An unusual route to a quinoline 1-oxide via intramolecular addition of an enolate to an aromatic nitro group

Article abstract of DOI:10.1515/HC.2011.043

A mixture of ethyl 4-(2-nitrophenyl)butenoates undergoes an unusual intramolecular cyclisation in the presence of a catalytic amount of potassium tert-butoxide. 2011 · Copyright by Walter de Gruyter.

Full text of DOI:10.1515/HC.2011.043

Heterocycl. Commun., Vol. 17(5-6), pp. 203–205, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.043
An unusual route to a quinoline 1-oxide via intramolecular
addition of an enolate to an aromatic nitro group
corresponding to each isomer in the 1H NMR spectrum. The
1H NMR signals of 4 were identified by comparison with the
literature values (Lee et al., 2001), which allowed for deduc-
tive inference of the signals corresponding to 5. A small por-
tion of this substance was left under inert atmosphere for
5 days at room temperature and the sample was reanalysed by
1H NMR, displaying a different distribution of isomers, with
a ratio of 1:2.6 in favour of 5. This suggests that double bond
isomerisation gives 5 as the thermodynamic isomer.
Nayara Da Rocha F. Moreira1, Tânia T. de Oliveira2,
Tanus J. Nagem1 and Jason G. Taylor1,*
1 Departamento de Química, ICEB, Universidade Federal
de Ouro Preto, Campus Universitário Morro do Cruzeiro,
35400–000, Ouro Preto-MG, Brazil
2 Departamento de Bioquímica e Biologia Celular,
Universidade Federal de Viçosa, Av. P.H. Rolfs, s/n,
36571–000, Viçosa-MG, Brazil
*Corresponding author
e-mail: jason@iceb.ufop.br
To confirm unequivocally the presence of the two isomeric
products, hydrogenation of the mixture to one single com-
pound was attempted (Scheme 3).
The expected saturated aliphatic ester was not observed.
Instead, a substituted indole 6 was isolated in good yield. The
spectral data for 6 were identical with those reported for the
compound that was obtained by using a different synthetic
route (Guerrero and Miranda, 2006). Evidently, the nitro
group is reduced faster than the alkene function resulting in
formation of a substituted aniline from 4, which then under-
goes an intramolecular Michael addition reaction to give a
cyclic precursor to 6. The cyclisation of the isomer 5 requires
a double bond migration in 5 to give 4. Numerous similar
isomerisations are known (Urones et al., 1999). The for-
mation of indole 6 from the intermediate indoline requires
a Pd-catalysed dehydrogenation reaction to take place. The
highly efficient Pd-catalysed aromatisation of indolines is
known (Bader et al., 1961).
By contrast, treatment of the mixture 4/5 with a catalytic
amount of potassium tert-butoxide in ethanol (Scheme 4)
gave a quinoline N-oxide 7, which was readily identified
by the downfield resonances characteristic of the quinoline
N-oxide structure (Yin et al., 2007) and comparison with an
authentic sample (Barczynski et al., 1974).
Currently, we are studying the scope, limitations and mech-
anism of this novel transformation that apparently involves an
intramolecular addition reaction of an ester enolate to a nitro
group. The results will be reported in due course.
Abstract
A mixture of ethyl 4-(2-nitrophenyl)butenoates undergoes an
unusual intramolecular cyclisation in the presence of a cata-
lytic amount of potassium tert-butoxide.
Keywords: cyclisation; enolate; intramolecular; nitro;
oxide; quinoline.
Introduction
The quinoline N-oxide core structure can be encountered
in a range of medicinal products exhibiting a diverse array
of biological activity (Albrecht et al., 1980; Werbel et al.,
1993; Mouaddib et al., 2000; Capraro et al., 2005; Andreev
et al., 2006). We were prompted to disclose our preliminary
results due to a recent publication (Okuma et al., 2010) in
which an α, β-unsaturated carbonyl system similar to the sub-
strate we are investigating (see 4/5 below) was cyclised under
Lewis acidic conditions. Herein, we report a complementary
approach utilising a base-induced intramolecular cyclisation
of the transient: an enolate with an aryl nitro group to provide
a 2-(ethoxycarbonyl)quinoline 1-oxide (7) in good yield.
Results and discussion
Experimental
For the synthesis of the precursor leading to the quinoline
1-oxide, we were initially guided by literature procedures
(Molina et al., 1996; Kambe et al., 2001), which described
the preparation of an aldehyde by employing a Wittig reac-
tion. Thus, compounds 1 and 2 were synthesised as shown in
Scheme 1.
Compounds 1 (Muchowski, 1971), 2 (Noland and Sellstedt, 1966)
and 3 (Kasim and Manfred, 2001; Spencer et al., 2007; Ngwendson
et al., 2008) were prepared as reported previously. Compound 7 has
been obtained previously by using an independent route (Barczynski
et al., 1974).
The subsequent Wittig reaction of 2 with phosphonium
ylide 3 yielded a mixture of inseparable isomers 4 and 5
with an initial ratio of 4.5: 1 in favour of 4 (Scheme 2). The
ratio was determined by integration of the methylene protons
Mixture of compounds 4 and 5
A solution of 2 (0.34 g, 1.3 mmol) in dichloromethane (15 mL) was
treated dropwise over 1 h at -10°C under a nitrogen atmosphere
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204 N.D.R.F. Moreira et al.
O
H
H
NO2
NO2
NO2
KOH
H
PCC
DCM, rt, 3 h
(2.5 equiv)
DMSO, rt, 5 h
OH
O
1
2
23% Yield
74% Yield
Scheme 1 Synthesis of 2-nitro-benzeneacetaldehyde.
NO2
OEt
OEt
NO2
Ph3P
H
77% Total yield
Intial 4/5 = 4.5:1
5 days 4/5 = 1:2.6
4
5
O
O
3
O
NO2
O
DCM, 0 oC, 2 h, N2
OEt
2
Scheme 2 Synthesis of isomers 4 and 5 by a Wittig reaction.
H
with a solution of 4 and 5 (310 mg, 1.3 mmol) in absolute ethanol
(20 mL). To the solution Pd/C (10%, 100 mg) was added and the
mixture was exposed to hydrogen using a balloon. The mixture was
vigorously stirred overnight and then filtered through a plug of celite.
The celite was rinsed with additional ethanol. The filtrate was con-
centrated on a rotary evaporator yielding indole 194 mg (73%) of
the indole 6 as pale yellow oil; Rf =0.5 (silica gel, hexanes/EtOAc,
7:3). Spectroscopic data are virtually identical with reported values
(Guerrero and Miranda, 2006).
N
OEt
10% Pd/C,H2
EtOH, rt, 24 h
4+5
O
6
73% Yield
Scheme 3 Domino nitro group reduction-conjugate addition-
Pd-catalysed dehydrogenation reaction.
O
N
O
2-(Ethoxycarbonyl)quinoline 1-oxide (7) A50-mLround-bottom
flask equipped with a magnetic stir bar was charged with a 1:2.6 mix-
ture of 4 and 5 (100 mg, 0.43 mmol). Absolute ethanol (15 mL) was
added, followed by potassium tert-butoxide (5 mg, 0.044 mmol) and
the mixture was stirred at room temperature for 2 h. Concentration
of the mixture under reduced pressure followed by silica gel chroma-
tography (hexanes/EtOAc, 5:1) of the oily residue gave 76 mg (83%)
tBuOK
EtOH, rt, 2 h
83% Yield
10 mol%
OEt
4+5
7
Scheme 4 Synthesis of a quinoline N-oxide.
1
of 7 as a pale yellow oil; Rf =0.3 (hexanes/EtOAc, 4:1); H NMR
with a solution of 3 (0.69 g, 1.95 mmol) in dichloromethane (15
mL). The mixture was then stirred for 2 h at 25°C and concentrated
under reduced pressure. The solid residue was dissolved in hexanes
(50 mL) and the mixture was stirred at 25°C for 0.5 h. The precipi-
tate of Ph3PO was filtered off and the filtrate was concentrated under
reduced pressure. The oily residue was purified by silica gel chroma-
tography eluting with hexanes/EtOAc (5:1) to afford a 4.5:1 ratio of
4:5. The ratio changed to 1:2.6 in favour of 5 after 5 days. Compound
4 is known and its spectroscopic data are virtually identical with the
reported literature values (Lee et al., 2001).
(400 MHz, CDCl3): δH 8.82 (1H, d, J=8 Hz), 7.91 (1H, d, J=8 Hz),
7.84 (1H, t, J=8 Hz), 7.70–7.76 (2H, m), 7.61 (1H, d, J=8 Hz), 4.59
(2H, q, J=7 Hz), 1.65 (3H, t, J=7 Hz); 13C NMR (100 MHz, CDCl3):
δC 162.4, 142.5, 137.8, 130.9, 130.6, 129.7, 128.2, 124.7, 121.1,
120.3, 62.6, 14.2; CI-MS: m/z 218 ([M+H]+, 100%), 202 (20%).
Acknowledgements
The authors thank the Conselho Nacional de Desenvolvimento
Científico e Tecnológico (CNPq), the Fundação Coordenação
de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and
the Fundação de Amparo à Pesquisa do Estado de Minas Gerais
(FAPEMIG) for financial support. We thank Dr. Robson J. de Cássia
FrancoAfonso and Dr. Maurício Xavier Coutrim for providing excel-
lent mass spectrometry service.
New compound 5 Pale yellow oil; Rf = 0.3 (silica gel, hexanes/
EtOAc, 4:1); IR (neat): υmax 2983, 1721, 1639, 1529, 1347, 1292,
1
1347, 1292, 1183, 1035, 976, 858, 787, 742, 664 cm-1; H NMR
(400 MHz, CDCl3): δH 7.95 (1H, d, J=7 Hz), 7.67 (1H, t, J=7 Hz),
7.36–7.45 (2H, m), 7.03 (1H, d, J=15 Hz), 6.39 (1H, dt, J=7 and 15
Hz), 4.24 (2H, q, J=7 Hz), 3.34 (2H, d, J=7 Hz), 1.31 (3H, t, J=7
Hz); 13C NMR (100 MHz, CDCl3): δC 166.1, 144.9, 133.5, 132.5,
128.8, 128.2, 127.5, 124.5, 123.3, 60.9, 35.6, 14.2; EI-MS: m/z 235
(M+, 5%), 190 (25%), 172 (25%), 162 (50%), 120 (100%), 116
(90%), 92 (45%), 77 (35%).
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Received September 2, 2011; accepted November 4, 2011
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