From quinoxaline, pyrido[2,3-b]pyrazine and pyrido[3,4-b]pyrazine to pyrazino-fused carbazoles and carbolines

Article abstract of DOI:10.3390/molecules23112961

2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4-b]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodoquinoxaline, 8-iodopyrido[2,3-b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids or anilines, and possible subsequent cyclizations to afford the corresponding pyrazino[2,3-a]carbazole, pyrazino[2',3':5,6] pyrido[4,3-b]indole and pyrazino[2',3':4,5]pyrido[2,3-d]indole, respectively. 8-Iodopyrido[2,3-b] pyrazine was subjected either to a copper-catalyzed C-N bond formation with azoles, or to direct substitution to introduce alkylamino, benzylamino, hydrazine and aryloxy groups at the 8 position. The 8-hydrazino product was converted into aryl hydrazones. Most of the compounds were evaluated for their biological properties (antiproliferative activity in A2058 melanoma cells and disease-relevant kinase inhibition).

Full text of DOI:10.3390/molecules23112961

molecules
Article
From Quinoxaline, Pyrido[2,3-b]pyrazine and
Pyrido[3,4-b]pyrazine to Pyrazino-Fused Carbazoles
and Carbolines
Frédéric Lassagne 1,*, Timothy Langlais 1, Elsa Caytan 1 , Emmanuelle Limanton 1,
Ludovic Paquin 1,*, Manon Boullard 1 , Coline Courtel 1, Idriss Curbet 1, Clément Gédéon 1,
Julien Lebreton 1, Laurent Picot 2,*, Valérie Thiéry 2 , Mohamed Souab 3, Blandine Baratte 3,
Sandrine Ruchaud 3, Stéphane Bach 3,
* *
, Thierry Roisnel 1 and Florence Mongin 1,
1
Univ Rennes, CNRS, Institut des Sciences Chimiques de Rennes (ISCR)-UMR 6226, F-35000 Rennes, France;
timothy.langlais@etudiant.univ-rennes1.fr (T.L.); elsa.caytan@univ-rennes1.fr (E.C.);
emmanuelle.limanton@univ-rennes1.fr (E.L.); manon.boullard@etudiant.univ-rennes1.fr (M.B.);
coline.courtel@etudiant.univ-rennes1.fr (C.C.); idriss.curbet@etudiant.univ-rennes1.fr (I.C.);
clement.gedeon@etudiant.univ-rennes1.fr (C.G.); julien.lebreton@etudiant.univ-rennes1.fr (J.L.);
thierry.roisnel@univ-rennes1.fr (T.R.)
2
3
Laboratoire Littoral Environnement et Sociétés, UMRi CNRS 7266, Université de La Rochelle,
17042 La Rochelle, France; valerie.thiery@univ-lr.fr
Sorbonne Universités, UPMC Univ Paris 06, CNRS USR3151, “Protein Phosphorylation and Human Disease”
Unit, Plateforme de criblage KISSf, Station Biologique de Roscoff, Place Georges Teissier, 29688 Roscoff,
France; mo.souab@gmail.com (M.S.); baratte@sb-roscoff.fr (B.B.); sandrine.ruchaud@sb-roscoff.fr (S.R.)
Correspondence: frederic.lassagne@univ-rennes1.fr (F.L.); ludovic.paquin@univ-rennes.fr (L.P.);
laurent.picot@univ-lr.fr (L.P.); bach@sb-roscoff.fr (S.B.); florence.mongin@univ-rennes1.fr (F.M.);
Tel.: +33-223-236-931 (F.M.)
*
Academic Editor: Richard A. Bunce
Received: 23 October 2018; Accepted: 11 November 2018; Published: 13 November 2018
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: 2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4-b]pyrazine
were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl
piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodo-
quinoxaline, 8-iodopyrido[2,3-b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained
were subjected to palladium-catalyzed couplings with arylboronic acids or anilines, and possible
subsequent cyclizations to afford the corresponding pyrazino[2,3-a]carbazole, pyrazino[20,30:5,6]
pyrido[4,3-b]indole and pyrazino[20,30:4,5]pyrido[2,3-d]indole, respectively. 8-Iodopyrido[2,3-b]
pyrazine was subjected either to a copper-catalyzed C-N bond formation with azoles, or to direct
substitution to introduce alkylamino, benzylamino, hydrazine and aryloxy groups at the 8 position.
The 8-hydrazino product was converted into aryl hydrazones. Most of the compounds were evaluated
for their biological properties (antiproliferative activity in A2058 melanoma cells and disease-relevant
kinase inhibition).
Keywords: pyrazine; deprotometalation; coupling; N-arylation; palladium; copper
1. Introduction
Quinoxalines and pyridopyrazines are aromatic heterocycles present in compounds endowed
with numerous interesting properties. Some derivatives are bioactive and are used as antimicrobial,
anti-inflammatory, antimalarial, anticancer and antidepressant compounds [
for example employed as organic dyes [ ], electroluminescent materials [
semiconductors [
1
,
2
]. Others are
3
4], and organic
5
]. Quinoxaline and pyridopyrazine substrates can be readily synthesized by
Molecules 2018, 23, 2961; doi:10.3390/molecules23112961
www.mdpi.com/journal/molecules

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condensation of 1,2-dicarbonyl compounds with 1,2-arylenediamines [
further elaboration.
6
] and lend themselves to
Deprotonative lithiation followed by interception of the arylmetals with electrophiles is an efficient
way to functionalize aromatic compounds [ 12]. However, reactions with substrates sensitive to
nucleophilic attack such as azines must be performed at very low temperatures to avoid secondary
reactions between arylmetals and functions [13 15]. The use of in situ metal traps avoids the use
of cryogenic conditions to achieve these reactions [16 17]. We have developed mixed lithium-zinc
combinations based on TMP (TMP = 2,2,6,6-tetramethylpiperidino) capable of deprotonating sensitive
substrates at temperatures close to rt [18 21]. In order to obtain original scaffolds such as
7–
–
,
–
pyrazino-fused carbazoles and carbolines, we decided to combine this deprotometalation under
in situ trapping conditions with palladium- and copper-catalyzed coupling reactions.
2. Results and Discussion
2.1. Synthesis
To functionalize 2,3-diphenylquinoxaline (1a) and 2,3-diphenylpyrido[2,3-b]pyrazine (2a),
two deprotonation methods were tested in tetrahydrofuran (THF) (Table 1, Method A and Method B).
Table 1. Deprotonative metalation of 2,3-diphenylquinoxaline (1a) and 2,3-diphenylpyrido[2,3-b]
-pyrazine (2a) and conversion to the halogeno derivatives.
.
Entry
Substrate
Method
Electrophile, Conditions
Product (E), Yield (%) 1
◦
1b (I), 74 2
1
1a (X = CH)
A
I2, THF, 0 C, 1 h
◦
2
3
4
1a (X = CH)
2a (X = N)
2a (X = N)
B
A
B
I2, THF, 0 C, 1 h
1b (I), 70
2b-I (I), 70
2b-I (I), 62
◦
I2, THF, 0 C, 1 h
◦
I2, THF, 0 C, 1 h
2b-Br (Br),
◦
5
6
2a (X = N)
2a (X = N)
B
B
Br2, −20 C, 1 h
60
2b-Cl (Cl),
◦
−20 C, 1 h
62
1
2
After purification (see experimental part).
The rest is 5,8-diiodo-2,3-diphenylquinoxaline (1b0; 7% yield;
see Figure 1). 1b0 was isolated in 70% yield by using ZnCl2·TMEDA (1 equiv) and LiTMP (3 equiv).
The lithium-zinc base of Method A is prepared from ZnCl2
tetramethylethylenediamine) and LiTMP in a 1:3 ratio. Previous studies have suggested that it
·
TMEDA (TMEDA = N,N,N0,N0-

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is a 1:1 LiTMP-Zn(TMP)2 combination. While LiTMP deprotonates the substrate, Zn(TMP)2 intercepts
the generated aryllithium [18 19 22]. A recent computer study on anisole showed that the reactive
,
,
species is solvated LiTMP. The effectiveness of the reaction derives from the stabilizing effect of the
transmetalation step [21].
It is possible to replace Zn(TMP)2 by ZnCl2 provided that there is no contact between LiTMP
and ZnCl2 in the absence of the aromatic compound [23,24]. Thus, Method B is limited to activated
substrates for which deprotonation is favored over reaction between LiTMP and ZnCl2.
Whereas Method A should provide a lithium arylzincate, Method B should rather generate an
arylzinc. Nevertheless, both species are known to react with iodine by aryl transfer.
Thus, 2,3-diphenylquinoxaline (1a) and 2,3-diphenylpyrido[2,3-b]pyrazine (2a) were involved in
Method A. After treatment at rt with the base for 2 h, addition of iodine led to iodoquinoxaline 1b and
iodopyrido[2,3-b] pyrazine 2b-I in 74 and 70% yield, respectively (entries 1 and 3).
To evaluate Method B, 1a and 2a were mixed with ZnCl2
·
TMEDA before addition of LiTMP at
−
20 ◦C and stirring for 0.5 h (Method B, entries 2 and 4). After subsequent interception with iodine,
1b and 2b-I were isolated in 70 and 62% yield, respectively (entries 2 and 4).
We explored the use of other electrophiles to intercept the heteroarylzinc chloride prepared from
2a by using Method B. Conversion to the corresponding bromide 2b-Br (60% yield, entry 5) and chloride
2b-Cl (62% yield, entry 6) was performed using bromine and trichloroisocyanuric acid, respectively,
as the electrophile.
0
Figure 1. ORTEP diagrams (30% probability) of 1b , 2d, 2f, 2i, 2p.
The deprotometalation-iodination sequence was successfully applied to 8-bromo-2,3-diphenyl
pyrido[3,4-b]pyrazine (3a) [25,26], but failed with 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine (4a) due
to significant degradation before trapping (Scheme 1). While the position of the iodo group in 3b was
evidenced by subsequent reaction, it was studied by advanced NMR experiments in the case of 4b
(see Supplementary Materials).
In order to prepare original pyrazino-fused carbazoles and carbolines, iodides 1b and 2b-I were
subjected to in Suzuki couplings [27
2-thienyl- (entries 2 and 3) and 2-aminophenyl- (entries 4 and 5) boronic acids led to the 5-arylated
derivatives 1c and 2d in 42-97% yields. The more electron-rich arylboronic acids and the less
electron-poor quinoxaline substrate 1b gave the best results.
,28] under standard conditions (Table 2) [29]. Phenyl- (entry 1),
-
e
,e

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Br
Br
H
N
N
Ph
Ph
(67% yield)
I
N
N
Ph
Ph
N
N
Method B
1) ZnCl2·TMEDA (1 equiv)
2) LiTMP (1.2 equiv)
THF, -20 °C, 30 min
3) I2, -20 °C to rt
3a
3b
Br
N
Ph
Br
I
N
Ph
(5% yield)
H
N
N
Ph
N
N
Ph
4a
4b
Scheme 1. Deprotonative metalation of 8-bromo-2,3-diphenylpyrido[3,4-b]pyrazine (3a) and
7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine (4a) followed by conversion to the halogeno derivatives.
Table 2. Suzuki coupling from 5-iodo-2,3-diphenylquinoxaline (1b) and 8-iodo-2,3-diphenyl
pyrido[2,3-b]pyrazine (2b-I).
Entry
Substrate
ArB(OH)2
Product (Ar), Yield (%) 1
1
1b (X = CH)
PhB(OH)2
1c (Ph), 42
1b (X = CH)
1d (2-thienyl), 97
2
3
4
5
2d (2-thienyl) 2, 75
2b-I (X = N)
1b (X = CH)
1e (2-aminophenyl), 92
2b-I (X = N)
2e (2-aminophenyl), 73
1
2
After purification (see experimental part). See Figure 1.
No intramolecular nitrene insertion into the corresponding diazino-fused carbazole and
-carboline was obtained for the azides coming from 1e and 2e 29]. We thus turned to the synthesis of
the original pyrazino[2,3-a]carbazole 1g and the corresponding pyrazino-fused -carboline 2g isomers
38] with intramolecular C-C bond formation
β
[
γ
by combining intermolecular C-N bond formation [30
(Scheme 2).
–
The first step, attempted from 1b by using catalytic palladium(II) acetate as transition metal source,
Xantphos as ligand, and sodium tert-butoxide as base in toluene [39], yielded only 16% of diarylamine
1f. Applying to 1b and 2b-I the conditions reported by Maes and co-workers for related reactions [29],
1f and 2f were obtained in 92 and 67% yield, respectively (Scheme 2, left). Inspired by Pieters and
co-workers, who cyclized 4-(2-chlorophenylamino)pyridine into 5H-pyrido[4,3-b]indole under these
conditions [40], we successfully employed catalytic (Pd2(dba)3) and tri-tert-butylphosphine as catalyst
precursors, diazabicyclo[5.4.0]undec-7-ene (DBU) as base, and dioxane as solvent for the second step.
After 10 min at 180 ◦C under microwave irradiation, the pyrazino-fused carbazole 1g and
2g were isolated in moderate yields (Scheme 2, right).
γ-carboline
We decided to combine both steps in an auto-tandem process under microwave irradiation
(Table 3). Using (Pd2(dba)3), we selected Xantphos for its higher efficiency in comparison with
tri-tert-butylphosphine. From 2b, best results were obtained with three equivalents of DBU as base
(entries 1 and 2). In addition, a longer reaction time was required to ensure complete conversion and
this afforded carboline 2g in 70% yield (entry 3).

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Scheme 2. Conversion of 5-iodo-2,3-diphenylquinoxaline (1b) and 8-iodo-2,3-diphenylpyrido[2,3-b]
pyrazine (2b-I) into 2,3-diphenyl-11H-pyrazino[2,3-a]carbazole (1g) and 2,3-diphenyl-11H-pyrazino
0
0
[2 ,3 :5,6]pyrido[4,3-b]indole (2g), respectively. Dba = dibenzylideneacetone.
Table 3. Study of the conversion of the 8-halogenated 2,3-diphenylpyrido[2,3-b]pyrazines 2b into
0
0
2,3-diphenyl-11H-pyrazino[2 ,3 :5,6]pyrido[4,3-b]indole (2g) under MW irradiation.
Entry
Substrate (X) n Equiv
Conditions 1
2f (%) 2
2g (%) 2
◦
1
2
3
4
5
2b-I (I)
2b-I (I)
2b-I (I)
2b-I (I)
2b-I (I)
2b-I (I)
2b-I (I)
2b-I (I)
2b-Br (Br)
2b-Cl (Cl)
1.2
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
180 C, 20 min
80
41
<5
75
23
20
◦
180 C, 20 min
59
◦
>95, 70 3
180 C, 60 min
◦
180 C, 60 min 4
25
75
<2
67
0
◦
180 C, 20 min 5
◦
6 6
7 7
8
9
10
180 C, 20 min
95
32
◦
180 C, 20 min
◦
66 8
35 9
22 10
180 C, 5 min
◦
180 C, 5 min
0
0
◦
180 C, 5 min
1
2
Maximum microwave power applied: 150–200 W at the beginning to reach the required temperature. Evaluated
3
4
from the NMR spectra of the crudes. Yield after purification. Microwave profile of irradiation: The sequence
‘Maximum microwave power applied: 150–200 W to reach 180 ◦C then 2 min at 180 ◦C before cooling to 100 ◦C’ was repeated
every 4 min. Then classical heating at 180 ◦C for 40 min. Without catalyst. By using 12 mol% Pd2(dba)3 and 30
5
6
7
8
9
10
mol% Xantphos. The rest was unreacted 2b-I (32%). The rest was unreacted 2b-Br (38%) and 2a (28%). The
rest was unreacted 2b-Cl (78%).
By testing a profile to maximize the microwave power, we noticed that an increase of the applied
power favored the formation of 2f over 2g (entry 4). By carrying out one third of the reaction time under
microwave irradiation and the rest by classical heating at the same temperature, a small microwave
effect was evidenced (entry 5). While 2g was not formed without catalyst, C-N bond formation giving
2f could take place (entry 6; see Figure 1). However, increasing the catalyst amount had no impact on
the conversion to 2g (entry 7). Finally, we intentionally chose a short reaction time (5 min) in order to
compare the palladium-catalyzed reactions under microwave irradiation from 2b-I (entry 7), 2b-Br
(entry 7) and 2b-Cl (entry 10). The results clearly showed decreasing reactivity from 2b-I to 2b-Cl
,
and thus, we selected iodo as halogeno group to pursue our investigations.
We applied the optimized procedure to the synthesis of the pyrazino-fused α-carboline 3g from
the bromoiodo substrate 3b and aniline. No trace of the expected product 3g was detected but the
formation of 3g0 due to competitive debromination was noted, showing a less obvious intramolecular
C-H arylation (Scheme 3, left). Consequently, we moved to the synthesis of the pyrazino-fused
δ
-carboline 3h. Upon treatment of 3b by 2-aminophenylboronic acid under standard conditions [29],
coupling and subsequent cyclization occurred, providing 3h in 65% yield (Scheme 3, right).

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Scheme 3. Conversion of 8-bromo-7-iodo-2,3-diphenylpyrido[3,4-b]pyrazine (3b) into 2,3-diphenyl-
0
0
11H-pyrazino[2 ,3 :4,5]pyrido[2,3-d]indole (3h) and ORTEP diagram (30% probability) of 3h.
To take advantage of the iodo group on 2b-I, C-N bond formation with azoles was attempted
under copper catalysis as reported previously [41 42] (Table 4). Thus, by treating 2b-I with pyrrole
,
(entry 1; see Figure 1), indole (entry 2), pyrazole (entry 3), imidazole (entry 4) or 1,2,4-triazole (entry
5), in the presence of catalytic copper(I) oxide, cesium carbonate, and dimethylsulfoxide (DMSO) at
110 ◦C for 24 h, the expected N-arylated azoles were obtained in 51 to 79% yields.
As previously mentioned [22], such reactions work far less efficiently when performed on
diiodides. Indeed, reacting the diiodide 1b0 with pyrazole only gave the monofunctionalized derivative
1k0, regardless of the amount of azole employed (Scheme 4).
0
Scheme 4. Copper-catalyzed N-arylation of 5,8-diiodo-2,3-diphenylquinoxaline (1b ).
Different amines and hydrazine reacted with 2b-I without recourse to catalyst (Table 5), affording
the corresponding secondary amines 2n
The latter was converted into the hydrazones 2r
their ability to potentially interact with binding sites of biological interest [43] (Scheme 5). Finally,
reaction of 2b with a phenol also proved possible without catalyst, giving the diaryl ether 2v in 64%
yield (Scheme 6).
-
p
(entries 1-3) and arylhydrazine 2q (entry 4) in good yields.
-
u
in the presence of aromatic aldehydes chosen for
-
I

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Table 4. Copper-catalyzed N-arylation of 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I) using azoles.
Entry
Azole
Product, Yield (%) 1
1
Pyrrole
2i, 67
2j, 51
2
Indole
3
4
Pyrazole
2k, 71
2l, 69
Imidazole
5
1,2,4-Triazole
2m, 79
1
After purification (see experimental part). The rest is starting material and the
corresponding deiodinated compound.
Scheme 5. Conversion of 8-hydrazino-2,3-diphenylpyrido[2,3-b]pyrazine (2q) into aryl hydrazones.

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Table 5. Conversion of 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I) into corresponding amines
and hydrazine.
Entry
R-NH2
Conditions
Product, Yield (%) 1
◦
1
iPrNH2 (1.2)
EtOH, 150 C, 18 h
2n, 69
◦
2
3
4-MeOC6H4CH2NH2 (1.2) EtOH, 150 C, 24 h
2o, 71
◦
2p 2, 79
PhCH2NH2 (1.2)
EtOH, 150 C, 24 h
iPrOH, reflux, 4 h
4
NH2NH2·H2O (10)
2q, 92
1
2
After purification (see the Materials and Methods section). See Figure 1.
Scheme 6. Conversion of 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I) into ether 2v.
2.2. Biological Activity
Some of the synthesized compounds were tested [44] for their antiproliferative activity in A2058
melanoma cells and proved to exert a modest to good activity (Figure 2). The best results were obtained
with the 4-(trifluoromethyl)benzaldehyde hydrazone 2u and the 8-benzylamino pyrido[2,3-b]pyrazine
2o which induced ~64% growth inhibition at 10−5 M.
Compounds 1c–e, 1g, 2d–g, 2i–v and 3h were evaluated [44] against a short panel of
disease-relevant protein kinases. Protein kinases are drug targets often deregulated in diseases such
as cancers and neurodegenerative disorders [45]. No significant inhibition of the following kinases
was observed: Cyclin-dependent kinases 2 (CDK2/Cyclin A), 5 (CDK5/p25) and 9 (CDK9/Cyclin T),
proto-oncogene kinase PIM1, CDC2-like kinase 1 (CLK1), dual specificity tyrosine phosphorylation
regulated kinase 1A (DYRK1A), glycogen-synthase kinase 3 (GSK3;
α/β or β), casein kinase 1 (CK1;
δ
/ε
or ), and mitotic kinase Haspin). Table S1 in Supplementary Materials shows the results obtained.
ε

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Figure 2. Antiproliferative activity of some of the synthesized compounds at 10−5 M after 72 h in
A2058 human melanoma cells.
3. Materials and Methods
3.1. General Information
All the reactions were performed under a dry argon atmosphere. THF was distilled over
sodium/benzophenone. Column chromatography separations were achieved on silica gel (40–63 µm).
Melting points were measured on a Kofler apparatus. IR spectra were taken on an ATR Spectrum 100
1
spectrometer (Perkin-Elmer). H- and 13C-Nuclear Magnetic Resonance (NMR) spectra were recorded
either on an Avance III spectrometer (291 K) at 300 MHz and 75 MHz, respectively, or on an Avance III
HD spectrometer (298 K) at 500 MHz and 126 MHz, respectively (Bruker, Billevica, Massachussets,
δ
USA). 1H chemical shifts ( ) are given in ppm relative to the solvent residual peak and 13C chemical
shifts are relative to the central peak of the solvent signal [46]. 2,3-Diphenylpyrido[2,3-b]pyrazine
2a) [ ], 8-bromo-2,3-diphenylpyrido[3,4-b]pyrazine (3a) [25 26] and 7-bromo-2,3-diphenylpyrido[2,3-b]
pyrazine (4a) [ ] were prepared as reported previously. The biological activity assays were performed
(
6
,
6
as reported previously [44].
3.2. Crystallography
The X-ray diffraction data were collected either using an APEXII Bruker-AXS diffractometer
(graphite monochromatized Mo-K radiation (
= 0.71073 Å)) for the compounds 1b0 and 2i, or using a
D8 VENTURE Bruker AXS diffractometer (multilayer monochromatized Mo-K radiation ( = 0.71073
Å)) equipped with a (CMOS) PHOTON 100 detector for 2f 2p 3h and 2d, at the temperature given in
the crystal data. For 1b0 and 2i, the structure was solved by direct methods using SIR97 [47]. For 2f
2p 3h and 2d, they were solved by dual-space algorithm using the SHELXT program [48]. Structural
α
λ
α
λ
,
,
,
,
refinements were performed with full-matrix least-square methods based on F2 (SHELXL) [49]. In the
case of 2f and 3h, the contribution of the disordered solvents to the calculated structure factors was
estimated following the BYPASS algorithm [50], implemented as the SQUEEZE option in PLATON [51];
a new data set, free of solvent contribution, was then used in the final refinement. All non-hydrogen
atoms were refined with anisotropic atomic displacement parameters. Except nitrogen linked hydrogen
atom that was introduced in the structural model through Fourier difference maps analysis (2f, 2p,
3h), H atoms were finally included in their calculated positions and treated as riding on their parent
atom with constrained thermal parameters. The molecular diagrams were generated by ORTEP-3
(version 2.02) [52].
3.3. Deprotometalation Followed by Trapping with Electrophiles
3.3.1. General Procedure 1
To a solution of 2,2,6,6-tetramethylpiperidine (0.51 mL, 3.0 mmol) in THF (3 mL) at 0 ◦C were
successively added BuLi (about 1.6 M hexanes solution, 3.0 mmol) and, 15 min later, ZnCl2
(0.25 g, 1.0 mmol). After 15 min at 0 C, the pyrazine (2.0 mmol) was introduced, and the mixture was
stirred for 2 h at rt before addition of I2 (0.76 g, 3.0 mmol) in THF (3 mL) at 0 ◦C. The mixture was
·
TMEDA [53
]
◦

Molecules 2018, 23, 2961
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stirred at this temperature for 1 h before addition of an aqueous saturated solution of Na2S2O3 (10 mL)
and extraction with EtOAc (3 20 mL). The combined organic layers were dried over MgSO4, filtered
×
and concentrated under reduced pressure. The crude product was purified by chromatography over
silica gel (the eluent is given in the product description).
3.3.2. 5-Iodo-2,3-diphenylquinoxaline (1b)
The general procedure 1 using 2,3-diphenylquinoxaline (1a, 0.56 g) gave 1b (eluent: heptane-
CH2Cl2 60:40; Rf = 0.55) in 74% yield as a pale yellow powder. Mp: 148 ◦C. IR: 486, 529, 551, 602, 689,
1
695, 701, 763, 776, 796, 892, 978, 1023, 1068, 1079, 1184, 1281, 1336, 1384, 1497, 1534, 3051 cm−1. H-NMR
(CDCl3): 7.31–7.41 (m, 6H), 7.48 (dd, 1H, J = 8.3 and 7.4 Hz), 7.54–7.57 (m, 2H), 7.64–7.67 (m, 2H),
8.15 (dd, 1H, J = 8.4 and 1.3 Hz), 8.36 (dd, 1H, J = 7.4 and 1.3 Hz). 13C-NMR (CDCl3): 102.8 (C), 128.3
(2CH), 128.5 (2CH), 129.2 (CH), 129.3 (CH), 129.9 (2CH), 130.0 (CH), 130.5 (2CH), 131.0 (CH), 138.2 (C),
138.7 (C), 140.1 (CH), 140.9 (C), 141.3 (C), 153.9 (C), 154.1 (C). Anal. Calc. for C20H13IN2 (408.24):
C 58.84, H 3.21, N, 6.86. Found: C 59.05, H 3.27, N, 6.70. 5,8-Diiodo-2,3-diphenylquinoxaline (1b0) was
similarly isolated (eluent: heptane-CH2Cl2 60:40; Rf = 0.69) in 7% yield as a yellow powder. Mp: 222
◦C. IR: 533, 572, 613, 649, 692, 771, 824, 893, 978, 1025, 1055, 1077, 1169, 1209, 1325, 1383, 1447, 2930,
1
3059 cm−1. H-NMR (CDCl3): 7.34–7.45 (m, 6H), 7.64–7.76 (m, 4H), 8.02 (s, 2H). 13C-NMR (CDCl3):
103.5 (2C), 128.4 (4CH), 129.7 (2CH), 130.4 (4CH), 137.7 (2C), 140.6 (2CH), 140.8 (2C), 154.5 (2C). Crystal
data for 1b0. C20H12I2N2, M = 534.12, T = 150(2) K, monoclinic, P 21, a = 10.1153(9), b = 5.8725(5)
,
c = 14.9603(14) Å,
β
= 98.489(4) ◦, V = 878.94(14) Å3, Z = 2, d = 2.018 g cm−3
,
µ
= 3.581 mm−1. A final
R(F2) = 0.0701 (R(F)
refinement on F2 with 3888 unique intensities and 217 parameters converged at
ω
= 0.0343) for 3602 observed reflections with I > 2σ(I). CCDC 1858478.
3.3.3. 8-Iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I)
The general procedure 1 using 2,3-diphenylpyrido[2,3-b]pyrazine (2a, 0.57 g) gave 2b-I (eluent:
◦
CH2Cl2; Rf = 0.34) in 70% yield as a whitish powder. Mp: 220 C. IR: 534, 562, 613, 624, 637, 699,
980, 1023, 1336, 1416, 1519, 1570, 3068 cm−1. H-NMR (CDCl3): 7.32–7.44 (m, 6H), 7.64–7.69 (m, 4H),
1
8.28 (d, 1H, J = 4.5 Hz), 8.70 (d, 1H, J = 4.6 Hz). 13C-NMR (CDCl3): 116.1 (C), 128.3 (2CH), 128.4 (2CH),
129.7 (CH), 129.8 (CH), 130.3 (2CH), 130.3 (2CH), 135.6 (CH), 136.6 (C), 137.6 (C), 137.6 (C), 149.1 (C),
153.6 (CH), 155.0 (C), 157.1 (C). Anal. Calc. for C19H12IN3 (409.23): C 55.77, H 2.96, N, 10.27. Found: C
55.91, H 3.06, N, 10.03.
3.3.4. 8-Bromo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-Br)
To a stirred mixture of 2,3-diphenyl pyrido[2,3-b]pyrazine (2a, 0.28 g, 1.0 mmol) and ZnCl2
TMEDA [53] (0.26 g, 1.0 mmol) in THF (1 mL) at
20 ◦C was added dropwise a solution of LiTMP
(prepared by adding BuLi (about 1.6 M hexanes solution, 1.2 mmol) to a stirred, cooled (
·
−
◦
20 C)
−
solution of 2,2◦,6,6-tetramethylpiperidine (0.24 mL, 1.2 mmol) in THF (2 mL) and stirring for 15 min)
◦
cooled at
−
20 C. After 30 min at
−
20 C, Br2 (97
µ
L, 2.0 mmol) was introduced, and the mixture was
stirred for 1 h before addition of an aqueous saturated solution of Na2S2O3 (5 mL) and extraction with
EtOAc (3 20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated
×
under reduced pressure. The crude product was purified by chromatography over silica gel (eluent:
CH2Cl2-EtOAc 90:10; Rf = 0.50) to give 2b-Br in 60% yield as a whitish powder. Mp: 183 ◦C. IR: 491,
538, 563, 615, 625, 649, 698, 767, 839, 985, 1021, 1049, 1090, 1179, 1241, 1336, 1387, 1421, 1460, 1524, 1584,
3067 cm−1. H-NMR (CDCl3): 7.32–7.42 (m, 6H), 7.63–7.66 (m, 4H), 8.00 (d, 1H, J = 4.7 Hz), 8.91 (d, 1H,
1
J = 4.7 Hz). 13C-NMR (CDCl3): 128.3 (CH), 128.4 (CH), 128.7 (CH), 129.7 (CH), 129.8 (CH), 130.3 (CH),
130.3 (CH), 134.7 (C), 136.3 (C), 137.7 (C), 137.9 (C), 150.1 (C), 153.4 (CH), 154.9 (C), 157.0 (C). Anal.
Calc. for C19H12BrN3 (362.23): C 63.00, H 3.34, N, 11.60. Found: C 63.24, H 3.58, N, 11.43.

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3.3.5. 8-Chloro-2,3-diphenylpyrido[2,3-b]pyrazine (2b-Cl)
To a stirred mixture of 2,3-diphenyl pyrido[2,3-b]pyrazine (2a, 0.28 g, 1.0 mmol) and ZnCl2
TMEDA [53] (0.26 g, 1.0 mmol) in THF (1 mL) at
20 ◦C was added dropwise a solution of LiTMP
(prepared by adding BuLi (about 1.6 M hexanes solution, 1.2 mmol) to a stirred, cooled (
·
−
◦
20 C)
−
solution of 2,2◦,6,6-tetramethylpiperidine (0.24 mL, 1.2 mmol) in THF (2 mL) and stirring for 15 min)
◦
cooled at
−
20 C. After 30 min at
−
20 C, trichloroisocyanuric acid (0.30 g, 1.3 mmol) was introduced
(CAUTION: dissolution of trichloroisocyanuric acid in THF at a temperature above 0 ◦C produces
intense heat), and the mixture was stirred at this temperature for 1 h before addition of water (5 mL) and
extraction with EtOAc (3
×
20 mL). The combined organic layers were dried over MgSO4, filtered and
concentrated under reduced pressure. The crude product was purified by chromatography over silica
gel (eluent: CH2Cl2-EtOAc 90:10; Rf = 0.60) to give 2b-Cl in 62% yield as a whitish powder. Mp: 180 C.
◦
IR: 534, 544, 617, 658, 699, 770, 851, 991, 1025, 1055, 1193, 1242, 1341, 1388, 1422, 1442, 1452, 1532,
1
1583, 3034, 3051 cm−1. H-NMR (CDCl3): 7.31–7.44 (m, 6H), 7.62–7.66 (m, 4H), 7.79 (d, 1H, J = 4.7 Hz),
9.02 (d, 1H, J = 4.7 Hz). 13C-NMR (CDCl3): 125.1 (CH), 128.3 (CH), 128.5 (CH), 129.7 (CH), 129.8 (CH),
130.2 (CH), 130.3 (CH), 133.7 (C), 137.8 (C), 138.1 (C), 144.5 (C), 150.5 (C), 153.3 (CH), 154.8 (C), 157.1
(C). Anal. Calc. for C19H12ClN3 (317.78): C 71.81, H 3.81, N, 13.22. Found: C 71.77, H 3.85, N, 13.14.
3.3.6. General Procedure 2
To a stirred mixture of the pyrazine (1.0 mmol) and ZnCl2
(1 mL) at
20 ◦C was added dropwise a solution of LiTMP (prepared by adding BuLi (about 1.6 M
hexanes solution, 1.2 mmol) to a stirred, cooled (
20 ◦C) solution of 2,2,6,6-tetramethylpiperidine
(0.24 mL, 1.2 mmol) in THF (2 mL) and stirring for 15 min) cooled at
20 ◦C. After 30 min at 20 ◦C,
·
TMEDA [53] (0.26 g, 1.0 mmol) in THF
−
−
−
−
I2 (0.37 g, 1.5 mmol) in THF (2 mL) was introduced, and the mixture was stirred at this temperature for
1 h before addition of an aqueous saturated solution of Na2S2O3 (5 mL) and extraction with EtOAc
(3
×
20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by chromatography over silica gel (the eluent is
given in the product description).
3.3.7. 8-Bromo-7-iodo-2,3-diphenylpyrido[3,4-b]pyrazine (3b)
The general procedure 2 using 8-bromo-2,3-diphenylpyrido[3,4-b]pyrazine (3a [25,26], 0.36 g)
gave 3b (eluent: CH2Cl2-petroleum ether 80:20; Rf = 0.44) in 67% yield as a red powder. Mp: 186–188
◦C. IR: 493, 529, 559, 600, 658, 695, 765, 984, 1025, 1055, 1117, 1238, 1315, 1373, 1399, 1446, 1493, 1551,
3034, 3060 cm−1 1H-NMR (CDCl3): 7.34–7.47 (m, 6H), 7.54–7.57 (m, 2H), 7.62–7.65 (m, 2H), 9.27
.
(s, 1H). 13C-NMR (CDCl3): 121.7 (C), 128.6 (2CH), 128.7 (2CH), 129.7 (C), 129.8 (2CH), 130.1 (CH),
130.5 (2CH), 130.5 (CH), 136.0 (C), 137.4 (C), 137.7 (C), 142.3 (C), 152.5 (CH), 156.2 (C), 158.6 (C).
Anal. Calc. for C19H11BrIN3 (488.13): C 46.75, H 2.27, N, 8.61. Found: C 46.89, H 2.49, N, 8.55.
8-Bromo-5,7-diiodo-2,3-diphenyl pyrido[3,4-b]pyrazine, also formed in <5% yield, was identified by
its 1H-NMR (CDCl3): 7.36–7.47 (m, 6H), 7.54–7.57 (m, 2H), 7.65–7.68 (m, 4H).
3.3.8. 7-Bromo-6-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (4b)
The general procedure 2 using 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine (4a [54], prepared in
90% yield [6], 0.36 g) gave 4b (eluent: CH2Cl2-heptane 70:30; Rf (heptane-CH2Cl2 80:20) = 0.80) in 5%
yield as a yellow powder. Mp: 150–152 ◦C. IR: 495, 547, 596, 615, 697, 731, 770, 778, 903, 937, 1025,
1
1060, 1107, 1178, 1274, 1332, 1390, 1448, 1502, 1562, 1603, 1699, 1768, 2734, 2940, 3064 cm−1. H-NMR
(CDCl3): 7.30–7.43 (m, 6H), 7.52–7.55 (m, 2H), 7.59–7.62 (m, 2H), 8.62 (s, 1H). 13C-NMR (CDCl3): 128.3
(2CH), 128.6 (2CH), 128.7 (C), 129.9 (CH), 129.9 (2CH), 130.0 (CH), 130.0 (C), 130.3 (2CH), 135.5 (C),
137.6 (C), 138.0 (C), 139.5 (CH), 148.0 (C), 155.9 (C), 157.1 (C). Anal. Calc. for C19H11BrIN3 (488.13):
C 46.75, H 2.27, N, 8.61. Found: C 46.93, H 2.38, N, 8.49.

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3.4. Suzuki Coupling Reactions
3.4.1. General Procedure 3
To a stirred mixture of the iodide (0.50 mmol) and Pd(PPh3)4 (29 mg, 25
µmol) in degassed
1,2-dimethoxyethane (5 mL) was added the boronic acid (0.60 mmol) and NaHCO3 (2.0 mmol) in
degassed water (1.6 mL). The resulting mixture was heated at 80 ◦C for 3 h and cooled to rt before
addition of water (5 mL) and extraction with EtOAc (3
×
10 mL). The combined organic layers were
washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure.
The crude product was purified by chromatography over silica gel (the eluent is given in the product
description).
3.4.2. 2,3,5-Triphenylquinoxaline (1c)
The general procedure 3 using 5-iodo-2,3-diphenyl quinoxaline (1b, 0.20 g) and phenylboronic
acid (73 mg) gave 1c (eluent: CH2Cl2-heptane 60:40; Rf = 0.35) in 42% yield as a white powder.
Mp: 150 ◦C. IR: 763, 804, 841, 927, 984, 1023, 1081, 1128, 1233, 1336, 1388, 1433, 1444, 1491, 1566, 2858,
1
2927, 2965, 3064 cm−1. H-NMR (CDCl3): 7.26–7.34 (m, 3H), 7.36–7.48 (m, 4H), 7.52–7.64 (m, 6H),
7.81–7.89 (m, 4H), 8.21 (dd, 1H, J = 7.3 and 2.5 Hz). 13C-NMR (CDCl3): 127.7 (CH), 128.0 (2CH),
128.1 (2CH), 128.5 (2CH), 128.7 (CH), 128.8 (CH), 129.0 (CH), 129.8 (CH), 129.9 (2CH), 130.3 (2CH),
130.4 (CH), 131.1 (2CH), 138.4 (C), 139.0 (C), 139.1 (C), 139.4 (C), 140.6 (C), 141.3 (C), 152.4 (C), 152.9 (C).
Anal. Calc. for C26H18N2 (358.44): C 87.12, H 5.06, N, 7.82. Found: C 87.25, H 5.22, N, 7.70.
3.4.3. 2,3-Diphenyl-5-(2-thienyl)quinoxaline (1d)
The general procedure 3 using 5-iodo-2,3-diphenylquinoxaline (1b, 0.20 g) and 2-thienylboronic
acid (77 mg) gave 1d (eluent: CH2Cl2-heptane 60:40; Rf = 0.20) in 97% yield as a yellow powder.
Mp: 210 ◦C. IR: 738, 766, 796, 828, 854, 916, 933, 969, 1025, 1053, 1083, 1163, 1238, 1336, 1390, 1442,
1
1495, 1562, 1592, 3064 cm−1. H-NMR (CDCl3): 7.18 (dd, 1H, J = 5.1 and 3.7 Hz), 7.32–7.40 (m, 6H),
7.51 (dd, 1H, J = 5.1 and 1.2 Hz), 7.58–7.61 (m, 2H), 7.67–7.70 (m, 2H), 7.76 (dd, 1H, J = 8.3 and 7.4 Hz),
7.88 (dd, 1H, J = 3.7 and 1.2 Hz), 8.08 (dd, 1H, J = 8.3 and 1.3 Hz), 8.13 (dd, 1H, J = 7.4 and 1.3 Hz).
13C-NMR (CDCl3): 126.7 (CH), 126.9 (CH), 127.5 (CH), 128.1 (CH), 128.2 (2CH), 128.5 (2CH), 128.8 (CH),
129.0 (CH), 129.0 (CH), 129.9 (2CH), 129.9 (CH), 130.6 (2CH), 133.0 (C), 137.6 (C), 138.8 (C), 138.9 (C),
139.2 (C), 141.4 (C), 152.3 (C), 153.2 (C). Anal. Calc. for C24H16N2S (364.47): C 79.09, H 4.43, N, 7.69.
Found: C 79.11, H 4.48, N, 7.72.
3.4.4. 2,3-Diphenyl-8-(2-thienyl)pyrido[2,3-b]pyrazine (2d)
The general procedure 3 using 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I, 0.20 g) and
2-thienylboronic acid (77 mg◦) gave 2d (eluent: CH2Cl2-EtOAc 95:5; Rf = 0.50) in 75% yield as a
pale yellow powder. Mp: 215 C. IR: 540, 695, 744, 1025, 1096, 1120, 1188, 1238, 1336, 1384, 1435, 1480,
1
551, 1568, 2927, 2965, 3060 cm−1. H-NMR (CDCl3): 7.23 (dd, 1H, J = 5.1 and 3.8 Hz), 7.32–7.45 (m, 6H),
7.66–7.72 (m, 5H), 7.98 (d, 1H, J = 4.8 Hz), 8.10 (dd, 1H, J = 3.8 and 1.2 Hz), 9.10 (d, 1H, J = 4.8 Hz).
13C-NMR (CDCl3): 120.3 (CH), 127.2 (CH), 128.3 (2CH), 128.4 (2CH), 129.2 (CH), 129.4 (CH), 129.5
(CH), 130.3 (2CH), 130.5 (2CH), 132.4 (CH), 132.4 (C), 136.0 (C), 138.2 (C), 138.3 (C), 140.9 (C), 150.2 (C),
153.1 (C), 153.9 (CH), 155.8 (C). Crystal data for 2d. C23H15N3S, M = 365.44, T = 150(2) K, triclinic, P 1,
◦
a = 6.6311(18), b = 9.939(3), c = 13.655(4) Å,
α
= 81.914(12),
β
= 80.405(11),
γ
= 89.955(10) , V = 878.3(4)
Å3, Z = 2, d = 1.382 g cm−3
,
µ
= 0.197 mm−1. A final refinement on F2 with 7113 unique intensities
and 236 parameters converged at
ω
R(F2) = 0.3351 (R(F) = 0.1327) for 6147 observed reflections with
I > 2σ(I). CCDC 1858479.

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3.4.5. 5-(2-Aminophenyl)-2,3-diphenylquinoxaline (1e)
The general procedure 3 using 5-iodo-2,3-diphenylquinoxaline (1b, 0.20 g) and 2-amino-
phenylboronic acid (82 mg) gave 1e (eluent: heptane-CH2Cl2 70:30; Rf = 0.31) in 92% yield as a
yellow powder. Mp: 178 ◦C. IR: 689, 702, 740, 771, 977, 1307, 1342, 1492, 1626, 3025, 3060, 3212, 3328,
1
3468 cm−1. H-NMR (CDCl3): 3.87 (br s, 2H, NH2), 6.85 (dd, 1H, J = 7.9 and 1.1 Hz), 6.92 (td, 1H,
J = 7.4 and 1.2 Hz), 7.21–7.30 (m, 5H), 7.35–7.40 (m, 3H), 7.47–7.50 (m, 2H), 7.55–7.58 (m, 2H), 7.78–7.86
(m, 2H), 8.20 (dd, 1H, J = 7.8 and 2.1 Hz). 13C-NMR (CDCl3): 116.5 (CH), 118.8 (CH), 125.7 (C),
128.1 (2CH), 128.5 (2CH), 128.9 (CH), 129.0 (CH), 129.0 (CH), 129.0 (CH), 129.9 (2CH), 130.2 (CH),
130.3 (2CH), 132.0 (CH), 132.3 (CH), 138.8 (C), 139.2 (C), 139.3 (C), 139.6 (C), 141.3 (C), 145.0 (C),
152.5 (C), 153.2 (C). Anal. Calc. for C26H19N3 (373.46): C 83.62, H 5.13, N, 11.25. Found: C 83.81, H 5.26,
N, 11.17.
3.4.6. 8-(2-Aminophenyl)-2,3-diphenylpyrido[2,3-b]pyrazine (2e)
The general procedure 3 using 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I, 0.20 g) and
2-aminophenylboronic acid (82 mg) gave 2e (eluent: CH2Cl2-EtOAc 70:30; Rf = 0.50) in 73% yield
as a yellow powder. Mp: 205 ◦C. IR: 687, 742, 766, 854, 981, 1015, 1047, 1237, 1307, 1382, 1489, 1623,
.
3024, 3055, 3345 cm−1 1H-NMR (CDCl3): 3.99 (br s, 2H, NH2), 6.87 (dd, 1H, J = 8.4 and 1.2 Hz),
6.94 (td, 1H, J = 7.4 and 1.2 Hz), 7.25–7.40 (m, 8H), 7.51–7.54 (m, 2H), 7.65–7.68 (m, 2H), 7.73 (d, 1H,
J = 4.5 Hz), 9.19 (d, 1H, J = 4.4 Hz). 13C-NMR (CDCl3): 116.9 (CH), 118.7 (CH), 122.6 (C), 126.3 (CH),
128.2 (2CH), 128.2 (2CH), 129.3 (CH), 129.5 (CH), 130.1 (CH), 130.1 (2CH), 130.1 (2CH), 132.0 (CH),
134.3 (C), 138.1 (C), 138.2 (C), 144.9 (C), 149.0 (C), 149.8 (C), 153.4 (C), 154.1 (CH), 155.7 (C). Anal. Calc.
for C25H18N4 (374.45): C 80.19, H 4.85, N, 14.96. Found: C 80.07, H 4.87, N, 14.85.
3.4.7. 2,3-Diphenyl-11H-pyrazino[20,30:4,5]pyrido[2,3-d]indole (3h)
In a tube containing a stirred mixture of 8-bromo-7-iodo-2,3-diphenylpyrido[3,4-b]pyrazine (3b
,
0.24 g, 0.50 mmol) and Pd(PPh3)4 (29 mg, 25 mol) in degassed 1,2-dimethoxyethane (5 mL) was
µ
introduced 2-aminophenylboronic acid (82 mg, 0.60 mmol) and Na2CO3 (2.0 mmol) in degassed
water (1.6 mL). The sealed tube was heated overnight at 140 ◦C and cooled to rt before addition of
saturated aqueous NaHCO3 (5 mL) and extraction with EtOAc (3
×
10 mL). The combined organic
layers were washed with brine (10 mL), dried over MgSO4, filtered and concentrated under reduced
pressure. The crude product was purified by chromatography over silica gel (eluent: CH2Cl2-EtOAc
90:10; Rf = 0.28) to give 3h in 65% yield as a yellow powder. Mp: 284–286 ◦C. IR: 695, 748, 763, 1025,
.
1092, 1190, 1236, 1315, 1328, 1336, 1376, 1446, 1495, 1540, 1624, 3034, 3064, 3420 cm−1 1H-NMR
(CDCl3): 7.30–7.42 (m, 7H), 7.50–7.60 (m, 6H), 8.45 (d, 1H, J = 7.9 Hz), 9.47 (s, 1H), 9.78 (br s, 1H).
13C-NMR (CDCl3): 111.9 (CH), 120.6 (CH), 121.3 (CH), 123.1 (C), 126.7 (C), 127.2 (CH), 128.4 (2CH),
128.5 (2CH), 129.2 (CH), 129.6 (CH), 130.0 (2CH), 130.1 (2CH), 132.4 (C), 134.9 (C), 138.4 (C), 138.6
(C), 138.8 (C), 139.5 (C), 146.5 (CH), 153.6 (C), 155.9 (C). Crystal data for 3h. C25H16N4, M = 372.42,
T = 150(2) K, orthorhombic, Pbca, a = 7.1524(9), b = 16.3313(17), c = 33.798(4) Å, V = 3947.9(8) Å3, Z = 8
d = 1.253 g cm−3 = 0.076 mm−1. A final refinement on F2 with 4429 unique intensities and 265
parameters converged at (I).
R(F2) = 0.1564 (R(F) = 0.0739) for 3511 observed reflections with I > 2
,
,
µ
ω
σ
CCDC 1858477. This compound was also obtained in 64% yield under microwave irradiation (300 W;
Monowave 300, Anton Paar, Graz, Austria) for 30 min at 150 ◦C.
3.5. 8-(2-Azidophenyl)-2,3-diphenylpyrido[2,3-b]pyrazine
To a stirred solution of 8-(2-aminophenyl)-2,3-diphenylpyrido[2,3-b]pyrazine (2e, 94 mg,
◦
0.25 mmol) in acetic acid (1.5 mL) at 0 C was added 1M aqueous NaNO2 (0.35 mL, 0.35 mmol).
◦
After stirring for 1 h at rt, the solution was cooled to 0 C before addition of 1M aqueous NaN3
(0.35 mL, 0.35 mmol). After stirring overnight at rt, 3 mL of saturated aqueous NaHCO3 were added.
Extraction with EtOAc (3
×
10 mL), washing of the combined organic layers with brine (10 mL),

Molecules 2018, 23, 2961
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drying over MgSO4, filtration and concentration under reduced pressure afforded a brown powder
which was purified by chromatography over silica gel (eluent: CH2Cl2-EtOAc 95:5; Rf = 0.50) to
1
afford the azide in 64% yield. IR: 685, 745, 1288, 1440, 1577, 2088, 2124, 3064 cm−1. H-NMR (CDCl3):
7.23–7.40 (m, 8H), 7.45–7.57 (m, 4H), 7.66–7.69 (m, 3H), 9.18 (d, 1H, J = 4.4 Hz). 13C-NMR (CDCl3):
118.8 (CH), 124.7 (CH), 126.0 (CH), 127.9 (C), 128.2 (2CH), 128.2 (2CH), 129.2 (CH), 129.5 (CH), 130.1
(2CH), 130.3 (2CH), 130.4 (CH), 132.5 (CH), 134.5 (C), 138.3 (C), 138.5 (C), 138.7 (C), 146.7 (C), 149.8 (C),
153.5 (CH), 153.7 (C), 155.8 (C).
3.6. Palladium-Catalyzed N-arylation
3.6.1. General Procedure 4
To a stirred mixture of the halide (0.50 mmol) and Cs2CO3 (0.48 g, 1.5 mmol) in 2-chloroaniline (63
µ
L, 0.60 mmol) was added a solution of the catalyst prepared by stirring Pd2(dba)3 (11 mg, 12.5
and Xantphos (16 mg, 27.5 mol) in degassed dioxane (2 mL) for 10 min at rt. The resulting mixture
was heated at 110 ◦C for 24 h and cooled to rt before addition of water (5 mL) and extraction with
EtOAc (3 10 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4,
µmol)
µ
×
filtered and concentrated under reduced pressure. The crude product was purified by chromatography
over silica gel (the eluent is given in the product description).
3.6.2. 5-(2-Chlorophenylamino)-2,3-diphenylquinoxaline (1f)
The general procedure 4 using 5-iodo-2,3-diphenylquinoxaline (1b, 0.20 g) gave 1f (eluent:
heptane-CH2Cl2 60:40; Rf = 0.42) in 92% yield as a yellow powder. Mp: 182 ◦C. IR: 695, 729, 748, 959,
1021, 1055, 1072, 1098, 1182, 1218, 1317, 1343, 1356, 1394, 1442, 1454, 1497, 1534, 1562, 1579, 1594, 1613,
1
3060, 3347 cm−1. H-NMR (CDCl3): 6.95 (td, 1H, J = 7.7 and 1.4 Hz), 7.27–7.39 (m, 7H), 7.46–7.52 (m,
2H), 7.55–7.62 (m, 4H), 7.64–7.66 (m, 2H), 7.71 (dd, 1H, J = 8.2 and 1.4 Hz), 8.56 (br s, 1H). 13C-NMR
(CDCl3): 109.1 (CH), 118.9 (CH), 118.9 (CH), 122.6 (CH), 125.1 (C), 127.6 (CH), 128.2 (2CH), 128.4 (2CH),
128.9 (CH), 128.9 (CH), 129.9 (2CH), 130.1 (2CH), 130.2 (CH), 130.9 (CH), 132.1 (C), 138.4 (C), 138.9 (C),
139.2 (C), 139.3 (C), 141.9 (C), 150.4 (C), 153.9 (C). Anal. Calc. for C26H18ClN3 (407.90): C 76.56, H 4.45,
N, 10.30. Found: C 76.89, H 4.58, N, 10.13.
3.6.3. 8-(2-Chlorophenylamino)-2,3-diphenylpyrido[2,3-b]pyrazine (2f)
The general procedure 4 using 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2◦b-I, 0.20 g) gave 2f
(eluent: CH2Cl2-EtOAc 90:10; Rf = 0.32) in 67% yield as a yellow powder. Mp: 202 C. IR: 542, 699, 755,
1
1021, 1102, 1242, 1313, 1336, 1356, 1437, 1452, 1534, 1558, 1583, 1646, 3060, 3322, 3631 cm−1. H-NMR
(CDCl3): 7.13–7.19 (m, 2H), 7.30–7.41 (m, 7H), 7.53 (dd, 1H, J = 8.0 and 1.5 Hz), 7.57–7.65 (m, 4H),
7.68 (dd, 1H, J = 8.1 and 1.5 Hz), 8.77 (br s, 1H, NH), 8.81 (d, 1H, J = 5.4 Hz, H6). 13C-NMR (CDCl3):
102.8 (CH), 122.2 (CH), 125.5 (CH), 127.2 (C), 127.5 (C), 127.8 (CH), 128.2 (2CH), 128.4 (2CH), 129.2 (CH),
129.4 (CH), 130.0 (2CH), 130.3 (2CH), 130.5 (CH), 136.2 (C), 138.4 (C), 138.5 (C), 147.0 (C), 150.3 (C),
151.1 (C), 155.0 (CH), 156.5 (C). Crystal data for 2f. C25H17ClN4, M = 408.88, T = 150(2) K, orthorhombic,
P c a 21, a = 15.3485(15), b = 18.8937(16), c = 6.9936(7) Å, V = 2028.1(3) Å3, Z = 4, d = 1.339 g cm−3
,
µ = 0.208 mm−1. A final refinement on F2 with 4578 unique intensities and 274 parameters converged
at ωR(F2) = 0.1478 (R(F) = 0.0583) for 4133 observed reflections with I > 2σ(I). CCDC 1858474.
3.7. Palladium-Catalyzed N-arylation
2,3-Diphenyl-11H-pyrazino[2,3-a]carbazole (1g) was prepared by adapting a reported
procedure [40]. To a stirred mixture of 5-(2-chlorophenylamino)-2,3-diphenylquinoxaline (1f, 0.24 g,
0.60 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL, 0.90 mmol), was added a solution of the
catalyst prepared by stirring Pd2(dba)3 (14 mg, 15 µmol) and P(tBu)3 (12 mg, 60 µmol) in degassed
dioxane (1 mL) for 10 min at rt. The resulting mixture was heated by microwave irradiation (300
W; Monowave 300, Anton Paar, Graz, Austria) for 10 min at 180 ◦C before addition of water (5 mL)

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and extraction with EtOAc (3
×
10 mL). The combined organic layers were washed with brine (10
mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was
purified by chromatography over silica gel (eluent: heptane-CH2Cl2 60:40; Rf = 0.48) to give 1g in 62%
yield as a yellow powder. Mp: 260 ◦C. IR: 1025, 1087, 1102, 1175, 1242, 1326, 1347, 1362, 1384, 1444,
1459, 1624, 1731, 2854, 2922, 3420 cm−1. H-NMR ((CD3)2SO): 6.86 (ddd, 1H, J = 8.0, 7.1 and 1.0 Hz),
1
6.91–6.97 (m, 6H), 7.01–7.10 (m, 3H), 7.14–7.17 (m, 2H), 7.28 (d, 1H, J = 8.3 Hz), 7.39 (d, 1H, J = 8.7 Hz),
7.84 (d, 1H, J = 7.8 Hz), 8.14 (d, 1H, J = 8.7 Hz), 12.13 (br s, 1H). 13C-NMR ((CD3)2SO): 112.2 (CH), 118.8
(CH), 119.7 (CH), 120.3 (CH), 120.7 (C), 122.7 (C), 124.2 (CH), 125.6 (CH), 128.0 (2CH), 128.0 (2CH),
128.5 (CH), 128.6 (CH), 129.7 (2CH), 129.9 (2CH), 130.0 (C), 134.3 (C), 139.0 (C), 139.2 (C), 139.8 (C),
139.9 (C), 150.7 (C), 151.4 (C). Anal. Calc. for C26H17N3 (371.44): C 84.07, H 4.61, N, 11.31. Found:
C 84.19, H 4.52, N, 11.12.
3.8. One-Pot Palladium-Catalyzed N-arylation/C-H Arylation
3.8.1. General Procedure 5
To a mixture of the halide (0.25 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (118
µL, 0.75 mmol),
2-chloroaniline (38 mg, 0.30 mmol), Pd2(dba)3 (9.2 mg, 10 mol) and Xantphos (13 mg, 22
µ
µmol),
was added degassed 1,4-dioxane (1 mL). The mixture was heated by microwave irradiation (150 W;
Monowave 300, Anton Paar, Graz, Austria) under the conditions given in the product description.
The cooled residue was taken up with EtOAc (20 mL). The organic layer was washed with brine
(10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was
purified by chromatography over silica gel (the eluent is given in the product description).
3.8.2. 2,3-Diphenyl-11H-pyrazino[20,30:5,6]pyrido[4,3-b]indole (2g)
The general procedure 5 (1 h at 180 ◦C) using 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I
0.10 g) gave 2g (eluent: CH2Cl2-EtOAc 90:10; Rf = 0.43) in 70% yield as a white powder. Mp > 260 ◦C
,
.
IR: 525, 542, 551, 626, 699, 750, 768, 1025, 1045, 1075, 1100, 1236, 1339, 1373, 1444, 1555, 1736, 2665,
1
3056 cm−1. H-NMR ((CD3)2SO): 7.40–7.45 (m, 7H), 7.55–7.63 (m, 5H), 7.77 (dd, 1H, J = 8.2 and 0.9 Hz),
8.42 (dt, 1H, J = 7.8 and 1.0 Hz), 9.87 (s, 1H), 13.19 (s, 1H). 13C-NMR ((CD3)2SO): 112.6 (CH), 118.2 (C),
120.7 (CH), 121.3 (CH), 121.4 (C), 126.4 (C), 126.5 (CH), 128.0 (CH), 128.0 (2CH), 128.1 (2CH), 128.8
(CH), 129.8 (2CH), 129.9 (2CH), 138.6 (C), 138.7 (C), 139.4 (C), 140.0 (C), 147.4 (C), 148.5 (CH), 151.4 (C),
153.4 (C). Anal. Calc. for C25H16N4 (372.43): C 80.63, H 4.33, N, 15.04. Found: C 80.54, H 4.28, N, 14.89.
3.8.3. 7-(Phenylamino)-2,3-diphenylpyrido[3,4-b]pyrazine (3g0)
◦
The general procedure 5 (40 min at 180 C) using 8-bromo-7-iodo-2,3-diphenylpyrido[3,4-b]
pyrazine (3b, 0.12 g) gave 3g0 (eluent: CH2Cl2-MeOH 99:1; Rf = 0.27) in 32% yield as a yellow powder.
Mp: 224–226 ◦C. IR: 699, 750, 770, 978, 1025, 1057, 1077, 1169, 1197, 1261, 1336, 1349, 1435, 1450, 1527,
1
1555, 1588, 1613, 2854, 2927, 2961, 3025, 3232 cm−1. H-NMR (CDCl3): 7.14 (p, 1H, J = 4.4 Hz), 7.23 (br s,
1H), 7.29–7.49 (m, 15H), 9.26 (s, 1H). 13C-NMR (CDCl3): 158.3 (C), 155.8 (C), 154.0 (CH), 151.4 (C),
146.3 (C), 139.8 (C), 138.8 (C), 138.7 (C), 132.4 (C), 129.8 (2CH), 129.7 (2CH), 129.7 (2CH), 129.5 (CH),
128.9 (CH), 128.4 (2CH), 128.4 (2CH), 124.1 (CH), 121.4 (2CH), 98.3 (CH). Anal. Calc. for C25H18N4
(374.45): C 80.19, H 4.85, N, 14.96. Found: C 80.17, H 4.99, N, 14.84.
3.9. Copper-Catalyzed N-arylation
3.9.1. General Procedure 6
A mixture containing the iodide (0.50 mmol) and azole (1.0 mmol), Cu2O (6.0 mg, 0.10 mmol),
Cs2CO3 (0.33 g, 1.0 mmol) and DMSO (0.5 mL) was stirred at 110 ◦C for 24 h. The cooled residue was
taken up with EtOAc (20 mL) and filtered through a Celite pad. The organic layer was washed with
water (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure.

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The crude product was purified by chromatography over silica gel (the eluent is given in the product
description).
3.9.2. 2,3-Diphenyl-8-(N-pyrrolyl)pyrido[2,3-b]pyrazine (2i)
The general procedure 6 using 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I, 0.20 g) and pyrrole
(67 mg) gave 2i (eluent: CH2Cl2-EtOAc 90:10; Rf = 0.47) in 67% yield as a yellow powder. Mp: 210 ◦C.
IR: 946, 1025, 1072, 1096, 1107, 1173, 1238, 1289, 1328, 1362, 1388, 1433, 1454, 1482, 1549, 1588, 3025,
1
3060, 3111, 3141, 3180 cm−1. H-NMR (CDCl3): 6.39–6.40 (m, 2H), 7.24–7.35 (m, 6H), 7.49–7.53 (m,
3H), 7.59–7.62 (m, 2H), 7.65–7.66 (m, 2H), 9.01 (d, 1H, J = 5.0 Hz). 13C-NMR (CDCl3): 112.0 (2CH),
115.1 (CH), 122.7 (2CH), 128.3 (2CH), 128.4 (2CH), 129.4 (C), 129.5 (CH), 129.8 (CH), 130.0 (2CH),
130.2 (2CH), 137.8 (C), 138.1 (C), 144.6 (C), 150.7 (C), 153.2 (C), 153.9 (CH), 156.0 (C). Crystal data
for 2i. C23H16N4, M = 348.40, T = 150(2) K, orthorhombic, P 21 21 21, a = 6.3672(5), b = 13.0997(10),
c = 21.5377(18) Å, V = 1796.4(2) Å3, Z = 4, d = 1.288 g cm−3
with 2367 unique intensities and 245 parameters converged at
,
µ
= 0.079 mm−1. A final refinement on F2
R(F2) = 0.1207 (R(F) = 0.0498) for 1679
ω
observed reflections with I > 2σ(I). CCDC 1858475.
3.9.3. 8-(N-indolyl)-2,3-diphenylpyrido[2,3-b]pyrazine (2j)
The general procedure 6 using 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I, 0.20 g) and indole
(0.12 g) gave 2j (eluent: CH2Cl2; Rf = 0.36) in 51% yield as a red powder. Mp: 136 ◦C. IR: 1023, 1154,
1
1208, 1236, 1324, 1356, 1379, 1442, 1454, 1478, 1519, 1555, 1577, 1592, 3240, 3339, 3639 cm−1. H-NMR
(CDCl3): 6.82 (d, 1H, J = 3.4 Hz), 7.22–7.44 (m, 8H), 7.53–7.56 (m, 2H), 7.67 (d, 1H, J = 8.3 Hz), 7.70–7.72
(m, 3H), 7.86 (dd, 1H, J = 4.9 and 1.2 Hz), 7.94 (d, 1H, J = 3.4 Hz), 9.17 (d, 1H, J = 4.9 Hz). 13C-NMR
(CDCl3): 106.1 (CH), 111.4 (CH), 118.0 (CH), 121.5 (CH), 122.1 (CH), 123.2 (CH), 128.4 (2CH), 128.4
(2CH), 128.5 (C), 129.7 (CH), 129.9 (CH), 130.1 (2CH), 130.3 (C), 130.3 (2CH), 130.5 (C), 130.8 (CH), 136.2
(C), 137.8 (C), 138.0 (C), 144.8 (C), 150.8 (C), 153.6 (CH), 156.4 (C). Anal. Calc. for C27H18N4 (398.47): C
81.39, H 4.55, N, 14.06. Found: C 81.26, H 4.67, N, 13.84.
3.9.4. 2,3-Diphenyl-8-(N-pyrazolyl)pyrido[2,3-b]pyrazine (2k)
The general procedure 6 using 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I, 0.20 g) and
pyrazole (68 mg) gave 2k (eluent: CH2Cl2-EtOAc 80:20; Rf = 0.47) in 71% yield as a pale yellow
powder. Mp: 200 ◦C. IR: 1027, 1032, 1092, 1164, 1229, 1324, 1356, 1388, 1532, 1549, 1592, 3034, 3060,
1
3159 cm−1. H-NMR (CDCl3): 6.55 (d, 1H, J = 2.2 Hz), 7.30–7.41 (m, 6H), 7.55–7.58 (m, 2H), 7.64–7.66
(m, 2H), 7.82 (s, 1H), 8.34 (dd, 1H, J = 5.3 and 2.4 Hz), 9.12 (dd, 1H, J = 5.2 and 2.2 Hz), 9.46 (t, 1H,
J = 2.5 Hz). 13C-NMR (CDCl3): 109.2 (CH), 115.0 (CH), 127.9 (C), 128.3 (2CH), 128.6 (2CH), 129.6 (CH),
129.8 (CH), 129.9 (2CH), 130.3 (2CH), 134.4 (CH), 137.6 (C), 138.3 (C), 142.5 (CH), 143.2 (C), 150.5 (C),
153.4 (C), 154.3 (CH), 156.1 (C). Anal. Calc. for C22H15N5 (349.40): C 75.63, H 4.33, N, 20.04. Found:
C 75.71, H 4.42, N, 19.86.
3.9.5. 8-(N-imidazolyl)-2,3-diphenylpyrido[2,3-b]pyrazine (2l)
The general procedure 6 using 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I, 0.20 g) and
imidazole (68 mg) gave 2l (eluent: EtOAc-MeOH 95:5; Rf = 0.48) in 69% yield as a yellow powder.
Mp: 209 ◦C. IR: 1019, 1053, 1075, 1105, 1115, 1169, 1236, 1319, 1334, 1379, 1429, 1446, 1459, 1482, 1549,
1
1594, 3064, 3124, 3639 cm−1. H-NMR (CDCl3): 7.32–7.45 (m, 7H), 7.56 (d, 2H, J = 6.6 Hz), 7.65–7.71 (m,
3H), 7.80 (br s, 1H), 8.82 (br s, 1H), 9.20 (d, 1H, J = 4.8 Hz). 13C-NMR (CDCl3): 115.6 (CH), 119.5 (CH),
128.3 (2CH), 128.4 (2CH), 128.9 (C), 129.7 (CH), 129.9 (CH), 129.9 (2CH), 130.1 (2CH), 130.3 (CH),
137.5 (C), 137.6 (C), 138.8 (CH), 141.4 (C), 150.7 (C), 154.1 (C), 154.2 (CH), 156.6 (C). Anal. Calc. for
C22H15N5 (349.40): C 75.63, H 4.33, N, 20.04. Found: C 75.74, H 4.37, N, 19.92.

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3.9.6. 2,3-Diphenyl-8-[1-(1,2,4-triazolyl)]pyrido[2,3-b]pyrazine (2m)
The general procedure 6 using 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I, 0.20 g) and
1,2,4-triazole (69 mg) gave 2m (eluent: CH2Cl2-EtOAc 80:20; Rf = 0.35) in 79% yield as an orange
◦
powder. Mp: 205 C. IR: 708, 995, 1025, 1049, 1079, 1124, 1158, 1223, 1242, 1276, 1332, 1386, 1403,
1459, 1508, 1551, 1590, 3064, 3146 cm−1. H-NMR (CDCl3): 7.35–7.49 (m, 6H), 7.59 (d, 2H, J = 7.0 Hz),
1
7.68 (d, 2H, J = 7.2 Hz), 8.22 (s, 1H), 8.37 (br s, 1H), 9.27 (br s, 1H), 10.16 (br s, 1H). 13C-NMR (CDCl3):
115.1 (CH), 127.3 (C), 128.2 (2CH), 128.5 (2CH), 129.8 (CH), 129.8 (2CH), 129.9 (CH), 130.1 (2CH),
137.3 (C), 137.7 (C), 140.4 (C), 147.2 (CH), 150.4 (C), 152.0 (CH), 154.1 (C), 154.5 (CH), 156.7 (C). Anal.
Calc. for C21H14N6 (350.39): C 71.99, H 4.03, N, 23.99. Found: C 72.19, H 4.15, N, 23.81.
3.9.7. 5-Iodo-2,3-diphenyl-8-(N-pyrazolyl)quinoxaline (1k0)
The general procedure 6 using 5-iodo-2,3-diphenylquinoxaline (1b0, 0.27 g) and pyrazole (68 mg)
gave 1k0 (eluent: CH2Cl2-heptane 80:20; Rf = 0.45) in 50% yield as an pale yellow powder. Mp: 200–202
◦
C. IR: 536, 585, 602, 692, 696, 755, 843, 894, 946, 1040, 1092, 1182, 1193, 1221, 1336, 1397, 1465, 1519, 1543,
1592, 3060, 3159 cm−1. H-NMR (CDCl3): 6.56 (dd, 1H, J = 2.6, 1.8 Hz), 7.35–7.45 (m, 6H), 7.57–7.60
1
(m, 2H), 7.70–7.73 (m, 2H), 7.82 (d, 1H, J = 1.8 Hz), 8.12 (d, 1H, J = 8.2 Hz), 8.43 (d, 1H, J = 8.3 Hz),
8.97–8.98 (m, 1H). 13C-NMR (CDCl3): 99.3 (C), 107.6 (CH), 123.7 (CH), 128.4 (2CH), 128.5 (2CH), 129.5
(CH), 129.6 (CH), 130.0 (2CH), 130.4 (2CH), 133.2 (C), 133.5 (CH), 137.1 (C), 137.8 (C), 138.2 (C), 139.7
(CH), 140.7 (C), 141.1 (CH), 153.0 (C), 153.6 (C). Anal. Calc. for C23H15IN4 (474.31): C 58.24, H 3.19, N,
11.81. Found: C 58.33, H 3.26, N, 11.68.
3.10. Nucleophilic Substitution Using Amines
3.10.1. General Procedure 7
A sealed tube containing the iodide (0.50 mmol) and amine (amount given in the product description)
in ethanol (2 mL) was heated (conditions given in the product description). The cooled residue was
concentrated before chromatography over silica gel (eluent given in the product description).
3.10.2. 8-(Isopropylamino)-2,3-diphenylpyrido[2,3-b]pyrazine (2n)
◦
The general procedure 7 (150 C, 18 h) using 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I, 0.20
g) and isopropylamine (51
yield as a beige powder. Mp: 179 C. IR: 699, 703, 772, 804, 1156, 1178, 1236, 1313, 1336, 1538, 1564, 1592,
2965, 3038, 3064, 3390 cm−1. H-NMR (CDCl3): 1.27 (d, 6H, J = 6.4 Hz, Me), 3.77 (dp, 1H, J = 7.9 and
µ
L, 0◦.60 mmol) gave 2n (eluent: CH2Cl2-EtOAc 50:50; Rf = 0.20) in 69%
1
6.4 Hz, CHMe2), 6.40 (br d, 1H, J = 8.0 Hz, NH), 6.45 (d, 1H, J = 5.5 Hz), 7.15–7.28 (m, 6H), 7.39–7.42
(m, 2H), 7.46–7.49 (m, 2H), 8.59 (dd, 1H, J = 5.4, 0.6 Hz). 13C-NMR (CDCl3): 22.3 (2CH3), 44.1 (CH),
100.7 (CH), 127.1 (C), 128.0 (2CH), 128.2 (2CH), 128.7 (CH), 129.0 (CH), 129.9 (2CH), 130.2 (2CH), 138.4
(C), 138.9 (C), 149.8 (C), 150.1 (C), 150.1 (C), 154.8 (CH), 155.8 (C). Anal. Calc. for C22H20N4 (340.43):
C 77.62, H 5.92, N, 16.46. Found: C 77.72, H 6.14, N, 16.19.
3.10.3. 8-(4-Methoxybenzylamino)-2,3-diphenylpyrido[2,3-b]pyrazine (2o)
◦
The general procedure 7 (150 C, 24 h) using 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I
,
0.20 g) and 4-methoxybenzylamine (78 µL, 0.60 mmol) gave 2o (eluent: CH2Cl2-EtOAc 50:50; Rf =
0.48) in 71% yield as a yellow powder. Mp: 190 ◦C. IR: 697, 832, 1175, 1236, 1302, 1341, 1437, 1459,
1
1510, 1585, 2828, 2910, 3064, 3232 cm−1. H-NMR (CDCl3): 3.81 (s, 3H, OMe), 4.55 (d, 2H, J = 5.9 Hz),
6.58 (d, 1H, J = 5.3 Hz), 6.90 (d, 2H, J = 8.7 Hz), 7.02 (t, 1H, J = 5.7 Hz), 7.27–7.35 (m, 8H), 7.49–7.51 (m,
2H), 7.58–7.61 (m, 2H), 8.69 (d, J = 5.3 Hz, 1H). 13C-NMR (CDCl3): 46.5 (CH2), 55.3 (CH3), 101.1 (CH),
114.3 (2CH), 127.2 (C), 128.0 (2CH), 128.2 (2CH), 128.6 (2CH), 128.8 (CH), 129.1 (CH), 129.1 (C), 129.9
(2CH), 130.3 (2CH), 138.5 (C), 138.8 (C), 150.0 (C), 150.2 (C), 150.9 (C), 154.9 (CH), 155.9 (C), 159.2 (C).
Anal. Calc. for C27H22N4O (418.50): C 77.49, H 5.30, N, 13.39. Found: C 77.58, H 5.44, N, 13.20.

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3.10.4. 8-(Benzylamino)-2,3-diphenylpyrido[2,3-b]pyrazine (2p)
◦
The general procedure 7 (150 C, 24 h) using 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I
,
0.20 g) and benzylamine (66 µL, 0.60 mmol) gave 2p (eluent: CH2Cl2-EtOAc 50:50; Rf = 0.50) in 79%
yield as a yellow powder. Mp: 238 ◦C. IR: 697, 768, 873, 1150, 1238, 1300, 1324, 1339, 1439, 1538, 1590,
1
2910, 3064, 3201 cm−1. H-NMR (CDCl3): 4.63 (d, 2H, J = 6.0 Hz), 6.56 (d, 1H, J = 5.4 Hz), 7.11 (t, 1H,
J = 6.0 Hz), 7.27–7.39 (m, 11H), 7.49–7.52 (m, 2H), 7.58–7.61 (m, 2H), 8.68 (d, 1H, J = 5.4 Hz). 13C-NMR
(CDCl3): 47.0 (CH2), 101.2 (CH), 127.2 (2CH), 127.2 (C), 127.8 (CH), 128.1 (2CH), 128.3 (2CH), 128.9
(CH), 128.9 (2CH), 129.1 (CH), 129.9 (2CH), 130.3 (2CH), 137.2 (C), 138.5 (C), 138.8 (C), 150.0 (C),
150.3 (C), 151.0 (C), 154.9 (CH), 156.0 (C). Crystal data for 2p. C26H20N4, M = 388.46, T = 150(2) K,
monoclinic, P 21/n,−a3= 6.0721(6), b = 12.8640(10), c = 25.460(2) Å,
β
= 91.436(4) ◦, V = 1988.1(3) Å3,
Z = 4, d = 1.298 g cm
, µ
= 0.078 mm−1. A final refinement on F2 with 4438 unique intensities and 274
parameters converged at
CCDC 1858476.
ω σ(I).
R(F2) = 0.1432 (R(F) = 0.0626) for 3710 observed reflections with I > 2
3.11. Nucleophilic Substitution using Hydrazine Hydrate: 8-Hydrazino-2,3-diphenylpyrido[2,3-b]pyrazine (2q)
A solution of 8-iodo-2,3-diphenyl pyrido [2,3-b]pyrazine (2b-I, 0.20 g, 0.50 mmol) and hydrazine
hydrate (0.25 mL, 5.0 mmol) in isopropanol (2 mL) was heated under reflux for 4 h. The cooled residue
was concentrated and taken up with EtOAc (20 mL). The organic layer was washed with water (10 mL),
dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound 2q in
◦
92% yield as a red powder. Mp > 250 C. 1H-NMR (CDCl3): 4.22 (br s, 2H, NH), 6.91 (d, 1H, J = 5.6 Hz),
7.22–7.36 (m, 7H), 7.40–7.43 (m, 2H), 7.48–7.51 (m, 2H), 8.60 (d, 1H, J = 5.6 Hz). 13C-NMR (CDCl3):
101.2 (CH), 126.2 (C), 128.2 (2CH), 128.3 (2CH), 129.0 (CH), 129.2 (CH), 129.9 (2CH), 130.3 (2CH),
138.4 (C), 138.7 (C), 149.7 (C), 150.3 (C), 153.0 (C), 155.0 (CH), 156.1 (C). Anal. Calc. for C19H15N5
(313.36): C 72.83, H 4.83, N, 22.35. Found: C 72.96, H 4.89, N, 22.31.
3.12. Condensation Reactions from the Hydrazine 2q
3.12.1. General Procedure 8
A sealed tube containing 8-hydrazino-2,3-diphenylpyrido[2,3-b] pyrazine (2q, 0.16 g, 0.50 mmol)
and the aldehyde (0.55 mmol) in ethanol (2 mL) was heated at 110 ◦C overnight. The cooled residue
was concentrated under vacuum, washed with methanol and isolated by filtration.
3.12.2. 2-Hydroxybenzaldehyde 2-[8-(2,3-diphenylpyrido[2,3-b]pyrazinyl)]hydrazone (2r)
General Procedure 8 using 2-hydroxybenzaldehyde (67 mg) gave 2r (Rf (CH2Cl2-EtOAc 80:20) = 0.44
)
in 60% yield as a yellow powder. Mp > 260 ◦C. IR: 952, 1019, 1096, 1163, 1233, 1270, 1309, 1328, 1422,
1
1540, 1562, 1594, 1618, 3064, 3317 cm−1. H-NMR (CDCl3): 6.96 (td, 1H, J = 7.5 and 1.1 Hz), 7.07 (d, 1H,
J = 8.2 Hz), 7.23–7.44 (m, 9H), 7.51–7.54 (m, 2H), 7.58–7.62 (m, 2H), 8.26 (s, 1H), 8.91 (d, 1H, J = 5.3 Hz),
9.71 (br s, 1H), 10.60 (br s, 1H). The 13C spectra could not be recorded due to low solubility in CDCl3
and DMSO. Anal. Calc. for C26H19N5O (417.47): C 74.80, H 4.59, N, 16.78. Found: C 74.72, H 4.39,
N, 16.67.
3.12.3. Piperonal 2-[8-(2,3-diphenylpyrido[2,3-b]pyrazinyl)]hydrazone (2s)
General Procedure 8 using piperonal (83 mg) gave 2s (Rf (CH2Cl2-EtOAc 80:20) = 0.37) in 70%
◦
yield as a yellow powder. Mp: 254 C. IR: 933, 1038, 1150, 1255, 1339, 1450, 1489, 1501, 1545, 1568, 1590,
2901, 3060, 3322, 3648 cm−1. H-NMR (CDCl3): 6.03 (s, 2H), 6.84 (d, 1H, J = 8.0 Hz), 7.07 (dd, 1H, J = 8.1
1
and 1.6 Hz), 7.28–7.42 (m, 7H), 7.50 (t, 3H, J = 6.6 Hz), 7.59 (d, 2H, J = 6.8 Hz), 7.97 (s, 1H), 8.85 (d, 1H,
J = 5.3 Hz), 9.66 (s, 1H). 13C-NMR ((CD3)2SO): 101.5 (CH2), 103.5 (CH), 104.9 (CH), 108.5 (CH), 123.0
(CH), 125.6 (C), 128.1 (2CH), 128.2 (2CH), 128.8 (CH), 129.1 (CH), 129.2 (C), 129.7 (2CH), 130.1 (2CH),

Molecules 2018, 23, 2961
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138.3 (C), 138.6 (C), 145.1 (CH), 147.7 (C), 148.1 (C), 148.8 (C), 149.6 (C), 150.0 (C), 154.5 (CH), 155.5 (C).
Anal. Calc. for C27H19N5O2 (445.48): C 72.80, H 4.30, N, 15.72. Found: C 72.95, H 4.44, N, 15.83.
3.12.4. 2-Hydroxy-4-methoxybenzaldehyde 2-[8-(2,3-diphenylpyrido[2,3-b]pyrazinyl)]hydrazone (2t
)
General Procedure 8 using 2-hydroxy-4-methoxybenzaldehyde (84 mg) gave 2t (Rf (CH2Cl2-
EtOAc 80:20) = 0.58) in 80% yield as a yellow powder. Mp > 260 ◦C. IR: 1032, 1135, 1163, 1238, 1291,
1
1339, 1431, 1439, 1461, 1510, 1543, 1566, 1631, 2845, 2931, 3004, 3056, 3176, 3317 cm−1. H-NMR (CDCl3):
3.85 (s, 3H), 6.52 (dd, 1H, J = 8.5 and 2.5 Hz), 6.58 (d, 1H, J = 2.5 Hz), 7.15 (d, 1H, J = 8.6 Hz), 7.19 (d, 1H,
J = 5.2 Hz), 7.28–7.43 (m, 6H), 7.50–7.54 (m, 2H), 7.58–7.61 (m, 2H), 8.19 (s, 1H), 8.88 (br s, 1H), 9.59 (br s,
1H), 10.81 (s, 1H). The 13C spectra could not be recorded due to low solubility in CDCl3 and DMSO.
Anal. Calc. for C27H21N5O2 (447.50): C 72.47, H 4.73, N, 15.65. Found: C 72.53, H 4.89, N, 15.60.
3.12.5. 4-(Trifluoromethyl)benzaldehyde 2-[8-(2,3-diphenylpyrido[2,3-b]pyrazinyl)]hydrazone (2u)
General Procedure 8 using 4-(trifluoromethyl)benzaldehyde (87 mg) gave 2u (Rf (CH2Cl2- EtOAc
80:20) = 0.51) in 73% yield as a yellow powder. Mp: 258–260 ◦C. IR: 1017, 1066, 1109, 1124, 1145, 1236,
1
1300, 1321, 1512, 1545, 1562, 1588, 3060, 3184, 3317, 3652 cm−1. H-NMR (CDCl3): 7.28–7.43 (m, 6H),
7.50–7.53 (m, 2H), 7.56–7.61 (m, 3H), 7.68 (d, 2H, J = 8.2 Hz), 7.87 (d, 2H, J = 7.8 Hz), 8.11 (s, 1H),
8.91 (d, 1H, J = 5.2 Hz), 9.90 (br s, 1H). 13C-NMR ((CD3)2SO, 333 K): 103.8 (CH), 124.0 (q, CF3,
J = 272 Hz), 125.4 (C), 125.5 (q, 2CH, J = 3.7 Hz), 127.1 (2CH), 127.8 (2CH), 127.9 (2CH), 128.7 (CH),
128.8 (CH), 129.2 (q, C-CF3, J = 31.7 Hz), 129.5 (2CH), 129.8 (2CH), 138.1 (C), 138.4 (C), 138.5 (C),
143.2 (CH), 147.4 (C), 149.4 (C), 150.3 (C), 154.3 (CH), 155.5 (C). Anal. Calc. for C27H18F3N5 (469.47):
C 69.08, H 3.86, N, 14.92. Found: C 69.25, H 3.97, N, 14.78.
3.13. Nucleophilic Substitution Using a Phenolate: Methyl 2-[8-(2,3-diphenylpyrido[2,3-b]pyrazinyl)]oxy-
5-methoxybenzoate (2v)
A mixture of 8-iodo-2,3-diphenylpyrido[2,3-b]pyrazine (2b-I, 0.20 g, 0.50 mmol), methyl
2-hydroxy-5-methoxy-benzoate (0.10 g, 0.55 mmol), K2CO3 (77 mg, 0.55 mmol) and DMSO (1 mL)
◦
was heated at 110 C for 2 h. The cooled residue was treated by an aqueous solution of Na2CO3
(10 mL) before extraction with Et2O (3
×
10 mL). The organic layer was dried over MgSO4, filtered and
concentrated under reduced pressure, and the residue was chromatographed over silica gel (eluent:
CH2Cl2-MeOH 95:5; Rf (CH2Cl2-EtOAc 95:5) = 0.50) to give the title compound 2v in 64% yield as a
beige powder. Mp: 206 ◦C. IR: 542, 698, 773, 856, 1021, 1072, 1109, 1205, 1235, 1263, 1333, 1350, 1434,
1468, 1496, 1554, 1594, 1719, 2845, 2956, 3041 cm−1. H-NMR (CDCl3): 3.65 (s, 3H), 3.90 (s, 3H), 6.64 (d,
1
J = 5.2 Hz, 1H), 7.19 (dd, 1H, J = 8.9, 3.0 Hz), 7.24 (d, 1H, J = 9.5 Hz), 7.30–7.40 (m, 6H), 7.55–7.58
(m, 3H), 7.61–7.64 (m, 2H), 8.86 (d, 1H, J = 5.2 Hz). 13C-NMR (CDCl3): 52.4 (CH3), 56.0 (CH3), 107.6
(CH), 116.3 (CH), 120.6 (CH), 124.6 (C), 125.0 (CH), 128.2 (2CH), 128.4 (2CH), 129.0 (C), 129.1 (CH),
129.4 (CH), 130.2 (2CH), 130.3 (2CH), 138.2 (C), 138.7 (C), 147.0 (C), 151.1 (C), 153.6 (C), 154.4 (CH),
156.6 (C), 157.4 (C), 163.0 (C), 164.7 (C). Anal. Calc. for C28H21N3O4 (463.49): C 72.56, H 4.57, N, 9.07.
Found: C 72.49, H 4.65, N, 9.01.
4. Conclusions
Original pyrazino-fused polycyclic scaffolds were synthesized by combining deproto-
metalation-iodolysis with palladium- or copper-catalyzed couplings or direct substitution reactions.
This study highlights the interest in preparing iodo derivatives of sensitive aromatic heterocycles by
using lithium-zinc basic combinations to access scaffolds of potential biological interest. Interestingly,
bromine and trichloroisocyanuric acid were successfully employed as electrophiles to intercept the
intermediate heteroarylzinc halides.
Supplementary Materials: Supplementary materials are available online.

Molecules 2018, 23, 2961
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Author Contributions: F.L., T.L., M.B., C.C., I.C., C.G. and J.L. synthesized and analyzed all compounds presented
in this article; E.C. contributed to the identification of some synthesized compounds by NMR; E.L. and L.P.
contributed with the experiments performed under microwave irradiation; L.P., M.S., B.B. and S.B. performed the
bioassays; T.R. collected the X-ray diffraction data and solved the structures. F.M. wrote the paper with the help of
E.C., L.P., V.T., S.R., S.B. and T.R.; F.L. started the project, designed the molecules and revised the paper.
Funding: This research received no external funding.
Acknowledgments: O. Lozach and T. Robert (KISSf screening facility) are acknowledged for their excellent
technical support, and William Erb for his relevant advice. F.M. and F.L. thank the Université de Rennes 1. L.P.
and V.T. thank the French Cancer League (Comité 17) for financial support and the Cancéropôle Grand Ouest
(axis: natural sea products in cancer treatment) for scientific support. S.B. and S.R. thank the Cancéropôle Grand
Ouest (axis: natural sea products in cancer treatment), IBiSA (French Infrastructures en sciences du vivant: biologie,
santé et agronomie) and Biogenouest (Western France life science and environment core facility network) for
supporting KISSf screening facility. We acknowledge FEDER founds (D8 VENTURE Bruker AXS diffractometer)
and Thermofisher (generous gift of 2,2,6,6-tetramethylpiperidine).
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the synthesized compounds are available from the corresponding authors.
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