Cu-Catalyzed Cascade Cyclization of Ketoxime Acetates and Alkynals Enabling Synthesis of Acylpyrroles

Article abstract of DOI:10.1002/cjoc.202000660

A facile copper-based catalytic system has been developed to enable efficient cyclization of methylketoximes and alkynals. This protocol provides a viable entry to synthetically and pharmaceutically useful 2-acylpyrroles with a broad range of compatible functionalities. Mechanistically, a key acyl migration is probably involved that leads to the formation of N-acyl pyrroles or otherwise NH pyrroles by further hydrolysis. More importantly, the present reaction system also gives an opportunity to realize three-component pyrrole assembly by simple addition of carboxylic acid.

Full text of DOI:10.1002/cjoc.202000660

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Cite this paper: Chin. J. Chem. 2021, 39, 1175—1180. DOI: 10.1002/cjoc.202000660
Cu-Catalyzed Cascade Cyclization of Ketoxime Acetates and
Alkynals Enabling Synthesis of Acylpyrroles
Zhenhua Xu, Ning Xian, Hongbiao Chen, Guo-Jun Deng, and Huawen Huang*
Key Laboratory for Green Organic Synthesis and Application of Hunan Province, Key Laboratory of Environmentally Friendly Chemistry and
Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan, Hunan 411105, China
Keywords
Copper catalysis | Nitrogen heterocycles | Cyclization | Ketoximes | Alkynals
Main observation and conclusion
A facile copper-based catalytic system has been developed to enable efficient cyclization of methylketoximes and alkynals. This pro-
tocol provides a viable entry to synthetically and pharmaceutically useful 2-acylpyrroles with a broad range of compatible functionali-
ties. Mechanistically, a key acyl migration is probably involved that leads to the formation of N-acyl pyrroles or otherwise NH pyrroles
by further hydrolysis. More importantly, the present reaction system also gives an opportunity to realize three-component pyrrole
assembly by simple addition of carboxylic acid.
Comprehensive Graphic Content
*E-mail: hwhuang@xtu.edu.cn
View HTML Article
Supporting Information
Chin. J. Chem. 2021, 39, 1175－1180
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Concise Report
products, yet the structurally important 2-acylpyrroles have not
been accessed by annulations of oximes. As our continuous inter-
est in N-heterocycle construction from O-acyl ketoximes, herein,
we report copper-catalyzed [3+2] formal annulations of methyl-
ketoximes and alkynals, which give a unique entry to valuable
2-acylpyrroles (Scheme 1, g). Notably, high levels of regioselectiv-
ity and chemoselectivity of this cyclization reaction were generally
observed, in which 2,5-disubstituted and 1,2,5-trisubstituted pyr-
role compounds were selectively generated via a key acyl migra-
tion. This protocol well complements to previous annulation reac-
tions of methylketoximes especially for pyrrole formation. Hence,
the chemoselective formation of two 2-acylpyrroles has been
disclosed for the first time.
Background and Originality Content
Pyrrole is one of privileged five-membered N-heterocycle
skeletons and constitutes core structures of numerous biologically
active molecules including naturally occurring alkaloids and drugs.
In particular, a pad of non-steroidal anti-inflammatory drugs (e.g.,
Ketorolac, Tolmetin, and Zomepirac)[1] and marine alkaloids with
high antibiotic activity against methicillin-resistant bacteria (e.g.,
Marinopyrroles)[2] bear a featured 2-acylpyrrole motif (Figure 1).
Additionally, pyrroles have been used as viable starting materials
for the synthesis of functional molecules.[3] Given the pharma-
ceutical and synthetic importance of pyrroles, it is highly desirable
to develop facile and practical methods for the preparation of
diversely substituted pyrroles.[4]
Results and Discussion
To commence the studies on pyrrole formation from ketox-
imes, acetophenone oxime acetate (1a) and 3-phenylpropiolal-
dehyde (2a) were selected as the model substrates to optimize
reaction conditions (Table 1). With additional Li2CO3 as the base,
the pyrrole formation reaction was achieved in dichloroethane
(DCE) under air when copper salts were used as the catalyst (en-
tries 1—8). Control experiments revealed that no product could
be detected (ND) in the absence of catalyst, while both reactants
were mostly recovered (entry 9). This result suggests that the
condensation of both substrates would not occur in the initial
step. Comparably, other metal salts such as FeCl2 and PdCl2 in-
stead of Cu salts were found to be ineffective in this reaction (en-
tries 10 and 11). When we screened a series of base and acid
additives (entries 12—18), the reaction proved optimal under
additive-free conditions, which afforded the 2-acylpyrrole product
in 72% yield (entry 12). With respect to acid additive, the addition
of AcOH (weak acid) declined the yield to 34% (entry 17). The
strong Brønsted acid trifluoroacetic acid (TFA) featured little im-
pact on the reaction productivity (entry 18). Then, the reaction
was performed in different solvents, of which DCE was superior to
the others including dimethyl sulfoxide (DMSO), N,N’-dimethylfor-
mamide (DMF), toluene, and CH3CN (entries 19—22). Finally, we
carried out the reaction under different atmosphere, where the
result under nitrogen was similar to that under air (entry 23), but
oxygen atmosphere reduced the reaction yield (entry 24). This
result also suggested that the oxygen atom of acyl group in the
product probably comes from the starting materials. The reaction
temperature was also screened to find that the reaction at 130 °C
was optimal (entries 25 and 26). Notably, in most cases we could
detect the formation of the by-product 2,6-diphenylpyridine dur-
ing the optimizing process.
Figure 1 Biologically active molecules containing 2-acylpyrrole moiety.
On the other hand, oximes are cheap and easily available raw
materials that have wide applications in chemical industry and
academia.[5] Specifically, O-acyl ketoximes have proved to be ver-
satile building blocks for the practical construction of N-hetero-
cycles.[6] For instance, intramolecular aza-Heck annulations of
olefin-attached ketoximes give a useful access to functionalized
pyrrolines or pyrroles,[7] which was pioneered by Narasaka and
coworkers (Scheme 1, a). In the last decade, intermolecular annu-
lation reactions with O-acyl methylketoximes have proved to be a
robust synthetic platform for pyrrole formation. Hence, the N-C-C
fragment of this kind of reactants was exploited to couple with a
range of unsaturated compounds including alkynes,[8] alkenes,[9]
isonitriles,[10] and α-amino acid ester,[11] leading to practical pro-
duction of diverse pyrrole derivatives (Scheme 1, b—f). The
homo-couplings of two molecule ketoximes were also realized to
furnish structurally symmetric 2,3,4,5-tetrasubstituted pyrroles.[12]
In spite of utilities, these methods restrict the type of pyrrole
Scheme 1 O-acyl oximes as building blocks for the synthesis of pyrrole
derivatives
Under the optimized reaction conditions, the model reaction
afforded 3a in 68% isolated yield. We next probe the substrate
scope of the copper-catalyzed [3+2] formal annulation reaction in
a facile additive-free system (Scheme 2). First, diverse oxime ace-
tates derived from acetophenones were subjected to the reaction
system to smoothly produce the corresponding 2-acyl-5-arylpyr-
roles in generally moderate yields (3a—3s). A broad range of func-
tionalities attached to the benzene ring of acetophenone oximes
including alkyl (3b—3d), halogen (F, Cl, Br, 3e—3g), and alkoxy (3h,
3i), were compatible with the present copper-catalytic system.
The electron effect of substituents on the yield is elusive; both
electron-withdrawing and donating functional groups gave the
pyrrole products in moderate yields. Notably, neighboring group
effect might benefit the desired transformation, therein ortho-
fluoro (3k) and ortho-methyl (3j) substrates gave higher yields of
products than their para- and meta-variants. Further, 1-(naph-
thalen-1-yl)ethanone oxime acetate delivered the target product
in modest yield (50%). The methylketoximes bearing a heteroaryl
moiety including furan, thiophene, and benzothiophene were also
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Chin. J. Chem. 2021, 39, 1175－1180

Cascade Cyclization of Ketoxime Acetates and Alkynals
Chin. J. Chem.
Table 1 Optimization of the reaction conditionsa
Scheme 2 Substrate scope for 2,5-disubstituted pyrroles
Catalyst
(15 mol%)
Additive
(30 mol%)
Solvent
(0.2 mol/L)
Entry
Yieldb/%
1
2
3
4
5
6
7
8
CuCl
CuBr
CuI
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMSO
DMF
toluene
CH3CN
DCE
DCE
DCE
DCE
44
52
45
36
34
28
36
32
ND
trace
ND
72 (68)
28
ND
32
42
34
69
ND
ND
26
CuBr2
CuCl2
Cu(OAc)2
CuOTf
Cu(MeCN)4PF6 Li2CO3
—
9
Li2CO3
Li2CO3
Li2CO3
—
K2CO3
Cs2CO3
KHCO3
Et3N
AcOH
TFA
—
—
—
—
—
—
—
—
10
11
12
13
14
15
16
17
18
19
20
21
22
23c
24d
25e
26f
FeCl2
PdCl2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
29
65
50
72
56
a Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), catalyst (15 mol%),
additive (30 mol%), solvent (1.0 mL), 130 °C, 12 h, under Air. b Yield was
1
determined by crude H NMR with 1,3,5-trimethoxybenzene as the inter-
nal standard; isolated yield was given in parentheses. c Under N2. d Under
O2. e At 140 °C. f At 120 °C.
effective substrates, giving the pyrrole-involved biheteroarenes
3u—3x in moderate yields (47%—61%). Apart from methylketox-
imes, the oxime substrates bearing other alkyl-substituted moiety
including propiophenone and tetralone were compatible to afford
the corresponding 3y and 3z, albeit in low yields. Subsequently,
the generality of alkynals was probed. The present copper cata-
lytic system was found to tolerate various substituted phe-
nylpropiolaldehydes, providing a viable access to functionalized
2,5-disubstituted pyrroles (3aa—3ag). Thienyl propiolaldehyde led
to the corresponding pyrrole 3ah in 30% yield. Among aliphatic
alkynals tested, however, only the bulky tertiary butyl substrate
worked, albeit in low yield (3ai, 35%), while linear alkynals fea-
tured very low reactivity (3aj). Unfortunately, acetenyl ketones
such as 1,3-diphenylprop-2-yn-1-one (3ak) did not work in the
present system.
synthetic examples with various useful functional groups (Scheme
3, 4a—4h). The structure of 4e was confirmed by single-crystal
X-ray diffraction analysis.[13]
Scheme 3 Formation of 1,2,5-trisubstituted pyrroles
In the process of optimization of reaction conditions and
studies on the substrate scope, we often observed the formation
of the 1,2-diacylpyrrole product. For example, under the optimal
reaction conditions, the 1-(2-benzoyl-5-phenyl-1H-pyrrol-1-yl)-
ethanone 4a was detected. We speculated this kind of product
would undergo hydrolysis to deliver the NH pyrrole 3a. To obtain a
suitable entry to 1,2-diacylpyrroles, we tried to modify the reac-
tion time and found that the formation of 4a was optimal within 1
h. Hence, the present copper-based catalytic system could also
provide a selective formation of 1,2-diacylpyrroles via [3+2] for-
mal annulations. The reaction generality was clarified by some
Given the established reactivity of the copper-catalyzed
system, we were attracted to disclose the action model of copper
catalysis and chemoselective formation of two types of pyrrole
Chin. J. Chem. 2021, 39, 1175－1180
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1177

Xu et al.
Concise Report
products. When radical scavenger was added, while 2,2,6,6-tetra-
methylpiperidine-1-oxyl (TEMPO) almost completely quenched
the reaction, the addition of 3,5-di-tert-butyl-4-hydroxytoluene
(BHT) had a slight effect on the efficiency (Scheme 4, a). These
results suggest that radical species may not be involved in the
process of reaction. Then, isotope labeling experiment with D2O
reveals that the hydrogen of pyrrole N1 derived from an inter-
molecular hydrolysis process rather than intramolecular hydrogen
transfer. The reaction with additional H218O afforded only 16O
product, indicating that the oxygen atom of the final product
came from acetate. We also used deuterated 3-phenylpropiolal-
dehyde (2a-D), which afforded deuterated pyrrole 3a-D with
diminished efficiency probably because of the reduced electro-
philicity of carbonyl by D atom. Finally, the hydrolysis of 4a to 3a
was performed under different conditions. The results indicate
that AcOH, which is gradually released in the activation process of
ketoxime acetates, plays an important role, and the copper
catalyst may also promote the hydrolysis.
Scheme 5 Possible reaction mechanism
Scheme 4 Control experiments
The robust nature of our copper-catalyzed additive-free sys-
tem was further mirrored by the successful gram-scale prepara-
tion with acceptable reaction yield (10 mmol, 48% yield, Scheme 6,
a). Moreover, carbonyl reduction with NaBH4 (Figure 6, b) and
bromination with NBS (Scheme 6, c) were performed to obtain
more diverse pyrrole products. Remarkably, when excessive ben-
zoic acid (3.0 equiv) was added within 1 h, the reaction system
provided a three-component pyrrole formation with promising
productivity (Scheme 6, d); therein acyloxy exchange with benzo-
yloxy probably occurred in the stage of intermediate A—E.
Scheme 6 Application of the protocol
On the basis of experimental results and literature,[14] a tenta-
tive reaction mechanism was proposed (Scheme 5). First, oxida-
tive addition (OA) of copper(I) to the N—O bond of oxime moiety
gave the imino copper(III) species A, with tautomerization to af-
ford the enamino copper complex B. The OA process rather than
condensation was proposed as the initial step on the basis of the
result of control experiment that both reactants were recovered
in the absence of copper catalyst. Subsequently, coordination of B
with alkynal 2 led to nucleophilic 1,2-addition to give intermediate
C, which underwent H2O elimination to furnish the enyne imino
copper(III) complex D. Then, intramolecular migration insertion of
N—Cu bond to C—C triple bond generated intermediate E, which
delivered to 2-methylene-2H-pyrrole F and copper(I) via reductive
elimination (RE) to finish the copper catalytic cycle. Finally, the
N-acylpyrrole product 4 was formed through aromatizative tau-
tomerization/acyl shift[15] and further hydrolysis gave the 2,5-di-
substituted pyrrole 3. Notably, [CuI]/[CuII] catalytic cycle is also
viable for the ketoxime activation, in which the corresponding
intermediate A’ is formed and the C—O bond formation from E’
proceeds with the aid of another [CuII] species (Scheme 5, bot-
tom).
Conclusions
In summary, we have developed a facile copper-based redox-
neutral system that enables [3+2] formal annulations of methyl-
ketoxime acetates with alkynals. A broad range of 2-acylpyrrole
products, which are hard to prepare by traditional methods, have
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Cascade Cyclization of Ketoxime Acetates and Alkynals
Chin. J. Chem.
been accessed. The reaction mechanism involves a copper cata-
lytic cycle and a key acyl shift that generates the N-acylpyrrole
intermediate products. Inspired by the insight into reaction
mechanism, a three-component reaction of methylketoximes,
alkynals, and carboxylic acids has been further disclosed with
promising productivity.
Smith, J. A. Chemoselective reduction of 2-acyl-N-sulfonylpyrroles:
Synthesis of 3-pyrrolines and 2-alkylpyrroles. Org. Biomol. Chem.
2011, 9, 3948–3953; (e) Li, Z.; Yan, N.; Xie, J.; Liu, P.; Zhang, J.; Dai, B.
Efficient Copper-Catalyzed Annulation of 2-Formylazoles with 2-Halo-
anilines for the Synthesis of Pyrrole- and Imidazole-Fused Quinoxa-
lines. Chin. J. Chem. 2015, 33, 589–593; (f) Qian, Y.; Shang, J.; Lyu,
Z.-H.; Huang, X.; Guan, A.-j.; Xu, L.-J.; Gong, H.-Y. Synthesis of
π-Extended Carbazoles via One-Pot C-C Coupling and Chlorination
Promoted by FeCl3. Chin. J. Chem. 2020, 38, 1538–1544.
Experimental
[4] (a) Estevez, V.; Villacampa, M.; Menendez, J. C. Recent advances in
the synthesis of pyrroles by multicomponent reactions. Chem. Soc.
Rev. 2014, 43, 4633–4657; (b) Xu, H.; Han, T.; Luo, X.; Deng, W.-P.
The construction of 3-azabicyclo[3.1.0]hexane backbone by the reac-
tion of allenes with allylamines via tandem Michael addition and
Copper-mediated oxidative carbanion cyclization. Chin. J. Chem.
2020, 39, 666–670; (c) Wang, M.-Y.; Li, W. Feng Ligand: Privileged
Chiral Ligand in Asymmetric Catalysis. Chin. J. Chem. 2020, 38, DOI:
10.1002/cjoc.202000508; (d) Xie, J.-Q.; Liang, R.-X.; Jia, Y.-X. Recent
Advances of Catalytic Enantioselective Heck Reactions and Reduc-
tive-Heck Reactions. Chin. J. Chem. 2021, 39, 710–728; (e) Yang,
W.-L.; Sun, Z.-T.; Sun, H.; Deng, W.-P. Nickel(II)-Catalyzed Diastereo-
and Enantioselective *3+2+ Cycloaddition of α-Ketoesters with
2-Nitrovinylindoles and 2-Nitrovinylpyrroles. Chin. J. Chem. 2019, 37,
216–220; (f) Cai, Q.; Zhou,W. Ullmann-Ma Reaction: Development,
Scope and Applications in Organic Synthesis. Chin. J. Chem. 2020, 38,
879–893.
[5] (a) Tabolin, A. A.; Ioffe, S. L. Rearrangement of N-oxyenamines and
related reactions. Chem. Rev. 2014, 114, 5426–5476; (b) Huang, H.; Ji,
X.; Wu, W.; Jiang, H. Transition metal-catalyzed C-H functionalization
of N-oxyenamine internal oxidants. Chem. Soc. Rev. 2015, 44, 1155–
1171; (c) Bolotin, D. S.; Bokach, N. A.; Demakova, M. Y.; Kukushkin, V.
Y. Metal-Involving Synthesis and Reactions of Oximes. Chem. Rev.
2017, 117, 13039–13122; (d) Choi, S.; Ha, S.; Park, C.-M. α-Diazo
oxime ethers for N-heterocycle synthesis. Chem. Commun. 2017, 53,
6054–6064; (e) Li, J.; Hu, Y.; Zhang, D.; Liu, Q.; Dong, Y.; Liu, H.
Transition Metal-Catalyzed Reactions Involving Oximes. Adv. Synth.
Catal. 2017, 359, 710–771; (f) Huang, H.; Cai, J.; Deng, G. J. O-Acyl
oximes: versatile building blocks for N-heterocycle formation in
recent transition metal catalysis. Org. Biomol. Chem. 2016, 14, 1519–
1530; (g) Reeta Rangarajan, T. M.; Singh, R. P.; Singh, M. An easy
access to oxime ethers by Pd-catalyzed C–O cross-coupling of
activated aryl bromides with ketoximes and chalcone oximes. Chin. J.
Chem. 2020, 38, 830–836.
[6] (a) Tang, X.; Huang, L.; Yang, J.; Xu, Y.; Wu, W.; Jiang, H. Practical
synthesis of pyrazoles via a copper-catalyzed relay oxidation strategy.
Chem. Commun. 2014, 50, 14793–14796; (b) Huang, H.; Cai, J.; Ji, X.;
Xiao, F.; Chen, Y.; Deng, G. J. Internal Oxidant-Triggered Aerobic
Oxygenation and Cyclization of Indoles under Copper Catalysis.
Angew. Chem. Int. Ed. 2016, 55, 307–311; (c) Huang, H.; Ji, X.; Tang,
X.; Zhang, M.; Li, X.; Jiang, H. Conversion of Pyridine to Imidazo[1,2-a]-
pyridines by Copper-Catalyzed Aerobic Dehydrogenative Cyclization
with Oxime Esters. Org. Lett. 2013, 15, 6254–6257; (d) Zhu, Z.; Tang,
X.; Li, J.; Li, X.; Wu, W.; Deng, G.; Jiang, H. Iron-Catalyzed Synthesis of
2H-Imidazoles from Oxime Acetates and Vinyl Azides under Redox-
Neutral Conditions. Org. Lett. 2017, 19, 1370–1373; (e) Tang, X.; Zhu,
Z.; Qi, C.; Wu, W.; Jiang, H. Copper-Catalyzed Coupling of Oxime
Acetates with Isothiocyanates: A Strategy for 2-Aminothiazoles. Org.
Lett. 2016, 18, 180–183; (f) Huang, H.; Xu, Z.; Ji, X.; Li, B.; Deng, G. J.
Thiophene-Fused Heteroaromatic Systems Enabled by Internal
Oxidant-Induced Cascade Bis-Heteroannulation. Org. Lett. 2018, 20,
4917–4920; (g) Huang, H.; Qu, Z.; Ji, X.; Deng, G.-J. Three-component
bis-heterocycliation for synthesis of 2-aminobenzo[4,5]thieno[3,2-d]-
thiazoles. Org. Chem. Front. 2019, 6, 1146–1150; (h) Huang, H.;
Wang, Q.; Xu, Z.; Deng, G. J. Tri‐Functional Elemental Sulfur Enabling
Bis‐Heteroannulation of Methyl Ketoximes with Methyl N‐Hetero-
arenes. Adv. Synth. Catal. 2019, 361, 591–596; (i) Xu, Z.; Huang, H.;
Chen, H.; Deng, G.-J. Catalyst- and additive-free annulation/aromati-
General procedure for the synthesis of benzothiazole heter-
ocycles
General procedure A. Oxime acetate 1 (0.3 mmol), aldehyde 2
(0.2 mmol), CuBr (4.5 mg, 0.03 mmol, 15 mol%), and DCE (1.0 mL)
were added successfully to a 10 mL oven-dried reaction vessel.
The sealed reaction vessel was stirred at 130 oC for 12 h. After
cooling to room temperature, the reaction was diluted with ethyl
acetate (10 mL) and the volatiles were removed under reduced
pressure. The residue was purified by column chromatography on
silica gel using petroleum ether/ethyl acetate (PE/EA) to yield the
desired product 3.
General procedure B. Oxime acetate 1 (0.3 mmol), aldehyde 2
(0.2 mmol), CuBr (4.5 mg, 0.03 mmol, 15 mol%), and DCE (1.0 mL)
were added successfully to a 10 mL oven-dried reaction vessel.
The sealed reaction vessel was stirred at 130 oC for 1 h. After
cooling to room temperature, the reaction was diluted with ethyl
acetate (10 mL) and the volatiles were removed under reduced
pressure. The residue was purified by column chromatography on
silica gel (PE/EA) to yield the desired product 4.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.202000660.
Acknowledgement
Support by the National Natural Science Foundation of China
(22071211), the Science and Technology Planning Project of Hu-
nan Province (2019RS2039), Hunan Provincial Natural Science
Foundation of China (2020JJ3032), the Hunan Provincial Innova-
tive Foundation of Postgraduate (CX20190482, XDCX2019B091),
and the Collaborative Innovation Center of New Chemical Tech-
nologies for Environmental Benignity and Efficient Resource Utili-
zation is gratefully acknowledged.
References
[1] Yuan, M.; Luo, M.; Song, Y.; Xu, Q.; Wang, X.; Cao, Y.; Bu, X.; Ren, Y.;
Hu, X. Identification of curcumin derivatives as human glyoxalase I
inhibitors: A combination of biological evaluation, molecular docking,
3D-QSAR and molecular dynamics simulation studies. Bioorg. Med.
Chem. 2011, 19, 1189–1196.
[2] Cheng, C.; Liu, Y.; Song, H.; Pan, L.; Li, J.; Qin, Y.; Li, R. Marinopyrrole
derivatives as potential antibiotic agents against methicillin-resistant
Staphylococcus aureus (II). Mar. Drugs 2013, 11, 2927–2948.
[3] (a) Leen, V.; Braeken, E.; Luckermans, K.; Jackers, C.; Van der
Auweraer, M.; Boens, N.; Dehaen, W. A versatile, modular synthesis
of monofunctionalized BODIPY dyes. Chem. Commun. 2009, 4515–
4517; (b) Frederich, J. H.; Harran, P. G. Modular access to complex
prodiginines: total synthesis of (+)-roseophilin via its 2-azafulvene
prototropisomer. J. Am. Chem. Soc. 2013, 135, 3788–3791; (c)
Jafarpour, F.; Hazrati, H.; Darvishmolla, M. Acylation of Pyrroles and
their Free (N-H)-DerivativesviaPalladium-Catalyzed Carbopalladation
of Nitriles. Adv. Synth. Catal. 2014, 356, 3784–3788; (d) You, H. T.;
Grosse, A. C.; Howard, J. K.; Hyland, C. J. T.; Just, J.; Molesworth, P. P.;
Chin. J. Chem. 2021, 39, 1175－1180
© 2021 SIOC, CAS, Shanghai, & WILEY-VCH GmbH
www.cjc.wiley-vch.de
1179

Xu et al.
Concise Report
zation leading to benzothiazoles and naphthothiazoles. Org. Chem.
Front. 2019, 6, 3060–3064; (j) Qu, Z.; Zhang, F.; Deng, G. J.; Huang, H.
Regioselectivity Control in the Oxidative Formal [3 + 2] Annulations
of Ketoxime Acetates and Tetrohydroisoquinolines. Org. Lett. 2019,
21, 8239–8243; (k) Xiao, F.; Yuan, S.; Huang, H.; Zhang, F.; Deng, G. J.
Copper‐Catalyzed Three‐Component Domino Cyclization for the
Synthesis of 4‐Aryl‐5‐(arythio)‐2‐(trifluoromethyl)oxazoles. Org. Lett.
2019, 21, 8533–8536; (l) Xu, Z.; Deng, G. J.; Zhang, F.; Chen, H.;
Huang, H. Three‐Component Cascade Bis‐heteroannulation of Aryl or
Vinyl Methylketoxime Acetates toward Thieno[3,2‐c]isoquinolines.
Org. Lett. 2019, 21, 8630–8634; (m) Ren, Z.‐H.; Zhang, Z.‐Y.; Yang,
B.‐Q.; Wang, Y.‐Y.; Guan, Z.‐H. Copper‐Catalyzed Coupling of Oxime
Acetates with Aldehydes: A New Strategy for Synthesis of Pyridines.
Org. Lett. 2011, 13, 5394–5397; (n) Huang, H.; Cai, J.; Xie, H.; Tan, J.;
Li, F.; Deng, G. J. Transition‐Metal‐Free N‐O Reduction of Oximes: A
Modular Synthesis of Fluorinated Pyridines. Org. Lett. 2017, 19,
3743–3746; (o) Bai, D.; Wang, X.; Zheng, G.; Li, X. Redox‐Divergent
Synthesis of Fluoroalkylated Pyridines and 2‐Pyridones through
Cu‐Catalyzed N‐O Cleavage of Oxime Acetates. Angew. Chem. Int. Ed.
2018, 130, 6743–6747; (p) Zhan, J.‐L.; Wu, M.‐W.; Wei, D.; Wei, B.‐Y.;
Jiang, Y.; Yu, W.; Han, B. 4‐HO‐TEMPO‐Catalyzed Redox Annulation of
Cyclopropanols with Oxime Acetates toward Pyridine Derivatives.
acetates with dialkyl acetylenedicarboxylates under aerobic condi‐
tions. Chem. Commun. 2013, 49, 9597–9579.
[9] (a) Yang, H.‐B.; NicklasSelander Divergent Iron‐CatalyzedCoupling of
O‐Acyloximes withSilyl Enol Ethers. Chem. ‐ Eur. J. 2017, 23, 1779–
1783; (b) Zhao, B.; Liang, H.‐W.; Yang, J.; Yang, Z.; Wei, Y. Copper‐
Catalyzed Intermolecular Cyclization between Oximes and Alkenes: A
Facile Access to Spiropyrrolines. ACS Catal. 2017, 7, 5612–5617.
[10] Senadi, G. C.; Lu, T. Y.; Dhandabani, G. K.; Wang, J. J. Palladium‐
Catalyzed Double‐Isocyanide Insertion via Oxidative N‐O Cleavage of
Acetyl Oximes: Syntheses of 2H‐Pyrrol‐2‐imines. Org. Lett. 2017, 19,
1172–1175.
[11] Miao, C.‐B.; Zheng, A.‐Q.; Zhou, L.‐J.; Lyu, X.; Yang, H.‐T. Copper‐Cat‐
alyzed Annulation of Oxime Acetates with α‐Amino Acid Ester
Derivatives: Synthesis of 3‐Sulfonamido/Imino 4‐Pyrrolin‐2‐ones. Org.
Lett. 2020, 22, 3381−3385.
[12] Ran, L.; Ren, Z.‐H.; Wang, Y.‐Y.; Guan, Z.‐H. Copper‐catalyzed
homocoupling of ketoxime carboxylates for synthesis of symmetrical
pyrroles. Green Chem. 2014, 16, 112–115.
[13] CCDC 2032630 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_ request/cif.
ACS Catal. 2019, 9, 4179–4188; (q) Meng, H.; Xu, Z.; Qu, Z.; Huang, H.; [14] (a) Cao, H.; Zhan, H.; Cen, J.; Lin, J.; Lin, Y.; Zhu, Q.; Fu, M.; Jiang, H.
Deng, G. J. Copper(0)/PPh3‐Mediated Bisheteroannulations of o‐Nitro‐
alkynes with Methylketoximes Accessing Pyrazo‐Fused Pseudo‐
indoxyls. Org. Lett. 2020, 22, 6117–6121; (r) Zhang, M.; Di, X.; Zhang,
M.; Zhang, J. Gold(I)‐catalyzed diastereo‐ and enantioselective syn‐
thesis of polysubstituted pyrrolo[3,4‐d][1,2]oxazines. Chin. J. Chem.
2018, 36, 519–525; (s) Zhao, B.; Tan, H.; Chen, C.; Jiao, N.; Shi, Z.
Photoinduced C‐C Bond Cleavage and Oxidation of Cycloketoxime
Esters. Chin. J. Chem. 2018, 36, 995–999; (t) Ran, C.‐K.; Huang, H.; Li,
X.‐H.; Wang, W.; Ye, J.‐H.; Yan, S.‐S.; Wang, B.‐Q.; Feng, C.; Yu, D.‐G.
Cu Catalyzed Selective OxyCyanoalkylation of Allylamines with
Cycloketone Oxime Esters and CO2. Chin. J. Chem. 2020, 38, 69−76.
[7] (a) Kitamura, M.; Narasaka, K. Synthesis of aza‐heterocycles from
oximes by amino‐Heck reaction. Chem. Rec. 2002, 2, 268–277; (b)
Narasaka, K.; Kitamura, M. Amination with Oximes. Eur. J. Org. Chem.
2005, 2005, 4505–4519; (c) Okamoto, K.; Oda, T.; Kohigashi, S.; Ohe,
K. Palladium‐catalyzed decarboxylative intramolecular aziridination
from 4H‐isoxazol‐5‐ones leading to 1‐azabicyclo[3.1.0]hex‐2‐enes.
Angew. Chem. Int. Ed. 2011, 50, 11470–11473; (d) Faulkner, A.;
Bower, J. F. Highly efficient Narasaka‐Heck cyclizations mediated by
P(3,5‐(CF3)2C6H3)3: facile access to N‐heterobicyclic scaffolds. Angew.
Chem. Int. Ed. 2012, 51, 1675–1679; (e) Du, W.; Zhao, M. N.; Ren, Z.
H.; Wang, Y. Y.; Guan, Z. H. Copper‐catalyzed 5‐endo‐trig cyclization
of ketoxime carboxylates: a facile synthesis of 2‐arylpyrroles. Chem.
Commun. 2014, 50, 7437–7439; (f) Faulkner, A.; Race, N. J.; Scott, J.
S.; Bower, J. F. Copper catalyzed Heck‐like cyclizations of oxime
esters. Chem. Sci. 2014, 5, 2416–2421; (g) Cai, Y.; Jalan, A.; Kubosumi,
A. R.; Castle, S. L. Microwave‐promoted tin‐free iminyl radical
cyclization with TEMPO trapping: a practical synthesis of 2‐acylpyr‐
roles. Org. Lett. 2015, 17, 488–491; (h) Faulkner, A.; Scott, J. S.;
Bower, J. F. An Umpolung Approach to Alkene Carboamination:
Palladium Catalyzed 1,2‐Amino‐Acylation, ‐Carboxylation, ‐Arylation,
‐Vinylation, and ‐Alkynylation. J. Am. Chem. Soc. 2015, 137, 7224–
7230; (i) Su, H.; Li, W.; Xuan, Z.; Yu, W. Copper‐Catalyzed Cyclization
and Azidation of γ,δ‐Unsaturated Ketone O‐Benzoyl Oximes. Adv.
Synth. Catal. 2015, 357, 64–70; (j) Chen, C.; Zhao, J.; Shi, X.; Liu, L.;
Zhu, Y.‐P.; Sun, W.; Zhu, B. Recent advances in cyclization reactions
of unsaturated oxime esters (ethers): synthesis of versatile function‐
alized nitrogen‐containing scaffolds. Org. Chem. Front. 2020, 7,
1948–1969; (k) Zhang, Z.; Li, J.; Huang, G.; Sun, K.; Zhang, G.; Ma, N.;
Liu, Q.; Liu, T. Copper(I)‐Catalyzed Intramolecular N−N Coupling of
Cyclopropyl O‐Acyl Ketoximes: Synthesis of Spiro‐fused Pyrazolin‐5‐
ones. Chin. J. Chem. 2016, 34, 1309−1320.
Copper‐Catalyzed C–O Bond Formation: An Efficient One‐Pot Highly
Regioselective Synthesis of Furans from (2‐Furyl)Carbene Complexes.
Org. Lett. 2013, 15, 1080–1083; (b) Yang, D.; Yu, Y.; Wu, Y.; Feng, H.;
Li, X.; Cao, H. One‐Pot Regiospecific Synthesis of Indolizines: A Solvent‐
Free, Metal‐Free, Three‐Component Reaction of 2‐(Pyridin‐2‐yl)ace‐
tates, Ynals, and Alcohols or Thiols. Org. Lett. 2018, 20, 2477–2480;
(c) Liu, W.; Zhang, Y.; He, J.; Yu, Y.; Yuan, J.; Ye, X.; Zhang, Z.; Xue, L.;
Cao, H. Transition‐Metal‐Free Three‐Component Reaction: Additive
Controlled Synthesis of Sulfonylated Imidazoles. J. Org. Chem. 2019,
84, 11348–11358; (d) Peng, S.; Song, Y.‐X.; He, J.‐Y.; Tang, S.‐S.; Tan,
J.‐X.; Cao, Z.; Lin, Y.‐W.; He, W.‐M. TsCl‐promoted sulfonylation of
quinoline N‐oxides with sodium sulfinates in water. Chin. Chem. Lett.
2019, 30, 2287−2290; (e) Wang, C.; Yu, Y.; Su, Z.; Li, X.; Cao, H. Metal‐
Free C–B Bond Cleavage: An Acid Catalyzed Three‐Component Reac‐
tion Construction of Imidazole‐Containing Triarylmethanes. Org. Lett.
2019, 21, 4420–4423; (f) Zhang, Z.‐H.; Dong, X.‐Y.; Du, X.‐Y.; Gu, Q.‐S.;
Li, Z.‐L.; Liu, X.‐Y. Copper‐catalyzed Enantioselective Sonogashira‐
type Oxidative Cross‐Coupling of Unactivated C(sp3)−H Bonds with
Alkynes. Nat. Commun. 2019, 10, 5689–5698; (g) Gu, Q.‐S.; Li, Z.‐L.;
Liu, X.‐Y. Copper(I)‐Catalyzed Asymmetric Reactions Involving Radi‐
cals. Acc. Chem. Res. 2020, 53, 170–181; (h) Dong, X.‐Y.; Zhang, Y.‐F.;
Ma, C.‐L.; Gu, Q.‐S.; Wang, F.‐L.; Li, Z.‐L.; Jiang, S.‐P.; Liu, X.‐Y. A
General Asymmetric Copper‐Catalyzed Sonogashira C(sp3)‐C(sp)
Coupling. Nat. Chem. 2019, 11, 1158–1166; (i) Dong, X.‐Y.; Cheng,
J.‐T.; Zhang, Y.‐F.; Li, Z.‐L.; Zhan, T.‐Y.; Chen, J.‐J.; Wang, F.‐L.; Yang,
N.‐Y.; Ye, L.; Gu, Q.‐S.; Liu, X.‐Y. Copper‐Catalyzed Asymmetric
Radical 1,2‐Carboalkynylation of Alkenes with Alkyl Halides and
Terminal Alkynes. J. Am. Chem. Soc. 2020, 142, 9501–9509.
[15] 1,7‐shift in previous studies: (a) Okajima, T.; Imafuku, K. Theoretical
Study on Chlorine and Hydrogen Shift in Cycloheptatriene and Cyclo‐
pentadiene Derivatives. J. Org. Chem. 2002, 67, 625–632. (b) Ven,
van de L. J. M.; Keulemans‐Lebbink, M.; Haan, de J. W.; Kloosterziel,
H. Photochemical sigmatropic 1,7‐shift of hydrogen in a semi‐cyclic
triene, 1‐vinylcyclopenta‐1,3‐diene. J. Chem. Soc. D 1970, 1509–1509.
(c) Poutsma, M. L. Further considerations of the sources of the
volatiles from pyrolysis of polystyrene. Polym. Degrad. Stab. 2009, 94,
2055−2064.
Manuscript received: December 5, 2020
Manuscript revised: January 18, 2021
Manuscript accepted: January 19, 2021
Accepted manuscript online: January 22, 2021
[8] Tang, X.; Huang, L.; Qi, C.; Wu, W.; Jiang, H. An efficient synthesis of
polysubstituted pyrroles via copper‐catalyzed coupling of oxime
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