Green Hydrothermal Synthesis of Fluorescent 2,3-Diarylquinoxalines and Large-Scale Computational Comparison to Existing Alternatives

Article abstract of DOI:10.1002/cssc.202100433

Here, the hydrothermal synthesis (HTS) of 2,3-diarylquinoxalines from 1,2-diketones and o-phenylendiamines (o-PDAs) was achieved. The synthesis is simple, fast, and generates high yields, without requiring any organic solvents, strong acids or toxic catalysts. Reaction times down to <10 min without decrease in yield could be achieved through adding acetic acid as promoter, even for highly apolar biquinoxalines (yield >90 % in all cases). Moreover, it was shown that HTS has high compatibility: (i) hydrochlorides, a standard commercial form of amines, could be used directly as combined amine source and acidic catalyst, and (ii) Boc-diprotected o-PDA could be directly employed as substrate that underwent HT deprotection. A systematic large-scale computational comparison of all reported syntheses of the presented quinoxalines from the same starting compounds showed that this method is more environmentally friendly and less toxic than all existing methods and revealed generic synthetic routes for improving reaction yields. Finally, the application of the synthesized compounds as fluorescent dyes for cell staining was explored.

Full text of DOI:10.1002/cssc.202100433

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Green Hydrothermal Synthesis of Fluorescent 2,3-
Diarylquinoxalines and Large-Scale Computational
Comparison to Existing Alternatives
[
a, b]
[c, d]
[c]
[c]
Fabián Amaya-García,
Jörg Menche,
Michael Caldera,
Anna Koren, Stefan Kubicek,
[c, d]
[a, b, c]
and Miriam M. Unterlass*
Here, the hydrothermal synthesis (HTS) of 2,3-diarylquinoxalines
from 1,2-diketones and o-phenylendiamines (o-PDAs) was
achieved. The synthesis is simple, fast, and generates high
yields, without requiring any organic solvents, strong acids or
toxic catalysts. Reaction times down to <10 min without
decrease in yield could be achieved through adding acetic acid
as promoter, even for highly apolar biquinoxalines (yield >90%
in all cases). Moreover, it was shown that HTS has high
compatibility: (i) hydrochlorides, a standard commercial form of
amines, could be used directly as combined amine source and
acidic catalyst, and (ii) Boc-diprotected o-PDA could be directly
employed as substrate that underwent HT deprotection. A
systematic large-scale computational comparison of all reported
syntheses of the presented quinoxalines from the same starting
compounds showed that this method is more environmentally
friendly and less toxic than all existing methods and revealed
generic synthetic routes for improving reaction yields. Finally,
the application of the synthesized compounds as fluorescent
dyes for cell staining was explored.
Introduction
the 1990s, Green Chemistry comprises the ambition to make
[2]
chemical synthesis and production more sustainable, which is
however quite complex: The generation of chemical com-
pounds involves several protagonists (i.e., precursors, the actual
transformation of precursors to products, products and side
products), and aspects of sustainability/green-ness are also
numerous (e.g., toxicity, hazardousness, renewability, (bio-)
degradability, recyclability) and have to be considered for all
involved protagonists. Research towards the improvement of
any of these aspects is important in its own right, and advances
in all aspects will collectively ultimately lead to fully sustainable
chemical synthesis and production. The aspect of the actual
transformation from precursors to products is already a major
focus in industry, but still lacks sufficient implementation on the
research lab-scale. This is especially true in organic synthesis,
which is often intensively employing multi-step syntheses and
purifications, often requiring toxic catalysts and large volumes
of petroleum-derived solvents and auxiliaries. Implementing
new synthetic approaches in organic research labs requires
fulfilling criteria such as (i) rapidity, (ii) efficiency (small number
of reaction steps, high yields, easy product purification), and (iii)
versatility (e.g., broad scope of starting compounds). New green
approaches are not exempt from fulfilling these criteria, and
additionally have to provide (iv) low environmental impact and
toxicity. Clearly, developing green synthesis routes is particu-
larly important for abundant compound classes.
The necessity of implementing and increasing sustainability in
all aspects of human life is nowadays widely accepted. For
instance, towards this end, the United Nations have in 2015
published the “2030 Agenda for Sustainable Development”
including the formulation of 17 “Sustainable Development
[1]
Goals”. Chemistry is a major cornerstone of modern life,
contributing both to the molecular understanding of various
natural and synthetic processes, and the design and manufac-
ture of various products, from personal care commodities to
pharmaceuticals and materials for devices. Hence, implement-
ing sustainable approaches in chemistry is potentially impactful
in numerous aspects of modern life. Conceptualized already in
[
a] F. Amaya-García, Prof. Dr. M. M. Unterlass
Institute of Applied Synthetic Chemistry
Technische Universität Wien
Getreidemarkt 9/163, 1060 Vienna (Austria)
E-mail: miriam.unterlass@tuwien.ac.at
b] F. Amaya-García, Prof. Dr. M. M. Unterlass
Institute of Materials Chemistry
[
[
Technische Universität Wien
Getreidemarkt 9/165, 1060 Vienna (Austria)
c] Dr. M. Caldera, A. Koren, Dr. S. Kubicek, Prof. Dr. J. Menche,
Prof. Dr. M. M. Unterlass
CeMM Research Center for Molecular Medicine of the Austrian Academy of
Sciences
Lazarettgasse 14, 1090 Vienna (Austria)
d] Dr. M. Caldera, Prof. Dr. J. Menche
Max Perutz Labs
[
Here, we have set out to both show that heteroaromatic
quinoxalines can be synthesized in nothing but liquid high-
temperature water (HTW), under so-called hydrothermal (HT)
conditions (Scheme 1A), and to demonstrate, for the first time,
the broad synthetic applicability of an organic hydrothermal
synthesis (HTS) with respect to substrate and product scope,
and compatibility with protecting group strategies. The moiety
Campus Vienna Biocenter 5, 1030 Vienna (Austria)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cssc.202100433
©
2021 The Authors. ChemSusChem published by Wiley-VCH GmbH. This is
an open access article under the terms of the Creative Commons Attribution
License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
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Scheme 1. (A) Synthetic approach of this work. (B) Classical synthesis towards 2,3-diarylquinoxalines. (C) Schematic of the physicochemical properties of water
ɛ=static dielectric constant, η=viscosity, 1=density, K =self-ionization of water) as a function of temperature (adapted from references [29,30]) and
(
w
examples of heteroaromatics obtained between 150–250°C (in the HT regime).
of choice, quinoxalines, also known as 1,4-benzopyrazines, are a
key scaffold among the important nitrogen-containing hetero-
aromatic compounds.
crystallization”, through which various minerals form naturally,
including many metal oxides (e.g., SiO , Al O ), many silicates
2
2
3
(e.g., olivine (Mg, Fe) SiO ), and all-natural zeolites. Interestingly,
2
4
Quinoxalines are widely used in medicine, for example, as
these minerals are all formed by cyclocondensation reactions
[3–5]
antibacterial, antifungal, or anticancer agents,
and also as
with H O as byproduct. At first glance, it seems counterintuitive
2
[6–8]
building blocks in advanced materials.
Various syntheses of
for a reaction product to form in its byproduct as medium. Yet,
research in the field of HTS of minerals has shown that HTW
possesses dehydrating abilities favoring (cyclo-)condensations
quinoxalines have been reported, most employing 1,2-diamines
in combination with different carbonyl compounds (Sche-
me 1B), that is, mainly diketones or α-substituted carbonyl
[22]
with H O as byproduct.
2
[
9–12]
[13]
compounds (e.g., α-hydroxyketones,
α-bromoketones or
In recent years, several reports provided evidence of the
suitability of HTS to also generate organic (cyclo-)condensation
[14]
α-oximeketones ), and the transformations require the pres-
ence of oxidizing agents. The vast majority of reported
syntheses of quinoxalines use traditional organic solvents and
[
23]
products. The reported examples to date comprise amides,
and in the realm of surprisingly apolar heteroaromatics: cyclic
[
24,25]
require reaction times (t ) of several hours. Furthermore, most
5- and 6-membered imides fused with aromatic rings,
benzimidazoles,
r
[26,27]
[28]
reported syntheses rely on catalysts, of which a wide variety has
and perinones. Besides the hydrothermal
[15]
been explored. A handful of works on quinoxaline synthesis
have targeted part of the aforementioned criteria (i)–(iv) for the
implementation of green synthesis. Specifically, reported green
regime, there are other regimes of liquid HTW: (i) the super-
critical regime (T >T (374.2°C) and p >p (22.1 MPa), with T
r
c
r
c
r
and p =reaction temperature and pressure, T and p =critical
temperature and pressure), and (ii) the subcritical or near-critical
r
c
c
approaches focus either on shortening t by using a combina-
r
[16–20]
tion of catalysts and microwave (MW) heating,
or using
regime (250°C<T <T and 1 bar<p <p ). These regimes vary
r
c
r
c
[21]
greener solvents. However, not a single work has to date
addressed all criteria. Herein, we have set out to show that all
criteria can be simultaneously fulfilled for quinoxalines through
HTS.
substantially in physicochemical properties, and consequently
also in the necessary equipment. First, the autogenous pressure
of water is still moderate until 250°C, but relatively high at
>250°C, that is, in proximity to the critical point. Hence,
synthesis in sub- and supercritical water places more stringent
demands on reaction vessel engineering than HTS. Second,
through structural changes in H O with T, properties that are
HTS designates using the reaction medium liquid water
above its boiling point but significantly below its critical point,
that is, broadly defined at reaction temperatures T of 100–
r
2
(l)
2
50°C, and more narrowly defined at approximately 150°C�
compounds for over 150 years. The technique is geomimetic by
imitating the natural mineral formation process “hydrothermal
very relevant for synthesis, such as density, viscosity, polarity,
and acidity/basicity, also change drastically and with different
T �250°C. HTS has been employed to generate inorganic
r
[29–31]
signatures.
The density and viscosity of H O decrease with
2 (l)
T, which is beneficial for mass transfer in all regimes, often
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resulting in astonishingly short t . Polarity-wise, the lower HT
quantitative yields are obtained at short reaction times (<1 h),
and purification is not required at all, given the absence of
other reagents such as catalysts or co-solvents. Hence, HTS
bears the potential to be an “ideal” technique for rapidly
providing access to a large number of derivatives. For harvest-
ing the potential of HTS, proof of the accessibility of further
than the reported functions is required, together with proof of
compatibility of HTS with organic synthesis requirements (e.g.,
broad scope, versatility). With this work, we have set out to
provide these proofs for 2,3-diarylquinoxalines.
r
regime is still quite polar, while the HT regime at 150°C�T �
r
2
50°C spans relative permittivities of approximately 41 (corre-
sponding to glycerol at RT) to approximately 25 (corresponding
to ethanol at RT), while the subcritical regime is already fairly
apolar, and the supercritical regime fully apolar (Scheme 1C).
Moreover, the maximal acidity and basicity of water through its
autoprotolysis are found at approximately 250°C but are lower
at both lower and higher T. Thus, around T ꢀ250°C Brønsted
r
acid/base catalysis is provided by the medium itself, which is
convenient for many reactions, including condensations. As
[23–28]
indicated by prior work,
and further substantiated through
this contribution, the HT range of approximately 250°C seems Results and Discussion
privileged for generating heteroaromatics through condensa-
tions, possibly enabled through an optimal combination and
interplay of the relevant physicochemical characteristics of the
medium.
To the best of our knowledge, there is only one report of
quinoxaline synthesis using water as solvent, and even at room
[21]
temperature.
Satisfactory yields for the condensation of
Water is the greenest possible solvent, as it is safer for the
scientist and for the environment than any other medium.
aliphatic 1,2-diketones with substituted o-phenylene diamines
are reported, but only very modest yields (<30%) are obtained
for examples employing aromatic 1,2-diketones. In particular,
the reaction between o-phenylendiamine (o-PDA) and 4,4’-
dimethoxybenzil to form quinoxaline 1 (Table 1) is obtained
with only 10% yield. The authors attribute this to the low
solubility of aromatic diketones in RT water. Considering that
[32]
Therefore, the different regimes of HTW have been exploited to
different extent in organic synthesis. The majority of studies
focused on the sub- and supercritical regimes (sometimes
collectively called “superheated water”). These studies include
hydrolyses, dehydrations, and oxidations of small organic
[33]
[31,34]
compounds,
and waste/biomass valorization.
Reactions
involving /heteroaromatic compounds in the super-/subcritical
regimes are limited to stability studies, showing that hetero-
aromatic compounds are initially stable, yet, with time undergo
Table 1. Screening of reaction conditions for synthesizing quinoxaline 1.
[35]
aquathermolysis towards open-chain derivatives.
Further-
more, a small number of works report the actual synthesis of
heteroaromatics in the moderate HT regime (RT to ꢀ150°C),
including pyrazoles, pyrazolones, cromenes, phenoxythiazines,
[36,37]
triazoles, and benzothiazoles.
The moderate reported
[a]
[b]
Entry
c
T
r
t
r
Additive
Yield
[%]
À 1
conditions of these syntheses seem suboptimal, for the, as we
believe, privileged temperature range of approximately 250°C
for forming heteroaromatics in water. This is substantiated
through all these reports employing highly polar starting
compounds and only generating fairly polar products, and
resulting in solely moderate to good yields.
[molL
]
[°C]
[min]
1
2
3
4
5
6
7
8
9
10
0.02
0.02
0.02
0.02
0.01
0.02
0.04
0.20
0.50
1.00
0.20
0.20
0.20
0.02
0.02
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
0.20
110
150
200
230
230
230
230
230
230
230
230
230
230
230
230
230
230
230
230
230
230
230
230
230
230
230
10
10
10
10
5
–
–
–
–
–
–
–
–
–
–
–
–
4
29
56
61
38
51
65
82
83
86
88
94
q
5
5
5
5
In summary, sub- and supercritical water are often not
amenable to heteroaromatics synthesis for degradation through
aquathermolysis, and furthermore require special equipment,
which limits implementation in standard organic synthesis
laboratories. On the other side, synthesis in H O at moderate T
5
1
1
1
1
2
3
10
30
60
10
10
10
10
10
10
10
10
10
10
10
10
10
2
r
–
(
9100°C), is practicable with standard laboratory equipment,
14
HOAc (10 equiv.)
DIPEA
89
39
q
1
1
1
5
6
7
but limited to polar starting compounds. In contrast, HTS is
bridging the gap. HTS is synthetically straightforward: an
aqueous dispersion of the stoichiometric amounts of the
starting compounds (typically, no excesses required) is heated
HOAc (4.3 equiv.)
HOAc (2.6 equiv.)
HOAc (1.0 equiv.)
oxalic acid (4.3 equiv.)
oxalic acid (2.6 equiv.)
oxalic acid (1.0 equiv.)
oxalic acid (0.1 equiv.)
oxalic acid (0.05 equiv.)
propionic acid (4.3 equiv.)
propionic acid (2.6 equiv.)
propionic acid (1.0 equiv.)
97
97
33
47
75
86
90
q
18
1
2
2
9
0
1
to T >100°C (typically 180–250°C) in a metal autoclave placed
r
in an oven, or in a glass vial inside a MW oven, and simply
22
23
[24,25,27,28]
cooled down after tr.
Product recuperation is also
2
2
4
5
effortless: While even apolar organic substrates can dissolve
95
97
and react in the HT regime, upon cooling back to RT, H O
26
2
becomes a highly polar medium again, and hence the organic
[
a] P at 230°C: 20–22 bar, at 200°C: 15–20 bar, at 150°C: 15–20 bar, and at
1
product phase separates from H O and can be collected by
110 °C: max. 5 bar. [b] Determined by
q=quantitative conversion.
H NMR spectroscopy;
2
simple filtration (if solid) or decantation (if liquid). Typically,
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the polarity of liquid water decreases with T, that is, high-
only H O, 4,4’-dimethoxybenzil and o-PDA, impurities would
2
temperature water is polarity-wise more similar to organic
have to arise from their degradation, decomposition or side
reactions. Aromatic diamines such as o-PDA are indeed known
to generate strongly colored products by oxidative autocon-
solvents, we hypothesized that H O at HT conditions might be a
2
suitable medium to obtain quinoxalines where aromatic
diketones are employed as starting materials.
[25,38]
densation to oligoimine species.
We think that such species
In order to determine the most suitable conditions for
synthesizing quinoxalines hydrothermally, we selected the
reaction between o-PDA and 4,4’-dimethoxybenzil to form 2,3-
bis(4-methoxyphenyl)quinoxaline (1) as model reaction. Equi-
molar quantities of the starting compounds were dispersed in
are also the origin of the colored impurity we find here. Further
purification either by reprecipitating in appropriate solvents or
flash column chromatography allowed for obtaining quinoxa-
line 1 with 87% yield. Based on this screening, the best
conditions to obtain 1 in nothing but water are T =230°C, t =
r
r
À 1
H O at RT and heated to the indicated temperatures. Experi-
1 h and c=0.2 molL with equimolar stoichiometry of starting
compounds. This result is surprising, since, to our knowledge,
the literature lacks procedures for synthesizing highly-conju-
gated heteroaromatic scaffolds in solely water without acidic/
basic promoters or further catalysts. Yet, we were curious to see
if the presence of promoters could speed up the HTS of 1 even
further.
2
ments at different T , t , and concentrations (c) of the starting
r
r
materials were conducted. The tested conditions are summar-
ized in Table 1.
In all experiments, the aqueous dispersion of the starting
compounds in 1:1 ratio was filled in a microwave vial and
heated to T as fast as possible (generally within 2 min). Then,
r
the reaction mixture was kept at T for the specified t and
On the one hand, previous work has shown that the HTS of
rylene bisimides, that is, the formation of the 6-membered
imide heterocycle by cyclocondensation, is accelerated in the
r
r
cooled back to RT (see the Supporting Information). After
cooling the reaction mixture, the crude products were isolated
1
[24]
by filtration and analyzed directly by H NMR spectroscopy to
presence of N,N-diisopropylethylamine (DIPEA). On the other
monitor the outcome of the reaction. Note that since o-PDA is
hand, acetic acid (HOAc) is a classic solvent to synthesize
quinoxalines in reflux for several hours, and has also been
employed as catalyst for quinoxaline synthesis in organic
solvents. Hence, we decided to test the amenability of the HTS
of 1 to both Brønsted acid and base catalysts using both DIPEA
and HOAc.
soluble in H O even at RT, any excess is washed away during
2
the product isolation by filtration and hence unreacted o-PDA is
not found in the crude product mixture. The crude products of
all experiments were mixtures exclusively composed of the
starting compound 4,4’-dimethoxybenzil and the target qui-
1
noxaline 1, which can be easily differentiated by H NMR
Interestingly, the presence of DIPEA decreased the yield of
quinoxaline 1 from 61 to 39% in the crude product, whereas
the presence of acetic acid increased the yield to 89% (Table 1,
entries 14 and 15). Intrigued by the remarkable influence of
acid catalyst on the reaction yield, we performed further
experiments with different amounts of HOAc. To our delight,
quinoxaline 1 could also be obtained at complete conversion in
only t =10 min at T =230°C in 5% HOAc (4.3 equiv.) (entry 16).
experiments in DMSO-d . Particularly, the methoxy protons in
6
the 4,4’-dimethoxybenzil appear as a singlet at δ =3.87 ppm (s,
H
6
3
H), whereas the same protons in quinoxaline 1 appear at δ =
.78 ppm (s, 6H) (see the Supporting Information for spectra).
H
First, the influence of T was evaluated to determine the lowest
r
required T for obtaining the highest possible yield of quinoxa-
line
1 (Table 1, entries 1–4). The results show that the
r
r
proportion of quinoxaline 1 in the crude product increases with
T . Interestingly, the proportion of 1 is only 4% at T =110°C.
Lower amounts of HOAc still yield quinoxaline 1 with remark-
able yields (97%, entries 17 and 18), yet 4,4’-dimethoxybenzyl
r
r
1
This suggests that T slightly above the boiling point of water
still can be observed in the H NMR spectra of the crude
r
are not sufficient, but that indeed HT conditions are needed to
complete the formation of 1. The best result in our screening
products. Encouraged by these results, experiments with oxalic
acid were performed (entries 19–23). First, the higher acidity of
oxalic acid (pK =1.27 and pK =3.86) seemed promising and
was obtained at T =230°C with 61% of 1. We next tested
r
a1
a2
À 1
different concentrations between 0.01 and 1 molL at this T
second, oxalic acid is industrially derived from biomass, which
makes it a sustainable choice. Interestingly, HOAc outperforms
oxalic acid at the tested concentrations (entries 16 and 19, 17
and 20, 18 and 21). We found that the presence of ꢁ1.0 equiv.
of oxalic acid gives lower reaction yields than the HTS experi-
ment without any acid catalyst (entry 11), whereas experiments
with 0.1 and 0.05 equiv. of oxalic acid yield quinoxaline 1 with
high yields (86 and 90% respectively, entries 22 and 23). Yet,
oxalic acid is employed at such high dilution in experiments
with 0.1 equiv. that these experiments are in fact more
comparable to pure water as reflected by the fact that their
yields are identical to those of pure water at the same T and t
r
(entries 5–10). The quantity of starting materials showed a
significant and counterintuitive effect on the yield of 1, which
À 1
saturated at around 80% at 0.2 molL . This was surprising as
we would have expected smaller amounts of starting com-
pounds to react more efficiently.
À 1
An even higher c (1 molL , Table 1, entry 10) did not
further improve the yield, but did also not decrease it. Then,
experiments at different t were conducted (entries 8, 11–13),
r
revealing that after t =1 h the crude reaction product is
r
composed exclusively of quinoxaline 1 (quantitative yield).
1
13
Interestingly, the H and C NMR spectra of the crude
product indicate that 1 is obtained without major impurities.
While pure 1 is typically of white color, the solid product
showed a dark brown color, suggesting the presence of
impurities at trace level. Since the reaction mixture contains
r
r
(entry 11). To understand the role of the pK values of the acid
a
catalysts, we tested propionic acid (pK =4.8) as a promoter and
a
found that it performs identical to HOAc at the employed
amounts (entries 24–26). We hypothesize that it is not the
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1
13
strength of the acid used, but that acetic acid is providing an
ideal pH that maximizes the reaction yield under the tested
conditions. Such privileged pH-ranges have been also observed
in other reactions of nucleophilic addition of amines to carbonyl
ucts were characterized by H and C NMR spectroscopy and
mass spectrometry (see the Supporting Information). Confirm-
ing our previous observation that the addition of 5% HOAc
speeds up the transformation, Method B generated quinoxa-
[39]
compounds. Note that for the earlier mentioned dehydrating
lines 1–6 in much shorter t without decreasing the correspond-
ing reaction yields (Scheme 2A, Method B).
r
[22]
ability of HT water, it is in principle conceivable that the
employed acids would dehydrate to the corresponding ketenes
After the expansion of the scope of 1,2-diketones, we next
turned to broadening the scope of the second substrate of
hydrothermal quinoxalines synthesis, using different o-PDAs
substituted with methyl, ketone, nitro, cyano and methyl ester
functional groups in combination with benzil. We successfully
obtained quinoxalines 7–11 in high yields using Method B
(Scheme 2A). Interestingly, neither the cyano nor the methyl
ester group were hydrolyzed at the employed reaction con-
ditions. Encouraged by these results, we also tested HT
conditions to synthesize biquinoxaline derivatives by reacting
3,3’-diaminobenzidine with different diketones and could thus
obtain compounds 12–14 with excellent yields (above 90% in
all cases, Scheme 2B). As biquinoxalines are more conjugated
than their monoquinoxaline counterparts, their HTS is even
more surprising.
(
e.g., HOAc could form ethenone H C=C=O). However, studies
2
have shown that ketene formation in high-temperature water
requires significantly higher temperatures of at least 650 K
[
40,41]
(
376°C) for detectable conversion.
Hence, we conclude that
ketene formation at the here used T (230°C) is highly unlikely.
To sum up, two sets of conditions were determined to
synthesize quinoxaline 1 hydrothermally with quantitative
À 1
yields: H O as solvent, T =230°C, t =1 h and c=0.2 molL
2
r
r
(
1
subsequently referred to as “Method A”) and T =230°C, t =
r
r
À 1
0 min and c=0.2 molL in 5% HOAc (“Method B”).
To further broaden the scope of the HTS of quinoxalines, we
next studied the reaction between o-PDA and different 1,2-
diketones via either Method A or B, or both. Method A
generated quinoxalines 2–6 with excellent yields ranging from
8
5 to 95% (isolated yield) (see Scheme 2). In general, the crude
The synthesis of target molecules of higher structural
complexity requires further protection and deprotection steps.
While necessary, these additional reaction steps reduce the
overall environmental friendliness of any synthetic route. For
products were all isolated by filtration and drying and, if
desired, can be further purified by flash column chromatog-
raphy (see the Supporting Information). All quinoxaline prod-
r
Scheme 2. Scope of 1,2-diketone and o-PDA in HTS of (A) quinoxalines and (B) biquinoxalines (p =20–22 bar).
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instance, diamines can be protected employing di-tert-butyldi-
in nothing but water (Method A) and with 5% HOAc (Method
B), as shown in Scheme 4. Interestingly, the H NMR spectrum of
1
carbonate (Boc O) and are often even commercially available in
2
the Boc-protected form. The deprotection step is usually
performed under strongly acidic conditions such as mixtures of
the crude product formed by Method A with t =10 min showed
r
signals corresponding to quinoxaline 1 together with additional
signals that suggested the presence of another compound in
the mixture (see the Supporting Information, Figure S29).
Purification of the crude reaction mixture by column chroma-
tography allowed us to obtain quinoxaline 1 and compound 1a
[42]
TFA/CH Cl or HCl in 1,4-dioxane. Deprotection by heating in
2
2
H O at 150°C for several hours is also possible, but rarely
2
[43]
used. Since these conditions correspond to a HT treatment,
we sought to perform a fully hydrothermal Boc-deprotection-
quinoxaline formation sequence in one step, hence eliminating
the necessity for intermediate isolation. To achieve this, the
reaction between the Boc-diprotected o-PDA and 4,4’-dimeth-
oxybenzil was performed according to Scheme 3.
1
13
with 51 and 48% yield, respectively. Through H and C NMR
experiments in combination with MS data, compound 1a could
be identified as 4-(3-(4-methoxyphenyl)quinoxaline-2-yl)phenol.
The formation of compound 1a is explained by the hydrolysis
of one methoxy group in quinoxaline 1. We tested longer
We found that quinoxaline 1 could be obtained with a 73%
1
yield (determined by H NMR spectroscopy) employing Method
reaction times (t =20 or 30 min) to deliberately hydrolyze both
r
À 1
B (T =230°C, t =10 min and c=0.2 molL ). Extending t to
ether groups, yet the second methoxy group was not hydro-
lyzed under the tested conditions.
r
r
r
3
0 min did not increase the yield. These results clearly show
that HT conditions allow for the deprotection and quinoxaline
formation at good yields in a single reaction step.
The crude product of the same reaction in 5% HOAc
(Method B) contained again both quinoxalines 1 and 1a, and
additionally the starting material 4,4-dimethoxybenzil (see the
Supporting Information, Figure S28). These findings clearly
show that o-PDA dihydrochloride can be employed as starting
material for synthesizing quinoxalines hydrothermally in shorter
tr without the need of HOAc. Moreover, too much acid
promotes the backreaction (hence remaining starting com-
pound 4,4’-dimethoxybenzil found by Method B). Additionally,
care should be taken when acid-labile functional groups are
present in the 1,2-diketone. We furthermore tested the use of o-
PDA·2HCl with benzil as 1,2-diketone without acid-labile groups
towards quinoxaline 6. Indeed, as methoxy groups are absent in
Prompted by our observation that HT synthesis of quinoxa-
lines is catalyzed by the presence of HOAc, we tested if the
inherent acidity of amine hydrochlorides as precursors would
be sufficient to promote the reaction. We hypothesized that
dihydrochloride derivatives would be a dual-role starting
material in the HT synthesis of quinoxalines as they could act
both as source of protons to catalyze the reaction and also as
source of o-PDA.
To test this hypothesis, we used the commercially available
o-PDA dihydrochloride (o-PDA·2HCl) as starting material. Note
that o-PDA·2HCl has a higher solubility in water than free o-
PDA. Then, 4,4’-dimethoxybenzyl and o-PDA hydrochloride
were reacted under HT conditions at T =230°C and t =10 min
benzil, ether hydrolysis cannot take place, and within t =
r
10 min quinoxaline 6 was obtained as only reaction product
with 97% yield. Experiments to synthesize quinoxaline 6 at
r
r
lower T revealed that it can be obtained without considerably
r
losing reaction yield at 200°C, whereas 180°C are not enough
to complete the reaction in t =10 min (see Figure S32). In
r
summary, the amenability of o-PDA·2HCl to the direct HTS of
quinoxalines is of particular practical relevance, as (i) amine
hydrochlorides are commercially available, (ii) amine hydro-
chlorides are much less prone to oxidation than free amines
and hence have higher storability and (iii) they also provide
higher water solubility than free amines.
Scheme 3. One-pot Boc-deprotection–quinoxaline formation sequence
under HT conditions (p =20–22 bar). Yields: 73% with t =10 min and 76%
with t =30 min.
r
r
r
Our versatile hydrothermal synthesis route towards a broad
range of quinoxalines is also particularly environmentally
friendly: We use solely water as solvent, or respectively an
aqueous 5% acetic acid solution corresponding virtually to
vinegar. Our route generates the products in high to excellent
yields at short reaction times, and does not rely on complex/
expensive reactants or catalysts or excesses of either of the
starting compounds. Our approach can also be adopted by any
organic synthesis laboratory without implementing a more
complex experimental set-up. Any novel approach towards the
synthesis of a known scaffold is expected to show similar or
better performance compared to the reported methods in
literature. In our case, this sort of comparison is a demanding
endeavor as there are hundreds of synthetic procedures
reported for quinoxalines. To systematically assess the perform-
ance of our hydrothermal synthesis of quinoxalines, we
Scheme 4. Reaction between o-PDA dihydrochloride and 1,2-diketones
under HT conditions (p =20–22 bar).
r
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performed a computational analysis comparing our synthesis to
all previous approaches reported in the literature.
To this end, we extracted all the reported syntheses for
quinoxalines 1–14 from the commercial database Reaxys® (see
Figure 1A for the data extraction and curation pipeline). A total
of 1033 syntheses towards compounds 1–14 are reported (see
the Supporting Information). As expected, the Hinsberg cycliza-
tion is the most used approach among the reported syntheses
(581 reactions, 56%) and the analysis per individual compound
also shows that the Hinsberg cyclization has been the most
Figure 1. (A) Overview of the reaction parameter extraction pipeline. (B) Differences between HTS of quinoxalines and the reported literature synthesis. The
spider plot depicts with dashed borders n=323 reactions that report all of the five parameters (solvent, catalyst, T , t and yield) used in the analysis. The black
r
r
solid line indicates the average of all the 323 considered reactions whereas the blue solid line represents the average of HT conditions. Spider plots for
individual compounds are included in the Supporting Information (Figure S36) The different histograms were plotted considering the number of reactions
that report the corresponding parameter: solvent (n=452), catalyst (n=484), T (n=479), t (n=538), yield (n=513). (C) Reaction space of 2,3-
r r
diarylquinoxalines with overlay of the 5 investigated features. Green depicts a more favourable reaction parameter whereas red indicates less favourable
conditions. (D) t-SNE dimension reduction depicting clusters of favourable reaction conditions. (E) Possible reaction strategies to improve reaction yields.
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frequent syntheses for all of the compounds except compound
. Only these reactions were employed in our computational
The distinct characteristics of HTS compared to classical
synthesis routes can be further assessed using a principal
component analysis (PCA), which maps the five dimensions of
each reaction to a two-dimensional point, such that the overall
variance across all reactions is maximized. Figure 1C shows the
resulting PCA mapping with reactions from the literature
indicated as circles and HTS as squares. Each panel shows the
distribution of one particular reaction parameter across all
reactions, highlighting generally favorable conditions in green
and unfavorable ones in red. The separation of the HTS cluster
from all other reactions exemplifies the distinct HT reaction
4
analysis. The remaining syntheses comprehend a variety of
reactions between o-PDA analogues and variants of 1,2-
diketones (e.g., benzoins, vicinal diols, α-substituted acetophe-
nones). Note that our analysis aims explicitly at evaluating the
reaction conditions for transforming starting compounds to
products, but does not account for their toxicity. All the
alternative synthesis would involve different requirements,
leading to inequitable comparisons. Therefore, these alternative
syntheses were not included in the analysis. To the best of our
knowledge, the analysis here presented is covering the highest
number of reported synthesis for the scope of compounds
presented in a work.
conditions. This separation is mostly driven by the high T used
r
in HTS and would likely be even larger if reaction pressure
would also be considered. We can further extract interesting
relationships between the reaction parameters by comparing
different panels. We observe, for example, that the yield seems
to correlate with the toxicity of the used catalyst, as indicated
by the reversed red and green colored areas in the yield and
catalyst panels of Figure 1C, whereas longer reaction times
alone do not appear to systematically relate to higher yields.
The correlation between time and temperature (and to a lesser
extent solvent toxicity) might indicate that increasing both
simultaneously occurs more frequently in reported reactions.
Next, we investigated similarities between different reac-
Among the 581 reported reactions, the numbers of reported
syntheses per compound are ranging from 1 to 164 (Supporting
Information, Table S1). This number is relatively small with
respect to the several thousand quinoxalines known to the
literature. For our subsequent analysis, we included the
following five, typically well-reported reaction parameters: (i)
temperature, (ii) time, (iii) yield, (iv) reaction solvent and (v)
catalyst. All other parameters, such as pressure or pH, were
discarded due to being overall poorly reported. We removed all
incompletely annotated reactions with missing information for
parameters (i)–(iii), resulting in 323 final syntheses. We assessed
[
44]
tions using the dimension reduction technique t-SNE
(T-
[32]
the toxicity of solvents and catalysts according to Byrne et al.
distributed stochastic neighborhood embedding) and subse-
quently applying a k-means clustering (k=8) to identify clusters
of reactions with similar reactions conditions (see Figure 1D,
clusters of similar reactions are indicated by the same color).
Interestingly, we found that the reaction conditions for the
same chemical compound are generally not similar for different
synthesis routes (Supporting Information, Figure S38). This may
reflect a tendency in the published literature to optimize the
reaction conditions only for one specific compound and
subsequently apply these conditions to a series of additional
compounds. A closer examination of the different clusters of
reactions with similar conditions (see the Supporting Informa-
tion, Figure S39 for individual cluster results and feature over-
lay) reveals that reactions with optimal yield can be typically
assigned to the usage of (i) higher T (cluster 0), (ii) increasing t
and the globally harmonized system (GHS), respectively (see the
Supporting Information, Figure S35 and method 5.1 for more
details). Our analysis shows that HTS of quinoxalines clearly
differs from classical reactions in several ways (Figure 1B).
First, the HT route uses by far the highest reaction temper-
ature. Second, HTS belongs to the fastest reaction types. Third,
our approach uses the cleanest solvent. The reported synthesis
of 1–14 use recommended solvents such as ethanol (37%),
water (25%), methanol (12%), glycerol (3%), mixtures of the
above (13%) or neat conditions (11%). Note that several of the
reported quinoxaline syntheses with alcohols as solvents
require HOAc as catalyst. In contrast, our HTS approach
generates high yields also in the absence of acid, provided
through the intrinsic acidity of H O(l) at T ꢀ250°C, and can
2
r
r
r
additionally be sped up through HOAc. Moreover, whereas
(cluster 7), (iii) usage of toxic solvents (cluster 4) or catalyst
(cluster 3 and 0) or (iv) addition of complex catalyst to the
reaction (cluster 2 and 5). Cluster 6 corresponds to reaction
conditions that do not apply any of the previously mentioned
methods, typically resulting in poor yield. From a data mining
perspective, such “negative data” are extremely valuable, as
they allow for extracting trends for systematically improving
reaction conditions (Figure 1E). Our analysis indicates that the
synthesis of quinoxalines at RT and without toxic catalysts and/
or solvents works poorly. Higher yields can be obtained by
using (i) toxic solvents, (ii) toxic/complex catalysts or (iii)
increasing the temperature often in combination with time.
Intriguingly, HTS follow all three approaches except for the
toxicity aspect: (i) HT conditions are intrinsically found at high
temperatures, (ii) high-temperature water behaves like an
organic solvent (in terms of polarity and viscosity), however
solvents such as MeOH or EtOH seem closely related to H O,
2
they are in fact quite different. In terms of hazardousness,
MeOH bears substantial flammability and toxicity risks. As
media, MeOH and EtOH are significantly less polar than H O: for
2
instance, the static dielectric constant (ɛ ) of MeOH at RT is
r
approximately 33, a value that is only matched by water at
2
20°C. Therefore, obtaining quinoxalines 1–14 in alcohols,
which are solvents of medium polarity, is much less surprising
than synthesizing them in H O. Moreover, our combination of
2
solvent/catalyst is one of the cleanest ones and among the
considered reactions, only the water/PEG600 combination is
comparably green. The yield of the HTS is overall comparable
with other reported reactions (see the Supporting Information,
Figure S36 for individual compound results). Note however, that
the literature is expected to be strongly biased towards positive
results in this regard.
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without being toxic, and (iii) HT water can act as both Brønsted
acid and base through its increased ionic product.
imaging biochemical processes with remarkable sensitivity and
[45]
temporal resolution.
Important properties of fluorescent
Finally, we explored a potential application of our newly
synthesized compounds. Quinoxalines are receiving a growing
interest due to their fluorescence properties. In solution,
quinoxalines have been shown to display solvatofluorochromic
behavior, and some representatives also exhibit aggregation-
probes for cell staining are cell permeability, high brightness
and photostability. The cell staining capacity of compounds 1–
12 was tested at different concentrations against a panel of
three different cell lines: HAP1 (near-haploid human cells),
SKUT1 (human uterine leiomyosarcoma cells) and H2122
(human lung cancer cells). Confocal microscopy images show
that among the tested quinoxalines 1, 4, 5 are cell permeable
and sufficiently bright at a micromolar concentration (Figure 2).
They exhibit blue emission and appear nicely distributed
throughout the cytoplasm in all three studied cell lines. While
some properties of the tested compounds such as solvato-
chromism are low compared to previously reported
[7,8]
induced emission in the solid state.
Therefore, we inves-
tigated the fluorescence properties of all the synthesized
quinoxalines 1–14. The results show that monoquinoxalines 1,
4
, 5, 7, and 11 exhibit blue fluorescence and the intensity is
higher in compounds with electron donating groups such as
methoxyphenyl, furane, and thiophene rings at positions C-2
and C-3 of the quinoxaline ring (Supporting Information,
Figure S40). The remaining monoquinoxalines did not show
fluorescence even at millimolar concentration. Moreover, all
biquinoxalines (12–14) exhibited blue fluorescence.
Given that quinoxalines are well-known to depict biological
activity, we decided to investigate compounds 1–12 as cell
stains. Fluorescent probes based on small compounds are
extremely useful in fluorescence microscopy as they allow
[46,47]
quinoxalines,
we believe that the cell permeability and
fluorescence of these relatively simple scaffolds is already
promising. Further work focusing on derivatization of these
scaffolds towards higher fluorescence intensities and longer
wavelengths of emission is currently ongoing.
Figure 2. Fluorescence microscopy images of the indicated cell lines after treatment with solutions 1.5 μm in DMSO of quinoxalines 1, 4 and 5
scale bar 200 μm). Results for all of the compounds are included in the Supporting Information (Figure S41).
(
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Conclusion
22 bar. The temperature was maintained for 60 min and afterwards
the mixture was cooled down to RT. The crude product was filtered
and dried in an oven. If necessary, the compounds could be further
purified by dissolving in acetone or THF and pouring the mixture
With this work, we report the synthesis of quinoxalines from
1
,2-diketones and o-phenylendiamine derivatives in nothing
but high-temperature water. The very short reaction times
30 min) make our approach highly practical. Catalysts are not
into water, or by flash column chromatography (SiO ), eluting with
2
petroleum ether/ethyl acetate 6:4.
(
General procedure for Method B: In a glass vial with a magnetic
stirrer, the respective 1,2-diketone (0.4 mmol) and the correspond-
ing o-phenylendiamine (0.4 mmol) were suspended in a solution of
5% HOAc (2 mL). Then, the glass vial was placed into the cavity of
the microwave reactor and the suspension was heated up as fast as
possible to 230°C. After 10 min, the mixture was cooled down,
filtered and dried. The crude samples could be purified as described
for Method A.
necessary, but if desired, the quinoxaline condensation can be
accelerated by 5% HOAc to reaction times of �10 min. The
target quinoxalines are obtained in high yields and we showed
that the reaction is tolerant to a broad array of functional
groups. Furthermore, o-phenylendiamine (o-PDA) dihydrochlor-
ide derivatives are suitable substrates that do not only provide
better solubility, but also generate an acidic environment
in situ, avoiding the addition of an acid catalyst whilst
autogenously speeding up the reaction. In addition, a sequence
of Boc-deprotection of amines could be coupled with the
formation of the quinoxaline ring in a one-pot fashion in
nothing but hot water. To date, hydrothermal (HT) synthesis of
highly conjugated organic compounds has been limited to
Database search and computational analysis
The complete computational analysis was performed using Phyton
v3.7.2. The employed code can be accessed as Jupyter notebooks
via Github under the following url: UnterlassLab github page
https://github.com/UnterlassLab/Computational_Analysis_HTS_2-3-
diarylquinoxalines. A step-by-step description of the analysis is
included in the Supporting Information (Data acquisition and
feature normalization, individual spider plots for each compound,
dimensionality reduction techniques and k-means cluster analysis).
[23]
[24]
[28]
[26]
amides, cyclic imides, perinones, and benzimidazoles.
With this work, we extend the scope of HT synthesis to another
heteroaromatic moiety. Our large-scale computational analysis
of what we believe are to date all synthetic means towards
quinoxalines 1–14 revealed that the hydrothermal approach is
particularly green. Nevertheless, in an effort to make hydro-
thermal synthesis (HTS) even greener, future work will focus on
exploring HTS in flow, which is expected to lower reaction times
even further, and to employ starting materials with lower
toxicity. Finally, we show that the synthesized quinoxalines are
promising candidates for developing cell staining probes. The
wavelengths of emission are mainly blue and their intensities
are low compared to reported dyes. Yet, the cell permeability
and fluorescence inside cells observed were promising in the
performed cell staining assays. In the future, we will further
explore these scaffolds for cell staining.
Fluorescence microscopy experiments
The cell lines HAP1 (near-haploid human cells), SKUT (human
uterine leiomyosarcoma cells) and H2122 (human lung cancer cells)
were grown in 96 well plates (15000 cells per well). The cells were
maintained under 5% CO atmosphere at 37°C. For cell staining
2
experiments, 100 mm stock solutions of compounds in DMSO were
diluted to 10 mm by hand and cells were treated with diluted
solutions of the compounds to get final concentrations of 45, 15, 5
and 1.5 μm. Cells were incubated for 45 min at 37 C under CO2
atmosphere and live-imaged using an Opera Phenix high-content
fluorescence microscope (PerkinElmer) with 40X objective.
Fluorescence microscopy images for all the compounds are
included in the Supporting Information.
°
Experimental Section
Acknowledgements
Materials and general methods
This work was funded by the Vienna Science and Technology
Fund (WWTF) under grant number LS17-051 and the Austrian
Science Fund (FWF) for supporting this project under grant no.
START Y1037-N28.
All chemicals were obtained from TCI or Sigma Aldrich and used
without further purification. Distilled water was employed in all the
experiments. The reactions were conducted in an Anton Paar
Monowave 400 microwave reactor, employing G30 and G10 glass
1
13
vials. H and C NMR spectra were recorded on a Bruker Avance
DRX-400 spectrometer. Samples were dissolved in CDCl3 (δ =
H
7
.26 ppm, δ =77.0 ppm) or DMSO-d (δ =2.50 ppm) and the
C
6
H
Conflict of Interest
spectra for all compounds are included in the Supporting
Information.
The authors declare no conflict of interest.
Hydrothermal synthesis of quinoxalines
Keywords: computational analysis
chemistry · hydrothermal synthesis · quinoxalines
· fluorescence · green
General procedure for Method A: In a glass vial with a magnetic
stirrer, the respective 1,2-diketone (0.4 mmol) and the correspond-
ing o-phenylendiamine (0.4 mmol) were suspended in water (2 mL).
Then, the glass vial was placed into the cavity of the microwave
reactor and the suspension was heated up as fast as possible to
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