Multistep microwave-assisted divergent synthesis of indolo-fused pyrazino-/diazepinoquinoxalinones on PEG support

Article abstract of DOI:10.1021/ol100436r

Synthesis of amino acid and indoline-substituted dinitrobenzene on a soluble polymer support (PEG) and its further reductive double-ring closure to afford structurally diverse indolo-fused pyrazino-/diazepinoquinoxalinones is described. Traceless synthesis of quinoxalinones coupled with application of the Pictet-Spengler-type condensation reaction furnished these novel scaffolds. These hitherto novel heterocycles are synthesized in shorter times under microwave irradiation conditions in comparison with that of classical reaction conditions.

Full text of DOI:10.1021/ol100436r

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2174-2177
Multistep Microwave-Assisted Divergent
Synthesis of Indolo-Fused Pyrazino-/
Diazepinoquinoxalinones on PEG Support
Jin-Ji Lai, Deepak B. Salunke, and Chung-Ming Sun*
Laboratory of Combinatorial Drug DiscoVery, Department of Applied Chemistry,
National Chiao Tung UniVersity, Hsinchu, 300-10, Taiwan
cmsun@mail.nctu.edu.tw
Received February 21, 2010
ABSTRACT
Synthesis of amino acid and indoline-substituted dinitrobenzene on a soluble polymer support (PEG) and its further reductive double-ring
closure to afford structurally diverse indolo-fused pyrazino-/diazepinoquinoxalinones is described. Traceless synthesis of quinoxalinones
coupled with application of the Pictet-Spengler-type condensation reaction furnished these novel scaffolds. These hitherto novel heterocycles
are synthesized in shorter times under microwave irradiation conditions in comparison with that of classical reaction conditions.
The CAS registry database consists of more than 24 million
organic chemical substances; however, half of these mol-
ecules can be described by just 143 shapes.1 This scenario
demands the clear need of new scaffold design from the
virtual chemical space to explore newer dimensions in drug
discovery process. Fused heterocyclic ring systems are often
considered as important privileged structures to identify the
novel leads in drug discovery.2 To speed up this discovery
process and maintain the balance between new chemical
entity syntheses and screening, several new techniques such
as parallel or combinatorial synthesis3 and multicomponent
reactions4 have been developed. Still, there is a need for new
tools to provide a fast and more efficient way to synthesize
novel chemical compounds.
In our view, by reducing in-pot reaction time and reloading
time (Figure 1), a multistep synthetic process on a polymer
support can become a powerful tool to provide numerous
(1) Lipkus, A. H.; Yuan, Q.; Lucas, K. A.; Funk, S. A.; Bartelt, W. F.,
III; Schenck, R. J.; Trippe, A. J. J. Org. Chem. 2008, 73, 4443–4451.
(2) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003, 103,
893–930.
Figure 1. In-pot and reloading reaction time.
(3) Lawrence, R. N. Drug DiscoV. Today 2000, 5, 172–175.
10.1021/ol100436r  2010 American Chemical Society
Published on Web 04/26/2010

compounds in a short time. Furthermore, a diversity-oriented
synthesis5 of newly designed scaffolds using this technique may
provide suitable compound libraries with additional complexity
in the structures. This paper describes the first diversity-oriented
traceless synthesis of new indolo-fused pyrazino- and diazepi-
noquinoxalinone libraries using such a multidisciplinary syn-
ergistic approach. No hits were found in Chemical Abstracts
with more than 80% similarity to the newly designed scaffolds.
Incorporation of tetrahedral carbon atoms in present ring systems
was intended to disrupt the typical one-dimensional planarity
of aromatic skeletons.6 This may create multidimensional
concave and convex surfaces in the molecule and can make
these skeletons privileged structures to design high affinity
ligands for future drug discovery.
Scheme 2. Reductive Double-Ring-Closure Reactions
These scaffolds incorporate the structural features of many
pharmacologically important heterocycles such as pyrazinone,
quinoxalinone, diazepine, diazepinoquinoxaline, N-fused indole,
pyrazinoquinoxaline, and diazepino-/pyrazinoindole.7 The closely
related molecules demonstrated high affinity for benzodiazepine
receptors,8 whereas Glamkowski observed potential antidepres-
sant, analgesic, as well as anti-inflammatory effects in in-
dolobenzodiazepine-related structures.9
A synthetic route to the targeted indolo-fused pyrazino-
or diazepinoquinoxalines is described in Schemes 1 and
Scheme 1
.
Synthesis of Amino Acid and Indoline-Substituted
Dinitrobenzene on a PEG Support
glycol) (PEG, mol wt ≈ 6000) support using 1,5-difluoro-
2,4-dinitrobenzene (DFDNB) and its further reductive double-
ring closure to structurally diverse skeletons in a divergent
fashion. DFDNB is preferred to construct the designed
skeletons because of its easy accessibility for two directional
elongations via utilization of two fluoro groups which could
be successively substituted by different nucleophiles. This
symmetric scaffold has been utilized for the construction of
various bioactive-fused heterocycles.10 Previously, we dem-
onstrated the use of this bifunctional cross-linker for the
synthesis of imidazoquinoxalinones on PEG support.11 The
present multistep process was executed using both classical
as well as microwave irradiation conditions.12
Esterification of the commercially available Fmoc-
protected amino acids with PEG in the presence of catalytic
p-toluenesulfonic acid (PTSA) in CH2Cl2 under microwave
irradiation (100 °C for 10 min) furnished Fmoc-protected
amino ester conjugates 1 (Scheme 1). Using this recipe and
following the conventional protocol reaction took several
hours for complete conversion. Similarly, a microwave-
mediated esterification reaction using DCC and catalytic
(4) Zhu, J.; Bienayme, H., Ed. Multicomponent reactions; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, Germany, 2005; 468 pp.
(5) Schreiber, S. L. Science 2000, 87, 1964–1969.
(6) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752–
6756.
2. The strategy involved synthesis of amino acid and
indoline-substituted dinitrobenzene 4 on a poly(ethylene
Org. Lett., Vol. 12, No. 10, 2010
2175

DMAP in CH2Cl2 in an open vessel system11,13 required 15
min of irradiation at a 150 W power output, whereas the
coupling reaction at room temperature14 took 48 h for the
complete disappearance of the starting materials.
From this point onward, the process is diversified to
accomplish reductive cyclizations to furnish aminoquinox-
alinones 5/6 with indole and indoline substitutions, respec-
tively (Scheme 2). Exposure of 4 to the catalytic transfer
hydrogenation conditions using palladium and ammonium
formate in refluxing methanol for 8 h or under microwave
irradiation (20 min, 180 °C) furnished indolylquinoxalinone
5 in a traceless fashion. Four transformations, (i) reduction
of two nitro functionalities, (ii) amide formation leading to
cyclative cleavage from the polymer support, (iii) oxidation
of newly generated dihydroquinoxalinone to quinoxalinone,
as well as (iv) oxidation of indoline to indole were observed
during this reaction. It should be mentioned that under these
conditions no additional oxidants17 or further air oxidation
step18 is required for the transformation of dihydroquinox-
alinone to quinoxalinone.
The expected indolinylquinoxalinone 6 was obtained from
the same intermediate 4 with the conventional protocol using
Zn and ammonium formate in methanol at room temperature.
This controlled reaction condition prevented the additional
oxidation of indoline to indole which was observed during
the earlier palladium-catalyzed transformation. The complete
cyclative cleavage during this reaction was monitored by
recording the proton NMR and IR spectrum of the recovered
polymer support. The upfield shift of the R-methylene
protons from δ 4.3 to 3.6 as well as disappearance of any
carbonyl stretching frequency confirmed the absolute trace-
less transformation. The polymer-free compounds 5 and 6
were obtained in excellent yields. The proton NMR monitor-
ing toward the formation of 5a and 6a from the key
intermediate 4a on a PEG support is shown in Figure 2. Six
To monitor the progression of the reaction, a small portion
of the reaction mixture was pulled out, the compound was
precipitated and washed with cold ether and dried, and the
proton NMR spectrum was recorded. Upon completion of
the reaction, the polymer-bound compound mixtures were
purified using a similar protocol, by precipitation and
washing with cold ether to remove excess reagents and dried
under vacuum. The crude product obtained was used as is
for reloading of next reaction mixtures. As we observed, use
of this PEG supported protocol drastically reduced the
reloading time.
In the next step, the amino functionality in compound 1
was unmasked using 10% piperidine in CH2Cl2 at room
temperature. The desired Fmoc deptotection using micro-
waves was achieved within 90 s (40 °C) leaving the polymer
support intact.15 The regenerated polymer bound amine 2
was then reacted with DFDNB in refluxing CH2Cl2 in the
presence of Et3N for 6 h to give polymer-bound dinitrofluoro-
substituted aniline compounds 3, ready for second ipso-fluoro
displacement. Because of probable low reactivity of the
immobilized aminoester-linked fluorodinitrobenzene 3, no
further double displacement was observed during this reac-
tion.
Our several efforts for the second aromatic substitution
on compound 3 by indoline using refluxing CH2Cl2 resulted
in an incomplete reaction (monitored by 1H NMR), whereas
in refluxing acetonitrile the reaction took 8 h for complete
conversion. It is noteworthy to mention that the microwave-
mediated acceleration in both ipso-fluoro displacement
reactions was also observed. The first aromatic displacement
using polymer-bound aminoester 2 was achieved in 8 min,
whereas the indoline substitution took 20 min for the
complete conversion in a microwave cavity. During all these
transformations, no yield loss was observed, suggesting the
presence of intact polymer support. Reaction progress and
stepwise transformations on a polymer support were cleanly
observed in proton NMR spectra.16
(7) (a) Li, X.; Yang, K.; Li, W.; Xu, W. Drugs Future 2006, 31, 979–
989. (b) Gupta, L.; Talwar, A.; Chauhan, P. M. S. Curr. Med. Chem. 2007,
14, 1789–1803. (c) Ramajayam, R.; Giridhar, R.; Yadav, M. R. Mini ReV.
Med. Chem. 2007, 7, 793–812. (d) Dunlop, J.; Marquis, K. L.; Lim, H. K.;
Leung, L.; Kao, J.; Cheesman, C.; Rosenzweig-Lipson, S. CNS Drug ReV.
2006, 12, 167–177
(8) Dodd, R. H.; Ouannes, C.; Potier, M. C.; de Carvalho, L. P.; Rossier,
J.; Potier, P. J. Med. Chem. 1987, 30, 1248–1254
(9) Glamkowski, E. J.; Fortunato, J. M.; Ong, H. H.; Allen, R. C.; Wilker,
J. C.; Geyer, H. M., III. J. Med. Chem. 1984, 27, 81–83
.
.
.
(10) (a) Yuan, Y.; Liu, G.; Li, L.; Wang, Z.; Wang, L. J. Comb. Chem.
2007, 9, 158–170. (b) Zhang, L.; Liu, G.; Zhang, S. D.; Yang, H. Z.; Li,
L.; Wu, X. H.; Yu, J.; Kou, B. B.; Xu, S.; Li, J.; Sun, G. C.; Ji, Y. F.;
Figure 2. Proton NMR monitoring toward the formation of 5a and
6a from key intermediate 4a.
Cheng, G. F. J. Comb. Chem. 2004, 6, 431–436
.
(11) Lin, M. J.; Sun, C. M J. Comb. Chem 2006, 8, 455–458
.
(12) All the microwave-assisted polymer-supported reactions were
performed in a CEM Discover Microwave in closed vessel system.
distinct sets of aromatic protons (Ha-f, as observed in 4a)
and two sets of methylene protons (Hg and Hh) were observed
(13) Lin, M. J.; Sun, C. M. Tetrahedron Lett. 2003, 44, 8739–8742
.
(14) Chen, C. H.; Chang, C. M.; Chen, H. Y.; Lai, J. J.; Sun, C. M.
J. Comb. Chem. 2007, 9, 618–626.
(15) We reported microwave-mediated Fmoc deprotection under open
vessel conditions: Wu, C. Y.; Sun, C. M. Synlett 2002, 1709–1711.
(16) The stepwise 1H NMR monitoring toward the formation of key
intermediates 4 on a PEG support is included in the Supporting Information.
(17) Aoki, K.; Obata, T.; Yamazaki, Y.; Mori, Y.; Hirokawa, H.; Koseki,
J.; Hattori, T.; Niitsu, K.; Takeda, S.; Aburada, M.; Miyamoto, K. Chem.
Pharm. Bull. 2007, 55, 255–267.
(18) Krchn`a´k, V.; Szabo, L.; Va´gner, J. Tetrahedron Lett. 2000, 41,
2835–2838.
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Org. Lett., Vol. 12, No. 10, 2010

Recently, while working on very similar substrates, Soural
et al.20 observed an interesting resistance of the nitro group
toward various reducing agents attributed to the presence of
ortho, para electron-donating amino substitutions in the ring
causing a double-resonance effect. In our hands, using Pd/C
or Zn and ammonium formate in methanol, no such
resistance was observed during this reductive cyclization.
The final step was to accomplish the second heterocy-
clization. Compound 5 on treatment with several ketones in
the presence of TFA in refluxing CHCl3 (8 h) or in a
microwave cavity (20 min, 150 °C) furnished the desired
novel indolo-fused pyrazinoquinoxalinone 7, whereas with
a similar recipe, compound 6 yielded an indolo-fused
diazepinoquinoxalinone 8 scaffold. During this Pictet-
Spengler-type condensation, 6 underwent an electrophilic
cyclization with ketones at the phenyl ring,9,21 while
compound 5 cyclized onto its electron-rich pyrrole ring22 to
furnish the required heterocycles in good to excellent yields
(80-92%, Table 1). Lower yields with pentan-3-one
(63-67%; Table 1, entries 7c and 8c) were attributed to the
additional steric hindrance, whereas an expected poor yield
with acetophenone (45%, entry 8g) confirmed the modest
reactivity of aromatic ketones toward the formation of
iminium intermediate with anilinic amines. An interesting
spirocyclic ring skeleton was also added to these novel
scaffolds using cyclic ketones such as cyclopentane and
cyclohexane.
Table 1. Indolo-Fused Pyrazino-/Diazepinoquinoxalinones (7/8)a
In conclusion, two novel heterocyclic library scaffolds
consisting of indole-fused pyrazino- and diazepinoquinox-
alinone skeletons with a two-point diversity were synthesized
in good to excellent yields. Our envisioned strategy to utilize
variable electron densities of indole and indoline rings of
compound 5 or 6 during the Pictet-Spengler-type cyclization
to furnish six-membered pyrazino or seven-membered di-
azepino rings was the key feature behind the success of this
diversified process. The total in-pot reaction time for the
synthesis of these newly designed molecules was drastically
reduced to ∼1.5 h under microwave irradiation conditions
in comparison with that of the classical reaction conditions
(total in-pot reaction time ∼60 h).
Acknowledgment. We thank the National Science Council
of Taiwan for financial assistance.
Supporting Information Available: Experimental pro-
cedures, characterization data for all new compounds,
stepwise proton NMR monitoring toward the formation of
1
key intermediate 4a on a PEG support, and copies of H
a Only the representative examples are shown in Table 1. A library of
total 30 compounds is included in the Supporting Information. b Yields were
determined on weight of purified samples.
and 13C NMR spectra for polymer free substrates 5 and 6
and products 7 and 8. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL100436R
for 6a, whereas the disappearance of these methylene protons
confirmed the additional palladium-mediated oxidation19 in
compound 5a.
(20) Krupkova, S.; Soural, M.; Hlavac, J.; Hradil, P. J. Comb. Chem.
2009, 11, 951–955.
(21) Zhang, L. H.; Meier, W.; Wats, E.; Costello, T. D.; Ma, P.; Ensinger,
C. L.; Rodgers, J. M.; Jacobson, I. C.; Rajagopalan, P. Tetrahedron Lett.
1995, 36, 8387–8390
(22) Zheng, L.; Xiang, J.; Dang, Q.; Guo, S.; Bai, X. J. Comb. Chem.
2005, 7, 813–815.
.
(19) Beller, M.; Breindl, C.; Riermeier, T. H.; Tillack, A J. Org. Chem.
2001, 66, 1403–1412.
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