Preparation of 3-Ethyloxindole-4,7-quinone

Article abstract of DOI:10.1039/a707530h

The preparation of 3-ethyloxindole-4,7-quinone 10 from 4,7-dimethoxyisatin 1 in four steps is described.

Full text of DOI:10.1039/a707530h

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190 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
1998, 190±191$
Preparation of 3-Ethyloxindole-4,7-quinone$
Lina K. Mehta, John Parrick* and Fereshteh Payne
Department of Chemistry, Brunel University, Uxbridge UB8 3PH, UK,
The preparation of 3-ethyloxindole-4,7-quinone 10 from 4,7-dimethoxyisatin 1 in four steps is described.
Quinone derivatives of simple heterocyclic systems are of
considerable chemical and biological interest.1 However,
few simple oxindole quinones are known though some
quinonoid, multi-ring systems containing the oxindole
moiety are reported.2 Our unsuccessful attempts to obtain
isatin-4,7-quinone resulted in the formation of 3,3-diphenyl-
oxindole-4,7-quinone.3 We now describe attempts to obtain
less substituted oxindole quinones.
An approach to oxindole-4,7-quinone 5 appeared to be by
oxidation with ceric ammonium nitrate (CAN) of 4,7-
dimethoxyoxindole 2 which was expected to be formed by
reduction of the available 4,7-dimethoxyisatin 1. Selective
reduction of the ketonic carbonyl group of isatins has been
achieved using a zinc±copper couple in acetic acid4 or by
the action of sodium ethoxide on the isatin hydrazone.5
Neither procedure gave the oxindole 2 from 1, though the
former method gave 3-acetoxy-4,7-dimethoxyoxindole 3.
Treatment of the isatin 1 with sodium borohydride6 in
methanol and in the presence of air for an extended period
of time gave 3,6-dimethoxyanthranilic acid (6) (79%). A
similar reaction with isatin gave methyl anthranilate (61%)
but when the reaction was performed under a nitrogen
atmosphere only a trace quantity of the anthranilate was
formed. The detailed mechanism for the formation of the
anthranilates is not known but the evidence indicates that
both reduction (by borohydride) and oxidation (by air) are
essential. Solvolysis of an intermediate seems to be a likely
Scheme 1
process for the formation of the ester. As expected, the
action of sodium methoxide in methanol did not give the
give support to the idea that the diculties experienced in
producing 5 do stem from the reactivity of the unsubstituted
3-position.
anthranilate. More satisfactory for the formation of 2 was
the application of another method used to convert isatin to
oxindole.7 Thus, reduction of the isatin 1 through formation
of the dithioketal 7 and its decomposition in re¯uxing
benzene in the presence of Raney nickel yielded 4,7-
dimethoxyoxindole 2. However, attempts to cause the
formation of the parent oxindole quinone 5 from 2 by the
action of CAN, periodate or nitric acid gave complex
mixtures. Therefore 2 was demethylated with aluminium
chloride in benzene to give the dihydroxyoxindole 4 but
attempts to oxidise 4 to 5 with silver oxide, nitric acid,
Fremy's salt or CAN again produced complex mixtures.
It seemed likely that failure to obtain 5 was due to the
presence of the unsubstituted methylene group because 3,3-
disubstituted oxindole-quinones are known.3 The reduction
of isatins through their dithioketals provided a means by
which this idea might be tested because prolonged re¯uxing
of isatin dithioketals in ethanol in the presence of Raney
nickel is known to yield 3-ethyloxindoles.8 Thus, re¯uxing
an ethanolic solution of 7 in the presence of Raney nickel
for 24 h gave a high yield of 3-ethyl-4,7-dimethoxyoxindole
8 and this was smoothly converted to the corresponding
dihydroxy compound 9. The phenol 9 was then oxidised by
silver carbonate on celite to 3-ethyloxindole-4,7-quinone 10,
though in low yield (Scheme 1). The isolation of 10 does
Experimental
Experimental procedures to obtain melting points, spectroscopic
data, elemental analyses and chromatographic separations were as
described.9 The accurate mass determination were performed by the
EPSRC Mass Spectrometry Service Centre, University of Wales,
Swansea. Raney nickel was obtained from Aldrich Chemical
Company and petroleum spirit refers to light petroleum (bp 40±
60 8C). Elemental analyses and 1H NMR and mass spectral data are
given in Table 1.
3-Acetoxy-4,7-dimethoxyoxindole 3.ÐA mixture of 4,7-dimethoxy-
isatin10 (1) (0.5 g, 2.4 mmol), a zinc±copper couple11 (1.5 g) and
glacial acetic acid (30 ml) was re¯uxed for 21 h. The mixture was
®ltered, the ®ltrate diluted and neutralised by the addition of sodium
carbonate. Extraction with ether and the usual work-up gave an
orange solid which was crystallised from a mixture of chloroform and
petroleum spirit and then from ethanol to give 3 (0.37 g, 61%), mp
193±195 8C; ꢀmax/cm 1 3190 (NH), 1730 (CO), 1640 (CO).
Methyl 2-Amino-3,6-dimethoxybenzoate 6.ÐA mixture of 4,7-
dimethoxyisatin 1 (0.5 g, 2.4 mmol), sodium borohydride (0.3 g) and
methanol (40 ml) was stirred for 12 h and then a further quantity of
borohydride (0.6 g) was added and the stirring continued for a
further 24 h. The mixture was neutralised by the addition of hydro-
chloric acid and extracted with chloroform. The extract yielded an
oil which was puri®ed by ¯ash column chromatography (petroleum
spirit±ethyl acetate, 13:9) and distillation (bp 136 8C/0.7 mm Hg) to
1
give 6 (0.35 g, 70%), bp 385 8C ꢀmax/cm 3510, 3400 (NH2), 1720
(CO).
*To receive any correspondence.
4,7-Dimethoxyisatin 3,3-Ethylenedithioketal 7.ÐA mixture of
ethane-1,2-dithiol (2.2 ml), 1 (1 g, 4.8 mmol) and boron tri¯uoride
etherate (1.2 ml) was stirred under nitrogen for 20 min. Methanol
(5 ml) was added, the solid ®ltered o€ and crystallised from acetic
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1998 191
Table 1 Elemental analyses±accurate mass and 1H NMR and mass spectral data of 2±4, 6±10
Found (Calcd) (%)
C
Compound
Formula
H
N
dH/ppm
m/z
‡
2
C10H11NO3
61.88
5.68
7.20 a3.55 (2 H, s, 3-H), 3.82 (3 H, s, OCH3), 3.87 (3 H, s,
193 (M , 100),
178 (M CO, 50)
‡
(62.17) (5.69) (7.25) OCH3), 6.52 (1 H, d, J 9 Hz, 5-H), 6.81 (1 H, d, J 9 Hz,
6-H), 7.55 (1 H, s, NHb)
5.41 a2.15 (3 H, s, COCH3), 3.74 (3 H, s, OCH3), 3.79 (3 H,
(57.37) (5.22) (5.57) s, OCH3), 6.11 (1 H, s, 3-H), 6.43 (1 H, d, J 9 Hz, 6-H),
6.78 (1 H, d, J 9 Hz, 5-H), 7.32 (1 H, s, NHb)
‡
3
4
6
7
8
C
12H13NO5
57.21
5.43
251 (M , 37), 209
(M COMe, 100)
‡
‡
165 (M , 100),
C8H7NO3
52.19
4.96
7.46 c3.25 (2 H, s, 3-H), 6.17 (1 H, d, J 8 Hz, 5-H), 6.47
‡
137 (M CO, 50)
(52.46) (4.95) (7.64) (1 H, d, J 8 Hz, 6-H), 8.49 (1 H, s, OHb), 8.69 (1 H, s,
OHc), 9.86 (1 H, s, NHb)
‡
211 (M , 100)
C
10H13NO4
57.15
6.24
6.40 a3.78 (3 H, s, OCH3), 3.81 (3 H, s, OCH3), 3.90 (3 H, s,
(56.87) (6.20) (6.63) CH3), 5.42 (2 H, s, NH2b), 6.14 (1 H, d, J 9 Hz, 4-H),
6.74 (1 H, d, J 9 Hz, 5-H)
‡
C12H13NO3S2 50.84
(50.86) (4.62) (4.94) OCH3), 6.61 (1 H, d, J 9 Hz, 5-H), 6.79 (1 H, d, J 9 Hz,
6-H), 7.35 (1 H, s, NHb)
6.27 a0.77 (3 H, t, J 7 Hz, CH3), 2.08 (2 H, dd, J 7 and 5 Hz,
4.62
4.92 a3.76 (4 H, m, 2xCH2), 3.81 (3 H, s, OCH3), 3.88 (3 H, s,
283 (M , 100),
223 (85)
‡
‡
C
12H15NO3
65.08
7.05
221 (M , 100),
206 (M Me, 52),
178 (58)
(65.14) (6.83) (6.33) CH2), 3.56 (1 H, t, J 5 Hz, 3-H), 3.77 (3 H, s, OCH3),
3.79 (3 H, s, OCH3), 6.42 (1 H, d, J 9 Hz, 6-H), 7.32
(1 H, s, NHb)
‡
9
C10H11NO3
62.17
5.89
7.07 c0.63 (3 H, t, J 7 Hz, CH3), 1.95 (2 H, dd, J 7 and 5 Hz,
193 (M , 100),
164 (M Et, 53)
‡
(62.17) (5.74) (7.25) CH2), 3.25 (1 H, t, J 5 Hz, 3-H), 6.17 (1 H, d, J 11 Hz,
5-H), 6.45 (1 H, d, J 11 Hz, 6-H), 8.46 (1 H, s, OHb)
8.67 (1 H, s, OHb), 9.79 (1 H, s, NHb)
10
C10H9NO3
191.0583
a0.64 (3 H, t, J 7 Hz, CH3), 2.43 (2 H, dd, J 7 and 4 Hz,
CH2), 3.38 (1 H, t, J 4 Hz 3-H), 6.61 (1 H, s, 5-H), 7.15
(1 H, s, 6-H), 9.91 (1 H, s, NHb)
191 (M , 56),
189 (100)
‡
(M , 191.0582)d
‡
aIn CDCl3. bExchanges with D2O. c[2H6]DMSO. dAccurate mass determination by E.I. mass spectrometry.
1
1
acid to give 7 (1.09 g, 80%), mp 225±226 8C; ꢀmax/cm 3180 (NH),
1715 (CO).
(40 mg, 27%), mp >300 8C (decomp. 140 8C);
(NH), 1720 (CO), 1670 (CO).
ꢀ
max/cm
3260
4,7-Dimethoxyoxindole 2.ÐA mixture of
7 (0.6 g, 2.1 mmol),
ethanol (50 ml) and Raney nickel was stirred and re¯uxed for 2.5 h.
The solution was decanted and the solid washed seven times with
warm ethanol. Evaporation of the solution gave a residue which
We thank the EPSRC Mass Spectrometry Service,
Swansea, for the accurate mass measurement.
was crystallised from ethanol as 2 (0.3 g, 73%), mp 201±202 8C;
1
max/cm 3200 (NH), 1690 (CO).
4,7-Dihydroxyoxindole 4.ÐA mixture of 2 (0.83 g, 4.3 mmol), sub-
ꢀ
Received, 20th October 1997; Accepted, 8th December 1997
Paper E/7/07530H
limed aluminium chloride (12.63 g) and benzene (60 ml) was
boiled under re¯ux for 2 h. The reaction mixture was poured into
crushed ice, extracted with ether, and the extract evaporated. Flash
chromatography (chloroform±methanol 13:1) gave a product which
was crystallised from water to give 4 (0.55 g, 79%), mp >300 8C
References
1 R. W. Middleton and J. Parrick, in The Chemistry of Quinonoid
Compounds, ed. S. Patai and Z. Rappoport, Wiley, Chichester,
1988, vol. 2, part 2, p. 1019.
1
(decomp. 210 8C); ꢀmax/cm 3970 (OH), 1680 (CO).
3-Ethyl-4,7-dimethoxyoxindole 8.ÐA mixture of
7
(0.8 g,
2.8 mmol), ethanol (100 ml) and Raney nickel (5 g) was stirred and
re¯uxed for 24 h. The solid was ®ltered o€, the ®ltrate evaporated
and the residue crystallised from ethyl acetate to give 8 (0.5 g,
2 M. Tisler, Adv. Heterocycl. Chem., 1989, 45, 37.
3 A. S. Ijaz, J. Parrick and A. Yahya, J. Chem. Res., 1990, (S)
116; (M) 0833.
4 T. A. Foglia and D. Swern, J. Org. Chem., 1968, 33, 4440.
5 A. H. Jackson, Chem. Ind. (London), 1965, 1652.
6 Products arising by reductive dimerization have been reported
from the action of sodium borohydride on isatins; R. L. Autrey
and F. C. Tahk, Tetrahedron, 1967, 23, 901.
7 C. Djerassi, M. Gorman and J. A. Henry, J. Am. Chem. Soc.,
1955, 77, 4647.
8 C. Djerassi and D. H. Williams, J. Chem. Soc., 1963, 4046.
9 A. R. Ahmad, L. K. Mehta and J. Parrick, J. Chem. Soc. Perkin
Trans 1, 1996, 2443.
1
80%), mp 134±135 8C; ꢀmax/cm 3180 (NH), 1700 (CO).
3-Ethyl-4,7-dihydroxyoxindole 9.ÐDry benzene (30 ml) was
added to 8 (0.28 g, 1.26 mmol) and sublimed aluminium chloride
(3.73 g) and the mixture re¯uxed for 2 h. The mixture was
poured into crushed ice, extracted with ether and the solvent
evaporated. The residue was puri®ed by ¯ash chromatography
(chloroform±methanol, 19:1) and crystallised from ethyl acetate to
1
give 9 (0.24 g, 79%), mp 213±215 8C ꢀmax/cm 3340 (OH), 3200
(NH), 1730 (CO).
3-Ethyloxindole-4,7-dione 10.ÐA mixture of 9 (0.16 g, 0.8 mmol),
dry THF (50 ml) and freshly prepared silver carbonate on celite12
(1.9 g) was re¯uxed for 2 h. The solid was separated, the solution
evaporated and the residue puri®ed by ¯ash column chromatog-
raphy (ethyl acetate±petroleum spirit) to give red crystals of 10
10 P. Nickel and R. Zimmermann, Arch. Pharm., 1977, 310, 537.
11 E. Le Go€, J. Am. Chem. Soc., 1964, 29, 2048.
12 V. Balogh, M. Fetizon and M. Gol®er, J. Org. Chem., 1971, 36,
1339.