Efficient synthesis of substituted quinoline-5,8-quinones from 8-hydroxyquinolines by photooxygenation

Article abstract of DOI:10.1016/S0040-4039(01)00727-4

Substituted quinoline-5,8-quinones were obtained in good yield by photooxygenation of substituted 8-hydroxyquinolines.

Full text of DOI:10.1016/S0040-4039(01)00727-4

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TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4329–4331
Efficient synthesis of substituted quinoline-5,8-quinones from
8-hydroxyquinolines by photooxygenation
Janine Cossy* and Damien Belotti
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received 16 March 2001; accepted 27 April 2001
Abstract—Substituted quinoline-5,8-quinones were obtained in good yield by photooxygenation of substituted 8-hydroxyquino-
lines. © 2001 Elsevier Science Ltd. All rights reserved.
Natural products that bear a 9,10-diazaanthracene-
dione moiety show interesting antitumor properties.
Anthracyclines,1 pluramycins2 as well as some enediyne
antibiotics such as dynemicin A and deoxydynemicin
A3 are typical examples. The antitumour activity of
these quinones is probably due to multiple mechanisms,
normally initiated by DNA intercalation. Formation of
DNA damaging anion-radical intermediates by reduc-
tion of the quinone unit is probably involved in their
cytotoxicity, at least in the case of anthracycline.4 Natu-
ral products such as azabenzisochromanquinones,5
streptonigrinone,6 lavendamycin,7 and cystodamine,8 in
In this letter, we report the synthesis of substituted
quinoline-5,8-quinones in good yield, by photosensi-
tized oxidation of readily available substituted 8-
hydroxyquinolines of type 1 (Scheme 1).
meso-Tetraphenylporphine (TPP) is well known to be a
highly effective triplet state photosensitizer16 and to be
able to efficiently produce singlet molecular oxygen, O2
(1Dg), under illumination in the presence of oxygen.17
TPP-sensitized photooxygenation of compounds of
type 1 in methylene chloride, at room temperature,
resulted in the formation of quinoline-5,8-quinones of
type 2 after treatment of the crude reaction mixture
with dry Na2SO4 and purification by chromatography
on silica gel.18 The results are reported in Table 1.
which
a
carbon of the benzene ring of the
anthraquinone is replaced by a nitrogen, also show
antitumor antibiotic activities. These compounds have
geometries similar to those of the parent
anthraquinones and hence are capable of intercalation
but with sites suitable for hydrogen bonding or ionic
interactions they show an increased affinity for DNA.
Additionally, the electron-withdrawing properties of the
heterocyclic rings must facilitate the formation of
anion-radicals. For these reasons, quinoline-5,8-
quinones are important synthetic intermediates for the
synthesis of a variety of biologically active compounds
such as azaanthraquinones.9
1
The structures of 2a–j were assigned by H NMR, 13C
NMR and by mass spectra. The most conspicuous
features in the 1H NMR spectra of quinoline-5,8-
quinones are two distinct doublets which correspond to
two olefinic protons in the range of 7.0–7.3 ppm with a
coupling constant of 10.0–11.0 Hz. Electron-donating
or electron-withdrawing substituants on C(2), C(3) or
C(4) can be present on 8-hydroxyquinolines without
A great number of reagents or methods suited for the
preparation of substituted quinoline-5,8-quinones has
been developed.10–13 Among these, Fremy’s salt is the
most widely used oxidizing agent for the transforma-
tion of substituted 8-hydroxyquinolines to substituted
quinoline-5,8-quinones.14 However, this reagent is best
suited to small scale experiments.15
O
O
R1
R1
R2
R3
R2
R3
hν > 495 nm
O2, ε TPP
N
N
CH2Cl2, rt
OH
1
2
Keywords: quinolines; phenols; quinones; oxygenation; photochem-
istry.
* Corresponding author.
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00727-4

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J. Cossy, D. Belotti / Tetrahedron Letters 42 (2001) 4329–4331
Table 1. Synthesis of quinoline-5,8-quinones 2 from 8-hydroxyquinolines 1
Entry
R1
R2
R3
Timea (h)
Yield% of 2b
a
b
c
d
e
f
g
h
i
H
H
H
CH3
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
CH3
H
H
CN
CHO
CO2Me
CON(i-Pr)2
CH2N(Boc)CH2Ph
CH2N(Boc)CH2CO2Me
2.5
2.5
2.0
2.0
8.0
5.5
2.0
2.0
2.5
2.0
82
80
82
72
73 (86)c,d
51 (68)c,e
81
89
53
j
H
H
50 (63)c,f
a All reactions were performed in CH2Cl2 on a 2 mmol scale. Reactions can be performed on a 20 mmol scale by irradiating for 10–12 h.
b Yield of isolated product after purification by chromatography on silica gel.
c Yield based on the transformed starting material.
d 15% of the starting material was recovered.
e 25% of the starting material was recovered.
f 21% of the starting material was recovered.
R1
R1
N
R2
R3
R2
R3
1O2
- H2O
O
2
O
N
OH
OH
1
3
Scheme 2.
affecting their transformation to quinoline-5,8-
quinones. The mechanism for the formation of the
quinoline-5,8-quinones 2 from 8-hydroxyquinolines 1
was assumed to be a [4+2] cycloaddition of singlet
oxygen to the phenolic ring which can afford hydroxy-
endoperoxides of type 3. This latter compound could
lead to quinoline-5,8-quinones after decomposition in
the presence of dry Na2SO4. All efforts to isolate 3 were
unsuccessful (Scheme 2).
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In conclusion, we have developed a very efficient syn-
thesis of quinoline-5,8-quinones from 8-hydroxyquino-
lines by using a photooxygenation in the presence of
TPP. This methodology allowed for the preparation of
new substituted quinoline-5,8-quinones on multigram
scale and in a highly concise way.
5. To¨dter, C.; Lackner, H. Liebigs Ann. Chem. 1996, 1385.
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Acknowledgements
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We are grateful to the Laboratoire L. Lafon for finan-
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18. General procedure: A solution of substituted 8-hydroxy-
quinoline (2 mmol) and TPP (6 mg, 0.01 mmol) in
CH2Cl2 (20 mL) was irradiated, under oxygen bubbling,
with a 1800 W xenon lamp through a UV cut-off glass
filter (u>495 nm) at 20°C. After 2–8 h (TLC monitoring),
the resulting mixture was treated with dry Na2SO4 (3 g)
for 3 h and then filtered. The solvent was evaporated in
vacuo and the residue was purified by flash column
chromatography on silica gel to give pure substituted
quinoline-5,8-quinone.
.