Novel and convenient synthesis of 4(1H)quinolones

Article abstract of DOI:10.1016/j.tetlet.2004.12.046

A rapid two-step synthesis of 4(1H)quinolones is described. The first step involves condensation of o-nitroacetophenone with N,N-dimethylformamide dimethylacetal yielding highly crystalline enamines. In the second step a reductive cyclization is achieved

Full text of DOI:10.1016/j.tetlet.2004.12.046

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 735–737
Novel and convenient synthesis of 4(1H)quinolones
Jan Tois,a Mikko Vahermob and Ari Koskinena,*
aLaboratory of Organic Chemistry, Helsinki University of Technology, PO Box 6100, FIN 02015, Finland
bDepartment of Pharmacy, Viikki Drug Discovery Technology Center, PO Box 56, FIN 00014 University of Helsinki, Finland
Received 29 October 2004; revised 26 November 2004; accepted 8 December 2004
Available online 21 December 2004
Abstract—A rapid two-step synthesis of 4(1H)quinolones is described. The first step involves condensation of o-nitroacetophenone
with N,N-dimethylformamide dimethylacetal yielding highly crystalline enamines. In the second step a reductive cyclization is
achieved under catalytic transfer hydrogenation (CTH) conditions. In all cases, the total time of this process was less than 3 h.
Ó 2004 Published by Elsevier Ltd.
The 4(1H)quinolone structure1 plays an extremely
important role in the field of pharmaceutical chemistry.
These compounds have been used as precursors for anti-
cancer agents,2 anti-malarial agents3 and reversible (H+/
K+) ATPase inhibitors (Fig. 1).4 Traditionally 4-substi-
tuted quinolones have been synthesized at high temper-
atures.5 Huang and Liu have even adopted this kind of
thermal cyclization reaction on solid phase.6 More
recently, Nishida et al. prepared 6-methoxy-4(1H)quino-
lone using an elegant ene–enol ether metathesis.3 Atkins
et al. have summarized other interesting synthetic routes
to these compounds.7 In fact, Atkins reported in this
O
N
OMe
OMe
N
N
O
O
5H-8, 9-dimethoxy-5-(2-N, N-dimethylaminoethyl) -
2, 3-methylenedioxydibenzo[c, h]1, 6-naphthyridin-6-one2
O
N
O
HO
N
MeO
H
N
PPMP-Quinine Hybrid3
H
N
N
O
OMe
3-butyryl-8-methoxy-4-[(2-methylphenyl)amino]quinoline4
Figure 1. Pharmaceutically interesting molecules prepared from 4-substituted quinolones.
Keywords: Quinolones; Leimgruber–Batcho; Pd catalysis.
*
Corresponding author. Tel.: +358 9 451 2526; fax: +358 9 451 2538; e-mail: ari.koskinen@hut.fi
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.12.046

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J. Tois et al. / Tetrahedron Letters 46 (2005) 735–737
etal in DMF at 100 °C (Scheme 1). In all cases the
O
O
O
reactions went to completion in 90 min or less according
to TLC. The solvent was evaporated in vacuo and the
crude enamines were crystallized from ethanol yielding
the enamines as mixtures of E- and Z-isomers. The
enamines were cyclized to quinolones 3 under catalytic
transfer hydrogenation conditions (CTH) using cyclo-
hexene as hydrogen source and 10% Pd–C as catalyst.9
The catalyst:substrate ratio was 1:5 by weight (4–
7 mol% of Pd). Even lower ratios accomplished the
cyclization but when a catalyst:substrate ratio of 1:1
was used, an unwanted side reaction occurred.10 In all
cases, the violent evolution of hydrogen was observed
when reaction temperatures reached 80 °C and the reac-
tion was complete in 60 min (or less) according to TLC.
(i)
(ii)
N
N
H
NO2
R
NO2
R
R
2
3
1
Scheme 1. Reagents and conditions: (i) DMF–DMA, DMF, 100 °C,
90 min; (ii) 10% Pd–C, cyclohexene, EtOH, reflux, 60 min.
paper a modified Leimgruber–Batcho8 procedure to
form the desired 3-substituted-4(1H)quinolone. How-
ever, there was only one example of this method. Herein,
we present our synthetic studies towards 4-substituted
quinolones without substituents on the 2- or 3-position
utilizing this efficient two-step procedure.
The enamines 2 were synthesized by heating the o-nitro-
acetophenones 1 with dimethylformamide dimethylac-
The results are summarized in Table 1. With pure iso-
mers as starting materials (1a, 1b, 1c, 1e), the reactions
Table 1. Starting materials, products, yields and reaction times
1
Enamine 2 (yield %) [time, min]
4(1H)quinolone 3 (yield %) [time, min]
O
O
O
N
N
NO2
NO2
H
3a, (85) [20]
O
1aa
2a, (95) [50]
O
O
O
O
O
O
O
N
O
N
H
NO2
NO2
O
1ba
2b, (78) [60]
3b, (91) [15]
O
O
MeO
HO
MeO
BnO
MeO
BnO
N
N
H
NO2
NO2
1cb
2c, (82) [60]
3c, (95) [60]
O
O
MeO
MeO
N
O
NO2
O
NO2
MeO
N
H
O
MeO
O2N
MeO
N
N
3d, (52) [60]
O2N
1dc
2d, (84) [40]
O
O
O
MeO
HO
MeO
TfO
MeO
TfO
N
H
NO2
NO2
1eb
2e, (87) [60]
3c, (70) [30]
a Commercially available.
b Synthesized from 4-hydroxy-3-methoxyacetophenone.
c A mixture of 3-methoxy-2-nitroacetophenone and 3-methoxy-4-nitroacetophenone was used as starting material.11

J. Tois et al. / Tetrahedron Letters 46 (2005) 735–737
737
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proceeded smoothly affording the desired enamines and
4(1H)quinolones in high yields. In the case of 1c it is
noteworthy that the hydrogenation of the benzyl group
and the reductive cyclization took place in one pot to
give directly 3c. To demonstrate the efficiency and
advantages of this process we tested this transformation
with a mixture of acetophenones 1d as starting materi-
als.11 The mixture of enamines 2d was formed in the
same ratio as the starting materials. To our delight the
reductive cyclization went as expected. The 6-methoxy-
4(1H)quinolone was formed and no side reaction caused
by the reduction product of the ÔwrongÕ isomer was
observed.
We also tested if it would be possible to deoxygenate 2e
under these conditions to afford 3d. Traces of 3d were
detected on TLC but we were able to isolate only 3c.
´
Wang, J. Synthesis 1987, 482–483; (d) Gall-Istok, K.;
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In summary, we have demonstrated that this Leimgruber–
Batcho analog is an extremely effective method for the
preparation of 4(1H)quinolones. Further modifications
of these synthesized molecules with asymmetric com-
pounds are now under investigation in our laboratories
and the results will be presented in due course.
8. Batcho, A. D.; Leimgruber, W. Org. Synth. 1985, 63, 214.
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10. A highly non-polar by-product was observed on TLC
when the catalyst:substrate ratio was 1:1. This side
product was not characterized.
Acknowledgements
This research is financially supported by the Finnish
National Technology Agency, TEKES.
11. Mixture 1d was prepared according to Robbins, R. J.;
Laman, D. M.; Falvey, D. E. J. Am. Chem. Soc. 1996, 118,
8127–8135; We were not able to separate the isomers and
the ratio of 3-methoxy-2-nitroacetophenone:3-methoxy-4-
nitro-acetophenone (56:44) was determined by NMR
spectrometry. We highly recommend the method pub-
References and notes
1. We will use this name throughout the text. In most
published articles the tautomeric form 4-hydroxyquinoline
is used. For discussion of the keto–enol tautomerism see,
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¨
3-methoxy-2-nitroacetophenone. Furstner, A.; Jumbam,
¨
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´
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