A direct method for oxidizing quinoxaline, tetraazaphenanthrene, and hexaazatriphenylene moieties using hypervalent λ3-iodinane compounds

Article abstract of DOI:10.1021/jo401872e

An efficient oxidation reaction of various electron-poor quinoxaline-core-containing compounds, such as quinoxalines, 1,4,5,8-tetraazaphenanthrenes, and 1,4,5,8,9,12-hexaazatriphenylene, using [bis(trifluoroacetoxy)iodo]benzene is reported. These compounds are converted into the corresponding quinoxalinediones in good to high yields at room temperature using an acetonitrile/water solvent mixture. This unprecedented reaction should enable the synthesis of a wide variety of compounds useful in several fields of chemistry.

Full text of DOI:10.1021/jo401872e

Note
pubs.acs.org/joc
A Direct Method for Oxidizing Quinoxaline, Tetraazaphenanthrene,
and Hexaazatriphenylene Moieties Using Hypervalent λ3‑Iodinane
Compounds
Ludovic Troian-Gautier,† Julien De Winter,‡ Pascal Gerbaux,‡ and Cecile Moucheron*,†
́
†Laboratoire de Chimie Organique et Photochimie, Universite
Bruxelles, Belgium
́
Libre de Bruxelles, 50 av. F. D. Roosevelt, CP160/08, B-1050
‡Mass Spectrometry Research Group, Interdisciplinary Center for Mass Spectrometry, University of Mons (UMons), 23 Place du
Parc, B-7000 Mons, Belgium
S
* Supporting Information
ABSTRACT: An efficient oxidation reaction of various electron-
poor quinoxaline-core-containing compounds, such as quinoxalines,
1,4,5,8-tetraazaphenanthrenes, and 1,4,5,8,9,12-hexaazatriphenylene,
using [bis(trifluoroacetoxy)iodo]benzene is reported. These com-
pounds are converted into the corresponding quinoxalinediones in
good to high yields at room temperature using an acetonitrile/water
solvent mixture. This unprecedented reaction should enable the synthesis of a wide variety of compounds useful in several fields
of chemistry.
uinones and quinoxalinedione derivatives play impor-
Q tant roles in organic chemistry, where they serve as
building blocks for novel molecules1,2 coordination polymers,3,4
and in coordination chemistry.5 In medicinal chemistry6 they
are used for their antibacterial, anti-inflammatory, or anti-
neoplastic effects as in the case of tanshiones,7,8 which may be
Figure 1. (Diacetoxyiodo)benzene (DIB) and [bis(trifluoroacetoxy)-
used against bone-resorptive diseases, or β-lapachone, which
iodo]benzene (BTI).
has significant antitumor activity against various forms of
cancer.9,10
compounds bearing a phenol group.30−36 Furthermore, BTI is
Even if quinoxalinediones may be synthesized by con-
densation of an o-phenylenediamine with oxalic acid,11 there is
currently no method to oxidize a quinoxaline moiety in good
also used to convert methoxy derivatives into the correspond-
ing quinones37 via oxidative demethylation. These hypervalent
iodine compounds also present the advantages of being
yield. Indeed, when a classical oxidant such as potassium
commercially available, not expensive, and rather easy to
permanganate is used with quinoxaline, the reaction yields only
synthesize.24−26 They have thus been widely used during the
past decade and have allowed different groups to synthesize a
wide variety of novel molecules.
pyrazine-2,3-dicarboxylic acid.12 Furthermore, when another
oxidation reagent such as m-CPBA,13 hydrogen peroxide,14
potassium persulfate,15 or the efficient oxygen-transfer reagent
HOF·CH3CN16 is used on quinoxaline, the reaction yields only
N-oxide or N,N′-dioxide, and no oxidation of the adjacent
carbon atom is observed.
Finally, for more elaborated systems, such as 1,4,5,8-
tetraazaphenanthrene (TAP)17,18 and 1,4,5,8,9,12-hexaazatri-
phenylene (HAT),19,20 the reactions are even more compli-
cated, since these highly electron-withdrawing molecules are
very reluctant to be oxidized.
In the course of our investigation of synthetic methodologies
for the oxidation of electron-withdrawing molecules, we
focused our research on well-known hypervalent iodine
derivatives,21−23 namely, (diacetoxyiodo)benzene (DIB)24 and
[bis(trifluoroacetoxy)iodo]benzene (BTI)25,26 (Figure 1).
These hypervalent λ3 compounds have attracted great interest
over the past decade because of their high versatility.27−29 For
instance, they are well-known to oxidize a wide variety of
In this paper, we report the use of [bis(trifluoroacetoxy)-
iodo]benzene as an oxidant for quinoxaline moieties. This
oxidation reaction presents a unique character that has, to the
best of our knowledge, never been reported in the literature for
this type of structure. This novel oxidation strategy allowed us
to convert substituted and unsubstituted quinoxalines, 1,4,5,8-
tetraazaphenanthrenes, and 1,4,5,8,9,12-hexaazatriphenylene
into the corresponding “quinoxalinediones” in high yields at
ambient temperature. The efficiency of this reaction is
particularly remarkable because oxidation of these electron-
poor polyazaaromatic compounds is generally unfeasible.
The study was initiated with attempts to oxidize two
hydroxy-1,4,5,8-tetraazaphenanthrene derivatives, 1a and 2a.
Received: August 23, 2013
© XXXX American Chemical Society
A
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Using DIB or BTI, we managed to convert both isomers 1a and
2a into the corresponding quinoxalinedione 1b in high yields
(Figure 2). The structure of this reaction product is in perfect
Figure 2. Oxidation of 1,4,5,8-tetraazaphenanthrene hydroxy deriva-
tives using DIB and BTI.
agreement with the reported literature on phenolic oxidation
using the λ3 hypervalent iodine compounds, where phenol
compounds yield the corresponding quinones.
In contrast, when BTI was used on the methoxy derivatives
3a and 4a, the product obtained after reaction surprisingly
corresponded to an oxidation of the unsubstituted quinoxaline
core (Figure 3). This result suggests that the moiety sensitive
Figure 4. Oxidation of unsubstituted quinoxaline-core-containing
compounds using BTI.
Figure 3. Oxidation of 1,4,5,8-tetraazaphenanthrene methoxy
derivatives using BTI.
Figure 5. Oxidation of various 1,4,5,8-tetraazaphenanthrene deriva-
tives using BTI.
toward BTI oxidation is the quinoxaline core and not the
methoxy substituent, as already reported in the literature for
other methoxy derivatives.37 Comparatively, no reaction
occurred when DIB was used instead of BTI.
Regarding quinoxalines, these molecules were substituted at
various positions by numerous functional groups, such as
halogen [chloride (14a, 15a, 16a), bromide (17a), iodide
(18a)], nitro (19a, 20a, 21a, 22a, 23a), hydroxyl (24a, 25a),
methoxy (26a, 27a), and methyl (28a). Once again, the results
showed that in all cases the oxidation occurred on the
quinoxaline core (Figure 6). These results indicate that in
quinoxaline oxidation BTI is very selective toward the
quinoxaline core and does not react with the variety of
substituents that were used. Nevertheless, if the quinoxaline is
substituted by a hydroxyl group on the benzene ring, only
phenolic oxidation occurs.33,38
To determine the key parameters required for the oxidation,
we investigated the reaction of BTI with several types of
system, namely pyrazine, pyridine, pyridine derivatives, and
quinoline. The comparison between pyrazine and pyridine
moieties should allow a determination of whether the reactive
subunit is the pyridinic one or if two nitrogen atoms are
required for the oxidation to occur. Comparison of pyrazine/
quinoxaline and pyridine/quinoline derivatives should indicate
whether the presence of a second fused aromatic ring is
necessary to form the reported oxidation products.
In order to verify this hypothesis, we investigated the action
of BTI and DIB on various unsubstituted quinoxaline-core-
containing compounds (Figure 4), such as quinoxaline (5a),
1,4,5,8-tetraazaphenanthrene (6a, TAP), and 1,4,5,8,9,12-
hexaazatriphenylene (7a, HAT). Although DIB was in all
cases unable to oxidize these molecules, BTI always yielded the
corresponding quinoxalinediones in good to high yields,
showing that the quinoxaline core is the reactive moiety and
that no particular functional group is required for the oxidation
to occur. This result is particularly remarkable because these
highly electron-poor heterocycles are generally inert toward
oxidation. We managed to scale-up the reaction up to 1 g of
compounds 5a, 6a, and 7a with no significant change in the
reaction yield.
To further extend the scope of this reaction, we used BTI on
various quinoxaline and 1,4,5,8-tetraazaphenanthrene com-
pounds. Electron-poor 1,4,5,8-tetraazaphenanthrene was sub-
stituted at position 2 or 3 by several functional groups, such as
methoxy (3a, 4a, 8a), chloride (9a and 10a), formyl (11a),
ethanoloxy (12a), and methyl (13a) groups (Figure 5). The
results showed that in all cases the product formed was the one
where the unsubstituted quinoxaline core was oxidized.
Despite our efforts, the reactions of BTI with pyridine and
quinoline derivatives never gave rise to the formation of the
expected oxidation products, nor did the reaction with pyrazine.
This strongly suggests that two nitrogen atoms and a second
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On the basis of our results, we could propose the following
mechanism (Figure 8). First, a nucleophilic attack of one of the
nitrogen atom from the quinoxaline core on the iodine atom
would take place. This attack would be followed by the addition
of water, leading to the hydroxy derivative. This nucleophilic
attack by water is most likely favored by the presence of the
second nitrogen atom, which decreases even more the electron
density on the carbon atom compared with that of the pyridinic
core. The second aromatic ring might also stabilize the
intermediate. Once the first hydroxy group is present on the
molecule, the standard mechanism proposed in the literature
for phenolic derivatives would take place.30
The hypothesis concerning this second step is strengthened
by the fact that 2- and 3-hydroxy-1,4,5,8-tetraazaphenanthrene
1a and 2a yield the same product 1b, where only phenolic
oxidation occurred and no oxidation of the unsubstituted
quinoxaline core was observed. If this hypothesis were not
correct, we should observe oxidation also in the unsubstituted
quinoxaline subunit. In order to confirm the mechanism
involving nucleophilic attack by water, an experiment was
conducted using H218O instead of H2O. This experiment
allowed us to isolate the desired 18O-enriched quinoxaline-
dione.
Figure 6. Oxidation of substituted quinoxalines using BTI.
In summary, we have reported the unprecedented use of
[bis(trifluoroacetoxy)iodo]benzene as an oxidant toward
quinoxaline-core-containing molecules. Oxidation using [bis-
(trifluoroacetoxy)iodo]benzene was investigated on a wide
variety of compounds, such as substituted and unsubstituted
quinoxalines, 1,4,5,8-tetraazaphenanthrenes, and 1,4,5,8,9,12-
hexaazatriphenylene. This reaction, carried out at room
temperature, always yielded the desired quinoxalinedione in
good to high yield. When hydroxyl derivatives were used, it was
always the phenolic moiety that was oxidized, which is in
agreement with literature. The phenolic group is more
nucleophilic than the nitrogen atom in the quinoxaline, which
probably explains this behavior. This reaction can be scaled-up
to a gram of compound with no significant loss in the reaction
yield.
conjugated aromatic ring must be present for the reaction to
occur.
In the cases of pyridine derivatives, quinoline derivatives, and
pyrazine, the product isolated after the reaction was
iodylbenzene (PhIO2), resulting from hydrolysis of the
trifluoroacetate groups or disproportionation of BTI (Figure
7). Even if it is commonly accepted that the hydrolysis of BTI
Figure 7. Hydrolysis reaction of BTI.
EXPERIMENTAL SECTION
produces PhIO, this hydrolysis is generally carried out under
alkaline conditions.39 Disproportionation or hydrolysis of BTI
leading to PhIO2 was confirmed by high-resolution mass
■
1
General. H NMR and 13C NMR spectra were recorded on a 300
MHz spectrometer using DMSO-d6 as the solvent. Chemical shifts are
reported in ppm using the relative solvent peak as a reference standard.
The mass spectrometric experiments were performed on a large-scale
tandem mass spectrometer having an E1B1E2E3B2E4 geometry,
where E stands for an electrostatic sector and B for a magnetic sector.
Electron ionization mass spectrometry (EI-MS) was performed by
scanning the field of the first magnetic field (B1). The mass-separated
ions were counted using an off-axis photomultiplier located after the
second electrostatic sector. Accurate mass measurements were
recorded using perfluorokerosene (PFK) as the internal calibrant by
scanning the accelerating voltage (voltage scan) and increasing the
resolution of the mass spectrometer to R = 10 000 at 5% of the peak
intensity. The ESI measurements were performed on a QToF2 mass
1
spectrometry, infrared spectroscopy, and H and 13C NMR
data, which are in agreement with the reported chemical
shifts.40 Furthermore, we also verified that this hydrolysis
product was not the oxidative species, confirming therefore that
BTI is the real oxidative species in the BTI-mediated
quinoxaline oxidation.
Thus, comparison of the results obtained with pyrazine and
quinoxaline derivatives indicates that even if two nitrogen
atoms are required for this particular oxidation, only
compounds containing at least one supplementary fused
aromatic ring allow isolation of the expected oxidized products.
Figure 8. Proposed mechanism for the quinoxaline-core-containing compounds using BTI.
C
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spectrometer. The HRMS measurements were performed at 10 000
resolution using m/z 322.7782 ions from a NaI solution (10 mg/mL
isopropanol/water) as the lock mass. Infrared spectra were recorded in
ATR mode on a germanium crystal.
146.6, 145.3, 127.7, 135.6. EI(+)-MS m/z (%): 238 (100) (M+ − CO),
266 (66) (M+), 210 (42) (M+ − 2CO). HRMS (EI, sector
instrument) m/z: [M+] calcd for C12H6N6O2 266.0552, found
266.0553. IR (neat) νmax/cm−1: 1690.6, 1627.4, 1375.8.
General Procedure for the Oxidation Using (Bisacetoxy)-
Iodobenzene or Bis(Trifluoroacetoxy)Iodobenzene. The starting
material (0.5 mmol) was dissolved in 15 mL of an acetonitrile/water
3:1 mixture. The mixture was stirred at room temperature, and
bis(trifluoroacetoxy)iodobenzene (1.1 mmol) or (bisacetoxy)-
iodobenzene (1.1 mmol) was then added. The reaction mixture was
stirred at room temperature for a period of 24 h. The reaction was
monitored using TLC (alumina, CHCl3/acetone 8:2). If needed,
another equivalent of bis(trifluoroacetoxy)iodobenzene was added
during the reaction. After completion, the reaction was concentrated
under vacuum, and the product was collected by filtration and washed
with water, acetonitrile, and diethyl ether. The product was finally
dried in a desiccator overnight at room temperature.
8,9-Dimethoxypyrazino[2,3-f ]quinoxaline-2,3(1H,4H)-dione
(8b). The product was obtained as a white solid with a yield of 83%
(113.7 mg) following the general procedure described for the
oxidation using bis(trifluoroacetoxy)iodobenzene. 1H NMR (300.1
MHz, DMSO-d6): δ 4.02 (s, 3H), 4.20 (s, 3H), 7.31 (d, 1H, J = 9 Hz),
7.48 (d, 1H, J = 9 Hz), 11.15 (bs, 1H), 11.85 (bs, 1H). 13C spectra for
compound 8b could not be obtained because of the extremely low
solubility of this compound in conventional organic solvents. EI(+)-
MS m/z (%): 246 (100) (M+ − CO), 274 (100) (M+). HRMS (EI,
sector instrument) m/z: [M+] calcd for C12H10N4O4 274.0702, found
274.0714. IR (neat) νmax/cm−1: 1720.4, 1677.1, 1352.3.
8-Chloropyrazino[2,3-f ]quinoxaline-2,3(1H,4H)-dione (9b).
The product was obtained as a pale-yellow solid with a yield of 82%
(102.2 mg) following the general procedure described for the
oxidation using bis(trifluoroacetoxy)iodobenzene. 1H NMR (300.1
MHz, DMSO-d6): δ 7.70 (d, 1H, J = 9.0 Hz), 7.77 (d, 1H, J = 9.0 Hz),
8.97 (s, 1H), 12.30 (bs, 2H). 13C NMR (75.5 MHz, DMSO-d6): δ
155.6, 155.1, 145.6, 144.0, 137.7, 129.8, 125.0, 122.1, 121.1, 120.1.
EI(+)-MS m/z (%): 220 (100) (M+ − CO), 248 (62) (M+), 192 (46)
(M+ − 2CO). HRMS (EI, sector instrument) m/z: [M+] calcd for
C10H5N4O2Cl 248.0101, found 248.0093. IR (neat) νmax/cm−1:
1682.6, 1379.3, 1141.5.
Pyrazino[2,3-f ]quinoxaline-2,3(1H,4H)-dione (1b). Product 1b
was obtained from different starting materials. When hydroxy
derivatives 1a and 2a were used, the conversion was achieved using
BTI or DIB as the oxidant. When the unsubstituted derivative 6a was
used, only BTI allowed the oxidation to occur. The product was
obtained as a white solid with yields ranging from 84% to 89%
1
depending on the starting material [1a, 2a, or 6a (89.5−96 mg)]. H
NMR (300.1 MHz, DMSO-d6): δ 7.67 (d, 1H, J = 9.0 Hz), 7.83 (d,
1H, J = 9.0 Hz), 8.93 (dd, 2H, J = 1.8 Hz), 12.05 (bs, 1H), 12.35 (bs,
1H). 13C NMR (75.5 MHz, DMSO-d6): δ 155.7, 155.1, 144.4, 138.7,
131.5, 124.5, 123.3, 119.9, 119.7. EI(+)-MS m/z (%): 186 (100) (M+
− CO), 214 (58) (M+), 158 (58) (M+ − 2CO). HRMS (EI, sector
instrument) m/z: [M+] calcd for C10H6N4O2 214.0491, found
214.0498. IR (neat) νmax/cm−1: 1680.8, 1360.8.
9-Chloropyrazino[2,3-f ]quinoxaline-2,3(1H,4H)-dione (10b).
The product was obtained as a yellow solid with a yield of 68% (84.4
mg) following the general procedure described for the oxidation using
1
bis(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6):
δ 7.67 (d, 1H, J = 9 Hz), 7.86 (d, 1H, J = 9 Hz), 8.94 (s, 1H), 12.07
(bs, 1H), 12.40 (bs, 1H). 13C NMR (75.5 MHz, DMSO-d6): δ 155.9,
155.3, 146.5, 144.1, 137.2, 126.1, 123.4, 120.2, 119.5. EI(+)-MS m/z
(%): 220 (100) (M+ − CO), 248 (58) (M+), 192 (42) (M+ − 2CO).
HRMS (EI, sector instrument) m/z: [M+] calcd for C10H5N4O2Cl
248.0101, found 248.0093. IR (neat) νmax/cm−1: 1730.9, 1369.2,
1128.7.
8-Methoxypyrazino[2,3-f ]quinoxaline-2,3(1H,4H)-dione
(3b). The product was obtained as a white solid with a yield of 69%
(84.6 mg) following the general procedure described for the oxidation
using bis(trifluoroacetoxy)iodobenzene. 1H NMR (300.1 MHz,
DMSO-d6): δ 4.04 (s, 3H), 7.57 (AB syst, 2H, J = 9.0 Hz), 8.60 (s,
1H) 12.07 (bs, 2H). 13C NMR (75.5 MHz, DMSO-d6): δ 155.5, 138.6,
136.2, 122.7, 121.2, 120.7, 119.7, 54.0. EI(+)-MS m/z (%): 216 (100)
(M+ − CO), 244 (86) (M+). HRMS (EI, sector instrument) m/z:
8-Formylpyrazino[2,3-f ]quinoxaline-2,3(1H,4H)-dione (11b).
The product was obtained as a pale-yellow solid with a yield of 92%
(111.1 mg) following the general procedure described for the
oxidation using bis(trifluoroacetoxy)iodobenzene. 1H NMR (300.1
MHz, DMSO-d6): δ 7.80 (d, 1H, J = 9.0 Hz), 8.02 (d, 1H, J = 9.0 Hz),
9.29 (s, 1H), 10.17 (s, 1H), 12.26 (bs, 1H), 12.50 (bs, 1H). 13C NMR
(75.5 MHz, DMSO-d6): δ 192.5, 155.8, 154.9, 145.1, 141.5, 137.5,
132.6, 127.0, 124.4, 121.3, 119.9. EI(+)-MS m/z (%): 214 (100) (M+
− CO), 242 (52) (M+), 158 (48) (M+ − 3CO), 186 (46) (M+ −
2CO). HRMS (EI, sector instrument) m/z: [M+] calcd for
[M+] calcd for C11H8N4O3 244.0596, found 244.0589. IR (neat) νmax
/
cm−1: 1693.4, 1378.6, 1327.5.
9-Methoxypyrazino[2,3-f ]quinoxaline-2,3(1H,4H)-dione
(4b). The product was obtained as a white solid with a yield of 76%
(92.6 mg) following the general procedure described for the oxidation
using bis(trifluoroacetoxy)iodobenzene. 1H NMR (300.1 MHz,
DMSO-d6): δ 4.19 (s, 3H), 7.41 (d, 1H, J = 9.0 Hz), 7.73 (d, 1H, J
= 9.0 Hz), 8.53 (s, 1H), 11.96 (bs, 1H), 12.26 (bs, 1H). 13C spectra for
compound 4b could not be obtained because of the extremely low
solubility of this compound in conventional organic solvents. EI(+)-
MS m/z (%): 216 (100) (M+ − CO), 244 (70) (M+). HRMS (EI,
sector instrument) m/z: [M+] calcd for C11H8N4O3 244.0596, found
244.0589. IR (neat) νmax/cm−1: 1713.1, 1682.17, 1578.0, 1346.8.
Quinoxaline-2,3(1H,4H)-dione (5b). Product 5b was obtained
from different starting materials. When hydroxy derivative 24a was
used, the conversion was achieved using BTI or DIB as the oxidant.
When the unsubstituted derivative 5a was used, only BTI allowed the
oxidation to occur. The product was obtained as a white solid with
yields ranging from 79 to 84% depending on the starting material [5a
C11H6N4O3 242.04399, found 242.0435. IR (neat) νmax/cm−1
:
1694.8, 1590.6, 1383.1, 875.5.
8-(2-Hydroxyethoxy)pyrazino[2,3-f ]quinoxaline-2,3(1H,4H)-
dione (12b). The product was obtained as a white solid with a yield
of 75% (102.6 mg) following the general procedure described for the
oxidation using bis(trifluoroacetoxy)iodobenzene. 1H NMR (300.1
MHz, DMSO-d6): δ 3.80 (m, 2H), 4.72 (m, 2H), 4.88 (t, 1H, J = 5.4
Hz), 7.40 (d, 1H, J = 9.0 Hz), 7.71 (d, 1H, J = 9.0 Hz), 8.51 (s, 1H),
11.95 (bs, 1H), 12.26 (bs, 1H). 13C NMR (75.5 MHz, DMSO-d6): δ
156.9, 155.7, 155.2, 138.2, 135.2, 128.5, 125.2, 122.9, 118.5, 115.3,
68.8, 59.4. HRMS (EI, sector instrument) m/z: [M+] calcd for
C12H10N4O4 274.0702, found 274.0703. IR (neat) νmax/cm−1: 3091.6,
1695.0, 1320.8, 833.4.
1
(64.1 mg) or 24a (68.1 mg)]. H NMR (300.1 MHz, DMSO-d6): δ
7.10 (m, 4H), 11.90 (bs, 2H). 13C NMR (75.5 MHz, DMSO-d6): δ
155.1, 125.6, 123.0, 115.1. EI(+)-MS m/z (%): 162 (100) (M+), 134
(60) (M+ − CO), 106 (56) (M+ − 2CO). HRMS (EI, sector
instrument) m/z: [M+] calcd for C8H6N2O2 162.0429, found
162.0435. IR (neat) νmax/cm−1: 1675.0.
8-Methylpyrazino[2,3-f]quinoxaline-2,3(1H,4H)-dione (13b).
The product was obtained as a white solid with a yield of 73% (83.1
mg) following the general procedure described for the oxidation using
1
bis(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6):
Dipyrazino[2,3-f:2′,3′-h]quinoxaline-2,3(1H,4H)-dione (7b).
The product was obtained as a beige solid with a yield of 91%
(121.2 mg) following the general procedure described for the
oxidation using bis(trifluoroacetoxy)iodobenzene. 1H NMR (300.1
MHz, DMSO-d6): δ 9.16 (d, 2H, J = 1.8 Hz), 9.17 (d, 2H, J = 1.8 Hz),
12.25 (bs, 2H). 13C NMR (75.5 MHz, DMSO-d6): δ 166.8, 1565,
δ 2.71 (s, 3H), 7.61 (d, 1H, J = 9.0 Hz), 7.73 (d, 1H, J = 9.0 Hz), 8.85
(s, 1H), 12.05 (bs, 1H), 12.24 (bs, 1H). 13C NMR (75.5 MHz,
DMSO-d6): δ 155.6, 155.1, 153.2, 145.2, 123.6, 122.5, 119.8, 119.5,
106.8, 21.9. HRMS (EI, sector instrument) m/z: [M+] calcd for
C11H8N4O2 228.0647, found 228.0651. IR (neat) νmax/cm−1: 1675.6,
1387.9, 861.2.
D
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6-Chloroquinoxaline-2,3(1H,4H)-dione (14b). The product was
obtained as a white solid with a yield of 82% (80.7 mg) following the
general procedure described for the oxidation using bis-
(M+ − O2 − NO2). HRMS (EI, sector instrument) m/z: [M+] calcd
for C8H4N3O4I 332.9247, found 332.9233. IR (neat) νmax/cm−1:
1691.9, 1395.1.
1
(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6): δ
6-Nitroquinoxaline-2,3(1H,4H)-dione (22b). Product 22b was
obtained from different starting materials. When hydroxy derivative
25a was used, the conversion was achieved using BTI or DIB as the
oxidant. When the unsubstituted derivative 22a was used, only BTI
allowed the oxidation to occur. The product was obtained as a pale-
yellow solid with yields ranging from 77 to 82% depending on the
7.11 (m, 3H), 11.97 (bs, 2H). 13C NMR (75.5 MHz, DMSO-d6): δ
155.0, 154.8, 126.9, 126.5, 124.8, 122.6, 116.6, 114.4. EI(+)-MS m/z
(%): 196 (100) (M+), 168 (48) (M+ − CO). HRMS (EI, sector
instrument) m/z: [M+] calcd for C8H5N2O2Cl 196.0039, found
196.0032. IR (neat) νmax/cm−1: 1691.4, 1392.4.
1
5-Chloroquinoxaline-2,3(1H,4H)-dione (15b). The product was
obtained as a beige solid with a yield of 88% (85.9 mg) following the
general procedure described for the oxidation using bis-
starting material [22a (80.6 mg) or 25a (85.1 mg)]. H NMR (300.1
MHz, DMSO-d6): δ 7.26 (d, 1H, J = 8.7 Hz), 7.97 (m, 2H), 12.26 (bs,
2H). 13C NMR (75.5 MHz, DMSO-d6): δ 155.1, 154.7, 142.1, 131.7,
126.1, 118.6, 115.5, 110.3. EI(+)-MS m/z (%): 207 (100) (M+), 179
(16) (M+ − CO). HRMS (EI, sector instrument) m/z: [M+] calcd for
C8H5N3O4 207.0280, found 207.0270. IR (neat) νmax/cm−1: 1693.3,
1337.7.
5-Chloro-6-nitroquinoxaline-2,3(1H,4H)-dione (23b). The
product was obtained as a pale-yellow solid with a yield of 85%
(101.9 mg) following the general procedure described for the
oxidation using bis(trifluoroacetoxy)iodobenzene. 1H NMR (300.1
MHz, DMSO-d6): δ 7.19 (d, 1H, J = 9.0 Hz), 7.82 (d, 1H, J = 9.0 Hz),
11.70 (bs, 1H), 12.39 (bs, 1H). 13C NMR (75.5 MHz, DMSO-d6): δ
155.2, 154.5, 142.3, 130.6, 124.6, 120.1, 113.7, 112.0. HRMS (EI,
sector instrument) m/z: [M+] calcd for C8H4N3O4Cl 240.9890, found
240.9891. IR (neat) νmax/cm−1: 1720.6, 1535.6, 1396.6.
1
(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6): δ
7.07 (m, 2H), 7.17 (m, 1H), 11.35 (bs, 1H), 12.06 (bs, 1H). 13C NMR
(75.5 MHz, DMSO-d6): δ 155.4, 154.8, 127.1, 123.7, 123.4, 122.9,
118.6, 114.2. HRMS (EI, sector instrument) m/z: [M+] calcd for
C8H5N2O2Cl 196.0039, found 196.0031. IR (neat) νmax/cm−1: 1674.2,
1394.9.
6,7-Dichloroquinoxaline-2,3(1H,4H)-dione (16b). The product
was obtained as a white solid with a yield of 82% (94.4 mg) following
the general procedure described for the oxidation using bis-
1
(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6): δ
7.25 (s, 2H), 12.01 (bs, 2H). 13C NMR (75.5 MHz, DMSO-d6): δ
154.7, 126.1, 124.3, 116.0. HRMS (EI, sector instrument) m/z: [M+]
calcd for C8H4N2O2Cl2 229.9650, found 229.9652. IR (neat) νmax
/
cm−1: 1686.9, 1396.9, 873.1.
6-Methoxy-7-nitroquinoxaline-2,3(1H,4H)-dione (26b). The
product was obtained as a yellow solid with a yield of 89% (105.1 mg)
following the general procedure described for the oxidation using
6-Bromoquinoxaline-2,3(1H,4H)-dione (17b). The product was
obtained as a white solid with a yield of 79% (95.0 mg) following the
general procedure described for the oxidation using bis-
1
bis(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6):
1
(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6): δ
δ 6.91 (s, 1H), 7.72 (s, 1H), 12.04 (bs, 2H). 13C NMR (75.5 MHz,
DMSO-d6): δ 155.3, 154.2, 149.6, 132.8, 131.8, 118.9, 112.5, 99.9,
56.7. EI(+)-MS m/z (%): 237 (20) (M+). HRMS (EI, sector
instrument) m/z: [M+] calcd for C9H7N3O5 237.0386, found
237.0391. IR (neat) νmax/cm−1: 1709.3, 1311.0.
7.05 (m, 1H), 7.25 (m, 2H), 11.97 (bs, 2H). 13C NMR (75.5 MHz,
DMSO-d6): δ 155.0, 154.8, 127.2, 125.4, 125.2, 117.2, 116.9, 114.2.
EI(+)-MS m/z (%): 240 (100) (M+), 212 (34) (M+ − CO). HRMS
(EI, sector instrument) m/z: [M+] calcd for C8H5N2O2Br 239.9534,
found 239.9539. IR (neat) νmax/cm−1: 1693.7, 1389.2.
5-Methoxy-6-nitroquinoxaline-2,3(1H,4H)-dione (27b). The
product was obtained as a white solid with a yield of 85% (101.2 mg)
following the general procedure described for the oxidation using
6-Iodoquinoxaline-2,3(1H,4H)-dione (18b). The product was
obtained as a white solid with a yield of 86% (123.5 mg) following the
general procedure described for the oxidation using bis-
1
1
bis(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6):
(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6): δ
δ 6.99 (d, 1H, J = 9.0 Hz), 7.76 (d, 1H, J = 9.0 Hz), 11.87 (bs, 1H),
12.28 (bs, 1H). 13C NMR (75.5 MHz, DMSO-d6): δ 155.0, 154.9,
141.4, 137.2, 131.4, 121.0, 119.9, 110.4, 62.8. HRMS (EI, sector
instrument) m/z: [M+] calcd for C9H7N3O5 237.0386, found
237.0394. IR (neat) νmax/cm−1: 1726.6, 1538.8, 1387.8.
6.91 (d, 1H, J = 8.1 Hz), 7.40 (m, 2H), 11.90 (bs, 1H), 11.95 (bs, 1H).
13C NMR (75.5 MHz, DMSO-d6): δ 154.9, 131.2, 127.3, 125.5, 122.9,
117.1, 85.8. EI(+)-MS m/z (%): 288 (100) (M+), 260 (22) (M+ −
CO). HRMS (EI, sector instrument) m/z: [M+] calcd for C8H5N2O2I
287.9396, found 287.9401. IR (neat) νmax/cm−1: 1693.9, 1383.2.
6-Chloro-7-nitroquinoxaline-2,3(1H,4H)-dione (19b). The
product was obtained as a white solid with a yield of 86% (103.5
mg) following the general procedure described for the oxidation using
5-Methylquinoxaline-2,3(1H,4H)-dione (28b). The product
was obtained as a white solid with a yield of 90% (79.4 mg) following
the general procedure described for the oxidation using bis-
1
1
(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6): δ
bis(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6):
δ 7.26 (s, 1H), 7.82 (s, 1H), 12.24 (bs, 2H). 13C NMR (75.5 MHz,
DMSO-d6): δ 155.0, 154.5, 130.9, 125.3, 119.8, 116.7, 112.9. EI(+)-
MS m/z (%): 241 (100) (M+). HRMS (EI, sector instrument) m/z:
[M+] calcd for C8H4N3O4Cl 240.9890, found 240.9882. IR (neat)
νmax/cm−1: 1695.4, 1397.7, 881.5.
2.34 (s, 3H), 6.93 (m, 1H), 6.99 (m, 2H), 11.22 (bs, 1H), 11.90 (bs,
1H). 13C NMR (75.5 MHz, DMSO-d6): δ 155.7, 154.8, 125.5, 124.7,
124.0, 123.9, 122.8, 113.2, 17.2. HRMS (EI, sector instrument) m/z:
[M+] calcd for C9H8N2O2 176.0586, found 176.0592. IR (neat) νmax
/
cm−1: 1679.8, 1396.9.
6-Bromo-7-nitroquinoxaline-2,3(1H,4H)-dione (20b). The
product was obtained as a white solid with a yield of 87% (124.2
mg) following the general procedure described for the oxidation using
ASSOCIATED CONTENT
■
1
bis(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6):
S
* Supporting Information
δ 7.43 (s, 1H), 7.79 (s, 1H), 12.22 (bs, 2H). 13C NMR (75.5 MHz,
DMSO-d6): δ 155.0, 154.6, 142.6, 130.9, 125.7, 119.8, 112.8, 106.9.
EI(+)-MS m/z (%): 285 (20) (M+), 253 (100) (M+ − CO), 207 (42)
(M+ − CO − NO2). HRMS (EI, sector instrument) m/z: [M+] calcd
for C8H4N3O4Br 284.9385, found 284.9376. IR (neat) νmax/cm−1:
1694.6, 1396.9, 881.3.
General information about spectroscopic apparatus and copies
of 1H, 13C, IR, MS, and HRMS spectra for the different
compounds when available. This material is available free of
charge via the Internet at http://pubs.acs.org.
6-Iodo-7-nitroquinoxaline-2,3(1H,4H)-dione (21b). The prod-
uct was obtained as a pale-yellow solid with a yield of 93% (154.5 mg)
following the general procedure described for the oxidation using
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cmouche@ulb.ac.be.
1
bis(trifluoroacetoxy)iodobenzene. H NMR (300.1 MHz, DMSO-d6):
δ 7.68 (s, 1H), 7.75 (s, 1H), 12.17 (bs, 2H). 13C NMR (75.5 MHz,
DMSO-d6): δ 155.0, 154.6, 146.0, 130.9, 126.4, 126.1, 112.3, 80.2.
EI(+)-MS m/z (%): 333 (10) (M+), 301 (100) (M+ − O2), 255 (36)
Notes
The authors declare no competing financial interest.
E
dx.doi.org/10.1021/jo401872e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(37) Tohma, H.; Morioka, H.; Harayama, Y.; Hashizume, M.; Kita, Y.
Tetrahedron Lett. 2001, 42, 6899.
(38) Keinan, S.; Paquette, W. D.; Skoko, J. J.; Beratan, D. N.; Yang,
W.; Shinde, S.; Johnston, P. A.; Lazo, J. S.; Wipf, P. Org. Biomol. Chem.
2008, 6, 3256.
(39) Saltzman, H.; Sharefkin, J. G. Org. Synth. 1963, 43, 658.
(40) Yusubov, M. S.; Chi, C.-W.; Park, J. Y.; Karimov, R.; Zhdankin,
V. V. Tetrahedron Lett. 2006, 47, 6305.
ACKNOWLEDGMENTS
■
The authors thank the Fonds National de la Recherche
Scientifique (FRS-FNRS) for financial support. L.T.-G. thanks
the Fonds pour la Recherche dans l’Industrie et l’Agriculture
(F.R.I.A.) for a Ph.D. fellowship. P.G. (senior research
associate) and J.D.W. are grateful to the FRS-FNRS for
financial support for the acquisition of the Waters Autospec 6F
and for continuing support.
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dx.doi.org/10.1021/jo401872e | J. Org. Chem. XXXX, XXX, XXX−XXX