Vinyldiazo Compounds as 3-Carbon Radical Acceptors: Synthesis of 4-Fluoroacridines via Visible-Light-Promoted Cascade Radical Cyclization

Article abstract of DOI:10.1021/acs.orglett.1c01204

Vinyldiazo reagents were developed as the radical acceptors in a visible-light-promoted sequential radical cyclization reaction, providing a mechanistically distinct pathway to achieve (3 + 3) cyclization. Using N-aryl chlorodifluoromethyl alkynyl ketoimines as the radical precursors, the reaction allows the introduction of a fluorine atom to the acridine skeleton during the construction of both the pyridine and benzene motifs from acyclic building blocks. The resulting 4-fluoroacridines exhibited pronounced fluorescent properties in the solid state.

Full text of DOI:10.1021/acs.orglett.1c01204

pubs.acs.org/OrgLett
Letter
Vinyldiazo Compounds as 3‑Carbon Radical Acceptors: Synthesis of
4‑Fluoroacridines via Visible-Light-Promoted Cascade Radical
Cyclization
Weiyu Li and Lei Zhou*
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ABSTRACT: Vinyldiazo reagents were developed as the radical
acceptors in a visible-light-promoted sequential radical cyclization
reaction, providing a mechanistically distinct pathway to achieve (3
+ 3) cyclization. Using N-aryl chlorodifluoromethyl alkynyl
ketoimines as the radical precursors, the reaction allows the
introduction of a fluorine atom to the acridine skeleton during the construction of both the pyridine and benzene motifs from acyclic
building blocks. The resulting 4-fluoroacridines exhibited pronounced fluorescent properties in the solid state.
table vinyldiazo compounds are versatile synthons in
organic synthesis and have been widely used in the
iodine atom transfer (Scheme 1b). To further explore the
synthetic utility of vinyldiazo species in radical reactions, we
envisaged that the trap of vinyl radicals by unsaturated systems
might lead to the discovery of new strategies for (3 + 3)
cyclization via fundamentally distinct routes (Scheme 1c).
Acridines have been applied in industry as pigments and
dyes for a long time.6 Acridine derivatives exhibit considerable
biological and pharmaceutical activities, such as anticancer,
antibacterial, and antimalarial.7 They have also found
applications in materials science as organic semiconductor
materials and fluorescent sensors.8 Consequently, the develop-
ment of efficient methods for the construction of this
compound class has been a significant task in heterocyclic
chemistry. Ring closures of suitable precursors to form the
pyridine skeleton are the most widely applied methods for the
preparation of acridines.9 Transition-metal-catalyzed benzan-
nulation of quinoline derivatives has also been reported.10
However, a facile method to access diversely substituted
acridines via cascade ring closures, allowing the formation of
both pyridine and benzene motifs from acyclic building blocks,
is still underdeveloped.
S
construction of carbo- or heterocyclic rings of various sizes.1
The decomposition of vinyldiazo compounds by transition
metals forms electrophilic metallo-vinylcarbenes that com-
monly serve as 3-carbon building units for (3 + n) cyclization
(Scheme 1a).2 Alternatively, vinyldiazo compounds can work
Scheme 1. Reactions of Vinyldiazo Compounds
We have previously reported a highly functionalized
difluoromethyl radical precursor,11 namely N-aryl chlorodi-
fluoromethyl alkynyl ketoimine (Scheme 2, compound 1),
which is readily prepared from ClF2CO2H, CCl4, and aniline
followed by a Sonogashira coupling with terminal alkyne.12 Its
reaction with alkenes provides a facile method for the synthesis
of gem-difluorinated fused quinolines by visible light photo-
as nucleophiles to undergo cycloadditions with electrophilic π-
bond motifs via a noncarbene route.3 Whereas most of these
cycloaddition reactions rely on dipoles as the key inter-
mediates, the use of vinyldiazo compounds in a radical
cyclization reaction has been less exploited despite its
attractiveness.4 Recently, our group reported a visible-light-
promoted radical 1,3-addition of perfluoroalkyl iodides to
vinyldiazoacetates under external photocatalyst and additive-
free conditions.5 The reaction proceeds through a radical
propagation pathway, in which the vinyl radicals generated by
the addition of Rf• to vinyldiazoacetates were terminated by
Published: May 24, 2021
https://doi.org/10.1021/acs.orglett.1c01204
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4279−4283
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Letter
a
Scheme 2. Synthesis of 4-Fluoroacridines via Cascade
Radical Cyclization
Table 1. Optimization of Reaction Conditions
3
4
b
b
entry
photocatalyst
base (equiv)
none
solvent
(%)
(%)
c
1
none
Ru(bpy)3Cl2
MeCN
MeCN
NR
37
39
55
c
2
nBu3N (0.2)/K2CO3
(2)
3
Ru(bpy)3Cl2
nBu3N (0.2)/K2CO3
(2)
MeCN
49
94
4
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
nBu3N (3)
K2CO3 (3)
Et3N (3)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
58
NR
65
71
67
56
55
60
57
43
83
74
11
69
83
5
6
7
122
80
76
iPr2NEt (3)
redox catalysis. We envisioned that the use of vinyldiazo
reagents to replace alkenes as the radical acceptors would lead
to 4-fluoroacridines. The working mechanism is shown in
Scheme 2. The addition of difluoromethyl radical A to
vinyldiazo compounds generates vinyl radical B, which
undergoes addition to C−C triplet bond of ketoimine 1
intramolecularly to give vinyl radical C. The intramolecular
homolytic aromatic substitution (HAS) of radical C, followed
by single electron oxidation and elimination of HF would
produce 4-fluoroacridine 3. Due to the higher bond
dissociation energy (BDE) of C−Cl bond, the termination of
vinyl radical B by a halogen atom transfer can be suppressed.
However enticing this proposal might appear, it was conceived
to have two major challenges: (1) How will initial radical A be
generated if less reactive C−Cl was used? (2) If photocatalyst
was employed to generate radical A, how will the background
pyrazole formation mediated by light or base be suppressed?13
Here, we report the results of our research.
8
Ru(phen)3Cl2 iPr2NEt (3)
83
9
Ir(ppy)3
iPr2NEt (3)
iPr2NEt (3)
iPr2NEt (3)
iPr2NEt (3)
iPr2NEt (3)
iPr2NEt (3)
iPr2NEt (3)
iPr2NEt (3)
iPr2NEt (3)
89
10
11
12
13
14
15
16
Ir(dFppy)3
Eosin Y
92
83
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
Ru(bpy)3Cl2
96
106
70
76
DCM
DCE
toluene
DCM
119
41
c,d
17
a
Reaction conditions: 1a (0.2 mmol), 2a (0.5 mmol), base,
photocatalyst, and solvent (1.5 mL) under the irradiation of a 5 W
b
blue LED at room temperature for 18 h. Yields of 3a and 4 were
determined by 1H NMR using 1,3,5-trimethoxybenzene as the
c
d
internal standard. 1.5 equiv of 2a. 5 mmol scale reaction, and 2a
was added in three portions.
In our previous report on radical 1,3-addition of
perfluoroalkyl iodides to vinyldiazoacetates, the initial Rf
radical was generated by forming a radical pair complex
between RfI and triplet free vinylcarbene.5 However, the direct
generation of gem-difluoromethyl A in the absence of
photocatalyst is less like due to the high dissociation energy
of C−Cl bond. As expected, when the MeCN solution of
alkynyl ketoimine 1a and ethyl vinyldiazoacetate 2a was
irradiated with a 5 W blue LED at room temperature, no
desired 4-fluoroacridine 3a was detected, while the conversion
of 2a to pyrazole was found as the major background reaction
(Table 1, entry 1). Therefore, we investigated the reaction
whereas more polar solvents such as DMSO and DMF and less
polar toluene were found to be unfavorable (Table 1, entries
12−16). In a gram scale reaction, adding 1.5 equiv of 2a in 3
portions over the course of the reaction produces 3a in the
yield of 69%, and byproduct pyrazole 4 could be minimized to
41% yield (Table 1, entry 17).
With the optimized conditions in hand (Table 1, entry 14),
the generality of this cascade radical cyclization reaction for the
synthesis of 4-fluoroacridine was explored using a variety of
alkynyl ketoimines 1b−1s and ethyl vinyldiazoacetate 2a
(Scheme 3). Initially, the effects of the substitutents at the
para-position of phenyl ring connected to the C−C triple bond
were evaluated. Substrates bearing methyl, halogen, and phenyl
groups worked well, affording the desired products 3a−3f in
71−79% yields. The reaction became sluggish when strong
electron-withdrawing nitro and electron-donating methoxy
groups were introduced (3g and 3h). The presence of a methyl
group at the meta-position and a fluoro group at the ortho-
position had no apparent effect on the reaction. When R1 was a
1-naphthyl and 3-thienyl group, the corresponding 4-
fluoroacridines 3k and 3l were obtained in the yields of 73
and 78%, respectively. It is worth mentioning that 9-
cyclopropyl-4-fluoroacridine 3m could be prepared by this
radical transformation. In addition, a terminal alkyne motif also
survived (3n), and no side product from radical addition to the
terminal CC bond was detected. Alkynyl ketoimines bearing
a substituent on the phenyl ring attached to the nitrogen atom
all reacted efficiently with 2a to give 7-bromoacridine 3o, 7-
n
using Ru(bpy)3Cl2 as the photocatalyst and Bu3N/K2CO3 as
the bases, which are the optimal conditions of our previous
report for the radical cyclization of 1a with alkenes. Although
the addition of photocatalyst and base favored the light-
mediated pyrazole formation, we observed the generation of 3a
in 37% yield (Table 1, entry 2). Increasing the amounts of 2a
to 2.5 equiv led to 3a in 49% yield, despite the yield of pyrazole
n
4 increasing to 94% (Table 1, entry 3). The use of Bu3N as
the sole base afforded 3a in 58% yield, while the replacement
n
of Bu3N by inorganic base K2CO3 shut down the reaction
i
completely (Table 1, entries 4 and 5). NEt3 and Pr2NEt gave
better yields compared with nBu3N (Table 1, entries 6 and 7).
Several photocatalysts, such as Ru(phen)3Cl2, Ir(ppy)3,
Ir(dfppy)3, and Eosin Y, were examined, but they were all
less efficient than Ru(bpy)3Cl2 (Table 1, entries 8−11).
Further inspection of the reaction conditions revealed that
dichloromethane (DCM) was the best solvent for the reaction,
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a
Scheme 3. Substrate Scope of Alkynyl Ketoimine 1
Scheme 4. Photocatalytic Radical Cyclization of Alkynyl
Ketoimine 1a with Various Vinyldiazo Compounds
a
a
All reactions were carried out under the conditions as described in
b
Scheme 3. Isolated yields. Vinyldiazo compounds were added in
three portions.
reaction of vinyl diazoketone with 1a to give 4-fluoroacridine
3ac.
a
Reaction conditions: alkynyl ketoimine 1 (0.2 mmol), ethyl
vinyldiazoacetate 2a (0.5 mmol), Ru(bpy)3Cl2 (1 mol %), and
iPr2NEt (0.6 mmol) in 1.5 mL of DCM under the irradiation of a 5 W
blue LED at room temperature for 18 h. Isolated yields.
The large conjugated systems give the potential for these 4-
fluoroacridines to show strong absorption and fluorescence
emission peaks at the long wavelengths. The absorption and
emission spectra of 4-fluoroacridines 3a, 3h, 3k, 3l, and 3r in
the solid state were shown in Figure 1a and 1b. Whereas all the
synthesized 4-fluoroacridines are essentially nonfluorescent in
solution, they showed fluorescence character under the
methoxyacridine 3p, 5,7-dichloro acridine 3p, and benzo[c]-
acridine 3r in good yields. A 7.5:1 mixture of two isomers 3s
and 3s′ was obtained in a total yield of 77% when a methyl
group was present at the meta-position, which provided two
nonequivalent sites for cyclization.
Next, we investigated the scope of vinyldiazo compounds,
which would introduce different substitutents to the 1-, 2-, or
3-position of acridines (Scheme 4). As expected, the nature of
the ester substituent has little impact on the reaction outcome.
Replacing the ethyl in the ester motif of vinyldiazoacetate with
n-butyl, allyl, and phenyl groups led to 4-fluoroacridines 3t, 3u,
and 3v in good yields (77, 76, and 74%, respectively). The use
of vinyldiazoacetates substituted at the alkenyl moiety proved
more challenging. In relation with the structure of the alkenyl
moiety, some points are remarkable: (i) the reaction is more
efficient for Cα-substituted (3z, 3aa) than for Cβ-substituted
vinyldiazoacetates (3w, 3x, and 3y); (ii) the presence of a
phenyl group at the Cβ position (3y) hampered the overall
efficiency of the reaction, which disfavored the radical addition
to the vinyl terminus of the vinyldiazoacetate; (iii) cyclic
vinyldiazoacetate was also a suitable substrate for the reaction,
producing cyclohexane-fused acridine 3ab in the yield of 63%.
Finally, we were delighted to find the electron-withdrawing
group was not limited to the ester group, as exemplified by
Figure 1. (a) Absorption spectra of 3a, 3h, 3k, 3l, and 3r. (b)
Fluorescence emission spectra of 3a, 3h, 3k, 3l, and 3r. (c) Digital
image of 3a in solid state under UV irradiation (365 nm). (d)
Fluorescence lifetime decay of 3a.
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irradiation of 365 nm UV light at room temperature. For
example, compound 3a is a faint yellow solid, which emits
green fluorescence upon UV light irradiation (Figure 1c). In
addition, the fluorescence lifetime of 3a was measured as 95.15
ns using the time-correlated single-photo counting (TCSPC)
technique (Figure 1d, for details, see the Supporting
Information).
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01204.
■
sı
Experimental details, characterization data, and NMR
spectra of all new products (PDF)
It is known that the excited state Ru2+* can be reduced to
Ru+ by accepting an electron from tertiary amine.14 The
luminescence quenching experiments demonstrated that
iPr2NEt displayed luminescence quenching of the [Ru-
(bpy)3]2+* excited state (Figure 2a). On the contrary, a
AUTHOR INFORMATION
Corresponding Author
■
Lei Zhou − School of Chemistry, Sun Yat-sen University,
Guangzhou 510006, China; orcid.org/0000-0002-8391-
8452; Email: zhoul39@mail.sysu.edu.cn
Author
Weiyu Li − School of Chemistry, Sun Yat-sen University,
Guangzhou 510006, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01204
Notes
The authors declare no competing financial interest.
Figure 2. (a) Stern−Volmer plot. (b) Time profile of photocatalytic
radical cyclization of 1a and 2a.
ACKNOWLEDGMENTS
■
We are grateful for the funds from the NSFC (Grant
21871300), the National Key Research Program of China
(Grant 2016YFA0602900), and the NSF of Guangdong
Province for Distinguished Young Scholars (Grant
2016A030306029).
decrease in [Ru(bpy)3]2+* luminescence was not observed by
adding substrates 1a (E1/2red = −1.24 V vs SCE, see Figure S6
in the Supporting Information), which indicates the oxidative
quenching of [Ru(bpy)3]2+* by 1a is less likely. Our previous
report has demonstrated that vinyldiazo compounds present
absorbance spectra in the visible region. Therefore, they were
also potential reagents to quench the excited [Ru(bpy)3]2+*.
However, the quenching ability of ethyl vinyldiazoacetate 2a is
REFERENCES
■
(1) Reviews: (a) López, E.; González-Pelayo, S.; López, L. A. Recent
Developments in Coinage Metal Catalyzed Transformations of
Stabilized Vinyldiazo Compounds: Beyond Carbenic Pathways.
Chem. Rec. 2017, 17, 312−315. (b) Cheng, Q.-Q.; Yu, Y.; Yedoyan,
J.; Doyle, M. P. Recent Developments in Coinage Metal Catalyzed
Transformations of Stabilized Vinyldiazo Compounds: Beyond
Carbenic Pathways. ChemCatChem 2018, 10, 488−496.
i
lower than that of Pr2NEt, seen by comparing the rates of
slope, revealing the electron transfer between [Ru((bpy)3]2+*
i
and Pr2NEt is still a major pathway to quench excited
photocatalyst (for details, see Figures S1−S3 in the Supporting
Information). The light “on/off” experiment disclosed that the
present radical cyclization reaction proceeded via a photoredox
catalytic mechanism, which is different from the radical-chain
propagation pathway for the radical 1,3-addition of RfI to
vinyldiazo compounds (Figure 2b).5 All of the results support
that difluoromethyl radical A was generated by the single
electron reduction of 1a by [Ru(bpy)3]+ (See Scheme S1 in
the Supporting Information for the complete mechanism).
In summary, vinyldiazo reagents were developed as the
radical acceptors in a sequential radical cyclization reaction,
which provided a mechanistically distinct pathway to achieve
(3 + 3) cyclization. Using N-aryl chlorodifluoromethyl alkynyl
ketoimines as the radical precursors, their reactions with
vinyldiazo compounds by visible light photoredox catalysis
afforded various 4-fluoroacridines in good yields. The reaction
allows the introduction of a fluorine atom to the acridine
skeleton during the construction of both the pyridine and
benzene motifs from acyclic building blocks. Additionally, the
synthesized compounds displayed a pronounced solid state
fluorescence. Because the presence of fluorine atoms on the
aromatic ring has been known to improve the thermal and
chemical stability of the acridines,15 we hope that this method
can find practical applications in medicinal chemistry and
materials science.
(2) For selected examples: (a) Marichev, K. O.; Wang, K.; Dong, K.;
Greco, N.; Massey, L. A.; Deng, Y.; Arman, H.; Doyle, M. P. Synthesis
of Chiral Tetrasubstituted Azetidines from Donor-Acceptor Azetines
via Asymmetric Copper(I)-Catalyzed Imido-Ylide [3 + 1]-Cyclo-
addition with Metallo-Enolcarbenes. Angew. Chem., Int. Ed. 2019, 58,
16188−16192. (b) López, E.; López, L. A. Synthesis of Function-
alized Cyclopentene Derivatives from Vinyldiazo Compounds and
Vinylazides through Sequential Copper-Promoted [3 + 2] Cyclo-
addition/Azide Rearrangement. Angew. Chem., Int. Ed. 2017, 56,
́
̃
5121−5124. (c) Deng, Y.; Massey, L. A.; Rodriguez Nunez, Y. A.;
Arman, H.; Doyle, M. P. Catalytic Divergent [3 + 3]- and [3 + 2]-
Cycloaddition by Discrimination Between Diazo Compounds. Angew.
Chem., Int. Ed. 2017, 56, 12292−12296. (d) Xu, X.; Doyle, M. P. The
[3 + 3]-Cycloaddition Alternative for Heterocycle Syntheses:
Catalytically Generated Metalloenolcarbenes as Dipolar Adducts.
Acc. Chem. Res. 2014, 47, 1396−1405. (e) Raj, A. S. K.; Liu, R.-S.
Gold-catalyzed [4 + 3]-Annulations of Benzopyriliums with Vinyl-
diazo Carbonyls to Form Bicyclic Heptatriene Rings with Skeletal
Rearrangement. Adv. Synth. Catal. 2020, 362, 2517−2522. (f) Raj, A.
S. K.; Liu, R.-S. Gold-Catalyzed Bicyclic Annulations of 2-
Alkynylbenzaldehydes with Vinyldiazo Carbonyls that Serve as Five-
atom Building Units. Angew. Chem., Int. Ed. 2019, 58, 10980−10984.
(3) (a) Doyle, M. P.; Yan, M.; Hu, W.; Gronenberg, L. Highly
Selective Catalyst-Directed Pathways to Dihydropyrroles from
Vinyldiazoacetates and Imines. J. Am. Chem. Soc. 2003, 125, 4692−
4693. (b) Xu, X.; Hu, W.-H.; Zavalij, P. Y.; Doyle, M. P. Divergent
Outcomes of Carbene Transfer Reactions from Dirhodium- and
4282
https://doi.org/10.1021/acs.orglett.1c01204
Org. Lett. 2021, 23, 4279−4283

Organic Letters
pubs.acs.org/OrgLett
Letter
Copper-Based Catalysts Separately or in Combination. Angew. Chem.,
Int. Ed. 2011, 50, 11152−11155. (c) Qian, Y.; Xu, X.; Wang, X.;
Zavalij, P. J.; Hu, W.; Doyle, M. P. Rhodium(II)- and Copper(II)-
Catalyzed Reactions of Enol Diazoacetates with Nitrones: Metal
Carbene versus Lewis Acid Directed Pathways. Angew. Chem., Int. Ed.
2012, 51, 5900−5903. (d) Jadhav, A. M.; Pagar, V. V.; Liu, R.-S.
Development of a Povarov Reaction/Carbene Generation Sequence
for Alkenyldiazocarbonyl Compounds. Angew. Chem., Int. Ed. 2012,
51, 11809−11813. (e) Pagar, V. V.; Liu, R.-S. Catalyzed Cyclo-
addition Reactions of Ethyl Diazoacetate, Nitrosoarenes, and
Vinyldiazo Carbonyl Compounds: Synthesis of Isoxazolidine and
Benzo[b]azepine Derivatives. Angew. Chem., Int. Ed. 2015, 54, 4923−
4926.
(4) (a) Sarabia, F. J.; Li, Q.; Ferreira, E. M. Cyclopentene
Annulations of Alkene Radical Cations with Vinyl Diazo Species
Using Photocatalysis. Angew. Chem., Int. Ed. 2018, 57, 11015−11019.
(b) Cho, Y. H.; Kim, J. H.; An, H.; Ahn, K.-H.; Kang, E. J.
Cycloaddition Reactions of Alkene Radical Cations using Iron(III)-
Phenanthroline Complex. Adv. Synth. Catal. 2020, 362, 2183−2188.
(5) Li, W.; Zhou, X.; Xiao, T.; Ke, Z.; Zhou, L. External
Photocatalyst-Free Visible Light-Promoted 1,3-Addition of Perfluor-
oalkyl Iodides to Vinyldiazoacetates. CCS Chem. 2021, 3, 794−805.
(6) Geddes, C. D. Optical Thin Film Polymeric Sensors for the
Determination of Aqueous Chloride, Bromide and Iodide Ions at
High pH, Based on the Quenching of Fluorescence of Two
Acridinium. Dyes. Dyes Pigm. 2000, 45, 243−251.
bekov, M. B.; Cantillo, D.; Kappe, C. O.; Surya Prakash, G. K.;
Nikolaev, V. A. Effect of Configuration of 2-inyldiazocarbonyl
Compounds on Their Reactivity: Experimental and Computational
Study. Org. Biomol. Chem. 2014, 12, 682−689.
(14) Narayanam, J. M. R.; Stephenson, C. R. J. Visible Light
Photoredox Catalysis: Applications in Organic Synthesis. Chem. Soc.
Rev. 2011, 40, 102−113.
(15) (a) Papagni, A.; Campiglio, P.; Campione, M.; Del Buttero, P.;
Mani, A.; Miozzo, L.; Tonelli, E. Synthesis and Physical Properties of
Polyfluoro-acridines bearing Perfluoroalkyl Chains. J. Fluorine Chem.
2008, 129, 294−300. (b) Del Buttero, P.; Gironda, R.; Moret, M.;
Papagni, A.; Parravicini, M.; Rizzato, S.; Miozzo, L. Orthogonal
Synthesis of Fluorinated Acridones and Acridines from Perfluor-
obenzophenone. Eur. J. Org. Chem. 2011, 2011, 2265−2271.
(7) (a) Denny, W. A. Acridine Derivatives as Chemotherapeutic
Agents. Curr. Med. Chem. 2002, 9, 1655−1665. (b) Dollinger, S.;
Lober, S.; Klingenstein, R.; Korth, C.; Gmeiner, P. A Chimeric Ligand
Approach Leading to Potent Antiprion Active Acridine Derivatives:
Design, Synthesis, and Biological Investigations. J. Med. Chem. 2006,
49, 6591−6595. (c) Ma, Z.; Choudhury, J. R.; Wright, M. W.; Day, C.
S.; Saluta, G.; Kucera, G. L.; Bierbach, U. A Non-Cross-Linking
Platinum−Acridine Agent with Potent Activity in Non-Small-Cell
Lung Cancer. J. Med. Chem. 2008, 51, 7574−7580.
(8) (a) Li, Z.-H.; Liu, R.; Tan, Z.-L.; He, L.; Lu, Z.-L.; Gong, B.
Aromatization of 9,10-Dihydroacridine Derivatives: Discovering a
Highly Selective and Rapid-Responding Fluorescent Probe for
Peroxynitrite. ACS Sens. 2017, 2, 501−505. (b) Papagni, A.; Del
Buttero, P.; Moret, M.; Sassella, A.; Miozzo, L.; Ridolfi, G. Synthesis
and Properties of Some Derivatives of 1,2,3,4-Tetrafluoroacridine for
Solid State Emitting Systems. Chem. Mater. 2003, 15, 5010−5018.
(9) For recent reviews, see: (a) Schmidt, A.; Liu, M. Recent
Advances in the Chemistry of Acridines. Adv. Heterocycl. Chem. 2015,
115, 287−353. (b) Vaghi, L.; Sanzone, A.; Sassi, M.; Pagani, S.;
Papagni, A.; Beverina, L. Synthesis of Fluorinated Acridines via
Sequential Micellar Buchwald−Hartwig Amination/Cyclization of
Aryl Bromides. Synthesis 2018, 50, 1621−1628. (c) Xiao, Y.; Hu, W.;
Sun, S.; Yu, J.-T.; Cheng, J. Recent Advances in the Synthesis of
Acridines and Phenazines. Synlett 2019, 30, 2113−2122.
(10) (a) Belmont, P.; Belhadj, T. An Efficient and Simple
Aminobenzannulation Reaction: Pyrrolidine as a Trigger for the
Synthesis of 1-Amino-acridines. Org. Lett. 2005, 7, 1793−1795.
(b) Belmont, P.; Andrez, J.-C.; Allan, C. S. M. New Methodology for
Acridine Synthesis using a Rhodium-catalyzed Benzannulation.
Tetrahedron Lett. 2004, 45, 2783−2786. (c) Cikotiene, I.;
Buksnaitiene, R.; Sazinas, R. Rapid access to benzo-annelated
heterocycles, naphthalenes, and polysubstituted benzenes through a
novel benzannulation reaction. Tetrahedron 2011, 67, 706−717.
(11) Xiao, T.; Li, L.; Xie, Y.; Mao, Z.-W.; Zhou, L. Synthesis of
Gem-Difluorinated Fused Quinolines via Visible Light-Mediated
Cascade Radical Cyclization. Org. Lett. 2016, 18, 1004−1007.
(12) Li, S.; Zhu, J.; Xie, H.; Chen, Z.; Wu, Y. Cu(I)-catalyzed
Coupling Reactions of Fluorinated Imidoyl Halides with Terminal
Alkynes: Convenient Synthesis of Fluorinated Alkynyl Imines. J.
Fluorine Chem. 2011, 132, 196−201.
(13) (a) Drikermann, D.; Kerndl, V.; Görls, H.; Vilotijevic, I.
Intramolecular Cyclization of Vinyldiazoacetates as a Versatile Route
to Substituted Pyrazoles. Synlett 2020, 31, 1158−1162. (b) Supurgi-
4283
https://doi.org/10.1021/acs.orglett.1c01204
Org. Lett. 2021, 23, 4279−4283