α-Nitro Epoxides in Organic Synthesis: Development of a One-Pot Organocatalytic Strategy for the Synthesis of Quinoxalines

Article abstract of DOI:10.1002/ejoc.201301591

A new strategy for the synthesis of biologically active quinoxalines by using versatile α-nitro epoxides as starting compounds has been developed. In addition, the in situ organocatalytic epoxidation of electron-poor nitro olefins followed by condensation with 1,2-phenylenediamines to provide quinoxalines in one pot has been demonstrated.

Full text of DOI:10.1002/ejoc.201301591

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FULL PAPER
DOI: 10.1002/ejoc.201301591
α-Nitro Epoxides in Organic Synthesis: Development of a One-Pot
Organocatalytic Strategy for the Synthesis of Quinoxalines
Mohammad M. Ibrahim,[a][‡][‡‡] Dominik Grau,[a][‡‡] Frank Hampel,[a] and
Svetlana B. Tsogoeva*[a]
Keywords: Synthesis design / Organocatalysis / Nitrogen heterocycles / Epoxidation / Nitro compounds
A new strategy for the synthesis of biologically active quin-
oxalines by using versatile α-nitro epoxides as starting com-
pounds has been developed. In addition, the in situ organo-
catalytic epoxidation of electron-poor nitro olefins followed
by condensation with 1,2-phenylenediamines to provide
quinoxalines in one pot has been demonstrated.
Introduction
Quinoxaline heterocycles are ubiquitous in pharmaceuti-
cal compounds. They are important subunits in many natu-
rally occurring pharmaceutical agents, for example, echino-
mycin, which shows, in addition to its antibiotic activity,
promising properties in anticancer therapy.[1] Among such
macromolecular compounds of natural origin, the prepara-
tion of low-weight molecules comprising the quinoxaline
moiety leads to compounds with promising bioactivity
against hepatitis C, depression,[2] and cancer (Figure 1).[3,4]
Owing to its extended π-system, the quinoxaline heterocycle
is also incorporated in macromolecular dyes for dye-sensi-
tized solar cells (DSSCs)[5,6] and photoabsorbent[7] or elec-
troluminescent materials.[8]
Figure 1. Selected examples of bioactive compounds comprising
quinoxaline subunits.
The common synthesis of quinoxalines goes back to the
traditional condensation of 1,2-dicarbonyl compounds or
α-halo-β-ketones with 1,2-phenylenediamine.[9] Neverthe- lenediamines[9] have some practical drawbacks, including
less, most of the known methods to synthesize the reaction high reaction temperatures, strongly acidic media, long re-
precursors (e.g., 1,2-dicarbonyl compounds) cannot be con- action times, critical product isolation, inconvenient rea-
sidered environmentally benign or facile. For example, the gents, or the use of expensive and environmentally detri-
oxidation of alkynes (one of the most common strategies mental metal catalysts. Thus, alternative one-pot ap-
towards 1,2-dicarbonyl compounds)[10] often requires rare proaches that involve environmentally friendly metal-free
or expensive materials and harsh reaction conditions. The reaction steps and use easily accessible starting compounds
oxidation of unsymmetrical benzoin is also a well known might offer an expedient complementary route to quinoxa-
synthetic route.[11] However, the preparation of benzoin re- lines.
quires toxic cyanation reagents.
Undoubtedly, epoxides represent particularly attractive
In addition, most of the condensation reactions of 1,2- and versatile starting compounds in organic synthesis.[12,13]
dicarbonyl compounds or α-halo-β-ketones with 1,2-pheny- Although the preparation and synthetic potential of un-
functionalized epoxides and epoxy ketones is already well
documented,[12,13] the synthesis and application of easily ac-
[a] Department of Chemistry and Pharmacy, Institute of Organic
Chemistry I, University of Erlangen-Nürnberg,
cessible α-nitro epoxides are scarcely known[14,15] and still
remain a challenging task.
Recently, we developed a two-step one-pot sequence to
yield various 1,3-thiazoles by organocatalytic epoxidation
of β-methyl-β-nitrostyrene (1, readily available from benzal-
dehyde and nitroethane by a one-pot Henry reaction/de-
hydration sequence) and the subsequent condensation with
Henkestraße 42, 91054 Erlangen, Germany
E-mail: svetlana.tsogoeva@fau.de
http://www.chemie.uni-erlangen.de/tsogoeva/
[‡] Present address: Department of Chemistry, Faculty of Science,
University of Al al-Bayt,
P. O. Box 130040, 25113 Al-Mafraq, Jordan
[‡‡]These authors contributed equally to this work.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301591.
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M. M. Ibrahim, D. Grau, F. Hampel, S. B. Tsogoeva
FULL PAPER
thioamide derivatives.[15] To the best of our knowledge, the Table 1. Optimization of conditions for the quinoxaline formation.
use of α-nitro epoxides for the synthesis of quinoxalines and
related heterocycles is not yet literature-known.
As a continuation of our interest in the exploration of
the potential of α-nitro epoxides for the preparation of
bioactive heterocyclic molecules, we envisioned the develop-
ment of a convenient synthetic method towards quinoxaline
heterocycles.
We thought that the formation of the quinoxaline prod-
Entry
Solvent
Additive (equiv.) c (m)
Yield [%][a]
uct 4 may occur through (1) the attack by one of the amine
functions of the diamine 3 at the less sterically hindered
position of the α-nitro epoxide 2 (aminolysis step), (2) a
further intramolecular attack by the second amine group,
followed by ring closure accompanied by the release of
nitrous acid, (3) subsequent dehydration, and (4) dehydro-
genation/aromatization steps (Scheme 1).
1
2
3
4
5
6
MeOH
MeOH
MeOH
H2O
–
1
1
1
1
1
1
1
1
1
63
43
43
46
53
37
37
65
62
54
67
TFA (0.1)
DBU (0.1)
–
–
–
–
–
–
–
–
buffer[b]
CHCl3
toluene
toluene
n-hexane
n-hexane
n-hexane
7
8[c]
9
10[d]
11
1
0.30
[a] Yield of the isolated product after column chromatography. [b]
Aqueous Na2PO3/NaHPO3 buffer, pH 7.2. [c] Reaction tempera-
ture: 70 °C. [d] Reaction temperature: 45 °C.
chloroform decreased the yield to 37% (Table 1, Entry 6).
When the reaction was performed in a nonpolar solvent
such as toluene at room temperature, the quinoxaline prod-
uct 4 was obtained in 37% yield, and an increase in reaction
temperature to 70 °C gave a higher yield (Table 1, Entries 7
and 8).
Clearly, the polarity of solvent does not strongly affect
the reaction yields (see Table 1). Hence, we propose that the
final aromatization step (Scheme 1), in which the solvent
does not play a vital role, is rate-determining.
Nonpolar n-hexane was selected for further investigation
because it was the best solvent in terms of cost, reaction
temperature, and yield compared to the other solvents used
in this step (Table 1, Entry 11). Furthermore, it was the
most suitable solvent for the epoxidation of electron-poor
nitro olefins.[15a]
On the basis of the results obtained from the single pro-
cess optimization of the condensation of nitro epoxide 2
with diamine 3, the development of a one-pot procedure
was performed (Table 2); the previously developed DBU-
catalyzed epoxidation of nitro olefins to nitro epoxides was
Scheme 1. Proposed mechanism for the quinoxaline formation
from α-nitro epoxides.
Here, we wish to report the results of the experiments
performed to demonstrate this hypothesized process. We
also report herein the one-pot methodology comprising the
organocatalytic generation of α-nitro epoxides with the 1,8-
diazabicycloundec-7-ene/tert-butyl hydroperoxide (DBU/
TBHP) system and their subsequent treatment with 1,2-
phenylenediamines to afford various substituted quinox-
alines in up to 82% yield after two steps.
Results and Discussion
The α-nitro epoxide 2 and 1,2-phenylenediamine (3) were employed.[15a]
selected as model substrates, and the reaction step for the
We started our investigation of the one-pot process by
quinoxaline formation was studied at room temperature in adding 2.0 equiv. of diamine 3 after 1 h reaction time for
different solvents such as methanol, water, chloroform, tol- the epoxidation in n-hexane, and the quinoxaline product 4
uene, and n-hexane. The reaction proceeded for 24 h in all was isolated in 30% yield over two steps (Table 2, Entry 1).
solvents with and without additives to give quinoxaline 4 Motivated by this result, we hoped to improve the yield
(Table 1).
further by using additives in the second step of the one-pot
MeOH was used as a reaction solvent without any addi- process. MeOH was used, because as shown in Table 1, the
tives to give quinoxaline 4 in 63% yield, and when it was formation of 4 was very efficient in this solvent (Table 1,
used with the addition of DBU (0.1 equiv.) or trifluoro- Entry 1). Thus, MeOH (13 equiv.) was added to the second
acetic acid (TFA; 0.1 equiv.) the yield decreased to 43% step of the one-pot process, and the yield improved to 49%
(Table 1, Entries 1–3). Surprisingly, the reaction gave mod- (Table 2, Entry 2). The combination of two additives,
erate yields when water or aqueous buffer were used as the MeOH (13 equiv.) and TFA (0.1 equiv.), reduced the yield
reaction solvents (Table 1, Entries 4 and 5). The use of to 38% (Table 2, Entry 3).
2
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α-Nitro Epoxides in Organic Synthesis
Table 2. Optimization of the one-pot process.[a]
Table 3. Scope of substrates.
Entry
Additive (equiv.)
Yield [%][b]
1
2
3
4
5
6
7
8
–
30
49
38
46
25
43
67
57
MeOH (13)
MeOH (13)/TFA (0.1)
KI (0.1)
HFiPr (0.28)
HFiPr (2.8)
HFiPr (28)
HFiPr (56)
[a] All reactions were performed with 1 (0.25 mmol, 1 equiv.) and
3 (0.50 mmol, 2 equiv.) in n-hexane (0.824 mL). [b] Yield of the
isolated product after column chromatography.
When potassium iodide (0.1 equiv) was added, the quin-
oxaline 4 was obtained in 46% yield (Table 2, Entry 4). As
the positive effect of 1,1,1,3,3,3-hexafluoro-2-propanol
(HFiPr) in the preparation of some heterocycles has been
reported,[16] it was tested as a cosolvent, and the yield of
quinoxaline was improved to 67% only by using 28 equiv.
of HFiPr (Table 2, Entries 5, 6, and 8 vs. Entry 7).
We next examined the scope of the two-step one-pot pro-
cess for different nitroalkenes and diamines under the opti-
mized reaction conditions. The results are summarized in
Table 3. Generally, most of the substrates provided moder-
ate to good yields with DBU applied at only 5 mol-% load-
ing. Moderate to very good yields (44–82%) were obtained
over two steps by using alkenes and diamines with R1 and/
or R2 = H and/or Me on the aromatic ring (Table 3, En-
tries 1–4). The yield of the corresponding quinoxaline was
53% with R1 = OMe and R2 = Me (Table 3, Entry 5). With
R1 = Br and R2 = H or Me, the quinoxalines were obtained
in 42 and 66% yield, respectively (Table 3, Entries 6 and 7).
Furthermore, a lower yield was obtained with an electron-
withdrawing substituent (CF3) on the aromatic ring
(Table 3, Entry 8).
[a] One-pot conditions from Table 2, Entry 7 were used for all en-
tries. [b] Yield of the isolated product after column chromatog-
raphy.
pain.[17e] To the best of our knowledge, the quinoxaline de-
rivatives 7 and 8 have not been reported previously.
To explore the possibility of extension of this method to
piperazine heterocycle synthesis, ethylenediamine was also
employed under the same reaction conditions starting from
1. However, the desired piperazine product did not form.
The results obtained by the use of aromatic and aliphatic
diamine substrates could be evidence of the inevitability of
the final aromatization step as driving force of this one-pot
sequence (Scheme 1).
Although quinoxalines 4–6 and 9–11 have been reported
previously,[17] only 4 and 5 were tested for their anticancer
activity,[17d] and only 11 was tested for the treatment of Figure 2. X-ray crystal structure of the quinoxaline 8.
Eur. J. Org. Chem. 0000, 0–0
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M. M. Ibrahim, D. Grau, F. Hampel, S. B. Tsogoeva
FULL PAPER
2,6,7-Trimethyl-3-phenylquinoxaline (5): White solid, m.p. 102–
104 °C (ref.[17b] 103–104 °C). 1H NMR (300 MHz, CDCl3): δ = 7.84
(s, 1 H), 7.79 (s, 1 H), 7.63–7.60 (m, 2 H), 7.53–7.45 (m, 3 H), 2.73
(s, 3 H), 2.48 (s, 3 H), 2.46 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 153.9, 151.3, 140.3, 139.9, 139.6, 139.3, 130.7, 128.9,
Compound 8 was recrystallized from ethanol. Notably, a
suitable crystal for the X-ray diffraction analysis of the new
quinoxaline 8 was obtained, and the structure was unam-
biguously determined by X-ray crystallography (Fig-
ure 2).[18]
128.7, 128.5, 128.3, 127.3, 24.2, 20.4, 20.3 ppm. IR (thin film): ν =
˜
3057, 2932, 2854, 1621, 1536, 1469, 1438 cm–1. MS (EI): m/z (%)
= 248 (58) [M]+, 247 (100) [M – H]+. HRMS (ESI): calcd. for
C17H17N2 [M + H]+ 249.13862; found 249.13984. C17H16N2·1/
8H2O: calcd. C 81.49, H 6.54, N 11.18; found C 81.74, H 6.83, N
11.17.
Conclusions
We have developed a synthetic route to functionalized
quinoxaline heterocycles that employs versatile α-nitro ep-
oxides as starting compounds. A two-step one-pot process,
which involves the epoxidation of easily accessible nitro ole-
fins with TBHP and the commercially available DBU as an
organocatalyst followed by the reaction with diamines un-
der very mild conditions has also been demonstrated.
The obtained quinoxalines are currently under biological
investigations, and the results will be reported elsewhere.
To extend the scope of the reactions with α-nitro epoxides,
further investigations are underway.
2-Methyl-3-p-tolylquinoxaline (6): Colorless oil. 1H NMR
(300 MHz, CDCl3): δ = 8.04–8.01 (m, 2 H), 7.74–7.65 (m, 2 H),
3
3
7.54 (d, J = 8.1 Hz, 2 H), 7.31 (d, J = 7.8 Hz, 2 H), 2.77 (s, 3 H),
2.43 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.0, 152.6,
141.0, 139.0, 136.1, 129.6, 129.22, 129.18, 129.14, 128.9, 128.2,
24.4, 21.4 ppm. IR (thin film): ν = 2917, 2854, 1710, 1611, 1552,
˜
1473, 1339 cm–1. MS (EI): m/z (%) = 234 (85) [M]+, 219 (100) [M –
CH3]+. C16H14N2·1/4H2O: calcd. C 80.47, H 6.12, N 11.73; found
C 80.45, H 6.05, N 11.86.
2,6,7-Trimethyl-3-p-tolylquinoxaline (7): White solid, m.p. 98 °C.
1H NMR (400 MHz, CDCl3): δ = 7.83 (s, 1 H), 7.77 (s, 1 H), 7.52
(d, 3J = 8.1 Hz, 2 H), 7.30 (d, 3J = 7.8 Hz, 2 H), 2.73 (s, 3 H), 2.48
(s, 3 H), 2.46 (s, 3 H), 2.42 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 154.0, 151.4, 140.02, 139.98, 139.5, 138.7, 136.5, 129.1,
128.9, 128.2, 127.3, 116.9, 24.3, 21.3, 20.4, 20.3 ppm. IR (thin film):
Experimental Section
General Information: 1H and 13C NMR spectra were recorded with
Bruker Avance (300 and 400) spectrometers. NMR spectra were
referenced to the residual solvent signal (1H: CDCl3, δ = 7.24 ppm;
13C: CDCl3, δ = 77.0 ppm) and recorded at ambient probe tempera-
ture. Mass spectra were obtained with Micromass Zabtec or Finni-
gan MAT 95 XP instruments. Thin-layer chromatography (TLC)
was performed on ALUGRAM® SIL G/UV254 (Macherey–Nagel)
and visualized by UV. Flash column chromatography was per-
formed with silica gel 60 m (Macherey–Nagel). Melting points were
determined with an Electrothermal-9002 apparatus. IR spectra
were recorded with samples as thin films with a Varian IR-660
spectrometer. All solvents were distilled before use. n-Hexane
(HPLC grade) was obtained from Fisher Scientific and used as re-
ceived. Nitro olefins were synthesized by the condensation of nitro-
ethane and the corresponding aldehydes according to a literature
procedure.[19] Other chemicals were used as received from common
commercial sources: TBHP (5–6 m in decane, Aldrich), DBU
(Fluka), 1,2-phenylenediamine (Aldrich), 4,5-dimethyl-1,2-pheny-
lenediamine (Aldrich).
ν = 2914, 2848, 1607, 1537, 1441, 1333 cm–1. HRMS (ESI): calcd.
˜
for C18H19N2 [M + H]+ 263.154275; found 263.154251. C18H18N2:
calcd. C 82.41, H 6.92, N 10.68; found C 82.05, H 6.84, N 10.64.
2-(4-Methoxyphenyl)-3,6,7-trimethylquinoxaline (8): Pale-yellow so-
1
lid, m.p. 115–116 °C. H NMR (300 MHz, CDCl3): δ = 7.81 (s, 1
3
3
H), 7.75 (s, 1 H), 7.59 (d, J = 8.7 Hz, 2 H), 7.01 (d, J = 8.7 Hz,
2 H), 3.86 (s, 3 H), 2.74 (s, 3 H), 2.47 (s, 3 H), 2.45 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 160.1, 153.5, 151.4, 140.0, 139.9,
139.4, 131.7, 130.4, 128.2, 127.3, 113.9, 113.8, 55.4, 24.4, 20.4, 20.3
ppm. IR (thin film): ν = 2965, 2838, 1605, 1509, 1437, 1327 cm–1.
˜
HRMS (ESI): calcd. for C18H19N2O [M + H]+ 279.149190; found
279.149360. C18H18N2O·1/4H2O: calcd. C 76.43, H 6.59, N 9.90;
found C 76.71, H 6.65, N 9.86.
2-(4-Bromophenyl)-3-methylquinoxaline (9): White solid, m.p. 100–
101 °C (ref.[17a] 103–104 °C). 1H NMR (300 MHz, CDCl3): δ =
8.09–8.02 (m, 2 H), 7.77–7.70 (m, 2 H), 7.65 (d, 3J = 8.6 Hz, 2 H),
3
7.53 (d, J = 8.6 Hz, 2 H), 2.76 (s, 3 H) ppm. 13C NMR (75 MHz,
General Procedure for the Two-Step One-Pot Synthesis of Quinox-
alines: A round-bottomed flask was charged with nitroalkene
(0.25 mmol) in n-hexane (0.824 mL). Then, TBHP (22.5 mg,
50.0 μL, 0.25 mmol, 1 equiv.) and DBU (1.90 mg, 1.87 μL, 5 mol-
%) were each added in one portion. The reaction mixture was
stirred at room temperature for 1 h. Then, 1,2-diamine derivative
(0.50 mmol, 2 equiv.) and HFiPr (0.74 mL, 7.00 mmol, 28.0 equiv.)
were added, and the reaction mixture was stirred for 24 h at room
temp. The solvents were evaporated, and the crude product was
purified by column chromatography [SiO2, petroleum ether/EtOAc
(PE/EtOAc) 20:1] to yield the desired product.
CDCl3): δ = 153.7, 152.1, 141.3, 140.9, 137.9, 131.8, 130.7, 130.0,
129.4, 129.2, 128.3, 123.5, 24.3 ppm. IR (thin film): ν = 3051, 2918,
˜
2853, 1724, 1586, 1480, 1337 cm–1. MS (EI): m/z = 298 and 300
[M]+ (1:1). C15H11BrN2·1/4H2O: calcd. C 59.33, H 3.82, N 9.22;
found C 59.45, H 4.13, N 9.36.
2-(4-Bromophenyl)-3,6,7-trimethylquinoxaline (10): White solid,
1
m.p. 141–142 °C. H NMR (300 MHz, CDCl3): δ = 7.81 (s, 1 H),
7.77 (s, 1 H), 7.63 (d, 3J = 8.6 Hz, 2 H), 7.51 (d, 3J = 8.6 Hz, 2 H),
2.71 (s, 3 H), 2.47 (s, 3 H), 2.46 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 152.6, 150.9, 140.6, 140.2, 139.9, 139.8, 138.2, 131.7,
130.7, 128.2, 127.4, 123.2, 24.1, 20.4, 20.3 ppm. IR (thin film): ν =
˜
2-Methyl-3-phenylquinoxaline (4): White solid, m.p. 54 °C (ref.[17a]
2911, 2846, 1546, 1482, 1334 cm–1. MS (ESI): m/z = 327 and 329
[M + H]+ (1:1). HRMS (ESI): calcd. for C17H16(79Br)N2 [M]+
327.04914; found 327.04915. C17H16BrN2·1/8H2O: calcd. C 61.97,
H 4.67, N 8.50; found C 61.77, H 4.64, N 8.56.
1
44–46 °C). H NMR (300 MHz, CDCl3): δ = 8.11–8.08 (m, 1 H),
8.06–8.03 (m, 1 H), 7.76–7.67 (m, 2 H), 7.65–7.61 (m, 2 H), 7.54–
7.47 (m, 3 H), 2.76 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 154.9, 152.5, 141.1, 140.9, 138.9, 129.7, 129.2, 129.0, 128.9, 128.5,
128.2, 24.3 ppm. IR (thin film): ν = 2908, 2813, 1523, 1469,
2-[4-(Trifluoromethyl)phenyl]-3-methylquinoxaline (11): White solid,
˜
1333 cm–1. MS (EI): m/z (%) = 220 (100) [M]+. C15H12N2·1/8H2O: m.p. 97 °C (ref.[17a] 94–96 °C). 1H NMR (300 MHz, CDCl3): δ =
calcd. C 80.96, H 5.55, N 12.59; found C 81.20, H 5.59, N 12.60.
8.11–8.05 (m, 2 H), 7.80–7.71 (m, 6 H), 2.44 (s, 3 H) ppm. 13C
4
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α-Nitro Epoxides in Organic Synthesis
[10]
a) W. Ren, Y. Xia, S.-J. Ji, Y. Zhang, X. Wan, J. Zhao, Org.
Lett. 2009, 11, 1841–1844; b) Y. Sawama, M. Takubo, S. Mori,
Y. Monguchi, H. Sajiki, Eur. J. Org. Chem. 2011, 3361–3367;
c) T. Nobuta, N. Tada, K. Hattori, S. Hirashima, T. Miura, A.
Itoh, Tetrahedron Lett. 2011, 52, 875–877.
a) K. Deuchert, U. Hertenstein, S. Huenig, G. Wehner, Chem.
Ber. 1979, 112, 2045–2061; b) T. E. Barta, M. A. Stealey, P. W.
Collins, R. M. Weier, Bioorg. Med. Chem. Lett. 1998, 8, 3443–
3448.
a) J. G. Smith, Synthesis 1984, 8, 629–656; b) I. Ojima (Ed.),
Catalytic Asymmetric Synthesis 2nd ed., Wiley, New York,
2000; c) J. Marco-Contelles, M. T. Molina, S. Anjum, Chem.
Rev. 2004, 104, 2857–2899; d) J. E. Bäckvall (Ed.), Modern Oxi-
dation Methods, Wiley-VCH, Weinheim, Germany, 2004; e) Q.-
H. Xia, H.-Q. Ge, C.-P. Ye, Z.-M. Liu, K.-X. Su, Chem. Rev.
2005, 105, 1603–1662; f) for a recent review on organocatalytic
epoxidation of α,β-unsaturated enones and enals, see: K. Weiß,
S. B. Tsogoeva, Chem. Rec. 2011, 11, 18–39.
NMR (100 MHz, CDCl3): δ =152.4, 152.0, 147.7, 142.6, 141.5,
140.9, 131.3, 130.3, 129.6, 129.4, 129.2, 128.4, 125.8, 125.6, 125.5,
125.4, 122.2 ppm. IR (thin film): ν = 3030, 2926, 1612, 1554, 1319
˜
cm–1. MS (MALDI-TOF): m/z (%) = 289 (80) [M + H]+.
C16H11F3N2·1/4H2O: calcd. C 65.64, H 3.96, N 9.57; found C
65.71, H 3.95, N 9.52.
[11]
[12]
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of all compounds.
Acknowledgments
The authors gratefully acknowledge the Deutsche Forschungsge-
meinschaft (DFG) for financial support (fellowship to Dr. M. M.
Ibrahim, project number TS 87/9-1). S. B. T. thank Dr. Hitesh Jal-
ani for useful discussions.
[13]
[14]
a) S. T. Oyama, Mechanisms in Homogeneous and Hetero-
geneous Epoxidation Catalysts, Elsevier, Amsterdam, 2008; b)
B. Marsh, D. R. Carbery, Annu. Rep. Prog. Chem. 2008, 104,
35–48; c) D. Díez, M. B. Múñez, A. B. Antón, P. García, R. F.
Moro, N. M. Garrido, I. S. Marcos, P. Basabe, J. G. Urones,
Curr. Org. Synth. 2008, 5, 186–216; d) R. Chawla, A. K. Singh,
L. D. S. Yadav, RSC Adv. 2013, 3, 11385–11403.
[1] D. Kong, E. J. Park, A. G. Stephen, M. Calvani, J. H. Cardel-
lina, A. Monks, R. J. Fisher, R. H. Shoemaker, G. Melillo,
Cancer Res. 2005, 65, 9047–9055.
[2] S. Y. Hassan, S. N. Khattab, A. A. Bekhit, A. Amer, Bioorg.
Med. Chem. Lett. 2006, 16, 1753–1756.
[3] M. Kovalenko, A. Gazit, A. Böhmer, C. Rorsman, L.
Rönnstrand, C.-H. Heldin, J. Waltenberger, F.-D. Böhmer, A.
Levitzki, Cancer Res. 1994, 54, 6106–6114.
a) H. Newman, R. B. Angier, Tetrahedron 1970, 26, 825–836;
b) H. Newman, R. B. Angier, J. Chem. Soc. D 1969, 369–370.
[4] M. N. Noolvi, H. M. Patel, V. Bhardwaj, A. Chauhan, Eur. J.
Med. Chem. 2011, 46, 2327–2346.
[5] T. Kono, T. N. Murakami, J.-I. Nishida, Y. Yoshida, K. Hara,
Y. Yamashita, Org. Electron. 2012, 13, 3097–3101.
[6] H. Li, T. M. Koh, A. Hagfeldt, M. Gratzel, S. G. Mhaisalkar,
A. C. Grimsdale, Chem. Commun. 2013, 49, 2409–2411.
[7] T.-C. Lin, W. Chien, C.-Y. Liu, M.-Y. Tsai, Y.-J. Huang, Eur.
J. Org. Chem. 2013, 4262–4269.
[8] K. R. J. Thomas, M. Velusamy, J. T. Lin, C.-H. Chuen, Y.-T.
Tao, Chem. Mater. 2005, 17, 1860–1866.
[9] a) A. Kumbhar, S. Kamble, M. Barge, G. Rashinkar, R. Salun-
khe, Tetrahedron Lett. 2012, 53, 2756–2760; b) S. B. Wadavrao,
R. S. Ghogare, A. V. Narsaiah, Org. Commun. 2013, 6, 23–30;
c) B. S. P. A. Kumar, B. Madhav, K. H. V. Reddy, Y. V. D. Na-
geswar, Tetrahedron Lett. 2011, 52, 2862–2865; d) Y. Suzuki,
M. Murofushi, K. Manabe, Tetrahedron 2013, 69, 470–473; e)
S. V. More, M. N. V. Sastry, C. C. Wang, C. F. Yao, Tetrahedron
Lett. 2005, 46, 6345–6348; f) H. R. Darabi, S. Mohandessi, K.
Aghapoor, F. Mohsenzadeh, Catal. Commun. 2007, 8, 389–392;
g) M. M. Heravi, M. H. Tehrani, K. Bakhtiari, H. A. Oskooie,
Catal. Commun. 2007, 8, 1341–1344; h) S. A. Raw, C. D.
Wilfred, R. J. K. Taylor, Chem. Commun. 2003, 18, 2286–2287.
[15] a) K. M. Weiß, S. Wei, S. B. Tsogoeva, Org. Biomol. Chem.
2011, 9, 3457–3461; b) S. Wei, K. M. Weiß, S. B. Tsogoeva,
Synthesis 2012, 44, 3441–3446.
[16] a) A. Heydari, S. Khaksar, M. Tajbakhsh, H. R. Bijanzadeh,
J. Fluorine Chem. 2009, 130, 609–614; b) S. Khaksar, A. Heyd-
ari, M. Tajbakhsh, S. M. Vahdat, J. Fluorine Chem. 2010, 131,
1377–1381.
[17] a) Y. Chen, K. Li, M. Zhao, Y. Li, B. Chen, Tetrahedron Lett.
2013, 54, 1627–1630; b) T. Huang, Q. Zhang, J. Chen, W. Gao,
J. Ding, H. Wu, J. Chem. Res. 2009, 761–765; c) C. S. Mahajan-
shetti, G. A. Bhat, Indian J. Chem. 1974, 12, 54–56; d) A. Gazit,
H. App, G. McMahon, J. Chen, A. Levitzki, F. D. Bohmer, J.
Med. Chem. 1996, 39, 2170–2177; e) Indian Patent Application,
IN2009MU01140, 2010.
[18] CCDC-962355 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[19] Y. Kawai, Y. Inaba, N. Tokitoh, Tetrahedron: Asymmetry 2001,
12, 309–318.
Received: October 23, 2013
Published Online: ᭿
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5

Job/Unit: O31591
/KAP1
Date: 02-01-14 13:34:57
Pages: 6
M. M. Ibrahim, D. Grau, F. Hampel, S. B. Tsogoeva
FULL PAPER
Organocatalysis
M. M. Ibrahim, D. Grau, F. Hampel,
S. B. Tsogoeva* ................................. 1–6
α-Nitro Epoxides in Organic Synthesis: De-
velopment of a One-Pot Organocatalytic
Strategy for the Synthesis of Quinoxalines
The reaction of easily accessible nitro
olefins with the tBuOOH/1,8-diazabicy-
cloundec-7-ene (TBHP/DBU) organocata-
lytic system gives rise to the corresponding
α-nitro epoxides, which are suitable for
subsequent reaction with 1,2-phenylenedia-
mines under mild conditions to give quin-
oxaline heterocycles in up to 82% yield.
Keywords: Synthesis design / Organocata-
lysis / Nitrogen heterocycles / Epoxidation /
Nitro compounds
6
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Eur. J. Org. Chem. 0000, 0–0