A facile method for building fused quinoxaline-quinolinones via an acidless post-Ugi cascade reaction

Article abstract of DOI:10.1016/j.cclet.2016.10.027

A series of quinolino[3,4-b]quinoxalin-6(5H)-ones have been synthesized using an Ugi/deprotection/cyclization (UDC) strategy, followed by a nucleophilic aromatic substitution reaction. This facile microwave-assisted method provided good yields and could potentially be used for the construction of a diverse library of quinolino[3,4-b]quinoxalin-6(5H)-ones for high-throughput screening in medicinal chemistry.

Full text of DOI:10.1016/j.cclet.2016.10.027

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CCLET 3862 1–5
Chinese Chemical Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
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Original article
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A facile method for building fused quinoxaline-quinolinones via an
acidless post-Ugi cascade reaction
a,b
Yong Lia,b, Jie Leia,b, Jia Xua,b, Dian-Yong Tangb, Zhong-Zhu Chenb, , Jin Zhu
,
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5
Q1
*
Chuan Xuc,
*
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10
a
Key Laboratory for Asymmetric Synthesis and Chiral Technology of Sichuan Province Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu 610041, China
Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI,
b
Chongqing University of Arts and Sciences, Chongqing 402160, China
c
Department of Oncology, Chengdu Military General Hospital, Chengdu 610083, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of quinolino[3,4-b]quinoxalin-6(5H)-ones have been synthesized using an Ugi/deprotection/
cyclization (UDC) strategy, followed by a nucleophilic aromatic substitution reaction. This facile
microwave-assisted method provided good yields and could potentially be used for the construction of a
diverse library of quinolino[3,4-b]quinoxalin-6(5H)-ones for high-throughput screening in medicinal
chemistry.
Received 8 August 2016
Received in revised form 11 October 2016
Accepted 14 October 2016
Available online xxx
Keywords:
Quinoxaline
Quinolino[3,4-b]quinoxalin-6(5H)-one
Ugi/deprotection/cyclization (UDC) strategy
Nucleophilic substitution reaction
One-pot
ã 2016 Zhong-Zhu Chen and Chuan Xu. Chinese Chemical Society and Institute of Materia Medica,
Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
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1. Introduction
[10] and Ugi/gold-catalyzed [11] reaction sequences have been
reported to provide efficient access to a wide variety of cyclic
scaffolds.
The quinoxaline skeleton is found in a wide range of biologically
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Nitrogen-containing heterocycles are important compounds
that can be found in a wide range of drugs and biologically relevant
molecules [1]. For this reason, research towards the development
of novel and efficient strategies for the construction of these
compounds represents one of the most active areas of present day
synthetic organic chemistry [2]. Multicomponent reactions (MCRs)
have become useful tools for the diversity-oriented synthesis of
complex heterocyclic compounds [3]. One of the powerful
multicomponent reactions is the Ugi reaction, which involves
the effective multicomponent reaction of an aldehyde (or ketone),
active natural products (1,2,5, Fig. 1) and synthetic compounds (3,
4, Fig. 1) [12]. Notably, quinoxaline derivatives have been reported
to display a wide range of biological properties, including
anticancer [13], antitumor (i.e., thymidylate synthase inhibitors)
[14], antibacterial [15], antifungal [16], antihypertensive [17] and
dopamine agonist [18] activities. In this study, we used a UDC,
followed by an intermolecular nucleophilic substitution reaction to
prepare a series of novel quinolino[3,4-b]quinoxalin-6(5H)-one
compounds. It is noteworthy, however, these compounds were
formed unexpectedly during our efforts to prepare a related
scaffold and therefore represent a serendipitous discovery.
The synthesis of a series of fused piperazine-benzimidazoles via
an UDC strategy was reported [19]. It was envisaged that we could
expand the scope of this research to the construction of much more
interesting and structurally complex compounds with a wide range
of biological activities. During the last decade, G-quadruplexes
have emerged as valid targets for the development of new
anticancer drugs [20]. Numerous compounds have been reported
to target these structures, and some of these compounds
progressed into preclinical or clinical trials for the treatment of
amine, isonitrile and carboxylic acid to afford an
a-acylamino
carboxamide adduct [4,5]. Tandem reaction sequences involving
the use of an Ugi reaction, followed by various post-condensation
transformations, represent extremely powerful synthetic methods
for the construction of heterocyclic compounds with elaborate
substitution patterns [6]. For example, Ugi/Buchwald–Hartwig/
Michael [7], Ugi/Heck [8], Ugi/Aldo [9], Ugi/Bischler Napieralski
* Corresponding authors.
E-mail addresses: 18883138277@163.com (Z.-Z. Chen), 1535486239@qq.com
(C. Xu).
http://dx.doi.org/10.1016/j.cclet.2016.10.027
1001-8417/ã 2016 Zhong-Zhu Chen and Chuan Xu. Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V.
All rights reserved.
Please cite this article in press as: Y. Li, et al., A facile method for building fused quinoxaline-quinolinones via an acidless post-Ugi cascade
reaction, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.027

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Fig. 1. Quinoxaline natural and prepared products.
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cancer. It is noteworthy that most of the compounds designed
against G-quadruplexes are based on polycyclic heteroaromatic
scaffolds, which could be constructed from Ugi products following
a series of nucleophilic substitution reactions to provide access to
additional aromatic ring structures. It was therefore envisioned
that the reaction of 2-oxo-2-phenylacetaldehyde 6a with isonitrile
7a, N-Boc-protected-phenylenediamine 8a and N-Boc amino acetic
acid 9 under the tandem UDC conditions would provide access to
the corresponding benzo[4,5]imidazo[1,2-a]pyrazine derivative
14, as shown in Scheme 1.
to provide the target compound 14 in the presence of an inorganic
base catalyst, such as Cs2CO3 or Na2CO3. In practice, however, the
UDC product resulting from the reaction of 11a was determined to
be the quinoxaline derivative 15a instead of the expected product
12. Notably, the formation of 15a involved the cleavage of the
amino acid group from 11a during the UDC strategy when the
cyclization was conducted under acidic condition. To develop a
detailed understanding and further expand the scope of this
process, we investigated the application of these reaction
conditions to a series of different starting materials (Scheme 2).
The results of these reactions revealed that they gave rise to the
corresponding quinoxaline products.
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2. Results and discussion
The Ugi product 10 was obtained following the reaction of the
N-Boc amino acetic acid 9 with N-Boc-protected-phenylenedi-
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The Ugi product 10a was obtained in good yield and subjected
to a Boc-deprotection step to afford intermediate 11a. It was
anticipated that compound 11a would react as indicated by the
arrows shown in Scheme 1 to give compound 12. This material
would then undergo a dehydrogenation reaction to give interme-
diate 13, followed by a nucleophilic aromatic substitution reaction
amine 8, 2-oxo-2-phenylacetaldehyde
6 and isonitrile 7 in
methanol at room temperature overnight, and used in the next
reaction without purification. The methanol solvent was removed
under a gentle stream of nitrogen to give a residue, which was
dissolved in 10% TFA/DCE and heated under microwave irradiation
Scheme 1. Ugi/deprotection/cyclization (UDC) strategy.
Please cite this article in press as: Y. Li, et al., A facile method for building fused quinoxaline-quinolinones via an acidless post-Ugi cascade
reaction, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.027

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Y. Li et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
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Scheme 2. Scope of the UDC strategy.
Scheme 3. Scope of this acid-free UDC strategy for the synthesis of quinolino[3,4-b]quinoxalin-6(5H)-ones.
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to give the cyclized intermediate 16. Then, it underwent a
deprotection step to give compounds 15a–g in 54%–72% yields
over the two steps. All of these reactions provided access to the
desired quinoxaline compounds via the UDC strategy. Although
this strategy did not provide access to the desired compounds, it
did provide an efficient method for the preparation of quinoxaline
derivatives, following the modification of the reaction conditions.
Overall, the outcome of this reaction can be attributed to the loss of
the amino acid moiety (glycine) under the microwave irradiation
conditions.
In addition, it is easy to consider an “acid-less” Ugi type reaction
and phenylphosphonic acid (PPOA) is usually used as the catalyst
[21–23]. We previously reported the intermolecular nucleophilic
substitution reaction of an Ugi product as a strategy for the
formation of compounds containing a new ring system via the
formation of a CꢀꢀN bond [24,25]. Based on these reports, it was
envisaged that the Ugi reaction products could also be used for the
design and synthesis of several new scaffolds. To test this
hypothesis, we conducted a series of acidless Ugi-type reactions
according to the UDC strategy, followed by an intermolecular
nucleophilic substitution reaction to provide access to a series of
novel quinolino[3,4-b]quinoxalin-6(5H)-one compounds. The
products resulting from this new method are shown in Scheme 3.
A three-component Ugi-type reaction involving 7, 8 and 17
provided access to the corresponding quinoxaline compound 20 in
two steps. A microwave temperature of 110 ꢁC was required to
affect the deprotection and cyclization steps of the UDC strategy.
The results of these experiments revealed that the use of
phenylphosphonic acid as a catalyst for the Ugi reaction provided
satisfactory yields. The last step in this process (i.e., the
nucleophilic substitution reaction), was performed with a series
of different isonitriles, leading to the formation of the correspond-
ing quinolino[3,4-b]quinoxalin-6(5H)-ones 20a–f in 37%–54%
yields over three steps. However, the use of tert-butyl isocyanide
under the conditions required of the UDC strategy gave yields of
54% and 63% for compounds 15f and 15g, respectively. The
nucleophilic substitution reactions of these two compounds were
initially tested at a high temperature of 180 ꢁC in dimethylforma-
mide. Under these conditions, however, large amounts of the
starting materials were recovered, with only trace quantities of the
desired products being identified by LC/MS. Several bases,
including K2CO3, Na2CO3 and NaOH, were also tested in the
reaction, but failed to provide an increase in the product yields. The
steric effect of the tert-butyl group was thought to be the main
reason for these results. The use of a one-pot procedure did not
require the conversion of a carboxylic acid, and was therefore more
suitable for the synthesis of a large number of compounds [26].
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3. Conclusion
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In conclusion, we have synthesized a series of quinolino[3,4-b]
quinoxalin-6(5H)-one derivatives using an Ugi/deprotection/
Please cite this article in press as: Y. Li, et al., A facile method for building fused quinoxaline-quinolinones via an acidless post-Ugi cascade
reaction, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.027

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cyclization (UDC) strategy followed
a nucleophilic aromatic
J = 6.0 Hz), 3.13 (s, 3H), 2.50 (s, 3H), 2.47 (s, 3H). 13C NMR (100 MHz,
CDCl3): 164.9, 152.7, 145.0, 142.5, 142.0, 141.0, 140.4, 140.2, 139.9,
substitution reaction. This multicomponent reaction proceeded
under acidless conditions to give the desired products in good
yields and could be used in a variety of applications in medicinal
chemistry.
d
139.2,138.3,138.1,128.8,128.2,128.0,127.9,127.8,127.5, 43.6, 22.4,
20.4, 20.2. LC/MS calcd. for C19H20N3O, 306 [M+H]+; found 306.
N-Cyclohexyl-3,6,7-trimethylquinoxaline-2-carboxamide
(15e): Yellow solid, yield 64%. 1H NMR (400 MHz, CDCl3):
d 7.92 (d,
144
4. Experimental
1H, J = 7.8 Hz), 7.79 (d, 2H, J = 5.7 Hz), 4.04–3.92 (m,1H), 3.10 (s, 3H),
2.49 (d, 6H, J = 3.9 Hz), 2.06 (d, 2H, J = 12.1 Hz), 1.79 (d, 2H,
145
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All reagents, unless otherwise stated, were used as received
from commercial suppliers. 1H NMR (400 MHz) and 13C NMR
(100 MHz) spectra were recorded on a Bruker Avance 400 spec-
trometer using CDCl3 or DMSO-d6 as solvent and TMS as internal
J = 10.2 Hz), 1.53–1.31 (m, 6H). 13C NMR (100 MHz, CDCl3):
d 164.0,
153.3, 142.7, 142.2, 141.9, 140.1, 138.1, 128.0, 127.5, 48.4, 33.1, 25.7,
25.0, 24.7, 20.5, 20.2. LC/MS calcd. for C18H24N3O [M+H]+, 298;
found 298.
standard (
d
in ppm). Abbreviations used for NMR signals are:
N-(tert-Butyl)-3-(2-fluorophenyl)quinoxaline-2-carboxamide
s = singlet, d = doublet, dd = doublet of doublets, dt = doublet of
triplets, q = quartet, t = triplet, td = triplet of doublets and m =
multiplet. LC/MS were recorded on a Shimadzu LCMS-2020. All
microwave irradiation experiments were carried out in a Biotage1
Initiator Classic microwave apparatus with continuous irradiation
power from 0 to 400 W with utilization of the standard absorbance
level of 250 W maximum power.
(15f): Yellow solid, yield 63%. 1H NMR (400 MHz, CDCl3)
d 8.24–
8.05 (m, 2H), 7.88–7.77 (m, 2H), 7.71 (td, J = 7.5, 1.7 Hz, 1H), 7.56 (s,
1H), 7.35–7.31 (m, 1H), 7.20 (dd, J = 10.9, 4.1 Hz, 1H), 7.11–6.99 (m,
1H), 1.51 (s, 9H). 13C NMR (100 MHz, CDCl3)
d 164.0, 161.4, 159.0,
148.77, 146.2, 142.7, 139.3, 131.6, 131.0, 130.9, 130.8, 130.4, 129.3,
129.2, 127.6, 127.4, 124.5, 124.5, 115.1, 114.8, 51.7, 28.6. LC/MS
calculated for C19H19FN3O [M+H]+, 324; found 324.
N-(tert-Butyl)-3-(2,4-dichlorophenyl)quinoxaline-2-carboxa-
157
4.1. General procedures for the preparation of compounds 15a–g
mide (15g): Yellow solid, yield 54%. 1H NMR (400 MHz, CDCl3):
d
8.17 (dd, 2H, J = 5.8, 4.0 Hz), 7.87 (dd, 2H, J = 6.2, 3.1 Hz), 7.69 (s, 1H),
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To a magnetically stirred solution of an aldehyde (0.50 mmol) in
MeOH (1.0 mL), an amine (0.50 mmol) was added in a 5 mL
microwave vial. The solution was stirred for 10 min at room
temperature. Then, an acid (0.50 mmol) and an isonitrile
(0.50 mmol) were added separately. The mixture was stirred at
room temperature overnight. The reaction was monitored by TLC
and the solvent was removed under a nitrogen stream. The residue
in the same vial was dissolved in 10% TFA/DCE (3.0 mL) and placed
back in microwave and heated to 110 ꢁC for 20 min. The microwave
vial was then cooled to room temperature, the solvent removed
under reduced pressure, the residue dissolved with EtOAc
(15.0 mL), washed with saturated Na2CO3 and brine. The organic
layer was dried over MgSO4 and concentrated. The residue was
purified by silica gel column chromatography using a gradient of
ethyl acetate/hexane (0–60%) to give the targeted compound 15a–
g.
7.54 (d, 1H, J = 8.1 Hz), 7.49–7.38 (m, 2H), 1.48 (s, 9H). 13C NMR
(100 MHz, CDCl3):
d 163.0, 151.0, 145.410, 142.5, 139.5, 137.6, 135.2,
133.4, 131.7, 131.0, 130.8, 129.4, 129.2, 128.9, 127.6, 51.5, 28.6. LC/MS
calcd. for C19H18Cl2N3O, 374 [M+H]+; found 374.
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4.2. General procedures for the preparation of compounds 20a–f
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To a magnetically stirred solution of an aldehyde (0.50 mmol) in
MeOH (1.0 mL), an amine (0.50 mmol) was added in a 5 mL
microwave vial. The solution was stirred for 10 min at room
temperature. Then, phenylphosphonic acid (0.05 mmol) and an
isonitrile (0.50 mmol) were added separately. The mixture was
stirred at room temperature overnight. The reaction was moni-
tored by TLC and the solvent was removed under a nitrogen stream.
The residue in the same vial was dissolved in 10% TFA/DCE (3.0 mL)
and placed back in microwave and heated to 110 ꢁC for 20 min. The
solvent was removed under a nitrogen stream and diluted with
DMF (3 mL) in the same vial. Cs2CO3 (2.0 mmol) was added and the
vial was placed back in microwave and heated to 150 ꢁC for 30 min.
The microwave vial was then cooled to room temperature, the
residue dissolved with EtOAc (15.0 mL), washed with brine. The
organic layer was dried over MgSO4 and concentrated. The residue
was purified by silica gel column chromatography using a gradient
of ethyl acetate/hexane (20%–80%) to afford products 20a–f.
5-Benzylquinolino[3,4-b]quinoxalin-6(5H)-one (20a): Yellow
N-Benzyl-3-(2,4-dichlorophenyl)-6,7-dimethylquinoxaline-2-
carboxamide (15a): Yellow solid, yield 67%. 1H NMR (400 MHz,
CDCl3):
d 8.24 (t, 1H, J = 5.5 Hz), 7.90 (d, 2H, J = 22.6 Hz), 7.49–7.45
(m, 2H), 7.41 (dd, 1H, J = 8.2, 1.9 Hz), 7.38–7.32 (m, 4H), 7.32–7.27
(m, 1H), 4.63 (d, 2H, J = 5.9 Hz), 2.53 (s, 6H). 13C NMR (100 MHz,
CDCl3):
d 165.8, 160.6, 157.3, 153.2, 143.9, 140.6, 138.6, 131.8, 130.6,
129.7, 129.1, 129.0, 128.7, 128.3, 128.0, 127.4, 44.0, 20.5, 20.4. LC/MS
calcd. for C24H20Cl2N3O, 436 [M+H]+; found 436.
N-Benzyl-3-phenylquinoxaline-2-carboxamide (15b): Yellow
solid, yield 65%. 1H NMR (400 MHz, CDCl3):
d
8.18 (d, 1H,
solid, yield 51%. 1HNMR (400 MHz, CDCl3):
d 9.02 (d, 1H,
J = 8.4 Hz), 8.10 (d, 1H, J = 8.2 Hz), 7.88–7.76 (m, 3H), 7.73–7.67 (m,
2H), 7.52–7.46 (m, 3H), 7.37 (d, 3H, J = 4.4 Hz), 7.34–7.28 (m, 1H),
J = 7.6 Hz), 8.48 (d, 1H, J = 8.1 Hz), 8.27 (d, 1H, J = 8.4 Hz), 7.92 (dt,
2H, J = 14.7, 7.0 Hz), 7.53 (t, 1H, J = 7.5 Hz), 7.45–7.27 (m, 7H), 5.73 (s,
4.66 (d, 2H, J = 6.0 Hz). 13C NMR (100 MHz, CDCl3):
d
164.9, 153.8,
2H). 13C NMR (100 MHz, CDCl3):
d 160.9, 145.1, 144.5, 143.1, 138.6,
145.0, 142.6, 139.3, 138.6, 138.0, 131.7, 130.4, 129.4, 129.2, 128.9,
128.8, 128.2, 128.0, 127.6, 43.8. LC/MS calcd. for C22H18N3O, 340 [M
+H]+; found 340.
136.0, 132.9, 132.4, 131.0, 130.7, 129.2, 128.9, 127.5, 126.8, 126.1,
123.5, 120.0, 115.9, 47.0. LC/MS calcd. for C22H16N3O, 338 [M+H]+;
found 338.
N-Benzyl-6,7-dimethyl-3-phenylquinoxaline-2-carboxamide
5-Cyclohexylquinolino[3,4-b]quinoxalin-6(5H)-one (20b): Yel-
(15c): Yellow solid, yield 72%. 1H NMR (400 MHz, CDCl3):
d
7.92 (s,
low solid, yield 48%. 1H NMR (400 MHz, CDCl3):
d 9.02 (d, 1H,
1H), 7.84 (s, 2H), 7.67 (dd, 2H, J = 6.5, 3.1 Hz), 7.47 (dd, 3H, J = 5.0,
J = 7.9 Hz), 8.41 (d, 1H, J = 8.3 Hz), 8.23 (d, 1H, J = 8.2 Hz), 7.94–7.78
(m, 2H), 7.63 (d, 2H, J = 4.0 Hz), 7.42–7.33 (m, 1H), 4.86–4.35 (m,
1H), 2.82 (d, 2H, J = 11.3 Hz), 2.04–1.78 (m, 6H), 1.48 (d, 2H,
1.7 Hz), 7.36 (d, 3H, J = 4.3 Hz), 7.34–7.28 (m, 1H), 4.64 (d, 2H,
J = 6.0 Hz), 2.52 (s, 6H). 13C NMR (100 MHz, CDCl3):
d 165.1, 152.9,
143.9, 142.8, 141.6, 141.3, 138.9, 138.3, 138.1, 128.9, 128.8, 128.3,
128.1,128.0,127.6, 43.8, 20.6, 20.4. LC/MS calcd. for C24H22N3O, 368
[M+H]+; found 368.
J = 13.7 Hz). 13C NMR (100 MHz, CDCl3):
d 160.7, 144.9, 144.4, 143.0,
139.3, 132.5, 132.0, 130.9, 130.5, 129.1, 126.4, 123.0, 120.4, 115.4,
58.8, 28.9, 26.7, 25.5. LC/MS calcd. for C21H20N3O [M+H]+, 330;
found 330.
N-Benzyl-3,6,7-trimethylquinoxaline-2-carboxamide
(15d):
Yellow solid, yield 58%. 1H NMR (400 MHz, CDCl3):
d
8.40 (s,
5-(2,6-Dimethylphenyl)quinolino[3,4-b]quinoxalin-6(5H)-one
1H), 7.77 (d, 2H, J = 18.1 Hz), 7.42–7.29 (m, 5H), 4.70 (d, 2H,
(20c): Yellow solid, yield 44%. 1H NMR (400 MHz, CDCl3):
d 9.08
Please cite this article in press as: Y. Li, et al., A facile method for building fused quinoxaline-quinolinones via an acidless post-Ugi cascade
reaction, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.027

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(dd, 1H, J = 7.7, 1.5 Hz), 8.44 (d, 1H, J = 8.4 Hz), 8.38–8.24 (m, 1H),
8.04–7.83 (m, 2H), 7.49–7.30 (m, 4H), 7.15–7.01 (m, 1H), 6.60 (d, 1H,
reactions towards cyclic constrained peptidomimetics, Beilstein J. Org. Chem.
10 (2014) 544–598.
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multicomponent reactions, Chem. Rev. 114 (2014) 8323–8359;
(b) Z. Hossaini, F. Rostami-Charati, S. Seyfi, M. Ghambarian, Multicomponent
reactions for the synthesis of functionalized 1,4-oxathiane-3-thiones under
microwave irradiation in water, Chin. Chem. Lett. 24 (2013) 376–378;
(c) G.R. Kuethe, J.T. Kuethe, Practical methodologies for the synthesis of
indoles, Chem. Rev. 106 (2006) 2875–2911.
J = 8.0 Hz), 2.07 (s, 6H). 13C NMR (100 MHz, CDCl3):
d 159.3, 145.5,
321
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326
144.6, 143.0, 138.8, 136.1, 135.3, 133.0, 132.6, 131.1, 130.8, 129.3,
128.7, 128.2, 126.1, 123.8, 119.8, 115.5, 17.7. LC/MS calculated for
C23H18N3O [M+H]+, 352; found 352.
3-Chloro-5-(2,6-dimethylphenyl)quinolino[3,4-b]quinoxalin-6
(5H)-one (20d): Yellow solid, yield 49%. 1H NMR (400 MHz, CDCl3):
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327
328
329
330
Chem. Int. Ed. 39 (2000) 3168–3210;
d
9.01 (d, 1H, J = 8.5 Hz), 8.50 (d, 1H, J = 5.9 Hz), 8.30 (d, 1H,
J = 8.5 Hz), 8.01–7.88 (m, 2H), 7.48–7.28 (m, 4H), 6.59 (d, 1H,
J = 1.3 Hz), 2.08 (s, 6H). 13C NMR (100 MHz, CDCl3):
159.3, 144.8,
(b) A. Dömling, Recent developments in isocyanide based multicomponent
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273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
ꢀ
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143.0, 139.7, 138.8, 135.9, 134.7, 133.3, 131.1, 129.6, 129.5, 129.2,
127.4,124.3,118.3, 115.3,17.7. LC/MS calcd. for C23H17ClN3O, 386 [M
+H]+; found 386.
331
332
3-Chloro-5-cyclohexylquinolino[3,4-b]quinoxalin-6(5H)-one
(20e): Yellow solid, yield 37%. 1H NMR (400 MHz, CDCl3):
d 8.91 (d,
333
334
1H, J = 8.5 Hz), 8.38 (d, 1H, J = 8.4 Hz), 8.19 (d, 1H, J = 8.5 Hz), 7.90 (s,
1H), 7.82 (s,1H), 7.57 (s,1H), 7.34 (dd,1H, J = 8.5,1.5 Hz), 2.79 (d, 2H,
J = 11.0 Hz), 2.02–1.78 (m, 6H), 1.50 (dd, 3H, J = 21.9, 11.5 Hz). 13C
335
336
NMR (100 MHz, CDCl3):
d 160.6, 144.3, 144.2, 143.1, 140.1, 138.1,
137.6, 132.7, 130.9, 130.7, 129.1, 127.6, 123.3, 118.9, 115.5, 59.2, 28.8,
26.6, 25.4. LC/MS calcd. for C21H19ClN3O, 364 [M+H]+; found 364.
5-Cyclohexyl-9,10-dimethylquinolino[3,4-b]quinoxalin-6(5H)-
337
338
339
340
one (20f): Yellow solid, yield 46%. 1H NMR (400 MHz, CDCl3):
d 9.00
(d, 1H, J = 7.9 Hz), 8.15 (s, 1H), 7.99 (s, 1H), 7.63 (d, 2H, J = 4.1 Hz),
7.47–7.31 (m, 1H), 2.82 (d, 2H, J = 11.0 Hz), 2.56 (d, 6H, J = 6.8 Hz),
341
342
2.01–1.69 (m, 7H), 1.56–1.44 (m, 2H). 13C NMR (100 MHz, CDCl3):
d
161.0, 144.2, 144.1, 143.6, 142.2, 141.8, 139.0, 131.5, 129.4, 127.9,
126.1, 122.9, 120.7, 115.3, 58.7, 28.9, 26.7, 25.5, 20.8, 20.6. LC/MS
calcd. for C23H24N3O [M+H]+, 358; found 358.
343
344
345
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348
349
295 Q2
296
The authors would like to thank the Chongqing Research
Program of Basic Research and Frontier Technology (Nos.
cstc2015jcyjA1328 and cstc2015zdcy-ztzx0191), the Scientific
Research Foundation of Chongqing University of Arts and
Sciences (Nos. R2013XY01 and R2013XY02). We would also like
to thank Ms. H.Z. Liu for obtaining the LC/MS and NMR data.
297
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352
298
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353
354
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Appendix A. Supplementary data
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357
358
302
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Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2016.10.027.
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