Palladium-catalyzed tandem C-C activation/cyclization induced by carbopalladation of functionalized nitriles: Synthesis of benzo dipyrromethenes

Article abstract of DOI:10.1021/acs.orglett.0c02478

A palladium-catalyzed carbon-carbon bond activation-initiated reaction of 2-(3-phenyloxiran-2-yl)benzonitriles with arylboronic acids is reported. Multiple chemical bonds were cleavaged and reconstructed via β-carbon elimination in this reaction, enabling the construction of valuable benzo-fused dipyrromethenes that are difficult to prepare by other methods. Additionally, a series of benzannulated boron dipyrromethenes are synthesized and show practical significance in terms of expanding the applications and types of fluorescent materials. The proposed mechanism is supported by preliminary mechanistic experiments.

Full text of DOI:10.1021/acs.orglett.0c02478

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Letter
Palladium-Catalyzed Tandem C−C Activation/Cyclization Induced
by Carbopalladation of Functionalized Nitriles: Synthesis of Benzo
Dipyrromethenes
Lepeng Chen,⊥ Julin Gong,⊥ Yetong Zhang, Yinlin Shao,* Zhongyan Chen, Renhao Li, and Jiuxi Chen*
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ABSTRACT: A palladium-catalyzed carbon−carbon bond activation-initiated reaction of 2-(3-phenyloxiran-2-yl)benzonitriles with
arylboronic acids is reported. Multiple chemical bonds were cleavaged and reconstructed via β-carbon elimination in this reaction,
enabling the construction of valuable benzo-fused dipyrromethenes that are difficult to prepare by other methods. Additionally, a
series of benzannulated boron dipyrromethenes are synthesized and show practical significance in terms of expanding the
applications and types of fluorescent materials. The proposed mechanism is supported by preliminary mechanistic experiments.
methene is an ideal monoanionic bidentate ligand and is
n the pursuit of efficient processes for the synthesis of target
Imolecules through environmentally benign and economic widely used as a boron-coordinated complex to synthesize
BODIPY, many examples of which are commercially available.
The main synthetic approach for dipyrromethenes involves
nucleophilic substitution of an aldehyde with pyrroles. Various
methods, which include metal-catalyzed coupling, nucleophilic
substitution, and photochemical strategies, have been
developed by the modification of the ready-made BODIPY
core to synthesize BODIPY derivatives with a long absorption/
emission wavelength.10 The most commonly used strategies
include ethynylaryl, aryl, and styryl substitution on the
BODIPY cores11 as well as aromatic ring fusion12 to expand
the conjugated system of BODIPY. Replacing the meso-carbon
atom with an aza-nitrogen atom to form an aza-BODIPY is
another common method.13 Among these, benzo-fused
BODIPYs usually possess more favorable fluorescence
characteristics. Currently, the main approaches for synthesizing
benzo dipyrromethenes include: (1) the retro-Diels−Alder
reaction14a,b of norbornane-derived pyrroles developed by Ono
et al. (Scheme 1c) and (2) nucleophilic substitution of 1-
formylisoindoles with pyrroles (Scheme 1d).14c These
methods suffer from several drawbacks such as low yield,
routes, the catalytic cascade reactions have attached consid-
erable interest as a powerful strategy.1 Metal-catalyzed
carbon−carbon activation is one of the most desirable
reactions because of the limited availability of effective
methods to cleave such thermodynamically stable bonds.2
Tremendous efforts to overcome this challenge have been
made so far, which mainly rely on the use of directing groups
or strained structures.3 Recently, transition-metal-catalyzed
transformations of unstrained C−C single bonds using
directing groups have attracted considerable interest because
they enable excellent control of chemo- and regioselectivity.4−7
For example, C−C bond cleavage of secondary and tertiary
alcohols through β-carbon elimination of transition metal
alcoholate intermediates has been successfully applied in the in
situ generation of aryl metal species for successive reactions
such as C−C bond formation (Scheme 1a).5a,d However, an
exploration of C−C activation-initiated cascade reactions that
involve the cleavage and reconstruction of multiple chemical
bonds for the synthesis of complex compounds is still required.
Although transition-metal-catalyzed Suzuki-type cross-coupling
of epoxides with boronic acids has been well developed, these
transformations exclusively provide alcoholic products
(Scheme 1b).8
Received: July 28, 2020
Boron dipyrromethenes (BODIPYs) are widely used as
fluorescent labeling reagents, laser dyes, chemosensors, photo-
sensitizers, and components of optoelectronic devices owing to
their tunable redox and photophysical properties.9 Dipyrro-
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of C−C single bonds, which is hard to achieve in the
construction of complex frameworks (Scheme 1e).
Scheme 1. Reaction Design for the Construction of Benzo
Dipyrromethenes
With the above-mentioned idea in mind, we initiated our
investigation. It was found that the reaction of (2,6-
dimethylphenyl)boronic acid (1a) with 2 equiv of 2-(3-(4-
(trifluoromethyl)phenyl)oxiran-2-yl)benzonitrile (2a) in
THF/H2O = 1:1 (3 mL) in the presence of Pd(CF3COO)2
catalyst (10 mol %), trifluoroacetic acid (TFA) (3 equiv), KF
(2 equiv), and 2,2′-bipyridine (20 mol %) at 110 °C for 24 h
under air atmosphere afforded the desired product (Z)-3-(2,6-
dimethylphenyl)-1-((3-(2,6-dimethylphenyl)-2H-isoindol-1-
yl)(4-(trifluoromethyl)phenyl)methylene)-1H-isoindole (3aa)
in 84% yield (see the Supporting Information Table S1). The
structure of 3aa was confirmed by X-ray crystallographic
analysis.
With the optimized conditions in hand, the generality of this
reaction with respect to various 2-(3-phenyloxiran-2-yl)-
benzonitriles was first investigated. As shown in Scheme 2,
better yields were notably obtained when electron-withdrawing
groups were attached to the aromatic ring Ar1. For example,
when a substrate bearing both 4-methyl and 3-nitro on the Ar1
was examined, 3ad was obtained in a low yield compared with
3ab and 3ac (Scheme 2, entries 1−3). Comparison of 3ae, 3af,
3ag, 3ah, 3ai, and 3aj with 3ak also showed that better
reaction efficiency was achieved when the aromatic ring Ar1
was possessed by stronger electron-withdrawing groups
(Scheme 2, entries 4−10).
However, the use of 2-(3-phenyloxiran-2-yl)benzonitriles
with electron-donating groups on the Ar1 ring was unsuccessful
in the reaction (Scheme 2, entry 11). Next, the substituent
effect of Ar2 was investigated. Both electron-withdrawing
groups and electron-donating groups on the Ar2 ring were
applied in the reaction, which all afforded the desired products
in moderate to good yields (Scheme 2, entries 12−16). The
steric effect of the substituent had an obvious influence on the
harsh conditions, low reaction efficiency, and limited substrate
scope. Therefore, a more efficient and straightforward method
toward benzo dipyrromethenes is highly desired. Herein, we
report a novel transformation for the building of a benzo
dipyrromethene skeleton by carbopalladation of epoxy-
substituted nitriles involving the cleavage and reconstruction
a
Scheme 2. Scope of the Palladium-Catalyzed Synthesis of Benzo Dipyrromethenes
a
Conditions: 1 (0.6 mmol), 2 (0.3 mmol), Pd catalyst (10 mol %), ligand (20 mol %), acid (3 equiv), KF (2 equiv), solvent (3 mL), 110 °C, 24 h,
air, isolated yield.
B
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a
Scheme 3. Scope of the Palladium-Catalyzed Synthesis of Benzo Dipyrromethenes
a
Conditions: 1 (0.6 mmol), 2 (0.3 mmol), Pd catalyst (10 mol %), ligand (20 mol %), acid (3 equiv), KF (2 equiv), solvent (3 mL), 110 °C, 24 h,
air, isolated yield.
reaction. For example, treatment of 2r and 2s with 1a provided
a trace amount of 3ar and a yield of 24% of 3as, respectively
(Scheme 2, entries 17 and 18), possibly because of the
unfavorable insertion of Pd−Ar species into the cyano group
by the steric hindrance. However, the reaction failed to deliver
the desired product when the Ar1 group was replaced by an
alkyl substituent such as tertiary butyl (Scheme 2, entry 19).
Analogous treatment of mesitylboronic acid with various 2-(3-
phenyloxiran-2-yl)benzonitriles under the optimal conditions
also afforded 3au−3az in slightly lower yields of 39−76% than
those achieved with 1a (Scheme 2, entries 20−25).
arylboronic acids were well tolerated and afforded the desired
products 3bk−3bm in yields of 52%−66% (Scheme 3, entries
11−13). However, less bulky arylboronic acid substrates, such
as phenylboronic acid and (4-(trifluoromethyl)phenyl)boronic
acid, could not undergo such a transformation (Scheme 3,
entries 14 and 15). Finally, 2-methyl, 2,4-dimethyl, and 2,4,6-
triisopropyl arylboronic acids were explored, affording the
corresponding products 3bp−3bs in yields of 29%−47%
(Scheme 3, entries 16−19).
Next, a series of benzannulated boron dipyrromethene
molecules were synthesized, and 4ab was confirmed by X-ray
crystallographic analysis (Scheme 4). Moreover, compound
After demonstrating the generality of this intriguing
palladium-catalyzed tandem annulation reaction with respect
to 2-(3-phenyloxiran-2-yl)benzonitriles, we then switched our
attention to arylboronic acids (Scheme 3). The steric effects of
the substituents on the arylboronic acids had a significant effect
on the reaction yields. Treatment of phenylboronic acid with
2b provided 3ba in a yield of 27%, while the ortho-tolylboronic
acid afforded the corresponding product 3bb with an increased
yield of 65% (Scheme 3, entries 1 and 2). 2-Isopropyl
phenylboronic acid and (2,4,6-triisopropylphenyl)boronic acid
afforded the desired 3bc and 3bd in comparable yields of 69%
and 66%, respectively (Scheme 3, entries 4 and 5). The
electronic effect of the substituent on the arylboronic acids
influenced the reaction to some extent. For example, (4-
methoxy-2,6-dimethylphenyl)boronic acid could also take part
in the reaction, which afforded the desired 3be in a yield of
57%, which was lower than that of 3ab. Similar results were
observed for 3bg versus 3bh, 3bi versus 3aj, and 3bj versus
3ak (Scheme 3, entries 5 and 7−10). This system was also
applicable for naphthalen-1-ylboronic acid, which afforded the
naphthalen-1-yl-containing product 3bf in a yield of 70%
(Scheme 3, entry 6). We next assessed the reaction of 2a with
arylboronic acids under our standard conditions. The bulky
Scheme 4. Synthesis of Benzo-Fused BODIPYs
4az can serve as a lysosome-targeted dye with near-infrared
emission for lysosome imaging in living cells with good
biocompatibility, expanding the applications of fluorescent
materials (see the Supporting Information Figure S72−Figure
S74).
To determine whether the electronic nature of the
substituent has an influence on the catalytic transformation,
intermolecular competition experiments were conducted with
an equimolar mixture of 2-(3-phenyloxiran-2-yl)benzonitriles.
A ratio of 17:2 was obtained between 3ab and 3al after 24 h,
which suggested that an electron-deficient substituent of Ar1 is
favorable for the reaction (Scheme 5, eq 1). To gain more
C
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cleavage and reconstruction of multiple chemical bonds
through β-carbon elimination for the construction of valuable
benzo-fused dipyrromethenes that are often difficult to prepare
by traditional routes. We expect that 4az will be useful as a
valuable tool for fluorescence imaging and sensing lysosome-
related physiological processes.
Scheme 5. Mechanistic Studies
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.0c02478.
Experimental procedures, characterization data, and
NMR spectra (PDF)
mechanistic insight into this reaction, we carefully examined
the byproducts formed in the reaction (Scheme 5, eq 2). We
detected the presence of isoquinoline 3aa-1, isoindole 3aa-2,
and benzo-fused dipyrromethenes 3aa-3 without an Ar1 ring as
well as eliminated 4-(trifluoromethyl)benzaldehyde 3aa-4. The
structures of 3aa-2 and 3aa-3 were confirmed by X-ray
crystallographic analysis.
Accession Codes
CCDC 1977594, 1977734−1977735, and 1977764 contain 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 Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
Based on the above observations and previous reports,15
a
plausible reaction mechanism was proposed (Scheme 6). The
reaction proceeds by forming palladium-aryl species generated
from the transmetalation process derived from the arylboronic
acid and Pd catalyst. Next, coordination and sequential
carbopalladation of the nitrile 2a afford the imine-Pd
intermediate A. The intramolecular nucleophilic attack of the
imine-Pd species to the oxacyclopropane skeleton affords
intermediate B owing to the electronic preference of α-ring
opening. Intermediate B further undergoes β-C elimination to
produce the isoindoyl palladium intermediate C accompanied
by the liberation of aromatic aldehyde 3aa-4. The
intermolecular nucleophilic attack of intermediate C to the
cyano group of 2a affords intermediate D, which undergoes
protonation and dehydration to afford Pd species and key
intermediate alkene E. Then, another palladium-aryl species
carbopalladation of the key intermediate E affords the imine-
Pd intermediate F. Sequential intramolecular insertion of the
imine-Pd bond to the CC double bond affords intermediate
G. Finally, β-H elimination of G provides the desired product
3.
AUTHOR INFORMATION
■
Corresponding Authors
Yinlin Shao − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. China;
orcid.org/0000-0003-1935-0345; Email: shaoyl@
wzu.edu.cn
Jiuxi Chen − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. China;
orcid.org/0000-0001-6666-9813; Email: jiuxichen@
wzu.edu.cn
Authors
Lepeng Chen − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. China
Julin Gong − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. China
Yetong Zhang − College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. China
In summary, we have developed a Pd-catalyzed C−C
activation-initiated reaction of 2-(3-phenyloxiran-2-yl)-
benzonitrile with arylboronic acids. The reaction involves the
Scheme 6. Proposed Mechanism
D
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Winter, A. H.; Miller, E. W.; Weinstain, R. J. Am. Chem. Soc. 2020,
142, 4970−4974.
Zhongyan Chen − College of Chemistry & Materials
Engineering, Wenzhou University, Wenzhou 325035, P. R.
China
Renhao Li − School of Pharmaceutical Sciences, Wenzhou
Medical University, Wenzhou 325035, P. R. China;
orcid.org/0000-0003-2451-2142
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Complete contact information is available at:
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Author Contributions
⊥L.C. and J.G. contributed equally to this work
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21572162), the Natural Science Foundation of Zhejiang
Province (No. LY20B020015), and the Foundation of
Wenzhou Basic Scientific Research Project (No. G20190009)
for financial support.
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