge the Texas Advanced Computing
Center (TACC) for providing computational resources.
Notes and references
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The O-benzoylhydroxylamine-mediated amidosulfonation
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substantially
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aniline as a typical nucleophile (Fig. S7†). The reactions of
both aniline and the deprotonated aniline with sulfonyl
radical 11, were highly endergonic, ruling out their
involvement in the amidosulfonation.
6436 | Chem. Sci., 2021, 12, 6429–6436
© 2021 The Author(s). Published by the Royal Society of Chemistry