Hetero Diels-Alder reactions of 1-acetylamino- and 1-dimethylamino-1- azadienes with benzoquinones

Article abstract of DOI:10.1016/S0040-4020(00)00058-2

Treatment of bromobenzoquinone with 2 equiv. of a 1-dimethylamino-1- azadiene afforded mixtures of the corresponding 1,8-diaza-9,10-anthraquinone and 1,5-diaza-9,10-anthraquinone. Double hetero Diels-Alder reactions between 1-dimethylamino-1-azadienes and

Full text of DOI:10.1016/S0040-4020(00)00058-2

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1561–1567
Hetero Diels–Alder Reactions of 1-Acetylamino- and
1-Dimethylamino-1-azadienes with Benzoquinones
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Jose Marıa Perez, Pilar Lopez-Alvarado, Carmen Avendan˜o and J. Carlos Menendez
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Departamento de Quımica Organica y Farmaceutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Received 22 October 1999; revised 21 December 1999; accepted 13 January 2000
Abstract—Treatment of bromobenzoquinone with 2 equiv. of a 1-dimethylamino-1-azadiene afforded mixtures of the corresponding
1,8-diaza-9,10-anthraquinone and 1,5-diaza-9,10-anthraquinone. Double hetero Diels–Alder reactions between 1-dimethylamino-1-
azadienes and 2,6-dibromobenzoquinone afford symmetrically substituted 1,8-diaza-9,10-anthraquinone derivatives in excellent yields.
3-Substituted 1-azadienes afford aromatic derivatives, while 4-substituted or 3,4-disubstituted 1-azadienes lead to 1,8-bis-(dimethyl-
amino)-1,4,5,8-tetrahydro-1,8-diaza-9,10-anthraquinones, which were aromatized under thermal conditions. The hetero Diels–Alder
reactions could also be controlled to give isolated 7-bromo-5,8-quinolinequinones, whose treatment with a second azadiene allowed the
preparation of unsymmetrical 1,8-diaza-9,10-anthraquinones. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
more flexible approach,9,10 hetero Diels–Alder reactions11
of quinolinequinones with 1-dimethylamino-1-azadienes12
yield mixtures of 1,8-diazaanthraquinones and their
1,5-diaza-regioisomers, which become the major products
by introduction of a halogen atom in the C-6 position of the
quinolinequinone derivative.13 We report here our research
into the synthesis of 1,8-diazaanthraquinones from benzo-
quinone derivatives.
Several families of antitumour natural products, including
the anthracyclines (e.g. doxorubicin and daunorubicin),1,2
the pluramycins (e.g. sapurimycin)3,4 and some of the
enediyne antibiotics, like dynemycin A and deoxydynemycin
A,5,6 contain a 9,10-anthraquinone substructure. The anti-
tumour activity of these quinones is normally ascribed to
several mechanisms, which are believed to follow DNA
intercalation. Generation of free oxygen radicals concomi-
tant with reduction of the quinone function is probably one
of the main of these mechanisms.
Methods and Results
In principle, double hetero Diels–Alder reactions of benzo-
quinone derivatives and suitably activated 1-azadienes
should provide a very simple synthesis of symmetrically
substituted 1,8-diazaanthraquinones. Unfortunately, the
only literature precedent of this reaction was discouraging,
since treatment of benzoquinone with excess methacrolein
dimethylhydrazone afforded 6-dimethylaminoquinolinequi-
none as the only reaction product rather than 3,6-dimethyl-
1,8-diazaanthraquinone.9 This result can be rationalized in
terms of a single hetero Diels–Alder cycloaddition,
followed by a two-step aromatization to quinolinequinone
with concomitant elimination of dimethylamine, addition of
the latter to quinolinequinone and new oxidation (Scheme
1).
It has been reasoned that isosteric substitution of one or both
of the carbon atoms of the benzene rings in the anthra-
quinone unit by nitrogen atoms should lead to analogues
with improved ability to generate radicals, owing to easier
reduction of the quinone function, while retaining the inter-
calating properties.7 For these reasons, the preparation of
azaanthraquinones as potential antitumour agents is a very
promising field of research. However, and in spite of this
interest, many types of azaanthraquinone systems remain
little studied due to limitations in the existing synthetic
methodology. Thus, the unsubstituted 1,8-diazaanthra-
quinone parent system has been prepared in 28% yield
using a sequence based on the directed ortho-lithiation of
N,N-diethylpyridine-2-carboxamide, followed by reaction
with 2-bromopyridine-3-carbaldehyde, new lithiation,
cyclization and air oxidation.8 In an alternative, potentially
We envisaged that the problem might be solved by replacing
1-dimethylamino-1-azadienes with 1-acetylamino-1-aza-
dienes, which, although less reactive, have the advantage
of not delivering nucleophilic species into the reaction
medium.14 Indeed, treatment of benzoquinone with
2 equiv. of 1-acetylamino-3-ethyl-1-azadiene in refluxing
Keywords: quinones; Diels–Alder reactions; benzoquinones; quinolines.
* Corresponding author. Tel.: ϩ34-91-3941821; fax: ϩ34-91-3941822;
e-mail:josecm@eucmax.sim.ucm.es.
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00058-2

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J. M. Perez et al. / Tetrahedron 56 (2000) 1561–1567
1562
Scheme 1.
toluene for 28 h afforded a 54% yield of 3,6-diethyl-1,8-
diazaanthraquinone 4 (Scheme 2). The fact that 4 was the
only isolated reaction product suggests that 3-
ethylquinolinequinone 3 was not an intermediate of the
reaction, because in that case a mixture of both possible
regioisomers should have been obtained.15 This suggests
that the second Diels–Alder reaction takes place on the
non-isolated 1,4-dihydroquinoline intermediate 2, in
which conjugation between the nitrogen and the C-5 car-
bonyl leaves the C6vC7–C8vO portion of the molecule as
a relatively isolated conjugated system with its electophilic
end at C-6, leading to the observed regioselectivity.
In an effort to achieve the same transformation under milder
conditions, we decided to study the reactions between 1-
dimethylamino-1-azadienes and halogenated benzoqui-
nones, since we expected that liberation of the correspond-
ing hydrogen halide from the primary Diels–Alder adduct
would trap dimethylamine and prevent its undesired addi-
tion to intermediate quinolinequinones. In an initial experi-
ment, we treated 1-dimethylamino-3-ethyl-1-azadiene 516
with 2-bromobenzoquinone, and obtained a 4:1 mixture of
the 1,8-diaza- and 1,5-diazaanthraquinones 4 and 6,
although the ratio changed to 2:1 after chromatography
owing to partial decomposition of 4 (Scheme 3). As
Scheme 2. Reagents and conditions: (i) p-Benzoquinone (2 equiv.), xylene, reflux, 28 h.
Scheme 3. Reagents and conditions: (i) CHCl3, rt, 3 min.

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J. M. Perez et al. / Tetrahedron 56 (2000) 1561–1567
1563
Scheme 4.
previously mentioned, this lack of regioselectivity seems to
indicate that, in this case, aromatization of the primary
adduct to 3-ethylquinolinequinone 3 takes place before the
start of the second Diels–Alder reaction. Assignment of the
1,5- and 1,8-diazaanthraquinone structures was based on
the fact that, owing to the different symmetry of both
systems, the carbonyls of the 1,5-diaza derivative are
equivalent, unlike those of the 1,8-diaza regioisomer.
Accordingly, two clearly differentiated infrared absorptions
at 1695.8 and 1668.4 cmϪ1 and two 13C NMR signals at
180.3 and 182.7 ppm were observed for compound 4,
while 6 showed single IR (1682.6 cmϪ1) and 13C NMR
(181.65 ppm) carbonyl signals.
thus formed would finally lead to compound 7 through a
5-exo-trig cyclization involving the C-5 carbonyl oxygen
(Scheme 4). Similar deviations of hetero Diels–Alder
reactions to formal [3ϩ2] cycloadditions leading to furo-
quinolines have been previously described in situations of
increased quinone polarity due to the presence of protic19,20
or Lewis21 acids, and also in cases where strong electron-
withdrawing groups were present in the quinone22,23 or in
the azadiene.24
In an effort to increase the regioselectivity of the second
cycloaddition, we decided to examine the reactions of
2,6-dibromobenzoquinone25 and several 1-dimethylamino-
1-azadienes (compounds 5 and 8–12).26,27 As shown in
Scheme 5, the reactions involving 4-unsubstituted azadienes
5, 8, 9, and 10 afforded good to excellent yields of
1,8-diazaanthraquinone derivatives, which were isolated
as the fully aromatic derivatives 4 and 13–15, respectively.
Instead, treatment of the 4-substituted azadienes 11 and 12
with 2,6-dibromo-benzoquinone gave the 1,8-bis-(dimethyl-
amino)-1,4,5,8-tetrahydro derivatives 16 and 17, arising
from double elimination of hydrobromic acid from the
primary Diels–Alder adduct. Compounds 16 and 17 were
unstable to acid, and their isolation required the addition of
triethylamine to the reaction medium to trap hydrobromic
acid. Steric compression between the C4- and C5-alkyl
groups and the C-10 carbonyl presumably prevented their
spontaneous aromatization through double elimination of
In the course of the above experiments, we noticed that
some reactions gave small amounts of the furo[2,3-f ]quino-
line derivative 7 together with compounds 4 and 6. Upon
closer examination, this behaviour could be attributed to the
use of two different batches of bromobenzoquinone, one of
which had been prepared by oxidation of 2-bromohydro-
quinone17 with cerium ammonium nitrate, while for the
other we had used acidic sodium dichromate for the
oxidation step, and therefore the quinone might have been
contaminated with traces of acid. Protonation of the quino-
line nitrogen of 3 under these conditions increases the
electron deficiency at the C-8 carbonyl and therefore the
electrophilic character of its conjugated position, favouring
a Michael addition of the azadiene to C-6.18 The intermediate
Scheme 5. Reagents and conditions: (i) CH2Cl2, rt, 1 min; (ii) CH2Cl2, Et3H, rt, 15 min; (iii) 110ЊC, 0.1 Torr, 2 h.

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J. M. Perez et al. / Tetrahedron 56 (2000) 1561–1567
1564
Scheme 6. Reagents and conditions: (i) (CH2Cl)2, 110ЊC, 2 h; (ii) CHCl3, rt, 12 h; (iii) CHCl3, Et3N, rt, 24 h.
dimethylamine, as observed during the preparation of
compounds 2 and 13–15.28 Indeed, aromatization of 16
and 17 proved more difficult than expected, but after several
unsuccessful attempts under varied literature conditions16,29
we found that heating the neat compounds 16 and 17 under
vacuum afforded excellent yields of their aromatic
derivatives (compounds 18 and 19, respectively).
19, showing the effect of a decreased steric compression
in compound 26.
Experimental
All reagents were of commercial quality (Aldrich, Fluka,
SDS, Panreac) and were used as received. Solvents (SDS)
were dried and purified using standard techniques.
‘Petroleum ether’ refers to the fraction boiling at 40–
60ЊC. Reactions were monitored by thin layer chromato-
graphy, on aluminium plates coated with silica gel
with fluorescent indicator (Macherey–Nagel Alugram Sil
G/UV254). Separations by flash chromatography were
performed on silica gel (SDS 60 ACC, 230–40 mesh).
Melting points were measured with a Reichert 723 hot
stage microsope, and are uncorrected. Infrared spectra
were recorded on a Perkin–Elmer Paragon 1000 FT-IR
spectrophotometer, with all compounds examined in KBr
pellets or as films on a NaCl disk. NMR spectra were
Finally, and in order to extend the synthetic scope of the
method, we decided to study the possibility of obtaining
unsymmetrically substituted derivatives of the 1,8-diaza-
anthraquinone system by combination of 2,6-dibromobenzo-
quinone with two different azadienes. This objective
required us to achieve single hetero Diels–Alder cyclo-
additions of 2,6-dibromobenzoquinone leading to 7-bromo-
5,8-quinolinequinones, which would then be submitted to a
second cycloaddition. After many unsuccessful attempts at
carrying out this transformation at room temperature, we
found that, in spite of the high reactivity of 2,6-dibromo-
benzoquinone, the best results were obtained by slow
addition of the azadiene onto a diluted, refluxing solution
of the starting quinone; this procedure cleanly afforded
mixtures of the desired 7-bromoquinolinequinones (20 or
21) and dimethylamine hydrobromide.30 Compounds 20
and 21 are relatively unstable in these mixtures since,
upon standing for a few hours, dimethylamine is easily
transferred from its hydrobromide to 20 or 21 leading to
mixtures of dimethylamino derivatives whose structure
was not investigated in detail. Since, on the other hand,
compounds 20 and 21 could not be properly purified by
column chromatography without extensive decomposition,
the best method consisted of simple filtration through a pad
of silica gel of a solution of the crude 20 or 21 in order to
eliminate dimethylamine hydrobromide, followed by
evaporation and immediate use for the second Diels–
Alder reaction. These conditions led to the results summar-
ized in Scheme 6, with good to excellent yields in the cases
where the final product was unsubstituted at one of the
pyridine rings (compounds 22 and 26). Other substituent
combinations led to less satisfactory results (35–43%
yields). It is noteworthy that compound 25, whose prepa-
ration required the use of the C-4 substituted crotonaldehyde
dimethylhydrazone, was isolated as a fully aromatic
derivative after 24 h at room temperature instead of the
drastic conditions required for the preparation of 18 and
1
obtained on Bruker AC-250 (250 MHz for H, 63 MHz for
13C) or Varian VXR-300 (300 MHz for 1H, 75 MHz for 13C)
spectrometers, with CDCl3 as solvent (Servicio de Espectros-
´
copıa, Universidad Complutense). Elemental analyses were
´
determined by the Servicio de Microanalisis, Universidad
Complutense, on Perkin–Elmer 2400 CHN and Leco
CHNS 932 analyzers.
Reaction of acetohydrazide (1) and p-benzoquinone
A solution of N0-(20-ethyl-2-propenylidene)acetohydrazide
114(39 mg, 0.27 mmol) and p-benzoquinone (30 mg,
0.27 mmol) in xylene (25 mL) was heated for 28 h at
140ЊC while air was bubbled through the reaction mixture,
with periodic additions of fresh xylene to prevent complete
evaporation. The solution was evaporated under reduced
pressure and chromatographed (AcOEt), affording 20 mg
(54%) of 3,6-diethyl-1,8-diaza-9,10-anthraquinone 4, as a
pale yellow solid; [Found: C, 72.50; H, 5.54; N, 10.50.
C16H14N2O2 requires C, 72.18; H, 5.26; N, 10.53%]; mp
222–224ЊC; nmax (KBr) 1696, 1668 cmϪ1; dH (CDCl3,
250 MHz) 8.92 (d, 2H, Jˆ1.7 Hz, H-2,7); 8.37 (d, 2H,
Jˆ1.7 Hz, H-4,5); 2.85 (q, 4H, Jˆ1.7 Hz, 2 CH2–CH3);
1,30 (t, 6H, 2 CH2–CH3); dC (CDCl3, 63 MHz) 182.7
(C-9), 180.3 (C-10), 155.7 (C-2,7), 146.8 (C-8a,9a), 145.3

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J. M. Perez et al. / Tetrahedron 56 (2000) 1561–1567
1565
(C-3,6), 133.8 (C-4,5), 129.7 (C-4a,10a), 26.4 (CH2–CH3),
14.6 (CH2–CH3).
50ЊC for 20 min. The residue was washed with Et2O
(2×15 mL), yielding the aromatic derivatives 4 and 13–15
as off-white or pale yellow solids.
Reaction of 2-ethyl-2-propenal dimethylhydrazone (5)
with 2-bromobenzoquinone
1,8-Diaza-9,10-anthraquinone (13). Yield, 184 mg (85%).
Mp Ͼ300ЊC; lit.8, mp Ͼ300ЊC. Spectral data for this
compound were identical to those previously described.8
(a) Preparation of 2-bromobenzoquinone. To a solution of
2-bromohydroquinone17 in acetonitrile (5 mL) was added
cerium ammonium nitrate (214 mg, 0.39 mmol), in small
portions. The orange suspension was stirred at room
temperature for 10 min, diluted with water (5 mL) and
extracted with CHCl3 (3×50 mL). The combined organic
layers were dried over Na2SO4 and evaporated, yielding
40 mg (82%) of analytically pure 2-bromobenzoquinone,
as yellow crystals. mp 54–55ЊC, lit.31 55–56ЊC; nmax
(KBr) 1667.1 cmϪ1; dH (CDCl3, 250 MHz) 7.29 (d, 1H,
J3,5ˆ2.3 Hz, H-3); 6.81 (dd, 1H, J3,5ˆ2.3 Hz,
J5,6ˆ10.1 Hz, H-5); 6.97 (d, 1H, J5,6ˆ10.1 Hz, H-4); dC
(CDCl3, 63 MHz) 184.7 (C-4), 179.3 (C-1), 138.2 (C-3),
137.2 (C-2), 136.8 (C-6), 135.9 (C-5).
3,5-Dimethyl-1,8-diaza-9,10-anthraquinone (14). Yield,
233 mg (95%). [Found: C, 70.19; H, 4.46; N, 11.46.
C14H10N2O2 requires C, 70.59; H, 4.20; N, 11.76%]; mp
263–264ЊC; nmax (KBr) 1696, 1670 cmϪ1; dH (CDCl3,
250 MHz) 8.94 (d, 2H, Jˆ1.5 Hz, H-2,7), 8.37 (d, 2H,
Jˆ1.5 Hz, H-4,5), 2.56 (s, 6H, 2 CH3). dC (CDCl3,
63 MHz) 182.6 (C-9), 180.0 (C-10), 156.2 (C-2,7), 146.6
(C-8a,9a), 139.2 (C-3,6), 134.8 (C-4,5), 129.4 (C-4a,10a),
18.9 (2 CH3).
3,5-Diethyl-1,8-diaza-9,10-anthraquinone (4). Yield 182 mg
(66%). See data above.
3,5-Di-n-butyl-1,8-diaza-9,10-anthraquinone (15). Yield,
241 mg (73%). [Found: C 74.14; H, 6.76; N, 8.35.
C20H22N2O2 requires C, 74.51; H, 6.88; N, 8.69%]; mp
132–134ЊC; nmax (KBr) 1700 and 1671 cmϪ1. dH (CDCl3,
250 MHz) 8.94 (d, 2H, Jˆ2.2 Hz, H-2,7), 8.39 (d, 2H,
Jˆ2.2 Hz, H-4,5), 2.83 (t, 4H, Jˆ7.6 Hz, CH2–CH2–
CH2–CH3), 1.8–1.6 (m, 4H, CH2–CH2–CH2–CH3), 1.40
(m, 4H, CH2–CH2–CH2–CH3), 0.95 (t, 6H, Jˆ7.3 Hz,
CH2–CH2–CH2–CH3). dC (CDCl3, 63 MHz) d 183.0
(C-9), 180.1 (C-10), 156.2 (C-2,7), 147.1 (C-8a,9a),
144.17 (C-3,6), 134.39 (C-4,5), 129.79 (C-4a,10a), 33.1
and 32.9 (CH2–CH2–CH2–CH3 and CH2–CH2–CH2–
CH3), 22.4 (CH2–CH2–CH2–CH3), 13.9 (C3,5–CH2–CH2–
CH2–CH3).
(b) Hetero Diels–Alder reaction. To a solution of 2-bromo-
benzoquinone (40 mg, 0.2 mmol) in CHCl3 (10 mL) was
added 2-ethyl-2-propenal dimethylhydrazone 516 (54 mg,
0.42 mmol). The solution was stirred at room temperature
for 5 min and evaporated, and the residue was further heated
in vacuo (water pump) at 50ЊC for 20 min. The residue was
characterized by 1H NMR spectroscopy as a 4:1 mixture of 4
and 6. Chromatography (AcOEt) yielded 20 mg (35%) of 4
and 10 mg (18%) of 3,5-diethyl-1,5-diaza-9,10-anthra-
quinone 6, both as pale yellow crystals. Data for 6:
[Found: C, 71.86; H, 5.50; N, 10.11. C16H14N2O2 requires
C, 72.18; H, 5.26; N, 10.53%]; mp 218–220ЊC; nmax (KBr)
1683 cmϪ1; dH (CDCl3, 250 MHz) 8.93 (d, 2H, Jˆ2.1 Hz,
H-2,6), 8.50 (d, 2H, Jˆ2.1 Hz, H-4,8), 2.85 (q, 2H,
Jˆ7.5 Hz, CH2–CH3), 1.35 (t, 3H, Jˆ7.5 Hz, CH2–CH3);
dC (CDCl3, 63 MHz) 181.6 (C-9,10), 155.7 (C-2,6), 146.50
(C-9a,10a), 145.6 (C-3,7), 135.5 (C-4,8), 130.6 (C-4a,8a),
26.6 (CH2–CH3), 14.8 (CH2–CH3).
Double hetero Diels–Alder reactions of 4-substituted 1-
dimethylamino-1-azadienes with 2,6-dibromobenzo-
quinone: general procedure
When the starting bromobenzoquinone had been prepared
by oxidation of 2-bromohydroquinone with acidic sodium
dichromate, the reaction yielded a 1:1 mixture of 4 and 6
(68%) and a small amount (17%) of 2-dimethylhydrazono-
methyl-2,6-diethyl-5-hydroxy-1,2-dihydrofuro[2,3-f ]quin-
oline (7), as a pale yellow oil. [Found: C, 68.79; H, 7.22; N,
13.21. C18H23N3O2 requires C, 68.98; H, 7.40; N, 13.41];
nmax (KBr) 3380, 1635 cmϪ1; dH (CDCl3, 250 MHz) 8.94
(d, 1H, Jˆ2.2 Hz, H-7), 8.52 (m, 1H, H-9), 7.99 (s, 1H,
OH), 6.94 (s, 1H, CHvNMe2), 6.67 (s, 1H, H-4), 3.80 (d,
1H, Jˆ15.8 Hz, H-3), 3.15 (d, 1H, Jˆ15.8 Hz, H-3), 2.85
(m, 4H, 2 CH2–CH3), 2.76 (s, 6H, NMe2), 1.34 (m, 6H, 2
CH2–CH3).
To a solution of 2,6-dibromobenzoquinone (200 mg,
0.75 mmol) in CHCl3 (10 mL) was added triethylamine
(2 equiv.) and the appropriate azadiene (2 equiv.). The
solution was stirred at room temperature for 15 min and
evaporated under reduced pressure. The residue was washed
with water (3×25 mL), yielding compounds 16 or 17 as
green solids, which were identified by their spectral data
and used for the next step without further purification.
The appropriate 1,8-bis(dimethylamino)-1,4,5,8-tetrahydro-
1,8-diaza-9,10-anthraquinone derivative 16 or 17 was
heated neat at 110ЊC and 0.1 mm for 2 h. The cooled
reaction mixture was washed with ethyl ether (2×15 mL),
affording the aromatic derivatives 18 and 19 as pale yellow
solids.
Double hetero Diels–Alder reactions of 4-unsubstituted
1-dimethylamino-1-azadienes with 2,6-dibromobenzo-
quinone: general procedure
1,8-bis(dimethylamino)-4,5-dimethyl-1,4,5,8-tetrahydro-
1,8-diaza-9,10-anthraquinone (16). dH (CDCl3, 250 MHz)
6.14 (d, 2H, Jˆ7.8 Hz, H-2,7), 5.02 (dd, 2H, Jˆ7.8 and 5.1
Hz, H-3,6), 3.48 (m, 2H, H-4,5), 2.64 (s, 12H, 2 NMe2), 1.08
(d, 6H, Jˆ6.6 Hz, 2 CH3); dC (CDCl3, 63 MHz) 182.3
(C-9); 172.4 (C-10); 137.8 (C-4a,10a); 122.2 (C-2,7);
To a solution of 2,6-dibromobenzoquinone (275 mg,
1.0 mmol) in CHCl3 (15 mL) was added the appropriate
azadiene26 (2 equiv.). The solution was stirred for 5 min at
room temperature and evaporated under reduced pressure,
and the residue was further heated in vacuo (water pump) at

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J. M. Perez et al. / Tetrahedron 56 (2000) 1561–1567
1566
119.4 (C-8a,9a); 112.2 (C-3,6); 44.8 (2 NMe2), 34.9 (C-4,5);
24.6 (2 CH3).
Jˆ7.7 and 1.7 Hz, H-4), 7.71 (dd, Jˆ7.5 and 4.8 Hz, H-3),
7.58 (s, 1H, H-6).
1,8-bis(dimethylamino)-4,5-diethyl-3,6-dimethyl-1,4,5,8-
7-bromo-3-methyl-5,8-quinolinequinone
(21).
dH
tetrahydro-1,8-diaza-9,10-anthraquinone
(17).
dH
(CDCl3, 250 MHz) 8.76 (d, 1H, Jˆ2.0 Hz, H-2), 8.10 (d,
(CDCl3, 250 MHz) 6.08 (s, 2H, H-2,7); 3.47 (t, 2H,
Jˆ4.1 Hz, H-4,5); 2.60 (s, 12H, 2 NMe2), 1.68 (s, 6H,
C(3,5)–CH3), 1.16 (m, 4H, 2 CH2–CH3), 0.78 (t, 6H,
Jˆ7.5 Hz, 2 CH2–CH3).
1H, Jˆ1.4 Hz, H-4), 6.94 (s, 1H, H-6), 2.48 (s, 3H, CH3).
3-Methyl-1,8-diaza-9,10-anthraquinone (22). Starting
from 117 mg (0.44 mmol) of 2,6-dibromobenzoquinone,
42 mg (1 equiv.) of the azadiene 8 and then 51 mg
(1.2 equiv.) of the azadiene 9, a yield of 89 mg (91%) of
compound 22 was obtained, as an off-white solid. [Found:
C, 69.32; H, 3.79; N, 12.29. C13H8N2O2 requires C, 69.63;
H, 3.59; N, 12.49]; mp 298–301ЊC; nmax (KBr) 1698 and
1673 cmϪ1. dH (CDCl3, 250 MHz) 9.16–9.12 (m, 1H, H-7),
8.95 (d, 1H, Jˆ1.7 Hz, H-2), 8.65–8.59 (m, 1H, H-5), 8.39
(d, 1H, Jˆ1.2 Hz, H-4), 7.80–7.72 (m, 1H, H-6), 2.56 (s,
3H, C3–CH3). dC (CDCl3, 63 MHz) 182.5 (C-9), 180.1
(C-10), 156.6 and 155.70 (C-2 and C-7), 148.9 (C-8a),
146.80 (C-9a), 139.6 (C-3), 135.3 and 134.9 (C-4 and
C-5), 130.04 (C-10a), 129.61 (C-4a), 128.3 (C-6), 19.1
(C3–CH3).
4,5-Dimethyl-1,8-diazaanthraquinone (18). Starting from
235 mg (0.72 mmol) of compound 16, a yield of 146 mg
(85%) of compound 18 was obtained. [Found: C, 70.67;
H, 4.20; N, 11.76. C14H10N2O2 requires C, 70.58; H, 4.20;
N, 11.76]; mp 245–247ЊC; nmax (KBr) 1670.2 cmϪ1. dH
(CDCl3, 250 MHz) 8.89 (d, 2H, Jˆ4.8 Hz, H-2,7), 7.49 (d,
2H, Jˆ4.8 Hz, H-3,5); 2.56 (s, 6H, 2 CH3). dC (CDCl3,
63 MHz) 186.5 (C-9); 181.1 (C-10); 153.6 (C-2,7); 151.2
(C-8a,9a); 150.4 (C-4,5); 131.7 (C-3,6); 129.9 (C-4a,10a);
22.5 (2 CH3).
4,5-Diethyl-3,6-dimethyl-1,8-diazaanthraquinone (19).
Starting from 286 mg (0.74 mmol) of compound 16, an
yield of 175 mg (80%) of compound 19 was obtained.
[Found: C, 73.17; H, 5.98; N, 9.43. C18H18N2O2 requires
C, 73.46; H, 6.12; N, 9.52]; mp 165–167ЊC; nmax (KBr)
1671.3 cmϪ1. dH (CDCl3, 250 MHz) 8.76 (s, 2H, H-2,7),
3.13 (q, 4H, Jˆ7.7 Hz, 2 CH2–CH3), 2.49 (s, 6H, 2 CH3),
1.33 (t, 6H, Jˆ7.7 Hz, 2 CH2–CH3); dC (CDCl3, 63 MHz)
182.9 (C-9); 180.1 (C-10); 155.0 (C-2,7); 153.8 (C-8a,9a);
147.5 (C-4,5); 138.5 (C-3,6); 130.5 (C-4a,10a); 23.4 (CH2–
CH3); 16.9 (C(4)–CH3); 13.5 (CH2–CH3).
3-Ethyl-6-methyl-1,8-diaza-9,10-anthraquinone
(23).
Starting from 115 mg (0.43 mmol) of 2,6-dibromobenzo-
quinone, 48 mg (1 equiv.) of azadiene 9 and then 44 mg
(1.2 equiv.) of azadiene 5, a yield of 42 mg (39%) of
compound 23 was obtained, as an off-white solid. [Found:
C, 71.13; H, 4.68; N, 10.97. C15H12N2O2 requires C, 71.41;
H, 4.79; N, 11.10]; mp 245–247ЊC; nmax (KBr) 1693 and
1667 cmϪ1. dH (CDCl3, 250 MHz) 8.95–8.93 (m, 1H,
H-2,7), 8.39–8.37 (m, 1H, H-4,5), 2.86 (q, 2H, Jˆ7.6 Hz,
C3–CH2–CH3), 2.55 (s, 3H, C6–CH3), 1.35 (t, 3H,
Jˆ7.6 Hz, C3–CH2–CH3). dC (CDCl3, 63 MHz) 182.9
(C-9), 180.1 (C-10), 156,5 and 155.9 (C-2 and C-7), 147.0
and 146.8 (C-8a and C-9a), 145.3 (C-3), 139.4 (C-6), 135.1
and 133.9 (C-4 and C-5), 129.8 and 129.6 (C-4a and C-10a),
26.5 (C3–CH2–CH3), 19.1 (C6–CH3), 14.7 (C3–CH2–CH3).
Preparation of unsymmetrical 1,8-diaza-9,10-anthra-
quinones: general procedures
A suspension of 2,6-dibromobenzoquinone in (ClCH2)2
(40 mL per 100 mg of dibromobenzoquinone) was stirred
at 110ЊC for 15 min. To the solution thus obtained was
3-n-Butyl-6-methyl-1,8-diaza-9,10-anthraquinone (24).
Starting from 75 mg (0.28 mmol) of 2,6-dibromobenzo-
quinone, 32 mg (1 equiv.) of azadiene 9 and then 35 mg
(1.2 equiv.) of azadiene 10, a yield of 34 mg (43%) of
compound 24 was obtained, as an off-white solid. [Found:
C, 72.60; H, 5.58; N, 9.66. C17H16N2O2 requires C, 72.84; H,
5.75; N, 9.99; mp 168–170ЊC; nmax (KBr) 1694 and
1665 cmϪ1; dH (CDCl3, 250 MHz) 8.92 (br. s, 2H, H-2,7),
8.36 (br. s, 2H, H-4,5), 2.80 (t, 2H, Jˆ7.6 Hz, C3–CH2–
CH2–CH2–CH3), 2.55 (s, 3H, C6–CH3), 1.68 (m, 2H, C3–
CH2–CH2–CH2–CH3), 1.38 (m, 2H, C3–CH2–CH2–CH2–
CH3), 0.93 (t, 3H, Jˆ7.3 Hz, C3–CH2–CH2–CH2–CH3); dC
(CDCl3, 63 MHz) 182.9 (C-9), 180.1 (C-10), 156,4 and
156.2 (C-2 and C-7), 147.0 and 146.9 (C-8a and C-9a),
144.15 (C-3), 139.4 (C-6), 135.1 and 134.3 (C-4 and C-5),
129.7 and 129.6 (C-4a and C-10a), 33.1 (C3–CH2–CH2–
CH2–CH3), 32.8 (C3–CH2–CH2–CH2–CH3), 22.35 (C3–
CH2–CH2–CH2–CH3), 19.09 (C6–CH3), 13.88 (C3–CH2–
CH2–CH2–CH3).
added
a solution of acrolein dimethylhydrazone 8
(1 equiv.) or methacrolein dimethylhydrazone 9 (1 equiv.)
in (ClCH2)2 (10 mL), dropwise over 1 h. The solution was
stirred at that temperature for 1 h, and an additional amount
of 0.1 equiv. of the azadiene was added. After further
30 min at 110ЊC, the reaction mixture was cooled and
evaporated. The residue was dissolved in ethyl acetate
(10 mL) and filtered through a pad of silica gel. Evaporation
of the solvent afforded a residue, which was characterized
by 1H NMR spectroscopy as the virtually pure 7-bromo-5,8-
quinolinequinone 20 or 7-bromo-3-methyl-5,8-quinoline-
quinone 21, which were immediately used without further
purification.
To a solution of 20 or 21 in CHCl3 (5 mL) was added the
appropriate second azadiene (1.2 equiv.). The solution was
stirred at room temperature for 12 h (24 h in the preparation
of compound 26) and evaporated. The residue was chroma-
tographed (AcOEt), yielding compounds 22–26 as off-
white, pale yellow or pale brown solids.
3,5-Dimethyl-1,8-diaza-9,10-anthraquinone (25). Starting
from 117 mg (0.44 mmol) of 2,6-dibromobenzoquinone,
49 mg (1 equiv.) of azadiene 9 and then 59 mg (1.2 equiv.)
of azadiene 11, a yield of 36 mg (35%) of compound 25
7-bromo-5,8-quinolinequinone
(20).
dH
(CDCl3,
250 MHz) 9.05 (dd, 1H, Jˆ4.7 and 1.7 Hz, H-2), 8.46 (dd,

´
J. M. Perez et al. / Tetrahedron 56 (2000) 1561–1567
1567
Menta, E.; Oliva, A.; Spinelli, S.; Beggiolin, G.; Giuliani, F. G.;
Pezzoni, G.; Tognella, S. Current Med. Chem. 1995, 2, 803.
8. Villacampa, M.; de la Cuesta, E.; Avendan˜o, C. Tetrahedron
1995, 51, 1259.
9. Potts, K. T.; Walsh, E. B.; Bhattacharjee, D. J. Org. Chem.
1987, 52, 2285.
10. Tapia, R. A.; Quintanar, C.; Valderrama, J. A. Heterocycles
1996, 43, 447.
11. Tietze, L. F.; Kettschau, G. Top. Curr. Chem. 1997, 189, 1.
was obtained, as a pale brown solid. [Found C, 70.39;
H, 4.53; N, 11.50. C14H10N2O2 requires C, 70.58; H, 4.23;
N, 11.76]; mp 177–179ЊC. nmax (KBr) 1697 and 1667 cmϪ1
.
dH (CDCl3, 250 MHz) 8.90–8.81 (m, 2H, H-2,7), 8.36 (br.
s, 1H, H-4), 7.51 (d, 1H, Jˆ4.8 Hz, H-6), 2.89 (s, 3H,
C4–CH3), 2.56 (s, 3H, C3–CH3). dC (CDCl3, 63 MHz)
185.1 (C-9), 181.1 (C-10), 157.2 and 156.3 (C-2 and C-7),
153.7 and 151.6 (C-5 and C-9a), 146.5 (C-8a), 139.4 (C-3),
134.9 (C-4), 131.3 (C-6), 130.5 (C-4a), 128.1 (C-10a), 22.9
(C5–CH3), 19.18 (C3–CH3).
´
12. Barluenga, J.; Tomas, M. Adv. Heterocycl. Chem. 1993, 57, 1.
´
13. Blanco, M. M.; de la Fuente, J. A.; Avendan˜o, C.; Menendez,
3-Ethyl-1,8-diaza-9,10-anthraquinone (26). Starting from
117 mg (0.44 mmol) of 2,6-dibromobenzoquinone, 49 mg
(1 equiv.) of azadiene 9 and then azadiene 5 (1.2 equiv.),
a yield of 78 mg (80%) of compound 26 was obtained, as a
pale yellow solid. [Found C, 70.42; H, 4.48; N, 11.56.
C14H10N2O2 requires C, 70.58; H, 4.23; N, 11.76]; mp
292–293ЊC; nmax (KBr) 1694.6 and 1670.1 cmϪ1. dH
(CDCl3, 250 MHz) 9.11 (dd, 1H, Jˆ4.6 and 1.7 Hz, H-7),
8.94 (d, 1H, Jˆ2.2 Hz, H-2), 8.61 (dd, 1H, Jˆ7.9 and
1.7 Hz, H-5), 8.38 (d, 1H, Jˆ2.2 Hz, H-4), 7.74 (dd, 1H,
Jˆ7.9 and 4.6 Hz, H-6), 2.89 (q, 2H, Jˆ7.8 Hz, CH2–CH3),
1.33 (t, 3H, Jˆ7.8 Hz, CH2–CH3), dC (CDCl3, 63 MHz)
182.6 (C-9), 180.1 (C-10), 156.2 and 155.9 (C-2 and C-7),
148.9 (C-8a), 146.9 (C-9a), 145.5 (C-3), 135.5 (C-4), 133.9
(C-5), 130.0 (C-4a), 129.1 (C-10a), 128.7 (C-6), 26.5 (CH2–
CH3), 14.7 (CH2–CH3).
J. C. Tetrahedron Lett. 1999, 40, 4097.
´
´
14. Perez, J. M.; Avendan˜o, C.; Menendez, J. C. Tetrahedron
1995, 51, 6573.
´
´
15. Villacampa, M.; Perez, J. M.; Avendan˜o, C.; Menendez, J. C.
Tetrahedron 1994, 50, 10047.
16. Waldner, A. Helv. Chim. Acta 1988, 71, 486.
17. Wichelhaus, H. Chem. Ber. 1879, 1500.
18. Hegedus, L. S.; Sestrick, M. R.; Michaelson, E. T.; Harrington,
P. J. J. Org. Chem. 1989, 54, 4141.
19. Nebois, P.; Fillion, H. Tetrahedron Lett. 1991, 32, 1307.
20. Nebois, P.; Fillion, H.; Benameur, L. Tetrahedron 1993, 49,
9767.
21. Echavarren, A. M. J. Org. Chem. 1990, 55, 4255.
´
22. Valderrama, J. A.; Gonzalez, M. F. Heterocycles 1993, 36,
1553.
´
23. Blanco, M. M.; Alonso, M. A.; Avendan˜o, C.; Menendez, J. C.
Tetrahedron 1996, 52, 5933.
´
´
´
24. Ramos, M. T.; Dıaz-Guerra, L.-M.; Garcıa-Copın, S.;
Acknowledgements
´
´
´
Avendan˜o, C.; Garcıa-Gravalos, D.; Garcıa de Quesada, T. Il
Farmaco 1996, 51, 375.
We thank Ms Eva Pascual-Alfonso for valuable suggestions
related to the preparation of compound 20. Financial
support from CICYT (project PTR-95-0230) is also grate-
fully acknowledged.
25. Perumal, P. T.; Bhat, M. V. Synthesis 1979, 205.
26. For the synthesis of the azadienes 5, 8, 9, 11 and 12, see Ref.
16. Methacrolein dimethylhydrazone 10 was prepared using simi-
lar conditions (see also Ref. 14). Acrolein dimethylhydrazone 8
´
was prepared according to: Gomez-Bengoa, E.; Echavarren, A. M.
J. Org. Chem. 1991, 56, 3497.
References
27. For the preliminary report of the double hetero Diels–Alder
reaction between 1-dimethylamino-1-azadienes and 2,6-dibromo-
1. Lown, J. W. Chem. Soc. Rev. 1993, 22, 165.
´
´
benzoquinone, see: Perez, J. M.; Avendan˜o, C.; Menendez, J. C.
2. Sengupta, S. K. Cancer Chemotherapeutic Agents; Foye, W. O.,
Ed.; American Chemical Society: New York, 1995 (Chapter 5).
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28. We have noticed a similar effect in the Diels–Alder reactions
of 2,5,8(1H)-quinolinetriones. See Refs. 14 and 23.
29. Nebois, P.; Barrett, R.; Fillion, H. Tetrahedron Lett. 1990, 31,
2569.
30. Similar conditions have been employed for the synthesis of
chloroquinolinequinones from 1-dimethylamino-1-azedienes and
5. Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; Van Duyne, G. D.;
Clardy, J. J. Am. Chem. Soc. 1990, 112, 3715.
´
the less reactive dichlorobenzoquinones. See: Levesque, S.;
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31. Braude J. Chem. Soc. 1945, 490.
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