6- endo -dig Cycloisomerization of N -Propargyl Aminoquinoxalines: A New Route to 1,4,8-Triazaphenanthrenes

Article abstract of DOI:10.1055/s-0035-1562443

We report the preparation of novel 1,4,8-triazaphenanthrenes and show that the target compounds are efficiently obtained from the corresponding 6-aminoquinoxalines after N-propargylation followed by copper-catalyzed 6-endo-dig cycloisomerization and aroma

Full text of DOI:10.1055/s-0035-1562443

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
A
paper
Synthesis
S. Vallerotto et al.
Paper
6
-endo-dig Cycloisomerization of N-Propargyl Aminoquinoxalines:
A New Route to 1,4,8-Triazaphenanthrenes
‡
Sara Vallerotto
R3
R3
‡
Gael Le Douaron
N
N
N
R2
R1
Guillaume Bernadat
HN
N
N
R2 Cu(I) or Ag(I)
Laurent Ferrié*
Bruno Figadère*
DMSO, 110 °C
R1
15 examples
up to 70% yield
one regioisomer
BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay,
92290 Châtenay-Malabry, France
bruno.figadere@u-psud.fr
laurent.ferrie@u-psud.fr
This paper is dedicated in the memory of Prof Jean F. Normant, a great
mentor and a wonderful person.
‡
S.V. and G.L.D. contributed equally to this work.
Received: 13.05.2016
Accepted after revision: 06.06.2016
Published online: 07.07.2016
dig cycloisomerization of quinoxalines 5a–m led, after fur-
ther spontaneous aromatization, to 1,4,6-triazaanthracene
6a–m or 1,4,8-triazaphenanthrene 7a–m (Scheme 1).
DOI: 10.1055/s-0035-1562443; Art ID: ss-2016-c0344-op
Abstract We report the preparation of novel 1,4,8-triazaphenan-
threnes and show that the target compounds are efficiently obtained
from the corresponding 6-aminoquinoxalines after N-propargylation
followed by copper-catalyzed 6-endo-dig cycloisomerization and aro-
matization. The cyclization was found to be completely regioselective.
6
3
O2N
NH2
NH2
O
H
2
O N
N
N
H2O
+
Δ
90%
R1
2
R1
O
1
a, R1 = Me
b, R = H
1
2
2
3b, R = Me
3a, R = H
1
1
H2N
N
3
6
3
R2
H2N
N
Key words copper, silver, regioselectivity, N-heterocycles, Lewis acids
1) R2Li
H2, Pd/C
2
R1
EtOH, 60 °C
N
R1
2
) MnO2
N
4c–m
2
4a, R1 = Me
b, R = H
80%
21–45%
We are currently involved in transition-metal-catalyzed
1
4
1
2a–i
4
synthesis of natural products and bioactive compounds.
3
R2
8
N
N
Recently, we prepared a library of 2,3-disubstituted 6-ami-
Br
5
?
HN
N
3
R2
R1
noquinoxalines that showed interesting neuroprotective
K2CO3
N
2
[
M]
activities on dopaminergic neurons in primary cultures.2i,3
1
solvent, Δ
(see Tables 1, 2)
6a–m
DMF, 100 °C
8–68%
7
2
R1
N
We then prepared the N-propargyl derivatives of the latter
and found that they also show interesting properties in sev-
eral in vitro models of Parkinson’s disease. The 6-endo-dig
cycloisomerization of the N-propargyl-6-aminoquinoxal-
4
2
+
5
a–m
N 6
3
R2
N
3
N
2
R1
4
1
7
a–m
ines, which has not been previously reported, could lead to
tricyclic compounds, namely 1,4,6-triazaanthracenes5
Scheme 1 Access to N-propargyl-6-aminoquinoxalines 5a–m
6
and/or 1,4,8-triazaphenanthrenes (also named pyrido[2,3-
g]quinoxaline and/or pyrido[3,2-f]quinoxaline), depending
on the regioselectivity of the cyclization. N-Propargyl-6-
aminoquinoxalines could be obtained in a straightforward
manner from nitrophenylenediamine 1 after condensation
with glyoxal 2b or pyruvaldehyde 2a to produce quinoxal-
ine 3a or 3b, which, after hydrogenolysis, led to aminoqui-
noxaline 4a and 4b.2i Disubstituted quinoxalines were pre-
pared by further addition of an aryllithium reagent on the
more reactive 3-position of aminoquinoxaline 4a and
The 6-endo-dig cycloisomerization is a well-known pro-
cess that can be performed thermally through a Claisen-
type rearrangement4 under high temperature, under harsh
a
4o
conditions (BF ·OEt), by using metal-catalysis with noble
3
4c
4b,f,g,j,m,q,s
4p
metals (platinum, gold,
(mercury ), substrate-dependent metals (iron and indi-
um ), or by using electrophilic reagents (such as halonium
palladium ), toxic metals
4k
4l,r
4t
and selenium but these lead to halogeno or seleno-cyclized
products).4 Thus, benign and affordable metal catalysts
e,k
2f,i,3
4h,s
4e,f,i
4b.
Propargylation of the amino group furnished the de-
such as silver
this reaction. When 5a was heated at reflux in toluene for
hours in the presence of CuCl (1 equiv), under the report-
and copper,
were studied to perform
3
sired N-propargyl-6-aminoquinoxaline 5a–m. The 6-endo-
5
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
Synthesis
S. Vallerotto et al.
Paper
ed conditions for cyclization of N-propargylanilines,4e 1,4,8-
triazaphenanthrene 7a was isolated as the sole product in
of silver nitrate led to the best yield for this transformation
(67%, entry 14). This observation was already reported for
the synthesis of acridines though 6-endo-dig cycloisomeri-
zation.4 Here again, a stoichiometric amount of silver salt
is necessary to reach full conversion. Gold was briefly stud-
30% yield (Table 1, entry 1) along with some unreacted
h
starting material 5a. We found, however, that the reaction
works better in dimethyl sulfoxide (DMSO) (60% yield, en-
try 2). It is important to stress that a stoichiometric amount
of catalyst is needed to reach almost full conversion, which
is probably due to deactivation of the catalyst by chelation
with the product, as observed in a previous report.4e The in-
fluence of the nature of catalyst (used in a stoichiometric
amount) was then studied, using DMSO as solvent. Cop-
per(II) catalysts were quite ineffective (entries 8 and 9),
whereas the hardest counter-anions for copper(I) (in the
meaning of the HSAB theory) worked best for this reaction
ied, but the use of a stoichiometric amount of NaAuCl is
4
not feasible because of the high cost of the metal, thus
when 5a was treated with 0.1 equiv of NaAuCl the desired
4
compound 6a was obtained in a reasonable yield (39% yield,
entry 19). Notably, in the absence of any catalyst, heating 5a
at 110 °C, or above, in DMSO for 4 hours did not give the de-
sired product, and starting material was recovered un-
changed (entry 20). The reaction is also less efficient in the
presence of air, probably due to some oxidation of Cu(I) into
less active Cu(II) (entry 10).
(
CuPF (MeCN) vs. Cu O; entries 3 and 4). In contrast, the
6 4 2
softer the counter-anion is, the worse the cycloisomeriza-
tion is (CuBr, CuI, CuCN; entries 5, 6, and 7, respectively).
To explain the complete regioselectivity of 5a cycliza-
tion yielding only 1,4,8-triazaphenanthrene 6a, we calcu-
lated the frontier molecular orbitals (FMO) of the starting
materials (see the Supporting Information). DFT calcula-
tions conducted on the unsubstituted quinoxaline 5b
showed a much higher electronic density in the HOMO at
the 5-position than at the 7-position, thus directing the cy-
clization to afford the corresponding 1,4,8-triazaphenan-
threne 6b (Figure 1). Blocking the 5-position of compound
5b by the presence of a chlorine atom did not allow us to
obtain the corresponding 1,4,6-triazaanthracene (results
not shown). The low electronic density of HOMO at the 7-
position of the latter could, again, explain the lack of reac-
tivity (no significant difference was observed for the FMO
of both compounds).
Table 1 Effect of the Transition-Metal Catalyst on the 6-endo-dig Cy-
5a
cloisomerization of Aminoquinoxaline
4
[
M] (100 mol%)
5
3
2
8N
N
3
2
HN
N
N
DMSO, N2, 110 °C, 5 h
N
1
5a
6a
Yield (%)c Entry
Yield (%)c
Entry
Catalyst
Catalyst
1
2
3
4
5
6
7
8
9
CuCla
CuCl
30
60
71
70
41
22
13
20
0
11
12
13
14
15
16
17
18
19
20
Ag
Ag
2
CO
3
25
30
57
67
58
58
60
30
39
0
2
O
CuPF
Cu
6
(MeCN)
4
AgF
2
O
AgNO
3
CuBr
CuI
AgOCN
AgSbF
CF CO
AcOAg
NaAuCl d
none
6
CuCN
CuCl
Cu(AcO)
Cu
Ob
3
2
Ag
2
2
4
10
2
44
a
b
c
Reaction performed in toluene.
Reaction performed under air atmosphere.
Isolated yield.
d
4
10 mol% NaAuCl was used.
Figure 1 Electronic isodensity surface at 50% probability level for the
highest occupied molecular orbital (HOMO) of N-propargyl-6-amino-
quinoxaline 5b, calculated at the B3LYP/6-31G* level (the colour of the
surfaces indicates the sign of the wavefunction)
We also studied the effect of silver salts, and found that
the reaction was as effective as with copper(I) salts; howev-
er, several observations can be made. The reactivity of silver
salts follows the general observation noted for copper(I)
salts (AgF; Table 1, entry 13, 57%), but the basicity of the
counter-anion was also important for the reactivity. The
best example is given by silver trifluoroacetate (60% yield,
entry 17), which gave a higher yield than with silver ace-
The cycloisomerization was applied to N-propargyl-6-
aminoquinoxaline derivatives 5b–m (see Table 2). Less ex-
pensive copper-mediated catalysis rather than silver was
applied to most examples. Cu O gave generally the best
2
yield, as shown in Table 2; however, CuCl was used for some
examples and nevertheless gave decent yields. The transfor-
mation takes place with a compound having no substituent
in positions 2 and 3 (entry 1), having one substituent in po-
tate (30% yield, entry 18). Ag O was also not efficient, in
2
contrast to Cu O (30% yield, entry 12). In general, less basic
2
counter-anions gave the best results. In particular, the use
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

C
Synthesis
S. Vallerotto et al.
Paper
sition 2 (entry 2) or two substituents at positions 2 and 3
entries 3–11). Not only terminal alkynes react, disubstitut-
[M]+
(
ed alkynes are also suitable; indeed, compound 5m cy-
HN
N
N
[M]+
HN
N
N
6-endo-dig
cloisomerized in the presence of AgNO (entry 12) to give
3
1,4,8-triazaphenanthrene 6m in moderate 43% yield, al-
though copper was ineffective in this case.
A
5b
[M]
H
The mechanism of the reaction is thought to proceed
through a Claisen-type reaction, in which the catalyst acti-
vates the triple bond of 5b by coordination, as presented in
intermediate A (Scheme 2). The ability of the metal to be
coordinated is directly linked to the ionic character of the
utilized salt, as shown in our study. Once activated, the
double bond attacks the electropositive triple bond from
[
O]
N
N
HN
N
N
N
N
H
N
N
B
[M]+
C
6b
Scheme 2 Putative mechanism for the cyclization of quinoxaline 5b
Table 2 6-endo-dig Cycloisomerization of Quinoxalines 5b–m
R3
H
N
N
N
R2
R1
catalyst (1 equiv)
R2
N
N
DMSO, 110 °C, N2
R1
5
h
N
R3
5b–m
6b–m
Entry
Substrate
R1
R2
R3
Catalyst
Product
Yield (%)a
1
2
3
4
5b
5c
5d
5e
H
H
H
Cu
Cu
2
2
O
O
6b
6c
6d
6e
65
70
54
61
H
Ph
Ph
H
H
H
Me
Me
CuCl
CuCl
p-Tol
OMe
5
5f
Me
H
CuCl
6f
62
OMe
OMe
6
5g
Me
H
CuCl
6g
51
OMe
F
7
8
9
5h
5i
Me
Me
H
H
CuCl
CuCl
6h
6i
52
64
Cl
Cl
Cl
5j
Me
Me
H
H
CuCl
CuCl
6j
62
61
1
0
1
5k
6k
1
5l
Me
Me
H
CuCl
6l
63
43
12
5m
H
Ph
AgNO
3
6m
a
Isolated yield.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
Synthesis
S. Vallerotto et al.
Paper
the more nucleophilic 7-position of the aniline, which gives
1H NMR spectra were recorded with a Bruker Avance 300 (300 MHz)
and a Bruker Avance 400 (400 MHz). Chemical shifts are expressed in
parts per million (ppm, δ) downfield from tetramethylsilane (TMS)
the cyclized alkenyl metal species B, similar to some car-
7
bocupration when M is copper. After prototropy, the metal
and are referenced to CHCl3 (δ = 7.26 ppm) as internal standard. 13
C
cation is released to give 7,8-dihydro-1,4,8-triazaphenan-
NMR spectra were recorded with Bruker Avance 300 (75 MHz) and
Bruker Avance 400 (100 MHz) spectrometers as solutions in CDCl3.
Chemical shifts are expressed in parts per million (ppm, δ) downfield
from tetramethylsilane (TMS) and are referenced to CHCl3 (δ = 77.0
ppm) as internal standard. Some signals are broadened due to some
slow conformational changes. High-resolution mass spectra (HRMS)
were measured with an LCT premier spectrometer. Some low-resolu-
tion mass spectra were recorded with an HP1100 spectrometer.
threne C, which, after hydrolysis, is spontaneously oxi-
8
dized to liberate the corresponding 1,4,8-triazaphenan-
threne 6b.
The regioselective 6-endo-dig cycloisomerization can
also be performed with N-dimethylpropargyl-6-aminoqui-
4e
noxalines 8a and 8b, with Cu O for example (Scheme 3).
2
The reaction was faster (1 h) probably because of a benefi-
cial Thorpe–Ingold effect of the two methyl groups. In this
case, no aromatization is possible and thus 7,8-dihydro-
Synthesis of N-Propargyl 6-aminoquinoxalines 5a–m; General
Procedure
7,7-dimethyl-1,4,8-triazaphenanthrenes 9a and 9b were
To a solution of 6-aminoquinoxaline derivative 4a–m (1 equiv), K CO3
2
obtained in good yields.
(
2 equiv), and n-Bu NI (0.2 equiv) in anhydrous DMF (2 mL/mmol of
4
4
a–m) under inert atmosphere was added propargyl bromide (80% in
9
toluene, 1.5 equiv) or 3-phenyl-propargyl bromide (1.5 equiv) and
heated at 70 °C for 24 h. The mixture was diluted with water, extract-
R1
Cu2O (1 equiv)
DMSO, 110 °C
R1
R2
HN
N
N
HN
N
N
ed with EtOAc, washed with brine, dried over MgSO , filtered, and
4
concentrated in vacuo. The residue was purified by silica gel flash
chromatography (CH Cl –EtOAc, 90:10 to 80:20) to afford monoprop-
R2
1
h
2
2
8
a: R1 = Me, R2 = H
b: R1 = Me, R2 = Ph
9a: R1 = Me, R2 = H, 67%
9b: R1 = Me, R2 = Ph, 64%
argyl derivatives 5a–m as brownish yellow solids.
8
2
-Methyl-N-propargyl-6-aminoquinoxaline (5a)
Scheme 3 Cyclization of quinoxalines 8a and 8b
Yield: 2.57 g (42%); brownish yellow solid.
1
H NMR (300 MHz, CDCl ): δ = 8.62 (s, 1 H), 7.83 (d, J = 9.0 Hz, 1 H),
3
In conclusion, N-propargyl-6-aminoquinoxaline deriva-
tives were cyclized in a highly regioselective 6-endo-dig
fashion to lead to the expected 1,4,8-triazaphenanthrenes
and 7,8-dihydro-7,7-dimethyl-1,4,8-triazaphenanthrenes.
The nature of catalyst was studied, leading to the conclu-
sion that the metal ion must be paired with a low coordi-
nating counteranion to give high yields. This is in agree-
ment with our proposed mechanism, in which the metal
needs to chelate the triple bond for further activation. Cu-
prous oxide or chloride and silver nitrate was found to be
the best catalysts for the transformation, considering their
reactivity and their availability as stoichiometric quantities
are needed to perform this cycloisomerization. Computa-
tional calculations allowed us to rationalize the observed
regioselectivity by comparing the reactivity of the positions
with respect to the HOMO orbitals of the substrates, which
showed that the 5-position was the more reactive in this
system. The bioactivity of the newly synthesized products
will be reported in due course.
7
.16 (dd, J = 9.0, 2.5 Hz, 1 H), 7.12 (d, J = 2.5 Hz, 1 H), 4.36 (br s, 1 H,
NH), 4.10 (dd, J = 5.9, 2.5 Hz, 2 H), 2.72 (s, 3 H), 2.30 (t, J = 2.5 Hz, 1 H).
13
C NMR (75 MHz, CDCl ): δ = 149.2, 146.6, 145.4, 142.5, 136.8, 128.9,
3
121.4, 105.1, 79.4, 71.5, 33.1, 21.6.
+
HRMS (ESI): m/z [M + H] calcd C12H12N : 198.1031; found: 198.1023.
3
N-Propargyl-6-aminoquinoxaline (5b)
Yield: 2.50 g (55%); brownish yellow solid.
1
H NMR (300 MHz, CDCl ): δ = 8.67 (d, J = 2.0 Hz, 1 H), 8.55 (d, J =
3
2.0 Hz, 1 H), 7.87 (d, J = 9.0 Hz, 1 H), 7.16 (dd, J = 9.0, 2.5 Hz, 1 H), 7.10
(d, J = 2.5 Hz, 1 H), 4.56 (br t, J = 5.8 Hz, 1 H, NH), 4.08 (dd, J = 5.8,
2.5 Hz, 2 H), 2.30 (t, J = 2.5 Hz, 1 H).
13C NMR (75 MHz, CDCl ): δ = 147.8, 145.2, 145.0, 141.1, 138.3, 130.2,
3
122.0, 105.1, 79.6, 72.0, 33.4.
+
MS (ESI): m/z = 197.0 (100) [M + H] .
3-Phenyl-N-propargyl-6-aminoquinoxaline (5c)
Yield: 290 mg (49%); brownish yellow solid.
1
H NMR (300 MHz, CDCl ): δ = 9.04 (s, 1 H), 8.15 (dd, J = 8.0, 1.5 Hz,
3
2
1
H), 7.90 (d, J = 8.5 Hz, 1 H), 7.60–7.66 (m, 3 H), 7.16 (s, 1 H), 7.15 (m,
H), 4.43 (br s, 1 H, NH), 4.11 (br m, 2 H), 2.29 (t, J = 2.5 Hz, 1 H).
1
3
All reactions involving moisture-sensitive reactants were performed
under a nitrogen atmosphere using oven-dried glassware. DMSO
C NMR (75 MHz, CDCl ): δ = 152.1, 148.1, 144.4, 141.1, 139.4, 136.9,
3
129.9, 129.8, 129.0 (2C), 127.5 (2C), 121.5, 105.5, 79.8, 72.0, 33.5.
(
standard grade quality) was directly used as received. Copper, silver
HRMS (ESI): m/z [M + H]+ calcd for C17H14N : 260.1183; found:
3
or gold salts were not further purified before reaction. Routine moni-
toring of reactions was performed using Riedel-de Haën, S, 0.063 mm,
260.1188.
0
.032 silica gel plates, and UV detection at both 254 and 364 nm
2
-Methyl-3-phenyl-N-propargyl-6-aminoquinoxaline (5d)
wavelength. Flash chromatography was performed using Riedel-de
Haën, S, 0.063 mm, 0.032 silica under moderate pressure with the ap-
Yield: 90.1 mg (40%); brownish yellow solid.
propriate solvent giving a migrate front (R ) in the range of 0.2 to 0.3.
f
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

E
Synthesis
S. Vallerotto et al.
Paper
1
HRMS (ESI): m/z [M + H]+ calcd for C18H15N F: 292.1250; found:
H NMR (400 MHz, CDCl ): δ = 7.81 (d, J = 8.8 Hz, 1 H), 7.61 (dd, J = 8.8,
3
3
1.6 Hz, 2 H), 7.50 (m, 3 H), 7.43–7.12 (d, J = 2.6 Hz, 1 H), 7.09 (dd, J =
292.1250.
8.8, 2.6 Hz, 1 H), 4.56 (br s, 1 H, NH), 4.01 (br s, 2 H), 2.67 (s, 3 H), 2.23
(
1
t, J = 2.4 Hz, 1 H).
2
(5i)
-Methyl-3-(4-chlorophenyl)-N-propargyl-6-aminoquinoxaline
3
C NMR (100 MHz, CDCl ): δ = 154.6, 147.9, 147.3, 142.8, 139.4,
3
1
3
36.3, 128.9, 128.8 (2C), 128.6, 128.3 (2C), 121.6, 105.2, 79.9, 71.7,
3.3, 23.6.
Yield: 160.0 mg (34%); brownish yellow solid.
1
H NMR (400 MHz, CDCl ): δ = 7.83 (d, J = 8.7 Hz, 1 H), 7.58 (d, J =
3
HRMS (ESI): m/z [M + H]+ calcd for C18H16N : 274.1344; found:
3
8.4 Hz, 2 H), 7.48 (d, J = 8.4 Hz, 2 H), 7.13 (dd, J = 8.7, 2.5 Hz, 1 H), 4.10
(d, J = 2.5 Hz, 1 H), 7.44 (br s, 1 H, NH), 4.05 (br s, 2 H), 2.68 (s, 3 H),
274.1342.
2.25 (t, J = 2.5 Hz, 1 H).
2-Methyl-3-p-tolyl-N-propargyl-6-aminoquinoxaline (5e)
13
C NMR (100 MHz, CDCl ): δ = 153.5, 147.7, 147.4, 142.9, 137.9,
3
Yield: 207.0 mg (40%); brownish yellow solid.
136.5, 134.9, 130.3 (2C), 129.1, 128.7 (2C), 121.9, 105.2, 79.9, 71.9,
33.4, 23.7.
1
H NMR (400 MHz, CDCl ): δ = 7.81 (d, J = 8.9 Hz, 1 H), 7.53 (d, J =
3
8.0 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.12 (d, J = 2.5 Hz, 1 H), 7.10 (dd,
HRMS (ESI): m/z [M + H]+ calcd for C18H15ClN : 308.0955; found:
3
J = 8.9, 2.5 Hz, 1 H), 4.48 (br s, 1 H, NH), 4.02 (br s, 2 H), 2.69 (s, 3 H),
308.0959.
2.42 (s, 3 H), 2.23 (t, J = 2.5 Hz, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 154.8, 148.1, 147.2, 142.9, 138.6,
2-Methyl-3-(3,4-dichlorophenyl)-N-propargyl-6-aminoquinox-
3
1
3
36.6, 136.3, 129.1 (2C), 128.9, 128.8 (2C), 121.5, 105.4, 80.0, 71.8,
3.4, 23.8, 21.3.
aline (5j)
Yield: 196.0 mg (50%); brownish yellow solid.
HRMS (ESI): m/z [M + H]+ calcd for C19H18N : 288.1501; found:
1
3
H NMR (400 MHz, CDCl ): δ = 7.85 (d, J = 9.0 Hz, 1 H), 7.77 (d, J =
3
288.1501.
2.0 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 1 H), 7.49 (dd, J = 8.2, 2.0 Hz, 1 H), 7.17
(dd, J = 9.0, 2.5 Hz, 1 H), 7.10 (d, J = 2.5 Hz, 1 H), 4.40 (t, J = 5.7 Hz, 1 H,
2-Methyl-3-(4-methoxyphenyl)-N-propargyl-6-aminoquinox-
NH), 4.07 (dd, J = 5.7, 2.5 Hz, 2 H), 2.70 (s, 3 H), 2.27 (t, J = 2.5 Hz, 1 H).
aline (5f)
13
C NMR (100 MHz, CDCl ): δ = 152.1, 147.5, 147.4, 142.9, 139.4,
3
Yield: 280.0 mg (71%); brownish yellow solid.
136.8, 133.1, 132.8, 131.1, 130.4, 129.2, 128.3, 122.3, 105.1, 79.8, 72.0,
33.5, 23.7.
1
H NMR (400 MHz, CDCl ): δ = 7.81 (d, J = 8.7 Hz, 1 H), 7.60 (d, J =
3
8.7 Hz, 2 H), 7.12 (d, J = 2.5 Hz, 1 H), 7.02 (d, J = 8.7 Hz, 2 H), 7.09 (dd,
HRMS (ESI): m/z [M + H]+ calcd for C18H14Cl N : 342.0565; found:
2
3
J = 8.7, 2.5 Hz, 1 H), 4.44 (br s, 1 H, NH), 4.03 (d, J = 2.4 Hz, 2 H), 3.86
342.0565.
(s, 3 H), 2.70 (s, 3 H), 2.24 (t, J = 2.4 Hz, 1 H).
13
C NMR (100 MHz, CDCl ): δ = 160.0, 154.4, 148.1, 147.2, 142.9,
2-Methyl-3-(naphthalen-2-yl)-N-propargyl-6-aminoquinoxaline
3
1
5
36.1, 131.9, 130.4 (2C), 128.9, 121.4, 113.8 (2C), 105.3, 80.0, 71.8,
5.3, 33.4, 23.9.
(5k)
Yield: 80.5 mg (28%); brownish yellow solid.
HRMS (ESI): m/z [M + H]+ calcd for C19H18N O: 304.1450; found:
1
3
H NMR (300 MHz, CDCl ): δ = 8.11 (s, 1 H), 7.97 (d, J = 8.4 Hz, 1 H),
3
304.1458.
7.92 (t, J = 4.7 Hz, 2 H), 7.86 (d, J = 8.5 Hz, 1 H), 7.75 (dd, J = 8.5, 1.7 Hz,
1
H), 7.51–7.57 (m, 2 H), 7.17 (d, J = 2.5 Hz, 1 H), 7.12 (dd, J = 9.0,
2
-Methyl-3-(3,4,5-trimethoxyphenyl)-N-propargyl-6-aminoqui-
2.5 Hz, 1 H), 4.48 (t, J = 5.5 Hz, 1 H), 4.04 (dd, J = 5.5, 2.5 Hz, 2 H), 2.74
(s, 3 H), 2.25 (t, J = 2.5 Hz, 1 H).
noxaline (5g)
13
Yield: 118.7 mg (42%); brownish yellow solid.
C NMR (75 MHz, CDCl ): δ = 154.6, 148.1, 147.3, 142.9, 136.8, 136.4,
3
1
133.1, 133.0, 129.0, 128.5, 128.4, 128.1, 127.7, 126.6, 126.4 (2C),
21.7, 105.3, 79.9, 71.8, 33.4, 23.8.
H NMR (400 MHz, CDCl ): δ = 7.78 (d, J = 9.6 Hz, 1 H), 7.08–7.11 (m,
H), 6.80 (s, 2 H), 4.64 (br s, 1 H, NH), 4.00 (br s, 2 H), 3.87 (s, 9 H),
.67 (s, 3 H), 2.21 (t, J = 2.5 Hz, 1 H).
3
1
2
2
HRMS (ESI): m/z [M + H]+ calcd for C22H18N : 324.1501; found:
3
13
324.1472.
C NMR (100 MHz, CDCl ): δ = 154.4, 153.1 (2C), 147.7, 147.4, 142.6,
3
1
5
38.5, 136.3, 134.9, 128.8, 121.7, 106.2 (2C), 104.9, 79.9, 71.6, 60.8,
6.1 (2C), 33.2, 23.6.
2-Methyl-3-biphenyl-N-propargyl-6-aminoquinoxaline (5l)
HRMS (ESI): m/z [M + H]+ calcd for C21H22N O : 364.1661; found:
Yield: 80.4 mg (23%); brownish yellow solid.
3
3
1
364.1659.
H NMR (400 MHz, CDCl ): δ = 7.86 (d, J = 8.9 Hz, 1 H), 7.73 (s, 4 H),
3
7.67 (dd, J = 7.4, 1.9 Hz, 2 H), 7.48 (t, J = 7.4 Hz, 2 H), 7.38 (tt, J = 7.4,
2
-Methyl-3-(4-fluorophenyl)-N-propargyl-6-aminoquinoxaline
1.9 Hz, 1 H), 7.16 (d, J = 2.7 Hz, 1 H), 7.14 (dd, J = 8.9, 2.7 Hz, 1 H), 4.40
(br s, 1 H, NH), 4.06 (d, J = 2.5 Hz, 2 H), 2.76 (s, 3 H), 2.26 (t, J = 2.5 Hz,
(5h)
1
H).
Yield: 74.0 mg (28%); brownish yellow solid.
13C NMR (100 MHz, CDCl
1
1
): δ = 154.4, 148.1, 147.3, 143.0, 141.6,
40.6, 138.4, 136.4, 129.4 (2C), 129.0, 128.8 (2C), 127.6, 127.2 (4C),
21.7, 105.4, 80.0, 71.9, 33.5, 23.8.
1
3
H NMR (400 MHz, CDCl ): δ = 7.97 (d, J = 9.2 Hz, 2 H), 7.64 (dd, J = 8.8,
.6 Hz, 1 H), 7.51 (dd, J = 9.2, 2.7 Hz, 1 H), 7.42 (d, J = 2.7 Hz, 1 H), 7.20
3
5
(t, J = 8.8 Hz, 2 H), 4.27 (s, 1 H, NH), 4.27 (d, J = 2.5 Hz, 2 H), 2.71 (s,
3
H), 2.26 (t, J = 2.5 Hz, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C24H18N : 348.1501; found:
3
13
348.1499.
C NMR (100 MHz, CDCl ): δ = 163.1 (d, J = 248.0 Hz), 154.0, 148.8,
3
C–F
1
1
48.2, 142.9, 136.5, 135.6 (d, JC–F = 2.0 Hz), 130.9 (d, JC–F = 8.5 Hz, 2C),
28.9, 121.8, 115.5 (d, JC–F = 22.4 Hz, 2C), 109.9, 80.0, 73.1, 40.4, 23.8.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
Synthesis
S. Vallerotto et al.
Paper
2-Methyl-5-phenyl-N-propargyl-6-aminoquinoxaline (5m)
dried over MgSO , filtered, and concentrated under reduced pressure.
4
The mixture was purified by silica gel flash chromatography (CH Cl –
EtOAc, 90:10 to 80:20) to afford 6a–m or 9a,b.
Yield: 30.4 mg (31%); brownish yellow solid.
2
2
1
H NMR (300 MHz, CDCl ): δ = 8.58 (s, 1 H), 7.80 (d, J = 9.0 Hz, 1 H),
3
7
7
2
.42–7.36 (m, 2 H), 7.30–7.25 (m, 3 H), 7.17 (dd, J = 9.0, 2.5 Hz, 2 H),
.13 (d, J = 2.5 Hz, 1 H), 4.52 (br s, 1 H, NH), 4.27 (d, J = 4.6 Hz, 2 H),
.67 (s, 3 H).
2
-Methyl-1,4,8-triazaphenanthrene (6a)
Yield and catalysts: see Table 1; light-beige solid.
1H NMR (300 MHz, CDCl
): δ = 9.44 (dd, J = 8.3, 1.7 Hz, 1 H), 9.07 (dd,
13
C NMR (75 MHz, CDCl ): δ = 149.4, 147.3, 145.8, 143.0, 137.2, 131.7,
3
3
1
29.3, 128.3, 128.2, 122.6, 121.8, 105.5, 85.2, 83.8, 34.4, 22.0.
J = 4.4, 1.7 Hz, 1 H, H-13), 8.83 (s, 1 H), 8.28 (d, J = 9.47 Hz, 1 H, H-7),
8.16 (d, J = 9.4 Hz, 1 H, H-8), 7.66 (dd, J = 9.4, 4.4 Hz, 1 H, H-12), 2.83
HRMS (ESI): m/z [M + H]+ calcd for C18H16N : 274.1344; found:
3
(
s, 3 H, CH3).
272.1341.
13
C NMR (75 MHz, CDCl ): δ = 154.1, 151.3, 148.5, 144.3, 141.1, 138.2,
3
1
32.7, 132.2, 130.1, 126.2, 122.1, 22.2.
Synthesis ofN-(1,1-Dimethyl)propargyl-6-aminoquinoxalines
a,b; General Procedure
8
HRMS (ESI): m/z [M + H]+ calcd for C12H10N : 196.0875; found:
3
196.0873.
To a solution of aminoquinoxaline 4a,b (1 equiv) in a 1:1 mixture of
THF/water (10 mL / 10 mL) with CuCl , (10 mg/mmol) and copper
2
dust (10 mg/mmol) under an inert atmosphere, was added triethyl-
1,4,8-Triazaphenanthrene (6b)
10
amine (1.4 equiv) and 3-chloro-3-methyl-1-butyne (1.4 equiv). The
mixture was stirred at r.t. for 12 h, hydrolyzed with sat. aq K CO , and
Yield: 91 mg (70%); light-beige solid.
2
3
1
H NMR (300 MHz, CDCl ): δ = 9.44 (ddd, J = 8.2, 1.7, 0.5 Hz, 1 H), 9.01
3
then extracted with CH Cl The combined organic layers were
2
2.
(dd, J = 4.4, 1.7 Hz, 1 H), 8.94 (d, J = 2.0 Hz, 1 H), 8.92 (d, J = 2.0 Hz,
washed with sat. aq NaCl, dried over Na SO , filtered then concentrat-
2
4
1
4
H), 8.28 (d, J = 9.2 Hz, 1 H), 8.17 (d, J = 9.2 Hz, 1 H), 7.65 (dd, J = 8.2,
.4 Hz, 1 H).
ed in vacuo. The residue was then purified by flash chromatography
(
CH Cl –EtOAc, 90:10 to 80:20) to afford the expected compound
2
2
13
C NMR (75 MHz, CDCl ): δ = 151.9, 149.1, 145.1, 143.8, 142.4, 140.9,
8a,b.
3
133.1, 132.7, 130.5, 126.4, 122.4.
HRMS (ESI): m/z [M + H]+ calcd for C11
H N : 182.0718; found:
2-Methyl-N-(1,1-dimethyl)-propargyl-6-aminoquinoxaline (8a)
8 3
182.0717.
Yield: 224 mg (80%); brownish yellow solid.
1
H NMR (300 MHz, CDCl ): δ = 8.47 (s, 1 H), 7.66 (d, J = 9.0 Hz, 1 H),
3
3
-Phenyl-1,4,8-triazaphenanthrene (6c)
7
1
.46 (d, J = 2.5 Hz, 1 H), 7.10 (dd, J = 9.0, 2.5 Hz, 1 H, H ), 4.59 (br s,
H, NH), 2.55 (s, 3 H), 2.35 (s, 1 H), 1.57 (s, 6 H).
7
Yield: 163 mg (70%); light-beige solid.
1
13
H NMR (400 MHz, CDCl ): δ = 9.66 (d, J = 8.3 Hz, 1 H), 9.46 (s, 1 H),
3
C NMR (75 MHz, CDCl ): δ = 149.0, 145.6, 145.4, 142.4, 136.6, 128.6,
3
9
.15 (br s, 1 H), 8.33 (dd, J = 8.3, 1.5 Hz, 2 H), 8.26 (t, J = 8.5 Hz, 2 H),
123.2, 107.7, 86.3, 71.2, 47.6, 29.8, 21.7.
7.72 (br m, 1 H), 7.61 (m, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C14H16N : 226.1344; found:
3
13
C NMR (100 MHz, CDCl ): δ = 151.9 (br), 150.7, 149.7 (br), 142.9,
226.1341.
3
1
1
40.7, 140.1, 136.5, 132.8, 132.4, 130.3, 130.2, 129.2 (2C), 127.5 (2C),
26.8 (br), 122.3 (br).
2
-Methyl-3-phenyl-N-(1,1-dimethyl)-propargyl-6-aminoquinox-
HRMS (ESI): m/z [M + H]+ calcd for C17
H N : 258.1031; found:
aline (8b)
12 3
258.1028.
Yield: 414.0 mg (65%); brownish yellow solid.
1
H NMR (400 MHz, CDCl ): δ = 7.81 (d, J = 9.0 Hz, 1 H), 7.61 (d, J =
3
2
-Methyl-3-phenyl-1,4,8-triazaphenanthrene (6d)
8
9
6
.3 Hz, 2 H), 7.56 (d, J = 2.5 Hz, 1 H), 7.41–7.50 (m, 3 H), 7.16 (dd, J =
.0, 2.5 Hz, 1 H), 4.32 (br s, 1 H, NH), 2.66 (s, 3 H), 2.40 (s, 1 H), 1.68 (s,
H).
Yield: 33.9 mg (54%); light-beige solid.
1
H NMR (400 MHz, CDCl ): δ = 9.42 (dd, J = 8.3, 0.8 Hz, 1 H), 9.03 (br s,
3
1
3
1 H), 8.23 (d, J = 9.2 Hz, 1 H), 8.12 (d, J = 9.2 Hz, 1 H), 7.76 (dd, J = 8.1,
C NMR (100 MHz, CDCl ): δ = 154.6, 147.8, 145.8, 142.6, 139.6,
3
1.5 Hz, 2 H), 7.48–7.59 (m, 4 H), 2.84 (s, 3 H); some signals are broad-
1
4
36.1, 128.8 (2C), 128.6, 128.5, 128.4 (2C), 123.2, 108.0, 86.4, 71.2,
7.8, 30.0 (2C), 23.6.
ened due to slow conformational changes.
13
HRMS (ESI): m/z [M + H]+ calcd for C20H20N : 302.1657; found:
3
C NMR (100 MHz, CDCl ): δ = 153.2, 152.4, 151.3 (br), 148.8 (br),
3
3
1
1
39.9, 138.8, 138.1, 132.5, 132.4, 129.7, 129.3 (2C), 129.0, 128.4 (2C),
26.4 (br), 122.0 (br), 24.1; some signals are broadened due to slow
02.1656.
conformational changes.
HRMS (ESI): m/z [M + H]+ calcd for C18
Synthesis of 1,4,8-Triazaphenanthrene 6a–m and 7,8-Dihydro-7,7-
dimethyl-1,4,8-triazaphenanthrenes 9a,b
H N : 272.1188; found:
14 3
272.1183.
To a solution of N-propargyl-6-aminoquinoxaline derivative 5a–m or
8
a,b (1 equiv) in DMSO (10 mL/mmol of 5a–m) was added the corre-
sponding copper or silver catalyst (see Table 2) under an inert atmo-
sphere. The resulting solution was stirred for 5 h at 110 °C. The reac-
2-Methyl-3-p-tolyl-1,4,8-triazaphenanthrene (6e)
Yield: 30.5 mg (61%); light-beige solid.
tion mixture was cooled to r.t., NH OH 28% (1 mL/mmol) was added,
and the reaction mixture was stirred for 10 min at r.t., then diluted
with water, extracted with EtOAc twice, washed with sat. aq NaCl,
1
4
H NMR (400 MHz, CDCl ): δ = 9.46 (dd, J = 8.2, 1.0 Hz, 1 H), 9.03 (dd,
3
J = 4.4, 1.8 Hz, 1 H), 8.24 (d, J = 9.2 Hz, 1 H), 8.15 (d, J = 9.2 Hz, 1 H),
7
.68 (d, J = 8.2 Hz, 2 H), 7.59 (dd, J = 8.2, 4.4 Hz, 1 H), 7.36 (d, J =
8
.2 Hz, 2 H), 2.87 (s, 3 H), 2.47 (s, 3 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

G
Synthesis
S. Vallerotto et al.
Paper
13
13
C NMR (100 MHz, CDCl ): δ = 153.3, 152.5, 151.3, 148.9, 139.9,
C NMR (100 MHz, CDCl ): δ = 152.3, 152.1, 151.4 (br), 149.2 (br),
3
3
1
1
39.1, 138.2, 136.1, 132.5, 132.2, 129.8, 129.3 (2C), 129.1 (2C), 126.4,
22.0, 24.2, 21.3.
140.3, 138.3, 137.4, 135.4, 132.9 (br), 132.5, 130.8 (2C), 129.8, 128.8
(2C), 125.7 (br), 122.4 (br), 24.1; some signals are broadened due to
slow conformational changes.
HRMS (ESI): m/z [M + H]+ calcd for C19H16N : 286.1344; found:
3
286.1344.
HRMS (ESI): m/z [M + H]+ calcd for C18H13ClN : 306.0798; found:
3
306.0800.
2-Methyl-3-(4-methoxyphenyl)-1,4,8-triazaphenanthrene (6f)
2-Methyl-3-(3,4-dichlorophenyl)-1,4,8-triazaphenanthrene (6j)
Yield: 30.2 mg (62%); light-beige solid.
1
Yield: 34.6 mg (62%); light-beige solid.
H NMR (400 MHz, CDCl ): δ = 9.45 (dd, J= 8.0, 0.8 Hz, 1 H), 9.03 (br s,
H), 8.23 (d, J = 9.3 Hz, 1 H), 8.12 (d, J = 9.3 Hz, 1 H), 7.75 (dd, J = 8.8,
.0 Hz, 2 H), 7.59 (dd, J = 8.0, 4.1 Hz, 1 H), 7.07 ( d, J = 8.8 Hz, 2 H), 3.90
3
1
1
2
H NMR (400 MHz, CDCl ): δ = 9.46 (dd, J = 8.3, 1.4 Hz, 1 H), 9.08 (br s,
3
1 H), 8.30 (d, J = 9.3 Hz, 1 H), 8.17 (d, J = 9.3 Hz, 1 H), 7.91 (d, J =
(s, 3 H), 2.87 (s, 3 H); some signals are broadened due to slow confor-
1.0 Hz, 1 H), 7.61–7.67 (m, 3 H), 2.88 (s, 3 H).
mational changes.
13
C NMR (100 MHz, CDCl ): δ = 152.1, 151.7, 150.7, 149.0, 140.5,
3
13
C NMR (100 MHz, CDCl ): δ = 160.4, 152.8, 152.4, 151.2 (br), 148.9
138.8, 138.3, 133.6, 133.2, 132.9, 132.5, 131.4, 130.5, 129.8, 128.6,
126.3, 122.3, 24.1.
3
(br), 139.7, 138.2, 132.5, 132.1, 131.2, 130.8 (2C), 129.8, 126.4 (br),
1
22.0 (br), 113.9 (2C), 55.4, 24.4; some signals are broadened due to
HRMS (ESI): m/z [M + H]+ calcd for C18H12Cl N : 340.0408; found:
2
3
slow conformational changes.
MS (ESI): m/z = 302.2 (100) [M + H]+.
340.0405.
HRMS (ESI): m/z [M + H]+ calcd for C19H16N O: 302.1293; found:
2-Methyl-3-(naphthalen-2-yl)-1,4,8-triazaphenanthrene (6k)
3
302.1296.
Yield: 30.1 mg (61%).; light-beige solid.
1
H NMR (400 MHz, CDCl ): δ = 9.57 (d, J = 6.6 Hz, 1 H), 9.17 (br s, 1 H),
3
2
-Methyl-3-(3,4,5-trimethoxyphenyl)-1,4,8-triazaphenanthrene
8
7
.35 (br s, 1 H), 8.26 (s, 1 H), 8.24 (br s, 1 H), 8.01 (d, J = 8.6 Hz, 1 H),
.98 (dd, J = 6.4, 5.0 Hz, 1 H), 7.96 (dd, J = 6.4, 5.0 Hz, 1 H), 7.91 (dd, J =
(6g)
Yield: 25.2 mg (51%); light-beige solid.
8.5, 1.5 Hz, 1 H), 7.74 (m, 1 H), 7.60 (m, 2 H), 2.95 (s, 3 H); some sig-
nals are broadened due to slow conformational changes.
1
H NMR (400 MHz, CDCl ): δ = 9.47 (d, J= 8.0 Hz, 1 H), 9.06 (br s, 1 H),
3
13
8.26 (d, J = 9.3 Hz, 1 H), 8.16 (d, J = 9.3 Hz, 1 H), 7.63 (dd, J = 8.0,
C NMR (100 MHz, CDCl ): δ = 153.4, 152.8, 140.2, 136.3, 135.9,
3
3
.9 Hz, 1 H), 6.98 (s, 2 H), 3.95 (s, 9 H), 2.88 (s, 3 H); some signals are
132.4, 133.4, 133.0, 132.6 (br), 129.8 (br), 129.1, 128.5, 128.2, 127.8,
127.0, 126.7, 126.7, 24.3; some signals are broadened and 4 C missing
due to slow conformational change.
broadened due to slow conformational changes.
13
C NMR (100 MHz, CDCl ): δ = 153.3 (2C), 153.1, 152.5, 151.4 (br),
3
1
1
49.0 (br), 140.1, 138.8, 138.0, 134.3, 132.5 (2C), 129.8, 126.3 (br),
22.1 (br), 106.8 (2C), 61.0, 56.4 (2C), 24.3; some signals are broad-
HRMS (ESI): m/z [M + H]+ calcd for C22H16N : 322.1344; found:
3
322.1344.
ened due to slow conformational changes.
HRMS (ESI): m/z [M + H]+ calcd for C21H20N O : 362.1505; found:
2-Methyl-3-biphenyl-1,4,8-triazaphenanthrene (6l)
3
3
362.1503.
Yield: 34.5 mg (63%); light-beige solid.
1
H NMR (400 MHz, CDCl ): δ = 9.52 (dd, J = 8.2, 1.3 Hz, 1 H), 9.07 (dd,
3
2
-Methyl-3-(4-fluorophenyl)-1,4,8-triazaphenanthrene (6h)
J = 4.5, 1.8 Hz, 1 H), 8.29 (d, J = 9.3 Hz, 1 H), 8.19 (d, J = 9.3 Hz, 1 H),
7.89 (dd, J = 8.6, 1.9 Hz, 2 H), 7.80 (dd, J = 8.6, 1.9 Hz, 2 H), 7.70 (d, J =
7.1 Hz, 2 H), 7.64 (dd, J = 8.2, 4.5 Hz, 1 H), 7.51 (td, J = 7.3, 1.9 Hz, 2 H),
Yield: 52% (19.0 mg); light-beige solid.
1
H NMR (400 MHz, CDCl ): δ = 9.46 (dd, J = 8.0, 1.5 Hz, 1 H), 9.07 (d,
3
7.41 (tt, J = 7.3, 1.9 Hz, 1 H), 2.94 (s, 3 H).
J = 3.0 Hz, 1 H), 8.26 (d, J = 9.3 Hz, 1 H), 8.15 (d, J = 9.3 Hz, 1 H), 7.78
13
(dd, J = 8.5, 5.0 Hz, 2 H), 7.62 (dd, J = 8.3, 4.2 Hz, 1 H), 7.27 (t, J =
C NMR (100 MHz, CDCl ): δ = 152.9, 152.6, 151.5, 149.0, 142.0,
3
8
.5 Hz, 2 H), 2.88 (s, 3 H).
140.4, 140.1, 138.3, 137.8, 132.6, 132.5, 129.9 (3C), 128.9 (2C), 127.8,
127.2 (4C), 126.5, 122.1, 24.3.
13
C NMR (100 MHz, CDCl ): δ = 163.3 (d, J = 250.8 Hz), 152.3, 152.2,
3
C–F
151.5, 148.9, 140.1, 138.2, 135.0 (d, JC–F = 3.1 Hz), 132.6, 132.5, 131.3
HRMS (ESI): m/z [M + H]+ calcd for C24H18N : 348.1501; found:
3
(
2
d, JC–F = 8.0 Hz, 2C), 129.8, 126.3, 122.1, 115.5 (d, JC–F = 21.5 Hz, 2C),
4.2.
HRMS (ESI): m/z [M + H]+ calcd for C18H13N F: 290.1094; found:
348.1499.
2-Methyl-5-phenyl-1,4,8-triazaphenanthrene (6m)
3
290.1094.
Reaction time: 1 h.
Yield: 86.0 mg (43%); light-beige solid.
2
-Methyl-3-(4-chlorophenyl)-1,4,8-triazaphenanthrene (6i)
1
H NMR (300 MHz, CDCl ): δ = 9.01 (d, J = 4.7 Hz, 1 H), 8.34 (d, J =
3
Yield: 30.4 mg (64%); light-beige solid.
8.9 Hz, 1 H), 8.32 (s, 1 H), 8.14 (d, J = 8.9 Hz, 1 H), 7.44 (d, J = 4.7 Hz,
1
H NMR (400 MHz, CDCl ): δ = 9.47 (d, J = 8.3 Hz, 1 H), 9.10 (br s, 1 H),
1 H), 7.43–7.39 (m, 3 H), 7.36–7.30 (m, 2 H), 2.68 (s, 3 H).
3
8
2
.29 (br d, J = 8.4 Hz, 1 H), 8.17 (d, J = 8.4 Hz, 1 H), 7.74 (d, J = 8.2 Hz,
H), 7.66 (br s, 1 H), 7.55 (d, J = 8.2 Hz, 2 H), 2.87 (s, 3 H); some sig-
13
C NMR (75 MHz, CDCl ): δ = 153.1, 150.1, 149.91, 149.8, 142.6,
3
142.3, 141.7, 139.1, 133.4, 128.1 (2C), 127.7 (2C), 127.1, 125.4, 124.1,
2.0.
nals are broadened due to slow conformational changes.
2
HRMS (ESI): m/z [M + H]+ calcd for C18H14N : 272.1188; found:
3
272.1178.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
Synthesis
S. Vallerotto et al.
Paper
7
,8-Dihydro-2,8,8-trimethylpyrido[3,2-f]quinoxaline (9a)
Med. Chem. 2003, 11, 5013. (d) Seck, M.; Franck, X.;
Hocquemiller, R.; Figadère, B.; Peyrat, J. F.; Provot, O.; Brion, J.
D.; Alami, M. Tetrahedron Lett. 2004, 45, 1881. (e) Hui, X.;
Desrivot, J.; Bories, C.; Loiseau, P.; Franck, X.; Hocquemiller, R.;
Figadère, B. Bioorg. Med. Chem. Lett. 2006, 16, 815. (f) Hui, X.;
Schmidt, F.; Fakhfakh, M. A.; Franck, X.; Hocquemiller, R.;
Figadère, B. Heterocycles 2007, 72, 353. (g) Schmidt, F.; Champy,
P.; Seon-Meniel, B.; Franck, X.; Raisman-Vozari, R.; Figadère, B.
Plos ONE 2009, 4, e6215. (h) Schmidt, F.; Le Douaron, G.; Amar,
M.; Seon-Meniel, B.; Raisman-Vozari, R.; Figadere, B. Bioorg.
Med. Chem. 2010, 18, 5103. (i) Le Douaron, G.; Schmidt, F.;
Amar, M.; Kadar, H.; Debortoli, L.; Latini, A.; Seon-Meniel, B.;
Ferrié, L.; Michel, P. P.; Touboul, D.; Brunelle, A.; Raisman-
Vozari, R.; Figadere, B. Eur. J. Med. Chem. 2015, 89, 467.
Reaction time: 1 h.
Yield: 67 mg (67%); light-beige solid.
1
H NMR (300 MHz, CDCl ): δ = 8.51 (s, 1 H), 7.59 (d, J = 9.0 Hz, 1 H),
3
7.33 (d, J = 10.0 Hz, 1 H), 6.92 (d, J = 9.0 Hz), 5.55 (d, J = 10.12 Hz, 1 H),
4
.16 (br s, 1 H, NH), 2.63 (s, 3 H), 1.36 (s, 6 H).
13
C NMR (75 MHz, CDCl ): δ = 148.6, 145.0, 142.9, 138.3, 136.6, 129.0,
3
128.3, 120.1, 118.4, 111.5, 52.6, 31.4 (2C), 21.9.
HRMS (ESI): m/z [M + H]+ calcd for C14H17N : 226.1344; found:
3
226.1349.
7,8-Dihydro-2,8,8-trimethyl-3-phenylpyrido[3,2-f]quinoxaline
(9b)
(
3) Le Douaron, G.; Ferrié, L.; Sepulveda, J. E.; Amar, M.; Seon-
Meniel, B.; Raisman-Vozari, R.; Michel, P. P.; Figadere, B. J. Med.
Chem. 2016, in press; DOI: 10.1021/acs.jmedchem.6600297.
Reaction time: 1 h.
Yield: 191.0 mg (64%); light-beige solid.
1
(4) (a) Scheurer, H.; Zsindely, J.; Schmid, H. Helv. Chim. Acta 1973,
6, 478. (b) Abbiati, G.; Acradi, A.; Bianchi, G.; Giuseppe, S. D.;
H NMR (400 MHz, CDCl ): δ = 7.70 (dd, J = 8.0, 1.5 Hz, 2 H), 7.65 (d,
3
5
J = 8.8 Hz, 1 H), 7.45–7.52 (m, 3 H), 7.42 (d, J = 9.8 Hz, 1 H), 6.93 (d, J =
8
1
Marinelli, F.; Rossi, E. J. Org. Chem. 2003, 68, 6959. (c) Pastine, S.
J.; Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055. (d) Zhang, X.;
Yao, T.; Campo, M. A.; Larock, R. C. Org. Lett. 2005, 7, 763.
(e) Holman, M. A.; Williamson, N. W.; Ward, A. D. Aust. J. Chem.
.8 Hz, 1 H), 5.52 (d, J = 9.8 Hz, 1 H), 4.07 (br s, NH, 1 H), 2.69 (s, 3 H),
.38 (s, 6 H).
13
C NMR (100 MHz, CDCl ): δ = 153.7, 147.0, 143.0, 139.9, 138.3,
3
1
5
35.7, 129.2 (2C), 128.7, 128.6, 128.2 (2C), 128.0, 119.9, 118.8, 111.7,
2.6, 31.4 (2C), 23.8.
2
2
005, 58, 368. (f) Kuninobu, Y.; Inoue, Y.; Takai, K. Chem. Lett.
007, 36, 1422. (g) Minnihan, E. C.; Colletti, S. L.; Toste, F. D.;
HRMS (ESI): m/z [M + H]+ calcd for C20H20N : 302.1657; found:
3
Shen, H. C. J. Org. Chem. 2007, 72, 6287. (h) Godet, T.; Belmont,
P. Synlett 2008, 2513. (i) Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett.
3
02.1650.
2008, 10, 2629. (j) Jiang, C.; Xu, M.; Wang, S.; Wang, H.; Yao, Z.-J.
J. Org. Chem. 2010, 75, 4323. (k) Zhang, X.; Yao, T.; Campo, M. A.;
Larock, R. C. Tetrahedron 2010, 66, 1177. (l) Komeyama, K.;
Igawa, R.; Takaki, K. Chem. Commun. 2010, 46, 1748. (m) Manzo,
A. M.; Perboni, A.; Broggini, G.; Rigamonti, M. Synthesis 2011,
127. (n) Majumdar, K. C.; Nandi, R. K.; Ganai, S.; Taher, A. Synlett
Computational Methods
The conformation of a model of derivative 5b was fully optimized
11
without constraint by using the DFT method with the hybrid
12
13
Becke3LYP functional and the 6–31G* base as implemented in the
14
Gaussian 09 software package. Vibrational analysis within the har-
monic approximation was performed at the same level of theory
upon geometrical optimization convergence, and the local minimum
was characterized by the absence of an imaginary frequency. Depic-
tion of the molecular geometry as well as orbitals was realized by us-
2011, 116. (o) Symeonidis, T. S.; Kalltsakis, M. G.; Litinas, K. E.
Tetrahedron Lett. 2011, 52, 5452. (p) Gurunathan, S.;
Paramasicam, T. P. Tetrahedron Lett. 2011, 52, 1783. (q) Zhu, M.;
Fu, W.; Xun, C.; Deng, D.; Ji, B.; Zou, G. J. Fluorine Chem. 2012,
135, 195. (r) Roy, B.; Ansary, I.; Samanta, S.; Majumdar, K. C. Tet-
rahedron Lett. 2012, 53, 5119. (s) Symeonidis, T. S.; Lykakis, I. N.;
Litinas, K. E. Tetrahedron 2013, 69, 4612. (t) Aichhorn, S.;
Himmelsbach, M.; Schöfberger, W. Org. Biomol. Chem. 2015, 13,
15
ing UCSF Chimera v1.10.2.
Acknowledgment
9373.
(
(
(
5) (a) Berger, D. M.; Dutia, M. D.; Demorin, F. F.; Boschelli, D. H.;
Powell, D. W.; Tsou, H.; Wissner, A.; Zhang, N.; Ye, F.; Wu, B. PCT
Int. Appl WO 2001047892, 2001. (b) Carta, A.; Briguglio, I.;
Piras, S.; Corona, P.; Boatto, G.; Nieddu, M.; Giunchedi, P.;
Marongiu, M. E.; Giliberti, G.; Iuliano, F.; Blois, S.; Ibba, C.;
Busonera, B.; La Colla, P. Bioorg. Med. Chem. 2011, 19, 7070.
6) (a) Lursker, F.; Evans, R. L. J. Am. Chem. Soc. 1946, 68, 874.
We thank Mrs. Blandine Seon-Meniel for the synthesis on a large scale
of compound 4d, Mrs. Karine Leblanc for MS and HPLC analyses, and
Mr. Jean-Christophe Jullian for 2D-NMR (400 MHz) analyses. S.V. and
G.L.D. thank the ministère de l'enseignement supérieur et de la re-
cherche for PhD fellowship.
(
b) Ohta, A.; Hasagow, K.; Amano, K.; Mori, C.; Ohsawa, A.;
Ikeda, K.; Watanabe, T. Chem. Pharm. Bull. 1979, 27, 2596.
c) Ganguli, B. S.; Singh, B.; Ferandes, P. S. Indian J. Heterocycl.
Supporting Information
(
Supporting information for this article is available online at
Chem. 1994, 269. (d) Kondo, S.; Shiozawa, T.; Terao, Y. Chem.
Pharm. Bull. 1997, 45, 722.
http://dx.doi.org/10.1055/s-0035–1562443.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
7) Hazra, C. K.; Oestreich, M. Org. Lett. 2012, 14, 4010.
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I