Sequential Cu-Catalyzed Four- and Five-Component Syntheses of Luminescent 3-Triazolylquinoxalines

Article abstract of DOI:10.1002/chem.201900277

3-Triazolylquinoxalines can be readily synthesized by applying two complementary synthetic protocols starting from heterocyclic π nucleophiles or (hetero)aryl glyoxylic acids in a consecutive four- or five-component reaction. Conceptually, the sequential use of a single cuprous salt for alkynylation and Cu-catalyzed alkyne-azide cycloaddition (CuAAC) in a one-pot fashion sets the stage for activation-alkynylation-cyclocondensation-CuAAC or glyoxylation-alkynylation-cyclocondensation-CuAAC sequences in good yields. The diversity-oriented generation of differently substituted 3-triazolylquinoxalines is an excellent entry to tunable emission solvatorchromic fluorophores with triazole ligation. The electronic structure, corroborated by DFT and TD-DFT calculations, rationalizes the charge transfer character of relevant absorptions and large Stokes shifts as well as the electronic innocence of the triazole substituents.

Full text of DOI:10.1002/chem.201900277

A Journal of
Accepted Article
Title: Sequentially Cu-catalyzed Four- and Five-Component Syntheses
of Luminescent 3-Triazolylquinoxalines
Authors: Franziska K. Merkt, Konstantin Pieper, Maximilian
Klopotowski, Christoph Janiak, and Thomas J. J. Müller
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To be cited as: Chem. Eur. J. 10.1002/chem.201900277
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Sequentially Cu-catalyzed Four- and Five-Component Syntheses
of Luminescent 3-Triazolylquinoxalines
[
a]
[a]
[b]
[b]
Franziska K. Merkt, Konstantin Pieper, Maximilian Klopotowski, Christoph Janiak, Thomas J. J.
[a]
Müller *
Dedication ((optional))
Quinoxalines have become increasingly important due to various
Abstract
[11]
intrinsic properties and they can also be synthesized by MCR
[
12]
approaches. Besides the strongly electron-withdrawing nature
of quinoxaline cores the pyridyl nitrogen centers can be ideally
3
-Triazolylquinoxalines can be readily synthesized by applying two
complementary synthetic protocols starting from heterocyclic
nucleophiles or (hetero)aryl glyoxylic acids in a consecutive five-
[13]
[14]
addressed by pH change,
polarity change,
metal ion coordination,
solvent
In addition
quinoxalines receive most interest as biologically active

[12,13,15]
[16]
or biological analytes.
or four-component reaction. Conceptually, the sequential use of a
single cuprous salt for alkynylation and Cu-catalyzed alkyne-azide
cycloaddition (CuAAC) in a one-pot fashion sets the stage for
activation-alkynylation-cyclocondensation-CuAAC or glyoxylation-
alkynylation-cyclocondensation-CuAAC sequences in good yields.
The diversity-oriented generation of differently substituted
[17]
[18]
compounds
as well as functional chromophores.
The
ligation of 1,2,3-triazoles and quinoxalines as electron deficient
[19]
moieties is particularly interesting and CuAAC
is a suitable
methodology for introducing this moiety. However, only the
construction of 3-triazolylquinoxalines has only been reported in
3-triazolylquinoxalines is an excellent entry to tunable emission
[20,21]
two publications with very few examples.
solvatorchromic fluorophores with triazole ligation. The electronic
structure, corroborated by DFT and TD-DFT calculations,
rationalizes the charge transfer character of relevant absorptions
and large Stokes shifts as well as the electronic innocence of the
triazole substituents.
[22]
Inspired by our chromogenic MCR concept and our particular
[12b,13,15,23]
interest in highly emission solvatochromic quinoxalines
we reasoned that 3-triazolylquinoxalines could be accessible by
combining
the
one-pot
glyoxylation-alkynylation-
cyclocondensation synthesis of 3-ethynylquinoxalines with
CuAAC in a one-pot fashion (Figure 1).
Introduction
The advent of the Cu(I)-catalyzed azide–alkyne cycloaddition
[
1]
[2]
(
CuAAC) by Meldal
and Sharpless
has considerably
popularized 1,4-disubstituted 1,2,3-triazoles as versatile building
[
3]
[4]
[5]
blocks in medicinal, bioorganic and materials chemistry.
The highly versatile and regioselective approach under mild
conditions has enabled the ready formation of bioisosteres of the
[
6]
amide linker for application in bioconjugation. In addition
CuAAC are excellently suited to be employed in multicomponent
Figure 1: Retrosynthetic analysis of
a
one-pot synthesis of
3-triazolylquinoxalines in the sense of
a
consecutive five-component
(glyoxylation-alkynylation-
[
7]
reactions (MCRs). Multicomponent syntheses of functional
heterocyclic scaffolds increasingly also involves transition metal
sequentially
Cu-catalyzed
GACC-CuAAC
cyclocondensation-CuAAC).
[
8]
catalysis. With this respect the catalyst economic reuse of a
[9]
Glyoxylation of electron rich -nucleophiles with oxalyl chloride
followed by Castro alkynylation furnishes ynediones,
are directly transformed by Hinsberg cyclization into 3-
ethynylquinoxalines in the sense of a glyoxylation-alkynylation-
cyclocondensation (GACC) sequence.
catalyst in the sense of sequential and tandem catalysis not
only is relevant for process development but also the
fundamental interest of reactivity tuning of a single catalyst
source by sequentially Pd-catalyzed reactions has found entry in
[
24]
which
[
12b]
[10]
The scope of
more complex one-pot syntheses of heterocycles.
ynedione intermediates can considerably be broadened by
activation of glyoxylic acids with oxalyl chlorides followed by
[
25]
Castro alkynylation,
which then concludes by Hinsberg
[
[
a]
b]
Dr. F. K. Merkt, B. Sc. K. Pieper, Prof. Dr. T. J. J. Müller
Institut für Organische Chemie und Makromolekulare Chemie
Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225
Düsseldorf (Germany) E-Mail: ThomasJJ.Mueller@uni-duesseldorf
M. Sc. M. Klopotowski, Prof. Dr. C. Janiak
cyclization in the sense of an activation-alkynylation-
[
15]
cyclocondensation (AACC) sequence. Conceptually intriguing
with this respect is that both GACC and AACC syntheses of 3-
ethynylquinoxalines are copper-catalyzed processes. Therefore,
the concatenation of GACC or AACC with CuAAC should lead to
a sequentially Cu-catalyzed process. Here we report the first
GACC-CuACC and AACC-CuAAC syntheses of 3-(1,2,3-
triazolyl)quinoxalines, their photophysical properties and their
TD-DFT calculated electronic structure.
Institut für Anorganische Chemie und Strukturchemie Heinrich-
Heine-Universität Düsseldorf
Universitätsstraße 1, 40225 Düsseldorf (Germany)
[
9]
Supporting information for this article is given via a link at the end
of the document.
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Results and Discussion
1,2-diaminoarenes, such as 4,5-dichlorobenzene-1,2-diamine
and 4,5-diaminophthalonitrile that have been successful proven
[
12b]
Synthesis and Structure
in the formation of 3-ethynylquinoxalines
or 3-amino-
[
13]
First we set out to test the initial conditions of CuAAC with
vinylquinoxalines could not successfully be transformed in this
sequence. In comparison to the four-step 3-ethynylquinoxaline
[
13]
3
-ethynylquinoxaline 1
and benzyl azide (2a) (Figure 2).
and 2a are almost quantitatively
[
12b,15a]
Indeed, compounds
1
synthesis
the higher yields of the five-step 3-triazolyl-
transformed at room temp in 1,4-dioxane in the presence of
mol% of CuI, the same catalyst source and loading as in the
quinoxaline formation also account to the increased stability of
the title compounds.
5
GACC and AACC sequences, to give the 3-(1,2,3-
triazolyl)quinoxaline derivative 3a in 94% yield.
While the GACC sequence for the formation of 3-ethynyl
quinoxalines is limited to certain electron-rich -nucleophiles the
AACC sequence starting from 2-(hetero)aryl glyoxylic acid is a
valuable complementary access to other electronic substitution
[
15]
patterns in 2-position of quinoxalines.
Therefore, the AACC-
CuAAC sequence was illustrated for three examples (Figure 3).
Starting from glyoxylic acids 8 activation with oxalyl chloride (5)
and subsequent Castro alkynylation of the glyoxalyl chloride with
(
trimethylsilyl)acetylene (6), followed by Hinsberg cyclization
with o-phenylenediamine (7a) and CuAAC with benzyl azide (2a)
furnishes the corresponding 3-(1,2,3-triazolyl)quinoxalines 3s-u
in good yield.
Figure 2: CuAAC of 3-ethynyl quinoxaline 1 and benzyl azide (2a) to
give 3-(1,2,3-triazolyl)quinoxaline derivative 3a.
Most advantageously, both sequences allow the use of the
components in almost equimolar amounts. The average yields
per bond forming step can be calculated for the GACC-CuAAC
sequence to 85-97%, while the AACC-CuAAC sequence gives
With these conditions for the CuAAC step in hand we started to
optimize the GACC-CuAAC sequence employing N-methylindole
(
4a), oxalyl chloride (5), (trimethylsilyl)acetylene (6), o-
phenylenediamine (7a) and benzyl azide (2a) to give 2-(1-
benzyl-1H-1,2,3-triazol-4-yl)-3-(1-methyl-1H-indol-3-yl)-
90-93%. Therefore, both one-pot multicomponent syntheses can
be considered to be highly efficient.
quinoxaline (3a) in
a
model reaction (see Supporting
Information, Table S1). It was found that a suitable amount of
potassium fluoride for desilylation with a slight excess of the
benzyl azide (2a) in a THF/MeOH mixture turned out to be
optimal. Furthermore for the CuAAC step using a small amount
of sodium ascorbate (10 mol%) finally resulted in a clean
transformation. With these optimized conditions in hand and
starting from -nucleophiles 4 the consecutive sequentially Cu-
catalyzed five-component GACC-CuAAC synthesis was
illustrated for 18 preparative examples, furnishing the title
compounds 3 in moderate to excellent yields (Table 1).
As -nucleophiles, N-methylindole (4a), N-methyl- (4b) or
phenylpyrrole (4c) as well as 2-methoxythiophene (4d) can be
employed easily (Table 1, entries 1-4). Much to our delight also
indolizine (4e), an isomer of indole leads to the formation of the
corresponding 3-triazolylquinoxaline 3e in 42%. The modular
nature of the reaction allows introduction of a variety of azides.
Among electron-rich to electron-poor benzylic substituents, also
aromatic azides can be employed. Moreover, sterically hindered,
aliphatic, as well as secondary substituted azides can be used to
construct 3-triazolylquinoxalines 3. Ester (2j) and amide
functionalized azides (2k) were also compatible with the reaction
sequence and produced compounds 3o and 3p in 53 and 38%
yield, respectively. This demonstrates the conceivable use of
this sequence for bioconjugation of peptides to suitable
quinoxaline fluorophores. 1,2-Diaminobenzene (7a) and
Figure 3: Consecutive four-component AACC-CuAAC synthesis of 3-(1,2,3-
triazolyl)quinoxalines 3.
The structures of all 3-triazolylquinoxalines 3 were unequivocally
1
13
characterized by
H
and
C NMR spectroscopy, mass
spectrometry, and combustion analysis. It is noteworthy that the
purification processes involved only silica gel column
chromatography in air, verifying that these 3-triazolyl-
quinoxalines are substantially stable towards air and moisture.
Interestingly, the single-crystal X-ray diffraction of N-
methylpyrrole substituted 3-triazolylquinoxaline 3b opens an
insight in the molecular structure in the solid state (Figure 4 and
5). Expectedly, the quinoxaline moiety is planar with a slight
thermic oscillation at the benzo backbone, while the N-methyl-
pyrrole substituent (66 °) and the triazolyl moiety are twisted out
of coplanarity.
2,3-diaminonaphthalene (7b) can be employed uneventfully in
the synthesis of 3-triazolylquinoxalines. Other
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Table 1: Consecutive five-component GACC-CuAAC synthesis of 3-(1,2,3-triazolyl)quinoxalines 3.
Entry
1
-Nucleophile 4
1,2-Diaminoarene 7
Azide 2
3-(1,2,3-Triazolyl)quinoxaline 3 (yield)
N-methylindole (4a)
ortho-phenylendiamine (7a)
benzyl azide (2a)
3a (82%)
2
N-methylpyrrole (4b)
7a
2a
3b (77%)
3
4
N-phenylpyrrole (4c)
7a
7a
2a
2a
3c (56%)
2-methoxythiophene (4d)
3d (72%)
5
6
indolizine (4e)
7a
7a
2a
3e (42%)
4a
(2-azidoethyl)benzene (2b)
3f (73%)
4
a
a
7a
7a
1-(azidomethyl)-4-chlorobenzene (2c)
7
3g (48%)
1-(azidomethyl)-
4
8
9
2-methylbenzene (2d)
3h (79%)
4a
4a
7a
7a
1-(azidomethyl)-3-fluorobenzene (2e)
1-azido-4-methoxybenzene (2f)
3i (58%)
10
3j (46%)
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1
2
1
4a
4a
7a
7a
(1-azidoethyl) benzene (2h)
3k (69%)
1
(azidomethylene) dibenzene (2g)
3l (56%)
1
3
4
4a
4b
7a
7a
1-azidohexane (2i)
3m (81%)
1
2i
3n (80%)
1
5
6
4a
4b
7a
7a
methyl 2-azidoacetate (2j)
3o (53%)
1
2-azido-N,N-dimethylacetamide (2k)
3p (38%)
1
7
8
4a
4b
2,3-diamino naphthalene (7b)
2a
2a
3q (74%)
1
7b
3r (74%)
There are three different ring-ring torsion angles between the
N-methylpyrrole (N), the quinoxaline (Q), the benzyl (B) and
the triazolyl (T) rings. The angle between Q and B is the
highest with 117° determined from the atoms C17-C16-N6-
N5. Between Q and N the angle is 60° (C2-C1-C9-N3) and
between Q and T (C1-C2-C14-C14) an angle of 33° is found.
A closer analysis of the crystallographic packing revealed a
centrosymmetric pairwise arrangement by strong --
interactions between the triazolyl rings (Figure ).
Figure 4: Molecular structure of compound 3b (thermal ellipsoids for N and
C shown at 50% probability). See the Supporting Information for further
details on the crystal structure.
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6800 to 12000 L/mol·cm and at least one additional
absorption band at higher energy can be detected (Table 2).
Series 1 and 2 were used to underline the electronic effects of
1
3
substituents R and R . The spectral comparison reveals that
3
the triazolyl substituent R has almost no effect on the
absorption and emission energies (Figure 7), whereas the
1
quinoxalinyl substituent
R
significantly affects both
absorption and emission bands (Figure 8). By increasing the
1
electron donating character of the heterocyclic substituent R
the absorption and the emission bands shift bathochromically
from 2-thienyl (3t, max,abs = 368 nm, max,em = 541 nm) over
1
1
-methylpyrrolyl (3b, max,abs = 384 nm, max,em = 548 nm) to
-methylindolyl (3a, max,abs = 393 nm, max,em = 541 nm) and
p-Me
2
NC
6
H
4
(3s, max,abs = 393 nm, max,em = 541 nm, Figure
Figure 5: Centrosymmetric pairwise --stacking in the structure of
compound 3b.
−1
8). The Stokes shifts vary in a range from 7000 to 8700 cm ,
except for the 2-thienyl derivative 3t, which is significantly
smaller with 4500 cm . The fluorescence quantum yields 
of the 3-triazolylquinoxalines are relatively small compared to
3-aminovinyl derivatives or 3-ethynylquinoxalines.
highest value can be found for the p-Me NC derivative 3s
(Table 2). Presumably, the low values of fluorescence
quantum yields  result from the torsion by the triazolyl
−
1
The two parallel triazolyl rings assume a close contact with a
centroid distance of 3.695 Ǻ, an interplanar separation of
f
[
23]
[12b,15]
3.615 Å, small slip angle of 11.9° (between centroid-centroid
The
vector and plane normal) and a small slippage of 0.76 Å,
which translate into a sizable overlap of the triazolyl-plane
2
6 4
H
[
26]
areas and can be classified as strong -stacking. No other
--stacking exists in the structure.
f

substituent, which hampers the planarization of the -system
in the ground and excited states.
Photophysical Properties
Table 2: UV/vis absorption and emission data of selected 2-substituted 3-
triazolylquinoxalines 3.
Previous studies on related quinoxaline chromophores have
shown interesting photophysical properties especially for
[
a]
[
12b,13,15]

[
max,abs [nm] (
[b]
[c]
Stokes shift 
̃
donor−acceptor-substituted derivatives,
which display
Compound
-1
-1

max,em [nm] (
f
)
[d]
-1
L·mol ·cm ])
[cm ]
bathochromically shifted emission maxima and large Stokes
shifts. Therefore, the polar anti-auxochromic substituent effect
of triazolyl units could be interesting with respect to its
solvatochromic effect. The photophysical properties of two
consanguineous series of 3-triazolylquinoxalines 3 recorded
2
62 (21700)
3
a
292 (15300)
541 (<0.01)
548 (<0.01)
613 (0.02)
7000
8300
8700
4500
7000
7000
7000
7000
3
93 (10100)
59 (23000)
2
3b
293 (9400sh)
84 (6800)
3
2 2
in CH Cl were studied by absorption and fluorescence
260 (22400sh)
spectroscopy (Figures 6-8). In series 1 the triazole substituent
3s
309 (16600)
4
3
R in position 3 of the quinoxaline core was chosen as benzyl
00 (8600)
1
and the quinoxaline substituent R were altered, whereas in
273 (18400)
1
series 2 the substituent R in position of 2 of the quinoxaline
3t
293 (14800sh)
440 (<0.01)
541 (<0.01)
547 (<0.01)
541 (<0.01)
540 (<0.01)
368 (12000)
core was kept constant as N-methylindol-3-yl and the triazole
3
substituent R was varied. The relative fluorescence quantum
265 (32000)
3g
yields 
literature procedures.
f
were determined with suitable standard according to
396 (10200)
[
27]
2
3
65 (32000)
96 (10200)
3
i
263 (22600)
3
j
290 (14600)
92 (9200)
3
2
64 (21400)
292 (15200)
91 (10000)
a] Recorded in CH Cl , c(3) = 10 M at T = 293 K. [b] Recorded in CH
3k
3
-
5
[
2
2
2
Cl
2
,
-
7
c(3) = 10 M at T = 293 K. [c] Relative fluorescence quantum yields were
determined employing literature procedures (±10 %) with coumarin 153
as a standard in methanol, exc = 420 nm (
[
27]
[
28]
f
= 0.45),
̃ = 1/max,abs 
1/max,em.
Figure 6: Two consanguineous series of 3-triazolylquinoxalines 3.
All eight investigated 3-triazolylquinoxalines 3 possess a
longest wavelength absorption maximum between  = 368
and 400 nm with molar absorption coefficients  ranging from
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substituents and a p-Me
the quinoxaline core. The R substituent on the triazole
moiety is kept constant as benzyl substituent. The
2
NC
6
H
4
substituent in 2-position of
3
a
computed equilibrium ground state structure of 3b matches
very well with the structure obtained from X-ray analyses. The
experimentally determined torsional angle between the N-
methylpyrrole substituent and quinoxaline core is well
reproduced by the computations (calc = 66° vs X-ray = 60°). A
closer inspection of the coefficient densities in the
Kohn−Sham frontier molecular orbitals of the three 3-tria-
zolylquinoxalines 3a,b and 3s reveals that the HOMO
coefficient densities are predominantly localized on the
1
heterocyclic substituent
R
(Figure 9). Accordingly the
coefficient densities in the LUMOs are localized on the
quinoxaline acceptor cores. In any case the 3-triazole moiety
only possesses a minor coefficient density. Expectedly, a
major electronic effect of the triazole on the relevant
electronic absorption and emission bands is not very likely.
This feature, however, is favorable for employing triazole
ligation between the chromophore and the substrate, as the
former will be undisturbed. The predominant localization of
the coefficient densities in HOMO and LUMO already
indicates proposed potential charge transfer (CT) character of
the relevant absorption bands.
-
5
Figure 7: Normalized UV/vis absorption (solid lines), c(3) = 10 M, and
-
7
emission (dashed lines), c(3)
exc
= 10 M,  = 420 nm, spectra of 3-
triazolylquinoxalines 3g, 3i-3k. Recorded in dichloromethane, T = 298 K.
-
5
Figure 8: Normalized UV/vis absorption (solid lines), c(3) = 10 M, and
-
7
emission (dashed lines), c(3)
triazolylquinoxalines 3a-3b and 3s-3t. Recorded in dichloromethane, T =
98 K.
exc
= 10 M,  = 420 nm, spectra of 3-
2
Electronic Structure of 3-Triazolylquinoxalines 3
A deeper understanding of the photophysical behavior of
selected 3-triazolylquinoxalines 3a,b and 3s was sought by
elucidating the electronic structure by calculating UV/vis
absorption spectra on the DFT level of theory, with a special
Figure
9:
Selected
DFT-computed
(PBEh1PBE/6-311++G(d,p))
Kohn−Sham frontier molecular orbitals of 3-triazolylquinoxalines 3a,b and
3s.
1
focus on comparison to the respective donor moiety R and
on the origin of the longest wavelength absorption maxima of
each structure. The geometries of the electronic ground-state
The optimized structures of 3a, 3b and 3s were submitted to
TD-DFT calculations to study the absorption characteristics in
more detail again applying PCM with dichloromethane as a
solvent (Table 3).
[
29]
structures were optimized using Gaussian09
with
[
30]
PBEh1PBE as functional and the Pople 6-311G++G(d,p)
[31]
basis set.
Since absorption properties were measured in
dichloromethane solutions, the polarizable continuum model
[
32]
(
PCM) with dichloromethane as a solvent was applied. All
minimum structures were unambiguously assigned by
analytical frequency analysis. The structures were chosen as
a
series of compounds with two different heterocyclic
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Table 3: TD-DFT calculations (PBEh1PBE/6-311++G(d,p)) of the absorption maxima of 3-triazolylquinoxalines 3a,b and 3s by applying PCM with
dichloromethane as solvent.
[
a]
-1
-1

max,abs [nm] ( [L·mol ·cm ])

max,calcd [nm]
288
Most dominant contributions
HOMOLUMO+1 (70%)
HOMO-1LUMO (77%)
HOMOLUMO (95%)
Oscillator strength
0.259
3
3
3
a
b
s
262 (21700)
2
92 (15300)
93 (10100)
309
0.069
3
370
0.143
259 (23000)
93 (9400sh)
84 (6800)
260 (22400sh)
09 (16600)
00 (8600)
250
HOMO-1LUMO+1 (37%)
HOMOLUMO+1 (79%)
HOMOLUMO (85%)
0.339
2
288
0.097
3
371
0.074
296
HOMOLUMO+2 (63%)
HOMOLUMO+1 (82%)
HOMOLUMO (98%)
0.162
3
311
0.128
4
391
0.184
-
5
[
2 2
a] Recorded in CH Cl , c(3) = 10 M at T = 293 K.
The computed results satisfactorily match with the
experimental absorption maxima. As expected, the longest
wavelength absorption bands of all three calculated 3-
triazolylquinoxalines originate from dominant contributions of
HOMO−LUMO based transitions. The relevant oscillator
strengths additionally indicate permitted electronic transitions.
In comparison, related 3-ethynylquinoxaline chromophores
adopt significantly higher values of the oscillator
characteristics
of
the
sequentially
Cu-catalyzed
multicomponent synthesis opens new avenues for
applications of tailored emissive chromophore libraries in
biophysical analytics. Further studies are currently under
investigation.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/chem.2014xxxxx.
Experimental details and full characterization of compounds 1
[
12b,15]
strengths
due to less steric strain of the alkynyl
1
13
substituent in comparison to the triazolyl moiety. In all three
calculated cases two additional absorption maxima at lower
wavelengths emanate predominantly from HOMOLUMO+1,
and 3, H and C NMR spectra of compounds 1 and 3,
selected UV/Vis and emission spectra of compounds 3, X-ray
structure data tables of compound 3b, DFT computed XYZ-
coordinates, energies, and absorption spectra of structures of
selected compounds 3.
HOMO-1LUMO,
HOMOLUMO+2,
and
HOMO-
1LUMO+1 transitions.
Experimental Section
Conclusions
Five-component synthesis of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-3-
(1-methyl-1H-indol-3-yl)quinoxaline (3a) (a typical procedure):
2.00 mmol of N-methylindole (4a) (268 mg, 1.00 equiv) in dry THF
In conclusion we have developed a straightforward approach
towards the synthesis of 3-triazolylquinoxalines based upon a
sequentially Cu-catalyzed process, consisting of Cu-catalyzed
alkynylation and CuAAC proceeding in a one-pot fashion.
Particularly interesting either electron rich -nucleophiles by
applying the glyoxylation-alkynylation-cyclocondensation-
CuAAC sequence or glyoxylic acids via the activation-
alkynylation-cyclocondendation-CuAAC sequence can be
complementarily employed to prepare extended substance
(
5.00 mL/mmol) was placed under nitrogen atmosphere in a sintered
screw-cap Schlenk tube, degassed with nitrogen, and cooled to 0 °C
water/ice, 5 min). Then, oxalyl chloride (5) (0.18 mL, 2.00 mmol,
.00 equiv) was added dropwise to the reaction mixture at 0 °C. The
(
1
mixture was then stirred for 1 h at 50 °C (oil bath). Thereafter, the
mixture was cooled to room temperature (water bath, 5 min). Then,
CuI (20 mg, 0.10 mmol, 5 mol %), one equivalent of TMSA (6), and
dry triethylamine (0.60 mL, 4.40 mmol, 2.20 equivs) were
successively added to the reaction mixture, and stirring at room
temperature was continued for 6 h. Then, 2 mL of methanol, 2.00
mmol of the o-diaminoarene (7a) (216 mg, 1.00 equiv), and acetic
acid (0.24 mL, 4.00 mmol, 2.00 equivs.) were added successively and
the mixture was stirred at 50 °C for 1 h. Then, potassium fluoride (236
mg, 4.00 mmol, 2.00 equivs) were added with 1.0 mL THF and 2 mL
methanol. The reaction mixture was stirred for 30 min at room
temperature. Last, benzylazide (2a) (292 mg, 2.20 mmol, 1.10 equiv,
for experimental details see Supp. Info. Table S2) was added with
libraries.
Moreover,
3-triazolylquinoxalines
possess
interesting photophysical properties. All generated triazolyl
based products are luminescent in solution and their
photophysical
characteristic
can
be
assessed
in
dichloromethane solution. The corresponding absorption and
emission maxima can be fine-tuned in accordance with the
substituent in 2-position of the quinoxaline core. Interestingly
the triazolyl moiety does not affect the absorption or emission
maxima, and hence qualifies as an excellent largely
electronically innocent linker for various biological substrates,
polymers and surfaces. The electronic structure, assessed by
DFT and TD-DFT calculations rationalize the pronounced
emission solvatochromicity and large Stokes shift as a
consequence of CT character of the relevant longest
wavelength absorption bands. The highly diversity-oriented
nature of the synthetic process and the one-pot
2
6 mL of THF and Na Asc (40 mg, 0.20 mmol, 10 mol%) and the
reaction mixture was stirred at room temperature for another 19 h.
Then 10 mL water was added, the phases were separated, and the
aqueous phase was extracted with dichloromethane (3 × 5 mL/10 mL,
monitored by TLC). The combined organic layers were dried with
anhydrous sodium sulfate. After removal of the solvents in vacuo, the
residue was absorbed onto Celite and purified chromatographically on
silica gel with petroleum ether (boiling range 40−60 °C)/ethyl acetate
to give the 3-triazolylquinoxaline 3a (680 mg, 83%) as a yellow solid,
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Chemistry - A European Journal
10.1002/chem.201900277
FULL PAPER
1
Mp 175 °C. H NMR (CDCl
7
3
, 300 MHz): 3.67 (s, 3 H), 5.42 (s, 2 H),
B. Sharpless, V. V. Fokin, Angew. Chem. 2004, 116,
.01-7.11 (m, 3 H), 7.16-7.23 (m, 1 H), 7.24-7.30 (m, 5 H), 7.42 (s, 1
4
018–4022; Angew. Chem. Int. Ed. 2004, 43, 3928–3932;
13
H), 7.62-7.77 (m, 3 H), 8.05-8.16 (m, 2 H). C NMR (CDCl
33.1 (CH ), 54.1 (CH ), 109.6 (CH), 113.2 (Cquat), 120.9 (CH), 121.3
CH), 122.5 (CH), 124.4 (CH), 126.7 (Cquat), 127.9 (CH), 128.7 (CH),
29.1 (CH), 129.2 (CH), 129.3 (CH), 130.3 (CH), 131.3 (CH), 134.3
Cquat), 137.1 (Cquat), 140.1 (Cquat), 141.6 (Cquat), 144.6 (Cquat), 146.6
3
, 75 MHz):
(
c) B. Helms, J. L. Mynar, C. J. Hawker, J. M. J. Fréchet,

3
2
J. Am. Chem. Soc. 2004, 126, 15020–15021. (d) P. Wu,
M. Malkoch, J. N. Hunt, R. Vestberg, E. Kaltgrad, M. G.
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Ed. 2006, 45, 5292-5296.
(
1
(
(
1
+
+
C
quat), 149.1 (Cquat). EI + MS (m/z (%)): 417 ([M+H] , 26), 416 ([M] ,
00), 387 ([C26H N ] , 15), 373 ([C26H N ] , 11), 298 (20), 297
20 4 20 3
+
+
+
(
(
(
[C19
[C17
[C17
H
13
H
11
H
11
N
4
N
5
N
4
] , 93), 296 (18), 295 (10), 287 (21), 285 (13), 284
] , 49), 283 (34), 282 (38), 281 (14), 271 (46), 270
] , 95), 269 (32), 268 ([C18
+
+
+
+
H
10
N
3
] , 15), 259 ([C17
H
12
N
H
3
] ,
+
+
+
2
3
2
9), 256 ([C17
4). IR (ATR): 
913 (w), 2901 (w), 2884 (w), 1526 (m), 1497 (w), 1476 (m), 1456
m), 1447 (m), 1423 (m), 1408 (w), 1368 (m), 1337 (m), 1296 (w),
275 (w), 1240 (m), 1211 (m), 1188 (w), 1161 (w), 1128 (m), 1092
H
11
N
3
] , 22), 255 (11), 155 ([C
3134 (w), 3061 (w), 3044 (w), 2955 (w), 2928 (w),
9
H
7 3
N ] , 12), 91 ([C
7
7
] ,
[
6]
(a) W. S. Horne, M. K. Yadav, C. D. Stout, M. R. Ghadiri,
J. Am. Chem. Soc. 2004, 126, 15366–15367. (b) C. W.
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(
1
(
(
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N 19.92.
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H N (416.5): C 74.98, H 4.84, N 20.18. Found: 74.70, H 5.13,
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Acknowledgements
For reviews on tandem and sequential catalysis, see: (a)
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the Deutsche Forschungsgemeinschaft (Mu 1088/9-1) for
financial support.
Keywords: Alkynylation
•
Click reaction
•
•
Copper
•
fluorescence
•
multicomponent reactions
sequential
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FULL PAPER
Entry for the Table of Contents
FULL PAPER
[a]
Franziska K. Merkt, Konstantin
[
a]
[b]
Pieper, Maximilian Klopotowski,
[
b]
Christoph Janiak, Thomas J. J.
[
a]
Müller *
Page No. – Page No.
Sequentially Cu-catalyzed Four- and
Five-Component Syntheses of
Luminescent 3-Triazolylquinoxalines
Catching Two Birds with A Single Cuprous Stone: The sequentially copper-
catalyzed alkynylation-alkyne-azide cycloaddition (CuAAC), preceded by
glyoxylation or activation and intercepted by Hinsberg cyclization, is the key to
consecutive multicomponent syntheses of 3-triazolylquinoxalines with tunable
emission properties in good yields.
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