Traceless polymer-supported divergent synthesis of quinoxalinones by microwave irradiation

Article abstract of DOI:10.1016/j.tet.2012.03.015

A novel protocol for rapid assemble of quinoxalinones framework has been demonstrated. This method incorporated with soluble polymer support provides a convenient approach for diversification of heterocyclic compounds and for easy purification via facile

Full text of DOI:10.1016/j.tet.2012.03.015

Tetrahedron 68 (2012) 3532e3540
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Traceless polymer-supported divergent synthesis of quinoxalinones by microwave
irradiation
Chien-Hung Shen, Chih-Chung Tseng, Cheng-Hsun Tasi, Suhas A. Shintre, Li-Hsun Chen,
*
Chung-Ming Sun
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 August 2011
Received in revised form 4 March 2012
Accepted 6 March 2012
Available online 13 March 2012
A novel protocol for rapid assemble of quinoxalinones framework has been demonstrated. This method
incorporated with soluble polymer support provides a convenient approach for diversification of het-
erocyclic compounds and for easy purification via facile precipitation from reaction matrix. The key
transformation of this study involves in situ reduction of aromatic nitro compound, tandem lactam-
ization concomitant with traceless cleavage of the polymer support under microwave irradiation in
a one-pot fashion. Moreover, forward synthetic routes were introduced to maximize complexity of the
master intermediate on which further chemical elaboration was applied. The strategy is envisaged to
apply for establishment of drug-like small-molecule libraries for high-throughput screening.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Heterocyclic compounds are pervasive in both academic and
pharmaceutical industry mainly focused on small-molecule drug
discovery due to their highly structural diversity.1 Quinoxalinones
are such the paradigm of framework exhibiting wide spectra of
bioactivities. The scaffold of quinoxalinones demonstrates on an-
timicrobial, antithrombotic, anti-tumor, and deconditioning activ-
ities.2 Ambident hydrogen bonding donoreacceptor system and
salt bridge acceptors (quaternized nitrogen atoms) may contribute
to the versatile pharmaceutical activity portfolio of quinoxalinones.
This privileged pharmacophore is highly visible in structur-
eeactivity relationship (SARs)-based drug design approaches for
developing chemotherapeutics (Fig. 1). For instance, inhibition of
quinoxalinone peptidomimetic analogue (I) on matrix metal-
loproteinases (MMPs) is potential lead for anticancer drug de-
velopment.3 Macrocyclic quinoxalinone (II) shows highly potent
cyclin-dependent kinases (Cdks) antagonism (nanomolar magni-
tude) offering an attractive target for cancer research.4 A class-B
calcium-channel blocker, a marketing drug named caroverine
(III), designed to enhance antispasmodic activity and tinnitus
treatments has also been found effective in scavenging of hydroxy
free radical.5 Moreover, tricyclic imidazoquinoxalinone (IV) reveals
activity against testis-specific serine/threonine kinase 1.6 These
functional molecules are potent drug leads in pharmaceutical
chemistry.
Fig. 1. Representative molecules of bioactive quinoxalinones.
Rapidly obtaining quinoxalinone core with diversified func-
tionality is essential for their bioactivity evaluation. Combinatorial
synthetic strategies offer great opportunities to generate sufficient
number of molecular libraries in a time efficient and parallel
fashion to fulfill demand of compounds for high-throughput
screening in medicinal chemistry.7 Although batch-wise linear
synthetic operations are still performed sporadically,8 protocols
involving the combinatorial concept using solid-phase organic
synthesis (SPOS) to furnish quinoxalinone scaffolds are more pre-
dominated and popular in nowadays strategy.9 Nevertheless, fun-
damental issues (e.g., prolonged reaction time, difficult to
characterize of intermediates, and limited reaction monitoring
* Corresponding author. Fax: þ886
3 5736007; e-mail address: cmsun@
mail.nctu.edu.tw (C.-M. Sun).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.015

C.-H. Shen et al. / Tetrahedron 68 (2012) 3532e3540
3533
method) encompass in solid-phase chemistry. The major in-
adequacy of SPOS in routine operational exercise attributes to bi-
phasic reaction media but this property is the advantage for ease of
purification of intermediates and the target molecules. In contrast
to biphasic reaction matrix used in SPOS system, homogenous
phase-tagged synthesis has been developed as an alternative
strategy in combinatorial chemistry aiming for easy reaction
monitoring and intermediates characterization by conventional
analytical methods (e.g., TLC, NMR, MS, and HPLC), meanwhile
remaining with advantageous aspects for parallel organic synthe-
sis.10 Soluble polymer-supported synthesis has been demonstrated
as a powerful platform in elaborating molecular complexity under
more familiar and convenient to operate environment in solution,
and the purification tasks are simply performed by recrystallization
at ambient temperature.11 Reaction parameters used in solution
phase are readily to be applied on the liquid phase soluble polymer-
support synthesis with non- or minimum-optimization, which
facilitated by microwave irradiation for molecular library con-
struction. Our strategy leading to the target heterocycles is based on
PEG-tagged master cores of which molecular complexity is maxi-
mized. This concept of divergent synthesis is envisaged to accu-
mulate sufficient molecular databases within a short time course for
bioassay screening and to telescope drug discovery process.
2. Results and discussion
PEG6000 (HO-PEG6000-OH; abbreviated as PEG thereafter in this
article) was chosen as a soluble polymer support in this study. The
synthetic efforts commenced on anchoring of Fmoce
onto the polymer to furnish the PEG-tagged Fmoce
L
-amino acids
L-amino acids
by treatment of N,N0-dicyclohexylcarbodiimide (DCC) as a coupling
reagent in the presence of DMAP as a catalyst in CH2Cl2 under
microwave irradiation for 30 min. It is worthy to mention that this
reaction proceeded sluggishly (8 h) without engagement of mi-
crowave reaction. The transformation was well monitored by TLC
minimizes unexpected outcomes and offers
interface.
a user-friendly
and the desired PEG-tagged FmoceL-amino acids were obtained in
The concept of soluble polymer-supported organic synthesis is
achieved by soluble macromolecule serving as a phase tag an-
chored with small molecules for chemical manipulations. Among
soluble polymer supports, polyethylene glycols (PEGs) with mo-
lecular weight 2000e20,000 are well documented and widely used
in combinatorial organic synthesis.12 PEGs with lower molecular
weight have higher loading capacities but exhibit less crystalline
propensity than that of higher molecular weight. PEG4000 and
PEG6000 are the most popular soluble polymer supports repre-
senting of molecular weight 4000 and 6000 with loading capacities
0.5 and 0.33 mmol gꢀ1, respectively. PEG4000 composing two hy-
droxy groups can be introduced onto small molecules as a pro-
tecting group or a traceless phase tag. This homopolymer features
in a wide range of solubility toward organic solvents in synthetic
tasks and aqueous media but precipitates in hexane, Et2O, and
tBuOMe at room temperature or below due to the helical backbone
of the polymer.13 As a result, the soluble PEG-tagged intermediates
can be easily isolated by simple precipitation/recrystallization
procedure from the reaction matrix and examined by general an-
alytical methods. This liquid phase PEG-tagged methodology is
compatible with microwave-assisted organic synthesis (MAOS) to
promote chemical transformations. Microwave technology has well
pronounced in chemistry synthesis in the past two decades and
automated parameters are established to fulfill nowadays de-
manding of compound libraries. By irradiating reaction mixture
with microwave energy under controlled conditions, heating effi-
ciency is more superior to that of by a traditional oil bath heating.
Reaction rate and yields are significantly enhanced by microwave
irradiation contributed synergically from microwave dielectric
heating and thermolytic effects.14 The versatile portfolio of MAOS is
rapidly adopted by medicinal chemists to facilitate synthesis of
molecular libraries in a combinatorial fashion within short period
for biological evaluation on drug discovery.15
a pure form by crystallization from cold Et2O followed by filtration
and flushing the filter cake with Et2O. The easy removal of excess
reagents and residues has well demonstrated in this approach be-
cause these chemicals (i.e., DCC and N,N0-dicyclohexylurea) are
particularly troublesome for purification tasks performed in tag-
free chemistry. Upon incubation of the PEG-tagged Fmoce
amino acids in a 10% solution of piperidine in CH2Cl2 at room
temperature for 1 h, free PEG-tagged -amino acids 1 were librated
L-
L
to which the essential aromatic core of the target heterocyclic
compounds was integrated with this soluble polymer platform
through an SNAr reaction manner. According to the procedure
adopted by our group,16b the PEG-tagged master scaffolds 2aec
were prepared by treatment of the PEGe -amino acid tags 1aec
L
with 1,5-difluoro-2,4-dinitrobenzen and Et3N in CH2Cl2 under mi-
crowave heating conditions for 30 min. Sequential chemical ma-
nipulations were achieved by a second SNAr reaction by subjection
of PEG-tags 2 with amino acid methyl ester HCl salts and aliphatic
amines individually under the microwave heating conditions
aforementioned. Privileged molecular platforms, PEG-tags 3 and 4,
were obtained after standard recrystallization/filtration exercises
employed on soluble polymer support chemistry (Scheme 1).
The quinoxalinone framework is typically afforded through
a syntheticsequence commencingfromcouplingof amineswith 1,5-
difluoro-2,4-dinitrobenzene (DFDNB) through a sequential aro-
matic nucleophilic substitution (SNAr) manner followed by re-
ductive cyclization. However, in solution phase operation, a critical
issue on this ipso-fluorous replacement process is often concomitant
with bis-substituted side product, which has adverse effects on both
separation tasks and reaction yields. Recently, our group has dem-
onstrated convenient approaches for synthesis of diversified qui-
noxalinone scaffold using soluble polymer support technology.16
Further study in this research field results in new discovery on
elaboration of novel quinoxalinone derivatives. Herein, we report
our latest achievement in developing of an efficient soluble PEG-
tagged traceless synthesis of new class quinoxalinone analogues
Scheme 1. Preparation of PEG-tagged master scaffold 2 and PEG-tagged molecular
platforms 3e4.Reagents and conditions: (a) DCC (1.2 equiv), DMAP (5 mol %), CH2Cl2,
m
W (270 W), 30 min; (b) piperidine (10% in CH2Cl2, v/v), rt, 1 h; (c) DFDNB (2.5 equiv),
Et3N (5.0 equiv), CH2Cl2, (270 W), 30 min; (d) amino acid methyl ester$HCl
(2.5 equiv), Et3N (5.0 equiv), CH2Cl2,
(270 W), 30 min; (e) R2NH2 (5.0 equiv),
CH2Cl2, W (270 W), 30 min.
mW
mW
m

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C.-H. Shen et al. / Tetrahedron 68 (2012) 3532e3540
Examining the PEG-tagged master scaffolds in the case of 2a
Table 1
(R1¼iPr) by conventional 1H NMR spectroscopy revealed expected
One-pot traceless reductive cyclization toward pyrazino[2,3-g]quinoxalindiones 5.
Reagents and conditions: (a) Pd/C (10 wt %), NH4HCO2 (20 equiv), MeOH, reflux, 4 h
coupling systems at aromatic region at which the coupling patterns
3
4
of JFeHc and JFeHd indicating that only one fluorous atom on
DFDNB was replaced by each amino acid nucleophile anchored on
the PEG-tag 1 (Fig. 2). No cross- or higher-order substitution re-
actions were concomitant with the desired transformation owning
to PEG-tag 2 as a unified form. This excellent mono-ipso-fluorous
substitution is probably beneficial from sterically hindered PEG
backbone at the reaction terminuses so that the multiple fluorous
replacement side-reactions are efficiently suppressed.
Entry
R1
R2
Product
Yielda (%)
1
2
3
iPr
iPr
Me
iPr
iBu
iPr
5a
5b
5c
71
73
66
a
Isolated yields.
Fig. 2. 1H NMR spectra of PEG-tagged L-amino acid 1a and master scaffold 2a.
With successfully secured essential portfolios, our strategy to
reach quinoxalinone core required full reduction of the aromatic
nitro groups, cyclization, and cleavage off the PEG vehicle. Inspired
by our previous investigation in this aspect, the latter two trans-
formations occur simultaneously upon anilines are formed. To
fulfill our original orchestration by this ‘one-pot’ setting, PEG-tags 3
were employed as test ground to test this reductive cyclization.
Gratifyingly, pyrazino[2,3-g]quinoxalindiones 5 were obtained by
subjection of PEG-tags 3 with catalytic amount of Pd/C and am-
monium formate under MeOH refluxing for 4 h (Table 1).
Scheme 2. One-pot traceless reductive lactamization to access diamines 7. Reagents
and conditions: (a) Pd/C (10 wt%), NH4HCO2 (20 equiv), MeOH, reflux, 4 h.
As expected, the tandem cyclization process took place upon the
aromatic nitro groups on PEG-tag 3 were reduced to the corre-
sponding bis-aniline 6 followed by lactam formation and aroma-
tization process. In addition, this reductive lactamization also
facilitates cleavage of the PEG carrier to liberate the soluble poly-
mer support so that the tag-free quinoxalinones were recruited
from liquid media after removal of PEG by crystallization and fil-
tration. Encouraged by the promising results, PEG-tags 4 were
subjected to the same reduction conditions to furnish diamines 7,
which will serve as repertoire building blocks to access elaborated
heterocycles. Privileged frameworks such as imidazoquinox-
alinones 8e10 are envisaged to be diversified from diamines 7
through tractable synthetic exercises (Scheme 2).
Analysis of the crude diamines, 7a as an example (R1¼R2¼iPr),
obtained from filtration liquid and the retrieved PEG support by 1H
NMR spectroscopy revealed a clean and efficient transformation as
designed. No heterocyclic compound was contaminated with the
PEG residue nor incomplete cleavage occurred, which augurs well
to apply this strategy to the preparation of molecular libraries in an
exquisite manner (Fig. 3).
Fig. 3. 1H NMR spectra of crude diamine 7a and retrieved PEG support.
manipulations on the diamino functionality. Treatment of diamines
7 with 1,10-thiocarbonyldiimidazole (TCDI) in DMF at 100 ꢁC for 2 h
gave thioxoimidazo[4,5-g]quinoxalinones 8 as a privileged core.
Due to poor solubility of the diamines 7 in most organic solvents
With secure of the front end precursors, forward synthetic ap-
proaches on diamines 7 were accomplished by late stage chemical

C.-H. Shen et al. / Tetrahedron 68 (2012) 3532e3540
3535
Table 3
resulting inferior outcomes, polar aprotic solvent DMF is required.
Besides, although milder and more facile reaction conditions (route
b) were found by employing thiophosgene, safety concerns rising
from highly toxic and volatile thiophosgene confine its application
on a routine basis. As a consequence, a variety of thioxoimidazo
[4,5-g]quinoxalinones 8 were synthesized by the original condi-
tions (route a, Table 2).
Nucleophilic alkylation of thioxoimidazo[4,5-g]quinoxalinones 8 owning to imida-
zoquinoxalinones 9
Entry
R1
R2
R3
Product
Yielda (%)
Table 2
Diversification of diamines 7 leading thioxoimidazo[4,5-g]quinoxalinones 8. Re-
agents and conditions: (a) TCDI (1.5 equiv), DMF, 100 ꢁC, 4 h; (b) Cl2CS (1.5 equiv),
DMF, 0 ꢁC, 0.5 h; (c) R3X (2.0 equiv), Et3N (5.0 equiv), DMF, rt, 4 h
1
2
iBu
iBu
nBu
9a
9b
91
80
Me
3
4
iBu
iBu
9c
90
88
iPr
9d
5
6
iBu
iPr
9e
9f
81
73
iPr
Entry
R1
R2
Product
Yielda (%)
7
Me
9g
88
1
2
iBu
iBu
8a
8b
80
79
a
Isolated yields.
3
4
iBu
iBu
iBu
iPr
8c
8d
82
75
Applying similar analogy on formation of imidazolone subunit
on quinoxalinones 8 by using triphosgene as a carbonylation agent
gave unanticipated outcomes and no imidazoquinoxalinedione was
observed under the reaction arrangements. Careful examination of
resulting product by means of NMR and mass spectrometry
revealed an imidazole fragment fused with the core skeleton
owning imidazoquinoxalinone 11. Because a methine group is re-
quired along with the two amino groups to form imidazole unit, we
prospect that DMF has participated in this transformation serving
as a congener of methine equivalence. The reaction mechanism was
proposed and delineated (Scheme 3).
5
6
iBu
iPr
8e
8f
74
72
iPr
7
Me
8g
70
Highly reactive Vilsmeier reagent (N-chloromethylene-N,N0-di-
methyl ammonium chloride) is generated in situ from DMF and
triphosgene17 to react with diamine 7 to give iminium ion on which
the adjacent amino group undergoes cyclization spontaneously via
5-exo-trig pathway to afford intermediate. Imidazoquinoxalinone
11 was formed after elimination of a molecule of dimethylamine
driving by nature of aromaticity. A minor modified reaction con-
dition using DMF/CH2Cl2 (1:9, v/v) as a co-solvent was applied to
a
Isolated yields.
Further nucleophilic alkylation of imidazothione motif on qui-
noxalinones 8 by organic halides realized alkylthioimidazo[4,5-g]
quinoxalinones 9 on which the alkyl spacer could enhance their
biological activity exerted by secondary interaction with the target
proteins (Table 3).
H
N
H
N
O
O
N
R
1
N
R
2
H
a) triphosgene
DMF, RT, 2 h
10
not observed
O
N
NH
2
R
1
N
NHR
H
2
O
N
N
N
7
H
R
N
1
R
2
1
2
i
11 R = R = Pr
Scheme 3. Reaction toward the formation of imidazoquinoxalinone 11. Reagents and conditions: (a) triphosgene (1.5 equiv), DMF, rt, 2 h.

3536
C.-H. Shen et al. / Tetrahedron 68 (2012) 3532e3540
circumvent this unexpected reaction pathway. To our delight, the
target heterocycles were finally obtained in good yields under such
reaction media (Table 4). Imidazo[4,5-g]quinoxalinediones 10 were
rapidly prepared by this revised arrangement of which DMF-
participated side reaction was suppressed while homogeneous
reaction media remained. These representative examples indicate
capability of diversification the highly versatile diamines 7 to in-
tricate heterocyclic compounds.
chromatography (TLC) was performed on Merck aluminum-backed
plates pre-coated with silica (0.2 mm, 60 F254), which were visu-
alized either by quenching of ultraviolet fluorescence (lmax¼254
and 366 nm) or by charring with 10% KMnO4 in 1 M H2SO4 or by
charring with 10% Ce(SO4)2 and 15% H2SO4. Microwave-assisted
reaction: All reactions involved microwave irradiation were per-
formed by a domestic microwave oven (max output: 270 W). In-
frared spectra: These were recorded as thin films, on
a PerkineElmer Paragon 1000 Fourier transform spectrometer.
Only selected absorbances (nmax) are reported. 1H NMR spectra:
These were recorded at either 300 MHz on a Bruker DRX-300 in-
strument. Chemical shifts (dH) are quoted in parts per million
(ppm), referenced to the appropriate residual solvent peak. Cou-
pling constants (J) are reported to the nearest 0.5 Hz. 13C NMR
spectra: These were recorded at 75 MHz on a Bruker DRX-300 in-
strument. Chemical shifts (dC) are quoted in parts per million, ref-
erenced to the appropriate residual solvent peak. Degenerate peaks
are suffixed by the number of carbons. Mass spectra: Low resolution
mass spectra (m/z) were recorded on either a VG platform II or VG
AutoSpec spectrometers, with only molecular ions (Mþ, MHþ,
MNaþ) and major peaks being reported with intensities quoted as
percentages of the base peak. High resolution mass spectrometry
(HRMS) measurements are valid to ꢂ5 ppm.
Table 4
Diversification of diamines 7 leading to imidazo[4,5-g]quinoxalinediones 10. Re-
agents and conditions: (a) triphosgene (1.5 equiv), DMF/CH2Cl2 (1:10, v/v), rt, 2 h
Entry
R1
R2
Product
Yielda (%)
1
2
3
Bn
Bn
Bn
10a
10b
10c
73
78
70
iBu
4.2. General procedure for purification of PEG-tagged
intermediates
Reaction mixture was diluted with cold Et2O to effect pre-
cipitation of PEG-tagged materials from the suspended solution
followed by filtration. The white filter cake was collected, washed
with minimal amount of ice-cold Et2O, and dried in vacuo. The
procedures were minor modified in a manner as described by
Janda.11
4
H
10d
68
a
Isolated yields.
4.3. General method for preparation of PEGeL-amino acid 1
3. Conclusion
4.3.1. PEGe
L
-amino acids 1. To a solution of PEG6000 (loading level
-amino
0.33 mmol gꢀ1) in CH2Cl2 (20 mL) were added N-Fmoce
L
In conclusion, a divergent synthetic strategy to access a series of
privileged pharmacophores consisting of quinoxalinone framework
from a master scaffold was established. In corporation with the
well-documented soluble polymer support phase-tagged technol-
ogy with our synthetic approach provides alternative purification
tactics, easy reaction monitoring, and intermediate characteriza-
tion by conventional methods. It is envisaged that this concept
delivers an elegant and general approach to be adopted for pre-
paring intricate polycyclic compounds by simple operations in
a parallel manner. Further elaboration of substrate scope and ap-
plying this concept to synthesize drug-like small molecules are
currently under investigation in our group.
acids (2.4 equiv), DCC (2.4 equiv), and DMAP (0.05 equiv). The re-
action mixture was irradiated in a domestic microwave oven at
270 W for 30 min before it was filtered through a plug of CeliteÒ
501 column. The mixture was purified by general purification pro-
cedure to give PEGeFmoce
To a stirred solution of PEGeFmoce
(10 mL) was added piperidine (1 mL). The reaction mixture was
stirred at room temperature for 1 h before it was purified in ac-
cordance with the general procedure to afford desired PEGe
acids 1.
L
-amino acids.
L
-amino acids in CH2Cl2
L-amino
4.4. Representative example for synthesis of PEGe
L-valine 1a
4. Experimental section
4.1. General directions
Using general method, PEG6000 (25 g, 4.167 mmol), N-Fmoce
valine (3.39 g, 10 mmol), DCC (2.06 g, 10 mmol), and DMAP
(61.1 mg, 0.5 mmol) were employed. The resulting reaction was
L
-
All reactions were performed under anhydrous conditions and
an atmosphere of nitrogen in flame-dried glassware. PEG6000
polymer support was commercially supplied from Fluka. Solvents
and reagents: All solvents were distilled before use. Commercial
grade solvents used for chromatography were distilled before use.
Anhydrous THF and Et2O were distilled from sodium/benzophe-
none ketyl under nitrogen immediately prior to use. Anhydrous
CH2Cl2 was distilled from CaH2 immediately prior to use. All re-
agents were used as commercially supplied and used without fur-
ther purification. Chromatography: Flash chromatography (FC) was
always performed on silica gel (Merck Kieselgel 60 F254 230e400
mesh) according to the method of W.C. Still.18 Thin layer
subjected to general purification procedure to give PEGe -valine 1a
(27.54 g, 96%).
L
4.5. General method for preparation of PEG-tagged master
scaffold 2
To a solution of PEGe -amino acids 1 in CH2Cl2 (20 mL) were
L
added 1,5-difluoro-2,4-dinitrobenzene (2.5 equiv) and Et3N
(5.0 equiv). The reaction vessel was equipped with a condenser and
was irradiated in a domestic microwave oven at 270 W for 30 min.
The resulting mixture was purified by general procedure to afford
PEG-tagged master scaffold 2.

C.-H. Shen et al. / Tetrahedron 68 (2012) 3532e3540
3537
4.6. Representative example for synthesis of PEG-tag 2a
Using general method, PEGe -valine 1a (5 g, 0.753 mmol), 1,5-
difluoro-2,4-dinitrobenzene (384 mg, 1.88 mmol), Et3N (0.525 mL,
3.765 mmol) were employed. The resulting reaction was subjected
to general purification procedure to afford PEG-tag 2a (5.13 g, 85%).
1H), 6.78 (s,1H), 4.29e4.21 (m,1H), 3.40 (t, J¼6 Hz, 2H), 3.26 (s, 3H),
2.84e2.62 (m, 5H), 1.68 (m, 1H), 1.62 (d, J¼6 Hz, 6H); 13C NMR
L
(150 MHz, MeOH-d): d 168.9, 153.7, 149.8, 139.5, 125.6, 124.5, 119.6,
110.7, 70.3, 63.3, 57.5, 38.4, 25.3, 9.2; IR (cmꢀ1, neat): 3066, 2927,
1649; MS (ESI-MS) m/z: 305 (MHþ); HRMS calcd for C16H24N4O2: m/
z 305.1977; found 305.1980.
4.7. General method for preparation of PEG-tags 3 and 4
4.9.2. 7-Amino-6-[(2-methoxyethyl)amino]-3-(2-methylpropyl)qui-
noxalin-2(1H)-one (7b). 1H NMR (300 MHz, MeOH-d):
d 7.60 (s,1H),
A solution of PEG-tagged master scaffold 2 in CH2Cl2 (20 mL)
was added with amino acid methyl ester HCl salts (2.5 equiv) or
primary amines (5.0 equiv) along with Et3N (5.0 equiv) when with
amino acid methyl ester HCl salts was used. The resulting mixture
was irradiated in a domestic microwave oven at 270 W for 30 min.
The reaction mixture was purified by general procedure to afford
PEG-tags 3 and 4.
6.85 (s, 1H), 4.88e4.28 (m, 1H), 3.45e3.32 (m, 5H), 2.91e2.71 (m,
4H), 1.70 (d, J¼9 Hz, 6H); 13C NMR (75 MHz, MeOH-d):
d 168.9,
153.7, 149.9, 139.4, 125.6, 124.5, 119.6, 110.7, 72.0, 63.3, 40.1, 25.3,
9.2; IR (cmꢀ1, neat): 2949, 1658; MS (ESI-MS) m/z: 291 (MHþ);
HRMS calcd for C15H22N4O2: m/z 291.1821; found 291.1822.
4.9.3. 7-Amino-3-(2-methylpropyl)-6-[(2-methylpropyl)amino]qui-
noxalin-2(1H)-one(7c). 1H NMR (300 MHz, MeOH-d):
d
7.60 (s, 1H),
4.8. General method for ‘one-pot’ traceless reductive
cyclization toward pyrazino[2,3-g]quinoxalindiones 5 (Table
1)
6.85 (s, 1H), 4.37e4.30 (m, 2H), 2.91e2.73 (m, 4H), 1.71e1.60 (m,
12H); 13C NMR (75 MHz, MeOH-d):
d 169.3, 154.1, 150.3, 139.8,
126.0, 124.9, 120.0, 111.1, 63.7, 29.0, 25.7, 19.2, 9.6; IR (cmꢀ1, neat):
2924, 2856, 1657; MS (ESI-MS) m/z: (MHþ); HRMS calcd for
C16H24N4O: m/z 288.1950; found 288.1953.
To a stirred solution of PEG-tags 3 in MeOH were added Pd/C
(10 wt %) and ammonium formate (20 equiv) at room temperature.
The resulting mixture was refluxed for 4 h before it was filtered
through a plug of CeliteÒ 501 column and the combined organic
layer was poured into ice-cold Et2O to effect precipitation of
PEG6000 support. The suspended solution was filtered and the
combined filtration liquid was concentrated in vacuo. The resulting
pale yellow oil was purified by flash column chromatography to
afford pyrazino[2,3-g]quinoxalindiones 5.
4.9.4. 7-Amino-3-(2-methylpropyl)-6-(propan-2-ylamino)quinox-
alin-2(1H)-one (7d). 1H NMR (300 MHz, MeOH-d):
d 7.60 (s, 1H),
6.85 (s, 1H), 4.35e4.30 (m, 1H), 3.08e3.03 (m, 1H), 2.91e2.70 (m,
2H), 1.70 (d, J¼9 Hz, 6H), 1.09 (d, J¼6 Hz, 6H); 13C NMR (75 MHz,
MeOH-d):
d 169.3, 154.1, 150.3, 139.8, 126.0, 124.9, 120.0, 111.1, 63.7,
43.4, 25.7, 21.8, 9.6; IR (cmꢀ1, neat): 2931, 2856, 1655; MS (ESI-MS)
m/z: 275 (MHþ); HRMS calcd for C15H22N4O: m/z 275.1872; found
275.1873.
4.8.1. 3,7-Diisopropyl-1,2,8,9-tetrahydropyrazino[2,3-g]quinoxaline-
2,8-dione (5a). 1H NMR (300 MHz, THF-d8):
d
11.38 (s, 1H), 8.10 (s,
4.9.5. 7-Amino-6-(cyclopentylamino)-3-(2-methylpropyl)quinox-
1H), 6.86 (s, 1H), 3.53 (septet, J¼6.8 Hz, 2H), 1.31 (d, J¼6.8 Hz, 12H);
alin-2(1H)-one (7e). 1H NMR (600 MHz, MeOH-d):
d 7.57 (s, 1H),
13C NMR (75 MHz, THF-d8):
d
163.1, 152.8, 131.9, 127.2, 126.8, 95.9,
6.82 (s, 1H), 4.31e4.27 (m, 1H), 3.44 (t, J¼6 Hz, 2H), 3.30e3.29 (m,
28.9, 18.0; IR (cmꢀ1, neat): 2967, 2869, 1681, 1457; MS (ESI-MS) m/z:
299 (MHþ); HRMS calcd for C16H19N4O2: m/z 299.1508; found
299.1510.
1H), 2.86 (t, J¼6 Hz, 2H), 2.71e2.68 (m, 2H), 1.67 (d, J¼6 Hz, 6H); 13C
NMR (75 MHz, MeOH-d):
d 169.3, 154.1, 150.3, 139.8, 126.0, 124.9,
120.0, 111.1, 63.7, 33.6, 25.7, 25.3, 23.8, 9.6; IR (cmꢀ1, neat): 2924,
2854, 1645; MS (ESI-MS) m/z: 301 (MHþ); HRMS calcd for
C17H24N4O: m/z 301.2028; found 301.2029.
4.8.2. 3-Isobutyl-7-isopropyl-1,2,8,9-tetrahydropyrazino[2,3-g]qui-
noxaline-2,8-dione (5b). 1H NMR (300 MHz, DMSO-d6):
d 12.41 (br
s, 1H), 7.94 (s, 1H), 7.10 (s, 1H), 3.43 (septet, 1H), 2.65 (d, J¼6.9 Hz,
4.9.6. 7-Amino-3-(propan-2-yl)-6-(propan-2-ylamino)quinoxalin-
2H), 2.20 (m, 1H), 1.22 (d, J¼6.6 Hz, 6H), 0.93 (d, J¼6.5 Hz, 6H); 13C
2(1H)-one (7f). 1H NMR (300 MHz, DMSO-d):
d 10.64 (s, 1H), 7.11 (s,
NMR (75 MHz, DMSO-d6):
d
165.2, 165.1, 160.8, 155.7, 155.1, 133.7,
1H), 6.79 (s, 1H), 6.20 (s, 1H), 2.08e1.86 (m, 1H), 1.23e1.21 (m, 1H),
129.1, 129.0, 127.8, 99.6, 42.2, 30.8, 27.1, 23.4, 20.9; IR (cmꢀ1, neat):
2964, 2869, 1660, 1457; MS (ESI-MS) m/z: 313 (MHþ); HRMS calcd
for C17H21N4O2: m/z 313.1664; found 313.1666.
1.16 (d, J¼6 Hz, 6H), 0.93 (d, J¼6 Hz, 3H), 0.85 (d, J¼6 Hz, 3H); 13C
NMR (75 MHz, MeOH-d):
d 169.4, 154.1, 150.3, 139.8, 126.0, 124.9,
120.0, 111.1, 63.7, 24.3, 20.3; IR (cmꢀ1, neat): 2924, 2854, 1649; MS
(ESI-MS) m/z: 261 (MHþ); HRMS calcd for C14H20N4O: m/z 261.1715;
found 261.1713.
4.8.3. 3-Isopropyl-7-methyl-1,2,8,9-tetrahydropyrazino[2,3-g]qui-
noxaline-2,8-dione (5c). 1H NMR (300 MHz, MeOH-d4):
d 7.94 (s,
1H), 7.11 (s, 1H), 3.43 (septet, J¼6.8 Hz, 1H), 2.40 (s, 3H), 1.22 (d,
4.9.7. 7-Amino-6-[(2-methoxyethyl)amino]-3-methylquinoxalin-
J¼6.8 Hz, 6H); 13C NMR (75 MHz, MeOH-d4):
d
165.2, 158.9, 155.8,
2(1H)-one (7g). 1H NMR (300 MHz, DMSO-d):
d
7.60 (s, 1H), 6.86 (s,
155.1, 134.0, 133.6, 129.1, 128.9, 127.6, 99.7, 30.8, 21.3, 20.9; IR (cmꢀ1
,
1H), 3.36 (s, 3H), 2.89e2.71 (m, 4H), 2.17 (s, 3H); 13C NMR
neat): 3417, 2967, 1687, 1459; MS (ESI-MS) m/z: 271 (MHþ); HRMS
calcd for C14H15N4O2: m/z 271.1195; found 271.1197.
(150 MHz, MeOH-d): d 168.9, 153.7, 149.9, 139.4, 125.6, 124.5, 119.6,
110.7, 70.3, 57.5, 38.4, 30.8; IR (cmꢀ1, neat): 2922, 2852, 1676; MS
(ESI-MS) m/z: (MHþ); HRMS calcd for C12H16N4O2: m/z 248.1273;
found 248.1270.
4.9. General method for synthesis of diamines 7
Using the general method for synthesis of pyrazino[2,3-g]qui-
noxalindiones 5 as described above, PEG-tag 4, Pd/C (10 wt %), and
ammonium formate (20 equiv) were employed. The resulting
mixture was purified by flash column chromatography to give di-
amines 7.
4.10. Synthesis of thioxoimidazo[4,5-g]quinoxalinones 8
(Table 2)
To a stirred solution of diamine 7 in DMF (5 mL) was added 1,10-
thiocarbonyldiimidazole (1.5 equiv) at room temperature. The re-
action mixture was warmed to 100 ꢁC for 2 h before it was diluted
with Et2O (20 mL) and washed with brine (2ꢃ5 mL). The combined
organic layer was dried over MgSO4 and contracted in vacuo. The
4.9.1. 7-Amino-6-[(3-methoxypropyl)amino]-3-(2-methylpropyl)qui-
noxalin-2(1H)-one (7a). 1H NMR (300 MHz, MeOH-d):
d 7.52 (s,

3538
C.-H. Shen et al. / Tetrahedron 68 (2012) 3532e3540
resulting pale yellow oil was purified by flash column chromatog-
raphy to furnish thioxoimidazo[4,5-g]quinoxalinones 8.
2852, 1662, 1467; MS (FABMS) m/z: 291 (MHþ); HRMS calcd for
C13H14N4O2S: m/z 290.0837; found 290.0833.
4.10.1. 7-Isobutyl-1-(3-methoxypropyl)-2-thioxo-2,3-dihydro-1H-
4.11. Synthesis of imidazoquinoxalinones 9 (Table 3)
imidazo[4,5-g]quinoxalin-6(5H)-one (8a). 1H NMR (300 MHz,
DMSO-d6):
d
7.44 (s,1H), 6.96 (s, 1H), 4.18e4.12 (m, 2H), 3.26 (t, 2H),
To a solution of diamine 7 in DMF (5 mL) were added organic
halides (2.0 equiv) and Et3N (5.0 equiv) at room temperature. The
reaction mixture was stirred at such temperature for 2 h before it
was diluted with Et2O (20 mL) and washed with brine (2ꢃ5 mL).
The combined organic layer was dried over MgSO4 and contracted
in vacuo. The resulting pale yellow oil was purified by flash col-
umn chromatography to furnish thioxoimidazo imidazoquinox-
alinones 9.
3.13 (s, 3H), 2.51 (d, J¼5.8 Hz, 2H), 2.06 (m, 1H), 1.94e1.81 (m, 2H),
0.81 (d, J¼6.4 Hz, 6H); 13C NMR (75 MHz, DMSO-d6):
d 170.7, 159.6,
155.5, 132.8, 130.7, 129.3, 128.8, 107.8, 95.2, 69.5, 58.5, 42.1, 41.5,
28.0, 27.1, 23.2; IR (cmꢀ1, neat): 3089, 2956, 2869, 1660, 1467; MS
(ESI-MS) m/z: 347 (MHþ); HRMS calcd for C17H23N4O2S: m/z
347.1542; found 347.1540.
4.10.2. 7-Isobutyl-1-(2-methoxyethyl)-2-thioxo-2,3-dihydro-1H-imi-
dazo[4,5-g]quinoxalin-6(5H)-one (8b). 1H NMR (300 MHz, DMF-
4.11.1. 2-(Allylthio)-1-butyl-7-isobutyl-1H-imidazo[4,5-g]quinox-
d7):
d
12.97 (s, 1H), 12.30 (s, 1H), 7.94 (s, 1H), 7.44 (s, 1H), 4.74 (t,
alin-6(5H)-one (9a). 1H NMR (300 MHz, CDCl3):
d 12.39 (s, 1H), 7.71
J¼5.4 Hz, 2H), 4.00 (t, J¼5.37 Hz, 2H), 3.49 (s, 3H), 2.90 (d, J¼7.1 Hz,
(s, 1H), 7.62 (s, 1H), 6.08 (m, 1H), 5.43 (dd, J¼16.9, 1.3 Hz, 1H), 5.25
(dd, J¼9.9, 0.9 Hz, 1H), 4.15 (t, J¼6.8 Hz, 2H), 2.95 (d, J¼6.0 Hz, 2H),
2.42 (m, 1H), 1.93e1.81 (m, 2H), 1.50e1.37 (m, 2H), 1.08 (d, J¼6.6 Hz,
2H), 2.49 (m, 1H), 1.16 (d, J¼6.6 Hz, 6H); 13C NMR (75 MHz, DMF-
d7):
d 171.9, 159.9, 155.5, 133.1, 131.5, 130.1, 129.2, 109.0, 94.9, 70.3,
58.8, 44.5, 42.3, 27.2, 22.9; IR (cmꢀ1, neat): 3417, 2956, 1664, 1417;
MS (EI) m/z: 332 (Mþ); HRMS calcd for C16H20N4O2S: m/z 332.1307;
found 332.1306.
6H), 0.98 (t, J¼7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 159.5, 157.1,
156.5, 145.1, 134.6, 132.8, 129.7, 127.9, 119.5, 107.6, 103.0, 44.8, 42.6,
35.6, 31.6, 27.6, 23.2, 20.6, 14.1; IR (cmꢀ1, neat): 2954, 2869, 1660,
1440; MS (EI) m/z: 370 (Mþ); HRMS calcd for C20H26N4OS: m/z
370.1827; found 370.1830.
4.10.3. 1,7-Diisobutyl-2-thioxo-2,3-dihydro-1H-imidazo[4,5-g]qui-
noxalin-6(5H)-one (8c). 1H NMR (300 MHz, DMSO-d6):
d 12.88 (s,
1H),12.31(s,1H), 7.71 (s,1H), 7.04 (s,1H), 4.06 (d, J¼7.5 Hz, 2H), 2.62
4.11.2. 7-Isobutyl-1-(3-methoxypropyl)-2-(methylthio)-1H-imidazo
(d, J¼7.0 Hz, 2H), 2.18 (m, 1H), 2.32 (m, 1H), 0.88 (t, J¼6.5 Hz, 12H);
[4,5-g]quinoxalin-6(5H)-one (9b). 1H NMR (300 MHz, CDCl3):
13C NMR (75 MHz, DMSO-d6):
d
171.4, 159.8, 155.5, 132.8, 131.1,
d
12.19 (s, 1H), 7.75 (s, 1H), 7.62 (s, 1H), 4.26 (d, J¼6.9 Hz, 2H), 3.39
129.6, 128.9, 108.6, 95.0, 51.1, 42.3, 27.9, 27.1, 23.4, 20.6; IR (cmꢀ1
,
(t, J¼5.7 Hz, 2H), 3.36 (s, 3H), 2.89 (t, J¼7.3 Hz, 2H), 2.87 (s, 3H),
neat): 3411, 2958, 2869, 2658, 1467; MS (EI) m/z: 330 (Mþ); HRMS
calcd for C17H22N4OS: m/z 330.1514; found 330.1524.
2.45e2.36 (m, 1H), 2.18e2.06 (m, 2H), 1.07 (d, J¼6.6 Hz, 6H); 13C
NMR (75 MHz, CDCl3):
d 159.5, 157.9, 157.0, 144.7, 134.8, 129.7,
128.0, 107.7, 102.7, 69.1, 59.1, 42.5, 41.7, 29.5, 41.7, 29.5, 27.5, 23.2,
15.0; IR (cmꢀ1, neat): 2950, 2825, 1668, 1448; MS (ESI-MS) m/z:
361 (MHþ); HRMS calcd for C18H25N4O2S: m/z 361.1698; found
361.1695.
4.10.4. 7-Isobutyl-1-isopropyl-2-thioxo-2,3-dihydro-1H-imidazo
[4,5-g]quinoxalin-6(5H)-one (8d). 1H NMR (300 MHz, DMSO-d6):
d
12.89 (s, 1H), 12.29 (s, 1H), 7.79 (s, 1H), 7.03 (s, 1H), 5.41 (septet,
J¼5.5 Hz, 1H), 2.70 (d, J¼5.8 Hz, 2H), 2.23 (m, 1H), 1.53 (d, J¼5.5 Hz,
6H), 0.93 (d, J¼5.8 Hz, 6H); 13C (NMR 75 MHz, DMSO-d6):
d
170.3,
4.11.3. 2-(Allylthio)-7-isobutyl-1-(2-methoxyethyl)-1H-imidazo[4,5-
159.9, 155.5, 133.3, 129.5, 128.6, 128.4, 109.3, 95.2, 48.5, 42.3, 27.3,
23.4, 20.1; IR (cmꢀ1, neat): 2952, 2850, 1633, 1461; MS (ESI-MS) m/
z: 317 (MHþ); HRMS calcd for C16H21N4OS: m/z 317.1436; found
317.1434.
g]quinoxalin-6(5H)-one (9c). 1H NMR (300 MHz, CDCl3):
d 11.82 (s,
1H), 7.77 (s, 1H), 7.59 (s, 1H), 6.06 (m, 1H), 5.41 (dd, J¼16.9, 1.2 Hz,
1H), 5.21 (d, J¼9.9 Hz, 1H), 4.34 (t, J¼5.6 Hz, 2H), 4.12 (d, J¼7.0 Hz,
2H), 3.76 (t, J¼5.5 Hz, 2H), 3.34 (s, 3H), 2.89 (d, J¼7.1 Hz, 2H), 2.41
(m, 1H); 13C NMR (75 MHz, CDCl3):
d 159.7, 156.8, 156.7, 144.7, 134.7,
4.10.5. 1-Cyclopentyl-7-isobutyl-2-thioxo-2,3-dihydro-1H-imidazo
132.8, 129.8, 128.1, 119.6, 108.2, 102.8, 70.6, 59.6, 45.0, 42.6, 35.8,
27.6, 23.2; IR (cmꢀ1, neat): 2954, 2877, 1652, 1444; MS (ESI-MS) m/
z: 373 (MHþ); HRMS calcd for C19H25N4O2S: m/z 373.1698; found
373.1697.
[4,5-g]quinoxalin-6(5H)-one (8e). 1H NMR (300 MHz, DMF-d7):
d
12.98 (s, 1H), 12.28 (s, 1H), 7.77 (s, 1H), 7.45 (s, 1H), 2.87 (d,
J¼6.2 Hz, 2H), 2.53e1.90 (m, 10H), 1.14 (d, J¼5.8 Hz, 6H); 13C NMR
(75 MHz, DMF-d7):
d 171.9, 160.0, 155.5, 133.6, 129.9, 128.9, 128.4,
109.0, 95.4, 57.0, 42.5, 28.5, 27.2, 25.5, 23.0; IR (cmꢀ1, neat): 3417,
2952, 2852, 1654, 1461; MS (ESI-MS) m/z: 343 (MHþ); HRMS calcd
for C18H22N4OS: m/z 342.1514; found 342.1511.
4.11.4. 7-Isobutyl-1-isopropyl-2-(3-methylbut-2-enylthio)-1H-imi-
dazo[4,5-g]quinoxalin-6(5H)-one (9d). 1H NMR (300 MHz, CDCl3):
d
12.40 (s, 1H), 7.87 (s, 1H), 7.60 (s, 1H), 5.44 (m, 1H), 4.73 (m, 1H),
4.10 (d, J¼7.9 Hz, 2H), 2.39 (d, J¼7.2 Hz, 2H), 2.40 (m, 1H),
4.10.6. 1,7-Diisopropyl-2-thioxo-2,3-dihydro-1H-imidazo[4,5-g]qui-
1.90e1.75 (m, 6H), 1.69 (d, J¼6.9 Hz, 6H), 1.15 (d, J¼6.6 Hz, 6H);
noxalin-6(5H)-one (8f). 1H NMR (300 MHz, DMSO-d6):
d
12.85 (s,
13C NMR (75 MHz, CDCl3):
d 159.5, 157.1, 156.9, 145.8, 139.3, 132.6,
1H), 12.24 (s, 1H), 7.76 (s, 1H), 7.04 (s, 1H), 5.40 (septet, J¼7.0 Hz,
129.3, 127.7, 117.9, 109.6, 102.9, 49.5, 42.6, 31.6, 27.5, 26.2, 23.1,
21.7, 18.5; IR (cmꢀ1, neat): 2954, 2856, 1656, 1461; MS (EI) m/z:
384 (Mþ); HRMS calcd for C21H28N4OS: m/z 384.1984; found
384.1964.
1H), 3.42 (septet, J¼6.8 Hz, 1H), 1.52 (d, J¼6.9 Hz, 6H), 1.20 (d,
J¼6.8 Hz, 6H); 13C NMR (75 MHz, DMSO-d6):
d 170.4, 164.1, 154.8,
133.3, 129.4, 128.5, 128.4, 109.4, 95.1, 48.5, 30.7, 20.9, 20.2; IR (cmꢀ1
,
neat): 2962, 2815, 1633, 1463; MS (ESI-MS) m/z: 303 (MHþ); HRMS
calcd for C15H19N4OS: m/z 303.1280; found 303.1282.
4.11.5. 1-Cyclopentyl-2-(4-fluorobenzylthio)-7-isobutyl-1H-imidazo
[4,5-g]quinoxalin-6(5H)-one (9e). 1H NMR (300 MHz, DMF-d7):
4.10.7. 1-(2-Methoxyethyl)-7-methyl-2-thioxo-2,3-dihydro-1H-imi-
d 12.31 (s, 1H), 8.07 (s, 1H), 7.82 (m, 2H), 7.75 (s, 1H), 7.35 (m, 2H),
dazo[4,5-g]quinoxalin-6(5H)-one (8g). 1H NMR (300 MHz, DMF-d7):
5.12 (quintet, J¼8.6 Hz, 1H), 4.93 (s, 2H), 2.93 (d, J¼6.6 Hz, 2H),
d
12.98 (s, 1H), 12.30 (s, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 4.74 (t,
2.55e2.18 (m, 9H), 1.16 (d, J¼6.6 Hz, 6H); 13C NMR (75 MHz, DMF-
J¼5.4 Hz, 2H), 4.00 (t, J¼5.4 Hz, 2H), 3.49 (s, 3H), 2.62 (s, 3H); 13C
d7): d 132.9, 159.9, 156.2, 155.6, 145.6, 134.4, 132.6, 131.9, 131.8, 129.1,
NMR (75 MHz, DMF-d7):
d
171.8, 157.7, 155.6, 133.0, 131.5, 130.3,
129.0, 116.1, 115.8, 109.6, 102.6, 57.9, 42.5, 35.9, 29.5, 27.2, 25.3, 23.0;
129.2, 108.9, 95.0, 70.3, 58.8, 44.5, 20.7; IR (cmꢀ1, neat): 3413, 2923,
IR (cmꢀ1, neat): 3318, 2952, 2869, 1652, 1442; MS (ESI-MS) m/z: 451

C.-H. Shen et al. / Tetrahedron 68 (2012) 3532e3540
3539
(MHþ); HRMS calcd for C25H27FN4OS: m/z 451.1968; found
451.1966.
d
12.32 (s, 1H), 11.23 (s, 1H), 8.00 (s, 1H), 7.51 (s, 1H), 6.88 (s, 1H),
4.19e4.15 (m, 1H), 1.87 (d, J¼5.5 Hz, 2H), 3.73e3.59 (m, 2H),
1.98e1.60 (m, 4H); 13C NMR (75 MHz, DMSO-d6):
167.0, 155.7,
d
4.11.6. (E)-2-(3,7-Dimethylocta-2,6-dienylthio)-1,7-diisopropyl-1H-
148.3, 132.5, 129.2, 128.8, 128.4, 108.0, 94.9, 77.4, 68.1, 45.2, 29.2,
26.0; IR (cmꢀ1, neat): 2925, 2857, 1729, 1691, 1494; MS (ESI-MS)
m/z: 287 (MHþ); HRMS calcd for C14H15N4O3: m/z 287.1144; found
287.1145.
imidazo[4,5-g]quinoxalin-6(5H)-one (9f). 1H NMR (300 MHz,
CDCl3):
d
12.27 (s,1H), 7.87 (s, 1H), 7.63 (s, 1H), 5.46 (t, J¼7.9 Hz,1H),
5.09 (m, 1H), 4.74 (septet, J¼6.9 Hz, 1H), 4.14 (d, J¼7.9 Hz, 2H), 3.69
(septet, J¼6.9 Hz, 1H), 2.12e2.08 (m, 4H), 1.79 (s, 3H), 1.69 (d,
J¼6.9 Hz, 6H), 1.68 (s, 3H), 1.61 (s, 3H), 1.39 (d, J¼6.8 Hz, 6H); 13C
4.13. 1,7-Diisopropyl-1H-imidazo[4,5-g]quinoxalin-6(5H)-one
(11)
NMR (75 MHz, CDCl3):
d 163.8, 156.7, 156.4, 145.4, 142.9, 142.3,
132.5, 132.2, 129.4, 127.6, 124.1, 117.6, 109.8, 102.8, 49.6, 40.0, 31.6,
31.0, 26.8, 26.1, 21.3, 20.5, 18.1, 16.8; IR (cmꢀ1, neat): 2971, 2869,
1660, 1440; MS (ESI-MS) m/z: 439 (MHþ); HRMS calcd for
C25H35N4OS: m/z 439.2531; found 439.2528.
To a stirred solution of diamine 7a (53 mg, 0.204 mmol) in DMF
(5 mL) was added triphosgene (90.6 mg, 0.305 mmol) at room
temperature. The reaction mixture was stirred at such temperature
for 2 h before it was diluted with Et2O (20 mL) and washed with
brine (2ꢃ5 mL). The combined organic layer was dried over MgSO4
and contracted in vacuo. The resulting pale yellow oil was purified
by flash column chromatography to furnish 1,7-diisopropyl-1H-
imidazo[4,5-g]quinoxalin-6(5H)-one 11 (46.5 mg, 85%) as a yellow
4.11.7. 2-(Allylthio)-1-(2-methoxyethyl)-7-methyl-1H-imidazo[4,5-
g]quinoxalin-6(5H)-one (9g). 1H NMR (300 MHz, CDCl3):
d 12.31 (s,
1H), 7.71 (s, 1H), 7.59 (s, 1H), 6.06 (m, 1H), 5.40 (d, J¼16.9 Hz, 1H),
5.21 (d, J¼10.0 Hz, 1H), 4.30 (t, J¼5.3 Hz, 2H), 4.10 (d, J¼6.9 Hz, 2H),
3.74 (t, J¼5.4 Hz, 2H), 3.32 (s, 3H), 2.65 (s, 3H); 13C NMR (75 MHz,
solid. 1H NMR (300 MHz, CDCl3):
d 12.70 (s, 1H), 8.18 (s, 1H), 7.88 (s,
CDCl3):
d 157.0, 156.9, 156.8, 144.9, 134.9, 132.8, 129.7, 128.1, 119.6,
1H), 7.81 (s, 1H), 4.68 (septet, J¼6.6 Hz, 1H), 3.68 (septet, J¼6.8 Hz,
107.9, 103.0, 70.7, 59.6, 44.9, 35.7, 21.2; IR (cmꢀ1, neat): 2884, 1659,
1444; MS (ESI-MS) m/z: 331 (MHþ); HRMS calcd for C16H19N4O2S:
m/z 331.1229; found 331.1226.
1H), 1.65 (d, J¼6.7 Hz, 6H), 1.36 (d, J¼6.8 Hz, 6H); 13C NMR (75 MHz,
CDCl3):
d 164.7, 156.3, 145.2, 144.2, 131.3, 130.5, 128.2, 109.7, 104.9,
48.7, 31.0, 22.9, 20.7; IR (cmꢀ1, neat): 3041, 2973, 1668, 1492; MS
(ESI-MS) m/z: 271 (MHþ); HRMS calcd for C15H19N4O: m/z 271.1559;
found 271.1557.
4.12. Preparation of imidazo[4,5-g]quinoxalinediones 10
(Table 4)
Acknowledgements
To a solution of diamine 7 in a mixed solvent of DMF/CH2Cl2
(1:10, v/v; 5 mL) was added triphosgene (1.5 equiv) at room tem-
perature. The reaction mixture was stirred at such temperature for
2 h before it was diluted with Et2O (20 mL) and washed with brine
(2ꢃ5 mL). The combined organic layer was dried over MgSO4 and
contracted in vacuo. The resulting pale yellow oil was purified by
flash column chromatography to furnish thioxoimidazo imidazo[4,5-
g]quinoxalinediones 10.
The authors thank the National Science Council of Taiwan for the
financial assistance and the authorities of the National Chiao Tung
University for providing the laboratory facilities. This paper is
particularly supported by ‘Aim for the Top University Plan’ of the
National Chiao Tung University and Ministry of Education, Taiwan,
R.O.C.
Supplementary data
4.12.1. 7-Benzyl-1-(2-methoxyethyl)-1H-imidazo[4,5-g]quinoxaline-
2,6(3H,5H)-dione (10a). 1H NMR (300 MHz, DMF-d7):
d 12.34 (s,
Supplementary data related to this article can be found in the
online version, at doi:10.1016/j.tet.2012.03.015.
1H), 11.37 (s, 1H), 7.67 (s, 1H), 7.63e7.36 (m, 5H), 7.28 (s, 1H), 4.34 (s,
2H), 4.28 (t, J¼5.3 Hz, 2H), 3.89 (t, J¼5.2 Hz, 2H), 3.47 (s, 3H); 13C
NMR (75 MHz, DMF-d7):
d 157.4, 155.7, 155.3, 139.0, 132.0, 129.8,
References and notes
129.2, 129.1, 128.9, 128.2, 126.9, 107.2, 94.8, 70.5, 58.6, 41.1, 39.9; IR
(cmꢀ1, neat): 2919, 1710, 1637, 1488; MS (ESI-MS) m/z: 351 (MHþ);
HRMS calcd for C19H19N4O3: m/z 351.1457; found 351.1460.
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4.12.2. 7-Benzyl-1-isobutyl-1H-imidazo[4,5-g]quinoxaline-
2,6(3H,5H)-dione (10b). 1HNMR (300 MHz, DMSO-d6):
d
7.35(s,1H),
7.28e7.12 (m, 5H), 3.57 (d, J¼7.2 Hz), 2.04 (m,1H), 0.81 (d, J¼6.6 Hz);
13C NMR (75 MHz, DMSO-d6):
157.2,156.0,155.4,138.3,131.4,129.7,
d
129.2,129.0,128.4,127.9,127.2,106.7, 95.2, 48.2, 27.9, 20.4; IR (cmꢀ1
,
neat): 3440, 2960, 1702, 1660, 1484; MS (ESI-MS) m/z: 349 (MHþ);
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4.12.3. 7-Benzyl-1-(3,3-diphenylpropyl)-1H-imidazo[4,5-g]quinoxa-
line-2,6(3H,5H)-dione (10c). 1H NMR (300 MHz, DMSO-d6):
d 12.31
(s, 1H), 11.16 (s, 1H), 7.29e7.09 (m, 16H), 6.85 (s, 1H), 4.04 (s, 2H),
3.99 (t, J¼7.5 Hz, 2H), 3.71 (t, J¼6.8 Hz, 1H), 2.38 (dt, J¼7.5, 6.8 Hz,
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d 166.9, 157.1, 155.4, 145.1, 138.6,
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131.6, 129.9, 129.3, 129.2, 128.5, 128.4, 128.3, 127.9, 127.1. 127.0,
106.5, 95.0, 48.9, 39.9, 39.5, 33.6; IR (cmꢀ1, neat): 2958, 1716, 1644,
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line-2,6(3H,5H)-dione (10d). 1H NMR (300 MHz, DMSO-d6):
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