Intramolecular cyclization of O-(3,5-diaminophenyl)-substituted ketoximes as a route to 6-amino-4-hydroxyindoles

Article abstract of DOI:10.1016/j.mencom.2011.07.008

O-(3,5-Diaminophenyl)-substituted ketoximes undergo acid-catalysed cyclization to afford 6-amino-4-hydroxyindoles.

Full text of DOI:10.1016/j.mencom.2011.07.008

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 196–197
Intramolecular cyclization of O-(3,5-diaminophenyl)-substituted
ketoximes as a route to 6-amino-4-hydroxyindoles
Galina V. Kokurkina, Mikhail D. Dutov,* Svyatoslav A. Shevelev and Bogdan I. Ugrak
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: dutov@ioc.ac.ru
DOI: 10.1016/j.mencom.2011.07.008
O-(3,5-Diaminophenyl)-substituted ketoximes undergo acid-catalysed cyclization to afford 6-amino-4-hydroxyindoles.
NO2
O-Arylated ketoximes 1 are known to undergo acid-catalysed
intramolecular cyclization to give 2-R1-3-R2-benzo[b]furans 2
(Scheme 1).1–4
N
CH2R
H2N
O
R2
Ar
X
X
3
H+
– NH4+
R = H, Alk
R1
N
CH2R2
O
O
NO2
OH
R1
R
R
1
2
R1 = Alk, Ar
R2 = H, Alk
Ar
Ar
+
O
NH
H2N
O2N
Scheme 1
4
5
Scheme 3
Formation of benzofurans 2 is supposed to proceed through acid-
catalysed [3,3]-sigmatropic rearrangement of the enamino tauto-
meric form of the ketoxime (A®B) followed by aromatization
of the six-membered ring (B®C), intramolecular addition of the
OH group to the C=NH2+ bond (C®D) and final elimination of
ammonium ion (D®2) (Scheme 2).3
NH2
CH2R
N
O
O2N
H
Ar
H
3
path a
path b
R2
R2
X
X
X
X
R1
R1
NH
NO2
R
NH2
R
H+
H+
Ar
NH2
Ar
Ar
N
O
O
NH2
1
A
H2N
O
R
O
R
O2N
H
R2
R2
H
X
R1
R1
NO2
OH
OH
Ar
NH2
NH2
NH2
O
O
OH
NH2
NH2
B
C
H2N
OH
O2N
R2
R1
NH3
R2
H
X
+
R1
NO2
R
R
O
– NH4
O
Ar
NH3
Ar
NH3
D
2
N
H
H2N
Scheme 2
O2N
– NH4
– NH4
We have recently shown5 that intramolecular cyclization of
ketoximes 3 bearing 3-amino-5-nitrophenyl substituent proceeds
differently: two isomeric products, namely, 6-amino-4-nitro-
benzofurans 4 and unexpected 4-hydroxy-6-nitroindoles 5 are
formed in equal amounts (Scheme 3).
It can be assumed that cyclization occurs both at the ortho
position to the nitro group and at the ortho position to the amino
group. In the former case, 6-amino-4-nitrobenzofuran 4 is formed
OH
NO2
R
R
O
Ar
Ar
N
H
O2N
H2N
4
5
Scheme 4
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 196–197
in the usual way (Scheme 4, pathway a), while in the latter case,
This work was supported by the Russian Foundation for Basic
Research (project no. 10-03-00623).
not OH group but more nucleophilic NH2 group adds to the
C=NH2+ bond to furnish 4-hydroxy-6-nitroindole 5 (Scheme 4,
pathway b).
References
To prove this mechanism, it seemed reasonable to perform
cyclization of O-(3,5-diaminophenyl)-substituted ketoximes 6
(Scheme 5). However, to access diamino compounds 6 by reduc-
tion of nitro group in precursors 3 was difficult. In fact, the pre-
viously used5 method of selective reduction of dinitrophenyl
ketoximes 1 with a considerable excess of hydrazine hydrate
catalyzed by FeCl3/activated carbon proved inefficient in case of
compounds 3 and resulted in resinification only. The procedure
involving hydrazine hydrate on Raney nickel under standard
conditions (MeOH, reflux for 1 h) resulted in oxime cleavage to
give 3,5-diaminophenol. Luckily, performing the reaction at room
temperature and prolonging exposure led to diaminooximes 6 in
acceptable yields. Cyclization of the latter in a mixture of ethanol
and concentrated HCl afforded 6-amino-4-hydroxyindoles 7 as the
only products, which unambiguously confirms our above mech-
anistic assumptions.
1 A. Mooradian and P. Dupont, Tetrahedron Lett., 1967, 407.
2 A. Mooradian and P. Dupont, J. Heterocycl. Chem., 1967, 4, 441.
3 P. R. Guzzo, R. N. Buckle and M. Chou, J. Org. Chem., 2003, 68, 770.
4 A.Alemagna, C. Baldoli, P. Bruttero, E. Licandro and S. Maiorana, Synthesis,
1987, 192.
5 S. S. Vorob’ev, M. D. Dutov, I. A. Vatsadze, E. P. Petrosyan, V. V. Kachala,
Yu. A. Strelenko and S. A. Shevelev, Izv. Akad. Nauk, Ser. Khim., 2007,
984 (Russ. Chem. Bull., Int. Ed., 2007, 56, 1020).
Received: 24th January 2011; Com. 11/3671
†
1H NMR spectra (in DMSO-d6) were recorded on a Bruker AM-300
NH2
NH2
spectrometer.
1
i
6a: yield 73%, mp 91–92°C. H NMR, d: 2.35 (s, 3H), 4.77 (s, 4H),
5.53 (s, 1H), 5.77 (s, 2H), 7.46 (s, 2H), 7.76 (s, 1H).
N
Ar
N
Ar
6b: yield 52%, mp 151–152°C. 1H NMR, d: 2.33 (s, 3H), 4.77 (s, 4H),
5.53 (s, 1H), 5.75 (s, 2H), 7.64–7.73 (m, 4H).
O2N
O
H2N
O
Me
Me
6c: yield 94%, mp 132–133°C. 1H NMR, d: 2.35 (s, 3H), 4.81 (s, 4H),
5.55 (s, 1H), 5.78 (s, 2H), 7.71 (d, 2H, J 5.8 Hz), 8.66 (d, 2H, J 5.8 Hz).
6d: yield 87%, oil. 1H NMR, d: 2.30 (s, 3H), 4.75 (s, 4H), 5.51 (s, 1H),
5.69 (s, 2H), 7.40–7.49 (m, 3H), 7.54–7.57 (m, 1H).
6a–e
(52–94%)
3a–e
OH
6e: yield 79%, oil. 1H NMR, d: 2.29 (s, 3H), 4.75 (s, 4H), 5.51 (s, 1H),
5.68 (s, 2H), 7.48–7.54 (m, 2H), 7.74 (m, 1H).
a Ar = Ph
ii
b Ar = 4-BrC6H4
c Ar = 4-pyridyl
d Ar = 2-ClC6H4
e Ar = 2,4-Cl2C6H3
Ar
7a: yield 57%, mp > 300°C. 1H NMR, d: 5.08 (s, 2H), 5.85 (s, 1H), 6.13
(s, 1H), 6.72 (s, 1H), 7.15–7.20 (m, 1H), 7.34–7.39 (m, 2H), 7.68–7.71
(m, 2H), 9.10 (s, 1H), 10.76 (s, 1H).
NH
H2N
7a–e
(54–79%)
1
7b: yield 61%, mp > 300°C. H NMR, d: 4.74 (s, 2H), 5.81 (s, 1H),
6.06 (s, 1H), 6.73 (s, 1H), 7.53 (d, 2H, J 8.3 Hz), 7.64 (d, 2H, J 8.4 Hz),
9.09 (s, 1H), 10.75 (s, 1H).
7c: yield 64%, mp > 300°C. 1H NMR, d: 4.93 (s, 2H), 5.84 (s, 1H), 6.07
(s, 1H), 7.00 (s, 1H), 7.61 (d, 2H, J 4.6 Hz), 8.46 (d, 2H, J 4.4 Hz), 9.27 (s,
1H), 10.93 (s, 1H).
Scheme 5 Reagents and conditions: i, N2H4·H2O (2 equiv.), Raney Ni,
activated catalyst, 50% slurry in water, MeOH, room temperature, 1.5 h;
ii, EtOH–HCl (1:1), reflux, 0.5–3 h.
7d: yield 54%, mp 163–164°C. 1H NMR, d: 4.98 (s, 2H), 5.85 (s, 1H),
6.11 (s, 1H), 6.88 (s, 1H), 7.21–7.26 (m, 1H), 7.36–7.41 (m, 1H), 7.51 (d,
1H, J 7.8 Hz), 7.66 (d, 1H, J 7.6 Hz), 9.13 (s, 1H), 10.66 (s, 1H).
7e: yield 79%, mp 171–172°C. 1H NMR, d: 4.91 (s, 2H), 5.84 (s, 1H),
6.09 (s, 1H), 6.93 (s, 1H), 7.47 (d, 1H, J 8.1 Hz), 7.65–7.69 (m, 1H), 9.17
(s, 1H), 10.71 (s, 1H).
The structures of the compounds synthesized were confirmed
by the 1H NMR spectroscopy, mass spectrometry (molecular ions
were recorded in all cases) and microanalysis.†
In conclusion, we have pioneered in indole preparation by
intramolecular cyclization of O-arylated ketoximes.
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