Carbene-catalyzed aroylation of a 2-chloroquinoxaline n-oxide with aromatic aldehydes at room temperature

Article abstract of DOI:10.1002/ejoc.201402252

Starting from easily accessible 2-chloro-3-(cyclopentyloxy)-7- fluoroquinoxaline 1-oxide, 12 new biologically promising aroylquinoxaline N-oxides were synthesized through carbene-catalyzed aroylation of the chloro nitrone unit with different aromatic aldehydes in the presence of 1,3-dimethylimidazolium iodide as the carbene precursor. The optimized reaction conditions tolerated a broad bandwidth of aldehydes and allowed the synthesis of the corresponding ketones in yields up to 87%. Studies of their biological activities resulted in interesting specific cytotoxic effects against tumor cell lines. Copyright

Full text of DOI:10.1002/ejoc.201402252

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402252
Carbene-Catalyzed Aroylation of a 2-Chloroquinoxaline N-Oxide with
Aromatic Aldehydes at Room Temperature[‡]
Jan Maichrowski,[a] Aman Bhasin,[b] Florenz Sasse,[b] and Dieter E. Kaufmann*[a]
Keywords: Nitrogen heterocycles / Aroylation / Carbenes / Homogeneous catalysis / Ketones
Starting from easily accessible 2-chloro-3-(cyclopentyloxy)-
7-fluoroquinoxaline 1-oxide, 12 new biologically promising
aroylquinoxaline N-oxides were synthesized through carb-
ene-catalyzed aroylation of the chloro nitrone unit with dif-
ferent aromatic aldehydes in the presence of 1,3-dimethyl-
imidazolium iodide as the carbene precursor. The optimized
reaction conditions tolerated a broad bandwidth of alde-
hydes and allowed the synthesis of the corresponding
ketones in yields up to 87%. Studies of their biological activi-
ties resulted in interesting specific cytotoxic effects against
tumor cell lines.
Introduction
Although quinoxalines are rarely found in nature, such
as the antibiotic echinomycin, which was first isolated from
Streptomyces echinatus in 1957,[1] a large number of quinox-
aline derivatives have been synthesized through various syn-
thetic routes.[2] Several examples of this important class of
N-heterocycles show highly diverse properties and are able
to act, for example, as anticancer agents[3] or as antagonists
for certain receptors in the human organism such as hista-
mine H4,[4] AMPA,[5] or Interleukin-8.[6] The easily acces-
sible quinoxaline N,NЈ-dioxides out of the Beirut reaction
of benzofurazan N-oxide with appropriate nucleophiles[7]
are also interesting representatives of the quinoxaline class
that show, among others, cancerostatic properties such as
thienylcarbonyl-substituted quinoxaline 1,4-dioxide 1 (Fig-
ure 1).[8] Beyond that, benzoylated N,NЈ-dioxide 2 was re-
ported to act as an antitrypanosomatid agent against the
pathogen of the Chagas disease Trypanosoma cruzi.[9]
During our ongoing studies on the synthesis of biolo-
gically active fluorinated quinoxaline N-monooxides,[10] our
aim was to synthesize structurally similar aroylquinoxalines
by means of a C–C coupling reaction of 2-chloro-3-(cyclo-
pentyloxy)-7-fluoroquinoxaline 1-oxide (5). This versatile
building block is easily accessible on a multigram scale by
the previously reported annulation reaction of 1,1,2-tri-
Figure 1. Reported bioactive aroylated quinoxaline N,NЈ-dioxides.
chloro-2-nitroethylene (TCNiE, 3) with p-fluoroaniline[11]
and subsequent O-alkylation of the obtained quinoxalinone
N-oxide scaffold with cyclopentanol under Mitsunobu con-
ditions[10] (Scheme 1).
Scheme 1. Synthesis of 2-chloro-3-(cyclopentyloxy)-7-fluoroquin-
oxaline 1-oxide (5) starting from TCNiE (3). Reagents and condi-
tions: (a) 4-fluoroaniline, NEt3, (MeOH), 40 °C; (b) cyclopentanol,
diethyl azodicarboxylate, PPh3, (THF), 0–40 °C.
In 1990, Miyashita and co-workers published an efficient
method for the nucleophilic aroylation of 4-chloro-1H-pyr-
azolo[3,4-d]pyrimidines with aromatic aldehydes in the
presence of 1,3-dimethylbenzimidazolium iodide, which
[‡] Chemistry of Functionalized Quinoxaline N-Oxides, III. Part
II: J. Maichrowski, E. G. Hübner, D. E. Kaufmann, Eur. J. Org. forms a catalytically active carbene species by reaction with
an appropriate base.[12] Later, the same research group ap-
Chem. 2013, 8185–8196.
[a] Institute of Organic Chemistry, Clausthal University of
plied this methodology to the synthesis of 4-aroylcinnolines,
1-aroylphthalazines, and 2-aroylquinoxalines by using aro-
matic aldehydes as substrates and catalytic amounts of 1,3-
dimethylimidazolium iodide.[13] Inspired by these good re-
sults, we wanted to investigate the hitherto unknown nu-
cleophilic aroylation of the chloro nitrone unit of our easily
accessible chloroquinoxaline 1-oxide 5.
Technology,
Leibnizstrasse 6, 38678 Clausthal-Zellerfeld, Germany
E-mail: dieter.kaufmann@tu-clausthal.de
www.ioc.tu-clausthal.de
[b] Department of Chemical Biology, Helmholtz Centre for
Infection Research,
Inhoffenstrasse 7, 38124 Braunschweig, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402252.
Eur. J. Org. Chem. 2014, 4457–4460
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4457

J. Maichrowski, A. Bhasin, F. Sasse, D. E. Kaufmann
SHORT COMMUNICATION
yields (Table 2). In general, the unsubstituted benzaldehyde,
electron-rich, and monohalogenated substrates such as 4-
bromo- and 2-fluorobenzaldehyde gave the best results
within short reaction times (0.5–1 h). Whereas bicyclic 2-
naphthaldehyde gave the corresponding ketone 7h in 87%
yield, isomeric 1-naphthaldehyde led to the desired product
7g in a lower yield of 60% under identical conditions,
most likely because of the higher steric hindrance of the α-
naphthoyl group relative to that of the β-naphthoyl substit-
uent (Table 2, Entries 7 and 8).
Results and Discussion
At first, we started to synthesize the required carbene
precursor 1,3-dimethylimidazolium iodide (6) by reaction of
1-methylimidazole with methyl iodide in THF. The almost
quantitatively obtained and very hygroscopic crude product
had to be recrystallized owing to trace amounts of water
that could not be completely removed by washing the salt
with different solvents such as dry n-hexane and dry Et2O.
Dry isopropyl alcohol proved to be the best solvent for the
recrystallization process under nitrogen, which led to the
desired imidazolium salt 6 in 81% yield and in excellent
purity according to analysis by NMR spectroscopy
(Scheme 2).
Table 2. Carbene-catalyzed aroylation reaction of O-alkylated quin-
oxaline N-oxide 5 with different aldehydes.
Scheme 2. Alkylation of 1-imidazole with methyl iodide.
Next, we applied the reported conditions for the aroyl-
ation of 2-chloroquinoxaline[13] to chloroquinoxaline N-ox-
ide 5 by using the synthesized azolium salt in catalytic
amounts. Although the reaction of 5 with benzaldehyde in
the presence of sodium hydride and catalyst 6 in dry THF
took place under reflux conditions, the desired benzoylated
product 7a could only be obtained in a moderate yield after
a reaction time of 2 h besides large amounts of unreacted
starting material (Table 1, Entry 1). Unfortunately, pro-
longation of the reaction time did not significantly affect
the outcome of this reaction. In contrast, the change to
DMF as a more polar aprotic solvent significantly in-
creased the reaction yield from 20 to 74% within a compar-
able reaction time and temperature. Surprisingly, a decrease
in the reaction temperature to room temperature allowed
the full conversion of 5 within 30 min and gave 7a in a very
good yield of 86% (Table 1, Entry 4).
Table 1. Optimization of the carbene-catalyzed aroylation of O-alk-
ylated chloroquinoxaline N-oxide 5 with benzaldehyde.[a]
Entry
Solvent
Temperature
Time [h]
Yield [%][b]
1
2
3
4
dry THF
dry THF
dry DMF
dry DMF
reflux
reflux
65 °C
r.t.
2
8
3
20
23
74
86
0.5
[a] Yield of isolated product after column chromatography.
[a] Reaction conditions: PhCHO (1.2 equiv.), NaH (1.3 equiv.), 1,3-
dimethylimidazolium iodide (6; 0.3 equiv.). [b] Yield of isolated
product after column chromatography.
As expected, nitro-substituted arenecarbaldehydes such
as 4-nitrobenzaldehyde were not tolerated as substrates in
These optimized reaction conditions were successfully this base-induced aroylation reaction because of the nitro
applied to a number of different aromatic and hetero- group’s reactivity towards sodium hydride as a strong base.
aromatic aldehydes, which allowed the isolation of aroyl- Surprisingly, also the reduced analogue, 4-(dimethylamino)-
ated quinoxaline N-oxides 7a–l in moderate to very good benzaldehyde, could not be converted into the correspond-
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Eur. J. Org. Chem. 2014, 4457–4460

Carbene-Catalyzed Aroylation of a 2-Chloroquinoxaline N-Oxide
ing ketone. We were pleased that a few heterocyclic sub- over, it represents a valuable and alternative preparation
strates such as nicotinaldehyde, thiophenecarbaldehydes, procedure for such heterocycles with respect to the estab-
and 3-furancarbaldehyde could also be applied to the nu- lished Beirut reaction. The new aroylquinoxaline N-oxides
cleophilic aroylation of 5.
displayed interesting specific cytotoxic effects against tumor
The newly synthesized aroylquinoxaline N-oxides were cell lines.
evaluated for their biological activity with several microor-
ganisms (Bacillus subtilis DSM10, Pseudomonas aeruginosa
Experimental Section
DSM50071, Escherichia coli TolC HZI strain, Staphylococ-
cus aureus DSM346, Chromobacterium violaceum
General Procedure for the Synthesis of Aroylated O-Alkylquinox-
DSM30191, Candida albicans DSM1386, and Mucor hi- aline 1-Oxides 7a–l: 1,3-Dimethylimidazolium iodide (6; 36 mg,
0.159 mmol), the aldehyde (1.2 equiv.), and sodium hydride (60 wt.-
% dispersion in mineral oil, 28 mg, 0.690 mmol) were added to a
stirred solution of 2-chloroquinoxaline N-oxide (5; 150 mg,
0.531 mmol) in dry DMF (2 mL) at 0 °C under nitrogen. The mix-
ture was stirred at room temperature for 30 min to 1 h. Then, water
(10 mL) was added, and the organic phase was extracted with di-
ethyl ether (3ϫ 10 mL). The combined organic extracts were dried
with sodium sulfate and then concentrated in vacuo. The residue
was purified by column chromatography (30 g of silica gel; petro-
leum ether/ethyl acetate, 15:1) and dried in vacuo.
emalis DSM2656), four mammalian cell lines, one estab-
lished mouse cell line, two human tumor cell lines, and pri-
mary healthy endothelial cells. Although the compounds
were not active against the microorganisms, many of the
aroylquinoxaline N-oxides had clear cytotoxic effects
(Table 3). The only compound that showed no toxicity was
pyridyl derivative 7i. Interestingly, some compounds dis-
played a striking preference for tumor cell lines over normal
human cells (HUVEC) and the mouse fibroblast cell line
L-929; for example, 7a and 7b showed good activity with
KB-3-1, which is a human cervix carcinoma cell line, and
A-549, human lung cancer cells, whereas the IC50 values for
the two nontumor-derived cell types were beyond the test
range.
2-Benzoyl-3-(cyclopentyloxy)-7-fluoroquinoxaline 1-Oxide (7a): The
general procedure gave 7a as
a pale yellow solid (161 mg,
1
0.457 mmol, 86%). M.p. 136, 261 °C (dec.). H NMR (600 MHz,
CDCl3): δ = 8.12 (dd, JH,F = 8.7 Hz, JH,H = 2.9 Hz, 1 H, 8-H),
7.90 (dd, JH,H = 9.2 Hz, JH,F = 5.1 Hz, 1 H, 5-H), 7.83 (dd, JH,H
= 8.4, 1.2 Hz, 2 H, 11-H, 11Ј-H), 7.65–7.62 (m, 1 H, 13-H), 7.53
(ddd, JH,H = 9.2, 2.9 Hz, JH,F = 7.8 Hz, 1 H, 6-H), 7.50–7.47 (m,
2 H, 12-H, 12Ј-H), 5.63–5.61 (m, 1 H, 14-H), 1.93–1.87 (m, 2 H,
15-H, 15Ј-H), 1.77–1.72 (m, 2 H, 15-H, 15Ј-H), 1.56–1.50 (m, 4 H,
16-H2, 16Ј-H2) ppm. 13C NMR (150 MHz, CDCl3): δ = 186.8 (o,
Table 3. Cytotoxicity of the quinoxaline derivatives against mam-
malian cells.[a]
Compound
IC50 [μgmL–1]
KB-3-1[c] A-549[d]
L-929[b]
HUVEC[e]
1
C9), 161.0 (o, d, JC,F = 250.9 Hz, C7), 156.5 (o, C3), 138.9 (o,
7a
7b
7c
7d
7e
7f
7g
7h
7i
Ͼ37
Ͼ37
30
10
10
Ͼ37
Ͼ37
Ͼ37
Ͼ37
Ͼ37
20
6
20
18
9
15
7
Ͼ37
Ͼ37
4.5
12
6
7
Ͼ37
12
Ͼ37
15
5.5
37
3
C4a), 135.1 (o, C10), 134.6 (+, C13), 134.4 (o, d, JC,F = 11.0 Hz,
3
C8a), 130.5 (o, C2), 130.0 (+, d, JC,F = 8.8 Hz, C5), 129.0 (+, 2
15
20
15
20
Ͼ37
4
Ͼ37
20
20
25
2
C, C12, C12Ј), 128.9 (+, 2 C, C11, C11Ј), 121.8 (+, d, JC,F
=
24.2 Hz, C6), 104.4 (+, d, 2JC,F = 27.5 Hz, C8), 80.6 (+, C14), 32.6
9
(–, 2 C, C15, C15Ј), 23.5 (–, 2 C, C16, C16Ј) ppm. IR (ATR): ν =
˜
5.5
6.5
8
Ͼ37
6.5
8
3087, 3059, 2975, 2953, 2923, 2877, 1670 (C=O), 1619, 1597, 1589,
1559, 1503, 1451, 1438, 1432, 1413, 1397, 1360, 1333, 1326, 1318,
1307, 1290, 1233, 1192, 1178, 1163, 1136, 1122, 1090, 1073, 1034,
1026, 1001, 990, 955, 940, 921, 897, 870, 852, 828, 809, 771, 759,
710, 693, 665, 653, 607, 593, 572, 552, 528, 452, 442, 411 cm–1. MS
(CI): m/z (%) = 353 (3) [M + H]+, 267 (5), 259 (36), 207 (3), 191
(26), 163 (100), 135 (5), 105 (17). HRMS (EI): m/z calcd. for
C20H17FN2O3 [M]+ 352.1223; found 352.1222.
7j
7k
7l
25
21
[a] Results of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol-
ium bromide (MTT) assay after 5 d of incubation. [b] Mouse fibro-
blasts. [c] Cervix carcinoma. [d] Lung carcinoma. [e] Endothelial
cells.
Supporting Information (see footnote on the first page of this arti-
cle): Further experimental details and copies of the 1H and 13C
NMR spectra.
Conclusions
Acknowledgments
We successfully synthesized 12 new aroylquinoxaline N-
oxides through the optimized carbene-catalyzed nucleo-
philic aroylation of easily accessible O-alkylated chloro-
quinoxaline N-oxide 5 with different aromatic aldehydes in
the presence of 1,3-dimethylimidazolium iodide as the carb-
ene precursor. To the best of our knowledge, this is the first
carbene-catalyzed aroylation reaction that could be applied
to the chloro nitrone unit of N-oxidized quinoxalines. Ow-
ing to its high substrate tolerance and use of cheap reagents,
this method allows easy access to a broad range of bio-
logically promising aroylated quinoxaline N-oxides. More-
The authors gratefully thank Dr. Gerald Dräger, Leibniz Univer-
sity Hannover, for measuring the high-resolution mass spectra.
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J. Maichrowski, A. Bhasin, F. Sasse, D. E. Kaufmann
SHORT COMMUNICATION
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Received: March 12, 2014
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