Catalytic Decarboxylative Radical Sulfonylation

Full text of DOI:10.1016/j.chempr.2020.02.003

Article
Catalytic Decarboxylative Radical
Sulfonylation
Jiayan He, Guangle Chen,
Benxiang Zhang, ..., Wen-Jing
Xiao, Feng Liu, Chaozhong Li
fliu2@suda.edu.cn (F.L.)
clig@mail.sioc.ac.cn (C.L.)
HIGHLIGHTS
Decarboxylative sulfonylation
enabled by copper catalysis and
photoredox catalysis
Broad substrate scope and wide
functional group compatibility
Improved synthesis of anti-
prostate cancer drug
bicalutamide
Sulfones are not only important structural motifs in pharmaceuticals and
agrochemicals but also versatile intermediates in organic synthesis. However,
C(sp3)-sulfonyl bond formations remain underdeveloped. In this issue of Chem, Li
and co-workers demonstrate that the merger of photo-organocatalysis and
copper-catalysis enables the decarboxylative radical sulfonylation with
organosulfinates at room temperature under redox-neutral conditions. The
method leads to the improved synthesis of anti-prostate cancer drug bicalutamide
and should find more important applications in drug discovery.
He et al., Chem 6, 1–11
May 14, 2020 ª 2020 Elsevier Inc.
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Article
Catalytic Decarboxylative
Radical Sulfonylation
Jiayan He,1 Guangle Chen,2 Benxiang Zhang,1 Yi Li,1 Jia-Rong Chen,3 Wen-Jing Xiao,3 Feng Liu,2,
*
and Chaozhong Li1,4,
*
SUMMARY
The Bigger Picture
Sulfones are not only important
structural motifs in
Sulfones are key structural motifs in pharmaceuticals and agrochemicals, and
their synthesis is of paramount importance in organic chemistry. While nucleo-
philic and electrophilic C(sp3)-sulfonylation are well documented, radical
C(sp3)-sulfonylation remains elusive. Herein, we report the decarboxylative
radical sulfonylation with sulfinates. With the merger of 4CzIPN (1,2,3,5-tetra-
kis(carbazol-9-yl)-4,6-dicyanobenzene) and Cu(OTf)2 as catalysts, the visible-
light-induced reaction of redox-active esters of aliphatic carboxylic acids with
organosulfinates at room temperature provides the corresponding decarboxy-
lative sulfonylation products in satisfactory yields. This redox-neutral protocol
exhibits broad substrate scope and wide functional group compatibility,
enabling the late-stage modification of complex natural products and bioactive
pharmaceuticals. The synthetic utility of the method is further demonstrated by
the improved synthesis of anti-prostate cancer drug bicalutamide. A mechanism
involving sulfonyl group transfer from Cu(II)–SO2R to alkyl radicals is proposed.
pharmaceuticals and
agrochemicals but also versatile
synthetic intermediates in organic
chemistry. Despite the significant
progress in the synthesis of
sulfones in recent years, C(sp3)-
sulfonyl bond formations remain
underdeveloped. In particular,
there have been no reports to
date of general methods for the
sulfonylation of alkyl radicals. In
this article, we introduce the
copper-catalyzed cross coupling
of sulfinates with alkyl radicals
generated via photoredox-
catalyzed decarboxylation of
redox-active esters derived from
aliphatic carboxylic acids. This
unprecedented protocol exhibits
broad substrate scope and wide
functional group compatibility,
allowing the late-stage
INTRODUCTION
Sulfones are ubiquitous in nature. They possess a wide variety of biological activities and
thus serve as important structural motifs in pharmaceuticals and agrochemicals. For
example, bicalutamide (CASODEX, AstraZeneca’s blockbuster drug) is an orally active,
nonsteroidal anti-androgen for the treatment of prostate cancer (Figure 1).1,2 Certinib
(Zykadia, Novartis) is a new drug approved by FDA (U.S. Food and Drug Administration)
in 2014 to treat anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer.3
Another example is oral drug apremilast (Otezla, Celgene), the only phosphodiesterase
4 (PDE4) inhibitor approved by FDA to treat active psoriatic arthritis and plaque psoriasis
with an annual sales of over 1.2 billion US dollars.4 In the meantime, sulfones are also ver-
satile synthetic intermediates in organic chemistry. They serve as the key building blocks
or reagents in many chemical transformations such as Julia–Lythgoe olefination5–7 and
fluoroalkylation.8 As a consequence, the synthesis of sulfones has received a consider-
able attention and significant progress has been achieved in recent years.9–13 However,
recent advances focus mainly on C(sp2)-sulfonyl bond formations such as aromatic or
vinylic sulfonylation, whereas C(sp3)-sulfonyl bond formations remain underdeveloped.
Conventional C(sp3)-sulfonylation methods include (1) nucleophilic sulfonylation of elec-
trophiles such as alkyl halides, epoxides, or Michael acceptors with organosulfinates or
thiosulfonates under basic conditions14 (Scheme 1A) and (2) electrophilic sulfonylation of
sulfonic acid derivatives such as sulfonate esters or sulfonyl chlorides with organometallic
reagents (Scheme 1B). However, the former suffers from the competing O-alkylation (to
give sulfinate esters), while the latter often leads to the corresponding sulfoxides.9 The
recently developed sulfonyl radical addition to unsaturated bonds such as alkenes pro-
vides a powerful means for C(sp3)-sulfonyl bond formations (Scheme 1C). This method
sulfonylation of complex
molecules. The synthetic utility of
the method is further
demonstrated by the improved
synthesis of anti-prostate cancer
drug bicalutamide.
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Figure 1. Structures of Representative Sulfone-Based Drugs Bicalutamide, Certinib, and
Apremilast
can be extended to three-component condensation involving the fixation of SO2.12,13
Nevertheless, the strategy is mainly limited to arenesulfonyl radicals (or aryl radicals
plus SO2), while examples14–17 of alkyl radical addition to SO2 (e.g., Reed reaction17
)
are rare due to the fast desulfonylation of alkanesulfonyl radicals. In fact, there have
been no reports to date of general methods for the sulfonylation of alkyl radicals. Given
that alkyl radicals are common intermediates easily generated from various types of
organic compounds, it is certainly highly desirable to develop efficient and general
methods for the sulfonylation of alkyl radicals (Scheme 1D). In particular, the decarbox-
ylative sulfonylation of aliphatic carboxylic acids should be an important transformation
useful in organic synthesis. To meet the challenge, we propose the concept of ‘‘RSO2-
group-transfer from Cu(II)–SO2R to alkyl radicals,’’ in accordance with our previous ideas
of Cu(II)-assisted CF3-group-transfer18–20 or F-atom-transfer.21 Specifically, we target the
copper-catalyzed cross coupling of sulfinates with alkyl radicals generated via photore-
dox-catalyzed22–27 decarboxylation of redox-active esters28–33 derived from aliphatic
carboxylic acids.34–43
RESULTS AND DISCUSSION
Carboxylic acids and sulfinates44 are both attractive raw materials for chemical syn-
thesis due to their ready availability, high stability, and low cost. Decarboxylative
cross coupling of aliphatic carboxylic acids with sulfinates should therefore be an
ideal method for sulfone synthesis. Given that sulfinates are much easier to be
oxidized than the corresponding carboxylic acids, direct oxidative decarboxylative
coupling is not feasible. Reductive decarboxylation of redox-active esters of carbox-
ylic acids might provide the solution.
1Key Laboratory of Organofluorine Chemistry and
Collaborative Innovation Center of Chemistry for
Life Sciences, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
2Jiangsu Key Laboratory of Neuropsychiatric
Diseases and Department of Medicinal
Chemistry, College of Pharmaceutical Sciences,
Soochow University, 199 Ren-Ai Road, Suzhou,
Jiangsu 215123, China
We then commenced our investigations with the redox-active ester of 4-phenylbu-
tanoic acid (1a) and sodium 4-methylbenzenesulfinate (2a) as the model substrates.
The redox-active ester was easily prepared by condensation of 4-phenylbutanoic
acid with N-hydroxyphthalimide (NHPI). After extensive screening of reaction condi-
tions (see Table S1 for details), we were pleased to find that, with 2 mol % 1,2,3,5-
tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN)45,46 and 20 mol % Cu(OTf)2 as
catalysts and 2 equiv of dibutyl hydrogen phosphate as the additive, the visible-
light-induced reaction of ester 1a and sulfinate 2a at room temperature (RT) for
12 h afforded the desired sulfone 3a in 95% yield (Table 1, entry 1). When the reac-
tion was performed in the absence of (BuO)2P(O)OH, the yield dropped to 65%
(Table 1, entry 2). Switching the additive to trifluoroacetic acid also led to a high
3CCNU-uOttawa Joint Research Centre, Hubei
International Scientific and Technological
Cooperation Base of Pesticide and Green
Synthesis, Key Laboratory of Pesticides &
Chemical Biology Ministry of Education, College
of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei 430079, China
4Lead Contact
*Correspondence: fliu2@suda.edu.cn (F.L.),
clig@mail.sioc.ac.cn (C.L.)
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A
C
B
D
Scheme 1. C(sp3)-Sulfonylation
product yield (Table 1, entry 3), while weak acids such as acetic acid showed no
improvement (Table 1, entry 4). Interestingly, the addition of 2,20-bipyridine
(20 mol %) significantly inhibited the reaction (Table 1, entry 5). Control experiments
revealed that photocatalyst 4CzIPN, copper catalyst, and visible light were all essen-
tial for the transformation (Table 1, entries 6–8). In addition, the redox-active ester
could be prepared in situ without purification, providing the sulfonylation product
in 85% yield (Table 1, entry 9). It is worth mentioning that the use of free 4-methyl-
benzenesulfinic acid in place of sodium 4-methylbenzenesulfinate resulted in a
very low (7%) yield of 3a. However, the combination of 4-methylbenzenesulfinic
acid with a weak base such as NaHCO3 or CF3CO2Na increased the product yield
to 51% and 89%, respectively (see Table S2). These experiments suggest that
(BuO)2P(O)OH or trifluoroacetic acid might serve as a buffer to adjust the pH value
of reaction solution. The use of (BuO)2P(O)OH or trifluoroacetic acid as the additive
proved to be even more critical in the decarboxylative sulfonylation of secondary
alkyl acids, resulting in a sharp increase in product yield by inhibiting the generation
of the alkene byproduct (see Table S2). While the detailed mechanism remains un-
clear for the remarkable acid effect, it might be possible that the presence of an
acid decreases the basicity of sulfinate and thus retards a-deprotonation of alkyl rad-
icals (to give alkene radical anions and hence alkenes after electron transfer). Note
that the CH groups adjacent to a carbon radical center are quite acidic as pointed
out by Studer and co-workers.47,48
With the optimized conditions in hand, we examined the scope of the method. As
shown in Scheme 2, various NHPI esters derived from primary and secondary alkyl acids
underwent smooth decarboxylative sulfonylation with sulfinate 2a to provide the corre-
sponding sulfones 3a–3v in good to excellent yields. The presence of a wide range of
functional groups was tolerated by the process. For example, terminal alkenes, alkynes,
alkyl or aryl bromides, aldehydes, ketones, esters, amides, sunfonamides, ethers, and
unprotected indoles all proved to be compatible with the reaction. Protected a-amino
acids were also suitable substrates, as evidenced by the synthesis of sulfone 3m. The
reaction could be operated in gram scale without the loss of efficiency. The method
was also applicable to NHPI esters derived from tertiary alkyl acids, albeit in a lower
efficiency (e.g., 3w) presumably because of steric hindrance.
The protocol has also shown a broad scope in terms of organosulfinates, as demon-
strated in Scheme 3. A number of arenesulfinates with either electron-withdrawing or
electron-donating substituents on the aromatic ring all underwent sulfonylation reac-
tions furnishing the corresponding sulfones 4a–4d in satisfactory yields. Moreover, the
protocol was also applicable to alkanesulfinates. Primary, secondary, and tertiary
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Table 1. Optimization of Conditions
Entrya
Variation from the ‘‘Standard Conditions’’
none
Yield (%)b
1
2
3
4
5
6
7
8
9
95 (92)
without (BuO)2P(O)OH
CF3CO2H in place of (BuO)2P(O)OH
CH3CO2H in place of (BuO)2P(O)OH
with 2,20-bipyridine (20 mol %)
without blue LED
65
93 (91)
51
0
0
without 4CzIPN
0
without Cu(OTf)2
0
In situ generation of 1a
85
a0.20 mmol scale, 2 equiv of 2a was used.
b1H NMR yield based on 1a with dibromomethane as the internal standard, isolated yield in parentheses.
alkanesulfinates were all suitable partners in the cross coupling, as exemplified by the
efficient synthesis of sulfones 4e–4k. An excellent chemoselectivity was observed in
the reaction of 1-allylcyclopropanesulfinate furnishing sulfones 4j and 4k in which the
allyl group remained intact. Nevertheless, the sulfonylation with pyridine-3-sulfinate
afforded sulfone 4l in a low yield due to the competing Minisci alkylation, and no desired
product could be observed in the sulfonylation with trifluoromethanesulfinate. The re-
sults also indicated that sulfonyl radicals were unlikely to be involved in the reaction
given the fast desulfonylation of alkanesulfonyl radicals.
The above results clearly demonstrate the broad substrate scope and wide functional
group compatibility of the method. In addition, the reactions were run at room temper-
ature under redox-neutral conditions free from external reducing or oxidizing agents.
These characteristics enabled the late-stage modification of complex natural products
or drug molecules (Scheme 4). For example, steroids such as dehydrocholic acid or
chenodeoxycholic acid were readily converted to the corresponding sulfones 5a or 5b
in high to excellent yield. Drug molecules such as isoxepac, chlorambucil, mycophenolic
acid, gibberellic acid, or indometacin were all transformed into the corresponding
sulfones highly efficiently. The protocol was also applicable to carbohydrate-containing
acids, as evidenced by the synthesis of 5f in 91% yield.
To further demonstrate the synthetic utility of the sulfonylation method, we chose
the anti-prostate cancer drug bicalutamide as the target molecule. Bicalutamide
and its analogs were achieved by multi-step synthesis starting from the commercially
4
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Scheme 2. Variation of NHPI Esters
aConditions: 1 (0.20 mmol), 2 (0.40 mmol), (BuO)2P(O)OH (0.40 mmol), Cu(OTf)2 (0.04 mmol),
4CzIPN (0.004 mmol), DME (1.0 mL), MeCN (1.0 mL), 3 W blue LED, RT, 12 h. Isolated yield based on
1.
b5 equiv of (BuO)2P(O)OH were used.
c2 equiv of CF3CO2H were used.
available and inexpensive (S)-malic acid (6). However, three steps were required for
the installation of the sulfonyl group in bicalutamide consisting of (1) Barton decar-
boxylative bromination of acid 7 with CBrCl3, (2) nucleophilic substitution of the re-
sulting bromide with 4-fluorobenzenethiol, and (3) subsequent oxidation with
mCPBA (meta-chloroperoxybenzoic acid). With the newly developed decarboxyla-
tive sulfonylation method, the three steps could be shortened into one (Scheme 5).
Specifically, the condensation of acid 7 with NHPI and DIC (diisopropylcarbodii-
mide) produced the corresponding NHPI ester, which, without purification, was sub-
jected to the treatment with p-fluorobenzenesulfinate under the optimized
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Scheme 3. Variation of Sulfinates
a,b
See Scheme 2.
conditions to provide sulfone 8 in 60% yield. The following hydrolysis of 8 with KOH
in aqueous methanol at room temperature afforded cleanly compound 9, which,
without purification, was subjected to the condensation with 4-cyano-3-trifluorome-
thylaniline according to the literature procedure,49 furnishing (R)-bicalutamide in
91% yield based on 8. The new synthetic route offers a more concise and efficient
entry to bicalutamide and avoids the use of toxic CBrCl3, odorous p-fluorobenzene-
thiol, and dangerous mCPBA.
To gain further insight into the sulfonylation, mechanistic studies were carried out
(Scheme 6). The reaction of the NHPI ester derived from cyclopropylacetic acid (10)
under the optimized conditions produced exclusively the ring-opening sulfonylation
product 3i in 88% yield. When the NHPI ester of hept-6-enoic acid (11) was subjected
to the treatment with sulfinate 2a under the optimized conditions, the cyclized product
3e was obtained in 50% yield along with the uncyclized product 12 isolated in 25% yield.
These radical clock experiments unambiguously demonstrated the intermediacy of alkyl
radicals. Additionally, radical trapping experiment with 1,1-diphenylethylene also sug-
gested the involvement of alkyl radicals rather than sulfonyl radicals (see Scheme S1).
Furthermore, copper(II) p-toluenesulfinate prepared from Cu(OH)2 and sodium p-tolue-
nesulfinate was treated with an equimolar amount of triethylborane (as the ethyl
radical precursor) in acetonitrile at room temperature under aerobic conditions, and
ethylsulfone 13 was achieved in 81% yield. This experiment provided a solid evidence
for the proposed mechanism of Cu(II)-assisted RSO2 group transfer. Finally, fluorescence
quenching experiments of 4CzIPN with 1a, Cu(OTf)2, or 4-methylbenzenesulfinic acid
6
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Scheme 4. Late-Stage Sulfonylation of Complex Molecules
a,b
See Scheme 2.
indicated the feasibility of electron transfer between 4CzIPN and redox-active esters (see
Figure S1).
On the basis of the above results, a plausible mechanism is proposed as depicted in Fig-
ure 2. Excitation of photocatalyst 4CzIPN generates the long-lived triplet-excited-state
[4CzIPN]* that undergoes single electron transfer with a NHPI ester to give the 4CzIPN
radical cation and the NHPI ester radical anion. The N–O bond cleavage takes place for
the NHPI ester radical anion to produce a carboxyl radical, which upon extrusion of CO2
generates the corresponding alkyl radical. In the meantime, transmetalation of sulfinate
anion forms the Cu(II)–SO2R intermediate. The alkyl radical is then intercepted by Cu(II)–
SO2R to provide the sulfone product and Cu(I). Finally, Cu(I) is oxidized by 4CzIPN radical
cation, leading to the regeneration of both Cu(II) and 4CzIPN catalysts.
The interception of alkyl radicals by Cu(II)–SO2R may proceed either via direct RSO2
group transfer or via the formation of R–Cu(III)–SO2R complex followed by reductive
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Scheme 5. Application in the Synthesis of Bicalutamide
elimination. Given that uncomplexed copper(II) sulfinate is a mild oxidant rather than
a reducing agent and the presence of 2,20-bipyridine inhibits the sulfonylation, the
direct RSO2 group transfer seems more likely the case. More mechanistic studies
are certainly required to provide a detailed understanding on the mechanism.
The ratio of cyclized product 3e versus uncyclized product 12 was 2:1 in the radical
clock experiment shown in Scheme 6. The rate constant for the cyclization of
hex-5-en-1-yl radical at 20ꢀC is known to be approximately 2.3 3 105 sꢁ1, as deter-
mined by Ingold and co-workers.50 By assuming that the active intermediate species
responsible for sulfonylation is of the same concentration as the catalyst Cu(OTf)2
(0.02 M) and remains constant throughout the reaction, the rate constant for the
toluenesulfonyl group transfer from Cu(II)–SO2Tol to a primary alkyl radical can
Scheme 6. Mechanistic Experiments
8
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Figure 2. Proposed Mechanism of Decarboxylative Sulfonylation
then be calculated to be around 2.3 3 107 Mꢁ1sꢁ1, which is much larger than the rate
constant for primary alkyl radical addition to an unactivated monosubstituted alkene
(103 ꢂ 104
M ) M
ꢁ1sꢁ1 51 or to benzene (3.8 3 102 ꢁ1sꢁ1).52 This well explains the
remarkable chemoselectivity in the reaction of 1-allylcyclopropanesulfinate
(to give 4j and 4k). Furthermore, it may also account for the low efficiency in the
reaction of pyridine-3-sulfinate (to give 4l), given that rate constants for radical addi-
tion to protonated 4-cyanopyridine (Minisci alkylation) range from 8.9 3 105 Mꢁ1sꢁ1
for n-butyl radical to 6.3 3 107 Mꢁ1sꢁ1 for t-butyl radical.52 Thus, the rate constant for
RSO2 group transfer determined above offers a quantitative view on the reaction
mechanism and sets the stage for the rational design of new synthetic methodology
based on radical sulfonylation.
Conclusions
In conclusion, the merger of photo-organocatalysis and copper catalysis enables
the successful development of a practical protocol for the sulfonylation of alkyl
radicals generated from aliphatic carboxylic acids. As the procedure is operation-
ally simple, catalytic in copper, broad in scope, free from external reducing or
oxidizing agents, tolerant of sensitive functional groups, and utilizes cheap and
stable sulfinates, the method should find widespread applications in sulfone
synthesis. It is also conceivable that more new methods of radical sulfonylation
will be developed given that alkyl radicals can be generated by many other
ways (such as hydrogen atom abstraction, olefin radical addition, etc.). Further-
more, the proposed mechanism of Cu(II)-assisted RSO2 group transfer should
stimulate further research toward the cross coupling of alkyl radicals with nucle-
ophiles other than sulfinates. The research in this direction is currently underway
in our laboratory.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.02.003.
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ACKNOWLEDGMENTS
This project was supported by the National Natural Science Foundation of China
(grants 21421002, 21532008, 21602239, and 21871285), the Strategic Priority
Research Program of the Chinese Academy of Sciences (grant XDB20020000), the
Shanghai Scientific and Technological Innovation Project (18JC1410600), the Natu-
ral Science Foundation of the Jiangsu Higher Education Institutions of China (grant
18KJA350001), and the Priority Academic Program Development of the Jiangsu
Higher Education Institutes (PAPD).
AUTHOR CONTRIBUTIONS
J.H., F.L., and C.L. initiated the project. J.-R.C., W.-J.X., F.L., and C.L. conceived and
designed the experiments. J.H., G.C., and B.Z. conducted the experiments and
analyzed the data. C.L. wrote the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: October 29, 2019
Revised: December 28, 2019
Accepted: February 7, 2020
Published: March 5, 2020
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