Copper-Catalyzed Radical Aryl Migration Approach for the Preparation of Cyanoalkylsulfonylated Oxindoles/Cyanoalkyl Amides

Article abstract of DOI:10.1021/acs.orglett.0c03973

A copper-catalyzed radical cross-coupling of oxime esters and activated alkenes is accomplished for the synthesis of cyanoalkylsulfonylated oxindoles and cyanoalkyl amides via an aryl migration strategy. Specifically, the subsequent mechanism research indicates that the unique desulfonylation and sulfone addition processes were involved in the transformation. This transformation is identified as having good functional group applicability with two different quaternary stereocenter in a regioselective manner, which is controlled by the substituent group of the nitrogen.

Full text of DOI:10.1021/acs.orglett.0c03973

pubs.acs.org/OrgLett
Letter
Copper-Catalyzed Radical Aryl Migration Approach for the
Preparation of Cyanoalkylsulfonylated Oxindoles/Cyanoalkyl
Amides
Ming Li, Cui-Tian Wang, Qiao-Fei Bao, Yi-Feng Qiu, Wan-Xu Wei, Xue-Song Li, Yu-Zhao Wang,
Zhe Zhang, Jin-Lin Wang, and Yong-Min Liang*
Cite This: Org. Lett. 2021, 23, 751−756
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ABSTRACT: A copper-catalyzed radical cross-coupling of oxime esters and activated alkenes is accomplished for the synthesis of
cyanoalkylsulfonylated oxindoles and cyanoalkyl amides via an aryl migration strategy. Specifically, the subsequent mechanism
research indicates that the unique desulfonylation and sulfone addition processes were involved in the transformation. This
transformation is identified as having good functional group applicability with two different quaternary stereocenter in a
regioselective manner, which is controlled by the substituent group of the nitrogen.
Scheme 1. Previous Studies of Oxime Esters and Alkene
s a versatile building blocks, cyanoalkyl is a synthetically
Aversatile intermediate in organic synthesis and exists
frequently in pharmaceutical molecules and natural products.1
Moreover, cyanoalkyl as an active group can substantially
transform into some other functional groups. Therefore,
considerable attention to the incorporation of cyanoalkyl
group has been noted.2 Over the past few years, a range of
elegant works have been established.3 Among such available
methodologies, C−C bond cleavage of cyclobutanone oxime
esters via an iminyl radical intermediate is one of the most
effective transformations.4,5 Earlier reports for iminyl radical
intermediate were disclosed by Zard and co-workers.6
Recently, visible-light photocatalysis iminyl radical-mediated
C−C bond cleavage to construct cyanoalkyl derivatives has
been achieved by Xiao7 and other groups.8 In 2017, the group
of Xiao reported a visible-light-driven iridium-catalyzed radical
addition cascade of oxime esters, which involved an iminyl
radical-mediated C−C bond cleavage. Soon after, a copper-
catalyzed multicomponent radical cross-coupling reaction of
redox-active oxime was also achieved by the Xiao group
(Scheme 1a).9
Sulfur-containing derivatives are widely used in the fields of
pharmacy and organic chemistry synthesis.10 Particularly,
sulfones are widely prevalent in agrochemicals, pharmaceut-
icals, and bioactive natural products.11 Thus, development of a
convenient route for the synthesis of sulfone has aroused
comprehensive attention from organic chemists.12 Although
sulfur dioxide as a readily available and inexpensive reagent
could be used to introduce SO2, specialized equipment and
safety concerns restricted the practicability. Considering the
Received: December 1, 2020
Published: January 21, 2021
https://dx.doi.org/10.1021/acs.orglett.0c03973
© 2021 American Chemical Society
Org. Lett. 2021, 23, 751−756
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a
disadvantages of sulfur dioxide, some of the sulfur dioxide
Table 1. Optimization of the Reactions Conditions
13
surrogates such as DABCO·(SO2)2 or inorganic sulfites14
were exploited. Specifically, the combination of aryldiazonium
tetrafluoroborates with DABCO·(SO2)2 has provided an
efficient protocol to insert SO2 in synthetic chemistry, and
significant works have been achieved.15 In this field, a range of
crucial reports for sulfonylation of the C(sp2)−H functional-
ization were disclosed by Wu16 and other groups;17 however,
the insertion of sulfur dioxide into the C(sp3)−H bond is still
rare.18 In 2019, Wu and co-workers reported photoredox-
catalyzed sulfonylation reaction for building the alkylsulfony
compound by using potassium metabisulfite as the source of
sulfur dioxide (Scheme 1b).19 Still, consideration of the
inconvenience of the preparation of DABCO (SO2)2 and the
redox property of salt metabisulfite, developing an easy and
redox-neutral reaction system is a challenge.
b
entry
copper/L
base
solvent
yield (%)
1
2
3
4
5
6
7
8
Cu(OTf)2/bpy
Cu(OTf)2/bpy
Cu(OTf)2/bpy
Cu(OTf)2/dtbpy
Cu(OTf)2/phen
Cu(OTf)2/L1
Cu(OAc)2/L1
CuSCN/L1
CuI/L1
Cu(OTf)2
CuI/phen
CuI/phen
CuI/phen
toluene
MeCN
dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
3a/40
3a/30
3a/20
3a/50
3a/60
3a/68
3a/45
3a/52
Over the past decade, Nevado20 and other groups developed
radical addition to the double bond of the tosyl acrylamides
system which was successfully implemented for oxindoles and
amides constructions. In this transformation, a quaternary
stereocenter was constructed via an intramolecular 1,4-aryl
migration/5-ipso cyclization and desulfonylation. Encouraged
by these elegant works, herein, we reported an efficient copper-
catalyzed radical ring-opening process of cycloketone oximes
with activated alkenes to prepare various oxindoles or amides
under thermal reaction conditions.
9
3a/44
3a/50
10
11
12
13
14
15
16
17
18
19
4aa/trace
4aa/43
4aa/44
4aa/50
4aa/56
4aa/68
4aa/75
4aa/60
4aa/n. r.
K2CO3
Na2CO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
CuI/Phen
CuBr2/Phen
CuCl2/phen
Cu(phen)Cl2
CuCl2
Building on the reports of iminyl radical generation from
cycloketone oximes, activated alkenes 1a with cycloketone
oxime ethers 2a were utilized as the model substrates to verify
our prediction. The expected product 3a was isolated in 40%
yield in the presence of Cu(OTf)2 and 2,2′-bipyridine under
an argon atmosphere at 80 °C for 24 h in toluene (Table 1,
entry 1). A brief screening of other commonly used solvents
indicated that toluene still was the best choice (entries 2 and
3). Then, a series of ligands were investigated, in which 2,9-
dimethyl-4,7-diphenyl-1,10-phenanthroline L1 presented effec-
tively (entries 4−6). To further improve the yield, other
copper salts such as Cu(OAc)2, CuSCN, and CuI were
examined with inapparent improvement observed (entries 7−
9). The control reaction indicated that the ligand could be
beneficial to this reaction (entry 10). Thereafter, the optimized
reaction conditions for the preparation of 4aa were attempted
by using activated alkenes 1aa with cycloketone oxime ethers
2a in MeCN under an argon atmosphere at 80 °C for 24 h.
With the addition of CuI/phen, only a trace amount of desired
product 4aa was observed (entry 11). Pleasingly, with the
addition of K2CO3, the desired amide could be increased to
43% (entry 12). A subsequent short survey on the base
indicated that NaHCO3 gave the highest yield (entries 13 and
14). Then, copper salts were further examined, which
identified that CuCl2 was the best one and afforded 68%
yield (entries 15 and 16). Replacing CuCl2/phen with
Cu(phen)Cl2 resulted in the final product 4aa in 75% yield
(entry 17). The control experiment indicated that copper is
indispensable in this transformation (entry 19).
a
Reaction conditions A: 1a (0.2 mmol), 2a (0.4 mmol), copper
catalyst (10 mol %), ligand (10 mol %), solvent (2 mL), Ar, 80 °C, 24
h. Reaction conditions B: 1aa (0.2 mmol), 2a (0.3 mmol), copper
catalyst (10 mol %), ligand (10 mol %), base (2.5 equiv), MeCN (3
mL), Ar, 80 °C, 24 h. L1 = 2,9-dimethyl-4,7-diphenyl-1,10-
b
phenanthroline. Isolated yields.
yields though the meta-position substituted benzosulfonamide
substrates resulted in a regioisomers reaction mixture (3f, 3l,
3m, 3o). The introduction of a larger steric hindrance group
on the para position was well tolerated and gave the desired
product 3d in 72% yield. Similarly, 2-naphthalene benzosulfo-
namide substrate 1q was also efficiently transformed in this
reaction. In addition, the substrates with strong electron-
withdrawing groups (CF3 or CN) also proceeded smoothly
and delivered the corresponding products (3j, 3k) in 53% and
41% yields, respectively. Multisubstituted allylamine 1n was
also applied with 50% yield obtained in this conversion. It was
noteworthy that alkene with aromatic heterocyclic worked well
and isolated oxindole 3p in a satisfactory yield. The influence
for the substituent of the N atom also was studied, resulting an
excellent yield (3r). The structure of products 3i and 3j were
also confirmed by X-ray crystal structure analysis (see the
Supporting Information).
Then, the reaction pattern for the construction of amides
was also investigated, and the results are summarized in
Scheme 3. Both electron-rich and -deficient groups on the
arylsulfonyl moiety were well tolerated under optimal reaction
conditions B. Substitutions on the ortho position, such as Me,
Cl, on the benzenesulfonyl group had no significant effect on
the yields, giving the target products 4af, 4am in good yields.
Sterically demanding butyl and 1-naphthalene groups were also
accommodated, affording the cyanoalkyl derivative 4ad, 4an in
moderate yields. Substrates bearing CF3, OCF3, CN, or NO2
furnished the corresponding transformation into the desired
amides 4ah−4aj, 4al in satisfactory yields. Notably, this
With the optimal reaction conditions established, the scope
of activated alkenes 1 with cycloketone oxime ethers 2a were
first investigated on a 0.2 mmol scale. As shown in Scheme 2,
this transformation proved to be well tolerated for various
activated alkenes under reaction conditions A. For instance, a
range of activated alkenes bearing different substituents on the
aryl ring preformed smoothly with cycloketone oxime ethers
2a to deliver the relevant products 3a−3o in moderate to good
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a
Scheme 2. Cu-Catalyzed Alkylnitriles/Sulfone Addition/
Desulfonylation/Cyclization
Scheme 3. Scope of the Alkylnitriles Reaction
a
a
Reaction conditions A: 1a (0.2 mmol, 1 equiv), 2a (0.4 mmol),
Cu(OTf)2 (10 mol %), L1 (10 mol %), toluene (2 mL), Ar, 80 °C, 24
a
b
Reaction conditions B: 1 (0.2 mmol, 1 equiv), 2 (0.3 mmol),
h. L1 = 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline. Isolated
Cu(phen)Cl2 (10 mol %), NaHCO3 (2.5 equiv), MeCN (3 mL), Ar,
80 °C, 24 h. Isolated yields.
yields.
b
Scheme 4. Control Experiments
reaction proceeded efficiently for the substrate including a
heterocyclic group (2-thienyl) with good compatibility, which
isolated the desired products in 50% yield. Next, the scope of
the cyclobutanone derived O-acyl oximes 2 was also evaluated.
The sterically more demanding substrate 1ar was also
applicable to this reaction. In contrast, the presence of electron
withdrawing group at the 3-position of O-acyl oximes
obviously decreased the yields (4ap, 4aq). Finally, the
analogous N-aryl-substituted substrates 1at and 1au furnished
the expected amides in 60% and 61% yields, respectively. In
addition, the structure of 4aa was determined by X-ray crystal
structure analysis. Also, the gram-scale experiment was
conducted to explore the practical applicability of this method.
As such, when this transformation was expanded to the 5
mmol scale, 4aa could be acquired in 68% yield.
To gain some insights into the mechanism of these
transformations, a series of control experiments were
performed under the optimal reaction conditions (Scheme
4). Upon the addition of 2.0 equiv of radical quenchers
TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl), reactions of
compound 1 were strongly inhibited, and the trapping product
b could be detected by GC-MS. Moreover, in the presence of
BHT (2,6-di-tert-butyl-4-methylphenol), the corresponding
capture product c was isolated under reaction conditions A/
B with 34%/ 43% yield. Finally, when stoichiometric amounts
of 1,1-diphenylene were added, the relevant radical trapping
product d was also isolated.
On basis of the control experiments and previous
research,20a,c,21 we proposed a plausible catalytic cycle for
this transformation in Scheme 5. Initially, iminyl radical species
A is generated via a single electron transfer (SET) and N−O
bond cleavage of substrate 2a under the copper catalyst. Then,
cyclic iminyl radical A undergoes a β−C−C bond scission to
afford cyanoalkyl radical B, which adds to a sulfonic, forming
radical C (R2 = alkyl group). Next, radical B/C interacts with
the activated alkene 1 to give a new radical intermediate D.
Further, an ipso-cyclization on the sulfonyl aromatic ring took
place and delivered intermediate E, which underwent rapid
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Authors
Scheme 5. Plausible Catalytic Cycles
Ming Li − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Cui-Tian Wang − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Qiao-Fei Bao − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Yi-Feng Qiu − College of Chemistry and Chemical
Engineering, Northwest Normal University, Lanzhou, Gansu
730070, China
Wan-Xu Wei − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Xue-Song Li − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Yu-Zhao Wang − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Zhe Zhang − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Jin-Lin Wang − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
desulfonylation, delivering a new C(sp2)−C(sp3) bond to
produce a key amidyl radical F. Finally, amidyl radical F
captures a hydrogen to offer product 4aa (R2 = aryl group).
Differently, when the substituent R2 on the N atom is an alkyl
group, amidyl radical F could undergo subsequent cyclization
to give the aryl radical G, which could go through an SET
process and β-H elimination to acquire the target product 3a.
It is worth noting that generation of a small number of product
3a′, which has no SO2 added in the product 3a, provides the
initial sulfur dioxide in this transformation.
In conclusion, we have established a multicomponent
reaction of cycloketone oximes, sulfur dioxide, and activated
alkenes in the presence of copper catalyst. The transformation
affords cyanoalkylsulfonylated oxindoles and cyanoalkyl
amides, constructing a quaternary stereocenter with the
manner of regioselectivity. In this reaction, in situ desulfony-
lation inserts sulfur dioxide, avoiding the addition of extra
sulfur dioxide. Further, this method exhibits good compatibility
with a broad range of activated alkenes, affording the desired
products in moderate to good yields.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03973
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge support grants from National Natural Science
Foundation of China (Grants NSF 21772075 and 21532001).
■
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03973.
Experimental procedures, compound characterization,
and NMR spectra (PDF)
Accession Codes
CCDC 2047428−2047430 contain the supplementary crys-
tallographic 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
Yong-Min Liang − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China;
orcid.org/0000-0001-8280-8211; Email: liangym@
lzu.edu.cn
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