CuII-Catalyzed Coupling with Two Ynone Units by Selective Triple and Sigma C-C and C-H Bond Cleavages

Article abstract of DOI:10.1021/acs.orglett.1c00371

We report a new copper-catalyzed [2 + 2 + 1] annulation process through the selective cleavage of sigma and triple C-C and C-H bonds using two ynone units. This new methodology involves breaking multiple chemical bonds in a single operation, including CC, C-C, C-H, and N-O. These high-value adducts lead to a diverse collection of synthetically challenging trisubstituted indolizines by the simultaneous engagement of different bond-breaking events and show excellent fluorescence in green aqueous solutions.

Full text of DOI:10.1021/acs.orglett.1c00371

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Letter
CuII-Catalyzed Coupling with Two Ynone Units by Selective Triple
and Sigma C−C and C−H Bond Cleavages
Jiang Nan,* Jiawen Zhang, Yan Hu, Chao Wang, Tingting Wang, Weitao Wang, Yangmin Ma,
and Michal Szostak*
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ABSTRACT: We report a new copper-catalyzed [2 + 2 + 1]
annulation process through the selective cleavage of sigma and
triple C−C and C−H bonds using two ynone units. This new
methodology involves breaking multiple chemical bonds in a single
operation, including CC, C−C, C−H, and N−O. These high-
value adducts lead to a diverse collection of synthetically
challenging trisubstituted indolizines by the simultaneous engage-
ment of different bond-breaking events and show excellent fluorescence in green aqueous solutions.
rguably, one of the greatest challenges in synthetic
chemistry is the selective breaking and reassembly of inert
synergistic merger of C−H functionalization14 with CC
bond cleavage is in infancy.
In this context, herein, we report a new copper-catalyzed [2
+ 2 + 1] annulation process through the selective cleavage of
sigma and triple C−C and C−H bonds using two ynone units
(Scheme 1B). The method accomplishes C−H functionaliza-
tion through a cascade C−H activation, C−C dissociation,
nucleophilic cyclization, and oxidative aromatization.
A
chemical bonds.1 In this fascinating field, carbon−carbon
bonds represent the most fundamental linkages in organic
molecules. The selective C−C bond cleavage is highly
challenging owing to the inherent strength of sigma and
multiple carbon−carbon bonds and the difficult-to-control site-
selectivity, yet such processes have a profound impact on
chemical synthesis.2,3 Indeed, the cleavage of C−C and CC
bonds has evolved in the past decade, resulting in an ever-
growing impetus in the functionalization of strained and
unstrained molecules.2 However, the selective cleavage of triple
CC bonds is poorly established and remains one of the
major research challenges arising from the larger dissociation
energy (>200 kcal/mol) compared with C−C sigma bonds
(∼85 kcal/mol) as well as the precarious electrophilic
reactivity of systems.3 Although methods including stoichio-
metric organometallic reactions,4a,b alkyne metathesis,4c−e
oxidative cleavage,4f−h and metal-catalyzed strategies4i−k have
been developed, the CC bond cleavage is regarded as a
unique activation mode that allows access to elusive motifs and
highly versatile building blocks.
The following features of our findings are noteworthy:1 the
unprecedented three-component domino transformation in-
volving selective sigma and triple C−C and C−H bond
scissions;2 the productive merger of CC, C(O)−C, and C−
H cleavages with the concomitant highly orchestrated assembly
of C−C, CC, and C−N bonds with high selectivity; (3) the
formal 1,3-O atom transfer; and (4) the concise assembly of
diversely trisubstituted indolizines, which are key structural
motifs in a large number of bioactive products and functional
molecules and typically require multistep synthesis with highly
functionalized reagents (Scheme 1C).15,16
Our investigation began with an examination of the relevant
reaction parameters by reacting isoquinoline N-oxide 1a with
two symmetric phenyl-substituted ynone units 2a. A
representative summary of the experimental results is
presented in Table 1. After extensive optimization, we were
delighted to find that using Cu(OAc)2 as a catalyst and toluene
as a solvent at 100 °C successfully generated the desired
product 3aa (entry 1). A solvent screen showed that PEG-200
Ynones feature two types of versatile and conjugated
functional moieties, namely, CO and CC bonds, and
have been delivered as multipurpose intermediates in the
synthesis of structurally complex organic architectures,
including in the construction of value-added motifs.5 In recent
years, increasing endeavors to develop the cleavage of carbon−
carbon bonds in ynones have been launched, albeit generating
a limited number of cases. In this domain, the groups of
Dong,6 Cheng,7 and Zhang8 described the functionalization of
C−C(CO) bonds (Scheme 1A). With regard to the more
challenging triple CC bond cleavage owing to the weaker
polarization, there are far fewer results, generally delivering
linear molecules.9−13 Likewise, the appealing and challenging
Received: February 1, 2021
Published: February 11, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00371
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1928−1933
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changes in the reaction temperature to either a higher or a
lower level did not increase the reaction efficacy (entries 10
and 11). Importantly, in the absence of a Cu catalyst, this
sequential C−C, CC, and C−H cleavage protocol was
completely shut down (entry 12). Further details of the
reaction optimization are summarized in the Supporting
Information (SI).
Scheme 1. Strategies for C−C and CC Cleavage of
Ynones
Having established the optimal reaction conditions, we next
evaluated the generality of this C−C, CC, and C−H
cleavage protocol. As shown in Scheme 2, a wide range of
Scheme 2. Substrate Scope of Ynones
a
Table 1. Optimization of the Reaction Conditions
b
entry
[M]
solvent
toluene
1,4-dioxane
DCE
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(acac)2
CuBr
CuSO4·5H2O
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
100
100
100
100
100
100
100
100
100
90
32
37
53
53
77 (72)
30
52
59
22
67
H2O
c
PEG-200
PEG-200
PEG-200
PEG-200
PEG-200
PEG-200
PEG-200
PEG-200
d
9
10
11
12
110
100
73
trace
a
Reaction conditions: 1a (0.20 mmol), 2a (0.50 mmol), catalyst (20
b
mol %), solvent (2.0 mL), T (°C, oil bath), 12 h, air. 1H NMR
yields. Isolated yield in parentheses. Ar atmosphere.
a
c
d
1.0 mmol scale.
ynone partners were found to be competent by reacting with
both isoquinoline and quinoline N-oxides (1a, 1b), delivering
the desired products in 49−88% yields. With regard to the
carbonyl fragment of ynones, in addition to alkoxy groups
(3ad, 3ae), various substituents on the aromatic ring were well
compatible, including electron-donating groups, such as methyl
(3ab) and methoxy groups (3ac, 3ag), as well as electron-
withdrawing groups, such as cyano (3ah′), nitro (3ai′),
trifluoromethoxy (3aj′), fluoro (3bm), bromo (3bn) and ester
was optimal and afforded the desired product in 72% yield
(entry 5). A high yield using the H2O system should be noted
(entry 4). Interestingly, other Cu(I) and Cu(II) catalysts,
including Cu(acac)2, CuBr, and CuSO4·5H2O, showed no
beneficial effect on the reaction (entries 6−8). Importantly,
using anaerobic conditions, the desired transformation was
dramatically inhibited, leading to 3aa in only 22% yield (entry
9), which confirmed the critical role of oxygen. Furthermore,
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groups (3bs′). Interestingly, when the CF3-containing
substrate 2l was subjected to the reaction, the corresponding
trisubstituted product was further converted into the
deacylation adduct 3al″ in 87% yield because the CF3 group
enhanced the electrophilicity of carbonyl carbon followed by
the attack of water. Notably, heterocyclic arenes such as thienyl
(3ak, 3bo) and furyl (3bt) are also well compatible. Next, the
alkynyl fragment, namely, the R′ moiety, was investigated. We
were delighted to find that a broad array of different functional
groups were tolerated, including alkoxy (3ad, 3ae), cyclopropyl
(3af), diversified arene (3bb, 3ac, 3bm, 3bn), alkyl (3bp,
3bq), and heteroarene groups (3bo, 3br), to forge structurally
diversified indolizines. When the reaction was performed on a
1.0 mmol scale, 3aa was obtained in 70% yield.
Encouraged by the reaction performance of both sym-
metrical and unsymmetrical ynones, we next sought to examine
the highly challenging incorporation of two different ynones,
which theoretically could lead to four regioisomers (Scheme
4). Indeed, subjecting aryl-ynones 2b and 2m to the reaction
Scheme 4. Coupling of Two Different Ynones
Strikingly, the unsymmetrical ynones unexpectedly delivered
the desired products via the exclusive cleavage of the CC
bond (3ag−3ak, 3bp−3bq, >10:1 rr) or the formation of O-
transfer products from C(O)−C dissociation (3ah′−3aj′);
however, some examples (3br−3bt) gave a mixture of two
separable regioisomers.
Next, we investigated the substrate scope of the N-oxide
component. As shown in Scheme 3, a broad range of functional
Scheme 3. Substrate Scope of N-Oxides
with quinoline N-oxide 1b provided a mixture of 3bb, 3bm,
3bu, and 3bv in a 1:2:2:1 ratio, albeit in a 64% total yield. In
contrast, the reaction of phenyl-ynone 2a and ester-ynone 2d
with isoquinoline N-oxide 1a, furnished only one product, 3aa,
and no other regioisomers (3ad, 3aw, 3ax) were detected,
providing the basis for the development of highly selective C−
C, CC, and C−H cleavage protocols with different ynone
units.
To demonstrate the utility of annulation products obtained
in this C−C, CC, and C−H cleavage protocol, we focused
on the photophysical property. These unique trisubstituted
indolizines showed high fluorescence in aqueous solutions,
which renders them promising for fluorescence imaging in
living cells. (See the SI.)
To shed light on the reaction mechanism, we performed a
number of experiments (Scheme 5). First, upon treatment with
radical scavengers, such as butylated hydroxytoluene (BHT),
TEMPO, or 1,1-diphenylethylene (DPE), no obvious decrease
in the reaction efficiency took place, which rules out the radical
pathway (Scheme 5A). Second, by omitting CuII from the
system, the C2−C−H alkenylation occurred, delivering the
diketone 4 along with a minor amount of monoketone 5
(Scheme 5B). Next, compound 4 was employed to react with
ynone 2a and successfully afforded 3ba in 82% yield (Scheme
5C). Moreover, compound 5 also proved to be competent to
give 3ba in 87% yield; however, it was practically unreactive in
the absence of CuII (Scheme 5D). These experimental results
provide strong evidence supporting 4 and 5 as key
intermediates. Finally, isotope-labeling experiments employing
ynone 18O-2r as the reaction partner led to the product 18O-
3br′ as well as 18O-3br (Scheme 5E), which shows that the O
atom of N-oxide successfully moved into the desired indolizine
in a 1,3-shift. (See the SI for details.)
groups with diverse electronic properties, such as methyl
(3ca), methoxy (3da, 3ga), and chloro (3ea), and including
highly valuable handles for further transformation, such as
bromo (3fa), ester (3ha), and polyhalogenated moieties (3ia),
were all found to be successfully accommodated in this newly
established C−C, CC, and C−H cleavage protocol.
Gratifyingly, when the sensitive pyridine ring was modified
with electron-donating (3ja) and electron-withdrawing groups
(3ka), this chemistry still worked smoothly to construct the
desired products in 71 and 65% yields. The structure of 3ga
was unambiguously confirmed by the X-ray crystallographic
analysis. However, in the current stage, the simple pyridine N-
oxide was not compatible, probably due to the more stable
aromatic system.
According to the previously discussed results and literature
precedents,17 a tentative mechanism for this unprecedented
C−C, CC, and C−H cleavage protocol is proposed
(Scheme 6). The reaction is initiated by a [3 + 2] cyclization
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Letter
entry into very useful indolizine scaffolds. Mechanistic studies
support a domino process involving a cascade C−H activation,
C−C cleavage, nucleophilic cyclization, and oxidative aroma-
tization. Further studies on the utility and applications of this
new methodology to unreactive bonds are currently ongoing in
our laboratory.
Scheme 5. Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00371.
Experimental procedures and spectral data (PDF)
Accession Codes
CCDC 2044939 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.
AUTHOR INFORMATION
Corresponding Authors
■
Jiang Nan − Shaanxi Key Laboratory of Chemical Additives
for Industry, College of Chemistry and Chemical Engineering,
Shaanxi University of Science and Technology, Xi’an 710021,
China; orcid.org/0000-0001-5570-6834;
Scheme 6. Proposed Mechanism
Email: nanjiang@sust.edu.cn
Michal Szostak − Shaanxi Key Laboratory of Chemical
Additives for Industry, College of Chemistry and Chemical
Engineering, Shaanxi University of Science and Technology,
Xi’an 710021, China; Department of Chemistry, Rutgers
University, Newark, New Jersey 07102, United States;
orcid.org/0000-0002-9650-9690;
Email: michal.szostak@rutgers.edu
Authors
Jiawen Zhang − Shaanxi Key Laboratory of Chemical
Additives for Industry, College of Chemistry and Chemical
Engineering, Shaanxi University of Science and Technology,
Xi’an 710021, China
Yan Hu − Shaanxi Key Laboratory of Chemical Additives for
Industry, College of Chemistry and Chemical Engineering,
Shaanxi University of Science and Technology, Xi’an 710021,
China
Chao Wang − Shaanxi Key Laboratory of Chemical Additives
for Industry, College of Chemistry and Chemical Engineering,
Shaanxi University of Science and Technology, Xi’an 710021,
China
Tingting Wang − Shaanxi Key Laboratory of Chemical
Additives for Industry, College of Chemistry and Chemical
Engineering, Shaanxi University of Science and Technology,
Xi’an 710021, China
Weitao Wang − Shaanxi Key Laboratory of Chemical
Additives for Industry, College of Chemistry and Chemical
Engineering, Shaanxi University of Science and Technology,
Xi’an 710021, China; orcid.org/0000-0003-3191-3980
Yangmin Ma − Shaanxi Key Laboratory of Chemical
Additives for Industry, College of Chemistry and Chemical
Engineering, Shaanxi University of Science and Technology,
Xi’an 710021, China
between N-oxide 1b and ynone 2p to give the five-numbered
product A. Subsequently, the formed isoxazoline undergoes
N−O ring-opening and a 1,4-proton shift to produce enol-
bonded product 4a, which undergoes C−C bond cleavage via
the retro-Claisen reaction to furnish 5a or 5b. The Michael
addition adduct B is formed from the reaction of 5a with the
second unit of ynone 2p, followed by nucleophilic addition to
give D, driven by the acidity of CuII. Finally, a sequential 1,3-
proton shift/oxidation occurs, leading to the construction of
indolizine 3bp and the concomitant regeneration of CuII. The
alternative O-transfer product 3bp′ is obtained from 5b via the
analogous pathway.
In conclusion, a new copper-catalyzed process through the
selective cleavage of sigma and triple C−C and C−H bonds
using two ynone units has been developed. The method
represents the first example of a three-component coupling
combining C−H activation with C−C and CC bond
cleavages in a single chemical operation and serves as a direct
Complete contact information is available at:
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Letter
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https://pubs.acs.org/10.1021/acs.orglett.1c00371
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the NSFC (21801159),
the China Postdoctoral Science Foundation (2018M640944),
and the Natural Science Foundation of Shaanxi Province of
China (2019JQ-776, 2020JQ-705).
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