A niobium-catalyzed coupling reaction of α-keto acids with: Ortho -phenylenediamines: Synthesis of 3-arylquinoxalin-2(1 H)-ones

Article abstract of DOI:10.1039/c9gc02662b

A general methodology to access valuable 3-arylquinoxalin-2(1H)-ones was developed, by the reaction of α-keto acids with ortho-phenylenediamines in the presence of ammonium niobium oxalate (ANO) as a catalyst. The reactions were conducted in only 10 min under ultrasonic irradiation as an alternative energy source, affording water as the only co-product. A total of twenty-three different 3-arylquinoxalin-2(1H)-ones were selectively obtained in good to excellent yields by this atom-efficient protocol. Additionally, ¹H-¹⁵N HMBC experiments were used to reveal the regioisomerism of the obtained products.

Full text of DOI:10.1039/c9gc02662b

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A niobium-catalyzed coupling reaction of α-keto
acids with ortho-phenylenediamines: synthesis of
Cite this: Green Chem., 2019, 21,
154
6
3-arylquinoxalin-2(1H)-ones†
Camila Ebersol, Nicole Rocha, Filipe Penteado,
Márcio S. Silva,
Daniela Hartwig, Eder J. Lenardão * and Raquel G. Jacob
*
A general methodology to access valuable 3-arylquinoxalin-2(1H)-ones was developed, by the reaction of
α-keto acids with ortho-phenylenediamines in the presence of ammonium niobium oxalate (ANO) as a
catalyst. The reactions were conducted in only 10 min under ultrasonic irradiation as an alternative energy
source, affording water as the only co-product. A total of twenty-three different 3-arylquinoxalin-2(1H)-
ones were selectively obtained in good to excellent yields by this atom-efficient protocol. Additionally,
Received 29th July 2019,
Accepted 10th October 2019
DOI: 10.1039/c9gc02662b
1
15
rsc.li/greenchem
H– N HMBC experiments were used to reveal the regioisomerism of the obtained products.
functional groups at the C3 position of the quinoxalin-2(1H)-
one core. However, the need for prior preparation of the start-
Introduction
Nitrogen heterocycles are one of the most important classes of ing quinoxalinones, together with the use of volatile solvents,
naturally occurring and synthetic compounds, with a number large excess of oxidants or strong bases are some limitations of
of biological activities, being present in countless marketable this strategy. One alternative approach to access 3-substituted
1
drugs, high-performance materials and dyes. Among these quinoxalinones is the reaction of ortho-phenylenediamine (1,2-
1
2
compounds, 3-substituted quinoxalin-2(1H)-ones are privileged diaminobenzene) with functionalized ketone derivatives.
chemical skeletons in drug discovery, which have been exten-
1
3
Since 1991, when Fontana and co-workers disclosed the
sively studied, presenting an impressive spectrum of important use of α-keto acid derivatives in the decarboxylative acylation
2
biological properties. For instance, the 3-phenol-quinoxalin-2 of N-heterocycles, they have emerged as green acyl transfer
1
4
(
(
1H)-one derivative A has demonstrated effective aldol reductase agents in
a
number of organic transformations.
3
ALR2) activity, the pyridyl derivative B has proved to be a Furthermore, α-keto acids have also been widely applied as car-
potent VEGFR-2 kinase inhibitor, blocking the angiogenesis bonyl partners in condensation/cyclization reactions, in the
4
process and showing anticancer activity, while the pyrrolidinyl presence of several nucleophiles, to access different hetero-
derivative C is a prolyl oligopeptidase inhibitor, exhibiting anti-
5
depressant activity. Another important compound is caroverine
(
D), a spasmolytic marketed drug (Tinnex®), which is indicated
6
for the treatment of tinnitus in humans (Fig. 1).
In view of the wide spectrum of pharmacological appli-
cations of 3-substituted quinoxalin-2(1H)-ones, the develop-
ment of efficient, general and selective synthetic methods to
access these compounds is of great interest. In this context,
several methodologies based on the C–H activation strategies
7
of pre-formed quinoxalin-2(1H)-ones, including arylation,
8
9
10
amidation, acylation, alkynylation and phosphonation reac-
tions, have emerged as robust alternatives to install valuable
1
1
LASOL - CCQFA, Universidade Federal de Pelotas - UFPel, P.O. Box 354, 96010-900
Pelotas, RS, Brazil. E-mail: lenardao@ufpel.edu.br, raquel.jacob@ufpel.edu.br
†
Electronic supplementary information (ESI) available: Detailed experimental
procedures and figures of NMR spectra of the prepared compounds. See DOI:
0.1039/c9gc02662b
1
Fig. 1 Bioactive 3-substituted quinoxalin-2(1H)-ones.
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Table 1 Optimization of the reaction conditions to prepare 3-phenyl-
a
quinoxalin-2(1H)-one 3a
b
b
Entry
ANO (mol%)
Solvent
EtOH
H O
2
MeCN
3a Yield (%)
4a Yield (%)
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
10
3
1
36
70
41
57
65
96
92
89
85
70
89
21
20
21
20
—
—
—
—
—
—
—
DMSO
Glycerol
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
Scheme 1 Previous and present work to prepare quinoxalin-2(1H)-
ones 3 from α-keto acids 1.
10
1
—
5
c
1
1
5
cyclic compounds. In this sense, α-keto acids have been used
as 2-carbon suppliers in reactions with o-phenylenediamines
to prepare 3-arylquinoxalin-2(1H)-ones. This protocol was
a
A mixture of 1a (0.3 mmol), 2a (0.3 mmol) and ANO in 0.5 mL of
solvent was sonicated (20% of amplitude) in an open flask for 10 min.
1
2
b
c
Isolated yield. The reaction was performed using conventional
originally used for analytical purposes, in the characterization heating (oil bath) at 70 °C, for 1 h.
1
6
of α-keto acids as the respective quinoxalinols and in the syn-
1
7
thesis of few bioactive derivatives. A second product that can
be obtained in this reaction, however, is the respective benz-
imidazole, and the ratio between the 6- and 5-membered pro-
ducts depends on several factors, such as the nature of the
solvent, the use or not of catalyst/additives, the temperature,
ined the effect of the solvent using 5 mol% of ANO as a catalyst
and ultrasound (US) as a non-conventional energy source.
As mentioned before, the formation of 2-phenylbenzimid-
azole 4a is a competitive reaction which contributes to decrease
the yield of the desired 3-phenylquinoxalin-2(1H)-one 3a. Both
the reaction yield and the selectivity to 3a were directly
affected by the solvent, as it can be seen in Table 1, entries
1–6. When EtOH was used as the solvent, a mixture of 3a and
1
5a,18
the structure of the reagents, etc.
These two products can
be separated by column chromatography; however, chromato-
graphy has been identified as a major contributor for solvent
waste within the medicinal chemistry discipline, mainly when
1
9
considering large scale production. In addition, the use of
acid additives, flammable VOCs and organochlorine solvents
under heating for a long period (up to 24 h) is the significant
4a was obtained in 57% overall yield with a 3a : 4a ratio of
63 : 37 (Table 1, entry 1). A remarkable increase in the reaction
1
8
yield to 90% was observed using H O as the solvent; however
2
drawback of the current protocols (Scheme 1).
the co-product 4a was still formed in a considerable amount
Recently, we have described the reaction of α-keto acids
with ortho-functionalized anilines (o-SH and o-OH) using
ammonium niobium oxalate (ANO) as a cheap, bench stable
and easy to handle catalyst, and PEG-400 as a solvent. Despite
the excellent yields obtained of the respective 2-arylbenzothi-
azoles and 3-aryl-2H-benzo[b][1,4]benzoxazin-2-ones under con-
ventional heating (100 °C, 2 h), it was observed that ultrasonic
irradiation could be successfully employed as a green, alterna-
tive energy source, in order to enhance the reaction efficiency
(
3a : 4a ratio of 78 : 22; Table 1, entry 2). The reaction yields
decreased when H O was replaced for the polar aprotic sol-
2
vents MeCN and DMSO, and a mixture of 3a and 4a was
obtained in 62% and 77% yields (Table 1, entries 3 and 4). The
expected 3-phenylquinoxalin-2(1H)-one 3a was the only
product (isolated in 65% yield) when glycerol was used as the
solvent (Table 1, entry 5). This result has motivated us to
explore the use of the equally non-volatile PEG-400 as the
solvent and to our delight, the product 3a was formed solely in
2
0
while reducing the reaction time.
96% yield after 10 min of sonication (Table 1, entry 6). Once
Accordingly, as a continuation of our efforts in the develop-
ment of green protocols to access valuable bioactive scaffolds, we
report herein the regioselective ultrasound-assisted niobium-cata-
lyzed reaction between aryl α-keto acids 1 and o-phenylenedi-
amines 2 to obtain 3-arylquinoxalin-2(1H)-ones 3 (Scheme 1).
the solvent with the best performance was found, the effect of
the catalyst amount was evaluated (1, 3 and 10 mol%) and a
slight decrease in the yields was observed in all cases,
although the selectivity to 3a remained unaffected (Table 1,
entries 7–9 vs. entry 6). However, in the absence of ANO as the
catalyst, a notable decrease in the reaction efficiency was
observed, and the product 3a was obtained in only 70% yield
Results and discussion
(
Table 1, entry 10). Finally, carrying out the reaction under con-
The reaction conditions were investigated as outlined in ventional heating (70 °C) led to an increase in the reaction
Table 1, employing phenylglyoxylic acid (PGA) 1a and time to 1 h, affording the desired product 3a in 89% yield
o-phenylenediamine 2a as starting materials. Firstly, we exam- (Table 1, entry 11). This outcome confirms that US irradiation
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plays a crucial role in the reaction, accelerating the process inseparable mixture of isomers (3k : 3k* ratio = 1.3 : 1) in 85%
1
remarkably. Considering the data from Table 1, the conditions yield. The electron-poor o-phenylenediamines 2d (R = 4-Cl)
1
of entry 6, i.e., the sonication of equivalent amounts of 1a and and 2e (R = 4-NO
2
) however were less reactive substrates and
2
a in the presence of ANO (5 mol%) as the catalyst and the respective products 3n and 3r* were isolated in 40%
PEG-400 as the solvent, were chosen for subsequent studies.
With the best conditions in hand, a study was carried out
(together with 35% of 4n) and 37% yields.
Following, we investigated the reactivity of differently sub-
in order to establish the scope and limitations of the protocol stituted α-keto acids 1 with o-phenylenediamine 2a. As can be
Table 2). The respective 3-arylquinoxalin-2(1H)-one 3 was the seen in Table 2, any remarkable influence was observed when
(
only product obtained in all the tested examples, except in the weak electron-donor (1b, R = 4-Me) and electron-withdrawing
1
reaction of 4-chlorobenzene-1,2-diamine 2d (R = 4-Cl) with (1d, R = 4-F and 1e, 4-Br) groups were attached in the para-
PGA 1a (R = H), which afforded an about 1 : 1 mixture of quin- position, and the respective products 3b, 3d and 3e were
oxalin-2(1H)-one 3n and 6-chloro-2-phenyl-1H-benzo[d]imid- obtained in 75%, 84% and 70% yields. 2-Bromophenyl-
azole 4n in 75% overall yield (Table 2). Similar to unsubsti- glyoxylic acid 1f (R = 2-Br) was also a good substrate for the
1
tuted o-phenylenediamine 2a (R = H), the electron-rich reaction, affording the expected product 3f in 82% yield, indi-
1
o-phenylenediamine 2b [R = 4,5-(Me)
2
] was a suitable sub- cating that the steric effect did not influence the reaction per-
strate in the reaction with PGA 1a, affording the respective quin- formance. The presence of the strong electron-donor methoxy
oxalin-2(1H)-one derivative 3g in 85% yield. The unsymmetri- group in 1c (R = 4-MeO) however negatively influenced the
1
cal electron-rich o-phenylenediamine 2c [R = 4-Me] was a reaction, and the respective quinoxalin-2(1H)-one 3c was
good substrate in the reaction with PGA 1a (R = H), affording obtained in only 34% yield. A similar reactivity was observed
the expected 3-arylquinoxalin-2(1H)-ones 3k and 3k* as an in the reactions of p-substituted arylglyoxylic acids 1b and 1d
with 4,5-dimethylbenzene-1,2-diamine 2b, with the respective
products 3h and 3i being isolated in 80% and 91% yields,
respectively. In this case, 2-bromophenylglyoxylic acid 1f was
less reactive, and the expected product 3j was obtained in 50%
yield.
Table 2 Substrate scope for the synthesis of 3-arylquinoxalin-2(1H)-
ones 3
a,b,c
Regarding unsymmetrical electron-rich o-phenylene-
1
diamine 2c [R = 4-Me], a notable loss of selectivity was
observed by employing phenylglyoxylic acid derivatives 1d (R =
4
-F) and 1f (R = 2-Br) as substrates, giving an inseparable
mixture of the products 3l : 3l* (3l : 3l* ratio = 1.5 : 1) and
m : 3m* (3m : 3m* ratio = 1.5 : 1) in 89% and 73% yields,
3
respectively (Table 2).
As mentioned before, for reactions with PGA 1a, the pres-
ence of a chlorine atom in the starting 4-chlorobenzene-1,2-
1
diamine 2d (R = 4-Cl) has changed the reactivity of the sub-
strate, causing the loss of selectivity for the phenylquinoxalin-
2
4
(1H)-one 3n. In the reaction of p-tolylglyoxylic acid 1b with
-chlorobenzene-1,2-diamine 2d, the expected quinoxalin-2
(
1H)-one was obtained in 85% overall yield, as a mixture of
7-chloro-3o (47%) and 6-chloro-3-(p-tolyl)quinoxalin-2(1H)-one
3o* (38%). A mixture of isomers was also obtained in the reac-
tion between 2d and 2-bromophenylglyoxylic acid 1f, which
afforded 3p and 3p* in 64% and 28% yields, respectively.
Interestingly, 2d reacted with the electron-poor 4-fluorophenyl-
glyoxylic acid 1d (R = 4-F) to give exclusively 7-chloro-3-(4-fluoro-
phenyl)quinoxalin-2(1H)-one 3q (58% yield) under the optimal
conditions. As anticipated for the reactions with PGA 1a, a
notable decrease in reactivity was observed when 4-nitro-
1
benzene-1,2-diamine 2e (R = 4-NO
2
) was used as a substrate.
For instance, products 3t (R = Me) and 3u (R = F) were obtained
in only 38% and 35% yields by the reaction of 2e with 1b and
1
d, respectively. The yield decreases even more when 2-bromo-
a
A mixture of 1 (0.3 mmol), 2 (0.3 mmol) and ANO (5 mol%) in phenylglyoxylic acid 1f was used, and a mixture of isomers 3s
PEG-400 (0.5 mL) was sonicated (20% of amplitude) in an open flask
for 10 min. Asterisk represents the presence of a regioisomer (substi-
tuted at C6). Isolated yield. Reaction performed in the absence of
ANO. Regioisomers ratio determined by H NMR (ref. 23).
and 3s* was obtained in 28% overall yield (Table 2).
b
c
d
As demonstrated in the optimization studies, the reaction
e
1
of 1a with 2a proceeded to some extent in the absence of ANO,
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affording 3-phenylquinoxalin-2(1H)-one 3a in 70% yield after
sonication for 10 min (Table 1, entry 10). Aiming to speculate
on the effectiveness of this catalyst-free approach, it was
extended to other substrates. Thus, phenylglyoxylic acid 1a
reacted with 4,5-dimethylbenzene-1,2-diamine 2b and 4-chloro-
benzene-1,2-diamine 2d to afford the expected products 3g
and 3n in 47% and 11% yields, respectively (Table 2). In the
case of 2d, 6-chloro-2-phenyl-1H-benzo[d]imidazole 4n was
also isolated in 13% yield. The reaction of 4-fluorophenyl-
glyoxylic acid 1d with 2d afforded, under the catalyst-free con-
ditions, 3q in 40% yield. Taken together, these results confirm
the importance of ANO as a catalyst in the developed reaction,
mainly regarding the reaction scope.
2
3
Fig. 2 Chemical shifts of sp and sp hybridized nitrogen atoms.
In order to show the synthetic usefulness of this protocol to
access the pharmaceutically interesting quinoxalin-2(1H)-one
As can be seen in Fig. 2, quinoxalin-2(1H)-one 3o has two
3
core,
a
gram-scale synthesis (5 mmol) was performed. types of nitrogen atoms: one sp hybridized nitrogen, associ-
1
5
Satisfactorily, the desired 3-phenylquinoxalin-2(1H)-one 3a was ated with a secondary amide group ( N NMR chemical shifts
obtained in 87% yield after 1 h under the optimal conditions, ranging from 110 to 160 ppm), and one sp hybridized nitro-
2
1
5
demonstrating the robustness of our methodology (Scheme 2). gen, related to a six-membered aromatic heterocycle ( N NMR
Considering that this important reaction, which gives chemical shifts ranging from 230 to 330 ppm). Thus, the corre-
access to biologically valuable compounds, can be driven lation between the hydrogen atoms from the phenyl ring of
towards the formation of two regioisomers when 4-substituted- the benzenediamine partner with these two types of nitrogen
benzene-1,2-diamines 2 are used, an accurate method for the atoms provides the unambiguous characterization of each
1
5
easy determination of the regioisomeric ratio is required. There regioisomer. The same profile is observed in the N NMR
1
15
are no additional data in the literature which can be explored to chemical shifts of the benzimidazole 4n (Fig. 2). In the H– N
identify quinoxalin-2(1H)-one regioisomers such as 3 and 3*. HMBC NMR spectra of the products 3r*, 3s*, 3t and 3u,
1
1
Chromatography and H NMR techniques are normally used to bearing a nitro group (R = NO
2
), another nitrogen atom was
1
7,18,21
access the regioisomeric ratio,
been employed to determine the ratio values, which is not a ( N NMR chemical shifts ranging from 355 to 395 ppm). It is
while X-ray analysis has also observed in the 2D spectra with a downfield chemical shift
1
5
22
1
15
trivial and fast routine confirmation. On the other hand, some worth mentioning that H– N HSQC NMR experiments failed
reports do not present any information about regioisomerism,
18,23
1
15
in providing the H– N correlation, probably due to a possible
1
15
neither improvement in the selectivity towards one of the two keto–enol tautomerism of the products 3. Finally, the H– N
24
possible regioisomers. Aiming to offer such a simple protocol to HMBC NMR experiment can be used for a routine analysis
determine the regioisomeric ratios of some of the 3-arylquinoxa- (2–5 hours) to access the regioisomers of the quinoxalin-2(1H)-
lin-2(1H)-ones 3 prepared in this work, we developed a 2D NMR- one
based experiment, by using H– N HMBC.
3
core, without additional parameter optimization,
employing samples of around 20 mg of the compound in
Initially, we set out COSY, HSQC, and HMBC 2D NMR 600 µL of DMSO-d solvent. In terms of parameter selection,
experiments to try undoubtedly identifying all hydrogen and the H– N HMBC NMR experiment is a consolidated tech-
1
15
6
1
15
2
5
1
carbon atoms in the quinoxalin-2(1H)-one 3 and benzimid- nique, and the delay optimization for JNH was not necessary
azole 4 which were prepared in this work (Fig. 2). However, for (95 Hz). For the long-range H– N correlation, a coupling con-
1
15
most of the analyzed compounds, the 2D NMR experiments stant of 5 Hz provided satisfactory correlations. Even if only one
1
15
were not enough to identify each hydrogen at the phenyl ring correlation is obtained in the H– N HMBC experiment,
from the benzenediamine partner, due to the consolidated equally we can determine the structural assignment of the
1
15
multiplicity standard. Then, to confirm the regioisomerism, regioisomer (Fig. 2, product 3n). For the H– N HMBC NMR
1
15
H– N HMBC NMR experiments were carried out to easily experiments of products 3r*, 3s*, 3t and 3u, containing the
obtain the characterization data. The evidence is based on the nitro group, a wider spectral window should be used to avoid
1
5
2
3
huge N NMR chemical shift difference between sp and sp
the folding process (see the ESI† for the pictures of the spectra).
Some additional experiments were performed aiming to
suppress or minimize the formation of the co-product 4n in
the reaction of 4-chlorobenzene-1,2-diamine 2d with PGA 1a
hybridized nitrogen atoms.
(
Table S1†). For this purpose, the energy source, the US inten-
sity and the catalyst parameters were evaluated. When the
intensity of US was increased to 60% of amplitude, the selecti-
vity was moved to benzimidazoles 4n and the overall yield was
inferior to that of the optimal conditions. For the reactions
employing conventional heating (70 °C, oil bath) or US
Scheme 2 Gram-scale synthesis of 3a.
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without a catalyst, the overall yields were unsatisfactory, and and the expected product 3a was obtained in 75% and 83%
the low selectivity was maintained. A similar study was per- yields, discarding the hypothesis of a radical pathway in the
formed for the reaction of 4-nitrobenzene-1,2-diamine 2e with reaction mechanism.
1
a, aiming to improve the yield of 3r. Again, no improvement in
Based on this and considering a possible anionic mecha-
the reaction performance was observed, with the degradation of nism, we have investigated what would be the rate-determining
the reagents being observed. Conclusively, these results indicate reaction step, since two main possibilities are allowed: (1)
the propensity for a decarboxylative coupling of the α-keto acid NH
2
-free group of 2a attacking the keto site of 1a, giving an
1
a with o-phenylenediamine 2d and the consequent formation imine intermediate, or (2) NH -free group attacking the car-
2
of 2-substituted benzimidazoles 4n under strong US irradiation boxylic acid site, giving an amide intermediate. Thus, by carry-
1
5a
(
see Scheme 3 for a plausible mechanism).
Finally, control experiments were designed in order to give under the standard reaction conditions, the respective decar-
substantial support to elucidate a possible reaction mecha- boxylated imine derivative 6 was formed in 79% yield, without
2
ing out an experiment using aniline 5 as a NH -free source,
1
8b
nism. Considering the usual reactivity of α-keto acid 1 through any amide derivative (Scheme 3, control experiments).
a radical mechanism, we have investigated the behavior of Additionally, the double bond isomerism of the product 6 was
1
4
the reaction between PGA 1a and o-phenylenediamine 2a in confirmed by the 2D NOESY NMR experiment (see the ESI†).
1
4
the presence of 2 equiv. of TEMPO (2,2,6,6-tetramethyl-1-piper-
idinyloxy) as a radical scavenger using both conventional a plausible mechanism was proposed. Initially, an ANO-cata-
heating and US conditions (Scheme 3, control experiments). In lyzed reaction between the keto portion and an NH -free unit
Based on these control experiments and in the literature,
2
both cases, no change in the reaction efficiency was observed, affords the Schiff-base intermediate I, which can follow two
2
main reaction pathways: (1) addition to the imine sp carbon
(
dashed arrow) and/or (2) the amide formation by an addition/
elimination to the acid portion (solid arrow). In our case, the
attack on the acid carbonyl site is favored, forming the fused
six-membered heterocycle intermediate II, which is dehydrated
to give the quinoxalin-2(1H)-one 3a. This selectivity to II over
the five-membered intermediate III (and so 4a) could be attrib-
uted to a complexation of the catalyst (ANO) to the carbonyl in
I, favoring the nucleophilic attack by the remaining NH
Scheme 3, reaction mechanism).
2
group
(
Conclusions
Herein we described an easy, mild and efficient protocol to
access 3-arylquinoxalin-2(1H)-ones. Ammonium niobium
oxalate proved to be an efficient catalyst for the reaction, pro-
moting the annulation between o-phenylenediamines and
α-keto acids in only 10 min. The reactions are highly selective,
producing water as the sole by-product. Ultrasound irradiation
was used as an alternative energy source and PEG-400 as a
1
15
green and cheap solvent. H– N HMBC NMR experiments
proved to be a robust and reliable technique to access quinoxa-
lin-2(1H)-one and benzimidazole regioisomers.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This study was financed in part by the Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brasil,
Finance Code 001. Financial support from FAPERGS (PqG
17/2551-0000987-8), CNPq and FINEP is acknowledged. CBMM
Scheme 3 Control experiments and plausible reaction mechanism.
(Brazil) is acknowledged for providing the ANO.
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