2-Aryl-3-arylaminoisoxazol-5(2H)-ones as sources of indoles and imidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/S0040-4020(02)01348-0

2-Aryl-3-arylaminoisoxazol-5(2H)-ones undergo solvolysis to form 1,3-dipoles that undergo intramolecular cyclisation to form either imidazopyridines or indoles. The mode of cyclisation is controlled by the electronegativity of the aryl substituents.

Full text of DOI:10.1016/S0040-4020(02)01348-0

Tetrahedron 58 (2002) 9965–9972
2-Aryl-3-arylaminoisoxazol-5(2H)-ones as sources of indoles and
imidazo[1,2-a]pyridines
b
b
David Jeffery,a Rolf H. Prager,a David Turner and Monica Dreimanis
,
*
aSchool of Chemistry, Physics and Earth Sciences, Flinders University of South Australia, G.P.O. Box 2100, Adelaide, SA 5001, Australia
bSchool of Medicine, Flinders University, G.P.O. Box 2100, Adelaide, SA 5001, Australia
Received 18 July 2002; revised 25 September 2002; accepted 17 October 2002
Abstract—2-Aryl-3-arylaminoisoxazol-5(2H)-ones undergo solvolysis to form 1,3-dipoles that undergo intramolecular cyclisation to form
either imidazopyridines or indoles. The mode of cyclisation is controlled by the electronegativity of the aryl substituents. q 2002 Published
by Elsevier Science Ltd.
1. Introduction
Worrall.3,4 Thus, the reaction of the sodium salt of diethyl
malonate in THF with various arylisothiocyanates gave the
thiocarbamates (2) in good yield, and these were converted
to the corresponding isoxazolone (3) by reaction with
2 equiv. of hydroxylamine (Scheme 2). As expected, the
presence of electron withdrawing groups in the isothio-
cyanate facilitated both the reaction with the malonate and
that with hydroxylamine. The highly acidic isoxazolones (3)
formed strong complexes with H2S, as shown by the
microanalytical data, and the release of gas on melting.
Since the reaction mixture from the formation of (3) was
acidified, it would appear that the adduct is more likely to be
a H-bonded complex than a salt. Similar strong association
with water was also noted. N-arylation of (3) with activated
chloroheterocycles then gave the desired starting materials
(4) (Scheme 2). While the formation of (4) appears trivial,
the reaction generally proceeded best in the absence of
solvent, by heating the required reagents in a sealed tube at
1308C for an hour. The failure to achieve reaction by prior
formation of the salt of (3), formed readily with potassium
carbonate, or the use of dipolar aprotic solvents, supports
our hypothesis that the reacting species is the salt (5).
We have recently reported1 that the reaction of 2-aryl-3-
arylaminoisoxazolones (1) with triethylamine leads to the
formation of indoles and carbon dioxide, an outcome that is
formally the same as that achieved by photolysis or
pyrolysis2 (Scheme 1). The evidence for the indole
structure, rather than that of an isomer, rested on the
number of aryl proton signals visible in the 1H NMR
spectrum. However, the unusual mechanism proposed
suggested to us that further investigation was warranted,
particularly by the introduction of both electron-donating
and withdrawing substituents into the 3-arylamino ring.
2. Discussion
The required analogues of isoxazolones (1) were syn-
thesised by N-arylation of the 2H-isoxazolones, which in
turn were made by a modification of the procedure of
The rearrangement of (4a), as shown in Scheme 1,
proceeded in 68% yield in refluxing ethanol for 1 h in the
presence of triethylamine. While the presence of a base was
required, other bases were trialled and gave the same
product in varying yields: pyrrolidine 38%, diisopropyl-
ethylamine 46%, and potassium carbonate 67%. The use of
sodium ethoxide or potassium t-butoxide, even at room
temperature, led to the formation of a plethora of products.
In practice, the use of potassium carbonate led to the
cleanest products, and was subsequently adopted.
Scheme 1.
Keywords: isoxazolones; 1,3-dipolar intermediates; indoles;
imidazopyridines.
All 2-arylisoxazolones (4a-4g) reacted with potassium
carbonate in ethanol, but those with electron withdrawing
*
Corresponding author. Tel.: þ61-8-82012357; fax: þ61-8-82012905;
e-mail: rolf.prager@flinders.edu.au
0040–4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)01348-0

9966
D. Jeffery et al. / Tetrahedron 58 (2002) 9965–9972
Scheme 2.
groups, 4d and 4f, reacted more slowly than the others, and
4d returned mainly starting material. The major product in
each case had similar spectral properties to those of the
product from 4a, which had been assigned the indole
structure.1 Isoxazolone (4b) gave significant amounts of a
second product, whose spectral properties were more
consistant with those expected for the indole. Thus, the
major product in each case had its structure reassigned as
the imidazo[1,2-a]pyridine (Scheme 3), and this assignment
has been confirmed by a single crystal X-ray structure of the
originally isolated product (6a).5 The imidazopyridine
structure (6b) could now clearly be deduced from the
similarity of the coupling pattern of the protons in the
methoxyphenyl ring to that in the starting material (4b), and
the indole structure (7b) had proton couplings similar to
those of the nitropyridyl ring in (4b).
with the presence of ortho or para methoxyl groups, is
reminiscent of that observed in the rearrangement of the
nitrene generated by pyrolysis of anthranils.6
Since the alkoxyphenyl ring does not undergo rearrange-
ment in the present case, we believe the change in product
composition in the presence of good electron donating
groups is consistent with the pathway shown in Scheme 4
below. This postulates that the weak base favours
tautomerisation of 4 to the H-3 tautomer (8) or the
5-hydroxy tautomer, the solvolysis of either being the key
step, giving a 1,3-dipolar intermediate (9), the electron
distribution in which will depend vitally on charge
delocalisation by substituent groups. The intermediate (9)
is readily convertible to either the imidazopyridine or the
indole. When the anion of isoxazolone (3a) was methylated,
the product (10) could not be induced to undergo similar
base catalysed reactions, indicating its solvolytic stability.
Nishiwaki and co-workers have proposed that 2-methyl-4-
nitroisoxazolone (11) is synthetically equivalent to the 1,3-
dipole (12), although the latter was not postulated as an
intermediate.7
With a number of imidazopyridine structures in hand, the
reason for the original misassignment was further investi-
1
gated. The H NMR spectra of all compounds (6) showed
H-7 to have meta coupling with H-5, but in none could the
resonance for H-5 be clearly observed. On the addition of
TFA, however, the very broad peak for H-5 at 9.9 ppm
became quite sharp, and a COSY spectrum now confirmed
its meta coupling with H-7. The reason for the extreme
broadening of this peak is unknown, though quadrupole
coupling with N-4 is implicated; the X-ray structure of 6a5
did not show any unusual interactions.
There is no spectral evidence to suggest that tautomers of
4 have significant populations, and while 5-hydroxy
tautomers have previously been proposed to account for
the products from photochemical reactions,2 in those
instances homolytic cleavage of the N–O bond had
occurred.
The proportion of indole (7) was highest for the 2,4-
dimethoxyphenyl analogue (4g) (7g/6g, 2:3). The change in
reaction pathway, from imidazopyridine towards indole,
In order to investigate the possibility that solvolysis required
only a polar solvent, 4g was refluxed for extended periods of
Scheme 3.

D. Jeffery et al. / Tetrahedron 58 (2002) 9965–9972
9967
Scheme 4.
time in ethanol and the more polar trifluoroethanol. The
reaction in ethanol, without base, occurred slowly over two
days, but a number of compounds, including indole (7g) and
imidazopyridine (6g) were formed. While isoxazolone (11)
was found to undergo cyclisation reactions with dimethyl
acetylenedicarboxylate,7 the latter is not compatible with
our required reaction conditions, being converted to the
ethoxyfumarate ester (13).
crystallisation from dilute solution, and the uncharged form
(15) after crystallisation from concentrated solution. The
proportions of 15 and 16 could be altered by the dielectric
constant of the solvent. Thus, reaction of 14 with potassium
carbonate in a largely aqueous environment led almost
exclusively to the indole (15), whereas the use of
benzyltrimethylammonium hydroxide in THF gave no
indole formation at all. The urea structure (16) is suggested
to arise from an early solvolysis intermediate as shown in
Scheme 5.
Finally, the isoxazolone (3g) was reacted with 4-chloro-2-
methylquinoline in boiling chlorobenzene to give the
N-arylated product (14). The 1H NMR upfield shifts of
H-3 and H-5 in the dimethoxybenzene ring confirms the
restricted rotation imposed by the H-bonding. The isoxa-
zolone (14) did not react with triethylamine, but did react
with potassium carbonate in ethanol to give two products,
15 and 16, separable by chromatography. The structure of
the indole (15) followed readily from its NMR spectra, but it
could be isolated in two tautomeric forms, which retained
different NMR spectra in chloroform, but which had the
same UV–Vis spectrum in methanol. The zwitterionic form
(15a) was obtained after chromatography on alumina, or
Preliminary results indicate that the dimethoxyphenyl
imidazopyridine (6g) and the dimethoxyphenyl indole (7g)
both exhibit significant cytotoxicity towards mammalian
cells. Human peripheral blood derived T-lymphocytes were
exposed to the chemicals in culture for 24 h either
unstimulated (non-dividing) or following stimulation with
the mitogen phytohaemagglutinin. Cytotoxicity was greater
towards non-dividing cells (IC50:2 mM, 10 mM) than
towards dividing cells (IC50:15 mM, 55 mM) with the indole
having the greater cytotoxicity in both cases. These results
are interesting and warrant further study of the mechanism
Scheme 5.

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D. Jeffery et al. / Tetrahedron 58 (2002) 9965–9972
of cytotoxicity, in particular to determine whether it is
mediated by interaction with DNA.
(t, 6H, J¼7.1 Hz); 13C NMR d 187.1, 165.7, 159.9, 139.6,
129.6, 115.2, 113.0, 108.4, 67.6, 63.0, 55.4, 13.9; Anal.
Calcd for C15H19N2O5S: C, 55.37; H, 5.89; N, 4.30; found:
C, 55.55; H, 5.86; N, 4.54.
3. Conclusion
4.1.3. Diethyl (4-nitrophenyl)thiocarbamoylmalonate
(2d). Diethyl malonate (0.95 mL, 6.24 mmol) gave 2d
(1.70 g, 5.00 mmol) as yellow crystals (80%) mp 87–908C
(lit.11 89–908C). IR 3297, 1746, 1720, 1626, 1580,
The base catalysed rearrangement of the 3-arylamino-
isoxazolones provides indoles and imidazo heterocycles
which are clearly suitable synthetic intermediates for a
series of new planar polycyclic heterocycles that could be
expected to intercalate with DNA.8,9
1520 cm21 1H NMR d 11.20 (bs, 1H), 8.24–8.35 (m,
;
2H), 8.05–8.17 (m, 2H), 5.09 (s, 1H), 4.31 (q, 4H,
J¼7.2 Hz), 1.33 (t, 6H, J¼7.2 Hz); 13C NMR d 188.4,
165.6, 145.2, 143.8, 124.6, 122.5, 67.8, 63.4, 13.9; Anal.
Calcd for C14H16N2O6S: C, 49.41; H, 4.74; N, 8.23; found:
C, 49.50; H, 4.90; N, 8.30.
4. Experimental
4.1. General procedures
4.1.4. Diethyl (4-methylphenyl)thiocarbamoylmalonate
(2e). Diethyl malonate (0.95 mL, 6.24 mmol) gave 2e
(1.20 g, 3.87 mmol) as yellow crystals (62%) mp 52–
548C (lit.10 55–568C). IR 3281, 1756, 1721, 1600, 1538,
Melting points were determined on a Reichert hot stage
1
microscope and are uncorrected. H (300 MHz) and 13C
(75.5 MHz) NMR measurements were recorded on a
Gemini Varian 300 spectrometer in deuteriochloroform
with tetramethylsilane as internal standard, unless otherwise
stated. Infrared spectra were recorded on a Perkin Elmer
1600 FT-infrared spectrophotometer, using fused sodium
chloride cells, measured as Nujol mulls or films. Electro-
spray ionisation (ESI) mass spectra were recorded by
Monash University, Melbourne. The protonated molecular
ion (MHþ) mass to charge ratio (m/z) is reported.
Microanalyses were performed by the University of
Otago, New Zealand. X-Ray crystal data were recorded by
the University of Canterbury.
1511 cm21 1H NMR d 10.75 (bs, 1H), 7.63 (d, 2H,
;
J¼8.5 Hz), 7.21 (d, 2H, J¼8.5 Hz), 5.09 (s, 1H), 4.30 (q,
4H, J¼7.2 Hz), 2.36 (s, 3H), 1.33 (t, 6H, J¼7.2 Hz); 13C
NMR d 187.2, 165.8, 137.0, 136.0, 129.4, 123.2, 67.3, 63.0,
21.1, 13.9; Anal. Calcd for C15H19NO4S: C, 58.23; H, 6.19;
N, 4.53; found: C, 58.38; H, 6.27; N, 4.65.
4.1.5. Diethyl (3,5-bistrifluoromethylphenyl)thiocarba-
moylmalonate (2f). Diethyl malonate (0.51 mL,
3.35 mmol) gave 2f (1.12 g, 2.95 mmol) as a yellow solid
(88%) mp 62–648C, after column chromatography. IR
1
3280, 1767, 1717, 1574 cm21; H NMR d 11.14 (bs, 1H),
8.36 (s, 2H), 7.77 (s, 1H), 5.10 (s, 1H), 4.32 (q, 4H,
J¼7.2 Hz), 1.34 (t, 6H, J¼7.2 Hz); 13C NMR d 188.9,
165.6, 139.7, 132.4 (q, J¼34 Hz), 123.0, 122.9 (q,
J¼273 Hz), 120.2, 67.4, 63.4, 13.9; Anal. Calcd for
C16H15F6NO4S: C, 44.55; H, 3.50; N, 3.25; found: C,
44.35; H, 3.79; N, 3.32.
4.1.1. Diethyl (4-methoxyphenyl)thiocarbamoylmalo-
nate (2b). To diethyl malonate (0.948 mL, 6.24 mmol) in
anhydrous THF (8 mL) was added sodium (0.144 g,
6.24 mmol) and the mixture was refluxed under nitrogen
for 2 h. The solution was cooled to room temperature,
4-methoxyphenylisothiocyanate (1.00 mL, 7.24 mmol) was
added dropwise, and the resulting yellow solution was
stirred at room temperature for 1.5 h before being quenched
with ice-cold water. The mixture was extracted with Et2O
(3£30 mL) and the aqueous phase was added dropwise to
vigorously stirred, ice-cold 1 M HCl (100 mL), yielding a
yellow precipitate. The precipitate was washed with water
and recrystallised from ethanol/light petroleum (1:1) to give
the thiocarbamate as yellow crystals (1.80 g, 5.55 mmol;
89%) mp 56–588C (lit.10 58.5–59.58C). IR 3260, 1760,
4.1.6. Diethyl (2,4-dimethoxyphenyl)thiocarbamoyl-
malonate (2g). Diethyl malonate (2.12 mL, 14.0 mmol)
gave 2g (4.36 g, 12.3 mmol) as yellow needles (88%) mp
86–878C. IR 3304, 1749, 1616, 1549, 1502, 1439, 1412,
1288, 1209, 1160, 1128, 1030 cm21; 1H NMR d 11.05 (bs,
1H), 8.86 (d, 1H, J¼9.4 Hz), 6.49 (m, 2H), 5.06 (s, 1H),
4.28 (q, 4H, J¼7.1 Hz), 3.90 (s, 3H), 3.81 (s, 3H), 1.31 (t,
6H, J¼7.1 Hz); 13C NMR d 184.4, 165.6, 158.6, 151.9,
123.0, 121.9, 103.1, 98.8, 68.2, 62.8, 56.2, 55.5, 13.9; Anal.
Calcd for C16H21NO6S: C, 54.07; H, 5.96; N, 3.94; found:
C, 53.78; H, 5.73; N, 3.98.
1
1717, 1613, 1534, 1511 cm21; H NMR d 10.71 (bs, 1H),
7.60–7.75 (m, 2H), 6.85–7.00 (m, 2H), 5.08 (s, 1H), 4.29
(q, 4H, J¼7.2 Hz), 3.81 (s, 3H), 1.32 (t, 6H, J¼7.2 Hz); 13C
NMR d 187.0, 165.8, 158.2, 131.6, 124.8, 114.0, 67.1, 63.0,
55.5, 13.9; Anal. Calcd for C15H19NO5S: C, 55.37; H, 5.89;
N, 4.30; found: C, 55.63; H, 5.91; N, 4.54.
4.1.7. Ethyl 3-(3-methoxyphenyl)amino-5-oxo-2,5-di-
hydroisoxazole-4-carboxylate (3c). Hydroxyammonium
chloride (0.214 g, 3.08 mmol) was dissolved in ethanol
(4 mL)/water (2 mL) and then neutralised with potassium
hydrogen carbonate (0.308 g, 3.08 mmol).3 The filtered
solution was added to the thiocarbamate (0.500 g,
1.54 mmol) and the mixture was refluxed for 17 h before
being cooled to room temperature. The reaction mixture was
quenched with 1 M HCl (5 mL) and extracted with CH2Cl2
(3£50 mL) and the extract dried (MgSO4). The solvent was
removed in vacuo yielding a yellow solid which was
recrystallised from ethanol to give isoxazolone 3c (320 mg,
The thiocarbamates below were made by the same
procedure.
4.1.2. Diethyl (3-methoxyphenyl)thiocarbamoylmalo-
nate (2c). Diethyl malonate (0.95 mL, 6.24 mmol) gave
2c (1.47 g, 4.49 mmol) as a yellow oil (72%). IR 3300,
1734, 1596, 1559, 1490, 1405 cm21; 1H NMR d 10.83 (bs,
1H), 7.61–7.65 (m, 1H), 7.18–7.35 (m, 2H), 6.78–6.87 (m,
1H), 5.08 (s, 1H), 4.29 (q, 4H, J¼7.1 Hz), 3.81 (s, 3H), 1.32

D. Jeffery et al. / Tetrahedron 58 (2002) 9965–9972
9969
1.16 mmol) as yellow needles (75%) mp 64–668C. IR 3309,
1732, 1674, 1586, 1557, 1495 cm21 1H NMR (CDCl3/
1751, 1671, 1619, 1588, 1514, 1438, 1324, 1210, 1200,
1107, 1029 cm21; H NMR d 9.62 (bs, 1H), 9.20 (bs, 1H),
1
;
TFA) d 10.20 (bs, 1H), 7.28–7.40 (m, 1H), 6.78–6.92 (m,
3H), 4.35 (q, 2H, J¼7.2 Hz), 3.83 (s, 3H), 1.37 (t, 3H,
J¼7.2 Hz); 13C NMR (CDCl3/TFA) d 169.7, 165.2, 163.9,
160.7, 135.5, 131.2, 114.5, 113.3, 108.5, 76.6, 61.8, 55.6,
13.9; Anal. Calcd for (C13H14N2O5)2H2S: C, 52.88; H, 5.12;
N, 9.49; found: C, 52.84; H, 5.46; N, 9.43.
7.24 (d, 1H, J¼7.8 Hz), 6.46–6.53 (m, 2H), 4.32 (q, 2H,
J¼7.1 Hz), 3.88 (s, 3H), 3.79 (s, 3H),1.35 (t, 3H, J¼7.1 Hz);
13C NMR d 167.2, 165.8, 165.2, 159.3, 152.3, 123.5, 117.6,
104.8, 99.9, 75.9, 60.4, 56.2, 55.6, 14.4; Anal. Calcd for
C14H16N2O6: C, 54.54; H, 5.23; N, 9.09; found: C, 54.48; H,
4.97; N, 8.89.
The compounds below were prepared by the same
procedure.
4.1.13. Ethyl 3-(4-methoxyphenyl)amino-2-(5-nitro-
pyrid-2-yl)-5-oxo-2,5-dihydroisoxazole-4-carboxylate
(4b). Isoxazolone 3b (100 mg, 0.359 mmol) and 2-chloro-5-
nitropyridine (0.063 g, 0.395 mmol) were heated neat in a
sealed vial flushed with nitrogen in a 1308C oven for 1 h.
The resulting product was recrystallised from ethanol to
give the isoxazolone as yellow crystals (84 mg,
0.208 mmol; 58%) mp 158–1618C. IR 1778, 1673, 1605,
1513, 1344, 1246 cm21; 1H NMR d 10.24 (bs, 1H), 8.91 (d,
1H, J¼2.6 Hz), 8.52 (dd, 1H, J¼9.0, 2.6 Hz), 7.50 (d, 1H,
J¼9.0 Hz), 7.08 (d, 2H, J¼8.9 Hz), 6.76 (d, 2H, J¼8.9 Hz),
4.24 (q, 2H, J¼7.1 Hz), 3.75 (s, 3H), 1.28 (t, 3H, J¼7.1 Hz);
13C NMR d 163.9, 163.6, 161.2, 158.1, 153.9, 143.6, 141.7,
134.2, 130.3, 124.0, 115.4, 114.5, 78.6, 61.0, 55.5, 14.3;
Anal. Calcd for C18H16N4O7: C, 54.00; H, 4.03; N, 13.99;
found: C, 53.54; H, 3.92; N, 14.01.
4.1.8. Ethyl 3-(4-methoxyphenyl)amino-5-oxo-2,5-dihy-
droisoxazole-4-carboxylate (3b). Thiocarbamate 2b
(500 mg, 1.54 mmol) gave 3b (229 mg, 0.83 mmol) as
yellow needles (54%) mp 163–1658C (accompanied by
bubbling). IR 3295, 1733, 1668, 1615, 1557, 1514 cm21; 1H
NMR (CDCl3/TFA) d 9.45 (bs, 1H), 7.17–7.28 (m, 2H),
6.89–7.01 (m, 2H), 4.32 (q, 2H, J¼7.2 Hz), 3.83 (s, 3H),
1.35 (t, 3H, J¼7.2 Hz); 13C NMR (CDCl3/TFA) d 169.9,
165.2, 164.8, 159.1, 126.8, 125.3, 115.4, 76.3, 61.6, 55.6,
14.0; Anal. Calcd for (C13H14N2O5)2H2S: C, 52.88; H, 5.12;
N, 9.49; found: C, 52.19; H, 4.79; N, 9.26.
4.1.9. Ethyl 3-(4-nitrophenyl)amino-5-oxo-2,5-dihydro-
isoxazole-4-carboxylate (3d). Thiocarbamate 2d (500 mg,
1.47 mmol) gave 3d (347 mg, 1.18 mmol) as yellow crystals
(80%) mp 161–1638C. IR 3457, 1721, 1623, 1587, 1509,
1345 cm21; 1H NMR (CDCl3/TFA) d 9.70 (bs, 1H), 8.33 (d,
2H, J¼9.0 Hz), 7.50 (d, 2H, J¼9.0 Hz), 4.38 (q, 2H,
J¼7.1 Hz), 1.39 (t, 3H, J¼7.1 Hz); 13C NMR (CDCl3/TFA)
d 169.8, 165.2, 163.4, 145.4, 140.7, 126.0, 121.7, 77.9, 62.5,
13.9; Anal. Calcd for (C12H11N3O6)2H2S: C, 46.45; H, 3.90;
N, 13.54; found: C, 47.91; H, 4.02; N, 13.77.
The compounds below were prepared by the same method.
4.1.14. Ethyl 3-(3-methoxyphenyl)amino-2-(5-nitro-
pyrid-2-yl)-5-oxo-2,5-dihydroisoxazole-4-carboxylate
(4c). Isoxazolone 3c (100 mg, 0.359 mmol) gave 4c (78 mg,
0.194 mmol) as orange crystals (54%) mp 164–1688C. IR
3583, 1780, 1700, 1669, 1602, 1496, 1456, 1338 cm21; 1H
NMR d 10.35 (bs, 1H), 8.91 (d, 1H, J¼2.6 Hz), 8.55 (dd,
1H, J¼9.1, 2.6 Hz), 7.54 (d, 1H, J¼9.1 Hz), 7.10–7.18 (m,
1H), 6.64–6.74 (m, 3H), 4.22 (q, 2H, J¼7.1 Hz), 3.73 (s,
3H), 1.25 (t, 3H, J¼7.1 Hz); 13C NMR d 163.7, 163.0,
160.4, 160.2, 153.9, 143.5, 141.5, 138.6, 134.3, 130.1,
114.9, 114.1, 111.9, 108.0, 79.0, 61.0, 55.4, 14.2; Anal.
Calcd for C18H16N4O7: C, 54.00; H, 4.03; N, 13.99; found:
C, 54.19; H, 3.92; N, 13.74.
4.1.10. Ethyl 3-(4-methylphenyl)amino-5-oxo-2,5-dihy-
droisoxazole-4-carboxylate (3e). Thiocarbamate 2e
(500 mg, 1.62 mmol) gave 3e (308 mg, 1.18 mmol) as
yellow crystals (73%) mp 166–1688C (accompanied by
bubbling). IR 3302, 1732, 1668, 1606, 1580, 1516 cm21; 1H
NMR (CDCl3/TFA) d 9.10 (bs, 1H), 7.24 (d, 2H, J¼8.6 Hz),
7.16 (d, 2H, J¼8.6 Hz), 4.31 (q, 2H, J¼7.2 Hz), 2.36 (s,
3H), 1.34 (t, 3H, J¼7.2 Hz); 13C NMR (CDCl3/TFA) d
169.8, 165.1, 164.4, 138.1, 131.6, 130.7, 122.8, 76.4, 61.5,
20.9, 14.0; Anal. Calcd for (C13H14N2O4)2H2S: C, 55.90; H,
5.41; N, 10.03; found: C, 55.23; H, 5.01; N, 9.86.
4.1.15. Ethyl 3-(4-nitrophenyl)amino-2-(5-nitropyrid-2-
yl)-5-oxo-2,5-dihydroisoxazole-4-carboxylate
(4d).
Isoxazolone 3d (100 mg, 0.341 mmol) gave 4d (65 mg,
0.157 mmol) as cream crystals (46%) mp 225–2288C. IR
3434, 1778, 1691, 1601, 1563, 1530, 1342 cm21; 1H NMR
(CDCl3/TFA) d 10.88 (bs, 1H), 9.04 (d, 1H, J¼2.3 Hz), 8.70
(dd, 1H, J¼9.1, 2.3 Hz), 8.23 (d, 2H, J¼8.8 Hz), 7.67 (d,
1H, J¼9.1 Hz), 7.36 (d, 2H, J¼8.8 Hz), 4.19 (q, 2H,
J¼7.1 Hz), 1.19 (t, 3H, J¼7.1 Hz); 13C NMR (CDCl3/TFA)
d 165.6, 163.5, 158.4, 153.0, 145.4, 143.7, 143.0, 142.0,
135.5, 125.3, 122.1, 114.1, 80.8, 62.5, 13.7; Anal. Calcd for
C17H13N5O8: C, 49.16; H, 3.15; N, 16.86; found: C, 48.60;
H, 2.91; N, 16.22.
4.1.11. Ethyl 3-(3,5-bistrifluoromethylphenyl)amino-5-
oxo-2,5-dihydroisoxazole-4-carboxylate (3f). Thiocarba-
mate 2f (350 mg, 0.81 mmol) gave 3f (288 mg, 0.74 mmol)
as white crystals (92%) sub. 1608C, dec. 2008C. IR 3238,
1
1716, 1674, 1586, 1538 cm21; H NMR (CDCl3/TFA) d
9.60 (bs, 1H), 7.82 (bs, 3H), 4.38 (q, 2H, J¼7.2 Hz), 1.38 (t,
3H, J¼7.2 Hz); 13C NMR (CDCl3/TFA) d 170.0, 165.2,
163.7, 136.2, 134.0 (q, J¼34 Hz), 122.8, 122.5 (q,
J¼273 Hz), 121.1, 77.5, 62.5, 13.8; Anal. Calcd for
C14H10F6N2O4: C, 43.76; H, 2.62; N, 7.29; found: C,
43.89; H, 2.62; N, 7.24.
4.1.16. Ethyl 3-(4-methylphenyl)amino-2-(5-nitropyrid-
2-yl)-5-oxo-2,5-dihydroisoxazole-4-carboxylate
(4e).
Isoxazolone 3e (100 mg, 0.381 mmol) gave 4e (84 mg,
0.221 mmol) as orange needles (58%)† mp 59–618C. IR
4.1.12. Ethyl 3-(2,4-dimethoxyphenyl)amino-5-oxo-2,5-
dihydroisoxazole-4-carboxylate (3g). Thiocarbamate 2g
(2.00 g, 5.63 mmol) gave 3g (1.34 g, 4.22 mmol) as white
needles (75%) from CH2Cl2/petroleum, mp 146–1488C. IR
†
Direct crystallisation gave the H2S complex, mp 150–1538C.
Chromatography yielded the uncomplexed material.

9970
D. Jeffery et al. / Tetrahedron 58 (2002) 9965–9972
3389, 1780, 1669, 1602, 1525, 1456, 1419, 1337 cm21; 1H
NMR d 10.31 (bs, 1H), 8.89 (d, 1H, J¼2.7 Hz), 8.53 (dd,
1H, J¼9.1, 2.7 Hz), 7.52 (d, 1H, J¼9.1 Hz), 7.03 (bs, 4H),
4.23 (q, 2H, J¼7.1 Hz), 2.27 (s, 3H), 1.26 (t, 3H, J¼7.1 Hz);
13C NMR d 163.8, 163.1, 160.6, 153.9, 143.5, 141.5, 136.4,
135.0, 134.2, 129.9, 122.0, 115.0, 78.7, 60.9, 20.9, 14.2;
Anal. Calcd for C18H16N4O6: C, 56.25; H, 4.20; N, 14.58;
found: C, 56.56; H, 4.19; N, 14.23.
Imidazopyridine (6b): mp 163–1668C. IR 3400, 1684,
1654, 1625, 1580, 1513, 1481, 1343, 1311, 1206,
1
1084 cm21; H NMR d 9.89 (bs, 1H), 8.68 (bs, 1H), 8.12
(dd, 1H, J¼9.8, 2.0 Hz), 7.58 (d, 2H, J¼8.9 Hz), 7.47 (d,
1H, J¼9.8 Hz), 6.92 (d, 2H, J¼8.9 Hz), 4.54 (q, 2H,
J¼7.1 Hz), 3.82 (s, 3H), 1.53 (t, 3H, J¼7.1 Hz); 13C NMR d
160.7, 155.8, 147.1, 136.8, 132.5, 126.8, 122.4, 121.0,
114.4, 113.8, 98.4, 61.0, 55.6, 14.6 (carbonyl unsighted);
HRMS calculated for C17H17N4O5 (MHþ): 357.1199;
found: 357.1204.
4.1.17. Ethyl 3-(3,5-bistrifluoromethylphenyl)amino-2-
(5-nitropyrid-2-yl)-5-oxo-2,5-dihydroisoxazole-4-car-
boxylate (4f). Isoxazolone 3f (70 mg, 0.182 mmol) gave 4f
(37 mg, 0.073 mmol) as white crystals (40%) mp 185–
1908C (sub. from 1668C). IR 1799, 1696, 1608, 1585, 1561,
4.1.20. Ethyl 6-nitro-2-(3-methoxyphenyl)amino-
imidazo[1,2-a]pyridine-3-carboxylate (6c). The above
procedure with 4c (0.040 g, 0.100 mmol) gave 6c as orange
crystals (0.023 g, 0.064 mmol; 64%) mp 171–1748C. IR
3392, 1679, 1604, 1580, 1548, 1486, 1346, 1315, 1200,
1515, 1348, 1288, 1186, 1127 cm21 1H NMR (CDCl3/
;
TFA) d 11.03 (bs, 1H), 9.08 (d, 1H, J¼2.4 Hz), 8.70 (dd,
1H, J¼9.0, 2.4 Hz), 7.73 (s, 1H), 7.71 (d, 1H, J¼9.0 Hz),
7.64 (s, 2H), 4.13 (q, 2H, J¼7.1 Hz), 1.15 (t, 3H, J¼7.1 Hz);
13C NMR (CDCl3/TFA) d 164.1, 162.8, 158.2, 153.2, 143.6,
141.7, 138.9, 135.4, 133.0 (q, J¼34 Hz), 122.5 (q,
J¼273 Hz), 122.2, 119.8, 113.8, 80.3, 61.9, 13.8; Anal.
Calcd for C19H12F6N4O6: C, 45.07; H, 2.39; N, 11.07;
found: C, 45.06; H, 2.13; N, 10.93.
1
1162, 1102 cm21; H NMR d 9.85 (bs, 1H), 8.89 (bs, 1H),
8.14 (dd, 1H, J¼9.5, 2.2 Hz), 7.51 (d, 1H, J¼9.5 Hz), 7.42–
7.47 (m, 1H), 7.13–7.30 (m, 2H), 6.57–6.66 (m, 1H), 4.55
(q, 2H, J¼7.1 Hz), 3.85 (s, 3H), 1.54 (t, 3H, J¼7.1 Hz); 13C
NMR d 160.4, 146.9, 140.5, 137.0, 129.9, 126.9, 122.4,
114.1, 111.2, 108.0, 104.9, 99.0, 61.1, 55.3, 14.6 (two
carbons unsighted); HRMS calculated for C17H17N4O5
(MHþ): 357.1199; found: 357.1195.
4.1.18. Ethyl 3-(2,4-dimethoxyphenyl)amino-2-(5-nitro-
pyrid-2-yl)-5-oxo-2,5-dihydroisoxazole-4-carboxylate
(4g). Isoxazolone 3g (250 mg, 0.811 mmol) gave 4g
(138 mg, 0.324 mmol) as yellow needles (40%) mp 182–
1868C. IR 1780, 1670, 1607, 1593, 1558, 1517, 1458, 1343,
1288, 1210, 1030 cm21; 1H NMR d 10.20 (bs, 1H), 8.90 (d,
1H, J¼2.2 Hz), 8.52 (dd, 1H, J¼9.0, 2.2 Hz), 7.50 (d, 1H,
J¼9.0 Hz), 6.97 (d, 1H, J¼8.9 Hz), 6.44 (d, 1H, J¼1.9 Hz),
6.26 (dd, 1H, J¼8.9, 1.9 Hz), 4.24 (q, 2H, J¼7.1 Hz), 3.86
(s, 3H), 3.74 (s, 3H), 1.28 (t, 3H, J¼7.1 Hz); 13C NMR d
163.7, 163.3, 160.5, 159.1, 154.0, 152.8, 143.5, 141.4,
134.1, 123.2, 119.7, 114.8, 104.0, 99.0, 78.6, 60.8, 55.9,
55.5, 14.3; Anal. Calcd for C19H18N4O8: C, 53.03; H, 4.22;
N, 13.02; found: C, 53.21; H, 4.23; N, 13.00.
4.1.21. Ethyl 6-nitro-2-(4-methylphenyl)amino-
imidazo[1,2-a]pyridine-3-carboxylate (6e). The above
procedure with 4e (0.050 g, 0.130 mmol) gave 6e as red
crystals (0.021 g, 0.062 mmol; 48%) mp 183–1878C. IR
3387, 1691, 1664, 1622, 1577, 1480, 1343, 1313, 1207,
1
1082 cm21; H NMR d 9.82 (bs, 1H), 8.78 (bs, 1H), 8.12
(dd, 1H, J¼9.7, 2.2 Hz), 7.55 (d, 2H, J¼8.2 Hz), 7.48 (d,
1H, J¼9.7 Hz), 7.16 (d, 2H, J¼8.2 Hz), 4.54 (q, 2H,
J¼7.1 Hz), 2.33 (s, 3H), 1.53 (t, 3H, J¼7.1 Hz); 13C NMR d
160.8, 147.0, 136.8, 136.7, 132.6, 129.7, 126.8, 122.4,
119.0, 113.9, 98.6, 61.0, 20.8, 14.6 (carbonyl unsighted);
Anal. Calcd for C17H16N4O4: C, 60.00; H, 4.74; N, 16.46;
found: C, 59.52; H, 4.73; N, 16.03.
4.1.19. Ethyl 2-(4-methoxyphenyl)amino-6-nitro-
imidazo[1,2-a]pyridine-3-carboxylate (6b) and ethyl
5-methoxy-2-(5-nitropyridyl-2-amino)indole-3-carboxyl-
ate (7b). N-aryl isoxazolone 4b (0.050 g, 0.125 mmol) and
potassium carbonate (0.086 g, 0.624 mmol) were refluxed in
ethanol (2 mL) for 1 h. After 15 min the solution turned from
orange to red. The solution was cooled, quenched with 1 M
HCl (5 mL) and extracted with CH2Cl2 (3£25 mL). The
organic extracts were washed with brine (1£20 mL), dried
(MgSO4), and evaporated, yielding a red solid which was
purified by flash chromatography on silica gel (CH2Cl2) to
firstlyelutetheindole7basanorangesolid(0.010 g, 23%)and
secondly the imidazopyridine 6b as a red solid (0.023 g, 52%).
4.1.22. Ethyl 6-nitro-2-(3,5-bistrifluoromethylphenyl)-
aminoimidazo[1,2-a]pyridine-3-carboxylate (6f). The
above procedure with 4f (0.020 g, 0.100 mmol) gave 6f
as yellow crystals (0.011 g, 0.061 mmol; 61%)
sublimes .1428C. IR 3393, 1674, 1625, 1598, 1473,
1380, 1345, 1315, 1276, 1176, 1124, 1087 cm21 1H
;
NMR d 9.94 (bs, 1H), 9.29 (bs, 1H), 8.28 (bs, 2H), 8.24
(dd, 1H, J¼9.6, 2.0 Hz), 7.66 (d, 1H, J¼9.6 Hz), 7.54
(bs, 1H), 4.61 (q, 2H, J¼7.2 Hz), 1.57 (t, 3H, J¼7.2 Hz);
13C NMR d 146.5, 140.9, 137.6, 132.5 (q, J¼33 Hz),
127.0, 123.3 (q, J¼273 Hz), 122.7, 118.0, 115.5, 115.0,
99.8, 61.6, 14.6 (two carbons unsighted); HRMS
calculated for C18H13F6N4O4 (MHþ): 463.0841; found:
463.0842.
Indole (7b): mp 209–2138C. IR 1654, 1637, 1607, 1560,
1507, 1491, 1458, 1342, 1323, 1212 cm21; 1H NMR d 11.41
(bs, 1H), 10.65 (bs, 1H), 9.21 (d, 1H, J¼2.7 Hz), 8.37 (dd,
1H, J¼9.4, 2.7 Hz), 7.40 (d, 1H, J¼2.5 Hz), 7.29 (d, 1H,
J¼8.8 Hz), 6.87 (d, 1H, J¼9.4 Hz), 6.83 (dd, 1H, J¼8.8,
2.5 Hz), 4.44 (q, 2H, J¼7.1 Hz), 3.88 (s, 3H), 1.49 (t, 3H,
J¼7.1 Hz); 13C NMR d 167.8, 156.2, 156.1, 145.2, 144.8,
138.3, 133.4, 126.5, 125.3, 111.7, 111.3, 110.6, 103.6, 89.6,
60.0, 55.8, 14.6; Anal. Calcd for C17H16N4O5: C, 57.30; H,
4.53; N, 15.72; found: C, 57.17; H, 4.39; N, 15.49.
4.1.23. Ethyl 6-nitro-2-(2,4-dimethoxyphenyl)amino-
imidazo[1,2-a]pyridine-3-carboxylate (6g) and ethyl
5,7-dimethoxy-2-(5-nitropyridyl-2-amino)indole-3-car-
boxylate (7g). The above procedure with 4g (0.050 g,
0.116 mmol) gave a red solid which was purified by flash
chromatography on silica gel (5:1 CH2Cl2/petroleum) to
firstly elute the indole 7g as yellow needles (0.013 g, 29%)
and secondly the imidazopyridine (6g) as red needles
(0.021 g, 47%).

D. Jeffery et al. / Tetrahedron 58 (2002) 9965–9972
9971
Indole (7g): mp 250–2538C. IR 3355, 1659, 1615, 1604,
1570, 1507, 1345, 1326, 1307, 1286, 1207 cm21; 1H NMR d
11.38 (bs, 1H), 10.61 (bs, 1H), 9.26 (d, 1H, J¼2.6 Hz), 8.37
(dd, 1H, J¼9.0, 2.6 Hz), 6.99 (d, 1H, J¼1.8 Hz), 6.86 (d,
1H, J¼9.0 Hz), 6.36 (d, 1H, J¼1.8 Hz), 4.43 (q, 2H,
J¼7.1 Hz), 3.97 (s, 3H), 3.88 (s, 3H), 1.49 (t, 3H,
J¼7.1 Hz); 13C NMR d 167.9, 157.0, 156.2, 146.1, 145.4,
143.7, 138.2, 133.2, 125.6, 116.5, 111.1, 94.8, 94.0, 90.3,
60.0, 55.8, 55.5, 14.6; HRMS calculated for C18H19N4O6
(MHþ): 387.1305; found: 387.1304.
118.5, 116.6, 104.2, 96.0, 95.3, 94.5, 60.4, 55.8, 55.7, 20.5,
14.4; HRMS calculated for C23H24N3O4 (MHþ): 406.1766;
found: 406.1767.
Chromatography of the original product on alumina gave
15a as orange plates after crystallisation from dilute ethanol
1
solution. H NMR d 8.12 (d, 1H, J¼8.0 Hz), 8.02 (d, 1H,
J¼8.0 Hz), 7.67 (t, 1H, J¼7.7 Hz), 7.51 (t, 1H, J¼7.7 Hz),
7.22 (s, 1H), 7.04 (d, 1H, J¼2.0 Hz), 6.37 (d, 1H,
J¼2.0 Hz), 4.42 (q, 2H, J¼7.1 Hz), 3.94 (s, 3H), 3.89 (s,
3H), 2.72 (s, 3H), 1.45 (t, 3H, J¼7.1 Hz). Crystallisation
from dichloromethane gave 15, identical with the sample
above.
Imidazopyridine (6g): mp 218–2218C. IR 3377, 1679,
1577, 1550, 1482, 1464, 1346, 1318, 1298, 1201,
1
1098 cm21; H NMR d 10.04 (bs, 1H), 9.13 (bs, 1H), 8.47
(d, 1H, J¼9.4 Hz), 8.12 (dd, 1H, J¼9.7, 2.4 Hz), 7.47 (d,
1H, J¼9.7 Hz), 6.54–6.58 (m, 2H), 4.53 (q, 2H, J¼7.1 Hz),
3.93 (s, 3H), 3.82 (s, 3H), 1.54 (t, 3H, J¼7.1 Hz); 13C NMR
d 160.5, 155.4, 149.0, 147.2, 136.8, 126.6, 122.9, 122.3,
118.5, 113.6, 104.0, 98.8, 98.7, 60.8, 55.8, 55.6, 14.5
(carbonyl unsighted); HRMS calculated for C18H19N4O6
(MHþ): 387.1305; found: 387.1302.
A second product, 16, was eluted with ethyl acetate as a
yellow powder. IR (film) 3290, 1717, 1683, 1605 cm21; 1H
NMR (conc. dependent) d 10.8 (bs, 1H), 8.5 (bs, 1H), 8.17
(s, 1H), 8.07 (d, 1H, J¼8 Hz), 7.92 (d, 1H, J¼8 Hz), 7.82 (d,
1H, J¼8 Hz), 7.50 (t, 1H, J¼8 Hz), 7.24 (t, 1H, J¼8 Hz),
6.42 (dd, 1H, J¼10, 2 Hz), 6.38 (d, 1H, J¼2 Hz), 3.80 (s,
3H), 3.76 (s, 3H), 2.70 (s, 3H); 13C NMR d 158.9, 157.3,
153.1, 151.5, 146.1, 144.6, 130.1, 126.8, 125.6, 122.9,
120.9, 120.2, 118.7, 109.6, 104.1, 99.0, 55.5, 24.3; HRMS
calculated for C19H20N3O3 (MHþ): 338.1504; found:
338.1494.
4.1.24. Ethyl 3-(2,4-dimethoxyphenyl)amino-2-(3-
methylquinolin-4-yl)-5-oxo-2,5-dihydroisoxazole-4-car-
boxylate (14). The isoxazolone 3g (0.500 g, 1.62 mmol)
and 4-chloroquinaldine (0.390 mL, 1.95 mmol) were
refluxed in chlorobenzene (15 mL) for 4 h. The solvent
was removed in vacuo yielding a brown solid which was
recrystallised from ethanol to give 14 as brown crystals
(0.426 g, 0.94 mmol; 58%) mp 183–1858C. IR 3277, 2980,
1772, 1670, 1612, 1514, 1497, 1411, 1210, 1041 cm21; 1H
NMR d 9.35 (bs, 1H), 8.03 (dd, 1H, J¼8.2, 1.4 Hz), 7.91
(dd, 1H, J¼8.4, 1.2 Hz), 7.68 (ddd, 1H, J¼8.4, 7.0, 1.4 Hz),
7.54 (ddd, 1H, J¼8.2, 7.0, 1.2 Hz), 6.84 (s, 1H), 6.77 (d, 1H,
J¼8.6 Hz), 5.98 (d, 1H, J¼2.6 Hz), 5.83 (dd, 1H, J¼8.6,
2.6 Hz), 4.44 (q, 2H, J¼7.1 Hz), 3.55 (s, 3H), 3.50 (s, 3H),
2.51 (s, 3H), 1.43 (t, 3H, J¼7.1 Hz); 13C NMR d 165.5,
165.3, 164.5, 159.9, 158.4, 153.6, 148.1, 141.7, 130.7,
128.1, 127.2, 125.9, 123.0, 122.4, 118.0, 116.8, 103.9, 98.6,
77.8, 60.7, 55.43, 55.38, 24.5, 14.5; Anal. Calcd for
C24H23N3O6: C, 64.14; H, 5.16; N, 9.35; found: C, 63.86;
H, 5.28; N, 9.46.
4.2. Cytotoxicity assay
Peripheral blood samples were obtained from a healthy
donor with informed consent. Lymphocytes were separated
from peripheral blood using Ficoll–Hypaque. Unstimulated
lymphocytes were suspended at 1£106 cells mL21 modified
McCoys 311 medium (medium) containing phytohaemag-
glutinin at 10 mg mL21 (PHA) in Sterilin tubes and cultured
with various concentrations of either 6g or 7g (range
0–100 mM) for 24 h at 378C in 10% CO2 in a fully
humidified incubator. The chemical was removed by
washing twice with medium. Surviving cells were counted
by Trypan Blue exclusion and plated into 96 well plates at
100,000 cells/well in medium (200 mL) containing PHA
and cultured in the described conditions. Viable cells in two
replicate wells were counted on days 4–6 or until viability
in the control wells began to diminish significantly. IC50
was calculated as the chemical concentration generating
50% inhibition of growth relative to control wells on the
same micro-well plate at maximum cell number expansion.
To establish cytotoxicity in dividing cells, peripheral T-cells
(1£106 mL21) were incubated in Sterilin tubes in medium
containing PHA for three days. Cells were aliquoted into
tubes at 1£106 mL21 in a conditioned medium (containing a
source of IL-2) for 24 h prior to 24 h exposure to the
chemical (range as above). The chemical was then removed
and the cells plated at 50,000 cells per well in conditioned
medium and counted on days 7–10 as described and the
IC50 was calculated.
4.1.25. Ethyl 5,7-dimethoxy-2-(2-methylquinolyl-4-ami-
no)indole-3-carboxylate (15). N-aryl isoxazolone 14
(0.100 g, 0.222 mmol) and potassium carbonate (0.154 g,
1.11 mmol) were refluxed in water (2 mL)/ethanol (0.5 mL)
for 1 h. The solution was cooled, quenched with 1 M HCl
(5 mL) and extracted with CH2Cl2 (3£50 mL). The organic
extracts were washed with brine (1£30 mL), dried (MgSO4)
and filtered. The solvent was removed in vacuo, yielding a
yellow-brown solid which was recrystallised from CH2Cl2
to give 15 as yellow crystals (0.054 g, 0.67 mmol; 60%) mp
210–2158C (sub. from 1688C). IR (film) 3344, 1643, 1598,
1513, 1441, 1205, 1164, 1122, 1074 cm21; lmax 290 nm (1
964 Lcm21 mol21), 354 (1 1540 Lcm21 mol21), 1400
1
236 Lcm21 mol21. H NMR d 11.81 (bs, 1H), 10.97 (s,
1H), 8.24 (d, 1H, J¼8.4 Hz), 8.01 (d, 1H, J¼8.1 Hz), 7.58
(t, 1H, J¼7.5 Hz), 7.44 (t, 1H, J¼7.5 Hz), 7.33 (s, 1H), 7.00
(d, 1H, J¼2.0 Hz), 6.39 (d, 1H, J¼2.0 Hz), 4.39 (q, 2H,
J¼7.1 Hz), 3.95 (s, 3H), 3.88 (s, 3H), 2.85 (s, 3H), 1.40 (t,
3H, J¼7.1 Hz); 13C NMR d 167.3, 157.1, 155.5, 149.6,
147.0, 139.7, 138.0, 132.9, 127.6, 126.1, 121.3, 120.5,
Acknowledgements
The authors are grateful to the Australian Research Council
for support of this project, and to Dr M. R. Taylor for
determining the X-ray structure of 3e.

9972
D. Jeffery et al. / Tetrahedron 58 (2002) 9965–9972
7. Nishiwaki, N.; Nakawishi, M.; Hida, T.; Miya, Y.; Tamura,
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