Copper(II)-Catalyzed Alkene Aminosulfonylation with Sodium Sulfinates for the Synthesis of Sulfonylated Pyrrolidones

Article abstract of DOI:10.1021/acs.orglett.9b00907

A copper-catalyzed direct aminosulfonylation of unactivated alkenes with sodium sulfinates for the efficient synthesis of sulfonylated pyrrolidones is described. This reaction features good functional group tolerance and wide substrate scope, providing an efficient and straightforward protocol to access this kind of pyrrolidones. Moreover, preliminary mechanistic investigations disclosed that a free-radical pathway might be invovled in the process.

Full text of DOI:10.1021/acs.orglett.9b00907

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper(II)-Catalyzed Alkene Aminosulfonylation with Sodium
Sulfinates For the Synthesis of Sulfonylated Pyrrolidones
Wei-Hao Rao,*,†,‡ Li-Li Jiang,† Xiao-Meng Liu,† Mei-Jun Chen,† Fang-Yuan Chen,† Xin Jiang,†
Jin-Xiao Zhao,† Guo-Dong Zou,† Yu-Qiang Zhou,† and Lin Tang†
†College of Chemistry and Chemical Engineering, Xinyang Normal University, Xinyang 464000, China
‡Henan Key Laboratory of Utilization of Non-Metallic Mineral in the South of Henan, Xinyang Normal University, Xinyang 464000,
China
S
* Supporting Information
ABSTRACT: A copper-catalyzed direct aminosulfonylation of
unactivated alkenes with sodium sulfinates for the efficient
synthesis of sulfonylated pyrrolidones is described. This
reaction features good functional group tolerance and wide
substrate scope, providing an efficient and straightforward protocol to access this kind of pyrrolidones. Moreover, preliminary
mechanistic investigations disclosed that a free-radical pathway might be invovled in the process.
toward the exploration of alkene difunctionalizations to
n recent years, significant progress in copper-catalyzed
1
Ialkene difunctionalizations has been gained, and numerous construct diversely functionalized pyrrolidones are highly
desired, which would further enrich the chemistry of alkene
difunctionalizations.
functionalized heterocycles have been conveniently con-
structed based upon this strategy,2 which not only allows
direct cyclization of easily accessible unsaturated starting
materials but also enables the simultaneous incorporation of a
second useful functional group in the cyclization process. In
this way, the molecular complexity can be rapidly and
efficiently assembled. Although diversely functionalized hetero-
cycles, such as cyclic amines,3 lactones,4 and cyclic ethers,5
have been successfully constructed in this area, examples of the
synthesis of functionalized pyrrolidones with this strategy
remain rare. For instance, seminal works by the Wang group
demonstrated the successful construction of amino-, azido-,
and trifluoromethyl-containing pyrrolidones via copper-cata-
lyzed alkene diamination,6a aminoazidation,6b and amino-
trifluoromethylation6c (Scheme 1a), where highly active
electrophiles are essential. However, these electrophiles require
additional preparation. Given the significance of pyrrolidones
in pharmaceutical and synthetic chemistry,7 continuous efforts
Sulfones are important structural motifs in pharmaceuticals
and advanced materials8 and function as useful precursors of
C−C double bonds in synthetic chemistry.9 Despite significant
achievements gained in framing this skeleton,10 applications of
the powerful and straightforward strategy of copper-catalyzed
alkene difunctionalizations toward the synthesis of function-
alized sulfones are still underexplored. In this regard, the
Buchwald group reported a copper-catalyzed oxysulfonylation
of unsaturated carboxylic acids with aryl sulfonyl chloride.11
Afterward, Zhang and et al. realized a copper-catalyzed alkene
azidosulfonylation with sodium sulfinates.12 Very recently, the
Li group explored the aminosulfonylation of unsaturated aryl
amides with sodium sulfinates,13 which could potentially be
beneficial to the synthesis of biologically active vicinal
aminosulfones.14 However, stoichiometric copper salts are
required and the substrate scope was limited to styrene-type
aryl amides. Herein, we report a copper-catalyzed version of
unsaturated aliphatic amides with sodium sulfinates (Scheme
1b), which provides an efficient approach to access structurally
novel sulfonylated pyrrolidones by merging pyrrolidone with
sulfone.
Scheme 1. Copper-Catalyzed Alkene
Aminofunctionalization For the Construction of Diversely
Functionalized Pyrrolidones
We commenced our study by the reaction of N-methoxy
unsaturated aliphatic amide 1 with PhSO2Na as the model
reaction (Table 1). To our delight, the desired product 1a was
obtained in 15% yield by using Cu(OAc)2 (10 mol %) as the
catalyst and Ag2CO3 (2 equiv) as the oxidant in DCM (entry
1; see the Supporting Information for detailed optimization).
Further evaluation of solvents (entries 2−9) revealed that the
reaction proceeded efficiently in DMF to afford the product 1a
Received: March 13, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00907
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
oxidant (2.0 equiv)
solvent
DCM
DCE
yield (%)
1
2
3
4
5
6
7
8
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
AgOAc
Ag2O
K2S2O8
DTBP
TBHP
PhI(OAc)2
−
15
32
58
12
0
0
85
trace
trace
76
71
trace
23
trace
35
trace
trace
0
DMSO
toluene
MeCN
1,4-dioxane
DMF
NMP
HFIP
DMF
DMF
DMF
DMF
DMF
9
10
11
12
13
14
15
16
17
18
19
DMF
DMF
DMF
DMF
c
d
Figure 1. Scope of alkenes. Reaction conditions: 1−25 (0.5 mmol),
Cu(OAc)2 (10 mol %), PhSO2Na (1 mmol, 2 equiv), and Ag2CO3 (1
mmol, 2 equiv) in DMF (5 mL) at 100 °C for 24 h under N2. Isolated
−
e
Ag2CO3
−
f
DMF
trace
1
yields. The dr ratios were determined by H NMR.
a
Reaction conditions: 1 (0.2 mmol), Cu(OAc)2 (10 mol %),
PhSO2Na (0.4 mmol, 2 equiv), and oxidant (2 equiv) in solvent (2
b
c
d
mL) at 100 °C for 24 h under N2. Isolated yields. Under air. Under
O2 atmosphere. Without Cu(OAc)2. With Cu(OAc)2 (2.0 equiv).
Besides monosubstituted alkenes, 1,1-disubstituted alkenes
were acceptable substrates in the aminosulfonylation trans-
formation, as evidenced by the successful formation of 11a−
15a in good yields. α-Monosubstituted usaturated tertiary
amides also reacted well to produce the desired products 16a−
22a in moderate yields, albeit in poor dr ratios. Incredibly,
when the benzyl group was replaced with a phenyl group, the
aminosulfonylation did not occur and the desired product 23a
was not obtained. Gratifyingly, an unsaturated secondary
amide was a suitable substrate, as manifested by the formation
of 24a in 76% yield. Unfortunately, with an unsaturated
aromatic amide substrate, the reaction did not occur and the
desired product 25a was not produced.
Subsequently, we examined the scope of sodium sulfinates
(Figure 2). A variety of sodium arylsulfinates bearing
substituents on the aryl ring were suitable for this trans-
formation and provided the desired product 1b−1m in
moderate to high yields, regardless of their electronic
properties. With sodium 4-toluenesulfinte, several unsaturated
quaternary amides could be subjected to this protocol to yield
the desired products 1b−1e in high yields. Notably, halides,
such as fluoride, chloride, and bromide, exhibited tolerance
under the standard reaction conditions (1i−1l), which
provided the opportunity for further derivation. Furthermore,
the useful trifluoromethyl group was compatible with this
protocol (1m).
e
f
in 85% isolated yield (entry 7). Encouraged by the results, we
next took a brief screening of several oxidants in order to
further improve the yield. Silver salts, such as AgOAc and
Ag2O (entries 10 and 11), as the oxidants could not give a
higher yield than Ag2CO3. The use of other oxidants, including
K2S2O8, DTBP, TBHP, and PhI(OAc)2, did not afford better
results (entries 12−15). In virtue of the robust utilization of
molecular oxygen as a green terminal oxidant in copper
catalysis,15 we subsequently examined air and molecular
oxygen as the oxidants. Unfortunately, neither air nor
molecular oxygen performed as expected (entries 16 and
17). A control experiment shows that copper was essential to
the reaction since no product 1a was detected under the same
conditions in the absence of Cu(OAc)2 (entry 18). Finally, a
stoichiometric amount of Cu(OAc)2 was used as the sole
oxidant; only traces of 1a were obtained (entry 19).
With the optimized conditions in hand, we next explored the
scope of N-methoxy unsaturated amides (Figure 1). Generally,
unsaturated quaternary amides underwent this transformation
smoothly and afforded the corresponding aminosulfonylation
products in good to high yields. It was also observed that the
reaction overwhelmingly preferred the 5-exo cyclization
process. Reaction of quaternary amides bearing α-Me, -Et,
and -Ph groups could proceed smoothly and generated the
desired products 1a−5a in good yields, albeit in poor dr ratios
for products 2a and 4a. Notably, substrate derived from
ibuprofen was compatible with this protocol and delivered the
desired product 6a in 73% yield, although with a poor dr ratio.
Meanwhile, an ester group at the α-site of substrate was well
tolerated, and the desired product 7a was obtained in 70%
yield and with a 3.6:1 dr ratio. Interestingly, several α-cyclic
substrates could be subjected to the aminosulfonylation and
provided α-spiro pyrrolidones 8a, 9a, and 10a in high yields.
As shown in Scheme 2, the structure of the amino-
sulfonylation product 11a was characterized by single crystal
X-ray diffraction (CCDC 1875942).
To prove the practicability of this transformation, a gram-
scale synthesis and removal of the OMe group were performed.
As shown in Scheme 3, the aminosulfonylation product 1a was
obtained in 81% yield under the standard conditions on a gram
scale. Next, treatment of 1a with SmI2 in THF at room
temperature for 10 min could readily remove the OMe group
and afforded the desired product 1n in 87% yield.16
B
DOI: 10.1021/acs.orglett.9b00907
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
pathway with a carbon-centered radical species is likely
involved in the aminosulfonylation process.
Based on our observations above and literature re-
ports,6,10c,11 a plausible catalytic cycle is proposed to elucidate
the aminosulfonylation reaction as depicted in Scheme 5.
Scheme 5. Proposed Mechanism
Figure 2. Scope of sodium sulfinates. Reaction conditions:
unsaturated amides (0.5 mmol), Cu(OAc)2 (10 mol %), ArSO2Na
(1 mmol, 2 equiv), and Ag2CO3 (1 mmol, 2 equiv) in DMF (5 mL) at
100 °C for 24 h under N2. Isolated yields.
Initially, ligand exchange of copper acetate with alkene 1
affords intermediate A. Then, A likely undergoes the
intramolecular aminocupration to furnish intermediate B in
an exo cyclization manner. Reaction of PhSO2Na and Ag2CO3
generates a phenylsulfonyl radical which would couple with B
to afford complex alkyl−Cu(III)−SO2Ph (C). An equilibrium
between complex C and the radical D possibly exists.
Subsequent reductive elimination of complex C would furnish
the aminosulfonylation 1a along with Cu(I) species. Finally,
oxidation of Cu(I) species with Ag2CO3 leads to the
regeneration of the Cu(II) catalyst.
In conclusion, we have developed a copper-catalyzed direct
aminosulfonylation of unactivated alkenes with sodium
sulfinates for the synthesis of sulfonylated pyrrolidones.
Good functional group tolerance and a wide substrate scope
are observed with this protocol. Moreover, preliminary
mechanistic investigations suggest that a free-radical pathway
might be invovled in the process.
Scheme 2. X-ray Structure of Compound 11a
Scheme 3. Gram-Scale Synthesis and Removal of OMe
Groupa
To gain mechanistic insights into the aminosulfonylation
reaction, some control experiments were conducted (Scheme
4). With addition of TEMPO (1.0 equiv) as a radical
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00907.
Scheme 4. Mechanistic Experiments
Experimental details and spectral data for all new
compounds (PDF)
Accession Codes
CCDC 1875942 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.
scavenger, the aminosulfonylation reaction was remarkably
suppressed and the yield of 1a was decreased to 34%, and the
TEMPO-trapped product 1o was isolated in 52% yield.
Moreover, 1,1-diphenyethylene as a radical scavenger also
suppressed the reaction and led to a lower yield of 1a, and a
trace amount of 1p was detected by HPLC-MS (see the
Supporting Information). These results clarify that a radical
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: whrao@xynu.edu.cn.
ORCID
Wei-Hao Rao: 0000-0001-6197-0148
C
DOI: 10.1021/acs.orglett.9b00907
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Lin Tang: 0000-0003-0477-2481
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Natural Science Foundation of
Henan Province (Grant No. 162300410235), the National
Natural Science Foundation of China (Grant No. 21807091),
the Youth Sustentation Fund of XYNU (Grant No. 2017-QN-
030), and Nanhu Scholars Program for Young Scholars of
XYNU is gratefully acknowledged. Dr. Qiu-Ju Zhou and Ms.
Ying Cui are also gratefully acknowledged for NMR assistance
and single X-ray characterization.
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