Visible-Light Driven Selective C-N Bond Scission in anti-Bimane-Like Derivatives

Article abstract of DOI:10.1021/acs.orglett.1c01376

In the present study, we report the photochemical transformation of pyrazolo[1,2-a]pyrazolone substrates that reach an excited state upon irradiation with visible light to initiate the homolytic C-N bond cleavage process that yields the corresponding N1-s

Full text of DOI:10.1021/acs.orglett.1c01376

pubs.acs.org/OrgLett
Letter
Visible-Light Driven Selective C−N Bond Scission in anti-Bimane-
Like Derivatives
Nejc Petek, Helena Brodnik, Uros Groselj, Jurij Svete, Franc Pozgan, and Bogdan Stefane*
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ABSTRACT: In the present study, we report the photochemical
transformation of pyrazolo[1,2-a]pyrazolone substrates that reach
an excited state upon irradiation with visible light to initiate the
homolytic C−N bond cleavage process that yields the correspond-
ing N1-substituted pyrazoles. Moreover, chemoselective heterolytic
C−N bond cleavage is possible in the pyrazolo[1,2-a]pyrazole core
in the presence of bromomalonate.
Scheme 1. Ring Scission of Pyrazolo[1,2-a]pyrazoles
or organic substrates that do not absorb visible light, it is
Fdifficult to use direct energy transfer applying visible light
to achieve transformation.1 In most cases, due to the poor
visible light absorption of the reaction substrates, it is necessary
to use photosensitizers to initiate the transformations.2 In the
past decade, numerous efficient photocatalysts, including
iridium, ruthenium, nickel, and copper complexes,3 as well as
various organic dyes,4 have been investigated for visible light
induced organic transformations to form carbon−carbon and
carbon-heteroatom bonds under very mild reaction conditions.
However, the high cost and sometimes complicated prepara-
tion of these photocatalysts limit their industrial application,
especially for large-scale syntheses.5 A novel strategy for radical
generation from catalytic visible-light-absorbing dithiocarba-
mates was recently presented by Melchiorre.6 The develop-
ment of visible light-induced organic reactions using photo-
active substrates without external photosensitizers or photo-
catalysts is considered a promising research direction, thus
offering a cost-effective and more environmentally friendly
approach to organic synthesis.7 Our group has explored the
potential of some azomethine imines as 1,3-dipoles in [3 + 2]-
annulation reactions.8 Recently, we have developed a visible-
light-induced aerobic oxidation of N1-substituted pyrazolidin-
3-ones to afford the corresponding azomethine imines, which
can be further reacted in situ with ynones under copper-
catalyzed [3 + 2] cycloaddition conditions to give the
corresponding pyrazolo[1,2-a]pyrazoles.9 N,N-Bicyclic pyrazo-
lidin-3-ones, that is, pyrazolo[1,2-a]pyrazol-1-one derivatives
exhibit pronounced bioactivity and have attracted much
attention in drug development.10 Among them, pyrazole
derivatives have been given special consideration in cancer
therapy.11 Stoichiometric oxidation-ring opening (Br2, CAN,
O2/Cu2+) of the corresponding pyrazolo[1,2-a]pyrazoles in the
presence of water as a nucleophile (Scheme 1a) was previously
explored by us and others and leads to N1-substituted
pyrazoles.12 Since pyrazolo[1,2-a]pyrazoles absorb in the
visible frequency range (up to 420 nm), we envisioned that
visible-light induced transformations of the pyrazolo[1,2-
a]pyrazole core could provide a mild and economical route
to valuable N1-substituted pyrazole derivatives, as shown in
Scheme 1b.
To investigate the feasibility of the proposed strategy, we
chose 1a (R1 = Me, R2 = 4-Cl-C6H4) with the absorption
maxima at 360 nm (εmax = 8400 M−1 cm−1, λem = 535 with Θf
= 0.11)13 as a model substrate for visible-light-induced C−N
bond cleavage in the pyrazolo[1,2-a]pyrazole core. Surpris-
ingly, irradiation of 1a with 400 nm 3 W LEDs for 24 h in
DCM at 25 °C led to the formation of the corresponding
aldehyde 2a in 78% yield. Careful examination of different
solvents (THF, EtOAc, MeCN, acetone, MeOH, and DMF)
Received: April 22, 2021
Published: June 2, 2021
https://doi.org/10.1021/acs.orglett.1c01376
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5294−5298
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revealed that DCM performed best in this protocol. Moreover,
a control experiment with longer wavelengths (450 nm LEDs)
slowed the conversion. The reaction was additionally tested in
dichloroethane at 50 °C for 12 and 24 h, resulting in lower
yields of 2a with notable side reactions (for details, see Table
SI1). Next, various substituted pyrazolo[1,2-a]pyrazoles 1 were
investigated to evaluate the generality of the transformation.
Here, C1 phenyl-, heteroaryl-, and alkyl-substituted substrates
afforded the corresponding aldehydes 2a−g in moderate to
good yields (Scheme 2). When vinyl-derived substituents were
Scheme 3. C7−N8 Bond Cleavage of Pyrazolo[1,2-
b
a]pyrazoles
Scheme 2. C1−N8 and C5−N4 Bond Cleavage of
b
Pyrazolo[1,2-a]pyrazoles
a
b
Gram scale yield. 1 (0.5 mmol), diethyl bromomalonate (2.0
equiv), 2,6-lutidine (1.5 equiv), DCM (2.5 mL), N2, 18 h.
isolated yield. When the N-methylpyrrole substituted bicycle 1
was reacted under standard conditions, the corresponding N-
acryloyl substituted pyrazole 4o was isolated in a 15% yield,
together with the C5′ malonyl substituted derivative 4o′ in a
50% yield. The coupling of this electron-deficient malonate
radical at the C2 position with electron-rich arenes, such as
a
b
Hydrogens are omitted for clarity. 1 (0.5 mmol), DCM (2.5 mL),
LED400nm, 25 °C, under N2 for 24−48 h.
introduced onto the C1 position of the pyrazolo[1,2-
a]pyrazole scaffold, the ring expansion products 3 were
formed, together with the formation of products 2 (Scheme
2, examples 3h and 3i). The formation of ring-expansion
products 3 commenced via C1−N8 homolytic bond cleavage
followed by radical 7-endo-trig cyclization.13
pyrroles, thiophenes, and furans under visible light-mediated
17
conditions was documented by Stephenson,15 Trapp,16 Noel,
̈
and Wu.18 To demonstrate the scalability of the method, a
gram-scale experiment was performed to give 4a with a
comparable 80% product yield.13
Optimization studies revealed that the presence of
nucleophiles, such as water (Table SI2, entry 10)13 in the
reaction mixture favored the formation of 5a as the major
product. This suggests the possibility of regioselective C5−N4
photoinduced nucleophilic ring opening of pyrazolo[1,2-
a]pyrazoles 1. To explore the substrate and nucleophile
range for these types of transformations, we investigated the
reaction of 1a with various nucleophiles (Scheme 4). In the
presence of diethyl bromomalonate (2.0 equiv) in DCM under
LED450nm irradiation for 19 h at 25 °C, followed by the
addition of water (10 equiv), substrate 1a was successfully
transformed to the corresponding acid 5a in an excellent 97%
yield after isolation (Scheme 4). It is worth noting that in this
case no additional base was required. In addition to water
(Scheme 4, examples 5a, 5g, and 5i), other nucleophiles were
also introduced. The reaction proved to be equally successful
in the presence of methanol and p-cresol, obtaining the
corresponding esters 5b, 5c, 5h, 5j, and 5k in good to excellent
yields. Aliphatic amines and anilines were also tolerated in this
protocol, giving the desired amides 5d and 5e in reasonable
64% and 63% yields, respectively. Moreover, L-alanine methyl
ester was successfully coupled under the developed protocol,
obtaining product 5f in a 60% yield. In addition, the reaction
result was not significantly altered by the substitution pattern
on the pyrazolo[1,2-a]pyrazole core, as exemplified by
products 5g−k. Interestingly, when bicycles 1 were reacted
in THF as the chosen solvent, the corresponding terminal
halohydrin esters 5l and 5m formed in reasonable yields as a
Considering the ability of 1a to act as a reducing agent in the
excited state (Eo*x ∼ − 1.8 V vs SCE),13 the photoreduction of
activated alkyl bromides, such as diethyl bromomalonate (Ered
= −0.62 V vs SCE) or 2-bromoacetophenone (Ered = −1.46 V
vs SCE), would be possible.14 For details and discussion on the
optimization studies, see Supporting Information. Detailed
screening of the reaction conditions revealed that 1a could be
converted to the N1-acryloyl-substituted pyrazole 4a and
isolated in 78% yield when irradiated with blue light (450 nm)
in the presence of diethyl bromomalonate (2.0 equiv) and 2,6-
lutidine (1.5 equiv) as the base in DCM. To explore the
substrate scope, the above optimized reaction conditions were
applied to a variety of substituted pyrazolo[1,2-a]pyrazoles 1
(Scheme 3). Bicycles 1 with electron-withdrawing groups on
the benzene ring, such as chloro and cyano, and electron-
donating substituents, such as methoxy and methyl, were well-
tolerated in the present transformation and showed no obvious
difference in reactivity, as the corresponding products 4a−g
were isolated in good yields. Moreover, the reaction result was
not altered when a naphthalene unit (example 4j) was
introduced. Notably, it was also possible to extend the
substrate range to carbonyl, aminocarbonyl, and carbamate
substituents on both pyrazole rings in bicyclic substrates,
resulting in good yields of the corresponding products 4k, 4l,
and 4n. Alkyl substitution was also tolerated as product 4i was
isolated in a 65% yield. Unfortunately, the styryl-substituted
pyrazolo[1,2-a]pyrazole 1 gave product 4h in a rather low 30%
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Letter
bicycle 1 to the S1 excited state, followed by ISC to the T1
excited state, which derives the corresponding biradical
intermediate after C5−N4 bond cleavage. Subsequently, 1,5-
hydrogen shift and aromatization gives the desired products,
pyrazoles 2 (Scheme 5a). In the case of C1-vinyl derived
substrates 1, homolytic C1−N8 bond cleavage becomes the
competitive reaction process yielding diazepine products 3
upon 7-endo-trig cyclization (Scheme SI9).13 In addition, the
reaction of 1a with diethyl bromomalonate was also studied
more in detail. The reaction of 1a with diethyl bromomalonate
was tested under standard reaction conditions in the presence
of TEMPO as a radical scavenging reagent (Scheme 5c). The
formation of the TEMPO-malonate product can be clearly
identified by HRMS analysis (exact mass: 316.2118
[C16H30NO5]) in the crude reaction mixture.13 This result
and the formation of diethyl malonate adduct 4o′ (Scheme 3)
suggest that the malonyl radical is most likely involved in this
transformation. The Stern−Volmer plot suggests that the
interaction between the excited pyrazolo[1,2-a]pyrazoles 1 and
diethyl bromomalonate (Figure SI9)13 exists. Following the
reaction progress by 1H NMR shows the formation of
intermediate I2 (Figure SI3),13 which upon the addition of
water converts to a corresponding carboxylic acid 5 or into
product 4 upon addition of 2,6-lutidine as the base. On the
basis of these experiments and related literature prece-
dents,15−18 a possible reaction mechanism is shown in Scheme
5c. The pyrazolo[1,2-a]pyrazole 1 was first excited with visible
light to form the excited 1*, which underwent single electron
transfer (SET) with diethyl bromomalonate to generate the
corresponding radical cation of 1. The mesolytic loss of a
bromide ion from the bromomalonate radical anion would
then provide the malonate radical. Deprotonation of the
radical cation intermediate of 1 yields the corresponding
radical intermediate I1, which in turn reacts with the malonyl
radical by SET to furnish the cationic intermediate I2. The
pyrazolium intermediate I2 can provide products 4 under basic
reaction conditions or alternatively give products 5 in the
presence of nucleophiles.
Scheme 4. C5−N4 Bond Cleavage of Pyrazolo[1,2-
d
a]pyrazoles
a
b
Degassed Me2CO (H2O, 10 equiv). MeOH (anhydrous, degassed,
c
2.5 mL). THF (anhydrous, degassed, 2.5 mL). [i] H2 (2 bar), 10%
Pd(C), 6 h. 1 (0.5 mmol), diethyl bromomalonate (2.0 equiv),
d
DCM (anhydrous, degassed, 2.5 mL), N2, 18 h, HNu (2.0 equiv).
result of tetrahydrofuran ring opening induced by the
pyrazolium intermediate I2 (Scheme 5).
Scheme 5. Mechanistic Insight
In summary, we have demonstrated a novel visible-light-
induced transformation of substituted pyrazolo[1,2-a]pyrazoles
1. Excitation leads to chemoselective C−N bond cleavage of
the pyrazolo[1,2-a]pyrazole scaffold, resulting in densely
substituted pyrazoles. The reaction outcome depends on the
nature of the substrates and the reaction protocol, thus
providing a versatile approach for functionalized pyrazole
derivatives originating from readily available starting materials.
Further investigations into applications of this methodology
are currently ongoing.
To gain more insight into the photoinduced transformation
of pyrazolo[1,2-a]pyrazoles 1, several control experiments
were conducted. First, an experiment was performed with on/
off irradiation with visible light. As shown in Figure SI2,13
continuous irradiation with visible light is essential for
successful transformation. A reaction with deuterated solvent
(CD2Cl2) was also performed in which no deuterated aldehyde
2D was detected. However, when the C1-deuterated substrate
1D (Scheme 5a) was reacted under the standard reaction
conditions, only deuterated aldehyde 2D was obtained.
Furthermore, a crossover experiment with equimolar mixture
of 1d (100% H on C1) and 1D (>98% D on C1) under the
standard reaction conditions resulted in no crossover product
being detected in the crude reaction mixture (Scheme 5b). To
clarify from which excited state of substrates 1 do the aldehyde
products 2 originate from, the reaction of 1a was caried out in
the presence of a triplet-annihilator, trans-stilbene (ET = 49.3
kcal/mol). It is noteworthy that 1 equiv of trans-stilbene
inhibits the reaction (Figure SI1),13 and a significant amount
of cis-stilbene (70%) is produced during the reaction. The
above experiments are consistent with visible light excitation of
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.1c01376.
Materials and methods, experimental procedures,
mechanistic and optimization studies, characterization
1
data, and H NMR and 13C NMR spectra (PDF)
Accession Codes
CCDC 2077375−2077377 contain the supplementary crys-
tallographic 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
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Enantioselective [2 + 2] Photocycloadditions Using Visible Light.
Science 2014, 344, 392. (d) Dai, C.; Narayanam, J. M. R.; Stephenson,
C. R. J. Visible-Light-Mediated Conversion of Alcohols to Halides.
Nat. Chem. 2011, 3, 140. (e) Xuan, J.; Zeng, T.-T.; Feng, Z.-J.; Deng,
Q.-H.; Chen, J.-R.; Lu, L.-Q.; Xiao, W.-J.; Alper, H. Redox-Neutral α-
Allylation of Amines by Combining Palladium Catalysis and Visible-
Light Photoredox Catalysis. Angew. Chem., Int. Ed. 2015, 54, 1625.
(f) Huang, H.; Jia, K.; Chen, Y. Hypervalent Iodine Reagents Enable
Chemoselective Deboronative/Decarboxylative Alkenylation by Pho-
toredox Catalysis. Angew. Chem., Int. Ed. 2015, 54, 1881.
(g) Musacchio, A. J.; Nguyen, L. Q.; Beard, G. H.; Knowles, R. R.
Catalytic Olefin Hydroamination with Aminium Radical Cations: A
Photoredox Method for Direct C−N Bond Formation. J. Am. Chem.
Soc. 2014, 136, 12217. (h) Zoller, J.; Fabry, D. C.; Ronge, M. A.;
Rueping, M. Synthesis of Indoles Using Visible Light: Photoredox
Catalysis for Palladium-Catalyzed C−H Activation. Angew. Chem., Int.
Ed. 2014, 53, 13264. (i) Tomita, R.; Yasu, Y.; Koike, T.; Akita, M.
Combining Photoredox-Catalyzed Trifluoromethylation and Oxida-
tion with DMSO: Facile Synthesis of α-Trifluoromethylated Ketones
from Aromatic Alkenes. Angew. Chem., Int. Ed. 2014, 53, 7144.
(4) For selected examples using organic dyes as the photocatalysts,
see: (a) Romero, N. A.; Margrey, K. A.; Tay, N. E.; Nicewicz, D. A.
Site-Selective Arene C−H Amination via Photoredox Catalysis.
Science 2015, 349, 1326. (b) Perkowski, A. J.; Cruz, C. L.;
Nicewicz, D. A. Ambient-Temperature Newman−Kwart Rearrange-
ment Mediated by Organic Photoredox Catalysis. J. Am. Chem. Soc.
2015, 137, 15684. (c) Tröster, A.; Alonso, R.; Bauer, A.; Bach, T.
Enantioselective Intermolecular [2 + 2] Photocycloaddition Reactions
of 2(1H)-Quinolones Induced by Visible Light Irradiation. J. Am.
Chem. Soc. 2016, 138, 7808. (d) Hari, D. P.; Schroll, P.; König, B.
Metal-Free, Visible-Light-Mediated Direct C−H Arylation of
Heteroarenes with Aryl Diazonium Salts. J. Am. Chem. Soc. 2012,
134, 2958. (e) Meng, Q.-Y.; Zhong, J.-J.; Liu, Q.; Gao, X.-W.; Zhang,
H.-H.; Lei, T.; Li, Z.-J.; Feng, K.; Chen, B.; Tung, C.-H.; Wu, L.-Z. A
Cascade Cross-Coupling Hydrogen Evolution Reaction by Visible
Light Catalysis. J. Am. Chem. Soc. 2013, 135, 19052. (f) Guo, W.; Lu,
L.-Q.; Wang, Y.; Wang, Y.-N.; Chen, J.-R.; Xiao, W.-J. Metal-Free,
Room-Temperature, Radical Alkoxycarbonylation of Aryldiazonium
Salts through Visible-Light Photoredox Catalysis. Angew. Chem., Int.
Ed. 2015, 54, 2265. (g) Xiao, T.; Li, L.; Lin, G.; Wang, Q.; Zhang, P.;
Mao, Z.; Zhou, L. Synthesis of 6-Substituted Phenanthridines by
Metal-Free, Visible-Light Induced Aerobic Oxidative Cyclization of 2-
Isocyanobiphenyls with Hydrazines. Green Chem. 2014, 16, 2418.
(5) (a) Fu, M.-C.; Shang, R.; Zhao, B.; Wang, B.; Fu, Y.
Photocatalytic Decarboxylative Alkylations Mediated by Triphenyl-
phosphine and Sodium Iodide. Science 2019, 363, 1429. (b) Liu, Q.;
Liu, F.; Yue, H.; Zhao, X.; Li, J.; Wei, W. Photocatalyst-Free Visible
Light-Induced Synthesis of β-Oxo Sulfones via Oxysulfonylation of
Alkenes with Arylazo Sulfones and Dioxygen in Air. Adv. Synth. Catal.
2019, 361, 5277. (c) Guillemard, L.; Colobert, F.; Wencel-Delord, J.
Visible-Light-Triggered, Metal- and Photocatalyst-Free Acylation of
N-Heterocycles. Adv. Synth. Catal. 2018, 360, 4184.
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
̌
Bogdan Stefane − Faculty of Chemistry and Chemical
Technology, University of Ljubljana, 1000 Ljubljana,
Slovenia; orcid.org/0000-0002-8709-9853;
Email: bogdan.stefane@fkkt.uni-lj.si
Authors
Nejc Petek − Faculty of Chemistry and Chemical Technology,
University of Ljubljana, 1000 Ljubljana, Slovenia
Helena Brodnik − Faculty of Chemistry and Chemical
Technology, University of Ljubljana, 1000 Ljubljana,
Slovenia; orcid.org/0000-0002-0099-2236
̌
̌
Uros Groselj − Faculty of Chemistry and Chemical
Technology, University of Ljubljana, 1000 Ljubljana,
Slovenia
Jurij Svete − Faculty of Chemistry and Chemical Technology,
University of Ljubljana, 1000 Ljubljana, Slovenia;
orcid.org/0000-0003-3339-3595
̌
Franc Pozgan − Faculty of Chemistry and Chemical
Technology, University of Ljubljana, 1000 Ljubljana,
Slovenia; orcid.org/0000-0001-6040-294X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01376
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the Slovenian Research Agency
through grant P1-0179 is gratefully acknowledged.
■
REFERENCES
■
(1) (a) Zeitler, K. Photoredox Catalysis with Visible Light. Angew.
Chem., Int. Ed. 2009, 48, 9785−9789. (b) Michelin, C.; Hoffmann, N.
Photosensitization and Photocatalysis−Perspectives in Organic Syn-
thesis. ACS Catal. 2018, 8, 12046.
(2) For recent reviews on visible light-induced photoredox catalysis,
see: (a) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Dual Catalysis
Strategies in Photochemical Synthesis. Chem. Rev. 2016, 116, 10035.
(b) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis.
Chem. Rev. 2016, 116, 10075. (c) Ravelli, D.; Protti, S.; Fagnoni, M.
Carbon−Carbon Bond Forming Reactions via Photogenerated
Intermediates. Chem. Rev. 2016, 116, 9850. (d) Lang, X.; Zhao, J.;
Chen, X. Cooperative Photoredox Catalysis. Chem. Soc. Rev. 2016, 45,
3026. (e) Kärkäs, M. D.; Porco, J. A.; Stephenson, C. R. J.
Photochemical Approaches to Complex Chemotypes: Applications
in Natural Product Synthesis. Chem. Rev. 2016, 116, 9683.
(f) Corrigan, N.; Shanmugam, S.; Xu, J.; Boyer, C. Photocatalysis
in Organic and Polymer Synthesis. Chem. Soc. Rev. 2016, 45, 6165.
(g) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Visible Light
Photoredox-Controlled Reactions of N-Radicals and Radical Ions.
Chem. Soc. Rev. 2016, 45, 2044.
(3) For selected examples using metal-based photocatalysts, see:
(a) Pirnot, M. T.; Rankic, D. A.; Martin, D. B. C.; MacMillan, D. W.
C. Photoredox Activation for the Direct β-Arylation of Ketones and
Aldehydes. Science 2013, 339, 1593. (b) Zuo, Z.; Ahneman, D. T.;
Chu, L.; Terrett, J. A.; Doyle, A. G.; MacMillan, D. W. C. Merging
Photoredox with Nickel Catalysis: Coupling of α-Carboxyl sp3-
Carbons with Aryl Halides. Science 2014, 345, 437. (c) Du, J.; Skubi,
K. L.; Schultz, D. M.; Yoon, T. P. A Dual-Catalysis Approach to
(6) (a) Schweitzer-Chaput, B.; Horwitz, M. A.; de Pedro Beato, E.;
Melchiorre, P. Photochemical Generation of Radicals from Alkyl
Electrophiles Using a Nucleophilic Organic Catalyst. Nat. Chem.
2019, 11, 129. (b) Spinnato, D.; Schweitzer-Chaput, B.; Goti, G.;
̌
Oseka, M.; Melchiorre, P. A. Photochemical Organocatalytic Strategy
for the α-Alkylation of Ketones by using Radicals. Angew. Chem., Int.
Ed. 2020, 59, 9485; Angew. Chem. 2020, 132, 9572.
(7) For selected recent examples, see: (a) Sahoo, B.; Hopkinson, M.
N.; Glorius, F. External-Photocatalyst-Free Visible-Light-Mediated
Synthesis of Indolizines. Angew. Chem., Int. Ed. 2015, 54, 15545.
(b) Liu, P.; Liu, W.; Li, C.-J. Catalyst-Free and Redox-Neutral Innate
Trifluoromethylation and Alkylation of Aromatics Enabled by Light. J.
Am. Chem. Soc. 2017, 139, 14315. (c) Dossena, A.; Sampaolesi, S.;
Palmieri, A.; Protti, S.; Fagnoni, M. Visible Light Promoted Metal-
and Photocatalyst-Free Synthesis of Allylarenes. J. Org. Chem. 2017,
82, 10687. (d) Li, J.; Zhu, D.; Lv, L.; Li, C.-J. Radical
Difluoromethylthiolation of Aromatics Enabled by Visible Light.
5297
https://doi.org/10.1021/acs.orglett.1c01376
Org. Lett. 2021, 23, 5294−5298

Organic Letters
pubs.acs.org/OrgLett
Letter
Chem. Sci. 2018, 9, 5781. (e) Liu, W.; Li, J.; Querard, P.; Li, C.-J.
Transition-Metal-Free C−C, C−O, and C−N Cross-Couplings
Enabled by Light. J. Am. Chem. Soc. 2019, 141, 6755. (f) Zhang, Y.;
Chen, W.; Jia, X.; Wang, L.; Li, P. A Visible-Light-Induced Oxidative
Cyclization of N-Propargylanilines with Sulfinic Acids to 3-Sulfonated
Quinoline Derivatives Without External Photocatalysts. Chem.
Commun. 2019, 55, 2785. (g) Zhao, L.; Li, P.; Zhang, H.; Wang, L.
Photoinduced Synthesis of α-Trifluoromethylated Ketones Through
the Oxidative Trifluoromethylation of Styrenes Using CF3SO2Na as a
Trifluoromethyl Reagent Without an External Photoredox Catalyst.
Org. Chem. Front. 2019, 6, 87. (h) Han, Y.; Jin, Y.; Jiang, M.; Yang,
H.; Fu, H. Photocatalyst-Free Visible-Light Photoredox Dearomatiza-
tion of Phenol Derivatives Containing Ketoximes: An Easy Access to
Spiropyrrolines. Org. Lett. 2019, 21, 1799. (i) Zhang, X.-Y.; Weng,
W.-Z.; Liang, H.; Yang, H.; Zhang, B. Visible-Light-Initiated,
Photocatalyst-Free Decarboxylative Coupling of Carboxylic Acids
with N-Heterocycles. Org. Lett. 2018, 20, 4686. (j) Quint, V.;
M. M.; Rizvi, M. A.; Akhter, M.; Shaquiquzzaman, M. Unveiling
Novel Diphenyl-1H-pyrazole Based Acrylates Tethered to 1,2,3-
Triazole as Promising Apoptosis Inducing Cytotoxic and Anti-
inflammatory Agents. Bioorg. Chem. 2019, 87, 667. (e) Omran, D. M.;
Ghaly, M. A.; El-Messery, S. M.; Badria, F. A.; Abdel-Latif, E.;
Shehata, I. A. Targeting Hepatocellular Carcinoma: Synthesis of New
Pyrazole-based Derivatives, Biological Evaluation, DNA Binding, and
Molecular Modeling Studies. Bioorg. Chem. 2019, 88, 102917.
(f) Husseiny, E. M. Synthesis, Cytotoxicity of Some Pyrazoles and
Pyrazolo[1,5-a]pyrimidines Bearing Benzothiazole Moiety and
Investigation of their Mechanism of Action. Bioorg. Chem. 2020,
102, 104053. (g) Forde, P. M.; Rudin, C. M. Crizotinib in the
Treatment of Non-Small-Cell Lung Cancer. Expert Opin. Pharmac-
other. 2012, 13, 1195.
̌
(12) (a) Preseren, A.; Svete, J.; Stanovnik, B. Oxidative Ring-
opening of rel-(2R,3R,5S)-5-Aryl-2-benzoylamino-6,7-bis-
(methoxycarbonyl)-2,3-dihydro-1-oxo-3-phenyl-1H,5H-pyrazolo[1,2-
a]-pyrazoles. Synthesis of rel-(2R,3R)-3-Phenyl-3-[5-aryl-3,4-bis-
(methoxycarbonyl)pyrazolyl-1]alanine Esters. J. Heterocycl. Chem.
1999, 36, 799. (b) Luo, N.; Zheng, Z.; Yu, Z. Highly Regioselective
[3 + 2] Annulation of Azomethine Imines with 1-Alkynyl Fischer
Carbene Complexes to Functionalized N,N-Bicyclic Pyrazolidin-3-
ones. Org. Lett. 2011, 13, 3384. (c) Yang, Z.-W.; Wang, J.-F.; Peng, L.-
J.; You, X.-L.; Cui, H.-L. Thermal 1,3-Dipolar Cycloaddition of
Azomethine Imines with Alkynes Affording N,N-Bicyclic Pyrazolidi-
nones Under Microwave Irradiation. Tetrahedron Lett. 2016, 57, 5219.
(13) For details see Supporting Infomation.
̀
Chouchene, N.; Askri, M.; Lalevée, J.; Gaumont, A.-C.; Lakhdar, S.
Visible-Light-Mediated α-Phosphorylation of N-Aryl Tertiary Amines
Through the Formation of Electron-Donor-Acceptor Complexes:
Synthetic and Mechanistic Studies. Org. Chem. Front. 2019, 6, 41.
(k) Franz, J. F.; Kraus, W. B.; Zeitler, K. No Photocatalyst Required-
Versatile, Visible Light Mediated Transformations with Polyhalo-
methanes. Chem. Commun. 2015, 51, 8280.
̌
̌
̌
(8) For review see: (a) Groselj, U.; Pozgan, F.; Stefane, B.; Svete, J.
Copper-Catalyzed Azomethine Imine−Alkyne Cycloadditions
(CuAIAC). Synthesis 2018, 50, 4501. For examples see: (b) Pusavec
̌
(14) Roth, H. G.; Romero, N. A.; Nicewicz, D. A. Experimental and
Calculated Electrochemical Potentials of Common Organic Molecules
for Applications to Single-Electron Redox Chemistry. Synlett 2016,
27, 714.
(15) (a) Furst, L.; Matsuura, B. S.; Narayanam, J. M. R.; Tucker, J.
W.; Stephenson, C. R. J. Visible Light-Mediated Intermolecular C−H
Functionalization of Electron-Rich Heterocycles with Malonates. Org.
Lett. 2010, 12, 3104. (b) Wallentin, C.-J.; Nguyen, J. D.; Finkbeiner,
P.; Stephenson, C. R. J. Visible Light-Mediated Atom Transfer Radical
Addition via Oxidative and Reductive Quenching of Photocatalysts. J.
Am. Chem. Soc. 2012, 134, 8875.
(16) Fuks, E.; Huber, L.; Schinkel, T.; Trapp, O. Investigation of
Straightforward, Photoinduced Alkylations of Electron-Rich Hetero-
compounds with Electron-Deficient Alkyl Bromides in the Sole
Presence of 2,6-Lutidine. Eur. J. Org. Chem. 2020, 2020, 6192.
(17) Bottecchia, C.; Martín, R.; Abdiaj, I.; Crovini, E.; Alcazar, J.;
Orduna, J.; Blesa, M. J.; Carrillo, J. R.; Prieto, P.; Noël, T. De novo
Design of Organic Photocatalysts: Bithiophene Derivatives for the
Visible-light Induced C−H Functionalization of Heteroarenes. Adv.
Synth. Catal. 2019, 361, 945.
̌
̌
̌
Kirar, E.; Groselj, U.; Mirri, G.; Pozgan, F.; Strle, G.; Stefane, B.;
Jovanovski, V.; Svete, J. Click” Chemistry: Application of Copper
Metal in Cu-Catalyzed Azomethine Imine−Alkyne Cycloadditions. J.
̌
̌
Org. Chem. 2016, 81, 5988. (c) Pusavec Kirar, E.; Groselj, U.;
̌
̌
̌
Golobic, A.; Pozgan, F.; Pusch, S.; Weber, C.; Andernach, L.; Stefane,
B.; Opatz, T.; Svete, J. Absolute Configuration Determination of 2,3-
Dihydro-1H,5H-pyrazolo[1,2-a]pyrazoles Using Chiroptical Methods
̌
at Different Wavelengths. J. Org. Chem. 2016, 81, 11802. (d) Pusavec
̌
̌
Kirar, E.; Drev, M.; Mirnik, J.; Golobic, A.; Dahmann, G.; Pozgan, F.;
̌
Stefane, B.; Svete, J.; et al. Synthesis of 3D-Rich Heterocycles:
Hexahydropyrazolo[1,5-a]pyridin-2(1H)-ones and Octahydro-2H-
2a,2a1-diazacyclopenta[cd]inden-2-ones. J. Org. Chem. 2016, 81, 8920.
̌
̌
̌
̌
(9) Petek, N.; Groselj, U.; Svete, J.; Pozgan, F.; Kocar, D.; Stefane, B.
Eosin Y-Catalyzed Visible-Light-Mediated Aerobic Transformation of
Pyrazolidine-3-one Derivatives. Catalysts 2020, 10, 981.
(10) (a) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles,
2nd ed.; Wiley-VHC: Weinheim, 2003. (b) Claramunt, R. M.;
Elguero, J. The Chemistry of Pyrazolidinones. A Review. Org. Prep.
Proced. Int. 1991, 23, 273. (c) Jungheim, L. N; Sigmund, S. K; Fisher,
J. W Bicyclic Pyrazolidinones, a New Class of Antibacterial Agent
Based on the β-Lactam Model. Tetrahedron Lett. 1987, 28, 285.
(d) Jungheim, L. N.; Sigmund, S. K. 1,3-Dipolar Cycloaddition
Reactions of Pyrazolidinium Ylides with Acetylenes. Synthesis of a
New Class of Antibacterial Agents. J. Org. Chem. 1987, 52, 4007.
(e) Ternansky, R. J.; Draheim, S. E. Structure-Activity Relationship
Within a Series of Pyrazolidinone Antibacterial Agents. 1. Effect of
Nuclear Modification on in Vitro Activity. J. Med. Chem. 1993, 36,
(18) Gu, G.; Huang, M.; Kim, J. K.; Zhang, J.; Li, Y.; Wu, Y. Visible-
Light-Induced Photocatalyst-Free C-3 Functionalization of Indoles
with Diethyl Bromomalonate. Green Chem. 2020, 22, 2543.
́
3219. (f) Panfil, I.; Urbanczyk-Lipkowska, Z.; Suwinska, K.; Solecka,
J.; Chmielewski, M. Synthesis of Pyrazolidinone Analogs of β-Lactam
Antibiotics. Tetrahedron 2002, 58, 1199.
(11) For examples see: (a) Rahmouni, A.; Souiei, S.; Belkacem, M.
A.; Romdhane, A.; Bouajila, J.; Ben Jannet, H. B. Synthesis and
Biological Evaluation of Novel Pyrazolopyrimidines Derivatives as
Anticancer and Anti-5-lipoxygenase Agents. Bioorg. Chem. 2016, 66,
160. (b) Thangarasu, P.; Manikandan, A.; Thamaraiselvi, S.
Discovery, Synthesis and Molecular Corroborations of Medicinally
Important Novel Pyrazoles; Drug Efficacy Determinations Through in
silico, in vitro and Cytotoxicity Validations. Bioorg. Chem. 2019, 86,
410. (c) Faria, J. V.; Vegi, P. F.; Miguita, A. G. C.; dos Santos, M. S.;
Boechat, N.; Bernardino, A. M. R. Recently Reported Biological
Activities of Pyrazole Compounds. Bioorg. Med. Chem. 2017, 25, 5891.
(d) Khan, M. F.; Anwer, T.; Bakht, A.; Verma, G.; Akhtar, W.; Alam,
5298
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