Solid-phase synthesis of quinoxaline derivatives using 6-amino-2,3- dichloroquinoxaline loaded on AMEBA resin

Article abstract of DOI:10.1016/j.tetlet.2005.05.096

The solid-phase synthesis of quinoxaline derivatives 1 was accomplished through successive introduction of building blocks such as amines, methoxide, acid chlorides, and isocyanates into 6-amino-2,3-dichloroquinoxaline 2 loaded on AMEBA resin 3. The metho

Full text of DOI:10.1016/j.tetlet.2005.05.096

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4979–4983
Solid-phase synthesis of quinoxaline derivatives using
6-amino-2,3-dichloroquinoxaline loaded on AMEBA resin
Moon-Kook Jeon, Dong-Su Kim, Hyun Ju La and Young-Dae Gong*
Korea Research Institute of Chemical Technology, PO Box 107, Yuseong-gu, Daejeon 305-600, South Korea
Received 14 March 2005; revised 19 May 2005; accepted 20 May 2005
Available online 9 June 2005
Abstract—The solid-phase synthesis of quinoxaline derivatives 1 was accomplished through successive introduction of building
blocks such as amines, methoxide, acid chlorides, and isocyanates into 6-amino-2,3-dichloroquinoxaline 2 loaded on AMEBA resin
3. The method made it possible to obtain the compound 1 in 63–100% purities and 36–89% isolated yields.
Ó 2005 Elsevier Ltd. All rights reserved.
Combinatorial chemistry along with high-throughput
screening has emerged as a powerful tool for efficient
drug discovery process.1 The synthesis of combinatorial
libraries based on the so-called privileged structures has
attracted particular attention because single scaffolds are
able to provide potent and selective ligands for a range
of different biological targets across and within different
target families through modification of functional
groups.2 From this point of view, the quinoxaline scaf-
fold is of particular interest for us in that its derivatives
exhibit various biological activities. A review of the bio-
logical activity of quinoxaline derivatives up to 1987 was
published.3a Apart from those described in the review,
they were reported to have a variety of activities such
as tranquilizing,3b antimycobacterial,3c,d cardiotonic,3e
antidepressant,3f and antitumor3g,h activities depending
on the substitution pattern on the scaffold. In addition,
they were shown to be 5-HT3 receptor antagonist,3i
NMDA receptor antagonist,3j PDGF–RTK inhibi-
tor,3k,l,m IL-8 receptor antagonist,3n and CCR1 antago-
nist3o in the same manner.
efforts.4 For such RTK-directed library construction,
we needed to develop a versatile method for the solid-
phase synthesis of quinoxaline derivatives. Recent re-
ports described the utilization of 4-fluoro-3-nitrobenzoic
acid attached to SynPhaseTM Rink Lanterns,5a polymer-
bound 1,2-diaza-1,3-butadienes,5b,c PAL resin-bound
amines,5d and polymer-linked 2-nitrophenylcarba-
mates5e to obtain the quinoxalines. Herein, we wish to
present the solid-phase synthesis of quinoxaline deriva-
tives 1 through successive introduction of the building
blocks into 6-amino-2,3-dichloroquinoxaline 26 loaded
on AMEBA resin 37 (Scheme 1). The method would
enable us to achieve diverse amino-related functionality
at 6 position as well as diversification at 2 and 3 position
of quinoxaline scaffold.
First of all it was needed to determine the order in which
the substituents should be combined into the (2,3-
dichloroquinoxalin-6-yl)amino resin 4. The model study
in solution by use of piperidine as an amine (Scheme 2)
confirmed that it was optimal to introduce the building
blocks in the order (4 ! 5 ! 6 ! 7) shown in Scheme 1.
When compound 13 was subjected to excess NaOMe in
DMF at rt, methoxylation was followed by debenzoyl-
ation to give 11 as the final product. The treatment of
benzoylated dichloroquinoxaline 14 with excess piperi-
dine in DMF at rt afforded the bisaminated product
15. The sequence 9 ! 10 ! 11 ! 12 did not bring about
any undesirable reaction. The reaction of 2,3-
dichloro-6-(2,4-dimethoxybenzylamino)quinoxaline 9,
prepared from the reductive amination of 2 with 2,4-
dimethoxybenzaldehyde under the standard condition
in 75% yield, with excess piperidine in DMF at rt gave
In connection with a project for exploring the novel po-
tent RTK inhibitors, we have designed some target com-
pounds for quinoxaline-based library construction
taking into account the structural features of the previ-
ously reported diverse drug-like small molecule inhibi-
tors identified through high-throughput screening
Keywords: Solid-phase synthesis; Quinoxaline; AMEBA resin.
*
Corresponding author. Tel.: +82 42 8607149; fax: +82 42 861
1291; e-mail: ydgong@krict.re.kr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.096

4980
M.-K. Jeon et al. / Tetrahedron Letters 46 (2005) 4979–4983
H2
N
N
N
Cl
Cl
H
N
N
N
Cl
Cl
H
2
NaBH(OAc)3
O
DCE
rt
3
4
H
N
H
NR1R2
Cl
N
N
NR1R2
OMe
N
N
HNR1R2
NaOMe
DMF
DIEA
N
rt
DMF, rt
or DMSO, 60 oC
6
5
O
R3
H
acid chloride
isocyanate
R3
N
N
NR1R2
OMe
N
N
NR1R2
OMe
50% TFA
DCM
O
(DIEA)
DCM
rt
N
N
rt
1
7
Scheme 1.
H2
N
N
N
Cl
Cl
H
N
MeO
N
Cl
Cl
2
R
H
NaBH(OAc)3
N
DCE
rt
OMe O
9
8
excess
DIEA
excess
benzoyl chloride
DIEA
piperidine
DMF, rt
DCM, rt
H
N
O
Ph
N
N
N
R
N
N
N
Cl
Cl
excess
benzoyl chloride
DIEA
R
Cl
DCM, rt
10
excess
DMF
14
NaOMe
rt
O
R
Ph
excess
DIEA
H
excess
piperidine
N
N
N
N
N
N
N
N
DMF, rt
NaOMe
R
DMF
O
R
Ph
Cl
OMe
rt
13
11
N
N
N
N
excess
benzoyl
chloride
DIEA
DCM, rt
N
15
O
Ph
N
N
N
N
R
R = 2,4-dimethoxybenzyl
OMe
12
Scheme 2.
3-piperidino derivative 10 as single regioisomer in 96%.
The subsequent methoxylation and benzoylation pro-
ceeded successfully to form 11 and 12 in 91% and
84%, respectively. The regiochemistry of the product
10 in the first step was assigned on the analogy of the
previous result obtained from the reaction of 6-amino-
2,3-dichloroquinoxaline 2 with amines.6a
BA resin 3 was obtained from Merrifield resin by the lit-
erature method.7c The loading of 2 on AMEBA resin 3
was accomplished by reductive amination in DCE in
the presence of NaBH(OAc)3 at rt. The completion
of the reaction was confirmed by the disappearance of
the aldehyde carbonyl band (1677 cmꢁ1) of AMEBA
resin 3 and the appearance of amino band (3414 cmꢁ1
)
on single bead ATR-FTIR spectrum. The polymer-
bound 6-amino-2,3-dichloroquinoxaline 4 was treated
with amines in the presence of DIEA to give the ami-
nated resins 5. The amination step was performed in
DMF at rt for secondary cyclic amines and in DMSO
at 60 °C for primary and secondary acyclic amines. In
the case of primary amines, the use of DMF as solvent
gave the corresponding dimethylamino derivative as a
According to the results obtained from the solution-
phase model study, the solid-phase synthesis of quinoxa-
line derivatives 1 was performed as shown in Scheme 1.
Compound 2 was prepared from the reduction of 2,3-di-
chloro-6-nitroquinoxaline6a in THF in the presence of
10% Pd/C and a few drops of concd HCl under H2
atmosphere (ꢀ40psi) at 50 °C in 83% yield and AME-

M.-K. Jeon et al. / Tetrahedron Letters 46 (2005) 4979–4983
Table 1. Purities and yields of the compounds 1
4981
Compound
R1R2N
R3
Puritya (%)
Yield (%b/%c)
1aad
1abd
1bad
1bbd
1cad
1cbd
1dae
1dbe
1ea
1eb
1ec
1ed
1ee
1ef
n-PrNH
n-PrNH
C6H5
C6H5NH
C6H5
93
92
69/41
71/40
80/55
87/63
100/87
84/65
82/67
90/73
100/88
92/79
85/70
66/36
87/75
84/67
80/71
85/71
80/65
i-PrNH
i-PrNH
98
89
C6H5NH
C6H5
BnNH
BnNH
88
85
C6H5NH
C6H5
Et2N
Et2N
97
94
C6H5NH
C6H5
Piperidino
Piperidino
Piperidino
Piperidino
Piperidino
Piperidino
Piperidino
Piperidino
Piperidino
Piperidino
Piperidino
Piperidino
Pyrrolidino
Pyrrolidino
Pyrrolidino
Pyrrolidino
Morpholino
Morpholino
Morpholino
Morpholino
Morpholino
Morpholino
4-Methylpiperazino
4-Methylpiperazino
4-Methylpiperazino
4-Methylpiperazino
95
93
4-MeOC6H4
4-PhC6H4
2-ClC6H4
4-BrC6H4
4-NCC6H4
4-O2NC6H4
BnNH
95
77
97
77
1eg
1eh
1ei
91
92
EtO2CCH2NH
4-MeOC6H4NH
Me
100
9094/66
86
1ej
1ek
1el
77/64
85/62
Cyclopropyl
MeOCH2
Cyclohexyl
2-Furyl
93
89
1fa
1fb
100/68
99/60
86
1fc
1fd
9097/73
88
92
4-t-BuC6H4NH
2-Thienyl
4-t-BuC6H4
2-FC6H4NH
2-ClC6H4NH
2-BrC6H4NH
t-BuCH2
81/69
97/80
100/83
95/70
70/59
82/42
94/75
90/75
1ga
1gb
1gc
1gd
1ge
1gf
90
85
85
63
85
89
1ha
1hb
1hc
1hd
2-FC6H4
4-ClC6H4
2-MeOC6H4NH
4-FC6H4NH
9098/72
85
91
99/68
97/89
a Determined on the basis of LC–MS spectrum of crude product after cleavage from the resin 7.
b Yield of crude product after cleavage from the resin 7 (six-step overall yield from Merrifield resin).
c Yield after column chromatography of crude product (six-step overall yield from Merrifield resin).
d The product was compound formed from benzoylation or phenyl isocyanate addition with amino group at 6 position, not with that at 3 position.
e Sterically hindered secondary acyclic amines such as diisopropylamine and dibenzylamine gave the corresponding 2,3-dimethoxy derivatives as
major products.
byproduct and the reaction proceeded much faster in
DMSO than in DMF for secondary acyclic amines. Sub-
sequent methoxylation of the (2-chloro-3-alkylamino
and 3-dialkylaminoquinoxalin-6-yl)amino resins 5 with
excess NaOMe in DMF at rt afforded the (3-alkyl-
amino- and 3-dialkylamino-2-methoxyquinoxalin-6-yl)-
amino resins 6, which were treated with acid chlorides
in the presence of DIEA or isocyanates alone in DCM
at rt. The fully derivatized resins 7 showed the corre-
sponding carbonyl bands on single bead ATR-FTIR
spectra. Finally, the desired quinoxaline derivatives 1
were obtained in good purities and yields by the cleav-
age from the resins 7 under the conditions of 50%
TFA/DCM at rt.8 The results are summarized in Table
1. The structures of compounds 1aa–hd were assigned
using a variety of amines, alkoxides, acid chlorides, and
isocyanates. On the other hand, investigation into a ver-
satile method for the quinoxaline derivatives regioiso-
meric with 1 is in progress.
Acknowledgements
We are grateful to the Ministry of Commerce, Industry
and Energy of Korea, the Center for Biological Modu-
lators, and Korea Research Institute of Chemical Tech-
nology for financial support of this research.
Supplementary data
1
on the basis of H NMR and MS spectral data.
1H NMR and MS spectral data of compounds 1aa–hd,
single bead ATR-FTIR spectra of resins 4, 5ea, 6ea,
and 7ea, LC–MS and H NMR spectra of compound
In brief, the quinoxaline derivatives 1 were prepared
using 6-amino-2,3-dichloroquinoxaline loaded on
AMEBA resin. The simple and efficient method for so-
lid-phase synthesis of quinoxaline derivatives will make
it possible to construct desired library with a larger size
1
1ea. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2005.05.096.

4982
M.-K. Jeon et al. / Tetrahedron Letters 46 (2005) 4979–4983
Mann, A. D.; Baer, T. A. Org. Process Res. Dev. 1999, 3,
177–183.
References and notes
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dichloroquinoxaline 2. To a solution of 2,3-dichloro-6-
nitroquinoxaline (2.00 g, 8.20 mmol) in THF (200 mL) were
added 10% Pd/C (200 mg) and a few drops of concd HCl.
The mixture was agitated under H2 atmosphere (ꢀ40psi) at
50 °C for 40h, filtered over Celite and magnesium sulfate,
and evaporated in vacuo. The residue was chromato-
graphed on a silica gel column and elution with methylene
chloride gave the compound 2 (1.46 g, 83%): 1H NMR
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(300 MHz, DMSO-d6):
J = 2.2 Hz, 1H), 7.30(dd, J = 9.2 and 2.2 Hz), 7.73 (d,
J = 9.2 Hz, 1H); (b) Preparation of AMEBA resin 3.7c
d 6.45 (br s, 2H), 6.85 (d,
A
mixture of Merrifield resin (1.6 mmol/g, 5.00 g, 8.0 mmol),
2-methoxy-4-hydroxybenzaldehyde (2.44 g, 16.0mmol),
potassium carbonate (2.22 g, 16.1 mmol), and potassium
iodide (40mg, 0.24 mmol) in DMF (50mL) was stirred at
55 °C for 16 h. The resin was filtered, washed several times
with DMF, toluene/H2O, MeOH, and DCM, and dried in a
vacuum oven to give 3 (5.81 g, 98%): Single bead ATR-
FTIR 3024, 2923, 2851, 1677 (C@O), 1598, 1578, 1492,
1464, 1452, 1422, 1292, 1259, 1197, 1162, 1113, 1102, 1027,
1016, 815, 757, 697 cmꢁ1; (c) Preparation of (2,3-dichloro-
quinoxalin-6-yl)amino resin 4. To a suspension of AMEBA
resin 3 (6.10g, theoretically 8.2 mmol) in DCE (50mL) at
rt was added 6-amino-2,3-dichloroquinoxaline 2 (2.64 g,
12.3 mmol) and sodium triacetoxyborohydride (2.62 g,
12.4 mmol). The mixture was stirred at rt for 20h and the
resin was filtered, washed several times with DCM, DMF,
MeOH, and DCM, and dried in a vacuum oven to give 4
(7.48 g, 97%): Single bead ATR-FTIR 3414 (NH), 3025,
2922, 2850, 1614, 1588, 1504, 1493, 1463, 1451, 1420, 1286,
1257, 1235, 1196, 1155, 1128, 1030, 1017, 995, 821, 758, 735,
698 cmꢁ1; (d) Preparation of (2-chloro-3-piperidin-1-yl-
quinoxalin-6-yl)amino resin 5ea (NR2 = piperidin-1-yl). A
mixture of the resin 4 (2.00 g, theoretically 2.1 mmol),
piperidine (914 mg, 10.7 mmol), and diisopropylethylamine
(2.77 g, 21.4 mmol) in DMF (20mL) was stirred at rt for
48 h. The resin was filtered, washed several times with
DMF, MeOH, and DCM, and dried in a vacuum oven to
give 5ea (2.07 g, 100%): Single bead ATR-FTIR 3410 (NH),
3024, 2920, 2848, 1613, 1588, 1530, 1504, 1493, 1463, 1451,
1283, 1195, 1157, 1130, 1114, 1029, 1013, 817, 757,
698 cmꢁ1; (e) Preparation of (2-methoxy-3-piperidin-1-
ylquinoxalin-6-yl)amino resin 6ea (NR2 = piperidin-1-yl).
To a suspension of the resin 5ea (2.07 g, theoretically
2.1 mmol) in DMF (20mL) at rt was added 25 wt. %
NaOMe in MeOH (3.81 g, 17.6 mmol) and the mixture was
stirred at rt for 20h. The resin was filtered, washed several
times with DMF, MeOH, and DCM, and dried in a
vacuum oven to give 6ea (2.05 g, 99%): Single bead ATR-
FTIR 3412 (NH), 3025, 2922, 2850, 1612, 1589, 1504, 1492,
1451, 1415, 1301, 1256, 1196, 1157, 1129, 1027, 1017, 817,
736, 698 cmꢁ1; (f) Preparation of N-benzoyl-(2-methoxy-3-
piperidin-1-ylquinoxalin-6-yl)amino resin 7ea (NR2 = pip-
eridin-1-yl, R1 = Ph). To a mixture of the resin 6ea (50mg,
theoretically 0.051 mmol) and diisopropylethylamine
(65 mg, 0.50 mmol) in DCM (2 mL) at rt was added
benzoyl chloride (21 mg, 0.15 mmol) and the mixture was
stirred overnight at rt. The resin was filtered, washed
several times with DCM, DMF, MeOH, and DCM, and
dried in a vacuum oven to give 7ea (53 mg, 96%): Single
bead ATR-FTIR 3025, 2923, 2852, 1649 (C@O), 1611,
1504, 1492, 1451, 1415, 1377, 1257, 1197, 1157, 1116, 1027,
927, 822, 758, 697 cmꢁ1; (g) Preparation of 6-benzamido-2-
methoxy-3-piperidin-1-ylquinoxaline 1ea (NR2 = piperidin-
1-yl, R1 = Ph). The resin 7ea (51 mg, theoretically
0.047 mmol) in 50% TFA/DCM (2 mL) was stirred at rt

M.-K. Jeon et al. / Tetrahedron Letters 46 (2005) 4979–4983
4983
for 1 h. The resin was filtered and washed with DCM.
The filtrate was evaporated in vacuo and the residue
was dissolved in acetone and passed through SAX
resin. The solvent was removed in vacuo to give the crude
product (17 mg, 100%) with 95% purity on the basis of
LC–MS. The crude product was further purified by a silica
gel column chromatography (5:1 mixture of methylene
chloride and ethyl acetate) to afford the pure compound 1ea
1
(15 mg, 88%): H NMR (500 MHz, acetone-d6): d 1.57 (m,
6H), 3.53 (m, 4H), 3.93 (s, 3H), 7.40(m, 2H), 7.46 (t,
J = 7.3 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.65 (dd, J = 8.8
and 2.4 Hz, 1H), 7.90(d,
J = 2.4 Hz, 1H), 9.50(br s, 1H); MS (ESI) m/z 363
J = 7.1 Hz, 2H), 8.23 (d,
([M+H]+).