Microwave-assisted solvent-dependent reaction: Chemoselective synthesis of quinoxalin-2(1 H)-ones, benzo[ d]imidazoles and dipeptides

Article abstract of DOI:10.1021/co2001247

A microwave-assisted solvent-dependent chemoselective reaction dealing with 4-arylidene-2-phenyloxazol-5-ones and diverse ortho-diamines to achieve three types of molecular scaffolds, 3-benzylquinoxalin-2(1H)-ones, benzimidazole and β-amino dipeptides is

Full text of DOI:10.1021/co2001247

RESEARCH ARTICLE
pubs.acs.org/acscombsci
Microwave-Assisted Solvent-Dependent Reaction: Chemoselective
Synthesis of Quinoxalin-2(1H)-ones, Benzo[d]imidazoles
and Dipeptides
Shu-Liang Wang,† Jie Ding,† Bo Jiang,† Yuan Gao,*,‡ and Shu-Jiang Tu*,†
†School of Chemistry and Chemical Engineering, Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Xuzhou Normal University, Xuzhou, 221116, P. R. China
‡School of Chemistry and Chemical Engineering, Shenzhen University, P. R. China
S Supporting Information
b
ABSTRACT: A microwave-assisted solvent-dependent chemo-
selective reaction dealing with 4-arylidene-2-phenyloxazol-5-
ones and diverse ortho-diamines to achieve three types of
molecular scaffolds, 3-benzylquinoxalin-2(1H)-ones, benzimi-
dazole and β-amino dipeptides is reported. The procedures
feature short reaction time, good to excellent yields, operational
simplicity, as well as easily available starting materials. These
compounds are of importance for organic chemistry and
medicinal chemistry research.
KEYWORDS: solvent-dependent reaction, chemoselective
synthesis, benzimidazole, 3-benzylquinoxalin-2(1H)-ones, β-
amino dipeptides
’ INTRODUCTION
using similar starting materials.12 However, these reactions suf-
fered from narrow scope of substrates and complex separation
process as the different byproducts were generated. Moreover, the
synthesis of benzimidazoles in AcOH employing similar reactants
under heating conditions has also been described.13 Thus these
reactions described above could not be controlled to provide the
quinoxalin-2(1H)-ones and benzimidazoles, respectively. There-
fore, our concern was whether the generation of quinoxalin-
2(1H)-ones or benzimidazoles can be controlled using the same
starting materials by varying the reaction conditions. Delightedly,
we found chemoselectivity of the reaction could be realized by
changing acidity of reaction media, and three different types of
products with good to excellent yields were generated, respec-
tively. We therefore describe here novel solvent-controlled reac-
tionsfor the chemoselective synthesisof quinoxalin-2(1H)-ones 3,
benzo[d]imidazoles 4, and dipeptides 5 from 4-arylidene-2-phe-
nyloxazol-5-ones 1 (Figure 1) and diverse ortho-diamines 2
(Figure 2) (Scheme 1).
Chemoselective reactions are of obvious value as organic
synthesis strives for ever-increasing levels of efficiency. In the
past several years, many investigators have investigated the
chemoselective control of reactions with metal catalysts,1aꢀd
while relatively few papers describe solvent-dependent chemo-
selective reactions.1eꢀg However, since solvent plays an impor-
tant role in all reactions, the development of solvent-dependent
chemoselectivity is a worthy goal.
Quinoxaline is an important class of benzo-heterocyclic
pyrazine compound and has been widely used as a key building
block for pharmaceutical agents. Its derivatives are endowed with
many pharmacological properties, such as hypoglycemic,2 anti-
inflammatory, antibacterial,3 and anti-HIV4 activity, as well as
useful activities in conditions like depression and Parkinson’s
disease.5 Quinoxalin-2(1H)-one as a class of important heter-
cyclic molecules in quinoxaline family has shown such biological
activities as glutamate blocker,6 treatment of sensorineural smell
disorders,7 DNA topoisomerase (Topo) II beta-inhibitor,8 and
antimycobacterial activity.9 In addtion, benzimidazole derivatives
also received much attention in clinical applications because of
their diverse biological activity.10 As a result, the synthesis of
these molecules have attracted considerable attention.11ꢀ13
Among them, the reaction of o-penylenediamine with 2-oxazo-
line-5-ones in BuOH led to the main quinoxalin-2(1H)-
ones accompanied with butyl acrylate and benzimidazoles.11
Subhashini et al. reported the synthesis of quinoxalin-2(1H)-ones
accompanied with benzimidazoles in AcOH at room temperature
’ RESULT AND DISCUSSION
Choosing an appropriate reaction medium is of crucial impor-
tance not only for successful microwave-promoted (MW) synth-
esis, but also for the effective control of chemoselective reactions.
To choose the optimum solvent, the microwave-assisted reaction
of oxazol-5(4H)-one 1{8} with benzene-1,2-diamine 2{1} was
Received: August 1, 2011
Published: August 04, 2011
r
2011 American Chemical Society
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RESEARCH ARTICLE
Figure 1. Diversity of 4-arylidene-2-phenyloxazol-5(4H)-ones 1{1ꢀ10}.
Figure 2. Diversity of aromatic diamines 2{1ꢀ8}.
Scheme 1. Solvent-Dependent Chemoselective Synthesis of
Compound 3, 4, and 5
Table 1. Reaction of 1{8} with 2{1} in Different Solvents
(Reaction Time = 15 min)
yieldb (%)
entry
solventa
EtOH
3{8,1}
4{8,1}
5{8,1}
1
2
3
4
5
6
7
16
24
0
30
41
30
53
85
0
0
0
glycol
H2O
0
DMF
19
0
0
AcOH
0
DMSO
glycol + TFAc
0
81
0
88
0
a 2.0 mL reaction volume. b Isolated yields. Mixture of trifluoroacetic
c
acid (TFA, 2 equiv. relative to reagents) in ethylene glycol.
(Table 1, entry 5), whereas the reaction in cosolvent of ethylene
glycol and TFA gave quinoxalin-2(1H)-one 3{8,1} in 88% yield
(Table 1, entry 7). Under aprotic conditions (DMSO solvent),
only the dipeptide 5{8,1} was observed (Table 1, entry 6). Thus,
the reaction could be directed cleanly to three different products,
quinoxalin-2(1H)-ones 3, benzimidazole 4 or dipeptides 5, by
changing the reaction medium (Scheme 2).
Scheme 2 shows a proposed reaction pathway. The dipeptides
5 are obtained from the expected initial condensation reaction of
diamines with 4-arylidene-2-phenyloxazol-5(4H)-ones, and do
not undergo cyclization in the absence of acid. The ability of
acetic and trifluoroacetic acids to direct the subsequent processes
examined at 120 °C in different solvents, such as ethanol,
ethylene glycol, H2O, N,N-dimethylformamide (DMF), AcOH,
dimethyl sulfoxide (DMSO), and a mixture of trifluoroacetic acid
(TFA) and ethylene glycol. All the reactions were carried out
under microwave irradiation. The results of the screening of
solvents are presented in Table 1 (entries 1ꢀ7). As shown in
Table 1, when ethanol, glycol, H2O, and DMF were selected as
the solvent, the compound 4{8,1} was obtained accompanied
with a small quantity of 5{8,1}. While acetic acid was used as the
solvent, only benzimidazole 4{8,1} was obtained with 85% yield
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RESEARCH ARTICLE
Scheme 2. Reasonable Mechanism for the Production of 3, 4, and 5
Table 2. Syntheses of Quinoxalin-2(1H)-ones 3
Scheme 3. Reaction between 4-Arylideneoxazol-5-ones and
Pyridyldiamine
entry
product
time/min
yield/%
1
3{1,1}
3{2,1}
3{5,1}
3{6,1}
3{7,1}
3{8,1}
3{10,1}
3{1,2}
3{2,2}
3{7,2}
3{8,2}
3{9,2}
3{2,3}
3{3,3}
3{7,3}
3{8,3}
3{10,3}
3{3,4}
3{1,8}
3{2,8}
3{3,8}
3{6,8}
3{7,8}
14
15
15
14
16
16
13
14
13
15
16
18
15
15
15
15
14
15
14
14
16
15
16
83
85
88
86
82
88
80
84
85
83
86
79
82
83
84
89
80
90
81
80
83
82
84
2
3
4
5
6
7
the appropriate solvent under microwave irradiation. Table 2
(entries 1ꢀ7) shows an exploration of the 4-arylidene-2-pheny-
loxazol-5-one substrate scope in a reaction with 1,2-phenylene-
diamine in the presence of TFA. The results indicated that both
electron-withdrawing and electron-donating functional groups
on the 4-arylidene aromatic ring were well tolerated in the
production of compounds 3. Moreover, the 2-thienyl substituted
2-phenyloxazol-5-one (Table 2, entry 7) also displayed high
reactivity under this standard condition. Table 2 (entries 8ꢀ18)
also shows excellent results with a set of 4-arylidene-2-phenylox-
azol-5-ones and the additional ortho-diamines 2{2}, 2{3}, and
2{4}. In all these cases, the reactions proceeded steadily to
produce the functionalized 3-benzylquinoxalin-2(1H)-ones in
good yields of 79ꢀ90%. All new compounds were characterized
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1
by IR, H NMR, and HRMS (ESI) spectroscopy, and the
structure of 3{8,1} was confirmed by single-crystal X-ray diffrac-
tion analysis (Supporting Information).
The reaction of the unsymmetrical pyridyldiamine 2{8} with
1{1,2,3,6,7} gave a single regioisomer of quinoxalinone 3-
{1,8}ꢀ3{7,8} (Table 2, entries 19ꢀ23) (Scheme 3), and the
structure of 3{1,8} was confirmed by single-crystal X-ray diffrac-
tion analysis. Because of its electronegativity, the pyridyl nitrogen
atom should deactivate the nucleophilicity of the o-amino group
to a greater extent than the m-amino group. However, the strong
acid used in these reactions should protonate the pyridyl nitro-
gen, leading to greater deactivation of the m-amino group.14 So,
in the present of TFA, the o-amino group preferentially attacks
to benzimidazole and quinoxalinone systems, respectively, is not
yet understood. The different acids apparently provide different
degrees of protonation of the competing amide groups, leading
to 5- or 6-membered ring closure as shown.
Under these optimized chemoselective conditions, a series of
3-benzylquinoxalin-2(1H)-ones, poly substituted benzo[d]im-
idazoles and β-amino dipeptides were selectively synthesized
with the reaction of 4-arylideneoxazol-5-ones 1 and diamines 2 in
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RESEARCH ARTICLE
Table 3. Syntheses of Benzimidazoles 4
Table 4. Syntheses of Dipeptides 5
entry
product
time/min
yield/%
entry
product
time/min
yield/%
1
4{1,1}
4{2,1}
4{5,1}
4{6,1}
4{7,1}
4{8,1}
4{2,2}
4{9,2}
4{1,5}
4{5,5}
4{2,6}
4{3,6}
4{5,6}
4{9,6}
15
14
14
14
15
15
13
15
15
15
16
16
15
16
92
87
89
76
82
85
86
82
85
82
83
81
86
78
1
5{5,1}
5{6,1}
5{8,1}
5{10,1}
5{1,2}
5{2,2}
5{3,2}
5{5,2}
5{7,2}
5{10,2}
5{7,7}
5{8,7}
15
14
15
15
16
15
14
15
15
13
15
15
81
82
84
72
82
83
80
76
73
70
79
82
2
2
3
3
4
4
5
5
6
6
7
7
8
8
9
9
10
11
12
13
14
10
11
12
Scheme 4. Reaction between 4-Arylideneoxazol-5-ones and
3,4-Diaminobenzoic Acid
the 4-arylidene-5-one 1 to afford the ring opened compound 5,
which is subsequently converted to the quinoxalinones 3.
The ability of acetic acid to change the pathway of the reaction
to give benzimidazoles 4 was validated with a series of compo-
nents as shown in Table 3. As before, both electron-withdrawing
and -donating groups were tolerated on the 4-arylidene-2-
phenyloxazol-5-one substrate. Moreover, monosubstituted
ortho-diamines 2{5 or 6} also resulted in desired products 4 in
good yields. The structural elucidation and the attribution of
relative stereochemistry were unequivocally determined by
NMR analysis and X-ray diffraction of single crystal that was
obtained by slow evaporation of the solvent, as in the case of
benzimidazoles 4{1,1}.
Similarly, intermediates 5 could be accessed in high yields in
DMSOsolventwithouttheadditionofacid, withthesamerange of
substrate tolerance as observed in the preparations of 3 and 4
(Table 4). The use of 3,4-diaminobenzoic acid 2{7} gave only one
of the two possible isomers in 5{7,7} and 5{8,7} with high
regioselectivity (Table 4, entries 11ꢀ12). This is attributed to
the greater nucleophilicity of the amino group in the meta position
relative to the carboxyl group, resulting in initial attack by that
amine center.14 It is worthy noted that the dipeptides with wide
spectrum of important bioactivities were synthesized by screening
the reaction solvents, which were significant intermediates for
pharmaceutical design and research.15
To substantiate the intermediacy of 5 in the production of 3
and 4 (Scheme 2), isolated 5{6,1} was subjected to the two acidic
conditions (TFA in ethylene glycol and AcOH). The expected
products, 3{6,1} and 4{6,1}, respectively, were isolated cleanly.
Furthermore, the addition of TFA to AcOH redirected the
reaction to 3{6,1}, favoring six-membered cyclization in the
presence of the stronger acid.
In conclusion, poly substituted 3-benzylquinoxalin-2(1H)-ones,
benzo[d]imidazoles, andβ-amino dipeptides were prepared from the
same substrates in convenient and highly selective fashion when
different solvents were used, varying the strength of the acidic reaction
environment. The reactions are fast and can be finished within
13ꢀ16 min with good to excellent chemical yields and chemo-
and regioselectivity that avoided tedious workup and purification
steps. Furthermore, the series of compounds produced are of general
interest for their chemical properties and potential physiological
activity, studies which are in progress in our laboratory.
’ EXPERIMENTAL PROCEDURES
Microwave irradiation was carried out with microwave oven
Emrys Creator from Personal Chemistry, Uppsala, Sweden.
Melting points were determined in open capillaries and were
uncorrected. IR spectra were taken on a FT-IR-Tensor 27
spectrometer in KBr pellets and reported in cmꢀ1. H NMR
1
spectra were measured on a Bruker DPX 400 MHz spectrometer
in DMSO-d6 with chemical shift (δ) given in parts per million
relative to TMS as internal standard. HRMS (ESI) was deter-
mined by using microTOF-Q II HRMS/MS instrument
(BRUKER). X-ray crystallographic analysis was performed with
a Siemens SMART CCD and a Siemens P4 diffractometer.
Typical Procedure for the Preparation of 3-(4-Methoxy-
benzyl)quinoxalin-2(1H)-one 3{8,1}. In a 10-mL Emrys reac-
tion vial, 4-(4-methoxybenzylidene)-2-phenyloxazol-5(4H)-one
(0.28 g, 1 mmol), benzene-1,2-diamine (0.11 g, 1 mmol), TFA
(0.23 g, 2 mmol), and ethylene glycol (1.5 mL) were mixed and
then capped. (The automatic mode stirring helped the mixing
and uniform heating of the reactants.) The mixture was heated
for 16 min at 120 °C under microwave irradiation. Upon com-
pletion, monitored by TLC, the reaction mixture was cooled to
room temperature. The solid product was poured into water and
neutralized with 10% NaOH, and then collected by B€uchner
filtration, subsequently washed with two different solvents of
ethanol and ethylether in sequence to give the pure yellow solid
(0.23 g, yield 88%). mp: 188ꢀ189 °C.
1H NMR (400 MHz, DMSO) (δ, ppm): 12.38 (s, 1H, NH),
7.72 (d, J = 8.0 Hz, 1H, ArH), 7.50ꢀ7.46 (m, 1H, ArH),
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RESEARCH ARTICLE
7.28ꢀ7.23 (m, 4H, ArH), 6.85 (d, J = 8.8 Hz, 2H, ArH), 4.05
(s, 2H, CH2), 3.70 (s, 3H, OCH3).
The mixture was heated for 14 min at 120 °C under microwave
irradiation. The subsequent operating procedure was same as
described above to give corresponding 4{6,1}.
IR (KBr): 3154, 3009, 2957, 2835, 2783, 2064, 1907, 1661,
1556, 1506, 1431, 1245, 1173, 1036, 905, 820, 751 cmꢀ1
.
In a 10-mL Emrys reaction vial, (Z)-N-(3-(2-aminophenyla-
mino)-3-oxo-1-phenylprop-1-en-2-yl)benzamide 5{6,1}(1.0 mmol),
TFA (0.23 g, 2 mmol), and AcOH (2.0 mL) were mixed and then
capped. (The automatic mode stirring helped the mixing and uniform
heating of the reactants.) The mixture was heated for 14 min at
120 °C under microwave irradiation. The subsequent operating
procedure was same as described above to also give corresponding
3{6,1}.
HRMS (ESI): m/z [M + H]+ C16H15N2O2 289.0953; found
289.0949.
(Z)-N-(1-(1H-Benzo[d]imidazol-2-yl)-2-(4-methoxyphenyl)-
vinyl)benzamide 4{8,1}. In a 10-mL Emrys reaction vial, 4-(4-
methoxybenzylidene)-2-phenyloxazol-5(4H)-one (0.28 g, 1 mmol),
benzene-1,2-diamine (0.11 g, 1 mmol) and AcOH (2.0 mL) were
mixed and then capped (The automatic mode stirring helped the
mixing and uniform heating of the reactants). The mixture was
heated for 15 min at 120 °C under microwave irradiation. Upon
completion, monitored by TLC, the reaction mixture was cooled to
room temperature. The solid product was mixed into water then
collected by B€uchner filtration and subsequently washed with two
different solvents of ethanol and ethylether in sequence to give the
pure yellow solid (0.32 g, yield 85%). mp: 258ꢀ260 °C
’ ASSOCIATED CONTENT
S
Supporting Information. Additional experimental de-
b
tails and crystallographic information file. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
1H NMR (400 MHz, DMSO) (δ, ppm): 12.45 (s, 1H, NH),
10.19 (s, 1H, NH), 8.11 (d, J = 7.2 Hz, 2H, ArH), 7.66ꢀ7.62 (m,
2H, ArH), 7.57 (t, J = 7.2 Hz, 3H, ArH), 7.52 (d, J = 6.0 Hz, 1H,
ArH), 7.17ꢀ7.15 (m, 2H, ArH), 6.95 (d, J = 8.8 Hz, 2H,
ArH),3.75 (s, 3H, OCH3).
’ AUTHOR INFORMATION
Corresponding Author
*Tel.: 0086-516-83500065. Fax: 0086-516-83500065. E-mail:
laotu@xznu.edu.cn.
IR (KBr): 3221, 3060, 2934, 2836, 2768, 2638, 1647, 1604,
1509, 1481, 1421, 1302, 1255, 1177, 1116, 1030, 984, 909, 825,
744, 707 cmꢀ1
.
’ ACKNOWLEDGMENT
HRMS (ESI): m/z [M + H]+ calcd for C23H19N3O2 370.-
1556; found 370.1553.
We are grateful to financial support from the National Science
Foundation of China (No. 21072163 and 21002083), Sci.
Foundation in Interdisciplinary Major Res. Project of XZNU
(No. 09XKXK01), and PAPD of Jiangsu Higher Education
Institutions.
(Z)-N-(3-(2-Aminophenylamino)-1-(4-methoxyphenyl)-3-
oxoprop-1-en-2-yl)benzamide 5{8,1}. In a 10-mL Emrys reac-
tion vial, 4-(4-methoxybenzylidene)-2-phenyloxazol-5(4H)-
one (0.28 g, 1 mmol), benzene-1,2-diamine (0.11 g, 1 mmol),
and DMSO (2.0 mL) were mixed and then capped. The mixture
was heated for 15 min at 110 °C under microwave irradiation.
The automatic mode stirring helped the mixing and uniform
heating of the reactants. Upon completion, monitored by TLC,
the reaction mixture was cooled to room temperature. The solid
product was added into water then collected by B€uchner filtra-
tion and subsequently washed with two different solvents of
ethanol and ethylether in sequence to give the pure yellow solid
(0.31 g, yield 81%). mp: 197ꢀ198 °C
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1H NMR (400 MHz, DMSO) (δ, ppm): 10.13 (s, 1H, NH),
9.44 (s, 1H, NH), 8.06 (d, J = 7.6 Hz, 2H, ArH), 7.62ꢀ7.60 (m,
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J = 8.0 Hz, 1H, ArH), 6.55 (t, J = 7.6 Hz, 1H, CH), 4.93 (s, 2H,
NH2), 3.76 (s, 3H, OCH3).
IR (KBr): 3354, 3252, 3034, 2960, 2837, 1641, 1603, 1512,
1482, 1304, 1254, 1179, 1030, 923, 831, 750 cmꢀ1
.
HRMS (ESI): m/z [M + H]+ calcd for C23H21N3O3
388.1661; found 388.1653.
Examination of Reaction Mechanism. In a 10-mL Emrys
reaction vial, (Z)-N-(3-(2-aminophenylamino)-3-oxo-1-phenylprop-
1-en-2-yl)benzamide 5{6,1} (1.0 mmol), TFA (0.23 g, 2 mmol) and
ethylene glycol (1.5 mL) were mixed and then capped. (The
automatic mode stirring helped the mixing and uniform heating of
the reactants.) The mixture was heated for 14 min at 120 °C under
microwave irradiation. The subsequent operating procedure was
same as described above to give corresponding 3{6,1}.
In a 10-mL Emrys reaction vial, (Z)-N-(3-(2-aminopheny-
lamino)-3-oxo-1-phenylprop-1-en-2-yl)benzamide 5{6,1}-
(1.0 mmol) and AcOH (2.0 mL) were mixed and then capped.
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