Synthetic studies of bioactive quinoxalinones: A facile approach to potent euglycemic and hypolipidemic agents

Article abstract of DOI:10.3987/COM-06-10793

Substituted quinoxalin-2-ones have been prepared in high yields in a one-pot reaction in which a 1:1 mixture of 1,2-diaminobenzene and appropriate ethyl 2-bromoalkyl/aryl acetate is subjected to microwave irradiation in presence of DBU at 190 °C for 6 min

Full text of DOI:10.3987/COM-06-10793

HETEROCYCLES, Vol. 68, No. 9, 2006
1931
HETEROCYCLES, Vol. 68, No. 9, 2006, pp. 1931 - 1939. © The Japan Institute of Heterocyclic Chemistry
Received, 25th May, 2006, Accepted, 18th July, 2006, Published online, 21st July, 2006. COM-06-10793
SYNTHETIC STUDIES OF BIOACTIVE QUINOXALINONES: A FACILE
APPROACH TO POTENT EUGLYCEMIC AND HYPOLIPIDEMIC
AGENTS
Sukanta Kamila and Edward R. Biehl*
Southern Methodist University, Dallas, Texas, USA, E-mail: ebiehl@smu.edu
Abstract – Substituted quinoxalin-2-ones have been prepared in high yields in a
one-pot reaction in which a 1:1 mixture of 1,2-diaminobenzene and appropriate
ethyl 2-bromoalkyl/aryl acetate is subjected to microwave irradiation in presence
of DBU at 190 oC for 6 min A possible mechanism is presented.
INTRODUCTION
The quinoxalinone ring is an important pharmacophore found in numerous biologically active
compounds. For example, quinoxalinone (1) serves as an inhibitor of aldose reductase,1 while
quinoxalinones (2) behave as agonists of γ-aminobutyric acid (GABA)/benzodiazepine receptor
complex.2,3 Recently, substituted 5-[4-[2-(6,7-dimethyl-1,2,3,4-tetrahydro-2-oxo-4-quinoxalinyl)-
ethoxy]phenyl]methylene]thiazolidine-2,4-dione (3) have been shown to exhibit remarkable euglycemic
and hypolipidemic activities.4 2,4-Diones (3) that posses an electron donating methyl group at the C-3
H
H3C
H3C
N
O
R
N
n=, 2,3,4,5,6
O
O
O
O
S
O
R
N
N
N
N
(CH2)n
R
O
N
R
S
N
O
NH
CO2Et
3
2
1
O
position of 1,2,3,4-tetrahydro quinoxalin-2-one decrease glucose level significantly more than those with
a phenyl ring at the C-3 position. Quinoxalinones are also used as intermediates in designing quinoxaline
derivatives with antimicrobial,5 antifungal,6 and anticancer7 activities. Consequently, a number of
combinatorial library synthesis of these class of compounds have been developed.8-12 In the past several
years, microwave (MW) assisted organic reactions have been found to be a rapid and powerful method
for developing libraries with high degree of molecular diversities. This new synthetic methodology has

1932
HETEROCYCLES, Vol. 68, No. 9, 2006
made a major impact on the discovery of new drugs, catalyst, and materials. Herein we report a MW
assisted one-pot synthesis of quinoxalinones from certain commerically available 1,2-diaminobenzenes
and ethyl 2-bromo-2-alkyl/aryl acetates in the absence of solid support or solvent.
RESULTS AND DISCUSSION
Assuming that a base might help to remove the –NH2 proton of the diamino compound, we irradiated 4a
o
and 5a in the presence of several bases for 6 min at 190 C and analyzed the crude reaction mixture by
GC/MS analysis. The results, which are shown in Table 1, show that the optimum yield of
3,4-dihydro-3-methyl-1H-quinoxalin-2-one (6a) was obtained using DBU as base. No further
improvement was observed by varying the amount of DBU, temperature or reaction time. In fact when
o
the reaction mixtures were heated longer than 6 min or above 200 C, intractable tarry mixtures were
obtained.
Table 1 Influence of Base on Yields of 3,4-Dihydro-3-methyl-1H-quinoxalin-2-one (6a)
Entry
1
Base
6a, Yields (%)
~ 10
Pyridine
DMF
2
~ 5
3
EtN(i-prop)2
~15
4
N-Methylpyrrolidine
N-Methylpiperidine
K2CO3
~30
5
~20
6
Trace
Trace
Trace
~30
7
K2CO3 / DMF
8
Pyridine / N-Methylpyrrolidine (1:1)
9
N-Methylpyrrolidine / N-Methylpiperidine (1:1)
DBU / N-Methylpiperidine (1:1)
DBU / N-Methylpyrrolidine
DBU
10
11
12
~70
~40
~90
We next extended this reaction (shown in Scheme 1) to the synthesis of a variety of 3,4-dihydro
quinoxalin-2-ones (6b-l) by MW irradiation of 1,2-diamino benzenes (4a,b) and ethyl
2-bromo-2-alkyl/aryl acetates (5a-f) in the presence of DBU at 190 o C for 6 min in a solvent-free
environment. The results shown in Table 2 show that good to excellent yields of 6a-l were obtained.

HETEROCYCLES, Vol. 68, No. 9, 2006
1933
H
N
Br
R1
R2
R3
O
R1
R2
NH2
NH2
R3
MW
DBU
o
O
N
H
190 C, 6- min
EtO
4
5
6
R1, R2= H, Me R3= alkyl or phenyl
Scheme 1
Additionally, when the unsymmetrical diamine (4c) was treated with 5a and DBU (see eq. 1) a 1:1
mixture of the 3,4-dihydro-3,6-dimethyl (6m) and 3,4-dihydro-3,7-dimethyl-1H-quinoxalin-2-one (6n)
was obtained in an overall yield of 88% indicating that the reaction is not regioselective. Complete
separation of 6m and 6n was not possible; however compound (6m) was obtained in sufficient purity
1
which allowed its structure to be identified by IR, H NMR, and 13C NMR spectroscopy as well as
elemental analysis.
H
N
H
N
DBU
Me
Me
O
Me
O
Me
NH2
NH2
Br
Me
O
(eq 1)
o
MW, 190 C, 6 min
N
H
N
H
Me
EtO
4c
5a
6m
6n
A possible mechanistic pathway (shown in Figure 2) involves the formation of the amidate derivative (7)
by the reaction of 4 with DBU, which then can attack the bromine-substituted carbon by a SN2 process to
give adducts (8) or add to the ester group to give intermediate (10). During this process HBr is
neutralized by DBU yielding DBU.HBr. When the reaction of 4a and 5a was stopped after 3 min and the
complex crude reaction mixture was analyzed by GC/MS analysis, unreacted starting material (4a) along
with intermediate (8a) (R1, R2 = H, R3 = Me, M+ =197 m/z) were observed. There were no traces of the
intermediate (10). This clearly indicates that the reaction proceeds in former pathway. In the second step,
the remaining amino group on 8 adds to the carbonyl carbon of the ester group forming the tetrahedron
intermediate (9) from which ethyl alcohol is eliminated to give the titled compound. (6).
H
N
Br
H
N
R3
O
R3
R1
R2
R3
R1
R2
R1
R2
NH2
NH2
R1
R2
NH
DBU
O
6
OH
OEt
-EtOH
EtO
N
H
-DBU.HBr
OEt
NH2
-HDBU
NH2
9
8
7
4
Br
R1
R2
NH2
NH
R
3
O
10
Scheme 2

1934
HETEROCYCLES, Vol. 68, No. 9, 2006
The elimination of ethyl alcohol was further confirmed by GC/MS analysis of the crude reaction product.
In a separate reaction, we found that 4 reacted with 5b when treated under similar MW conditions, but in
the absence of DBU, they failed to react, presumably because free HBr protonated the remaining amino
group, thus rendering it non-nucleophilic.
Table 2 Preparation of 3,4-dihydroquinoxalin-2-ones (6)
Yield
%
Entry
Yield
%
Entry
1
4
5
6
4
5
6
NH2
NH2
Br
Me
O
H
N
Br
Pr
O
H
N
Me
O
Pr
O
EtO
EtO
98%
91%
97%
93%
89%
86%
7
a
92
96
91
87
70
71
N
H
N
H
a
5a
d
d
6a
6b
g
H
N
Me
Me
NH2
NH2
H
N
Me
Me
Pr
2
5a
Me
Me
Me
N
H
O
8
b
a
b
a
b
N
H
O
b
a
h
Br
H
N
Br
Bu
O
H
N
Bu
O
EtO
O
EtO
3
4
5
6
9
N
H
O
N
H
5b
e
e
6c
i
H
N
H
N
Me
Me
Bu
O
Me
Me
N
H
b
a
5b
10
11
12
N
H
O
j
6d
Me
H
N
H
N
B
r
Ph
O
Me
Br
Ph
O
Me
Me
EtO
EtO
O
N
H
O
N
H
f
f
5c
5c
6e
6f
k
H
N
H
N
Me
Me
Me
Me
Ph
O
Me
Me
N
H
b
N
H
O
l

HETEROCYCLES, Vol. 68, No. 9, 2006
1935
In support of this mechanism, the reaction (entries 11 and 12) of ethyl 2-bromo-2-phenylacetate (5f) gives
the corresponding products (6k, l) in lower yields (70, 71%) reflecting a decrease in the electrophilicity of
the ester carbonyl group in 8 by the resonance effect of the phenyl group.
In conclusion, we have developed a new high yield solvent free one-pot synthesis of potential
biologically important quinoxalin-2-ones (6a-l). The 3,3-dimethyl derivative (6e) had been previously
prepared from an enamine, derived from 2-nitroaniline and an appropriately 2-substituted aldehyde, with
CO in the presence of Pd(dba)2, but in only 11% yield.13 Although the 3-butyl derivative (6i) was
prepared in a decent 81% yield by the reaction of 4a with ethyl 2-bromohexanoate and potassium
o
carbonate, the reaction required stirring overnight followed by heating for 3 h at 120 C.14 Recent
reports15,16 showed that quinoxalin-2-ones can be prepared MW irradiation; however these reactions
were supported on soluble polymer. However, the successful use of MW irradiation reported herein
requires no solid support or solvent, thus providing another example of a “green” synthesis of biologically
important organic molecules.
EXPERIMENTAL
Melting points were taken on a Mel-Temp capillary apparatus and are uncorrected with respect to stem
1
correction. H and 13C NMR spectra were recorded on a 400 MHz Bruker ADVANCE DRX-400
Multinuclear NMR spectrometer. Chemical shifts are reported in reference to TMS as internal standard.
GC/MS experiment was done in HP Gas Chromatograph Electron Ionization Detector (GCD System,
G1800C). IR spectra were recorded on a Nicolet MAGNA-IR 560- spectrometer (E. S.P). Elemental
analysis was obtained from Southern Methodist University Analytical Service Laboratories. All
chemicals were purchased from Fisher Scientific or Aldrich chemicals. Microwave experiment was done
in CEM-Discover (From CEM Corporation, POB 200) instrument at 150 W output power.
General Procedure for the Synthesis of Compounds (6a- 6n) via Microwave Irradiation.
A mixture of 1,2-diaminophenol (200 mg, 1.6 mmol) and ethyl alkyl/aryl-2-bromoacetate (1.6 mmol) and
DBU (370 mg, 2.5 mmol) was placed in a sealed test tube and irradiate at 190 oC for 6 min at 150 W out
put. The resulting mixture was dissolved in AcOEt and washed with brine. The AcOEt layer was
separated and dried over Na2SO4. Evaporation of the solvent afforded crude product mixtures. The solid
products were recrystallized from AcOEt-hexane whereas the liquid products were purified by column
chromatography using 40% AcOEt-hexane as eluent. The results are shown below.
o
3,4-Dihydro-3-methyl-1H-quinoxalin-2-one (6a): Separated as brownish solid, mp 118-120 C. IR
1
(KBr) νc=o 1677 cm-1. H NMR (CDCl3): δ 1.48 (d, J= 6.4 Hz, 3H, CH3), 3.88 (br s, 1H, NH), 4.03-4.05
(m, 1H, CH), 6.69 (d, J = 7.8 Hz, 1H, aromatic), 6.75-6.79 (m, 2H, aromatic), 6.88-6.91 (m, 1H,

1936
HETEROCYCLES, Vol. 68, No. 9, 2006
13
aromatic), 9.13 (br s, 1H, NH). C NMR (CDCl3): δ 18.3 (CH3), 52.3 (CH), 114.4 (CH), 115.9 (CH),
119.9 (CH), 124.1 (CH), 126.1 (CH), 133.8 (C), 170.1 (C). Anal. Calcd for C9H10N2O: C, 66.65; H, 6.21;
N, 17.27. Found: C, 66.69; H, 6.21; N, 17.31.
3,4-Dihydro-3,6,7-trimethyl-1H-quinoxalin-2-one (6b): Separated as reddish white solid. mp 153-155
1
oC. IR (KBr) νc=o 1676 cm-1. H NMR (acetone-d6): δ 1.32 (d, J = 6.3 Hz, 3H, CH3), 2.04 (s, 3H, CH3),
2.09 (s, 3H, CH3), 3.81 (br s, 1H, NH), 5.04 (br s, 1H, NH), 6.53 (s, 1H, aromatic), 6.61 (s, 1H, aromatic),
9.22 (br s, 1H, NH). 13C NMR (acetone-d6): δ 17.2 (CH3), 18.4 (CH3), 18.8 (CH3), 52.2 (CH), 115.7 (CH),
116.4 (CH), 124.9 (C), 126.4 (C), 130.7 (C), 132.7 (C), 169.1(C). Anal. Calcd for C11H14N2O: C, 69.45;
H, 7.42; N, 14.73. Found: C, 69.46; H, 7.43; N, 14.77.
3-Ethyl-3,4-dihydro-1H-quinoxalin-2-one (6c): Separated as colorless gummy liquid. IR (CHCl3) νc=o
1678 cm-1. 1H NMR (CDCl3): δ 1.05 (t, 3H, CH3), 1.81-1.91 (m, 2H, CH2), 3.89 (br s, 1H, NH), 4.00 (br s,
1H, CH), 6.68 (d, J = 7.8 Hz, 1H, aromatic), 6.73-6.77 (m, 2H, aromatic), 6.90 (dd, J = 2.5, 7.8 Hz, 1H,
aromatic), 9.2 (br s, 1H, NH). 13C NMR (CDCl3): δ 10.0 (CH3), 25.5 (CH2) , 57.9 (CH), 114.3 (CH),115.8
(CH), 119.6 (CH), 124.2 (CH), 125.7 (C), 133.4 (C), 169.7 (C). Anal. Calcd for C10H12N2O : C, 68.16; H,
6.86; N, 15.90. Found: C, 68.16; H, 6.86; N, 15.98.
3-Ethyl-3,4-dihydro- 6,7-dimethyl-1H-quinoxalin-2-one (6d): Separated as colorless gummy liquid. IR
1
(CHCl3) νc=o 1678 cm-1. H NMR (CDCl3): δ 1.04 ( t, 3H, CH3), 1.77-1.87( m, 2H, CH2), 2.16 (s, 3H,
CH3), 2.17 (s, 3H, CH3), 3.82 (br s, 1H, NH), 3.86 (br s, 1H, NH), 6.35 (s, 1H, aromatic), 6.55 (s, 1H,
aromatic), 9.08 (br s, 1H, NH). 13C NMR (CDCl3): δ 10.1 (CH3), 19.2 (CH3), 19.7 (CH3), 25.2 (CH2),
58.2 (CH), 114.3 (CH), 116.0 (CH), 127.7 (C), 132.1 (C), 132.2 (C), 136.3 (C), 169.7 (C). Anal. Calcd
for C12H16N2O: C, 70.56; H, 7.90; N, 13.71. Found: C, 70.59; H, 8.01; N, 13.73.
3,4-Dihydro-3,3-dimethymethyl-1H-quinoxalin-2-one (6e): Separated as brownish solid. mp 135-136
1
oC. IR (KBr) νc=o 1679 cm-1. HNMR (CDCl3): δ 1.43 (s, 6H, CH3 X 2), 3.72 (br s, 1H, NH), 6.68-6.80
(m, 3H, aromatic), 6.91 (dd, J = 3.1, 7.5 Hz, 1H, aromatic), 9.03 (br s, 1H, NH). 13C NMR (CDCl3): δ
23.9 (CH3 X 2), 59.3 (CH), 114.3 (CH), 115.3 (CH), 123.2 (CH), 124.6 (C), 124.9 (C), 127.8 (C), 135.4
(C), 169.9 (C). Anal. Calcd for C10H12N2O: C, 68.16; H, 6.86; N, 15.90. Found: C, 68.18; H, 6.87; N,
15.91.
3,4-Dihydro-3,3,6,7-tetramethyl-1H-quinoxalin-2-one (6f): Separated as brownish solid. mp 78-80
oC. IR (KBr) νc=o 1678 cm-1. 1HNMR (CDCl3): δ 1.40 (s, 6H, CH3 X 2), 2.17 (s, 6H, CH3 X 2), 3.81 (br s,
1H, NH), 6.38 (s, 1H, aromatic), 6.49 (s, 1H, aromatic), 9.03 (br s, 1H, NH). 13C NMR (CDCl3): δ 15.5
(CH3 X 2), 19.2 (CH3), 19.7 (CH3), 55.9 (CH), 114.3 (CH), 116.5 (CH), 126.8 (C), 132.0 (C), 132.2 (C),
136.3 (C), 169.3 (C). Anal. Calcd for C12H16N2O: C, 70.56; H, 7.90; N, 13.71. Found: C, 70.55; H, 7.93;
N, 13.75.

HETEROCYCLES, Vol. 68, No. 9, 2006
1937
3,4-Dihydro-3-propyl-1H-quinoxalin-2-one (6g): Separated as yellowish gummy liquid. IR (CHCl3)
c=o 1678 cm-1. 1HNMR (CDCl3): δ 1.31 ( t, J= 6.9 Hz, 3H, CH3), 1.48-1.83 (m, 4H, CH2 X 2), 3.15-3.20
ν
(m, 1H, CH), 3.33 (br s, 1H, NH), 6.68-6.79 (m, 3H, aromatic), 6.83-6.91 (m, 1H, aromatic), 9.01 (br s,
1H, NH). 13C NMR (CDCl3): δ 14.1 (CH3), 18.9 (CH2), 34.3 (CH2), 56.6 (CH), 114.5 (CH), 116.8 (CH),
121.1 (CH), 124.2 (CH), 133.4 (C), 138.4 (C), 170.0 (C). Anal. Calcd for C11H14N2O: C, 69.45; H, 7.42;
N, 14.73. Found: C, 69.50; H, 7.43; N, 14.75.
3,4-Dihydro- 6,7-dimethyl-3-propyl-1H-quinoxalin-2-one (6h): Separated as yellowish gummy liquid.
IR (CHCl3) νc=o 1676 cm-1. 1HNMR (CDCl3): δ 0.98 (t, J= 7.3 Hz, 3H, CH3), 1.42-1.76 (m, 4H, CH2 X 2),
2.36 (s, 6H, CH3 X 2), 3.15 (br s, 1H, CH), 3.88 (br s, 1H, NH), 6.49 (s, 1H, aromatic), 6.55 (s, 1H,
aromatic), 9.06 (br s, 1H, NH). 13C NMR (CDCl3): δ 14.1 (CH3), 18.9 (CH3), 19.2(CH3), 19.7(CH3), 34.0
(CH2), 56.8 (CH), 114.3 (CH), 116.0 (CH), 123.6 (C), 127.7 (C), 130.9 (C), 132.1 (C), 169.9 (C). Anal.
Calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83. Found: C, 71.55; H, 8.31; N, 12.87.
3-Butyl-3,4-dihydro-1H-quinoxalin-2-one (6i): Separated as white solid. mp 90-92oC. IR (KBr) νc=o
1678 cm-1. 1H NMR (CDCl3): δ 0.96 (t, J= 7.1 Hz, 3H, CH3), 1.31-1.34 (m, 4H, CH2), 1.76-1.86 (m, 2H,
CH2), 3.91 (t, J= 4.7 Hz, 1H, CH), 3.34 (br s, 1H, NH), 6.64-6.86 (m, 4H, aromatic), 9.5 (br s, 1H, NH).
13C NMR (CDCl3): δ 14.3 (CH3), 22.9 (CH2), 27.8 (CH2), 32.0 (CH2), 56.8 (CH), 112.9 (CH), 116.8 (CH),
121.1 (CH), 124.2 (CH), 124.6 (CH), 134.4 (C), 169.0 (C). Anal. Calcd for C12H16N2O: C, 70.56; H,7.90;
N, 13.71. Found: C, 70.58; H, 7.96; N, 13.71.
3-Butyl-3,4-dihydro-6,7-dimethyl-1H-quinoxalin-2-one (6j): Separated as yellowish solid. mp 85-88
oC. IR (KBr) νc=o 1679 cm-1. 1H NMR (CDCl3): δ 0.94 (t, J = 7.1 Hz, 3H, CH3), 1.37-1.46 (m, 4H, CH2),
1.73-1.83 (m, 2H, CH2), 2.16 (s, 6H, CH3 X 2), 3.82-3.87 (m, 1H, CH), 6.50 (s, 1H, aromatic), 6.55 (s,
1H, aromatic), 8.88 (br s, 1H, NH). 13C NMR (CDCl3): δ 14.3 (CH3), 19.2 (CH3), 19.7 (CH3), 22.8 (CH2),
27.9 (CH2), 31.7 (CH2), 57.0 (CH), 116.0 (CH), 116.9 (CH), 123.5 (C), 127.7 (C), 130.9 (C), 132.2 (C),
169.8 (C). Anal. Calcd for C14H20N2O: C, 72.38; H, 8.68; N, 12.06. Found: C, 72.41; H, 8.69; N, 12.06.
o
3,4-Dihydro- 3-phenyl-1H-quinoxalin-2-one (6k): Separated as white solid. mp 195-197 C. IR (KBr)
1
ν
c=o 1666 cm-1. H NMR (CDCl3): δ 5.10 (br s, 1H, CH), 6.68-6.77 (m, 5H, aromatic), 6.65 (dd, J = 7.5
Hz, 7.8 Hz, 1H, aromatic), 7.28-7.36 (m, 2H, aromatic), 10.83 (br s, 1H, NH). 13C NMR (CDCl3): δ 59.7
(CH), 113.7 (CH), 114.8 (CH), 117.7 (CH), 123.5 (CH), 125.6 (C), 127.5 (CH), 128.8 (CH), 133.8 (C),
140.8 (C), 167.1 (C). Anal. Calcd for C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C, 74.99; H, 5.44;
N, 12.51.
3,4-Dihydro- 6,7-dimethyl-3-phenyl-1H-quinoxalin-2-one (6l): Separated as light blue gummy liquid.
1
IR (CHCl3) νc=o 1669 cm-1. H NMR (CDCl3): δ 2.17 (s, 3H, CH3), 2.20 (s, 3H, CH3), 5.04 (s, 1H, CH),
6.49-6.55 (m, 4H, aromatic), 7.31-7.35 (m, 3H, aromatic), 10.81 (br s, 1H, NH). 13C NMR (CDCl3): δ

1938
HETEROCYCLES, Vol. 68, No. 9, 2006
18.9 (CH3), 19.1 (CH3), 59.3 (CH), 113.1 (CH), 121.5 (C), 121.8 (CH), 127.1 (CH), 127.4 (C), 129.0
(CH), 129.8 (CH), 133.3 (C), 140.1 (C), 168.3 (C). Anal. Calcd for C16H16N2O: C, 76.16; H, 6.39; N,
11.10. Found: C, 76.18; H, 6.40; N, 11.15.
3,4-Dihydro-3,6-dimethyl-1H-quinoxalin-2-one (6m): Separated as a viscous liquid. IR (CHCl3) νc=o
1
1678 cm-1. H NMR (CDCl3): δ 1.46 (d, J= 6.3 Hz, 3H, -CH3), 2.25 (s, 3H, -CH3), 3.80 (br s, 1H, NH),
3.98-4.04 (m, 1H, CH), 6.50-6.62 (m, 2H, aromatic), 6.69-6.71 (m, 1H, aromatic), 9.22 (br s, 1H, NH).
13C NMR (CDCl3): δ 18.1 (CH3), 20.9 (CH3), 52.3 (CH), 114.5 (CH), 115.7 (CH), 120.5 (CH), 124.5 (C),
129.7 (C), 133.9 (C). 170.5 (C). Anal. Calcd for C10H12N2O: C, 68.16; H, 6.86; N, 15.90. Found: C.
68.27; H, 6.91; N, 16.13.
ACKNOWLEDGEMENTS
We thank the Robert Welch Foundation, Houston, Texas for partial financial support of this work.
REFERENCES
1. R. Sages and J. W. Lyga, J. Heterocycl. Chem., 1998, 25, 1474.
2. (a) R. E. TenBrink, W. B. Im, V. H. Sethy, A. H. Tang, and D. B. Carter, J. Med. Chem., 1994, 37,
758.
(b) E. J. Jacobsen, R. E. TenBrink, L. S. Stelzer, K. L. Belonga, D. B. Carter, H. K. Im, W. B. Im, V.
H. Sethy, A. H. Tang, P. F. VonVoigthander, and J. D. Petke, J. Med. Chem., 1996, 39, 158.
(c) E. J. Jacobsen, L. S. Stelzer, R. E. TenBrink, K. L. Belonga, D. B. Carter, H. K. Im, W. B. Im, V.
H. Sethy, A. H. Tang, P. F. VonVoigtlander, J. D. Petke, W. Z. Zhong, and J. W. Mickelson, J. Med.
Chem., 1999, 42, 1123.
3. D. S. Lawrence, J. E. Copper, and C. D. Smith, J. Med. Chem., 2001, 44, 594.
4.
D. Gupta, N. N. Ghosh, and R. Chandra, Bioorg. Med. Chem. Lett., 2005, 15, 1019.
5. (a) P. Sanna, A. Carta, M. Loriga, S. Zanetti, and L. Seehi, Il Farmaco, 1999, 54, 161 and 167. (b)
M. M. Ali, M. M. F. Ismail, M. S. A. EL-Gaby, M. A. Zahran, and Y. A. Ammar, Molecules, 2000,
5, 864.
6.
A. Carta, P.Sanna, L. Gherardini, D. Usai, and S. Zanetti, Il Farmaco, 2001, 56, 933.
7. A. Carta, P. Sanna, M. Loriga, M. G. Setzu, P. L. Colla, and R. Loddo, Il Farmaco, 2002, 57, 19.
8. J. Lee, D. Gauthier, and R. A. Rivero, J. Org. Chem., 1999, 64, 3060.
9. J. P. Mayer, G. S. Lewis, M. J. Curtis, and J. Zhang, Tetrahedron Lett., 1997, 38, 8445.
10. E. Laborde, B. T. Peterson, and L. Robinson, J. Comb. Chem., 2001, 3, 572.
11. A. N. Acharya, J. M. Ostresh, and R. A. Houghten, Tetrahedron, 2002, 58, 221.

HETEROCYCLES, Vol. 68, No. 9, 2006
1939
12. R. J. Holland, I. R. Hardcaste, and M. Jarman, Tetrahedron Lett., 2002, 43, 6435.
13. B. C. G. Soderberg, J. M. Wallace, and J. Taamariz, Org. Lett., 2002, 4, 1339.
14. K. S. Kim, L. Qian, J. E. Bird, K. E. J. Dickinson, S. Moreland, T. R. Schaeffer, T. L. Waldron, C.
L. Delaney, H. N. Weller, and A. V. Miller, J. Med. Chem., 1993, 36, 2335.
15. C. –Li. Tung and C. –M. Sun, Tetrahedron Lett., 2004, 45, 1159.
16. W.–J. Chang, W.–B. Yeh, and C.–M. Sun, Synlett, 2003, 1688.