Palladium-catalyzed cross-coupling of 2-chloroquinoxaline N-Oxides with arylboronic acids

Article abstract of DOI:10.1002/ejoc.201300707

A selection of 2-chloro-substituted O-alkylquinoxaline N-oxides, easily accessible by the one-step annulation reaction of 4-fluoroaniline with 1,1,2-trichloro-2-nitroethylene and subsequent O-alkylation, was arylated at the chloronitrone unit in yields up to 96 %. This first efficient Pd-catalyzed Suzuki-Miyaura reaction of chloroquinoxaline N-oxides with arylboronic acids led to new 2-arylquinoxaline N-oxides. The scope and limitations of this arylation reaction were investigated, and the role of some sterically demanding boronic acids in the cross-coupling reaction was evaluated by means of DFT calculations. Additionally, the Pd-catalyzed C-arylation of the amide unit of selected quinoxalinone derivatives was accomplished. For the first time the chloronitrone unit of 2-chloroquinoxaline N-oxides was arylated with arylboronic acids under Suzuki-Miyaura cross-coupling conditions in good to very good yields. The scope and limitations of the applied protocols were investigated as well as the dependency of the yield of the reaction on the steric bulk of the arylboronic acid by means of DFT calculations. Copyright

Full text of DOI:10.1002/ejoc.201300707

FULL PAPER
DOI: 10.1002/ejoc.201300707
Palladium-Catalyzed Cross-Coupling of 2-Chloroquinoxaline N-Oxides with
Arylboronic Acids[‡]
Jan Maichrowski,[a] Eike G. Hübner,[a] and Dieter E. Kaufmann*[a]
Keywords: Nitrogen heterocycles / N-oxides / Cross-coupling / Phosphane ligands / Density functional calculations
A selection of 2-chloro-substituted O-alkylquinoxaline N-ox-
ides, easily accessible by the one-step annulation reaction of
4-fluoroaniline with 1,1,2-trichloro-2-nitroethylene and sub-
sequent O-alkylation, was arylated at the chloronitrone unit
in yields up to 96%. This first efficient Pd-catalyzed Suzuki–
scope and limitations of this arylation reaction were investi-
gated, and the role of some sterically demanding boronic ac-
ids in the cross-coupling reaction was evaluated by means of
DFT calculations. Additionally, the Pd-catalyzed C-arylation
of the amide unit of selected quinoxalinone derivatives was
Miyaura reaction of chloroquinoxaline N-oxides with aryl- accomplished.
boronic acids led to new 2-arylquinoxaline N-oxides. The
aryl-substituted N,NЈ-oxidized quinoxalines has especially
promising biological properties. Among them, fluo-
Introduction
Since the first reported synthesis of quinoxaline in 1884 rophenyl-substituted N,NЈ-dioxide 1 shows selective antitu-
by O. Hinsberg[1] starting from o-phenylenediamine and berculotic activity against M. tuberculosis (Figure 1).[3]
glyoxal, numerous substituted members of this class of N-
Likewise, the phenylated ester derivative 2 inhibits the
heterobicycles have been prepared in various ways.[2] Due growth of certain strains of the malaria pathogen P. falcipa-
to the broad spectrum of bioactivities, the quinoxaline N- rum in micromolar concentrations,[4] whereas the thienyl-
oxides and N,NЈ-dioxides in particular became the focus of bearing N,NЈ-dioxide 3 shows good antitrypanosomal
attention of many scientific groups. A subset of (hetero)- properties against the flagellate protozoan T. cruzi, which
Figure 1. Bioactive aryl-substituted quinoxaline N,NЈ-dioxides.
causes the Chagas disease.[5] In addition to their antimicro-
[‡] Chemistry of Functionalized Quinoxaline N-Oxides, II. Part I:
bial properties, some arylated quinoxaline N,NЈ-dioxides
even possess antitumor or cancerostatic properties, such as
sulfone Q39 (4), which is known to inhibit cell proliferation
of certain human cancer cell lines at remarkably low con-
centrations.[6] The 6-chloro-2-(4-chlorophenyl)quinoxaline
N,NЈ-dioxide (5) has been discussed as a hypoxia-selective
antitumor agent.[7]
J. Maichrowski, M. Gjikaj, E. G. Hübner, B. Bergmann, I. B.
Müller, D. E. Kaufmann, Eur. J. Org. Chem. 2013, 2091–2105.
[a] Institute of Organic Chemistry, Clausthal University of
Technology,
Leibnizstr. 6, 38678 Clausthal-Zellerfeld, Germany
E-mail: dieter.kaufmann@tu-clausthal.de
www.ioc.tu-clausthal.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300707.
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J. Maichrowski, E. G. Hübner, D. E. Kaufmann
FULL PAPER
A general and versatile approach for the direct synthesis
of aryl- and heteroaryl-substituted N,NЈ-dioxidized quinox-
alines is the Beirut reaction of benzofurazan N-oxides
(BFOs) 6 with appropriate nucleophiles, such as CH-acidic
carbonyl compounds
7 in the presence of a base
(Scheme 1).[8] The BFO derivatives for this reaction can be
accessed by oxidation of the corresponding o-nitroanilines
with sodium hypochlorite,[9] whereas most of the commonly
used nucleophiles such as acetophenone (7; R3 = H, Ar =
Ph) are commercially available.
Scheme 3. Palladium-catalyzed cross-coupling of 11 with aryl-
boronic acids.[15]
Despite their good results with the cross-coupling of the
sulfanyl-substituted derivative 11, C–C coupling of the
analogous 2-chloro-substituted 3-methylquinoxaline-N,NЈ-
dioxide with tolylboronic acid applying Suzuki–Miyaura
conditions was not successful. To the best of our knowl-
edge, the cross-coupling of a chloronitrone unit of quinoxal-
ine N-oxides with boronic acids has not been accomplished
to date. Therefore, due to our interest in fluorinated bioac-
tive quinoxalines, as described previously, we planned to
synthesize 2-chloro-substituted O-alkylquinoxaline N-ox-
Scheme 1. Beirut reaction for the synthesis of aryl-substituted quin-
oxaline N,NЈ-dioxides.
Among others, mono-N-oxidized arylquinoxalines can ides such as 15a–c (Scheme 4). We started with the one-step
be accessed through the introduction of an aryl substituent annulation reaction of 4-fluoroaniline with 1,1,2-trichloro-
by means of metal-catalyzed C–C coupling reactions. The 2-nitroethylene (TCNiE, 13)[16] and subsequent O-alkyl-
synthetically most useful arylation reactions have been re- ation of the obtained quinoxalinone N-oxide 14 with dif-
ported for the unsubstituted quinoxaline N-oxide (9), which ferent alcohols under adapted Mitsunobu conditions.[17]
was coupled with aryl chlorides,[10] arylsulfonylhydraz-
Because of the easy and reliable synthetic access to the
ides,[11] sodium sulfinates,[12] aryl tosylates[13] and even non- O-alkylated quinoxaline N-oxides 15a–c and the previously
activated arenes such as benzene[14] through palladium ca- described biological properties of several aryl-substituted
talysis (Scheme 2).
N-oxides, we investigated the Suzuki–Miyaura reaction of
Recently, Dahbi and Bisseret published a mild method the chloronitrone unit of our 2-chloroquinoxaline N-oxides
for the palladium-catalyzed cross-coupling of a benzyl- with various arylboronic acids. The combination of this
sulfanyl-substituted quinoxaline N,NЈ-dioxide 11 with a powerful type of cross-coupling reaction together with spe-
broad range of arylboronic acids in the presence of an ex- cially designed phosphine ligands is known to tolerate a
cess of copper(I) thiophene-2-carboxylate (CuTC) broad variety of heterocycles and, additionally, to show
(Scheme 3).[15]
wide functional group tolerance.
Scheme 2. C–C coupling reactions of unsubstituted quinoxaline N-oxide (9) with substrates 10a–c.[10–14]
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Arylation of 2-Chloroquinoxaline N-Oxides
Scheme 4. Synthesis of fluorinated 2-chloro-substituted O-alkylquinoxaline N-oxides 15a–c starting from TCNiE (13) and 4-fluoro-
aniline.[17]
Through the use of this system in a slightly modified pro-
cedure [Pd(OAc)2, XPhos, K3PO4, 1,4-dioxane and water]
Results and Discussion
To establish reaction conditions for this C–C coupling
at 100 °C, we were able to increase the yield of 16a to 88%
we used 2-chloro-3-(cyclopentyloxy)-7-fluoroquinoxaline
within a considerably shorter reaction time of 4 h.
N-oxide (15a) as starting material, because it has good solu-
bility and is easily accessible on a multigram scale with high
Additionally, we could successfully apply the optimized
conditions for the cross-coupling of 15a with phenylboronic
yields. The first test reaction with phenylboronic acid under
acid to a number of substituted boronic acids and to two
Suzuki–Miyaura cross-coupling conditions similar to a
other O-alkylated quinoxaline N-oxides 15b and 15c, lead-
procedure developed by Fitzgerald, Liu and Mani[18]
ing to 14 new arylated N-oxides (Table 1).
[Pd(OAc)2, PPh3, K3PO4, MeCN] allowed the correspond-
In general, the unsubstituted phenylboronic acid as well
ing phenylated N-oxide 16a to be isolated in a promising
as electron-rich substrates such as 4-tolylboronic acid and
yield (Scheme 5).
bicyclic 1-naphthylboronic acid gave the best results for the
three selected chloroquinoxaline N-oxides 15a–c under the
standard coupling conditions with very good yields up to
96%.
In contrast, arylboronic acids with electron-withdrawing
substituents such as halogens, especially the (2,4-di-
fluorophenyl)boronic acid, gave the corresponding coupled
product 16i in only poor yield. These arylboronic acids are
known to undergo a competitive protodeboronation reac-
Scheme 5. Palladium-catalyzed cross-coupling of 15a with phen-
tion. In the case of the 3-chlorophenylboronic acid, a con-
secutive reaction of the resulting product 16h could be ob-
served when 2.0 equiv. boronic acid was used. This problem
was avoided by reducing the amount of the coupling sub-
strate to 1.1 equiv., which led to the formation of the de-
sired product in 60% yield.
ylboronic acid under Suzuki–Miyaura conditions.
Our initial attempts to optimize the reaction either by
increasing the temperature or the amount of base did not
prove successful. We then applied a highly active catalyst
system developed by Buchwald and Billingsley for the
Suzuki–Miyaura cross-coupling of heteroaryl halides with
heteroarylboronic acids [Pd2(dba)3 or Pd(OAc)2, and the bi-
phenyl-based monophosphine ligands SPhos (17), XPhos
(18) or BrettPhos (19); Figure 2].[19]
Fortunately, the reaction conditions reported here even
allowed the twofold cross-coupling of 1,4-phenylene-di-
boronic acid to give the 1,4-phenylene-bis(quinoxaline N-
oxide) 16l. The heterocyclic thienyl-2-boronic acid could
also be converted into the corresponding thienyl-substituted
N-oxide 16k, but only in moderate yield (34%; a large
amount of starting material was reisolated). The yield could
be increased to 61% by extending the reaction time (8 h).
To further improve the introduction of a thienyl-substituent
into the quinoxaline N-oxide scaffold we investigated the
reaction conditions of the interesting C–C coupling method
developed by Burke, Knapp and Gillis, who used stable N-
methyliminodiacetic acid (MIDA) boronates for the slow
release of rather unstable boronic acids such as (2-thienyl)-
boronic acid in situ.[20] By applying this procedure, we were
able to isolate the thienyl-bearing N-oxide 16k out of the
reaction with the MIDA-protected boronate 20, albeit in
Figure 2. Structures of the biphenyl-based monophosphine ligands
SPhos (17), XPhos (18), and BrettPhos (19).
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J. Maichrowski, E. G. Hübner, D. E. Kaufmann
FULL PAPER
Table 1. Cross-coupling of O-alkylated quinoxaline N-oxides under
Suzuki–Miyaura conditions.[a]
Scheme 6. Cross-coupling of 2-chloro-3-(cyclopentyloxy)-7-fluoro-
quinoxaline 1-oxide (15a) with the MIDA-boronate of thienyl-2-
boronic acid 20.
able as substrates under the chosen reaction conditions,
such as (5-chloropyridin-2-yl)boronic acid or (2,6-dimeth-
ylphenyl)boronic acid (Figure 3).
Figure 3. Unsuitable boronic acids for the examined Suzuki–
Miyaura coupling reaction of chloroquinoxaline N-oxides.
Pyridinylboronic acids are also known to undergo fast
competitive protodeboronation. In the case of the dimeth-
ylated substrate, the second methyl group in this electron-
rich derivative, in comparison to the (2-tolyl)boronic acid
used for the synthesis of 16d, clearly prohibits the cross-
coupling (69 vs. 0% yield). In general, Suzuki–Miyaura
coupling reactions are known for their efficient formation
of bis-ortho-substituted biaryls even under standard condi-
tions. Under the applied reaction conditions of this paper,
however, cross-coupling of a twofold ortho-substituted
phenylboronic acid with 15a did not succeed, although
Buchwald et al. had reported the preparation of even tet-
rakis-ortho-substituted biaryls under similar conditions in
good yields.[21] It remains unclear which step of the catalytic
cycle is responsible for this lack of reaction. Therefore, we
decided to study the steric influence of the tolylboronic ac-
ids by means of density functional theory (DFT) calcula-
tions. Rotational barriers of ortho-heteroatom-substituted
biphenyls have been calculated this way to determine steric
effects.[22] As an indicator of the steric hindrance of the in-
troduced aryl moieties the rotational barriers of these aryl
groups around the newly formed C–C bond were calculated
(Figure 4).
Whereas the calculated rotational barriers for the 3- and
4-methylphenyl-substituted derivatives 16b and 16c are
rather low (approximately 20 kJ/mol), the 2-tolyl-bearing
N-oxide exhibits a considerably higher energy barrier
(97 kJ/mol), indicating a certain steric hindrance of this aryl
group, thus resulting in a decreased yield of compound 16d
(69%). Moreover, the inaccessible 2,6-dimethylphenyl-sub-
[a] Reaction conditions: ArB(OH)2 (2.0 equiv.), Pd(OAc)2 (5 mol-
%), XPhos (10 mol-%), K3PO4 (3.0 equiv.). [b] Isolated yield after
column chromatography. [c] ArB(OH)2 (1.1 equiv.) was used.
[d] Prolonged reaction time of 8 h. [e] Twofold cross-coupling prod-
uct.
lower yield (27%) than in the reaction with unprotected stituted N-oxide shows the highest rotational barrier
boronic acid (Scheme 6). (around 160 kJ/mol), which demonstrates the steric demand
In addition to the successfully used substrates for the of this aryl substituent and gives a possible explanation for
cross-coupling reaction of the chloroquinoxaline N-oxides why the introduction of this group did not succeed. In ad-
15a–c, some (hetero)arylboronic acids proved to be unsuit- dition, the calculated structure of this N-oxide clearly shows
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Arylation of 2-Chloroquinoxaline N-Oxides
Figure 4. Calculated rotational barriers around the newly formed C–C bond for methylphenyl-substituted O-alkylquinoxaline N-oxides
16b–d in comparison to the isolated yields (DFT functional: B3LYP, basis set: LACVP*).
the steric hindrance of the two methyl groups in the proxim- chlorinated analogue 14 with ethyl mercaptan,[17] was cho-
ity of both the N-oxide moiety and the O-alkyl substituent sen as substrate.
(Figure 5).
By deprotonation in the presence of sodium hydride and
subsequent reaction with p-tosyl chloride, the amide could
be converted into the corresponding tosylate 22 (Scheme 7).
Figure 5. Calculated structure of the inaccessible 2,6-dimeth-
ylphenyl-substituted quinoxaline N-oxide.
Scheme 7. Synthesis of the 3-(tosyloxy)quinoxaline N-oxide 22.
Unfortunately, tosylate 22 did not react with the selected
According to a known procedure developed by Buch-
wald, Bhayana and Fors for the Suzuki–Miyaura coupling 4-tolylboronic acid under the conditions described in litera-
of C(sp2)-tosylates such as 2-(tosyloxy)quinoxaline with ture [2.0 equiv. ArB(OH)2, 2 mol-% Pd(OAc)2, 4 mol-%
hetero(aryl) boronic acids[23] in the presence of a highly ef- BrettPhos, 3.0 equiv. K3PO4, t-amyl alcohol or toluene as
ficient catalyst system with BrettPhos (19) as ligand, we de- solvent, 110 °C]. Changing the reaction conditions did not
cided to also investigate the arylation of the amide unit of lead to the desired arylated compound, which may be ex-
our compounds after conversion into a tosylate. To avoid plained by a strong complexation of the palladium catalyst
the favored cross-coupling reaction at the chloronitrone by substrate 22, which may act as a bidentate ligand (N-
moiety, the ethylsulfanyl-substituted quinoxalinone N-oxide oxide moiety, ethylsulfanyl substituent) towards the palla-
21, derived from the previously described reaction of the dium center. Therefore, we decided to validate the reaction
Eur. J. Org. Chem. 2013, 8185–8196
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J. Maichrowski, E. G. Hübner, D. E. Kaufmann
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Scheme 8. Cross-coupling reaction of 2-tosyloxyquinoxaline (24) with (4-tolyl)boronic acid.
Scheme 9. Cross-coupling reaction of 2-(tosyloxy)quinoxaline 27 with (4-tolyl)boronic acid.
conditions for the cross-coupling reaction of 4-tolylboronic anyl-substituted quinoxalinone N-oxide 21 but, again, the
acid with the unsubstituted 2-(p-tosyloxy)quinoxaline (24), desired arylated product could neither be detected nor iso-
which could be synthesized from 2-quinoxalinone (23) in lated, presumably again due to complexation of the palla-
77% yield (Scheme 8). Under slightly modified conditions dium catalyst.
with XPhos as the ligand but similar to the procedure devel-
Therefore, the reduced fluoroquinoxalinone 26 was used
oped by Buchwald et al.,[23] we were able to obtain arylated as substrate and, in this case, the tolylated fluoroquinox-
quinoxaline 25 within a short reaction time (4 h) in excel- aline 28 could be isolated directly in 57% yield (Scheme 9).
lent yield.
This experimental result supports the assumed complex-
As a next step, the unoxidized derivative of tosylate 22 ation of the palladium catalyst by the quinoxaline N-oxides
was chosen as a subject. Reduction of 21 was selectively 21 and 22 via the N-oxide moiety and the sulfanyl group,
accomplished by the use of Lawesson’s reagent in 86% which, as a consequence, is responsible for the infeasibility
yield. The reduced species 26 was subsequently converted of the cross-coupling reaction of these derivatives under the
into tosylate 27 in almost quantitative yield (Scheme 9). The chosen conditions.
reduced tosylate 27 could be efficiently converted into the
corresponding arylated fluoroquinoxaline 28 in 79% yield
under the same conditions used for the synthesis of 2-(p-
tolyl)quinoxaline (25) but with a prolonged reaction time
Conclusions
(14 h). An interesting method for the direct C–C arylation
A number of new 2-arylated O-alkylquinoxaline N-ox-
of tautomerizable heterocycles such as 2-quinoxalinone (23) ides 16a–n were synthesized in yields up to 96% through
was reported by Kang and co-workers.[24] By tautomerizing cross-coupling of the chloronitrone unit of easily accessible
the C=O bond of the amide unit in the presence of NEt3 quinoxaline N-oxides 15a–c with arylboronic acids by em-
and subsequent reaction with bromo-tris-pyrrolidino phos- ploying a modified method of Buchwald et al. with XPhos
phoniumhexafluorophosphate (PyBroP, 29) a heterocyclic as the ligand. To the best of our knowledge, this is the first
phosphonium salt was formed in situ, which was sub- successful Pd-catalyzed cross-coupling reaction of a chloro-
sequently subjected to Suzuki–Miyaura coupling conditions nitrone unit of quinoxaline N-oxides with arylboronic acids.
yielding the unsubstituted tolylquinoxaline 25 in 94% Furthermore, the steric influence of some boronic acids was
yield.[24] Because of these promising results by Kang et al., evaluated by means of DFT calculations and compared to
we tried to apply the reported conditions to the ethylsulf- the yield of the reaction, giving a possible explanation for
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Arylation of 2-Chloroquinoxaline N-Oxides
tilled water (0.1 mL) were added and the mixture was stirred for
4 h at 100 °C. Upon completion of the reaction, the cooled suspen-
sion was diluted with ethyl acetate (10–15 mL) and washed with
saturated NaCl solution (5 mL) and water (5 mL). The organic
phase was dried with Na2SO4 and the solvent was removed with a
rotary evaporator. Finally, the obtained residue was purified by col-
umn chromatography and dried in vacuo.
the absence of the coupling reaction in the case of sterically
demanding substrates. Additionally, arylation of the amide
moiety of the sulfanyl-substituted quinoxalinone N-oxide
21 has been investigated. Possibly due to complexation of
the palladium catalyst in the presence of both the sulfanyl
group and the N-oxide moiety, the arylation of the amide
function only proceeds when the corresponding reduced
species are chosen as substrates.
3-(Cyclopentyloxy)-7-fluoro-2-phenylquinoxaline N-Oxide (16a):
Following general procedure I: 2-chloro-3-(cyclopentyloxy)-7-
fluoroquinoxaline N-oxide (15a; 150 mg, 0.531 mmol), phenyl-
boronic acid (129 mg, 1.061 mmol), XPhos (25.0 mg, 0.053 mmol),
Pd(OAc)2 (6.0 mg, 0.027 mmol) and K3PO4 (338 mg, 1.592 mmol);
column chromatography (PE/EtOAc, 20:1; 35 g silica gel) gave 16a
(151 mg, 0.466 mmol, 88%) as a pale-yellow solid; m.p. 76 °C,
Experimental Section
General: All chemicals and anhydrous DMF were obtained from
commercial suppliers and used without further purification; anhy-
drous dioxane and toluene were distilled from sodium. TLC was
performed on Merck aluminium-backed TLC plates (with silica gel
60 F254) and flash chromatography was carried out on Macherey–
299 °C (dec.). IR (KBr): ν = 3064, 2959, 2872, 1621, 1586, 1552,
˜
1505, 1450, 1427, 1413, 1374, 1341, 1314, 1290, 1278, 1235, 1188,
1158, 1121, 1101, 1074, 1051, 1025, 1001, 988, 972, 958, 951, 905,
Nagel silica gel 60 m (0.040–0.063 mm) with mixtures of petroleum 890, 852, 825, 789, 770, 744, 722, 713, 691, 666, 637, 617, 583, 554,
1
ether (PE) and ethyl acetate (EtOAc) as eluents. The melting points
were determined with a differential scanning calorimeter “DSC 6”
by Perkin–Elmer. FTIR spectra were taken with a Bruker “Alpha-
T” spectrometer (KBr pellets). ATR-IR spectra were measured on
the same instrument with a Bruker “Alpha Platinum ATR” single
reflection diamond ATR module. All NMR spectra were recorded
with a Bruker NMR spectrometer “Avance III 600 MHz” at 25 °C.
If not otherwise stated 1H NMR spectra were measured at
508, 417 cm–1. H NMR (600 MHz, CDCl3): δ = 8.20 (dd, JH,F
=
9.0, JH,H = 3.0 Hz, 1 H, 8-H), 7.84 (dd, JH,H = 9.2, JH,F = 5.1 Hz,
1 H, 5-H), 7.68–7.66 (m, 2 H, 10-H, 10Ј-H), 7.52–7.45 (m, 4 H, 6-
H, 11-H, 11Ј-H, 12-H), 5.64–5.61 (m, 1 H, 13-H), 2.00–1.94 (m,
2 H, 14-H, 14Ј-H), 1.81–1.77 (m, 2 H, 14-H, 14Ј-H), 1.70–1.58 (m,
4 H, 15-H2, 15Ј-H2) ppm. 13C NMR (150 MHz, CDCl3): δ = 160.9
(o, d, JC,F = 248.7 Hz, C7), 157.2 (o, C3), 137.8 (o, C4a), 134.7
(o, d, JC,F = 11.0 Hz, C8a), 133.7 (o, C2), 130.3 (+, 2 C, C10,
C10Ј), 129.7 (+, C12), 129.6 (+, d, JC,F = 8.8 Hz, C5), 127.9 (+,
2 C, C11, C11Ј), 127.7 (o, C9), 120.7 (+, d, JC,F = 25.3 Hz, C6),
1
3
1
3
600 MHz, and H broadband-decoupled 13C NMR and 13C NMR
2
DEPT-135 spectra at 150 MHz using CDCl3 or [D6]DMSO as sol-
vent. The 15N NMR spectra were measured at 61 MHz with nitro-
methane as internal standard (δ = 0.0 ppm). Chemical shifts δ are
reported in ppm with the solvent residual peak used as the internal
reference [CDCl3: 7.26 ppm (1H), 77.0 ppm (13C); [D6]DMSO:
2.49 ppm (1H), 39.7 ppm (13C)]. Mass spectra were measured with
a Varian triple quadrupole mass spectrometer “320 MS” connected
to a Varian gas chromatograph “450-GC” through direct exposure
probe (DEP) using electronic ionization (EI at 20 or 70 eV). High-
resolution mass spectra were recorded with a Waters mass spec-
trometer “VG Autospec” (EI), with a Waters mass spectrometer
“Q-Tof Premier” coupled with a Waters “Acquity UPLC” (ESI) or
with a Micromass mass spectrometer “LCT” coupled with a Waters
“Alliance 2965 HPLC” (ESI) at the university of Hannover.
2
104.9 (+, d, JC,F = 27.5 Hz, C8), 80.0 (+, C13), 32.6 (–, 2 C, C14,
C14Ј), 23.7 (–, 2 C, C15, C15Ј) ppm. MS (EI, 70 eV): m/z (%) =
324 (65) [M]+, 308 (4) [M – O]+, 255 (67), 239 (33), 228 (100), 212
(34), 200 (60), 187 (9), 174 (7), 147 (5), 108 (46). HRMS (EI): m/z
calcd. for C19H17FN2O2 [M]+ 324.1274; found 324.1272.
3-(Cyclopentyloxy)-7-fluoro-2-(p-tolyl)quinoxaline N-Oxide (16b):
Following general procedure I: 2-chloro-3-(cyclopentyloxy)-7-
fluoroquinoxaline N-oxide (15a; 150 mg, 0.531 mmol), (4-tolyl)-
boronic acid (144 mg, 1.061 mmol), XPhos (25.0 mg, 0.053 mmol),
Pd(OAc)2 (6.0 mg, 0.027 mmol) and K3PO4 (338 mg, 1.592 mmol);
column chromatography (PE/EtOAc, 30:1; 35 g silica gel) gave 16b
(173 mg, 0.511 mmol, 96%) as a pale-yellow solid; m.p. 106 °C,
298 °C (dec.). IR (KBr): ν = 3088, 3035, 2966, 2942, 2923, 2869,
˜
All density-functional theory (DFT) calculations were carried out
by using the Jaguar 7.7.107 software[25] running on Linux 2.6.18–
238.el5 SMP (x86_64) on two AMD Phenom II X6 1090 T proces-
sor workstations (Beowulf-cluster) parallelized with OpenMPI.
MM2 optimized structures were used as starting geometries. Com-
plete geometry optimizations were carried out on the implemented
LACVP* [Hay–Wadt effective core potential (ECP) basis on heavy
atoms, N31G6* for all other atoms] basis set and with the B3LYP
density functional. All calculated structures were proven to be true
minima by the absence of imaginary frequencies. Plots were ob-
tained by using Maestro 9.1.207, the graphical interface of Jaguar.
Rotational barriers were calculated fully relaxed, fixing one torsion
angle around the rotated bond, and optimizing all remaining de-
grees of freedom. Torsion angles were modified in steps of 10°.
1606, 1589, 1552, 1516, 1499, 1436, 1404, 1370, 1336, 1317, 1308,
1291, 1277, 1234, 1200, 1185, 1122, 1099, 1081, 1042, 1019, 966,
953, 933, 889, 870, 825, 797, 770, 762, 709, 617, 581, 554, 513,
1
418 cm–1. H NMR (600 MHz, CDCl3): δ = 8.20 (dd, JH,F = 9.1,
JH,H = 2.9 Hz, 1 H, 8-H), 7.83 (dd, JH,H = 9.1, JH,F = 5.2 Hz, 1 H,
5-H), 7.59 (d, JH,H = 8.1 Hz, 2 H, 10-H, 10Ј-H), 7.45 (ddd, JH,H
=
8.8, 2.9, JH,F = 8.1 Hz, 1 H, 6-H), 7.31 (d, JH,H = 8.1 Hz, 2 H, 11-
H, 11Ј-H), 5.64–5.61 (m, 1 H, 14-H), 2.43 (s, 3 H, 13-H3), 2.01–
1.95 (m, 2 H, 15-H, 15Ј-H), 1.82–1.77 (m, 2 H, 15-H, 15Ј-H), 1.72–
1.66 (m, 2 H, 16-H, 16Ј-H), 1.65–1.59 (m, 2 H, 16-H, 16Ј-H) ppm.
1
13C NMR (150 MHz, CDCl3): δ = 160.9 (o, d, JC,F = 247.6 Hz,
C7), 157.2 (o, C3), 139.9 (o, C12), 137.6 (o, C4a), 134.8 (o, d, 3JC,F
= 11.0 Hz, C8a), 133.9 (o, C2), 130.2 (+, 2 C, C10, C10Ј), 129.5 (+,
3
d, JC,F = 8.8 Hz, C5), 128.6 (+, 2 C, C11, C11Ј), 124.7 (o, C9),
Synthesis of 2-Aryl-Substituted O-Alkylquinoxaline N-Oxides 16a– 120.5 (+, d, 2JC,F = 24.2 Hz, C6), 104.9 (+, d, 2JC,F = 27.5 Hz, C8),
n. General Procedure I: Under a nitrogen atmosphere in an oven-
dried Schlenk tube equipped with a cooling finger, 2-chloroquinox-
aline N-oxide (1.0 equiv.), boronic acid (2.0 equiv.), Pd(OAc)2
(5 mol-%), XPhos (19, 10 mol-%) and K3PO4 (3.0 equiv.) were
added, followed by evacuation of the reaction vessel and backfilling
with nitrogen. Anhydrous 1,4-dioxane (4 mL) and degassed dis-
79.9 (+, C14), 32.7 (–, 2 C, C15, C15Ј), 23.7 (–, 2 C, C16, C16Ј),
21.6 (+, C13) ppm. 15N NMR (61 MHz, CDCl3): δ = –83.6 (N1),
–133.6 (N4) ppm. MS (EI, 70 eV): m/z (%) = 338 (51) [M]+, 322
(14) [M – O]+, 269 (39), 254 (50), 242 (57), 226 (48), 213 (31),
202 (11), 137 (9), 120 (40), 105 (100). HRMS (EI): m/z calcd. for
C20H19FN2O2 [M]+ 338.1431; found 338.1429.
Eur. J. Org. Chem. 2013, 8185–8196
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8191

J. Maichrowski, E. G. Hübner, D. E. Kaufmann
3-(Cyclopentyloxy)-7-fluoro-2-(m-tolyl)quinoxaline N-Oxide (16c): low solid; m.p. 107 °C, 301 °C (dec.). IR (KBr): ν = 3097, 3012,
FULL PAPER
˜
Following general procedure I: 2-chloro-3-(cyclopentyloxy)-7-
fluoroquinoxaline N-oxide (15a; 150 mg, 0.531 mmol), (3-tolyl)-
2962, 2941, 2872, 2837, 1608, 1576, 1552, 1516, 1500, 1469, 1439,
1409, 1370, 1341, 1317, 1301, 1287, 1258, 1237, 1184, 1177, 1124,
boronic acid (144 mg, 1.061 mmol), XPhos (25.0 mg, 0.053 mmol), 1098, 1047, 1029, 955, 892, 868, 825, 800, 770, 621, 557, 547, 528,
1
Pd(OAc)2 (6.0 mg, 0.027 mmol) and K3PO4 (338 mg, 1.592 mmol); 418 cm–1. H NMR (600 MHz, CDCl3): δ = 8.20–8.18 (m, 1 H, 8-
column chromatography (PE/EtOAc, 15:1; 30 g silica gel) gave 16c
(152 mg, 0.449 mmol, 85%) as a colourless solid; m.p. 75 °C,
H), 7.83–7.81 (m, 1 H, 5-H), 7.72–7.70 (m, 2 H, 10-H, 10Ј-H), 7.44
(ddd, JH,H = 9.1, 2.8, JH,F = 7.8 Hz, 1 H, 6-H), 7.03–7.00 (m, 2 H,
11-H, 11Ј-H), 5.64–5.61 (m, 1 H, 14-H), 3.88 (s, 3 H, 13-H3), 2.01–
1.95 (m, 2 H, 15-H, 15Ј-H), 1.83–1.78 (m, 2 H, 15-H, 15Ј-H), 1.73–
1.60 (m, 4 H, 16-H2, 16Ј-H2) ppm. 13C NMR (150 MHz, CDCl3):
308 °C (dec.). IR (KBr): ν = 3101, 2963, 2922, 2876, 2853, 1618,
˜
1589, 1556, 1503, 1434, 1376, 1339, 1317, 1291, 1278, 1237, 1191,
1174, 1120, 1105, 1088, 1051, 999, 972, 958, 939, 912, 889, 865,
846, 817, 796, 759, 696, 631, 555, 535, 480, 414 cm–1. 1H NMR
(600 MHz, CDCl3): δ = 8.21–8.19 (m, 1 H, 8-H), 7.85–7.83 (m, 1 H,
1
δ = 160.9 (o, d, JC,F = 248.7 Hz, C7), 160.5 (o, C12), 157.2 (o,
3
C3), 137.4 (o, C4a), 134.8 (o, d, JC,F = 11.0 Hz, C8a), 133.5 (o,
3
5-H), 7.49–7.48 (m, 1 H, 14-H), 7.46 (ddd, JH,H = 9.1, 2.8, JH,F
=
C2), 132.1 (+, 2 C, C10, C10Ј), 129.5 (+, d, JC,F = 8.8 Hz, C5),
7.8 Hz, 1 H, 6-H), 7.45–7.43 (m, 1 H, 12-H), 7.40–7.37 (m, 1 H, 11-
120.4 (+, d, 2JC,F = 25.3 Hz, C6), 119.6 (o, C9), 113.3 (+, 2 C, C11,
2
H), 7.28–7.27 (m, 1 H, 10-H), 5.64–5.61 (m, 1 H, 16-H), 2.42 (s, C11Ј), 104.9 (+, d, JC,F = 27.5 Hz, C8), 80.0 (+, C14), 55.3 (+,
3 H, 15-H3), 1.99–1.93 (m, 2 H, 17-H, 17Ј-H), 1.82–1.77 (m, 2 H, C13), 32.7 (–, 2 C, C15, C15Ј), 23.7 (–, 2 C, C16, C16Ј) ppm. MS
17-H, 17Ј-H), 1.71–1.59 (m, 4 H, 18-H2, 18Ј-H2) ppm. 13C NMR (EI, 70 eV): m/z (%) = 354 (100) [M]+, 338 (18) [M – O]+, 285 (47),
1
(150 MHz, CDCl3): δ = 160.9 (o, d, JC,F = 248.7 Hz, C7), 157.2
270 (49), 258 (19), 242 (30), 227 (21), 215 (18), 199 (18), 187 (10),
135 (14), 120 (15), 105 (30). HRMS (EI): m/z calcd. for
(o, C3), 137.7 (o, C4a), 137.5 (o, C13), 134.8 (o, d, 3JC,F = 11.0 Hz,
C8a), 133.9 (o, C2), 130.7 (+, C14), 130.5 (+, C10), 129.5 (+, d, C20H19FN2O3 [M]+ 354.1380; found 354.1381.
3JC,F = 8.8 Hz, C5), 127.8 (+, C11), 127.6 (o, C9), 127.3 (+, C12),
3-(Cyclopentyloxy)-7-fluoro-2-[4-(methylthio)phenyl]quinoxaline N-
120.7 (+, d, 2JC,F = 25.3 Hz, C6), 104.9 (+, d, 2JC,F = 27.5 Hz, C8),
80.0 (+, C16), 32.7 (–, 2 C, C17, C17Ј), 23.7 (–, 2 C, C18, C18Ј),
21.5 (+, C15) ppm. MS (EI, 70 eV): m/z (%) = 338 (42) [M]+, 322
(14) [M – O]+, 270 (73), 254 (68), 241 (100), 226 (85), 213 (68),
202 (33), 149 (9), 137 (12), 108 (63). HRMS (EI): m/z calcd. for
C20H19FN2O2 [M]+ 338.1431; found 338.1432.
Oxide (16f): Following general procedure I: 2-chloro-3-(cyclopent-
yloxy)-7-fluoroquinoxaline N-oxide (15a; 150 mg, 0.531 mmol), 4-
(methylthiophenyl)boronic acid (178 mg, 1.061 mmol), XPhos
(25.0 mg, 0.053 mmol), Pd(OAc)2 (6.0 mg, 0.027 mmol) and K3PO4
(338 mg, 1.592 mmol); column chromatography (PE/EtOAc, 10:1;
35 g silica gel) gave 16f (151 mg, 0.408 mmol, 77%) as a yellow
3-(Cyclopentyloxy)-7-fluoro-2-(o-tolyl)quinoxaline N-Oxide (16d): solid; m.p. 99 °C, 281 °C (dec.). IR (KBr): ν = 3099, 3062, 2956,
˜
Following general procedure I: 2-chloro-3-(cyclopentyloxy)-7-
2935, 2866, 1618, 1591, 1553, 1502, 1434, 1414, 1402, 1370, 1340,
fluoroquinoxaline N-oxide (15a; 150 mg, 0.531 mmol), (2-tolyl)-
1316, 1290, 1268, 1235, 1184, 1121, 1099, 1042, 1014, 953, 892, 869,
1
boronic acid (144 mg, 1.061 mmol), XPhos (25.0 mg, 0.053 mmol), 823, 780, 647, 554, 514, 418 cm–1. H NMR (600 MHz, CDCl3): δ
Pd(OAc)2 (6.0 mg, 0.027 mmol) and K3PO4 (338 mg, 1.592 mmol); = 8.19 (dd, JH,F = 9.1, JH,H = 2.9 Hz, 1 H, 8-H), 7.83 (dd, JH,H
=
column chromatography (PE/EtOAc, 15:1; 30 g silica gel) gave 16d
9.1, JH,F = 5.2 Hz, 1 H, 5-H), 7.66–7.64 (m, 2 H, 10-H, 10Ј-H),
(124 mg, 0.366 mmol, 69%) as a colourless solid; m.p. 78 °C,
7.47–7.44 (m, 1 H, 6-H), 7.35–7.33 (m, 2 H, 11-H, 11Ј-H), 5.64–
5.61 (m, 1 H, 14-H), 2.54 (s, 3 H, 13-H3), 2.01–1.95 (m, 2 H, 15-H,
15Ј-H), 1.83–1.78 (m, 2 H, 15-H, 15Ј-H), 1.72–1.60 (m, 4 H, 16-H2,
311 °C (dec.). IR (KBr): ν = 3111, 3077, 3026, 2971, 2955, 2869,
˜
1626, 1589, 1552, 1505, 1433, 1409, 1384, 1371, 1333, 1313, 1293,
1278, 1235, 1213, 1185, 1164, 1127, 1097, 1051, 1039, 1029, 952,
1
16Ј-H2) ppm. 13C NMR (150 MHz, CDCl3): δ = 160.9 (o, d, JC,F
931, 892, 872, 837, 822, 809, 769, 742, 722, 713, 636, 555, 537, 518,
= 248.7 Hz, C7), 157.1 (o, C3), 141.1 (o, C12), 137.6 (o, C4a), 134.8
1
3
488, 415 cm–1. H NMR (600 MHz, CDCl3): δ = 8.21 (dd, JH,F
=
(o, d, JC,F = 11.0 Hz, C8a), 133.2 (o, C2), 130.8 (+, 2 C, C10,
3
9.0, JH,H = 2.8 Hz, 1 H, 8-H), 7.88 (dd, JH,H = 9.1, JH,F = 5.2 Hz,
1 H, 5-H), 7.49 (ddd, JH,H = 9.1, 2.8, JH,F = 7.9 Hz, 1 H, 6-H),
C10Ј), 129.5 (+, d, JC,F = 8.8 Hz, C5), 125.0 (+, 2 C, C11, C11Ј),
2
2
123.9 (o, C9), 120.6 (+, d, JC,F = 25.3 Hz, C6), 104.9 (+, d, JC,F
7.40–7.38 (m, 1 H, 12-H), 7.35–7.34 (m, 1 H, 13-H), 7.32–7.29 (m, = 27.5 Hz, C8), 80.0 (+, C14), 32.7 (–, 2 C, C15, C15Ј), 23.7 (–,
1 H, 11-H), 7.24 (dd, JH,H = 7.7, 1.1 Hz, 1 H, 10-H), 5.62–5.59 (m, 2 C, C16, C16Ј), 15.2 (+, C13) ppm. MS (EI, 70 eV): m/z (%) = 370
1 H, 16-H), 2.16 (s, 3 H, 15-H3), 1.97–1.91 (m, 2 H, 17-H, 17Ј-H), (41) [M]+, 354 (39) [M – O]+, 302 (20), 286 (100), 258 (61), 243
1.75–1.69 (m, 2 H, 17-H, 17Ј-H), 1.61–1.55 (m, 4 H, 18-H2, 18Ј- (45), 210 (12), 199 (11), 149 (52), 119 (40), 108 (30). HRMS (EI):
1
H2) ppm. 13C NMR (150 MHz, CDCl3): δ = 160.8 (o, d, JC,F
=
m/z calcd. for C20H19FN2O2S [M]+ 370.1151; found 370.1149.
248.7 Hz, C7), 157.6 (o, C3), 138.2 (o, C4a), 137.8 (o, C14), 134.8
3-(Cyclopentyloxy)-7-fluoro-2-[4-(trifluoromethoxy)phenyl]quin-
oxaline N-Oxide (16g): Following general procedure I: 2-chloro-3-
(cyclopentyloxy)-7-fluoroquinoxaline N-oxide (15a; 150 mg,
0.531 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (219 mg,
1.061 mmol), XPhos (25.0 mg, 0.053 mmol), Pd(OAc)2 (6.0 mg,
0.027 mmol) and K3PO4 (338 mg, 1.592 mmol); column
chromatography (PE/EtOAc, 15:1; 30 g silica gel) gave 16g (175 mg,
0.429 mmol, 81%) as an orange solid; m.p. 121 °C, 292 °C (dec.).
3
(o, C2), 134.7 (o, d, JC,F = 11.0 Hz, C8a), 130.1 (+, C13), 129.6
3
(+, d, JC,F = 8.8 Hz, C5), 129.6 (+, C12), 129.5 (+, C10), 128.0
(o, C9), 125.7 (+, C11), 120.7 (+, d, 2JC,F = 25.3 Hz, C6), 104.9 (+,
d, 2JC,F = 27.5 Hz, C8), 79.8 (+, C16), 32.7 (–, C17), 32.6 (–, C17Ј),
23.6 (–, 2 C, C18, C18Ј), 19.3 (+, C15) ppm. MS (EI, 70 eV):
m/z (%) = 338 (23) [M]+, 323 (48) [M – CH3]+, 269 (6), 255 (100),
237 (20), 224 (23), 211 (16), 199 (11), 135 (11), 116 (12), 108 (35).
HRMS (EI): m/z calcd. for C20H19FN2O2 [M]+ 338.1431; found
338.1432.
IR (KBr): ν = 3099, 3067, 3052, 2968, 2879, 1623, 1606, 1592, 1553,
˜
1512, 1500, 1436, 1410, 1367, 1344, 1313, 1291, 1263, 1228, 1187,
1171, 1158, 1124, 1114, 1098, 1044, 1021, 956, 921, 890, 875, 866,
845, 829, 806, 782, 713, 674, 644, 557, 538, 510, 419 cm–1. 1H NMR
(600 MHz, CDCl3): δ = 8.18 (dd, JH,F = 9.0, JH,H = 2.8 Hz, 1 H,
8-H), 7.85 (dd, JH,H = 9.1, JH,F = 5.2 Hz, 1 H, 5-H), 7.77–7.74 (m,
2 H, 10-H, 10Ј-H), 7.48 (ddd, JH,H = 9.1, 2.8, JH,F = 7.8 Hz, 1 H,
5-H), 7.35–7.33 (m, 2 H, 11-H, 11Ј-H), 5.65–5.62 (m, 1 H, 14-H),
3-(Cyclopentyloxy)-7-fluoro-2-(4-methoxyphenyl)quinoxaline N-Ox-
ide (16e): Following general procedure I: 2-chloro-3-(cyclopent-
yloxy)-7-fluoroquinoxaline N-oxide (15a; 150 mg, 0.531 mmol), (4-
methoxyphenyl)boronic acid (161 mg, 1.061 mmol), XPhos
(25.0 mg, 0.053 mmol), Pd(OAc)2 (6.0 mg, 0.027 mmol) and K3PO4
(338 mg, 1.592 mmol); column chromatography (PE/EtOAc, 20:1;
35 g silica gel) gave 16e (155 mg, 0.437 mmol, 82%) as a pale-yel- 2.02–1.96 (m, 2 H, 15-H, 15Ј-H), 1.81–1.77 (m, 2 H, 15-H, 15Ј-
8192
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8185–8196

Arylation of 2-Chloroquinoxaline N-Oxides
4
2
4
H), 1.70–1.61 (m, 4 H, 16-H2, 16Ј-H2) ppm. 13C NMR (150 MHz, = 15.4, JC,F = 3.3 Hz, C9), 111.5 (+, dd, JC,F = 22.0, JC,F
=
CDCl3): δ = 161.0 (o, d, 1JC,F = 249.8 Hz, C7), 156.9 (o, C3), 149.9 3.3 Hz, C13), 104.9 (+, d, JC,F = 27.5 Hz, C8), 104.4 (+, t, JC,F
2
2
3
(o, C12), 137.9 (o, C4a), 134.7 (o, d, JC,F = 11.0 Hz, C8a), 132.4
= 25.3 Hz, C11), 80.2 (+, C15), 32.7 (–, C16), 32.6 (–, C16Ј), 23.7
(o, C2), 132.3 (+, 2 C, C10, C10Ј), 129.7 (+, d, 3JC,F = 8.8 Hz, C5), (–, C17), 23.6 (–, C17Ј) ppm. MS (EI, 70 eV): m/z (%) = 360 (88)
126.2 (o, C9), 121.0 (+, d, JC,F = 25.3 Hz, C6), 120.4 (o, q, JC,F [M]+, 344 (3) [M – O]+, 292 (100), 272 (87), 264 (67), 248 (57), 236
2
1
2
= 258.6 Hz, C13), 120.1 (+, 2 C, C11, C11Ј), 104.9 (+, d, JC,F
=
(34), 228 (17), 216 (38), 197 (9), 141 (52), 130 (9), 120 (9), 108 (94).
27.5 Hz, C8), 80.3 (+, C14), 32.7 (–, 2 C, C15, C15Ј), 23.7 (–, 2 C, HRMS (EI): m/z calcd. for C19H15F3N2O2 [M]+ 360.1086; found
C16, C16Ј) ppm. MS (EI, 70 eV): m/z (%) = 408 (45) [M]+, 392 (9) 360.1088.
[M – O]+, 339 (99) [M – CF3]+, 323 (52) [M – OCF3]+, 312 (51),
296 (45), 284 (18), 255 (31), 243 (18), 227 (23), 215 (45), 199 (27),
3-(Cyclopentyloxy)-7-fluoro-2-(naphthalen-1-yl)quinoxaline N-Ox-
ide (16j): Following general procedure I: 2-chloro-3-(cyclopent-
yloxy)-7-fluoroquinoxaline N-oxide (15a; 150 mg, 0.531 mmol), (1-
naphthyl)boronic acid (183 mg, 1.061 mmol), XPhos (25.0 mg,
189 (29), 161 (9), 149 (9), 108 (100). HRMS (EI): m/z calcd. for
C20H16F4N2O3 [M]+ 408.1097; found 408.1096.
2-(3-Chlorophenyl)-3-(cyclopentyloxy)-7-fluoroquinoxaline N-Oxide
(16h): Following general procedure I: 2-chloro-3-(cyclopentyloxy)-
7-fluoroquinoxaline N-oxide (15a; 150 mg, 0.531 mmol), (3-chloro-
phenyl)boronic acid (91 mg, 0.584 mmol), XPhos (25.0 mg,
0.053 mmol), Pd(OAc)2 (6.0 mg, 0.027 mmol) and K3PO4 (338 mg,
1.592 mmol); column chromatography (PE/EtOAc, 10:1, 35 g silica
gel) gave 16j (177 mg, 0.473 mmol, 89%) as a pale-yellow solid;
m.p. 138 °C, 283 °C (dec.). IR (KBr): ν = 3104, 3039, 2958, 2941,
˜
0.053 mmol), Pd(OAc)2 (6.0 mg, 0.027 mmol) and K3PO4 (338 mg, 2909, 2869, 1621, 1591, 1552, 1499, 1465, 1434, 1379, 1346, 1311,
1.592 mmol); column chromatography (PE/EtOAc, 15:1; 30 g silica
gel) gave 16h (115 mg, 0.321 mmol, 60%) as a colourless solid; m.p.
1293, 1254, 1230, 1194, 1170, 1121, 1091, 1058, 1044, 1032, 999,
969, 953, 893, 878, 839, 823, 799, 774, 697, 653, 535, 531, 482,
1
85 °C, 301 °C (dec.). IR (KBr): ν = 3108, 3064, 2969, 2953, 2872,
414 cm–1. H NMR (600 MHz, CDCl3): δ = 8.24 (dd, JH,F = 8.9,
˜
1619, 1593, 1586, 1568, 1552, 1505, 1442, 1402, 1373, 1341, 1334,
1314, 1306, 1290, 1264, 1237, 1191, 1167, 1127, 1107, 1079, 1052,
1034, 998, 985, 978, 956, 935, 908, 898, 879, 845, 826, 806, 787,
JH,H = 2.7 Hz, 1 H, 8-H), 8.00 (d, JH,H = 8.2 Hz, 1 H, 12-H), 7.95–
7.92 (m, 2 H, 5-H, 14-H), 7.61 (dd, JH,H = 8.2, 7.2 Hz, 1 H, 11-H),
7.57–7.55 (m, 1 H, 10-H), 7.55–7.50 (m, 2 H, 6-H, 15-H), 7.45–7.41
(m, 1 H, 16-H), 7.34 (dd, JH,H = 8.4, 0.8 Hz, 1 H, 17-H), 5.63–5.60
1
770, 749, 719, 689, 667, 641, 535, 418 cm–1. H NMR (600 MHz,
CDCl3): δ = 8.18 (dd, JH,F = 9.0, JH,H = 2.8 Hz, 1 H, 8-H), 7.85 (m, 1 H, 19-H), 1.93–1.83 (m, 2 H, 20-H, 20Ј-H), 1.71–1.57 (m,
(dd, JH,H = 9.1, JH,F = 5.2 Hz, 1 H, 5-H), 7.68 (s, 1 H, 14-H), 7.59–
7.57 (m, 1 H, 10-H), 7.50–7.46 (m, 1 H, 6-H), 7.45–7.42 (m, 2 H,
11-H, 12-H), 5.65–5.62 (m, 1 H, 15-H), 2.00–1.94 (m, 2 H, 16-H,
2 H, 20-H, 20Ј-H), 1.52–1.38 (m, 4 H, 21-H2, 21Ј-H2) ppm. 13C
1
NMR (150 MHz, CDCl3): δ = 160.9 (o, d, JC,F = 248.7 Hz, C7),
3
158.0 (o, C3), 138.4 (o, C4a), 134.8 (o, d, JC,F = 11.0 Hz, C8a),
16Ј-H), 1.82–1.79 (m, 2 H, 16-H, 16Ј-H), 1.71–1.61 (m, 4 H, 17-H2, 133.7 (o, C2), 133.5 (o, C13), 130.8 (o, C18), 130.2 (+, C12), 129.7
1
3
17Ј-H2) ppm. 13C NMR (150 MHz, CDCl3): δ = 161.0 (o, d, JC,F
(+, d, JC,F = 8.8 Hz, C5), 128.7 (+, C14), 128.4 (+, C10), 126.6
3
= 248.7 Hz, C7), 156.8 (o, C3), 137.9 (o, C4a), 134.7 (o, d, JC,F
=
(+, C16), 126.1 (+, 2 C, C9, C15), 125.2 (+, C11), 124.5 (+, C17),
121.0 (+, d, JC,F = 25.3 Hz, C6), 105.0 (+, d, JC,F = 27.5 Hz,
C8), 79.9 (+, C19), 32.6 (–, C20), 32.5 (–, C20Ј), 23.5 (–, 2 C, C21,
2
2
11.0 Hz, C8a), 133.8 (o, C9), 132.3 (o, C2), 130.5 (+, C14), 129.8
(+, C12), 129.7 (+, d, 3JC,F = 8.8 Hz, C5), 129.4 (o, C13), 129.1 (+,
C11), 128.6 (+, C10), 121.1 (+, d, JC,F = 25.3 Hz, C6), 104.9 (+, C21Ј) ppm. MS (EI, 70 eV): m/z (%) = 374 (54) [M]+, 358 (13) [M –
2
2
d, JC,F = 27.5 Hz, C8), 80.3 (+, C15), 32.7 (–, 2 C, C16, C16Ј),
23.6 (–, 2 C, C17, C17Ј) ppm. MS (EI, 70 eV): m/z (%) = 358 (8)
[M]+, 342 (2) [M – O]+, 291 (27), 274 (20), 262 (47), 255 (100), 246
(21), 234 (14), 227 (58), 210 (13), 199 (41), 149 (6), 139 (11), 108
(53). HRMS (EI): m/z calcd. for C19H16ClFN2O2 [M]+ 358.0884;
found 358.0882.
O]+, 305 (48), 289 (62), 261 (48), 250 (68), 153 (25), 140 (21), 127
(57), 115 (50), 108 (18). HRMS (ESI): m/z calcd. for C23H19FN2O2
[M + H]+ 375.1509; found 375.1509.
3-(Cyclopentyloxy)-7-fluoro-2-(thiophen-2-yl)quinoxaline N-Oxide
(16k): Following general procedure I: 2-chloro-3-(cyclopentyloxy)-
7-fluoroquinoxaline N-oxide (15a; 150 mg, 0.531 mmol), (thio-
phen-2-yl)boronic acid (136 mg, 1.061 mmol), XPhos (25.0 mg,
0.053 mmol), Pd(OAc)2 (6.0 mg, 0.027 mmol) and K3PO4 (338 mg,
1.592 mmol); reaction time: 8 h; column chromatography (PE/
3-(Cyclopentyloxy)-2-(2,4-difluorophenyl)-7-fluoroquinoxaline
N-
Oxide (16i): Following general procedure I: 2-chloro-3-(cyclopent-
yloxy)-7-fluoroquinoxaline N-oxide (15a; 150 mg, 0.531 mmol),
(2,4-difluorophenyl)boronic acid (168 mg, 1.061 mmol), XPhos EtOAc, 30:1, 35 g silica gel) gave 16k (106 mg, 0.321 mmol, 60%)
(25.0 mg, 0.053 mmol), Pd(OAc)2 (6.0 mg, 0.027 mmol) and K3PO4
(338 mg, 1.592 mmol); column chromatography (PE/EtOAc, 30:1;
35 g silica gel) gave 16i (44 mg, 0.122 mmol, 23%) as a pale-yellow
as a yellow solid; m.p. 121 °C, 274 °C (dec.). IR (KBr): ν = 3145,
3094, 3078, 2953, 2868, 1613, 1593, 1553, 1505, 1497, 1470, 1437,
1423, 1403, 1384, 1346, 1311, 1290, 1243, 1228, 1198, 1178, 1124,
˜
solid; m.p. 108 °C, 180 °C (dec.). IR (KBr): ν = 3111, 3081, 3064, 1091, 1078, 1067, 1028, 998, 951, 903, 875, 858, 848, 825, 777, 743,
˜
2973, 2876, 1618, 1596, 1586, 1556, 1515, 1496, 1436, 1422, 1379,
1340, 1316, 1291, 1271, 1250, 1233, 1188, 1144, 1122, 1108, 1091,
1042, 962, 952, 905, 889, 845, 829, 782, 772, 736, 724, 710, 621,
611, 594, 555, 527, 508, 477, 468, 451, 415 cm–1. 1H NMR
714, 697, 669, 647, 618, 565, 551, 508, 422 cm–1. 1H NMR
(600 MHz, CDCl3): δ = 8.75 (dd, JH,H = 4.2, 1.0 Hz, 1 H, 12-H),
8.24 (dd, JH,F = 9.0, JH,H = 2.9 Hz, 1 H, 8-H), 7.80 (dd, JH,H
=
9.0, JH,F = 5.3 Hz, 1 H, 5-H), 7.67 (dd, JH,H = 5.1, 1.0 Hz, 1 H,
(600 MHz, CDCl3): δ = 8.18 (dd, JH,F = 9.0, JH,H = 3.0 Hz, 1 H, 10-H), 7.41 (ddd, JH,H = 9.0, 2.9, JH,F = 7.8 Hz, 1 H, 6-H), 7.32
8-H), 7.87 (dd, JH,H = 9.2, JH,F = 5.1 Hz, 1 H, 5-H), 7.54–7.48 (m, (dd, JH,H = 5.1, 4.2 Hz, 1 H, 11-H), 5.88–5.85 (m, 1 H, 13-H), 2.18–
2 H, 6-H, 14-H), 7.05–7.01 (m, 1 H, 13-H), 6.99–6.96 (m, 1 H, 11-
2.12 (m, 2 H, 14-H, 14Ј-H), 2.09–2.03 (m, 2 H, 14-H, 14Ј-H), 1.96–
H), 5.64–5.61 (m, 1 H, 15-H), 2.00–1.93 (m, 2 H, 16-H, 16Ј-H), 1.89 (m, 2 H, 15-H, 15Ј-H), 1.81–1.74 (m, 2 H, 15-H, 15Ј-H) ppm.
1
1.81–1.74 (m, 2 H, 16-H, 16Ј-H), 1.69–1.58 (m, 4 H, 17-H2, 17Ј- 13C NMR (150 MHz, CDCl3): δ = 161.2 (o, d, JC,F = 248.7 Hz,
1
3
H2) ppm. 13C NMR (150 MHz, CDCl3): δ = 164.1 (o, dd, JC,F
=
=
C7), 155.2 (o, C3), 134.8 (o, C4a), 133.5 (o, d, JC,F = 11.0 Hz,
3
1
3
3
252.0, JC,F = 12.1 Hz, C12), 161.1 (o, dd, JC,F = 254.2, JC,F
C8a), 133.3 (+, C12), 130.8 (+, C10), 129.2 (+, d, JC,F = 8.8 Hz,
1
12.1 Hz, C10), 160.9 (o, d, JC,F = 248.7 Hz, C7), 157.2 (o, C3),
C5), 129.1 (o, C2), 128.8 (o, C9), 126.7 (+, C11), 119.8 (+, d, 2JC,F
3
2
138.4 (o, C4a), 134.6 (o, d, JC,F = 11.0 Hz, C8a), 132.8 (+, dd,
= 25.3 Hz, C6), 104.6 (+, d, JC,F = 27.5 Hz, C8), 81.0 (+, C13),
3JC,F = 11.0, 3JC,F = 5.0 Hz, C14), 129.8 (+, d, 3JC,F = 8.8 Hz, C5),
129.0 (o, C2), 121.2 (+, d, 2JC,F = 25.3 Hz, C6), 112.5 (+, dd, 2JC,F
32.9 (–, 2 C, C14, C14Ј), 24.0 (–, 2 C, C15, C15Ј) ppm. MS (EI,
70 eV): m/z (%) = 330 (100) [M]+, 314 (12) [M – O]+, 262 (69), 246
Eur. J. Org. Chem. 2013, 8185–8196
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8193

J. Maichrowski, E. G. Hübner, D. E. Kaufmann
FULL PAPER
(39), 234 (75), 218 (38), 205 (21), 192 (23), 180 (15), 173 (13), 161
(11), 149 (14), 129 (11), 120 (15), 111 (69). HRMS (EI): m/z calcd.
for C17H15FN2O2S [M]+ 330.0838; found 330.0839.
(6.6 mg, 0.029 mmol) and K3PO4 (372 mg, 1.753 mmol); column
chromatography (PE/EtOAc, 10:1; 30 g silica gel) gave 16n (163 mg,
0.522 mmol, 89%) as a pale-yellow solid; m.p. 123 °C, 311 °C
(dec.). IR (ATR): ν = 3099, 3039, 2974, 2928, 2874, 2867, 1615,
˜
2,2Ј-(1,4-Phenylene)bis[3-(cyclopentyloxy)-7-fluoroquinoxaline N-
Oxide] (16l): Following general procedure I: 2-chloro-3-(cyclopent-
yloxy)-7-fluoroquinoxaline N-oxide (15a; 150 mg, 0.531 mmol),
benzene-1,4-diboronic acid (352 mg, 2.122 mmol), XPhos (25.0 mg,
0.053 mmol), Pd(OAc)2 (6.0 mg, 0.027 mmol) and K3PO4 (676 mg,
3.180 mmol); column chromatography (PE/EtOAc, 8:1Ǟ5:1; 30 g
silica gel) gave 16l (67 mg, 0.117 mmol, 44%) as a pale-yellow solid;
1607, 1589, 1549, 1516, 1497, 1471, 1464, 1450, 1433, 1407, 1384,
1362, 1340, 1325, 1310, 1290, 1277, 1232, 1186, 1177, 1146, 1119,
1103, 1095, 1041, 1020, 957, 945, 916, 888, 865, 837, 819, 802, 768,
724, 709, 698, 661, 654, 638, 621, 579, 555, 532, 521, 515, 485, 432,
1
411, 405 cm–1. H NMR (600 MHz, CDCl3): δ = 8.20 (dd, JH,F
=
9.1, JH,H = 2.9 Hz, 1 H, 8-H), 7.82 (dd, JH,H = 9.1, JH,F = 5.2 Hz,
1 H, 5-H), 7.60 (d, JH,H = 8.1 Hz, 2 H, 10-H, 10Ј-H), 7.45 (ddd,
JH,H = 9.1, 2.9, JH,F = 7.8 Hz, 1 H, 6-H), 7.32 (d, JH,H = 8.1 Hz,
2 H, 11-H, 11Ј-H), 7.32 (d, JH,H = 8.1 Hz, 2 H, 11-H, 11Ј-H), 5.52
(sept, JH,H = 6.2 Hz, 1 H, 14-H), 2.44 (s, 3 H, 13-H3), 1.36 (d, JH,H
= 6.2 Hz, 6 H, 15-H3, 15Ј-H3) ppm. 13C NMR (150 MHz, CDCl3):
δ = 160.9 (o, d, 1JC,F = 248.7 Hz, C7), 157.1 (o, C3), 139.9 (o, C12),
m.p. 245 °C, 290 °C (dec.). IR (KBr): ν = 3102, 2961, 2872, 1623,
˜
1591, 1550, 1500, 1439, 1407, 1366, 1340, 1314, 1296, 1273, 1237,
1185, 1122, 1097, 1036, 955, 868, 836, 820, 783, 553, 528, 418 cm–1.
1H NMR (600 MHz, CDCl3): δ = 8.22 (dd, JH,F = 9.0, JH,H
=
2.9 Hz, 2 H, 8-H, 8Ј-H), 7.87–7.85 (m, 6 H, 5-H, 5Ј-H, 10-H, 10Ј-
H, 10ЈЈ-H, 10ЈЈЈ-H), 7.48 (ddd, JH,H = 9.1, 2.9, JH,F = 7.8 Hz, 2 H,
6-H, 6Ј-H), 5.67–5.65 (m, 2 H, 11-H, 11Ј-H), 2.03–1.97 (m, 4 H, 12-
H, 12Ј-H, 12ЈЈ-H, 12ЈЈЈ-H), 1.85–1.80 (m, 4 H, 12-H, 12Ј-H, 12ЈЈ-H,
12ЈЈЈ-H), 1.74–1.68 (m, 4 H, 13-H, 13Ј-H, 13ЈЈ-H, 13ЈЈЈ-H), 1.66–
1.61 (m, 4 H, 13-H, 13Ј-H, 13ЈЈ-H, 13ЈЈЈ-H) ppm. 13C NMR
3
137.7 (o, C4a), 134.8 (o, d, JC,F = 9.9 Hz, C8a), 133.8 (o, C2),
3
130.4 (+, 2 C, C10, C10Ј), 129.4 (+, d, JC,F = 8.8 Hz, C5), 128.7
2
(+, 2 C, C11, C11Ј), 124.7 (o, C9), 120.6 (+, d, JC,F = 24.2 Hz,
C6), 105.0 (+, d, 2JC,F = 27.5 Hz, C8), 70.5 (+, C14), 21.8 (+, C15,
C15Ј), 21.7 (+, C13) ppm. MS (EI, 70 eV): m/z (%) = 312 (100)
[M]+, 296 (9) [M – O]+, 269 (75), 253 (37), 242 (72), 226 (43), 213
(64), 205 (89), 175 (13), 134 (10), 108 (63). HRMS (EI): m/z calcd.
for C18H17FN2O2 [M]+ 313.1352; found 313.1354.
1
(150 MHz, CDCl3): δ = 161.0 (o, d, JC,F = 249.8 Hz, 2 C, C7,
C7Ј), 157.1 (o, 2 C, C3, C3Ј), 137.8 (o, 2 C, C4a, C4aЈ), 134.8 (o,
3
d, JC,F = 11.0 Hz, 2 C, C8a, C8aЈ), 133.1 (o, 2 C, C2, C2Ј), 130.0
(+, 4 C, C10, C10Ј, C10ЈЈ, C10ЈЈЈ), 129.6 (+, d, 3JC,F = 8.8 Hz, 2 C,
C5, C5Ј), 129.0 (o, 2 C, C9, C9Ј), 120.9 (+, d, 2JC,F = 25.3 Hz, 2 C,
3-(Ethylthio)-6-fluoroquinoxalin-2(1H)-one (26): To a stirred sus-
pension of 3-(ethylsulfanyl)-6-fluoroquinoxalin-2(1H)-one N-oxide
2
C6, C6Ј), 105.0 (+, d, JC,F = 27.5 Hz, 2 C, C8, C8Ј), 80.2 (+, 2 C,
C11, C11Ј), 32.7 (–, 4 C, C12, C12Ј, C12ЈЈ, C12ЈЈЈ), 23.8 (–, 4 C, (21; 200 mg, 0.832 mmol) in anhydrous THF (5 mL), Lawesson’s
C13, C13Ј, C13ЈЈ, C13ЈЈЈ) ppm. MS (EI, 70 eV): m/z (%) = 570 (4) reagent (337 mg, 0.832) was added under a nitrogen atmosphere.
[M]+, 554 (8) [M – O]+, 538 (33) [M – O – O]+, 485 (4), 470 (9), The mixture was stirred for 2.5 h at 40 °C, then the solvent was
434 (5), 417 (8), 402 (100), 390 (8), 374 (29), 346 (35), 239 (12), removed in vacuo and the residue was purified by column
215 (16), 202 (14), 152 (25), 108 (39). HRMS (EI): m/z calcd. for chromatography (PE/EtOAc, 10:1; 30 g silica gel) to give 26
C32H28F2N4O4 [M]+ 570.2079; found 570.2074.
(161 mg, 0.718 mmol, 86%) as a pale-yellow solid; m.p. 247 °C. IR
(KBr): ν = 3078, 3054, 3032, 3011, 2978, 2955, 2925, 2895, 2868,
˜
3-Ethoxy-7-fluoro-2-(p-tolyl)quinoxaline N-Oxide (16m): Following
general procedure I: 2-chloro-3-ethoxy-7-fluoroquinoxaline N-ox-
ide (15b; 150 mg, 0.618 mmol), (4-tolyl)boronic acid (168 mg,
1.236 mmol), XPhos (29.0 mg, 0.062 mmol), Pd(OAc)2 (6.9 mg,
0.031 mmol) and K3PO4 (394 mg, 1.855 mmol); column
chromatography (PE/EtOAc, 10:1; 35 g silica gel) gave 16m
(165 mg, 0.553 mmol, 89%) as a pale-yellow solid; m.p. 159 °C,
2815, 2736, 1676 (C=O), 1639, 1613, 1526, 1495, 1467, 1433, 1406,
1379, 1343, 1258, 1147, 1118, 1079, 1055, 972, 878, 866, 853, 810,
1
759, 634, 607, 581, 438 cm–1. H NMR (600 MHz, [D6]DMSO): δ
= 12.51 (br. s, 1 H, NH), 7.43 (dd, JH,F = 9.4, JH,H = 2.6 Hz, 1 H,
5-H), 7.31–7.25 (m, 2 H, 7-H, 8-H), 3.08 (q, JH,H = 7.5 Hz, 2 H, 9-
H2), 1.30 (t, JH,H = 7.5 Hz, 3 H, 10-H3) ppm. 13C NMR (150 MHz,
1
[D6]DMSO): δ = 162.4 (o, C3), 158.2 (o, d, JC,F = 239.9 Hz, C6),
317 °C (dec.). IR (KBr): ν = 3089, 2992, 2968, 2951, 2903, 1622,
˜
3
152.7 (o, C2), 132.7 (o, d, JC,F = 11.0 Hz, C4a), 126.9 (o, C8a),
1609, 1593, 1573, 1548, 1518, 1500, 1466, 1436, 1409, 1386, 1370,
1340, 1311, 1291, 1280, 1237, 1187, 1130, 1102, 1074, 1047, 1026,
961, 876, 866, 833, 822, 799, 772, 760, 701, 624, 558, 511, 425 cm–1.
3
2
117.0 (+, d, JC,F = 9.9 Hz, C8), 116.1 (+, d, JC,F = 24.2 Hz, C7),
2
112.3 (+, d, JC,F = 23.1 Hz, C5), 23.2 (–, C9), 13.8 (+, C10) ppm.
MS (EI, 70 eV): m/z (%) = 224 (56) [M]+, 198 (51), 190 (39), 170
(42), 163 (24), 140 (32), 135 (33), 108 (100). HRMS (EI): m/z calcd.
for C10H9FN2OS [M]+ 224.0420; found 224.0421.
1H NMR (600 MHz, CDCl3): δ = 8.20 (dd, JH,F = 9.1, JH,H
=
2.9 Hz, 1 H, 8-H), 7.84 (dd, JH,H = 9.1, JH,F = 5.2 Hz, 1 H, 5-H),
7.61–7.60 (m, 2 H, 10-H, 10Ј-H), 7.47 (ddd, JH,H = 9.1, 2.9, JH,F
=
7.8 Hz, 1 H, 6-H), 7.34–7.32 (m, 2 H, 11-H, 11Ј-H), 4.54 (q, JH,H Synthesis of Tosylated Quinoxalines 22, 24 and 27. General Pro-
= 7.0 Hz, 2 H, 14-H2), 2.44 (s, 3 H, 13-H3), 1.38 (t, JH,H = 7.0 Hz, cedure II: To a stirred suspension of sodium hydride (60 wt.-% in
3 H, 15-H3) ppm. 13C NMR (150 MHz, CDCl3): δ = 161.0 (o, d, mineral oil, 1.1 equiv.) in anhydrous DMF under a nitrogen atmo-
1JC,F = 248.7 Hz, C7), 157.5 (o, C3), 140.0 (o, C12), 137.5 (o, C4a),
sphere at room temp., the corresponding quinoxalinone (1.0 equiv.)
3
135.0 (o, d, JC,F = 11.0 Hz, C8a), 133.6 (o, C2), 130.2 (+, 2 C, was gradually added. The mixture was stirred until hydrogen gas
3
C10, C10Ј), 129.5 (+, d, JC,F = 8.8 Hz, C5), 128.8 (+, 2 C, C11, evolution ceased, then p-TsCl (1.1 equiv.) was added and the re-
2
C11Ј), 124.6 (o, C9), 120.7 (+, d, JC,F = 25.3 Hz, C6), 105.0 (+,
sulting solution was stirred at room temp. for 1.5 to 2.0 h. After
completion of the reaction the product was purified in the de-
2
d, JC,F = 27.5 Hz, C8), 63.4 (–, C14), 21.6 (+, C13), 14.3 (+,
C15) ppm. MS (EI, 70 eV): m/z (%) = 298 (37) [M]+, 282 (16) [M – scribed manner.
O]+, 269 (33) [M – CH2CH3]+, 253 (16), 241 (14), 226 (30), 210
2-(Ethylthio)-7-fluoro-3-(tosyloxy)quinoxaline N-Oxide (22): Fol-
(16), 202 (14), 186 (7), 149 (8), 120 (43), 108 (69), 91 (100). HRMS
lowing general procedure II: NaH (60 wt.-%, 92 mg, 2.29 mmol), 3-
(ethylsulfanyl)-6-fluoroquinoxalin-2(1H)-one N-oxide (21; 500 mg,
2.08 mmol) in anhydrous DMF (10 mL), p-TsCl (436 mg,
2.29 mmol); reaction time: 1.5 h; purification: After dilution with
Et2O (50 mL) the organic phase was washed with brine (20 mL)
and H2O (3ϫ 15 mL). The organic phase was dried with Na2SO4
(EI): m/z calcd. for C17H15FN2O2 [M]+ 298.1118; found 298.1118.
7-Fluoro-3-isopropoxy-2-(p-tolyl)quinoxaline N-Oxide (16n): Fol-
lowing general procedure I: 2-chloro-7-fluoro-3-isopropoxyquinox-
aline N-oxide (15c; 150 mg, 0.584 mmol), (4-tolyl)boronic acid
(159 mg, 1.169 mmol), XPhos (28.0 mg, 0.058 mmol), Pd(OAc)2
8194
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8185–8196

Arylation of 2-Chloroquinoxaline N-Oxides
and the solvent was removed in vacuo, then the residue was purified
by column chromatography (PE/EtOAc, 3:1; 50 g silica gel) to give
22 (644 mg, 1.63 mmol, 78%) as a pale-yellow solid; m.p. 108 °C,
7.3 Hz, 3 H, 15-H3) ppm. 13C NMR (150 MHz, CDCl3): δ = 162.6
1
4
(o, d, JC,F = 250.9 Hz, C6), 151.6 (o, C2), 147.7 (o, d, JC,F
=
3
3.3 Hz, C8a), 145.9 (o, C12), 141.9 (o, d, JC,F = 13.2 Hz, C4a),
203 °C (dec.). IR (ATR): ν = 3094, 2991, 2943, 2883, 1617, 1597,
133.7 (o, C3), 133.6 (o, C9), 129.8 (+, d, 3JC,F = 9.9 Hz, C8), 129.7
˜
2
1496, 1458, 1448, 1408, 1383, 1372, 1352, 1310, 1293, 1280, 1242,
1207, 1192, 1178, 1123, 1093, 1079, 1048, 1021, 971, 892, 871, 845,
839, 812, 798, 776, 765, 752, 728, 701, 680, 668, 651, 603, 580, 555,
(+, 2 C, C11, C11Ј), 129.2 (+, 2 C, C10, C10Ј), 118.1 (+, d, JC,F
2
= 25.3 Hz, C7), 111.6 (+, d, JC,F = 23.1 Hz, C5), 23.9 (–, C14),
21.8 (+, C13), 13.7 (+, C15) ppm. MS (EI, 70 eV): m/z (%) = 378
(13) [M]+, 314 (13), 236 (12), 223 (86), 191 (16), 167 (100), 155 (22),
140 (11), 108 (22). HRMS (ESI): m/z calcd. for C17H15FN2O3S2
[M + H]+ 379.0586; found 379.0583.
1
537, 500, 469, 462, 433, 413 cm–1. H NMR (600 MHz, CDCl3): δ
= 8.09 (dd, JH,F = 8.8, JH,H = 2.8 Hz, 1 H, 8-H), 8.06–8.04 (m,
2 H, 12-H, 12Ј-H), 7.85 (dd, JH,H = 9.1, JH,F = 5.1 Hz, 1 H, 5-H),
7.48 (ddd, JH,H = 9.1, 2.8, JH,F = 7.7 Hz, 1 H, 6-H), 7.41–7.40 (m,
2 H, 13-H, 13Ј-H), 3.35 (q, JH,H = 7.4 Hz, 2 H, 9-H2), 2.48 (s, 3 H,
15-H3), 1.29 (t, JH,H = 7.4 Hz, 3 H, 10-H3) ppm. 13C NMR
C–C Coupling of (Tosyloxy)quinoxalines. General Procedure III:[23]
Under
a nitrogen atmosphere, an oven-dried Schlenk tube
equipped with a cooling finger was filled with the tosyloxyquinox-
aline (1.0 equiv.), boronic acid (2.0 equiv.), Pd(OAc)2 (4 mol-%),
XPhos (19; 8 mol-%) and K3PO4 (3.0 equiv.) followed by evacua-
tion of the reaction vessel and backfilling with nitrogen. Anhydrous
toluene was then added and the mixture was stirred at 100 °C for
the appropriate time. After completion of the reaction, the cooled
suspension was diluted with ethyl acetate (5 mL) and washed with
saturated NaCl solution (5 mL) and water (5–10 mL). The organic
phase was dried with Na2SO4 and the solvent was removed with a
rotary evaporator. Finally, the obtained residue was purified by col-
umn chromatography and dried in vacuo.
1
(150 MHz, CDCl3): δ = 162.8 (o, d, JC,F = 254.2 Hz, C7), 152.0
3
(o, C3), 146.1 (o, C14), 137.0 (o, d, JC,F = 11.0 Hz, C8a), 135.7
(o, C2), 135.4 (o, C4a), 133.6 (o, C11), 131.1 (+, d, 3JC,F = 8.8 Hz,
C5), 129.7 (+, 2 C, C13, C13Ј), 129.2 (+, 2 C, C12, C12Ј), 121.2 (+,
2
2
d, JC,F = 25.3 Hz, C6), 104.0 (+, d, JC,F = 27.5 Hz, C8), 26.6 (–,
C9), 21.8 (+, C15), 15.1 (+, C10) ppm. MS (EI, 20 eV): m/z (%) =
394 (3) [M]+, 377 (27) [M – OH]+, 304 (13), 223 (25), 196 (18), 190
(12), 155 (100). HRMS (ESI): m/z calcd. for C17H15FN2O4S2 [M +
H]+ 395.0536; found 395.0537.
2-(Tosyloxy)quinoxaline (24): Following general procedure II: NaH
(60 wt.-%, 151 mg, 3.76 mmol), 2-quinoxalinone (23; 500 mg,
3.42 mmol) in anhydrous DMF (5 mL), p-TsCl (665 mg,
3.49 mmol); reaction time: 1.5 h; purification: After dilution with
brine (20 mL) the organic phase was extracted with Et2O (3ϫ
20 mL). The combined organic phases were dried with Na2SO4 and
the solvent was removed in vacuo, then the residue was purified by
column chromatography (PE/EtOAc, 3:1; 50 g silica gel) to give 24
(795 mg, 2.65 mmol, 77%) as a colourless solid; m.p. 100 °C,
2-(p-Tolyl)quinoxaline (25): Following general procedure III: 2-tos-
yloxyquinoxaline (24; 450 mg, 1.5 mmol), (4-tolyl)boronic acid
(408 mg, 3.0 mmol), XPhos (57.0 mg, 0.12 mmol), Pd(OAc)2
(13.0 mg, 0.06 mmol) and K3PO4 (955 mg, 4.5 mmol) in anhydrous
toluene (8 mL); column chromatography (PE/EtOAc, 30:1; 100 g
silica gel) gave 25 (319 mg, 1.448 mmol, 97%) as a colourless solid;
m.p. 97 °C. IR (KBr): ν = 3056, 3028, 3016, 2922, 2859, 1613, 1578,
˜
1545, 1489, 1467, 1450, 1430, 1310, 1288, 1276, 1264, 1231, 1213,
1185, 1137, 1125, 1045, 1015, 956, 933, 830, 753, 714, 670, 607,
305 °C (dec.). IR (ATR): ν = 3102, 3033, 2926, 1597, 1575, 1569,
˜
1496, 1401, 1378, 1362, 1338, 1311, 1292, 1265, 1213, 1199, 1190,
1172, 1129, 1121, 1088, 1016, 991, 982, 966, 917, 907, 877, 846,
815, 804, 793, 769, 703, 670, 648, 633, 615, 578, 548, 540, 532, 526,
485, 481, 452, 417, 411 cm–1. 1H NMR (600 MHz, CDCl3): δ =
8.65 (s, 1 H, 3-H), 8.11–8.09 (m, 1 H, 5-H), 8.03–8.01 (m, 2 H, 10-
H, 10Ј-H), 7.91–7.89 (m, 1 H, 8-H), 7.78–7.73 (m, 2 H, 6-H, 7-H),
7.38 (dd, JH,H = 8.5, 0.6 Hz, 2 H, 11-H, 11Ј-H), 2.46 (s, 3 H, 13-
H3) ppm. 13C NMR (150 MHz, CDCl3): δ = 150.9 (o, C2), 145.9
(o, C12), 141.2 (o, C4a), 139.7 (o, C8a), 139.1 (+, C3), 133.3 (o,
C9), 131.1 (+, C7), 129.8 (+, 2 C, C11, C11Ј), 129.7 (+, C6), 129.1
(+, C5), 129.0 (+, 2 C, C10, C10Ј), 128.5 (+, C8), 21.7 (+,
C13) ppm. MS (CI): m/z (%) = 301 (4) [M + H]+, 236 (100), 208
(16), 155 (23), 145 (9), 91 (20).
1
555, 487, 478, 408 cm–1. H NMR (600 MHz, CDCl3): δ = 9.31 (s,
1 H, 3-H), 8.15–8.13 (m, 1 H, 8-H), 8.11–8.09 (m, 3 H, 5-H, 10-H,
10Ј-H), 7.78–7.75 (m, 1 H, 7-H), 7.74–7.71 (m, 1 H, 6-H), 7.37 (dd,
JH,H = 7.9, 0.6 Hz, 2 H, 11-H, 11Ј-H), 2.45 (s, 3 H, 13-H3) ppm.
13C NMR (150 MHz, CDCl3): δ = 151.8 (o, C2), 143.3 (+, C3),
142.3 (o, C8a), 141.4 (o, C4a), 140.5 (o, C12), 134.0 (o, C9), 130.2
(+, C7), 129.9 (+, 2 C, C11, C11Ј), 129.5 (+, C8), 129.3 (+, C6),
129.1 (+, C5), 127.4 (+, 2 C, C10, C10Ј), 21.4 (+, C13) ppm. MS
(EI, 70 eV): m/z (%) = 220 (100) [M]+, 205 (6) [M – CH3]+, 193
(21), 178 (4), 165 (9), 116 (7), 110 (9).
3-(Ethylthio)-6-fluoro-2-(p-tolyl)quinoxaline (28): Following general
procedure III: 2-(ethylthio)-7-fluoro-3-(tosyloxy)quinoxaline (27;
378 mg, 1.0 mmol), (4-tolyl)boronic acid (272 mg, 2.0 mmol),
2-(Ethylthio)-7-fluoro-3-(tosyloxy)quinoxaline (27): Following gene-
ral procedure II: NaH (60 wt.-%, 64 mg, 1.605 mmol), 3-(eth- XPhos (38.0 mg, 0.08 mmol), Pd(OAc)2 (9.0 mg, 0.04 mmol) and
ylthio)-6-fluoroquinoxalin-2(1H)-one (26; 300 mg, 1.338 mmol) in K3PO4 (637 mg, 3.0 mmol) in anhydrous toluene (6 mL); column
anhydrous DMF (5 mL), p-TsCl (281 mg, 1.472 mmol); reaction chromatography (PE/EtOAc, 30:1; 30 g silica gel) gave 28 (237 mg,
time: 2.0 h; purification: After dilution with Et2O (15 mL) the or-
ganic phase was washed with brine (5 mL) and H2O (3ϫ 5 mL).
The organic phase was dried with Na2SO4 and the solvent was
removed in vacuo to give 27 (479 mg, 1.266 mmol, 95%) as a pale-
0.794 mmol, 79%) as a pale-yellow solid; m.p. 107 °C. IR (KBr): ν
˜
= 3078, 3052, 3031, 2963, 2930, 2869, 1616, 1566, 1538, 1510, 1487,
1443, 1413, 1382, 1347, 1316, 1306, 1286, 1257, 1225, 1211, 1185,
1154, 1118, 1092, 1051, 1025, 992, 969, 855, 840, 830, 815, 787,
774, 757, 726, 712, 626, 614, 567, 507, 478, 424, 411 cm–1. 1H NMR
(600 MHz, CDCl3): δ = 8.03–8.01 (m, 1 H, 8-H), 7.67–7.66 (m, 2 H,
11-H, 11Ј-H), 7.59–7.57 (m, 1 H, 5-H), 7.38 (ddd, JH,H = 9.1, 2.8,
JH,F = 8.2 Hz, 1 H, 7-H), 7.34–7.32 (m, 2 H, 10-H, 10Ј-H), 3.27 (q,
yellow solid; m.p. 114 °C, 302 °C (dec.). IR (ATR): ν = 3094, 2977,
˜
2932, 1619, 1595, 1582, 1552, 1497, 1448, 1387, 1371, 1299, 1282,
1259, 1230, 1215, 1192, 1174, 1136, 1116, 1091, 1065, 1056, 1017,
983, 967, 960, 890, 865, 833, 811, 797, 775, 758, 744, 718, 698, 688,
662, 623, 613, 606, 580, 545, 532, 519, 496, 485, 474, 444, 429, 415,
JH,H = 7.5 Hz, 2 H, 14-H2), 2.45 (s, 3 H, 13-H3), 1.40 (t, JH,H
=
406 cm–1. 1H NMR (600 MHz, CDCl3): δ = 8.10–8.08 (m, 2 H, 10- 7.5 Hz, 3 H, 15-H3) ppm. 13C NMR (150 MHz, CDCl3): δ = 162.8
1
H, 10Ј-H), 7.79 (dd, JH,H = 9.2, JH,F = 5.7 Hz, 1 H, 8-H), 7.54 (dd,
JH,F = 9.2, JH,H = 2.8 Hz, 1 H, 5-H), 7.40–7.39 (m, 2 H, 11-H, 11Ј-
H), 7.34 (ddd, JH,H = 9.2, 2.8, JH,F = 8.1 Hz, 1 H, 7-H), 3.27 (q,
(o, d, JC,F = 250.9 Hz, C6), 157.0 (o, C3), 152.9 (o, C2), 142.2 (o,
3
d, JC,F = 13.2 Hz, C4a), 139.9 (o, C12), 136.4 (o, C8a), 134.2 (o,
3
C9), 131.1 (+, d, JC,F = 9.9 Hz, C8), 129.2 (+, 2 C, C11, C11Ј),
2
JH,H = 7.3 Hz, 2 H, 14-H2), 2.47 (s, 3 H, 13-H3), 1.41 (t, JH,H
=
128.9 (+, 2 C, C10, C10Ј), 117.8 (+, d, JC,F = 25.3 Hz, C7), 111.4
Eur. J. Org. Chem. 2013, 8185–8196
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8195

J. Maichrowski, E. G. Hübner, D. E. Kaufmann
FULL PAPER
(+, d, JC,F = 20.9 Hz, C5), 25.1 (–, C14), 21.5 (+, C13), 13.8 (+,
C15) ppm. MS (EI, 70 eV): m/z (%) = 298 (25) [M]+, 283 (16) [M –
CH3]+, 269 (21) [M – CH2CH3]+, 255 (9), 237 (6), 214 (5), 180 (96),
152 (45), 124 (27), 120 (42), 105 (100). HRMS (EI): m/z calcd. for
C17H15FN2S [M]+ 298.0940; found 298.0942.
2
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Received: May 14, 2013
Published Online: October 11, 2013
8196
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8185–8196