Light-Driven Intramolecular C?N Cross-Coupling via a Long-Lived Photoactive Photoisomer Complex

Article abstract of DOI:10.1002/anie.201906112

Reported herein is a visible-light-driven intramolecular C?N cross-coupling reaction under mild reaction conditions (metal- and photocatalyst-free, at room temperature) via a long-lived photoactive photoisomer complex. This strategy was used to rapidly prepare the N-substituted polycyclic quinazolinone derivatives with a broad substrate scope (>50 examples) and further exploited to synthesize the natural products tryptanthrin, rutaecarpine, and their analogues. The success of gram-scale synthesis and solar-driven transformation, as well as promising tumor-suppressing biological activity, proves the potential of this strategy for practical applications. Mechanistic investigations, including control experiments, DFT calculations, UV-vis spectroscopy, EPR, and X-ray single-crystal structure of the key intermediate, provides insight into the mechanism.

Full text of DOI:10.1002/anie.201906112

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Light-driven intramolecular C-N cross-coupling via a long-lived
photoactive photoisomer complex
Authors: Ke Zheng, Dong Jing, Cong Lu, Zhuo Chen, Songyang Jin,
Lijuan Xie, Ziyi Meng, and Zhishan Su
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201906112
Angew. Chem. 10.1002/ange.201906112
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http://dx.doi.org/10.1002/ange.201906112

10.1002/anie.201906112
Angewandte Chemie International Edition
RESEARCH ARTICLE
Light-driven intramolecular C-N cross-coupling via a long-lived
photoactive photoisomer complex
Dong Jing#, Cong Lu#, Zhuo Chen, Songyang Jin, Lijuan Xie, Ziyi Meng, Zhishan Su and Ke Zheng*
Abstract: We report herein a visible-light-driven intramolecular C-N
cross-coupling reaction under mild conditions (metal & photocatalyst
free, at room temperature) via a long-lived photoactive photoisomer
complex. This strategy is applied by rapidly preparing the N-
substituted polycyclic quinazolinone derivatives with
a broad
substrate scope (>50 examples) and further exploited to synthesize
the natural products tryptanthrin, rutaecarpine, and their analogues.
The success of gram-level synthesis and solar-driven transformation,
as well as promising tumor-suppressing biological activity, proves the
potential of this strategy for practical applications. Mechanistic
investigation, including control experiments, DFT calculations, UV-vis
spectroscopy, EPR, and X-ray single-crystal structure of the key
intermediate, provides insight into the mechanism. We expect this
report will provide new opportunities to perform photoredox
transformations under more environmentally friendly photocatalyst-
free conditions.
Introduction
Over the past decade, the field of photochemistry has attracted
considerable attention from the chemistry community for the
development of sustainable bond-forming platforms.[1] Visible-
light photoredox catalysis has been proven to be a powerful and
environmentally friendly tool to initiate a variety of organic
reactions.[2] However, due to the weak interaction of simple
organic molecules with visible light, most synthetic strategies rely
upon the use of photoredox catalysts (PCs), such as Ru-
complexes,[3] Ir-complexes,[4] organic dyes,[5] as well as other
photosensitizers.[6] Most recently, the Melchiorre group and other
groups developed a visible-light-induced organic reaction that
relied on the formation of EDA complex[7,8] or excited state of
Scheme 1. a) Photoactive EDA Complexes as Photosensitizers; b)
Photoisomerization in Organic Synthesis; c) C-N Bond Formation via Long-lived
Photoactive Photoisomer Complexes.
delivery,[12] sensing,[13] fluorescent probes and photoregulated
biological functions.[14] The unique chemical property of
photochromic units is their ability to reversibly transform between
colored and colorless states upon light irradiation.[15] This offers
an opportunity to attempt to enable photoexcitation with visible
light, even though starting molecules have no absorbance in the
visible region. Actually, photoisomerization of suitable organic
molecules is an important strategy in photochromism, which has
been used in photochemical synthesis for more than 50 years.[16]
organocatalytic intermediates[2e,9]
,
which enabled radical
transformations to develop under photocatalyst-free conditions
(Scheme 1a).
Since first reported by Lifschitz in 1919,[10a] photochromism[10]
has attracted considerable attention for its wide application in
materials and life science, such as data storage,[11] cargo
As
a
representative, the highly reactive hydroxy-o-
quinodimethanes B, generated upon photoenolization of 2-alkyly
benzophenones A, have been well studied in various fields.[17] In
fact, since Yang and Rivas’s work in 1961, there have only been
a small number of reports (including [4+2]-cycloaddition, Michael
addition, trifluoromethylation, and CO2-carboxylation) utilizing the
photochemical properties of photoisomers B in organic synthesis
(Scheme 1b).[18] Most recently, the Melchiorre and Bach groups
have described that the transformation of the photoisomers B
could be performed with an enantioselective approach.[19] As far
as we know, one of the major issues limiting the application of this
versatile intermediate is the characteristically short lifetime of
[*]
Prof. K. Zheng, D. Jing, C. Lu, S. Jin, L. Xie, Z. Meng, Z. Su
Key Laboratory of Green Chemistry & Technology, Ministry of
Education, College of Chemistry, Sichuan University, Chengdu
610064, P. R. China
E-mail: kzheng@scu.edu.cn
Z. Chen
Shanghai Key Laboratory of New Drug Design, School of Pharmacy,
East China University of Science and Technology, Shanghai
200237, P. R. China Department
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
[#]
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Angewandte Chemie International Edition
RESEARCH ARTICLE
Table 1: Screening of the Reaction Conditions[a]
photoisomers, which quickly and efficiently convert back to the
20]
starting molecule.[18d,
Early in 1977, the Wirz group
demonstrated that the unstable photoisomers could be stabilized
by using hydrogen-bond acceptor solvents, which might raise its
possibility for the application in organic synthesis.[21] Moreover,
Jacobsen and other chemists[22] have shown that organocatalysts
can accelerate reactions via hydrogen-bonding with substrates.
Inspired by these pioneering works, we hypothesized that in the
presence of a suitable catalyst (hydrogen-bonding acceptor/
donor) the coordination of the catalyst to the unstable
photoisomer might retard the intramolecular hydrogen back-
transfer, thus affording a long-lived complex (B...Cat, Scheme 1b).
If so, it should be possible to design a photo-chemistry processing
system from a long-lived photoactivate complex.
Quinazolinone is an attractive scaffold which plays an extensive
role in pharmaceutical chemistry and provides a privileged
structure in medicinal chemistry.[23] The intramolecular C-N cross-
coupling reaction has proven to be an efficient strategy for the
synthesis of such species.[24] In particular, Toste and Sigman
reported an asymmetric synthesis of quinazolinone derivatives by
an intramolecular C-N bond formation using chiral triazole-
containing phosphate anions as catalysts, wherein a bidentate
binding model was proposed for the interaction of the catalyst and
reactive intermediate through a multidimensional correlation
analysis.[25] In this report, we reveal that a long-lived photoactivate
photoisomer can, in fact, trigger a photochemical catalytic radical
process that enables intramolecular C-N cross-coupling reactions
with high yields under irradiation of visible light. Using this strategy,
more than 50 fused N-substituted polycyclic quinazolinone
derivatives are constructed under mild conditions. Notably, most
of these represent new chemical entities and have never been
reported before. This study offers the demonstration of using a
long-lived photoactivate photoisomer in synthetic applications.
entry
variation from the "standard conditions"
t (h)
yield (%)[b]
1
2
3
4
5
6
7
8
9
None
K2HPO4 instead of 3c
3a instead of 3c
3b instead of 3c
without 3c
2
94
NR
43
10
10
10
24
6
52
trace
86
4a instead of 4b
without 4b
10
10
10
68
under N2
NR
trace
without light
[a]Reaction conditions: (0.075mmol) 1a, solvent (0.5 mL), air, irradiation
with 10 W purple LED (395 nm) at rt. [b]Isolated yield. (R)-BPA = (R)-(-)-
1,1'-Binaphthyl-2,2'-diyl hydrogenphosphate.
yield for the desired product 2a (94% yield; Table 1, entry 1).[26] It
is worth noting that using (R)-BPA 3c was critical for achieving the
high yield. Lower yields were observed when using K2HPO4,
H3PO4 3a, or diphenylphosphinic acid 3b as catalysts (Table 1,
entries 2-5). A brief survey of solvents showed that the dioxane
could give the best result (more details see SI, Table S3). A
reducing agent was added to inhibit the oxidation by-product and
pinacolborane 4b proved to be the most effective at facilitating
transformation (Table 1, entries 6-7). The control experiments
indicated that O2 and light were crucial for this reaction (entries 8-
9).
During our investigations, we noticed that a marked yellow color
appeared when the colorless solution was under irradiation for 30
min. As shown in Scheme 2a, the UV-vis absorption spectra
showed that both (R)-BPA 3c (curve a) and 1a (curve b), as well
as the combination of them (curve c), displayed no absorbance
around 395 nm. Therefore, this showed the possibility that the
substrate and (R)-BPA 3c worked as a photosensitizer, or that the
Results and Discussion
Reaction Optimization. Scheme 1c depicts our design for
utilizing the photoactivity of the long-lived photoisomer complex.
First, photoirradiation of the starting material 2-aminobenzamide
1 forms the highly-energetic colored photoisomer I via the Norrish
Type II photoisomerization. We envisioned that the newly-formed
short-lived photoisomer I could be stabilized by the coordination
of the phosphoric acid via hydrogen bonding, creating the
photoisomer complex II (Supported by the results of the DFT
calculation; for more detail see SI). The resulting long-lived
photoisomer complex II might induce a SET process, affording the
contact radical pair III. Finally, the N-substituted polycyclic
quinazolinone products 2 was produced by the intramolecular C-
N cross-coupling.
To evaluate the feasibility of this concept, the 2-
(phenylamino)benzamide 1a was selected as the model substrate
for demonstrating the practicability of intramolecular C-N cross-
coupling reactions under irradiation by 10 Watt, 395 nm light.
Initial optimization studies revealed that using a catalytic amount
of phosphoric acid ((R)-BPA 3c as a catalyst with 2 equiv. PinBH
as a reductant in dry 1,4-dioxane) under irradiation of purple LED
(395 nm) for 2 hours in the ambient atmosphere gave the best
Scheme 2. a) UV−Vis Absorption Spectra. All the experiments were carried out
under 5×10-4 M; b) Reaction Profile.
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10.1002/anie.201906112
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RESEARCH ARTICLE
Table 2: Substrates Scope for the Synthesis of N-substituted Quinazolinone Derivatives[a]
[a]Reactions were performed with substrate 1 (0.075 mmol), 3c (0.0075 mmol, 10 mol%), 4b (0.15 mmol, 2.0 equiv), 0.5 mL dioxane. The reaction
mixture was stirred under 10 W LED (395 nm) at rt. Isolated yield (The average of at least two independent experiments). [b]Without 4b.
formation of EDA complex was excluded. Compared to no-color-
change and no-detected red-shift with the mixture of 1a and 3c
under dark conditions for 30 minutes, when the mixture was
irradiated by light for 30 minutes (curve e) a significant red-shift
and a new tailing band from 380 to 420 nm appeared. These
results indicated that the long-lived photoactivate photoisomer
complex II might be generated under the irradiation of light, which
was consistent with the mechanism proposed in Scheme 1c. The
reaction profile in Scheme 2b further lent support to the
hypothesis that the formation of the photoactivate photoisomer
complex II happens during the reaction course. The time-
dependent conversion curve of 2a illustrates that the
transformation rate was slow in the initial stage (first ten minutes)
and increased sharply after 20 minutes along with a remarkable
color change (from colorless to a marked yellow), which is
probably due to the low conversion of colored photoactive species
in the initial stage and the accumulation of them after a period of
irradiation under light. Moreover, as the reaction progresses, the
yellow solution faded and eventually turned to a pale-yellow,
suggesting that these colored photoactive species were the key
intermediates in the catalytic cycle, and consuming them also
accompanied the generation of the product 2a.
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Substrate Scope and Synthetic Applications. Next, with
optimal conditions in hand, the substrate scope was extended. As
summarized in Table 2, the reaction displayed a broad scope with
2-aminobenzamide 1 and excellent yields were achieved (up to
99% yield). The results indicated this method exhibited excellent
functional group tolerance. A wide variety of 2-aminobenzamide
bearing different substituents (R1 or R2), including F, Cl, Br, Me,
OMe, CF3, and OH on benzene rings A & B, had been
successfully applied to the reaction to produce the desired
products with moderate to excellent yields in less than 5 hours (up
to 98% yield, 2a-2r). This demonstrated the high efficiency of this
protocol. The structure of the product was further confirmed by X-
ray diffraction analysis of 2i. To our delight, for N-aryl substituted
substrates, a wide range of functional groups (R3) at different
positions on benzene ring C was also well tolerated, affording
cyclization products in high to excellent yields (up to 99% yield,
2s-2ab). However, the substrate 1z with nitro group substituent at
the 4-position gave lower yield in some cases. We were also
pleased to discover that N-alkyl substituted substrates 1ac and
1ad were also decently tolerated, giving the corresponding
products in moderate yields. However, for the substrates with
substituted on the amino, the dealkylated products 8a were
obtained as main products. Similar investigations were set up for
benzene ring D. The substrates with methyl or ester group
substituted on ring D performed well, finishing the corresponding
products in excellent yields (2ae and 2af). To our surprise, the
substrates with a methyl group at the reactive site also went
smoothly, furnishing the product with a quaternary carbon center
in 87% yield (2ag). Additionally, the corresponding isoindoline
product (2ah) could be obtained in good yield under optimal
conditions.
To further evaluate the potential of this strategy, we applied it
to the synthesis of the natural product rutaecarpine’s analogues.
A series of benzamides with tetrahydro-1H-pyrido[3,4-b]indoleyl
(5a-5f) were proven suitable for this transformation as highlighted
in Table 3, and the corresponding N-substituted analogues (6a-
6f) were produced with high yields in one and a half hours.
Moreover, the benzamides with N-methyl indoleyl 5g and
thiopheneyl 5h were successfully subjected to the reaction, giving
the desired products 6g and 6h with good to high yields. It should
be noted that most of these fused N-substituted polycyclic
quinazolinone derivatives (2 and 6) represent new chemical
entities.
Encouraged by the above results, we further applied this
system to the cyclization of 2-aminobenzamides 7 and furnished
the corresponding products 8a-8f in high yields without using the
reductant pinacolborane (Table 4). Notably, the natural products
tryptanthrin, rutaecarpine, and their analogues (8g-8i) were
achieved in up to 82% yields. This strategy proved to be an
efficient and easy way to produce these valuable natural products
and their analogues. Furthermore, the synthetic utility of this
protocol was fully demonstrated by the gram-level synthesis and
the product 2a was obtained with 95% yield in 1.2 hours. With
solar being a clean and renewable energy source,[27] results also
showed that this transformation could also be driven by sunlight
with 86%, thereby demonstrating the potential to make this
strategy environmentally friendly (more detail see SI, Scheme S1).
Table 3. The Synthesis of N-substituted Rutaecarpine Analogues[a]
Biological activity. To demonstrate the biological application of
this strategy, the obtained polycyclic quinazolinones were
assayed for growth inhibitory activities on human cancer cell lines
H3122 (lung cancer), MDA-MB-231 (breast cancer), and RS4;11
(leukemia) using the CCK8 assay. Most of them exhibited anti-
tumor effects against these human cancer cell lines (more data
see SI). Interestingly, compared to quinazolinone 8a, significant
improvement of anti-tumor activity was observed for the new N-
substituted polycyclic quinazolinone scaffolds 2a and 6a.
Introduction of a methoxy group on ring B (compound 2o) led to
H3122 (IC50 = 0.31 μM), and RS4;11 (IC50 = 0.05 μM) cell lines.
These preliminary results suggest that these new N-substituted
polycyclic quinazolinone scaffolds have remarkable medicinal
potential in oncology due to their promising features as anti-tumor
candidates. Further structural optimization and SAR of these new
scaffolds are currently in progress.
[a]Reactions were performed under standard conditions. Isolated yield (The
average of at least two independent experiments).
Table 4. Substrates Scope for 2-Aminobenzamides 7[a]
Table 5. In Vitro Antitumor Activity of the Polycyclic Quinazolinones (IC50, μM)
Compounds
MDA-MB-231
H3122
>100
10.72
0.31
RS4;11
>100
2.23
GES-1
>100
50.3
8a
>100
2a
14.64
[a]Reactions were performed with substrate (0.075 mmol), 3c (0.0075
mmol, 10 mol%), 0.5 ml dioxane. The reaction mixture was stirred under
10 W LED (395 nm) at rt. Isolated yield (The average of at least two
independent experiments).
2o
6a
0.40
0.05
>100
>100
58.4
0.46
0.33
0.12
Evodiamine
0.52
0.41
0.08
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RESEARCH ARTICLE
Mechanistic Studies. Several control experiments were
performed to gain insights into the nature of this photochemistry
strategy. Our proposed mechanism utilizes long-lived
photoisomer complexes that are stabilized by the coordination of
the ligand BPA via hydrogen bonding (Scheme 1c) as critical
intermediates. First, we wanted to verify the mechanics of the
hydrogen bonding. The results showed that for the substrates 9
without carbonyl group under standard conditions (Scheme 3a)
no cyclization products were observed. Also, NMR spectroscopy
of the mixture of 1a and 3c revealed that both the NH group and
carbonyl group of the 1a have H-bonding interactions with 3c,
which was consistent with the mechanism proposed in Scheme
1c (More detail see SI, Scheme S7). The results of the control
experiments indicated that the absence of either light or O2
completely suppressed the reaction (Table 1, entries 8 & 9).
Moreover, when the reaction proceeded in the absence of both
(R)-BPA and pinacolborane, moderate conversion of 1a with
oxidation products (10 & 11) were observed, even with the
reaction time extended to 48 hours (Scheme 3b). These results
suggested that the formation of a photoactive photoisomer
complex followed by the activation of O2 was necessary to initiate
the photochemistry process. When the reaction was performed in
the presence of the photocatalysts (such as Eosin Y, TPP or
Ru(bpy)3Cl2), which produced the singlet oxygen through energy
transfer process,[28] low yields were obtained (more detail see SI,
Table S8). These results indicate that the excited singlet oxygen
could not trigger this photochemical catalytic coupling process
and that the pathway including the formation of a radical pair via
the SET process was more likely a part of this reaction. Besides
the evidence from the UV-vis absorption spectra and the reaction
profile in Scheme 2, further support for the formation of the long-
lived photoactivate photoisomer complex came from the
phenomenon of light on/off experiments. A marked yellow solution,
which was formed via the irradiation under light for 30 minutes,
would turn back to colorless along with a disappearance of the
red-shift under dark condition for two hours (more detail see SI,
Scheme S3).
To further verify the mechanism of this method, the unstable
key intermediate 10 (colorless) and oxidation product 11 (light
yellow)[29] were carefully isolated from the reaction mixture by
chromatography at a low temperature (-20 ℃). The most infusive
result was from the structural identification of the unstable
hydroperoxide intermediate 10 (grown by slow evaporation of the
solvent at -15 ℃ and under the dark conditions of a glovebox) by
the single-crystal X-ray diffraction analysis, which provided direct
evidence for the formation of hydroperoxide as a key intermediate
in the catalytic cycle. Moreover, the pH-dependent intermediate
10 could be transformed to the final product 2a with quantitative
yield within five minutes in the presence of (R)-BPA only, with no
need for light, O2, or pinacolborane (Scheme 3c). These results
indicated that the (R)-BPA played a key role in the reaction
process, either by stabilizing the photoactive photoisomer or by
accelerating the cyclization step. Moreover, the oxidation product
11 could be easily transformed to product 2a by adding
pinacolborane as a reductant under standard conditions (Scheme
3d). That is why the increased yield was obtained with adding
pinacolborane (from 68% to 94%; Table 1, entry 6). In addition,
when radical inhibitor TEMPO (2,2,6,6-tetramethylpiperidine-1-
oxyl) was added to this reaction, less than 5% 2a was obtained.
The radical capture product was detected by HRMS, and the
superoxide radical anion was confirmed by EPR spectroscopy
(see SI, Scheme S5). This all suggests a radical process was
involved in this reaction.
Scheme 4. Proposed Mechanism
On the basis of the above observations and reported
literature,[21, 30] a possible mechanism is presented in Scheme 4.
This photocatalyzed intramolecular C-N cross-coupling reaction
is initiated by a photoisomerization of 1 upon irradiation with
visible light, thereby producing the photoactivate photoisomer I,
which displays obvious absorbance around 395 nm and has a
Scheme 3. Control Experiments
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10.1002/anie.201906112
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RESEARCH ARTICLE
short lifetime. The long-lived photoisomer complex II is generated
by the coordination of (R)-BPA 3c via hydrogen bonding, which
can induce the SET process by irradiation of visible light to
generate the radical pair III. The resulting superoxide radical
anion O2•− abstracts a hydrogen atom from the intermediate III to
produce the amino radical IV, followed by intramolecular 1,6-HAT,
thereby generating the carbon-centered radical V. Then, the
radical recombination of V and HO2 form the key intermediate
hydroperoxide VI, which is easily converted to the iminium ion VII
under acidic conditions provided by Brønsted acid 3c (via a
Keywords: visible light • photoisomer • metal- and photocatalyst-
free reaction • quinazolinones derivatives • biological activity
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subsequent
pH-dependent
equilibrium
under
acidic
conditions).[31] Finally, the polycyclic quinazolinone product is
formed through intramolecular nucleophilic addition with the
release of H2O2. As an alternative pathway, the oxidation
byproduct VIII forms hydroperoxide VI and is efficiently converted
to product under standard conditions.
[3]
[4]
Conclusion
In summary, we have developed a novel, visible-light-mediated
intramolecular C-N cross-coupling reaction via a long-lived
photoactive photoisomer complex. A series of fused N-substituted
polycyclic quinazolinone derivatives, as well as their natural
products, were synthesized under mild conditions. Moreover, this
study confirmed the structure of a hydroperoxide intermediate by
the single-crystal X-ray characterization, which provided a
shortcut to significant insight into the mechanism. It should be
noted that, the success of gram-level synthesis and the potential
of solar-driven transformation makes this approach very
promising with its environmental and economical applications.
Our laboratory continues to explore the biological activity
capabilities of these new compounds for oncological medicinal
applications using asymmetric synthesis.
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Experimental Section
Experimental Details. To an oven-dried quartz tube (10 mL) was charged
with 0.5 mL dry 1,4-dioxane, 0.075 mmol 1a (24.3 mg), 3c 10 mol % (2.6
mg), 4b 2.0 equiv (22.0 uL), then closed under air. Then put the quartz
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certain time. After the reaction was completed, the product was directly
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Acknowledgements
We thank the National Natural Science Foundation of China (Nos.
21602142), and Fundamental Research Funds for the Central
Universities. We thank the Xiaoming Feng laboratory (SCU) for
access to equipment. We also thank the comprehensive training
platform of the Specialized Laboratory in the College of Chemistry
at Si-chuan University for compound testing. We appreciate
valuable suggesttions from Prof. J. Chruma (Sichuan university).
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Entry for the Table of Contents
RESEARCH ARTICLE
Dong Jing#, Cong Lu#, Zhuo Chen+,
Songyang Jin, Lijuan Xie, Ziyi Meng,
Zhishan Su and Ke Zheng*
Page No. – Page No.
Light-driven intramolecular C-N cross-
coupling via a long-lived photoactive
photoisomer complex
Text for Table of Contents
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