The use of enehydrazines in the Nenitzescu reaction

Article abstract of DOI:10.1070/MC2004v014n02ABEH001879

The Nenitzescu reaction involving a nitroenehydrazine 1 has been studied for the first time, and novel 1-aminoindole derivatives have been synthesised.

Full text of DOI:10.1070/MC2004v014n02ABEH001879

, 2004, 14(2), 73–74
The use of enehydrazines in the Nenitzescu reaction
Valeriya M. Lyubchanskaya,a Svetlana A. Savina,a Lyudmila M. Alekseeva,a Alexander S. Shashkovb
and Vladimir G. Granik*a
a State Scientific Centre for Antibiotics, 117105 Moscow, Russian Federation. Fax: +7 095 231 4284; e-mail: makar-cl@Ropnet.ru
b N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5328
10.1070/MC2004v014n02ABEH001879
The Nenitzescu reaction involving a nitroenehydrazine 1 has been studied for the first time, and novel 1-aminoindole derivatives
have been synthesised.
The Nenitzescu reaction, which is the basis for the synthesis
of 5-hydroxyindole and 5-hydroxybenzofuran derivatives,
allows the structures of starting compounds, i.e., quinones and
NO2
NO2
NO2
i
ii
HN
N
Me
enamines, to be varied over a wide range.1–3 Nontraditional
final products can often be obtained from nontrivial starting
compounds.4,5 In this work, we synthesised 1-methyl-2-nitro-
vinylhydrazine 1† by the transamination of 2-dimethylamino-
1-nitroprop-1-ene.6 To date, enehydrazines have not been used
as enamine components in the Nenitzescu reaction. It was found
that the condensation of compound 1 with p-benzoquinone
results in corresponding hydrazone 4-[(1-methyl-2-nitrovinyl)-
hydrazono]cyclohexa-2,5-dienone 2.‡ Thus, the Michael C–C
addition, which is mandatory for the Nenitzescu reaction, does
not occur in this case; compound 1 acts as a hydrazine
derivative rather than an enamine. Therefore, the condensation
of compound 1 with benzaldehyde gave N-benzylidene-N'-
(1-methyl-2-nitrovinyl)hydrazine 3.§ The interaction of the
latter with p-benzoquinone occurred as a Nenitzescu reaction to
give 1-(benzylideneamino)-2-methyl-3-nitro-1H-indol-6-ol 4.¶
The acetylation of the latter gave an O-acetyl derivative,
1-benzylidenamino-2-methyl-3-nitro-6-acetoxy-1H-indole 5.††
The position of the hydroxy (or acetoxy) group in compounds 4
and 5 was determined using the HMBC spectra of compound 5.
The C3a signal (d 117.3 ppm) has correlation peaks with 5-H
signals of 7.20 (dd, J1 8.6 Hz, J2 1.2 Hz) and with 7-H signals
of 7.59 (d, J2 1.2 Hz), which show unambiguously that
6-hydroxy (4) and then 6-acetoxy (5) derivatives are formed.
HN
NH2
Me
Me2N
Me
1
O
iii
2
NO2
Me
NO2
NO2
Me
4
7
3
5
iv
v
2
HN
N
Me
1
6
N
N
HO
AcO
CHPh
N
N
3
PhHC
PhHC
4
5
vi, vii
O2N
Me
2
'
NO2
1
'
5
2
6
4
OAc
Me
1
3
N
AcO
N
N
AcO
Ac
NHAc
CHPh
6
7
†
1H NMR spectra were recorded on AC-200 (Bruker) and DRX-500
viii
ix
(Bruker) spectrometers. Mass spectra were recorded on a Finnigan SSQ
mass spectrometer with direct sample injection into the ion source.
For compound 1: yield 73%, mp 83–85 °C (benzene). 1H NMR
([2H6]DMSO) d: 2.01 (s, 3H, 1-Me), 5.00 (br. s, 2H, NH2), 6.31 (s, 1H,
2-H), 11.23 (br. s, 1H, NH). MS, m/z: 117. Found (%): C, 30.97; H, 5.96;
N, 35.65. Calc. for C3H7N3O2 (%): C, 30.77; H, 6.03; N, 35.88.
NO2
Me + 4 (from 6)
N
NHAc
HO
‡
For compound 2: yield 37%, mp 111–113 °C (decomp.). 1H NMR
([2H6]DMSO), d: 2.45 (d, 3H, 1-Me, J 1.2 Hz), 6.90, 7.70 (2m, 2×2H,
C6H4), 7.95 (q, 1H, 2-H, J 1.2 Hz, JCH–NH 1.2 Hz), 10.37 (br. s, 1H, NH).
MS, m/z: 207.
8
Scheme 1 Reagents and conditions: i, hydrazine hydrate (22 mmol) was
added to a suspension of 2-dimethylamino-1-nitroprop-1-ene (20 mmol) in
10 ml of isopropanol; the mixture was stirred (20 °C, 1 h) and evaporated.
The residue was triturated with cold isopropanol and the precipitate was
filtered off; ii, a mixture of p-benzoquinone (5 mmol) and compound 1
(5 mmol) in 5 ml of AcOH (20 °C, 2 h), and the precipitate was filtered off;
iii, a mixture of compound 1 (2 mmol), EtOH (10 ml), and benzaldehyde
(2 mmol) was stirred (20 °C, 1 h) and the precipitate was filtered off; iv, a
§
For compound 3: yield 88%, mp 175–177 °C (EtOH). 1H NMR
([2H6]DMSO) d: 2.22 (s, 3H, 1-Me), 6.74 (s, 1H, 2-H), 7.49, 7.75 (m,
5H, Ph), 8.61 (s, 1H, CHPh), 12.43 (br. s, 1H, NH). MS, m/z: 205.
Found (%): C, 58.49; H, 5.40; N, 19.95. Calc. for C10H11N3O2 (%): C,
58.53; H, 5.40; N, 20.48.
¶
For compound 4: yield 22%, mp 263–265 °C (EtOH). 1H NMR
([2H6]DMSO) d: 2.85 (s, 3H, 2-Me), 6.87 (dd, 1H, 5-H, J1 8.6 Hz, J2
1.2 Hz), 6.97 (d, 1H, 7-H, J2 1.2 Hz), 7.60 (m, 3H, 3'-H, 4'-H, 5'-H),
8.03 (d, 2H, 2'-H, 6'-H, J 7.4 Hz), 7.98 (d, 1H, 4-H, J 8.6 Hz), 9.12 (s,
1H, CHPh). MS, m/z: 295. Found (%): C, 65.63; H, 4.47; N, 13.75. Calc.
for C16H13N3O3 (%): C, 65.08; H, 4.44; N, 14.23.
mixture of -benzoquinone (4.6 mmol), -toluenesulfonic acid (4.6 mmol),
p
p
and compound 3 (4.6 mmol) in 12 ml of AcOH was stirred (20 °C, 3 h) and
the precipitate was filtered off; v, a mixture of compound 4 (6.4 mmol)
and Ac2O (20 ml) was refluxed for 1 h, diluted with water, and filtered; vi,
a mixture of compound 4 (1.1 mmol), Ac2O (3 ml), and 1 drop of H2SO4
was stirred for 1.5 h at 20 °C; compound 6 was filtered off; the mother
liquor was diluted with water and the precipitate formed was chromato-
graphed on a column with silica gel (ethyl acetate) to isolate compounds 6
and 7; vii, a mixture of compound 4 (1.5 mmol), Ac2O (4.5 mmol), a drop
of H2SO4, and 10 ml of AcOH was stirred for 2 h at 50 °C; viii, a mixture
of compound 6 (1.4 mmol), HCl (1 ml), EtOH (40 ml), and H2O (1 ml) was
refluxed for 20 min and evaporated; the residue was triturated with ethanol;
compound 4 was filtered off and compound 8 was isolated from the mother
liquor; ix, a mixture of compound 7 (1.4 mmol), piperidine (2.8 mmol),
benzene (20 ml), and EtOH (5 ml) was refluxed for 6 h and evaporated; the
residue was triturated with benzene and the precipitate was filtered off.
†† For compound 5: yield 70%, mp 182–183 °C (EtOH). 1H NMR
([2H6]DMSO) d: 2.27 (s, 3H, 6-OCOMe), 2.87 (s, 3H, 2-Me), 7.20 (dd,
1H, 5-H, J1 8.6 Hz, J2 1.2 Hz), 7.59 (d, 1H, 7-H, J2 1.2 Hz), 7.60 (t, 2H,
3'-H, 5'-H, J 7.4 Hz), 7.67 (t, 1H, 4'-H, J 7.4 Hz), 8.05 (d, 2H, 2'-H,
6'-H, J 7.4 Hz), 8.20 (d, 1H, 4-H, J1 8.6 Hz), 9.14 (s, 1H, CHPh).
13C NMR ([2H6]DMSO) d: 12.3 (2-Me), 20.6 (6-OCOMe), 104.6 (C7),
117.3 (C3a), 118.8 (C5), 120.1 (C4), 125.0 (C3), 128.9, 130.6, 131.9 (Ph),
130.6 (C7a), 141.2 (C2), 147.7 (C6), 166.6 (CHPh), 169.1 (OCOMe).
MS, m/z: 337. Found (%): C, 64.09; H, 4.51; N, 12.31. Calc. for
C18H15N3O4 (%): C, 64.09; H, 4.48; N, 12.46.
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, 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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