Synthesis of quinoxaline 1,4-dioxides from 5,6-diethylbenzofuroxan on silica gel

Article abstract of DOI:10.3987/COM-05-10382

5,6-Diethylbenzofuroxan (1) and 5-ethylbenzofuroxan (2) were synthesized in good yield via oxidation of o-nitroanilines by sodium hypochlorite. 4-Ethylbenzofuroxan (3) was prepared by the photochemical decomposition of 2-ethyl-6-nitrophenyl azide (3N).

Full text of DOI:10.3987/COM-05-10382

HETEROCYCLES, Vol. 65, No. 7, 2005
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HETEROCYCLES, Vol. 65, No. 7, 2005, pp. 1589 - 1600
Received, 21st February, 2005, Accepted, 22nd April, 2005, Published online, 25th April, 2005
SYNTHESIS OF QUINOXALINE 1,4-DIOXIDES FROM
5,6-DIETHYLBENZOFUROXAN ON SILICA GEL
*
Nobuo Sekimura, Hiroaki Saito, Shinichi Miyairi, and Tohru Takabatake
College of Pharmacy, Nihon University,
7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan
Abstract-5,6-Diethylbenzofuroxan (1) and 5-ethylbenzofuroxan (2) were
synthesized in good yield via oxidation of o-nitroanilines by sodium hypochlorite.
4-Ethylbenzofuroxan (3) was prepared by the photochemical decomposition of
1
2-ethyl-6-nitrophenyl azide (3N). H-NMR spectrum showed that the compound
(3) rapidly rearranges between the two unsymmetrical bicyclic structures at 296.8
K. The 4-ethyl group may possibly function as a barrier against molecular
rearrangement. Quinoxalines yields depended on the enol content in β-keto esters
or 1,3-diketones. A comparison of the reactivity of 1 with benzoylacetone was
made with that of other benzofuroxans. The reaction of 1 condensed with the
carbonyl compound better than other benzofuroxans.
INTRODUCTION
Benzofuroxan (benzofurazan N-oxide) has been shown to have numerous pharmacological and industrial
applications.1a-d As a part of benzofurazan chemistry, reactions of various benzofuroxans with active
methylene compounds catalyzed by silica gel2 or molecular sieves3-4 yield the corresponding quinoxaline
1,4-dioxides, and the antibacterial activity of quinoxaline 1,4-dioxides has been reported.5
Pyrido[2,3-b]pyrazine 1,4-dioxides have been obtained from a reaction of pyrido[2,3-c]furoxan with
active methylene compounds catalyzed by treatment with silica gel, alumina, or molecular sieves6 and the
antibacterial activity of pyrido[2,3-b]pyrazine 1,4-dioxides has been reported.7 Reactions of
benzofuroxan with various phenolic compounds catalyzed by silica gel, alumina, or molecular sieves

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HETEROCYCLES, Vol. 65, No. 7, 2005
provide the corresponding phenazine 5,10-dioxide derivatives8 and the antibacterial activity of phenazine
5,10-dioxide derivatives has been reported.9 The toxicity of benzofurazans in Escherichia coli has been
reported to be caused by an increase in intracellular flux of superoxide on aerobic incubation.10 The
superoxide production was confirmed using the cytochrome c reduction method and ESR spectra.11
1
4,7-Dimethylbenzofurazan was transformed by O2 into 4,7-dimethylbenzofurazan 4,7-endoperoxide, in
excellent yields.12
This paper presents the synthesis of novel substituted quinoxaline dioxides from novel benzofuroxan
derivatives with the enolic form of β-keto esters or 1,3-diketones catalyzed by silica gel.
RESULTS AND DISCUSSION
In this study, 5,6-diethylbenzofuroxan (1) and 5-ethylbenzofuroxan (2) were synthesized in good yield
from oxidation of o-nitroanilines. 3,4-Diethyl-6-nitroaniline13 (1NA) or 3-ethyl-6-nitroaniline14 (2NA)
was oxidized by sodium hypochlorite to give corresponding benzofuroxans. 4-Ethylbenzofuroxan (3) was
synthesized from 2-ethyl-6-nitroaniline (3NA). 2-Ethyl-6-nitroaniline (3NA) sulfate was diazotized by
sodium nitrite, and the diazo compound was converted to 2-ethyl-6-nitrophenyl azide (3N) by sodium
azide followed by the photochemical decomposition of the azide in methanol (Scheme 1).
Scheme 1
C2H5
C2H5
NH2
NO2
N
C2H5
C2H5
NaOCl
NaOCl
O
N
O
1NA
1
C2H5
NH2
NO2
C2H5
N
O
N
O
2NA
2
C2H5
1) H2SO4 + NaNO2
2) NaN3
C2H5
C2H5
NH2
N3
N
hν(Pyrex filter)
O
N
NO2
NO2
O
3N
3
3NA

HETEROCYCLES, Vol. 65, No. 7, 2005
1591
1
The compound (3) has an interesting H-NMR spectrum which showed two kinds of singlets from δ 1.1
to 1.4 ppm at 296.8 K. The spectrum showed different chemical shifts that looked like they were derived
from two compounds. The two kinds of signals changed to one kind of signal at 354 K (Figure 1). After
cooling, the 1H-NMR spectrum returned to the former spectrum at 296.8 K spectrum.
Figure 1
In general, benzofuroxan derivatives rapidly rearrange between the two unsymmetrical bicyclic structures
via a transitional ring opened dinitroso form.1a-d We believe that the compound (3) must undergo the
similar molecular rearrangement as other benzofuroxans. Then, two different kinds of 1H-NMR spectra of
the compound (3) were obtained at room temperature. The 296.8 K spectrum indicated the two equivalent
unsymmetrical forms, and that at 354 K indicated the rapidly equilibrating mixture of the two equivalent
unsymmetrical forms.
Next, for comparison with the chemical shift of ethyl protons of 2-ethylbenzofurazan (3Z), which has no
N-oxide group and tautomerism, the compound (3Z) was prepared by reduction of the compound (3) with

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HETEROCYCLES, Vol. 65, No. 7, 2005
trimethyl phosphite in excellent yield (Scheme 2). 1H-NMR spectrum of the compound (3Z) did not show
two kinds of signals as in compound (3), but only one signal at room temperature (δ 1.35 (t, 3H, J = 7.6
Hz), 3.00(q, 2H, J = 7.6 Hz) ).
Scheme 2
C2H5
C2H5
P(OCH3)3
N
N
N
O
O
N
O
3
3Z
It may be inferred that the effect of benzofuroxan tautomerism shows the two kinds of signals in the
1H-NMR spectrum of compound (3) at room temperature. By comparing chemical shift of methyl proton
of compound (3) with that of compound (3Z), we could assign a larger signal from the tautomer (3a) and
a smaller signal from the tautomer (3b). The tautomer ratio in DMSO-d6 at 296.8 K was determined from
methyl proton integration of the ethyl group (Figure 2).
Figure 2
C2H5
C2H5
O
N
C2H5
N
N
N
O
O
O
O
N
O
N
75%
25%
(in DMSO-d6)
(in DMSO-d6)
at 296.8 K
at 296.8 K
3b
3a
The above extra phenomenon exhibited by the compound (3) can be explained in terms of a weak
hydrogen bonding between the oxygen atom of the N-oxide group and the ethyl group (Figure 3).

HETEROCYCLES, Vol. 65, No. 7, 2005
1593
Figure 3
H
H
C
O
H2C
H
N
O
N
Ikekawa and Sato also reported the presence of a weak hydrogen bonding between the oxygen atom of
the N-oxide group and the hydrogen atom of the 2-methyl group as in the case of 2-methylpyridine
1-oxide.15 The oxygen atom of the N-oxide group of the compound (3) is attracted by the methyl
hydrogen atom of the 4-ethyl group. The ethyl group may then possibly function as a barrier against
molecular rearrangement and so molecular rearrangement is so slow that different chemical shifts exist at
room temperature. As a result of this effect of the 4-ethyl group, it is understandable that slow molecular
rearrangement occurs and that there is more tautomer (3a) present than tautomer (3b) at room
temperature.
Table 1
O
Silica gel
N
N
R1
O
N
N
H2
C
C2H5
C2H5
C2H5
C2H5
O
R2
R1
O
O
R2
O
O
1
5a~d
4a~d
Yield (%)
Enol Content
of 4(%)
(in Ethanol)
Compound
R2
R1
No.
5a~d
4a
0
0
OCH3 OCH3
CH3
12.6 8
4b
OCH3
25
84 8
94 8
43
74
4c
CH3 CH3
CH3
4d

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HETEROCYCLES, Vol. 65, No. 7, 2005
Reaction of various β-keto esters and 1,3-diketones (4a-d) with compound (1) was examined (see Table
1). The method for synthesizing quinoxaline 1,4-dioxides derivatives was as follows: A solution of
benzofuroxans and β-keto esters or 1,3-diketones in CH2Cl2 was evaporated in the presence of silica gel.
Both benzofuroxans and β-keto esters or 1,3-diketones were adsorbed on the silica gel followed by
o
standing at 110 C. The reaction mixture was chromatographed to give the corresponding isomeric
quinoxaline 1,4-dioxides derivatives.
Compound (4a) failed to react with compound (1) and unreacted 1 was almost completely recovered. The
enol form of carbonyl compounds was previously shown to be necessary for the formation of
quinoxalines, whose yields depended on the enol content in 1,3-diketones.2 Silica gel may serve to
enhance the stability of the enol form of carbonyl compounds and the dehydration capacity of catalysts
may significantly determine the possibility of synthesis.
Table 2
O
R1
R1
R2
R3
R2
R3
N
CH3
O
N
H2
C
Silica gel
O
+
CH3
N
O
O
N
O
O
5d~g
Product
No. and R
Substrate
Yield
(%)
R1 = H
1
5d
74
R2 = R3 = C2H5
R1 = R3 = H
R2 = C2H5
5e
5f
52[a]
2
3
R1 = R2 = H
R3 = C2H5
R1 = C2H5
5g
0
R2 = R3 = H
[a] Combined yield of compounds (5e) + (5f)

HETEROCYCLES, Vol. 65, No. 7, 2005
1595
A comparison of the reactivity of compound (3) with benzoylacetone was made with that of other
benzofuroxans. Table 2 shows the reaction of compound (1) to proceed in good yield. In contrast,
compound (2) condensed with the carbonyl compound less than compound (1), and compound (3) did not
react at all. Compound (3) was recovered almost unchanged in the reaction with benzoylacetone.
In these reactions, hyperconjugation of the 4-ethyl group with the N-oxide group may possibly lessen the
electron affinity of 1-nitrogen atoms (Figure 4).
Figure 4
H
C
H
C
CH3
H
CH3
H
N
N
O
O
N
O
N
O
Additionally, in the compound (3) reaction (Table 2), it seems that steric hindrance between the 4-ethyl
group and the N-oxide group contributes to the weakening of the stability of the transition state in the
condensation reaction.
Figure 5
CH3
C
Silica gel
O
H
O
H
Si
Si
O
C
H
O
O
R
N
HO
C
O
O
Ph
N
O
O
N
O
O
N
CH3
CH3
CH3
R
R
R
R
CH3
O
H
O
C O
H
N
H
C O
N
O
C
C
H
N
O
N
O
N
O
C
O
Ph
N
O
C
C O
C O
Ph
H
H
H2O
Ph
Ph
O
H
H
O Si
O Si
H
O
O
H
O

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HETEROCYCLES, Vol. 65, No. 7, 2005
Therefore, the effect reflects inactivation of the nucleophilic attack toward benzoylacetone in the first step
of quinoxaline synthesis. The reaction mechanism may thus be considered to be as shown in Figure 5.
EXPERIMENTAL
Melting points were determined with a Yanagimoto micromelting point apparatus and are uncorrected.
１
The IR spectra were recorded on a JASCO ir-810 spectrophotometer. The H-NMR spectra were
recorded on a JNM-LA 600 FT NMR System with TMS as the internal standard. The MS spectra were
recorded on a JEOL JMS-GCmate spectrometer with an electron beam energy of 70 eV. Microanalysis
was performed at the microanalytical laboratory of the Center for Instrumental Analysis in the College of
Science & Technology, Nihon University.
5,6-Diethybenzofuroxan (1).
A mixture of 3,4-diethyl-6-nitroaniline(1NA)(90 mg, 0.46 mmol) , KOH(2 g, 36 mmol) and H2O (2 mL)
in MeOH (10 mL) was cooled until the temperature of the solution becomes 0 oC. The 4% NaOCl
solution (6 mL, 3.36 mmol) was added slowly with stirring. After 15 min with stirring at rt, the mixture
was washed with CH2Cl2 50 mL (two times) to remove 5,6-diethylbenzofuroxan. Recrystallization from
o
-1
MeOH-H2O (10:1(v/v)) afforded light yellow needles. 78 mg (88 %). mp 95-97 C; IR (KBr) cm :
１
ν 1623, 1591, 1478, 1376; H-NMR (DMSO-d6): δ 1.23(br t, 6H, J = 7.2 Hz), 2.69(br q, 4H, J = 7.2 Hz),
7.39(br s, 2H); HRMS (EI) m/z: 192.0898. Calcd for C10H12N2O2: M, 192.0899. Anal. Calcd for
C10H12N2O2: C, 62.49; H, 6.29; N, 14.57. Found: C, 62.40; H, 6.27; N, 14.44.
5-Ethybenzofuroxan (2).
A mixture of 3-ethyl-6-nitroaniline(1NA)(90 mg, 0.54 mmol) , KOH(2 g, 36 mmol) and H2O (2 mL) in
MeOH (10 mL) was cooled until the temperature of the solution becomes 0 oC. The 4% NaOCl solution
(6 mL, 3.36 mmol) was added slowly with stirring. After 15 min with stirring at rt, the mixture was
washed with CH2Cl2 50 mL (two times) to remove 5-ethylbenzofuroxan. Recrystallization from
o
-1
MeOH-H2O (10:1(v/v)) afforded light yellow needles. 72 mg (81 %). mp 39-41 C; IR (KBr) cm :
１
ν 1617, 1585, 1483, 1380; H-NMR (CDCl3): δ 1.21 (t, 3H, J = 7.5 Hz), 2.69(q, 2H, J = 7.5 Hz), 7.11(br
s-like, 1H), 7.30 (br s-like, 1H), 7.48 (br s-like, 1H); HRMS (EI) m/z: 164.0586. Calcd for C8H8N2O2:
M,164.0586. Anal. Calcd for C8 H8 N2 O2 : C, 58.53; H, 4.91; N, 17.06. Found:
C, 58.36; H, 4.99; N, 16.84.

HETEROCYCLES, Vol. 65, No. 7, 2005
1597
2-Ethyl-6-nitrophenylazide (3N).
A solution of 2-ethyl-6-nitroaniline (3NA) (166 mg, 1 mmol) in 20 % hydrochloric acid (6 mL) was
cooled until the temperature of the solution became 0-5 oC and then the resulting mixture was treated with
sodium nitrite (69 mg, 1 mmol) in H2O (1 mL). To the resulting solution of the diazonium ion was added
sodium azide (65 mg, 1 mmol) in H2O (1 mL) and the solution was maintained at 0-5 oC. Stirring was
then continued for 0.5 h at rt. The reaction mixture was then diluted with H2O. The precipitate was
collected, washed with H2O and dried overnight. It was purified by column chromatography (Wakogel
C-200, Wako Pure Chemical Industries) to give 2-ethyl-6-nitrophenylazide (3N), (n-hexane/CH2Cl2
o
-1
(3:2)) yellow oil, 165 mg (86 %). 56-57 C (decomp); IR (KBr) cm : ν 2124, 1530, 1445, 1348;
1
H-NMR (CDCl3): δ 1.26 (t, 3H, J = 7.4 Hz), 2.80(q, 2H, J = 7.4 Hz), 7.25(t, 1H, J = 8.0 Hz),
7.47(dd, 1H, J = 1.5, 8.0 Hz), 7.81(dd, 1H, J = 1.5, 8.0 Hz); HRMS (EI) m/z: 192.0648. Calcd for
C8H8N4O2: M, 192.0647.
4-Ethylbenzofuroxan (3).
Compound (3N) (192 mg, 1 mmol) was dissolved in CH3CN (10 mL) and placed in a merry-go-round
type apparatus. The solution was irradiated using a 400W high pressure mercury lamp with a Pyrex filter
at rt. After irradiation for 2 h, the solution was evaporated. It was purified by preparative TLC (Merck,
Silica gel plate 60 F254 Art. 1.05717) to give 4-ethylbenzofuroxan (3) (n-hexane/ CH2Cl2 (1:1)), 77 mg
o
-1
(46 %). Recrystallization from n-hexane afforded light yellow needles. mp 61-62 C; IR (KBr) cm :
1
ν 1615, 1576, 1482, 1381; H-NMR (DMSO-d6): at 296.8 K, δ 1.19(t, 0.75H, J = 7.3 Hz), 1.31(t, 2.25H,
J = 7.3 Hz), 2.90(q, 2H, J = 7.3 Hz), 7.1-7.6 (m, 3H); HRMS (EI) m/z:164.0591. Calcd for C8H8N2O2: M,
164.0586. Anal. Calcd for C8H8N2O2: C, 58.53; H, 4.91; N, 17.06. Found: C, 58.47; H, 4.98; N, 17.08.
4-Ethylbenzofurazan (3Z).
A solution of compound (3) (164 mg, 1 mmol) and trimethyl phosphite (2 mL, 17 mmol) was refluxed for
0.5 h. It was purified by preparative TLC (Merck, Silica gel plate 60 F254 Art. 1.05717) to give
4-ethylbenzofurazan (3Z) (n-hexane/ CH2Cl2 (1:1)) as white needles. Yield 111 mg (75%). mp 30-31 oC;
1
IR (KBr): ν 1619, 1531, 1400, 1354 cm-1; H-NMR (CDCl3): δ 1.35 (t, 3H, J = 7.6 Hz), 3.00(q, 2H, J =
7.6 Hz), 7.36(d, 1H, J = 6.6 Hz) , 7.54(dd, 1H, J = 8.9, 6.6 Hz) , 7.85(d, 1H, J = 8.9 Hz); HRMS (EI) m/z:
Found:148.0634. Calcd for C8H8N2O (M):148.0637; Anal. Calcd for C8H8N2O: C, 64.85; H, 5.44; N,
18.91. Found: C, 64.64; H, 5.53; N, 18.73.

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HETEROCYCLES, Vol. 65, No. 7, 2005
Synthesis of Quinoxaline derivatives.
To a solution of benzofuroxans (0.1 mmol) and β-keto esters or 1,3-diketones (0.1 mmol) in CH2Cl2 (10
mL) was added silica gel (Wakogel C-200, 2 g) and the mixture was evaporated in an evaporator at 30 °C.
The silica gel containing adsorbed benzofuroxans and β-ketoesters or 1,3-diketones was allowed to stand
for 2 h at 110 °C. It was purified by preparative tlc (Merck silica gel plate 60 F
quinoxaline derivatives (CH2Cl2/ MeOH (98:2)).
Art. 5717) to give
254
2-Carbomethoxy-3-methyl-6,7-diethylquinoxaline 1,4-dioxide (5b).
Compound (5b): Yield 7 mg (25 %). Recrystallization from MeOH afforded yellow powder. mp 148-150
1
oC; IR (KBr): ν 1743 cm-1; H-NMR (DMSO-d6): δ 1.27(t, 3H, J = 7.4 Hz), 1.28(t, 3H, J = 7.4 Hz),
2.41(s, 3H), 2.87(q, 2H, J = 7.0 Hz), 2.88(q, 2H, J = 7.0 Hz), 4.01(s, 3H), 8.16(s, 1H) , 8.24(s, 1H);
HRMS (EI) m/z: Found:290.1270. Calcd for C15H18N2O4 (M):290.1266; Anal. Calcd for C15H18N2O4: C,
62.06; H, 6.25; N, 9.65. Found: C, 61.93; H, 6.22; N, 9.40.
2-Acetyl-3-methyl-6,7-diethylquinoxaline 1,4-dioxide (5c).
Compound (5c): Yield 15 mg (52 %). Recrystallization from MeOH afforded yellow powder. mp
o
1
190-192 C; IR (KBr): ν 1718 cm-1; H-NMR (DMSO-d6): δ 1.28(t, 3H, J = 6.4 Hz), 1.29(t, 3H, J = 6.4
Hz), 2.35(s, 3H), 2.64(s, 3H), 2.89(q, 2H, J = 7.0 Hz), 2.90(q, 2H, J = 7.0 Hz), 8.21(s, 1H) , 8.27(s, 1H);
HRMS (EI) m/z: Found:274.1320. Calcd for C15H18N2O3 (M):274.1317; Anal. Calcd for C15H18N2O3: C,
65.68; H, 6.61; N, 10.21. Found: C, 65.79; H, 6.61; N, 10.14.
2-Benzoyl-3-methyl-6,7-diethylquinoxaline 1,4-dioxide (5d).
Compound (5d): Yield 25 mg (74 %). Recrystallization from MeOH afforded yellow powder. mp
198-200 oC; IR (KBr): ν 1721 cm-1; 1H-NMR (DMSO-d6): δ 1.28 (t, 3H, J = 7.5 Hz), 1.31 (t, 3H, J = 7.5
Hz), 2.29(s, 3H), 2.89(q, 2H, J = 7.5 Hz), 2.92(q, 2H, J = 7.5 Hz) ,7.57(t-like, 2H, J = 7.7Hz), 7.76(t-like,
1H, J = 7.7 Hz), 8.03(d, 2H, J = 7.2 Hz), 8.15(s, 1H), 8.32(s, 1H); HRMS (EI) m/z: Found:336.1473.
Calcd for C20H20N2O3 (M):336.1473; Anal. Calcd for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C,
71.70; H, 6.27; N, 8.26.
2-Benzoyl-3-methyl-6-ethylquinoxaline 1,4-dioxide,
3-Benzoyl-2-methyl-6-ethylquinoxaline 1,4-dioxide (5e，5f).
We could not separate 5e and 5f. Compound (5e，5f): Yield 16 mg (52 %). Recrystallization from MeOH
o
afforded yellow powder. A mixture of 5e and 5f had mp 115-117 C; IR (KBr): ν 1718cm-1; 1H-NMR

HETEROCYCLES, Vol. 65, No. 7, 2005
1599
(CDCl3): Major compound : Minor compound = 3 : 1 (The ratio was determined from methyl proton
integration.), Major compound δ 1.36(t, 3H, J = 7.6 Hz), 2.50(s, 3H), 2.92(q, 2H, J = 7.6 Hz), 7.53(t-like,
2H, J = 7.6 Hz), 7.68(t-like, 1H, J =7.6 Hz), 7.77(dd, 1H, J = 2.0, 8.9 Hz), 7.90(d, 2H, J = 8.2 Hz), 8.36(d,
1H, J = 2.0 Hz), 8.59(d, 1H, J = 8.9 Hz). Minor isomer δ 1.39(t, 3H, J= 7.6 Hz), 2.46(s, 3H), 2.95(q, 2H,
J = 7.6 Hz), 7.53(t-like, 2H, J = 7.6 Hz) 7.68(t-like, 1H, J = 7.6 Hz), 7.76(dd, 1H, J = 2.0, 8.9 Hz), 7.89(d,
2H, J = 8.2 Hz), 8.43(d, 1H, J = 2.0 Hz), 8.57(d, 1H, J = 8.9 Hz). HRMS (EI) m/z: Found: 308.1157.
Calcd for C18H16N2O3 (M):308.1161; Anal. Calcd for C18H16N2O3: C, 70.12; H, 5.23; N, 9.09. Found: C,
69.91; H, 5.42; N, 8.91.
ACKNOWLEGMENT
This research was partially supported by Nihon University Individual Research Grant for 2003 & A Grant
from “Academic Frontier” Project for Private Universities :matching fund subsidy from MEXT (Ministry
of Education, Culture, Sports, Science and Technology )2002-2006.
REFERENCES AND NOTES
1.
For comprehensive reviews see: [a] A. J. Boulton and P. B. Ghosh, Adv. Heterocyclic Chem., 1969,
10, 1; [b] A. Gasco and A. J. Boulton, Adv. Heterocyclic Chem., 1981, 29, 251; [c] P. B. Ghosh, B.
Ternai and M. W. Whitehouse, Med. Res. Rev., 1981, 1, 159; [d] A. R. Katritzky and M. F. Gordeev,
Heterocycles, 1993, 35, 483.
2.
3.
4.
5.
6.
7.
8.
9.
M. Hasegawa and T. Takabatake, Synthesis, 1985, 938.
T. Takabatake and M. Hasegawa, J. Heterocycl. Chem., 1987, 24, 529.
T. Takabatake, Y. Hasegawa, and M. Hasegawa, J. Heterocycl. Chem., 1993, 30, 1477.
T. Takabatake, Y. Takabatake, T. Miyazawa, and M. Hasegawa, Yakugaku Zasshi, 1996, 116, 491.
T. Takabatake, T. Miyazawa, and M. Hasegawa, Heterocycles, 1997, 45, 107.
T. Miyazawa, T. Takabatake, and M. Hasegawa, Yakugaku Zasshi, 1997, 117, 126.
T. Takabatake, T. Miyazawa, M. Kojo, and M. Hasegawa, Heterocycles, 2000, 53, 2151.
T. Takabatake, T. Miyazawa, A. Takei, and M. Hasegawa, Medicine and Biology, 2001, 142, 5.
10. T. Takabatake, M. Hasegawa, T. Nagano, and M. Hirobe, Chem. Pharm. Bull., 1990, 38, 128.
11. T. Takabatake, M. Hasegawa, T. Nagano, and M. Hirobe, J. Biol. Chem., 1992, 267, 4613.

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HETEROCYCLES, Vol. 65, No. 7, 2005
12. T. Takabatake, T. Miyazawa, M. Hasegawa, and C. S. Foote, Tetrahedron Lett., 2001, 42, 987.
13. J. P. Lambooy, J. Am. Chem. Soc., 1949, 71, 3756.
14. C. Hansch, J. Org. Chem., 1955, 20, 1026.
15. N. Ikekawa and Y. Sato, Pharm. Bull., 1954, 2, 400.