Davis-Beirut Reaction: A Photochemical Br?nsted Acid Catalyzed Route to N-Aryl 2 H-Indazoles

Article abstract of DOI:10.1021/acs.orglett.9b02213

The Davis-Beirut reaction provides access to 2H-indazoles from aromatic nitro compounds. However, N-aryl targets have been traditionally challenging to access due to competitive alternate reaction pathways. Previously, the key nitroso imine intermediate w

Full text of DOI:10.1021/acs.orglett.9b02213

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Davis−Beirut Reaction: A Photochemical Brønsted Acid Catalyzed
Route to N‑Aryl 2H‑Indazoles
Niklas Kraemer,†,§ Clarabella J. Li,†,§ Jie S. Zhu,† Julio M. Larach,† Ka Yi Tsui,† Dean J. Tantillo,†
Makhluf J. Haddadin,‡ and Mark J. Kurth*,†
†Department of Chemistry, University of California Davis, 1 Shields Avenue, Davis, California 95616, United States
‡Department of Chemistry, American University of Beirut, Beirut, Lebanon
S
* Supporting Information
ABSTRACT: The Davis−Beirut reaction provides access to
2H-indazoles from aromatic nitro compounds. However, N-
aryl targets have been traditionally challenging to access due
to competitive alternate reaction pathways. Previously, the key
nitroso imine intermediate was generated under alkaline
conditions, but as reported here, the photochemistry of o-
nitrobenzyl alcohols empowered Brønsted acid catalyzed
conditions for accessing N-aryl targets. Anilines and alkyl
amines give different outcomes under optimized conditions; the proposed mechanism was studied using quantum chemical
calculations.
Scheme 1. N-Aryl Targets via the DBR
itrogen-containing heterocycles are medicinal chemistry
Nand natural product staples, and the indazole core forms
the backbone of a variety of biologically important molecules,
having shown analgesic,1 antiviral,2 antichasic,3 antitumor,4
and anticancer properties.5 Indeed, indazole derivatives are
privileged among nitrogen heterocycles and they afford access
to the corresponding indazolones,6 another family of bio-
logically relevant compounds.6a,b Typically, indazoles and
indazolones are synthesized with the N−N bond already in
place, sometimes with the aid of transition metal catalysts,7
using the Cadogan cyclization,8 or via redox manipulation
strategies.9
The Davis−Beirut reaction (DBR) is a redox neutral method
for the conversion of o-nitrobenzyl amines to 2H-indazoles.10
The formation of an N−N bond is a key step in the DBR, but
this reaction poorly accommodates reactions with anilines to
form the corresponding N-aryl products (Scheme 1A),11 even
though the N−N bond forming reaction between anilines and
aryl nitroso groups is well established in the Mills reaction.12 In
many cases, C−N bond cleavage is favored over N−N bond
formation when anilines are used in the DBR.11b,13 This issue
likely arises from the fact that the Mills reaction is acid
catalyzed while the DBR is typically carried out under alkaline
conditions. This limitation has been disappointing because it
significantly impacts the substrate scope of the DBR. We
speculated that the presence of a Brønsted acid would
significantly impact the reactivity of nitroso intermediates 2
and 3 (Scheme 2), enabling Mills-like N−N bond formation.
The traditional DBR is, unfortunately, incompatible with
Brønsted acids because KOH is used to generate the nitroso
species. However, our group recently demonstrated that the
key nitroso imine intermediate can be generated in situ under
photochemical conditions14 in aqueous PBS solution and
Scheme 2. Generating Key Intermediates in Situ
subsequently intercepted by primary amines (Scheme 2).15
Kambe16 and Chen17 more recently reported similar photo-
chemical methods leading to indazolones, but it should be
noted that accessing N-aryl products using their methods
remains problematic. Development of these photochemical
methods gave us the experimental flexibility required to study
Received: June 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02213
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Letter
the highly reactive nitroso intermediates under Brønsted acid
catalysis (Scheme 1B).
propargyl alcohol and m-cresol failed to give indazoles 10a/
10b and 11, respectively. When carried out in tert-butanol,
indazole 12 was not obtained. Instead, N-aryl indazolone 12a
(64%; 12b in 71% from p-anisidine) was formed, either by
addition of H2O instead of tert-butanol to 57 (see Figure 4) or
by acid-mediated hydrolysis of indazole 12 (see SI for
additional discussion). Obtaining 12a and 12b represents a
major improvement over other direct methods for N-aryl
indazolone synthesis (see Scheme 1A).11b,15−17 While p-
aminopyridine did not give 13, naphthalen-2-amine success-
fully gave 14 in 75% yield. Comparing 15 vs 16 highlights the
role of reactive intermediate steric demands, while comparing
18 vs 19a/19b/20 highlights substrate electonic effects on
reaction outcome. Due to the short reaction time and limited
UV exposure, starting material aryl halides did not undergo
bond scission during the course of the reaction;15,17 the
successful preparation of indazoles 21−26 demonstrates the
tolerance of various halogens. While p-iodoaniline and m-
chloroaniline give the corresponding indazoles in good yield
(77% and 75%, respectively), the use of o- and m-bromoaniline
resulted in lower yields (36% and 43%, respectively). Finally,
when the synthesis of 5 was performed on a 300 mg scale, an
82% yield was obtained.
When we treated 1 equiv of o-nitrobenzyl alcohol, 1 equiv of
aniline, catalytic amounts of H2SO4, and iPrOH in a quartz test
tube with >365 nm light18 for 24 h, indazole 5 was obtained in
61% yield. We were delighted by this result because secondary
alcohols have never been successfully incorporated using this
chemistry due to their reduced nucleophilicity relative to
MeOH or EtOH.19 Indeed, exploiting the nonreactivity of
iPrOH with nitroso imines was central in the strategy we
previously employed for direct indazolone synthesis via the
DBR.11b Incorporating N-aryl and O-isopropyl substituents
into this heterocyclic framework represents the most
challenging substitution pattern for the DBR.
After optimizing the reaction (see Supporting Information
[SI]; Table S1 for details), the substrate scope was explored
(Figure 1). EtOH, MeOH, cyclopentanol, and 2-methoxye-
thanol provided indazoles (6−9) in excellent yields, but allyl/
Intramolecular DBRs are expected to give polycyclic
indazoles when anilines with tethered alcohols are used due
to intramolecular incorporation of the alcohol nucleophile
(Figure 2).20 However, since alkoxy indazoles are also known
to undergo hydrolysis to indazolones when treated with a
Figure 1. N-Aryl 2H-indazole synthesis. Reaction conditions:
ThermalSpa photolysis of o-nitrobenzyl alcohol (0.5 mmol, 1
equiv), aniline (0.25 mmol, 0.5 equiv), alcohol solvent (10 mL),
H2SO4 (10 μL), rt, 4 h. Isolated yields are reported. a 300 mg scale
reaction.
Figure 2. Tethered alcohol reactivity. Reaction conditions: Thermal-
Spa photolysis of 1 (0.5 mmol, 1 equiv), amine (0.25 mmol, 0.5
equiv), DMF or PrOH (10 mL), H2SO4 (10 μL), rt, 4 h. Isolated
i
yields are reported.
B
DOI: 10.1021/acs.orglett.9b02213
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Brønsted acid, it was not straightforward to predict the
outcome under acid-mediated reaction conditions.21 Indeed,
i
when 27 was reacted with 1 in PrOH, indazole 28 and
indazolone 29 were obtained in 23% and 25% yields,
respectively. With the realization that the synthesis of 29
traditionally required a three-step sequence (N-alkylation,
DBR, then KI/Δ),6c we attempted to improve the yield of the
indazolone product by screening additional solvents: DCM,
THF, and DMF. While both DCM and THF gave complex
mixtures, DMF gave indazolone 29 in 73% yield; subsequent
Figure 3. Different modes of nitroso imine protonation.
i
reactions were performed in parallel using both PrOH and
with DFT after systematic conformational searches were
performed using Spartan10 (see SI for details). At equilibrium,
protonation of the imine nitrogen is clearly favored over
protonation of the nitroso group at either N or O: 45 was
thermodynamically favored over 44 by 31.6 kcal/mol and over
46 by 12.3 kcal/mol.
There are three known productive pathways leading to
different heterocycles from the same nitroso intermediates
(Figure 4): Pathway A leads to indazolones,11b Pathway B
leads to 2H-indazole N-oxides,13 and Pathway C leads to 3-
alkoxy 2H-indazoles.10,11 We studied all three pathways to
understand the divergent reactivity between alkyl and aryl
amines. First, Pathway B reaction energetics for both N-alkyl
and N-aryl analogues were examined and ring closure to give
the corresponding 2H-indazole N-oxide was found to be
kinetically feasible at room temperature for both substrates,
although the N-aryl case has a higher barrier (Figure 4;
Pathway B).13 The 2H-indazole N-oxide product from this
cyclization is thermodynamically downhill in both cases, but
less so for the aryl case. Consequently, ring opening back to
the nitroso imine is more likely with N-aryl substrates.
DMF. Using 30 in the reaction gave 6−5−7−6 fused indazole
i
31 in 87% and 61% yields in PrOH and DMF, respectively;
indazolone 32 was not formed in either solvent. When
secondary alcohol 33 was employed as a substrate, the reaction
gave 37% of indazole product 34 and 0% of the indazolone
product 35 (iPrOH as solvent). When DMF was used as the
solvent, 13% of 34 and 0% of 35 were obtained. While using
tert-butyl alcohol in the intermolecular reaction exclusively
gave indazolone 12a/12b, using tertiary alcohol-containing
substrate 36 surprisingly only gave fused indazole product 37
in 64% with iPrOH and 86% with DMF. Even though m-cresol
did not participate in the intermolecular example to give 11,
the reaction of 2-aminophenol (39) as a substrate with 1 in
iPrOH gave the desired 6−5−5−6 fused indazole 40, albeit in
only 15% yield due to the formation of 41 (39%) as a side
product. When the reaction was carried out in DMF, the yield
of 40 slightly increased to 28%. The surprising lack of
formation of 38 led us to wonder whether indazolone 29 arose
via an acid-mediated process from polycyclic indazole 28 or
from direct cyclization at the hemiaminal stage (Figure 4;
Pathway A).
Next, we examined ring closure reactions for hemiaminals
and hemiaminal ethers (Figure 4, Pathways A and C). For the
N-alkyl analogues, all modes of cyclization are predicted to be
kinetically feasible at room temperature, but Pathways A and C
have higher predicted barriers than Pathway B. In addition,
charge separated N−N cyclization intermediates 53 and 66 are
predicted to be formed in uphill processes. After the ring
closing events for Pathways A and C, we expect that solvent-
assisted proton transfer leads to the neutral cyclization
products (54 and 67, which are thermodynamically downhill).
For N-aryl analogues, we failed to identify any productive
transition state structures for Pathways A and C. We also were
unable to locate 49 or 62 as minima on the potential energy
surface; i.e. their N−N bonds are prone to barrierless cleavage.
To estimate the difficulty of such an N−N cyclization, we
optimized the geometries of 49 and 62 while constraining the
N−N distance (1.558 Å). Their relative energies exceed 20
kcal/mol, suggesting that their formation is neither kinetically
nor thermodynamically favorable. We also considered the
possibility of a concerted but asynchronous reaction that
combines the cyclization and internal proton transfer events,
thereby avoiding the formation of the charge separated
cyclized species, but predicted barriers exceeded 27 kcal/mol
for both Pathways A and C for the N-aryl analogues (see SI for
details). In all cases examined, cyclizations for N-alkyl
analogues had lower barriers and were more exergonic.
Based on our calculations, it is reasonable to expect that N−
N bond formation from hemiaminal intermediates is not
responsible for the N-aryl indazolones presented in Figures 1
and 2. Instead, they must be derived from Brønsted acid
catalyzed indazole rearrangements. Indeed, the computational
results lead us to suggest that N−N bond formation generally
Furthermore, as the problems with electron-rich anilines
foreshadowed, employing butylamine instead of aniline failed
to provide the corresponding indazole product (Scheme 3).
Scheme 3. Reactivity of Alkyl Amines
When 0.5 equiv of butylamine was used, a complex mixture
was obtained. In contrast, using 1 equiv of butylamine gave
2H-indazole N-oxide 42 in 21% yield13 and using 2 equiv of
butylamine gave indazolone 43 in 63% yield.15
To set the stage for constructing a mechanistic model for
this reaction, a better understanding of the interactions of 3
and Brønsted acid was needed. Since nitroso imine 3 has the
potential to be protonated at the nitroso oxygen, nitroso
nitrogen, or imine nitrogen, we used quantum chemical
calculations to study all three cases (Figure 3). Structures were
optimized with the PCM(DMSO)-M06-2X/6-31+G(d,p)22
and PCM(DMSO)-B3LYP-D3(BJ)/6-31+G(d,p)23 density
functional theory (DFT) methods. The geometries of the
lowest energy conformers for each structure were optimized
C
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Figure 4. Different modes of cyclization. Reported here are free energies in units of kcal/mol, calculated at PCM(DMSO)-M06-2X/6-31+G(d,p).
Electronic energies are shown in italic. Energies in blue and black are for phenyl and butyl reactions, respectively. Constrains are applied to the
nitrogen atoms (in red) during geometry optimization.
proceeds via Pathway B for N-aryl substrates. The proposed
mechanistic model for the work described here is represented
by 1 → 2 → 48 → 55 → 57 → indazole, where 2 → 48 → 55
and 57 → indazole are catalyzed by the Brønsted acid. This
mechanistic model is fully consistent with the poor perform-
ance of alkyl amines because their nucleophilicity enables
competing Pathway A. We tested this proposed mechanistic
model by subjecting N-oxide 42 to the optimized reaction
conditions in MeOH, which provided the expected 3-methoxy-
2H-indazole product in 50% yield, whereas previously heat was
required for this transformation.13 Although using an aryl N-
oxide would have been preferred, they could not be isolated
without significant decomposition due to their ring opening
back to nitroso imine.13
reaction is as follows. First, it catalyzes aniline’s condensation
with nitroso benzaldehyde 2 to give nitroso imine 55. Second,
when alcohol reacts with 55 to give unproductive hemiaminal
ether 61, the Brønsted acid accelerates C−O bond cleavage/
CN bond formation to regenerate nitroso imine 55, which
gives 55 additional opportunities to cyclize to N-oxide 57.
Brønsted acid also catalyzes the reaction of alcohol solvent
with N-oxide 57 to deliver 3-alkoxy 2H-indazole by
protonating at the oxygen of 57. Thus, in contrast to our
̀
initial hypothesis vis-a-vis the Mills reaction, N−N bond
formation is not Brønsted acid catalyzed in this reaction.
Indeed, the originally discovered Davis−Beirut reaction
involves base-mediated conversion of 58 to 3-alkoxy 2H-
indazole; i.e., N−N bond formation does not require a
Brønsted acid.
Our results clarify the role of the Brønsted acid in this
transformation. Since the predicted equilibrium suggests that
the formation of 2H-indazole N-oxide is not being catalyzed
In summary, the photochemistry of 1 unlocks previously
incompatible reaction conditions for the DBR; the conse-
quence is greatly improved DBR flexibility and synthetic utility.
Inter- and intramolecular examples were both probed
experimentally, and the mechanistic model of this Brønsted
i
and catalyzing PrOH addition to nitroso imine is also not
predicted to be productive for accessing the 3-isopropoxy 2H-
indazoles, the most reasonable role of Brønsted acid in this
D
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2010, 12, 2524. (d) Zhu, C.; Kalin, A. J.; Fang, L. Acc. Chem. Res.
2019, 52, 1089.
acid catalyzed reaction was studied using quantum chemical
calculations. A Brønsted acid facilitates the reaction, but it does
not directly catalyze N−N bond formation. Rather, it catalyzes
formation of 2 to 55 and conversion of 57 to alkoxy 2H-
indazole.
́
(7) (a) Halland, N.; Nazare, M.; R’kyek, O.; Alonso, J.; Urmann, M.;
Lindenschmidt, A. Angew. Chem., Int. Ed. 2009, 48, 6879. (b) Jin, T.;
Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 3323. (c) Shamsabadi,
́
A.; Chudasama, V. Chem. Commun. 2018, 54, 11180. (d) Thome, I.;
Besson, C.; Kleine, T.; Bolm, C. Angew. Chem., Int. Ed. 2013, 52,
ASSOCIATED CONTENT
* Supporting Information
7509.
■
S
(8) (a) Genung, N. E.; Wei, L.; Aspnes, G. E. Org. Lett. 2014, 16,
3114. (b) Nykaza, T. V.; Harrison, T. S.; Ghosh, A.; Putnik, R. A.;
Radosevich, A. T. J. Am. Chem. Soc. 2017, 139, 6839. (c) Schoene, J.;
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02213.
́
Bel Abed, H.; Schmieder, P.; Christmann, M.; Nazare, M. Chem. - Eur.
J. 2018, 24, 9090.
(9) (a) Correa, A.; Tellitu, I.; Domínguez, E.; SanMartin, R. J. Org.
Chem. 2006, 71, 3501. (b) Lin, W.; Hu, M.-H.; Feng, X.; Cao, C.-P.;
Huang, Z.-B.; Shi, D.-Q. Tetrahedron 2013, 69, 6721. (c) Yu, D.-G.;
Suri, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135, 8802.
(10) Kurth, M. J.; Olmstead, M. M.; Haddadin, M. J. J. Org. Chem.
2005, 70, 1060.
(11) (a) Mills, A. D.; Nazer, M. Z.; Haddadin, M. J.; Kurth, M. J. J.
Org. Chem. 2006, 71, 2687. (b) Zhu, J. S.; Kraemer, N.; Shatskikh, M.
E.; Li, C. J.; Son, J.-H.; Haddadin, M. J.; Tantillo, D. J.; Kurth, M. J.
Org. Lett. 2018, 20, 4736.
Experimental procedures, compound characterization,
1H and 13CNMR spectra, computational details (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mjkurth@ucdavis.edu.
ORCID
Jie S. Zhu: 0000-0003-3009-4135
Dean J. Tantillo: 0000-0002-2992-8844
Mark J. Kurth: 0000-0001-8496-6125
Author Contributions
§N.K. and C.J.L. contributed equally.
(12) Merino, E. Chem. Soc. Rev. 2011, 40, 3835.
(13) Zhu, J. S.; Li, C. J.; Tsui, K. Y.; Kraemer, N.; Son, J.-H.;
Haddadin, M. J.; Tantillo, D. J.; Kurth, M. J. J. Am. Chem. Soc. 2019,
141, 6247.
̌
́
(14) (a) Klan, P.; Solomek, T.; Bochet, C. G.; Blanc, A.; Givens, R.;
Rubina, M.; Popik, V.; Kostikov, A.; Wirz, J. Chem. Rev. 2013, 113,
Notes
̈
119. (b) Il’ichev, Y. V.; Schworer, M. A.; Wirz, J. J. Am. Chem. Soc.
2004, 126, 4581. (c) Gaplovsky, M.; Il’ichev, Y. V.; Kamdzhilov, Y.;
The authors declare no competing financial interest.
̈
Kombarova, S. V.; Mac, M.; Schworer, M. A.; Wirz, J. Photochemical &
Photobiological Sciences 2005, 4, 33.
(15) Zhu, J. S.; Kraemer, N.; Li, C. J.; Haddadin, M. J.; Kurth, M. J.
J. Org. Chem. 2018, 83, 15493.
(16) Yang, T.; Lu, H.; Qiu, R.; Hong, L.; Yin, S.-F.; Kambe, N.
Chem. - Asian J. 2019, 14, 1436.
(17) Nie, H.-J.; Guo, A.-D.; Lin, H.-X.; Chen, X.-H. RSC Adv. 2019,
9, 13249.
(18) Aung, T.; Liberko, C. A. J. Chem. Educ. 2014, 91, 939.
(19) Phan, T. B.; Breugst, M.; Mayr, H. Angew. Chem., Int. Ed. 2006,
45, 3869.
(20) Butler, J. D.; Solano, D. M.; Robins, L. I.; Haddadin, M. J.;
Kurth, M. J. J. Org. Chem. 2008, 73, 234.
(21) Conrad, W. E.; Fukazawa, R.; Haddadin, M. J.; Kurth, M. J.
Org. Lett. 2011, 13, 3138.
(22) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215.
(23) (a) Cammi, R.; Mennucci, B.; Tomasi, J. In Computational
Chemistry: Reviews of Current Trends; Leszczynski, J., Ed.; World
Scientific Publishing Co. Pte. Ltd.: Singapore, 2003; Vol. 8. (b) Becke,
A. D. J. Chem. Phys. 1993, 98, 5648. (c) Grimme, S.; Ehrlich, S.;
Goerigk, L. J. Comput. Chem. 2011, 32, 1456. (d) Lee, C.; Yang, W.;
Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785.
(e) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett.
1989, 157, 200.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge financial support from the
National Institutes of Health (DK072517 and DK067003 to
M.J.K.) and NSF XSEDE program (CHE030089 to D.J.T.).
Funding for NMR spectrometers was provided by National
Science Foundation (DBI722538 and CHE9808183) and
National Institute of Environmental Health (ES005707-13).
N.K. is supported by the UC Davis Provost’s Undergraduate
Fellowship. J.S.Z. is supported by the UC Davis Tara K.
Telford CF Fund, UC Davis Dissertation Year Fellowship, and
R. Bryan Miller Graduate Fellowship. The authors thank the
Shaw group (UC Davis) for use of their Teledyne ISCO
CombiFlash and Mr. David Favela (Olson group, UC Davis)
for assistance with synthesis of 36.
REFERENCES
■
(1) Fletcher, S.; McIver, E.; Lewis, S.; Burkamp, F.; Leech, C.;
Mason, G.; Boyce, S.; Morrison, D.; Richards, G.; Sutton, K.; Brian
Jones, A. Bioorg. Med. Chem. Lett. 2006, 16, 2872.
(2) Kim, D.; Wang, L.; Caldwell, C. G.; Chen, P.; Finke, P. E.; Oates,
B.; MacCoss, M.; Mills, S. G.; Malkowitz, L.; Gould, S. L.; DeMartino,
J. A.; Springer, M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Danzeisen,
R.; Carver, G.; Carella, A.; Holmes, K.; Lineberger, J.; Schleif, W. A.;
Emini, E. A. Bioorg. Med. Chem. Lett. 2001, 11, 3103.
́
(3) Vega, M. C.; Rolon, M.; Montero-Torres, A.; Fonseca-Berzal, C.;
́
́
́
Escario, J. A.; Gomez-Barrio, A.; Galvez, J.; Marrero-Ponce, Y.; Aran,
V. J. Eur. J. Med. Chem. 2012, 58, 214.
(4) Wang, H.; Han, H.; Von Hoff, D. D. Cancer Res. 2006, 66, 9722.
(5) Kawanishi, N.; Sugimoto, T.; Shibata, J.; Nakamura, K.;
Masutani, K.; Ikuta, M.; Hirai, H. Bioorg. Med. Chem. Lett. 2006,
16, 5122.
(6) (a) Haddadin, M. J.; Conrad, W. E.; Kurth, M. J. Mini-Rev. Med.
Chem. 2012, 12, 1293. (b) Schmidt, A.; Beutler, A.; Snovydovych, B.
Eur. J. Org. Chem. 2008, 2008, 4073. (c) Donald, M. B.; Conrad, W.
E.; Oakdale, J. S.; Butler, J. D.; Haddadin, M. J.; Kurth, M. J. Org. Lett.
E
DOI: 10.1021/acs.orglett.9b02213
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