Oxygenation of 2,3-dihydroindoles

Article abstract of DOI:10.1016/S0040-4020(02)01198-5

Isatogens (3-oxo-3H-indole 1-oxides) possess interesting biological properties and development of a general method to construct these derivatives has now been developed. Indolines (2,3-dihydroindoles) and isatogens have been prepared in an efficient route starting from indoles substituted in position 2. Reduction of the 2-substituted indoles was performed with tin and hydrochloric acid to give racemic indolines, which were converted to isatogens by 3-chloroperoxybenzoic acid (m-CPBA).

Full text of DOI:10.1016/S0040-4020(02)01198-5

Tetrahedron 58 (2002) 9187–9191
Oxygenation of 2,3-dihydroindoles
*
¨
Johnny Slatt and Jan Bergman
¨ ¨
Unit for Organic Chemistry, Department of Biosciences, Karolinska Institute and Sodertorn University College, Novum Research Park,
SE-141 57 Huddinge, Sweden
Received 22 July 2002; revised 29 August 2002; accepted 19 September 2002
Abstract—Isatogens (3-oxo-3H-indole 1-oxides) possess interesting biological properties and development of a general method to construct
these derivatives has now been developed. Indolines (2,3-dihydroindoles) and isatogens have been prepared in an efficient route starting from
indoles substituted in position 2. Reduction of the 2-substituted indoles was performed with tin and hydrochloric acid to give racemic
indolines, which were converted to isatogens by 3-chloroperoxybenzoic acid (m-CPBA). q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Isatogens, more comprehensively named as 3-oxo-3H-
indole 1-oxides (1), are brightly coloured solids that do
not occur naturally. Although the first isatogen (3-oxo-1-
oxy-3H-indole-2-carboxylic acid ethyl ester) was reported
as early as 1881,1,2 no generally applicable synthetic
methodology is available for this chemically interesting
class of compounds, which have properties similar to those
of quinones.3 Isatogen and indoxyl form adducts analogous
with quinhydrones.4 Isatogens form spin trap adducts
capable of trapping hydroxyl and superoxide radicals.5
Isatogens can readily undergo nucleophilic attack in the
2-position.6 In mammalian systems isatogens are known as
inhibitors of the synthesis of adenosine triphosphate (ATP)
from mitocondrial preparations.7 Many isatogens are
antifungal8 and augment smooth muscle dilatation.9 In
vitro screening tests have shown that isatogens possess
moderate antibacterial effects (Fig. 1).10
Direct oxidation of indole to isatogen is only possible if
MoO5·HMPA is used.11 Isatogens have most frequently
been synthesised via alkynic derivatives such as 2.
Scheme 1.
¨
Krohnke’s route via pyridinium salt 3 is also commonly
used. A less common route goes via a-(o-nitrobenzoyl)-b-
morpholinostyrenes (4).12 Sometimes the cyclisation, 5 to 1,
is useful (Scheme 1).13
Oxidative transformations of 2,3-dihydroindoles (indolines)
to isatogens have only briefly been indicated as a useful
route.14–17 Reductions of indole or 2-alkylindole have been
performed in acetic acid with sodium cyanoborohydride,
whereas 2-phenylindoles require a stronger acid.18–21
Enantioselective reduction is also possible but requires
high pressure and use of the [Rh(nbd)2]SbF6 complex.22
Indoline derivatives are also useful precursors for
1-hydroxyindoles23 which gives isatogen when oxidised
with benzoperoxoic acid.17,24
Figure 1.
Keywords: isatogen; 2,3-dihydroindoles; quinhydrones.
*
Corresponding author. Tel.: þ46-8-608-9204; fax: þ46-8-608-1501;
e-mail: jabe@biosci.ki.se
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01198-5

¨
J. Slatt, J. Bergman / Tetrahedron 58 (2002) 9187–9191
9188
AcOH 8 drops and heated for 1 h at 808C. The solvent was
evaporated to yield a grey solid, which was added to PPA
(50 ml) and an exothermic reaction ensured whereupon the
mixture was heated slowly to 1208C and kept at this
temperature for 1 h. The mixture was poured into ice and
neutralised with 2 M NaOH to give a beige solid which was
collected and dried. Yield 18.0 g (80.6%). Mp. 233–2348C
(Lit.,25 232–2338C). IR (KBr) 3431.1, 1607.5, 1545.4,
1499.8, 1454.0, 1431.0, 1397.3, 1350.3, 1310.0, 1287.8,
1254.1, 1180.7, 1113.2, 1051.3, 1026.5, 833.6, 786.1, 748.9,
739.9, 529.6 cm21. 1H NMR (DMSO-d6) 3.83 (s, 3H), 6.74
(s, 1H), 6.94–7.07 (m, 4H), 7.35–7.37 (m, 1H), 7.77–7.80
(m, 1H), 7.78–7.81 (m, 2H), 11.45 (1H, br s) ppm. 13C
NMR (DMSO-d6) 55.1, 97.2, 111.0, 114.3, 119.1, 119.6,
120.9, 124.9, 126.3, 128.8, 136.9, 137.7, 158.7 ppm.
Scheme 2.
2. Results and discussion
4.1.2. 2-(3-Methoxyphenyl)-1H-indole (6c). 3-Methoxy-
acetophenone (5.5 g, 36.6 mmol) and phenylhydrazine
(3.6 ml, 36.6 mmol) were added to a mixture with EtOH
(10 ml) and glacial AcOH 10 drops. The phenylhydrazone
obtained was then treated as described for compound 6b.
Yield 6.7 g (81.9%). Mp 1318C (Lit.,26 1418C). IR (KBr)
3393.9, 1601.2, 1481.8, 1434.1, 1349.9, 1303.0, 1263.8,
1219.8, 1175.7, 1165.2, 1088.1, 1036.4, 851.5, 808.7, 783.8,
We have, via Fischer indole synthesis, obtained 2-phenyl-
indoles 6 in good yields. This reaction works very well with
electron donating precursors. If the synthesis is performed
via the phenylhydrazone the yields become higher, and the
products are generally very pure and no further purification
is necessary. Reductions of indoles 6 to indoline derivatives
7 has been performed in a mixture containing hydrochloric
acid, ethanol and excess of tin. The indolines obtained are
often very pure, and if not they can easily be purified by
distillation. Oxidation of the indolines with 3 equiv. of
m-CPBA in methanol gave the corresponding isatogens 8.
Pure products could be obtained by flash column chroma-
tography with hexane and ethyl acetate (80/20) as eluent.
Recrystallisation in a polar solvent like ethanol often gave
crystals as long brightly coloured needles (Scheme 2).
1
757.8, 677.8, 506.2 cm21. H NMR (DMSO-d6) 3.84 (s
1H), 6.87–6.92 (m, 2H), 6.97–7.02 (m, 1H), 7.08–7.12 (m,
1H), 7.33–7.46 (m, 4H), 7.51–7.54 (m, 1H), 11.51 (s,
NH) ppm. 13C NMR (DMSO-d6) 3.84, 55.1, 98.9, 110.3,
111.2, 113.0, 117.4, 119.3, 120.0, 121.6, 128.5, 129.9,
133.5, 137.0, 137.4, 159.7 ppm.
4.1.3. 2-(3,4-Dimethoxyphenyl)-1H-indole (6d). 3,4-
Dimethoxyacetophenone (3.0 g, 16.7 mmol) and phenyl-
hydrazine (1.6 ml, 16.7 mmol) were added to a mixture of
EtOH (10 ml) and glacial AcOH 5 drops and heated
subsequently 808C 1 h. The solvent was evaporated to
give a yellow solid. PPA (10 ml) was added and the mixture
was heated at 1208C for 15 min and poured on ice and
neutralised with 2 M NaOH to give a yellow solid. Yield
2.21 g (60%). Mp 184–1858C (Lit.,27 185–1868C). IR
(KBr) 3372.2, 1592.1, 1507.3, 1455.7, 1345.7, 1259.1,
a
b
c
d
e
f
R1
H
H
H
OH
H
R2
H
R3
H
6 (%)
–
7 (%)
87.1
55.2
69.6
47.2
97.3
8 (%)
68.0
63.5
53.0
64.0
60.0
H
OMe
OMe
H
80.6
60.0
99.3
99.1
OMe
H
H
Cl
1164.2, 1141.9, 1020.7, 897.2, 797.0, 750.3, 518.0 cm21
.
1H NMR (DMSO-d6) 3.79 (s, 3H), 3.86 (s, 3H), 6.80 (s, 1H),
6.94–7.08 (m, 3H), 7.36–7.50 (m, 4H), 11.42 (bs,
NH) ppm. 13C NMR (DMSO-d6) 55.6, 55.7, 97.7, 109.0,
111.0, 112.2, 117.2, 119.3, 119.7, 121.1, 125.2, 128.8,
136.9, 138.0, 148.5, 149.1 ppm.
3. Conclusion
In summary, we have demonstrated the application and
versatility of 2-substituted indolines 7 as precursors for
2-substituted isatogen derivatives 8.
4.1.4. 2-(1H-Indol-2-yl)-phenol (6e). 2-Hydroxyaceto-
phenone (5.95 g, 43.7 mmol) and phenylhydrazine (4.2 ml,
43.7) were added to a mixture of EtOH (20 ml) and glacial
AcOH 8 drops, and then treated with PPA (25 ml) as
described above. Yield 9.08 g (99.3%). Mp 1678C (Lit.,28
1808C). IR (KBr) 3426.6, 1606.4, 1481.3, 1460.0, 1305.0,
1280.7, 1231.8, 1100.5, 789.5, 749.8, 738.0, 667.6, 555.2,
4. Experimental
4.1. General aspects
1
NMR spectra were recorded at 300 MHz for H and 75 or
125 MHz for 13C; d values are given in ppm, coupling
constants are reported in Hertz. Infrared spectra were
recorded on a FT-IR instrument. All reagents were of
commercial quality and were used as received. All solvents
were purified by distillation or were HPLC grade.
525.9 cm21 1H NMR (DMSO-d6) 6.88–7.21 (m, 7H),
.
7.45–7.53 (m, 2H), 7.73–7.77 (m, 1H), 11.1 (bs, NH) ppm.
13C NMR (DMSO-d6) 100.7, 111.3, 116.5, 118.8, 118.9,
119.4, 119.7, 120.9, 127.4, 128.2, 128.3, 135.3, 136.2,
154.3 ppm.
4.1.1. 2-(4-Methoxyphenyl)-1H-indole (6b). 4-Methoxy-
acetophenone (15 g, 0.1 mol) was mixed with phenyl-
hydrazine (9.8 ml, 0.1 mol) in EtOH (20 ml) and glacial
4.1.5. 2-(4-Chlorophenyl)-1H-indole (6f). 4-Chloroaceto-
phenone (6.22 g, 40.2 mmol) and phenylhydrazine (3.95 ml,

¨
J. Slatt, J. Bergman / Tetrahedron 58 (2002) 9187–9191
9189
40 mmol) were added to a mixture of EtOH (10 ml) and
glacial AcOH 8 drops, and then treated as described for 6e.
Yield 9.18 g (99.1%). Mp 2078C (Lit.,29 204–2058C). IR
(KBr) 3426.4, 1540.2, 1480.6, 1450.2, 1424.0, 1348.2,
1299.3, 1241.8, 1188.1, 1096.0, 1010.0, 933.3, 831.8, 794.0,
749.1, 725.2, 657.2, 512.1 cm21. 1H NMR (DMSO-d6) 6.90
(bs, 1H), 6.97–7.01 (m, 1H), 7.07–7.12 (m, 1H), 7.39–7.41
(m, 1H), 7.48–7.53 (m, 3H), 7.85–7.88 (m, 2H), 11.56 (bs,
NH). 13C NMR (DMSO-d6) 99.2, 111.2, 119.4, 120.1,
121.8, 126.5, 128.5, 128.8, 131.1, 131.7, 136.3, 137.2.
and then treated as described for compound 7a. Compound
7c was obtained as a colourless liquid. Yield 1.25 g (47%).
Bp 194–1958C/0.1 mm. IR (KBr) 2931.9, 1606.2, 1516.3,
1482.1, 1462.2, 1417.5, 1371.7, 1260.3, 1234.0, 1184.3,
1
1135.8, 1027.3, 892.4, 859.9, 810.2, 748.3 cm21. H NMR
(DMSO-d6) 2.73–2.78 (m, 1H), 3.19–3.323 (m, 1H), 3.73
(s, 3H), 3.74 (s, 3H), 4.54–4.60 (m, 1H), 6.0 (s, NH), 6.47–
6.60 (m, 2H), 6.89–7.05 (m, 5H) ppm. 13C NMR (DMSO-
d6) 55.3, 55.4, 66.2, 67.0, 106.5, 110.3, 111.6, 117.0, 119.5,
123.8, 127.3, 128.1, 134.8, 148.2, 148.8, 151.3 ppm.
4.1.6. 2-Phenyl-2,3-dihydro-1H-indole (7a). 2-Phenyl-
indole (6a) (1.5 g, 7.8 mmol) was dissolved a mixture of
EtOH (9 ml) and conc. hydrochloric acid (6 ml) and
refluxed in the presence of tin (5 g, 42.1 mmol) for 6 h.
The cooled solution was then decanted from excess of tin
into KOH (20%, aqueous) to give a white solid. The basic
mixture was extracted with ether (3£30 ml), and the
combined ether layers were filtered through celite, dried
with MgSO4 and evaporated to give 2-phenylindoline 1.32 g
(87.1%). Mp. 54–558C (Lit.,18 46–478C). IR (KBr) 3367,
4.1.10. 2-(2,3-Dihydro-1H-indol-2-yl)-phenol (7e). 2-(1H-
Indol-2-yl)-phenol (3.0 g, 14.3 mmol) was dissolved a
mixture of EtOH (20 ml) and conc. hydrochloric acid
(25 ml) and tin (15.0 g, 0.13 mol) and then treated as
described for compound 7d. Yield 1.53 g (47.2%). Mp.
1128C. IR (KBr) 3328.9, 2894.2, 1608.1, 1590.1, 1493.4,
1461.4, 1388.2, 1357.7, 1244.8, 1236.1, 1030.1, 993.6,
923.3, 869.6, 841.9, 764.1, 752.1, 707.4, 645.9, 593.3,
1
532.7, 496.0 cm21. H NMR (DMSO-d6) 2.61–2.69 (m,
1H), 3.38–3.47 (m, 1H), 5.02–5.07 (m, 1H), 5.92 (bs, NH),
6.52–6.61 (m, 2H), 6.72–6.82 (m, 2H), 6.92–7.08 (m, 3H),
7.31–7.33 (m, 1H), 9.54 (s, 1H) ppm. 13C NMR (DMSO-d6)
57.3, 66.4, 108.3, 115.0, 117.2, 118.7, 124.2, 126.3, 127.1,
127.5, 127.9, 130.6, 151.8, 154.6 ppm. Calcd for C14H13N:
C, 79.59; H, 6.20; N, 6.63. Found: C, 79.52; H, 6.28; N,
6.70.
1
1608, 1483, 1463, 1454, 1362, 1246, 747, 705 cm21. H
NMR (DMSO-d6) 2.74 (dd, 1H, J¼9.0, 15.5 Hz), 3.28 (dd,
1H, J¼9.0, 15.5 Hz), 4.83–4.90 (m, 1H), 6.09 (s, NH),
6.52–6.57 (m, 2H),6.92–7.00 (m, 2H), 7.21–7.46 (m,
5H) ppm. 13C NMR (DMSO-d6) 38.9, 62.3, 107.9, 117.1,
124.1, 126.2, 126.8, 127.2, 127.4, 128.3, 145.1, 151.9 ppm.
4.1.7. 2-(4-Methoxyphenyl)-2,3-dihydro-1H-indole (7b).
2-(4-Methoxyphenyl)-1H-indole (7.5 g, 33.6 mmol) was
added to a solution of EtOH (30 ml), conc. hydrochloric
acid (25 ml) and tin (0.25 mol 30 g), and then treated as
described for 7a. Yield 4.18 g (55.2%). Mp. 578C (Lit.,30
61–628C). IR (KBr) 3377.5, 1607.4, 1511.8, 1483.0,
1461.7, 1290.5, 1246.8, 1167.0, 1030.2, 832.5, 813.0,
4.1.11. 2-(4-Chlorophenyl)-2,3-dihydro-1H-indole (7f).
2-(4-Chlorophenyl)-1H-indole (4.28, 18.8 mmol) was dis-
solved in a mixture of EtOH (25 ml) and conc. hydrochloric
acid (25 ml) and tin (15.0 g, 12.6 mol). Yield 4.2 g (97.3%).
Mp 698C. IR (KBr) 3344.3, 1607.3, 1481.5, 1484.0, 1409.7,
1346.0, 1321.5, 1291.4, 1242.9, 1143.8, 1085.8, 1042.0,
1012.6, 919.1, 850.3, 825.4, 751.7, 719.7, 704.3, 670.4,
749.3, 680.5, 631.9, 600.0, 539.7 cm21
.
1H NMR
628.1, 579.5, 543.3, 529.9 cm21 1H NMR (DMSO-d6)
.
(DMSO-d6) 2.68–2.76 (m, 1H), 3.27–3.37 (m, 1H), 3.73
(s, 3H), 4.78–4.84 (m, 1H), 6.03 (s, NH), 6.52–6.56 (m,
2H), 6.87–7.05 (m, 4H), 7.29–7.34 (m, 2H) ppm. 13C NMR
(DMSO-d6) 39.1, 55.0, 61.9, 107.9, 113.6, 113.9, 117.0,
124.1, 127.2, 127.3, 127.5, 127.6, 136.9, 151.9, 158.3 ppm.
2.66–2.75 (m, 1H), 3.34–3.48 (m, 1H), 4.36–4.39 (m, 1H),
6.13 (bs, NH), 6.52–6.57 (m, 2H), 6.92–7.00 (m, 2H),
7.36–7.43 (m, 4H) ppm. 13C NMR (DMSO-d6) 38.9, 61.6,
108.0, 117.3, 124.2, 127.2, 127.3, 128.1, 128.2, 131.3,
144.2, 151.8 ppm. Calcd for C14H12N: C, 73.20; H, 5.27; N,
6.10. Found: C, 73.25; H, 5.21; N, 6.06.
4.1.8. 2-(3-Methoxyphenyl)-2,3-dihydro-1H-indole (7c).
2-(3-Methoxy-phenyl)-indole (3.0 g, 13.4 mmol) was dis-
solved in a mixture of EtOH (30 ml), conc. hydrochloric
acid (25 ml) and tin (10.0 g, 84.3 mmol), and then treated as
described for 7a. Compound 7c was obtained as a colourless
liquid. Bp 169–1718C/0.1 mm. Yield 2.1 g (69.6%). IR
(KBr) 3366.9, 1608.8, 1483.2, 1464.3, 1433.6, 1399.4,
1349.7, 1319.9, 1248.5, 1153.9, 1040.0, 1018.0, 994.6,
4.1.12. 1-Oxy-2-phenyl-indol-3-one (8a). 2-Phenyl-2,3-
dihydro-1H-indole (100 mg, 0.51 mmol) was dissolved in
MeOH (20 ml) and m-CPBA (60 mg) and was added in
aliquots. After approximately 5 min the solution turns deep
red and the reaction mixture was left over night. The solvent
was evaporated and the residue was extracted with EtOAc
and Na2CO3 until the water phase was colourless. The
solvent was evaporated to give a bright orange solid, which
was recrystallised from EtOH, to give small orange flakes.
Yield 78 mg (68%). Mp. 1858C (Lit.,31 1868C). IR (KBr)
1705.7, 1597.5, 1523.4, 1481.3, 1447.0, 1388.2, 1314.0,
1283.3, 1181.8, 1073.8, 875.6, 759.9, 686.1, 668.2, 536.9,
1
958.5, 877.6, 781.4, 748.7, 697.0, 532.5 cm21. H NMR
(DMSO-d6) 2.69–2.77 (m, 1H), 3.29–3.40 (m, 1H), 4.84–
4.85 (m, 1H), 6.09 (s, NH), 6.52–6.56 (m, 2H), 6.81–6.82
(m, 1H), 6.91–6.99 (m, 4H), 7.21–7.26 (m, 1H) ppm. 13C
NMR (DMSO-d6) 38.9, 54.9, 62.3, 107.9, 111.8, 112.2,
117.1, 118.4, 124.1, 127.2, 127.4, 129.6, 146.8, 151.9,
159.3 ppm. Anal. Calcd for C15H15NO: C, 79.97; H, 6.71;
N, 6.22. Found: C, 80.01; H, 6.69; N, 6.28.
1
510.2 cm21. H NMR (CDCl3) 7.49–7.27 (m, 7H), 8.63–
8.67 (m, 2H) ppm. 13C NMR (CDCl3) 114.2, 121.6, 127.8,
128.5, 129.8, 130.2, 130.7, 131.2, 134.8, 135.1, 147.8,
186.9 ppm.
4.1.9. 2-(3,4-Dimethoxyphenyl)-2,3-dihydro-1H-indole
(2.5 g,
11.9 mmol) was dissolved in a mixture of EtOH (30 ml),
conc. hydrochloric acid (25 ml) and tin (10.0 g, 84.3 mmol),
(7d).
2-(3,4-Dimethoxyphenyl)-1H-indole
4.1.13. 2-(4-Methoxyphenyl)-1-oxy-indol-3-one (8b). 2-
(4-Methoxyphenyl)-2,3-dihydro-1H-indole (210 mg, 0.93
mmol) was dissolved in MeOH (20 ml) and m-CPBA

¨
J. Slatt, J. Bergman / Tetrahedron 58 (2002) 9187–9191
9190
(0.6 g), was added as described for compound 8a. The crude
product purified by flash chromatography with hexane/
EtOAc 80/20, gave deep red long needles. Yield 150 mg
(63.5%). Mp. 1928C (Lit.,32 1878C). IR (KBr) 1689.9,
1598.9, 1557.8, 1529.9, 1492.9, 1456.0, 1379.5, 1301.8,
1261.5, 1178.5, 1019.8, 876.1, 876.1, 832.7, 784.5, 756.1,
(0.9 g) was added as described for compound 8a. Yield
202 mg (60.0%). Mp. 1748C (Lit.,34 1748C). IR (KBr)
1704.0, 1587.6, 1521.5, 1484.0, 1380.9, 1284.3, 1180.0,
1094.7, 1010.0, 876.6, 832.3, 784.0, 761.3, 538.6, 513.8,
1
466.1, 450.0 cm21. H NMR (CDCl3) 7.26–7.68 (m, 6H),
8.62–8.65 (m, 2H) ppm. 13C NMR (CDCl3) 114.2, 121.7,
122.6, 124.3, 128.8, 128.9, 131.2, 131.3, 134.9, 136.6,
147.7, 186.6 ppm.
1
697.9, 522.1 cm21. H NMR (CDCl3) 3.89 (s, 3H), 7.01–
7.04 (m, 2H), 7.42–7.68 (m, 4H), 8.72–8.75 (m, 2H) ppm.
13C NMR (CDCl3) 55.3, 113.8, 114.0, 118.7, 121.4, 122.7,
129.7, 130.6, 131.9, 134.7, 147.9, 161.2, 187.3 ppm.
Acknowledgements
4.1.14. 2-(3-Methoxyphenyl)-1-oxy-indol-3-one (8c).
2-(3-Methoxyphenyl)-2,3-dihydro-1H-indole
(250 mg,
¨
Stiftelsen for strategisk forskning (NNDD) for financial
support.
1.1 mmol) was dissolved in MeOH (50 ml) and m-CPBA
(0.70 g), was added as described for compound 8a. The
product purified by flash chromatography with hexane/
EtOAc 80/20 appeared as long deep red needles. Yield
180 mg (64%). Mp. 140–1418C). IR (KBr) 1715.4, 1702.6,
1600.0, 1575.0, 1519.7, 1480.1, 1453.9, 1380.1, 1299.0,
1252.2, 1181.8, 1050.0, 873.9, 775.5, 760.5, 680.5, 613.4,
References
1. Baeyer, A. Ber. Dtsch. Chem. Ges. 1881, 14, 1741–1746.
2. Baeyer, A. Ber. Dtsch. Chem. Ges. 1882, 15, 50–61.
3. Bunney, J. E.; Hooper, M. J. Chem. Soc. (B) 1970,
1239–1241.
1
536.3 cm21. H NMR (CDCl3) 3.90 (s, 3H), 7.05 (dd, 1H,
J¼2.5, 5.8 Hz), 7.40–7.76 (m, 1H), 7.53–7.61 (m, 1H),
7.67–7.71 (m, 3H), 8.26–8.33 (m, 2H) ppm. 13C NMR
(CDCl3) 55.3, 112.0, 114.2, 117.7, 120.5, 121.6, 122.7,
126.9, 129.5, 131.2, 132.0, 134.8, 147.8, 159.4, 186.8 ppm.
Calcd for C15H11N: C, 71.14; H, 4.38; N, 5.53. Found: C,
71.04; H, 4.46; N, 5.47.
4. Hiremath, S. P.; Hooper, M. Adv. Heterocycl. Chem. 1978, 22,
123–181.
5. Nepveu, F.; Souchard, J-P.; Rolland, Y.; Dorey, G.; Spedding,
M. Biochem. Biophys. Res. Commun. 1998, 242, 272–276.
6. Hooper, M.; Robertson, J. W. Tetrahedron Lett. 1971, 24,
2139–2140.
4.1.15. 2-(3,4-Dimethoxyphenyl)-1-oxy-indol-3-one (8d).
2-(3,4-Dimethoxyphenyl)-2,3-dihydro-1H-indole (200 mg,
0.9 mmol) was dissolved in MeOH (50 ml) and m-CPBA
(0.50 g), was added as described for compound 8a. The
product purified by flash chromatography with hexane/
EtOAc 80/20 appeared as long deep red needles. Yield
119 mg (53%). Mp. 2278C (Lit.,33 2278C). IR (KBr) 1703.1,
1592.7, 1569.6, 1527.9, 1492.2, 1456.9, 1439.1, 1388.2,
1362.7, 1323.0, 1285.4, 1266.2, 1239.1, 1185.6, 1148.6,
1088.2, 1023.8, 869.7, 808.5, 784.8, 759.9, 705.5, 635.8,
7. Sweetman, A. J.; Green, A. P.; Hooper, M. Biochem. Biophys.
Res. Commun. 1974, 58, 337–343.
8. Hagen, H.; Kohler, R. D.; Pommer, E. H. Eur. Pat. 54147;
Chem. Abstr. 1982, 97, 216 185.
¨ ¨
9. Slatt, J.; Bergman, J.; Erlinge, D.; Wihlborg, A.-K.; Malmsjo,
M., unpublished results.
10. Hooper, M.; Patterson, D. A.; Wibberley, D. G. J. Pharm.
Pharmacol. 1965, 17, 734–741.
11. Chien, C.-S.; Takanami, T.; Kawasaki, T.; Sakamoto, M.
Chem. Pharm. Bull. 1985, 33, 1843–1848.
1
603.7, 535.7 cm21. H NMR (CDCl3) 3.97–3.99 (m, 6H),
6.95–6.95 (m, 1H), 7.49–7.54 (m, 1H), 7.60–7.63 (m, 1H),
7.67–7.69 (m, 2H), 8.41–8.44 (m, 2H) ppm. 13C NMR
(CDCl3) 55.9 (2C), 110.0, 110.8, 113.8, 119.1, 121.5, 122.2,
122.7, 130.7, 131.7, 134.9, 148.0, 148.5, 151.1, 187.3 ppm.
12. Bhamare, N. K.; Kamath, H. V.; Kulkarni, S. N. Indian
J. Chem. Sect. B 1985, 7, 667–669.
´
13. Genisson, V. A.; Bouniol, A.-V.; Nepveu, F. Synlett 2001, 5,
700–702.
14. Swain, J. PhD Thesis, Sunderland, 1980.
15. Morpeth, A. G. PhD Thesis, Sunderland, 1989.
16. Stoddart, B. PhD Thesis, Sunderland, 1990.
17. Bristow, T. H. C.; Foster, H. E.; Hooper, M. J. Chem. Soc.,
Chem. Commun. 1974, 677.
4.1.16. 2-(2-Hydroxyphenyl)-1-oxy-indol-3-one (8e).
2-(2,3-Dihydro-1H-indol-2-yl)-phenol (400 mg, 1.9 mmol)
was dissolved in MeOH (50 ml) and m-CPBA (0.98 g), was
added as described for compound 8a. The product purified
by flash chromatography with hexane/EtOAc 80/20
appeared as long deep red needles. Yield 289 mg (64%).
Mp. 1608. IR (KBr) 3426.1, 1725.4, 1598.4, 1564.6, 1535.4,
1459.9, 1340.4, 1307.4, 1282.0, 1258.0, 1225.6, 1183.2,
1153.9, 1059.2, 1035.8, 946.4, 881.3, 756.7, 704.0, 682.0,
611.5, 532.0, 493.4 cm21. 1H NMR (CDCl3) 7.04–7.11 (m,
2H), 748–7.62 (m, 2H), 7.71–7.75 (m, 3H), 7.82–7.85 (m,
1H), 9.28 (s, 1H) ppm. 13C NMR (CDCl3) 112.8, 114.7,
120.5, 120.7, 122.9, 123.0, 131.0, 131.2, 134.3, 135.6,
136.9, 147.3, 159.3, 184.8 ppm. Calcd for C14H9N: C,
70.29; H, 3.79; N, 5.86. Found: C, 70.21; H, 3.68; N, 5.77.
18. Pictet, A. Chem. Ber. 1886, 19, 1063–1066.
19. Fischer, E. Chem. Ber. 1888, 21, 1071–1076.
20. Stoermer, R. Chem. Ber. 1898, 31, 2523–2541.
21. Bowden, B. F.; Read, R. W.; Ritchie, E.; Taylor, W. C. Aust.
J. Chem. 1975, 28, 65–80.
22. Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am.
Chem. Soc. 2000, 122, 7614–7615.
23. Somei, M. Adv. Heterocycl. Chem. 2002, 82, 101–155.
24. Bond, C. C.; Hooper, M. Synthesis 1974, 443.
25. Sakamoto, T.; Takao, K.; Yoshinori, T.; Takazawa, N.;
Yamanaka, H. J. Chem. Soc., Perkin Trans. 1 1996, 16,
1927–1934.
´
26. Inion, H.; De Vogelaer, H.; Van Durme, E.; Descamps, M.;
4.1.17. 2-(4-Chlorophenyl)-1-oxy-indol-3-one (8f). 2-(4-
Chlorophenyl)-2,3-dihydro-1H-indole (0.3 g, 1.3 mmol)
was added to a solution of MeOH (80 ml) and m-CPBA
Brotelle, R.; Charlier, R.; Colot, M. Eur. J. Med. Chem. 1975,
10, 276–285.

¨
J. Slatt, J. Bergman / Tetrahedron 58 (2002) 9187–9191
9191
27. Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.
Tetrahedron 1963, 19, 247–288.
31. Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am.
Chem. Soc. 2000, 31, 7614–7615.
28. Inion, H.; Vogelaer, H. D.; Descamp, M.; Bauthier, J.; Colot,
M.; Richard, J.; Charlier, R. Eur. J. Med. Chem. Chim. Ther.
1977, 12, 483–484.
32. Bond, C. C.; Hooper, M. J. Chem. Soc. 1969, 18, 2453–2460.
33. Sahasrabudhe, A. B.; Kamath, V. H.; Bapat, B. V.; Kulkarni,
S. N. Indian J. Chem., Sect. B 1980, 230–232.
29. Brown, F.; Mann, F. G. J. Chem. Soc. 1948, 847–858.
30. Bowden, B. F.; Read, R. W.; Ritchie, E.; Taylor, W. C. Aust.
J. Chem. 1975, 28, 65–80.
¨
34. Krohnke, F.; Vogt, I. Chem. Ber. 1952, 85, 368–371.