, 2004, 14(2), 73–74
One correlation peak of the C3a signal with H-7 is possible for
the structure with 5-OAc. Note that a 6- (rather than 5-)
hydroxyindole is formed, which is typical of the Nenitzescu
reaction involving nitroenamines.7 The reaction of compound 4
in acetic anhydride in the presence of a catalytic amount of
concentrated H2SO4 results in the cleavage of the indole ring
at the 1,2-bond accompanied by the acetylation of OH and
NH groups and the formation of 3-[acetyl-2-(benzylidene)-
hydrazino]-4-[2-(acetoxy)-1-nitropropen-1-yl]phenyl acetate 6.‡‡
O2N
Me
O2N
Me
OH
OAc
4
AcO
AcO
AcO
N
N
HO
N N
Ac
CHPh
CHPh
H
6
1
The structure of compound 6 was proven by H and 13C NMR
NO2
O2N
Me
spectra, which differ considerably from those of compound 5.
First, owing to the existence of geometric isomers, the spectra
of compound 6 contain a double set of signals, which were
assigned on the basis of COSY, NOESY, HSQC and HMBC
Me
OH
NH
N
NH2
HO
N
1
spectra. Furthermore, the H NMR spectrum contains double
Ac
Ac
signals of four methyl groups, three of which are acetyl groups.
The latter have correlation peaks with C=O signals in the region
d 168.0–171.0 of the HMBC spectrum. On the other hand,
signals of the 2'-methyl group are considerably upfield shifted
(1.81, 1.90 ppm) in comparison with the methyl group signals
in the spectrum of compound 5 (2.87 ppm). We observed a
similar shift on transition from non-cyclic intermediates (hydro-
quinone adducts) to final compounds (e.g., indole-type ones)
formed in the Nenitzescu reaction.7 The chemical shifts of the
benzylidene proton differ significantly in both 1H and 13C NMR
spectra: d 9.14 and 166.6 (5); d 7.88, 8.06 and 79.1, 83.1
(6). The reaction also gives 1-acetylamino-2-methyl-3-nitro-6-
acetoxyindole 7,§§ i.e., a hydrolysis product of the Shiff base
and an O- and N-acetylation product. Acetylation under dif-
ferent conditions (AcOH, Ac2O, H2SO4, heating) also gives
compounds 6 and 7, but their ratio changes essentially: indole 7
becomes the main reaction product. The acid hydrolysis of
compound 6 gives unexpectedly 1-acetylamino-2-methyl-3-nitro-
6-hydroxyindole 8¶¶ in a high yield. A small amount of indole 4
was isolated as a by-product.
A
B
O2N
Me
O2N
Me
OH
NH
OAc
8
N
AcO
NH
NHCOMe
Me OH
Scheme 2
furthermore, the 1H NMR spectra of compound 8 do not contra-
dict to the assumed structure of B. However, a comparison of
1H and 13C NMR spectra of compounds 7 and 8 makes it
possible to assume that indole derivative 8 is formed. In fact,
while the majority of chemical shifts in compound 8 do not
change considerably in comparison with compound 7, the H-5,
H-7 and C5, C7 signals are shifted upfield by 0.29, 0.61 and 5.0,
8.4 ppm, respectively. These data allow us to assume that
compounds 7 and 8 only differ by substituents at the position 6.
This is also confirmed by the difference NOE spectra of
compound 8: H-7 (d 6.71 ppm) and 2-Me (d 2.64 ppm) signals
are observed upon pre-irradiation of COMe protons (2.18 ppm),
which is only possible in compound 8.
To explain the transformation of compound 6 into indole 8
(acyl migration is observed), we propose a scheme according to
which the hydrolysis of the Schiff base and acetoxy groups is
accompanied by an acylotropic rearrangement. Such rearrange-
ments were observed before.9,10
The formation of indole 4 in this reaction probably occurs by
a simpler scheme, viz., N-deacylation and hydrolysis of acetoxy
groups in compound 6, and the indole ring closure. Thorough
proof was required to determine the structure of compound 8,
since possible transformation of hypothetical intermediate pro-
duct A (Scheme 2) into cinnoline derivative B with the closure
of a six-membered pyridazine ring could not be ruled out.
Compounds 8 and B have identical elemental compositions;
The structure of compound 8 was also confirmed by an
independent synthesis. The deacetylation of indole 7 by reflux-
ing in benzene in the presence of piperidine gave indole 8. The
TLC characteristics of the samples are identical; a mixing test
did not show any melting point depression. The derivatives of
1-amino-6-hydroxyindole, which were synthesised for the first
time using the Nenitzescu reaction, are of interest in terms of
their chemical and biological properties.
‡‡ For compound 6: yield 63% (vi) or 18% (vii), mp 183–185 °C
This study was supported by the Russian Foundation for
Basic Research (grant no. 02-03-32119).
1
(EtOH). H NMR ([2H6]DMSO) d: 1.90, 1.81 (2s, 2×3H, 2'-Me), 1.74,
2.10, 2.19, 2.70 (4s, 4×3H, NAc, 2'-OAc), 2.34 (s, 6H, 1-OAc), 7.70,
7.75 (2d, 2×1H, 2-H, J 1.7 Hz), 7.06–7.37 (m, 6H, Ph, 5-H), 7.88, 8.08
(2s, 2×1H, CHPh), 8.09, 8.15 (2d, 2×1H, 5-H, J 8.6 Hz). 13C NMR
([2H6]DMSO) d: 11.4, 11.5 (2'-Me), 20.1, 20.4, 20.5, 20.6, 20.9, 21.12
(NCOMe, 2'-OCOMe, 1-COMe), 79.1, 83.1 (CHPh), 105.5, 105.6 (C2),
116.3 (C4), 118.9, 119.4 (C5), 119.9, 120.3 (C6), 125.0 (C1' ), 128.9,
128.4, 128.6, 130.0 (Ph), 135.0 (C3), 144.4, 145.2 (C2' ), 148.5 (C1),
168.0–171.0 (NCOMe, 2'-OCOMe, 1-COMe). MS, m/z: 439. Found
(%): C, 59.88; H, 4.82; N, 9.64. Calc. for C20H19N3O6 (%): C, 60.13; H,
4.81; N, 9.56.
§§ For compound 7: yield 48% (vi) or 37% (vii), mp 239–240 °C
(EtOH). 1H NMR ([2H6]DMSO) d: 2.19 (s, 3H, 1-NCOMe), 2.30 (s, 3H,
6-OCOMe), 2.66 (s, 3H, 2-Me), 7.16 (dd, 1H, 5-H, J1 8.6 Hz, J2 1.2 Hz),
7.32 (d, 1H, 7-H, J2 1.2 Hz), 8.12 (d, 1H, 4-H, J1 8.6 Hz), 11.55 (br. s,
1H, NH). 13C NMR ([2H6]DMSO) d: 11.4 (2-Me), 20.4, 20.8 (1-NCOMe,
6-OCOMe), 103.8 (C7), 116.3 (C3a), 118.9 (C5), 120.1 (C4), 124.2 (C3),
134.2 (C7a), 144.4 (C2), 147.9 (C6), 169.2, 169.3 (1-NCOMe, 6-OCOMe).
MS, m/z: 291. Found (%): C, 53.48; H, 4.55; N, 14.15. Calc. for
C13H13N3O5 (%): C, 53.61; H, 4.50; N, 14.43.
¶¶ For compound 8: yield 92% (viii) or 90% (ix), mp 262 °C (decomp.,
PriOH). 1H NMR ([2H6]DMSO) d: 2.18 (s, 3H, 1-NCOMe), 2.64 (s, 3H,
2-Me), 6.71 (d, 1H, 7-H, J2 1.2 Hz), 6.87 (dd, 1H, 5-H, J1 8.6 Hz, J2
1.2 Hz), 7.90 (d, 1H, 4-H, J1 8.6 Hz), 9.56 (br. s, 1H, 6-OH), 11.35 (br. s,
1H, NH). 13C NMR ([2H6]DMSO) d: 11.4 (2-Me), 20.3 (1-NCOMe),
95.4 (C7), 111.4 (C3a), 113.9 (C5), 120.4 (C4), 124.4 (C3), 135.3 (C7a),
142.3 (C2), 155.6 (C6), 169.0 (1-NCOMe). MS, m/z: 249. Found (%): C,
53.03; H, 4.60; N, 16.49. Calc. for C11H11N3O4 (%): C, 53.01; H, 4.45;
N, 16.86.
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Received: 18th December 2003; Com. 03/2205
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