Synthesis of 2-aza-1-cyano-4-hydroxyanthraquinones

Article abstract of DOI:10.1055/s-2007-970778

Phthalide annulation of 2-alkylpyridin-3-ones results in the formation of the unexpected 2-aza-1-cyano-4-hydroxy-anthraquinones, the cyano moiety originating from the 3-cyanophthalide. These compounds hold great potential against Epstein-Barr Virus Early

Full text of DOI:10.1055/s-2007-970778

LETTER
741
Synthesis of 2-Aza-1-cyano-4-hydroxyanthraquinones
Synthesis of
2
v
-Aza-1-cyano
e
-4-hydrox
n
yanthraquinones Claessens, Jan Jacobs, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 28 December 2006
Dedicated to Prof. M. Yus on the occasion of his 60th birthday
glycerol-3-phosphate-dependent mitochondrial O2 assi-
miliation of the long bloodstream forms of Trypanosoma
congolense.8 In addition, 2-aza-anthraquinone derivatives
interfere with the activity of DNA topoisomerases and
Abstract: Phthalide annulation of 2-alkylpyridin-3-ones results in
the formation of the unexpected 2-aza-1-cyano-4-hydroxy-an-
thraquinones, the cyano moiety originating from the 3-cyanophtha-
lide. These compounds hold great potential against Epstein–Barr
Virus Early Antigen (EBV-EA) activation and as antimicrobial attract considerable attention in cancer chemotherapy as
intercalating DNA-binding agents.9 SAR studies revealed
compounds
that there is a definite correlation between the IC5O of
Epstein–Barr Virus Early Antigen activation (EBV-EA)
and both the HOMO and charges at the carbonyl (C-10
and O-2, being the oxygen of the carbonyl group at C-10)
of 2-aza-anthraquinones.10 Following trends were ob-
served to be important. A higher HOMO, a higher charge
at C-10 and a lower charge at O-2 give a better IC50 for
EBV-EA. Another SAR study revealed that Ghose–
Crippen log P and LUMO are useful parameters for esti-
mating the antimicrobial activity of azafluorenones, 1-
aza-anthraquinones and 2-aza-anthraquinones.11 A low
LUMO and a low log P value correlates with high anti-
microbial activity. The following structure–activity
relationship was postulated: 1) activity decreased in the
order 2-aza-anthraquinones > 1-aza-anthraquinones >
azafluorenones and 2) hydroxyl groups at the peri-
carbonyl position enhance the activity.
Key words: quinones, annulations, antiviral, phthalide, aza-anthra-
quinones
The phthalide annulation reaction is a powerful tool in the
construction of 1,4-naphthalenediols with annulated
rings.1 A multitude of natural products or promising syn-
thetic compounds have been synthesized using this reac-
tion in which a 3-cyano- or 3-phenylsulfonylphthalide is
reacted with a suitable 1,4-Michael-type acceptor.2 Re-
cently, we published a synthesis of pentalongin (1), the
active principle of the medicinal plant Pentas longiflora.3
In this way, the 3-cyanophthalide was reacted with 6H-
pyran-3-one, resulting in 5,10-dihydroxy-1H-ben-
zo[g]isochromen-4-one. Further elaboration of the result-
ing naphthalenediol gave a straightforward synthesis of
pentalongin 1. When looking for new applications of the
phthalide reaction, the synthesis of aza-analogues of pen-
talongin was envisaged. The corresponding nitrogen ana-
logues of pentalongin (2) are not stable, due to their
spontaneous oxidation towards 2-aza-anthraquinones, e.g.
3 (Scheme 1).
OH
O
O
OH
R
N
R
N
PG
OH
PG
O
5
4
These 2-aza-anthraquinones 3 evoke much interest owing
to their potent physiological activities.4 Among others,
they have been reported to show antimicrobial activities5
and they display anti-Epstein–Barr virus activities.6 The
unsubstituted 2-aza-anthraquinone 3 has a reported IC50
value of 4.2 mM against Plasmodium falciparum7 and
inhibits the glucose-dependent cellular respiration and
O
O
R
N
annulation
O
+
7
CN
6
PG = protecting group
Scheme 2
1
O
O
O
1
8
5
R2
2
7
R1
O
9
N
N
ox.
R1
10
R = H
3
6
4
O
O
O
2
1
2
3
Scheme 1
SYNLETT 2007, No. 5, pp 0741–0744
1
6.
0
3.
2
0
0
7
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970778; Art ID: G37206ST
© Georg Thieme Verlag Stuttgart · New York

742
S. Claessens et al.
LETTER
In this respect, it is necessary to have access to new 2-aza- using dimethyl sulfate and potassium carbonate in reflux-
anthraquinones together with the introduction of hydroxyl ing acetone. The N-Boc deprotection was achieved using
groups and eventually other functionalities. Hereby, we trifluoroacetic acid in dichloromethane. After two hours
wish to present a new synthesis of 2-aza-anthraquinones. stirring at room temperature the Boc moiety was cleaved.
Knowing the ability of aromatization, it was predicted that As predicted, the intermediate amine is not stable and ar-
the phthalide annulation product 5 would tautomerize and omatization occurred towards 4-hydroxy-2-aza-an-
aromatize towards 4-hydroxy-2-aza-anthraquinones 4. In thracene 14. However, the last step, in which 4-hydroxy-
order to succeed the annulation, a successful synthesis of 2-aza-anthracene 14 was about to be oxidized to the target
the Michael-accepting pyridone derivatives 7 is required 2-aza-anthraquinone 15 using cerium(IV) ammonium ni-
(Scheme 2). Based on the preliminary results in the syn- trate (CAN), was an unexpected failure (Scheme 4). In or-
thesis of pentalongin,3a the synthesis of pyridone 7 was der to overcome these oxidation problems a new strategy
started from butadiene monoxide. The Boc-protected was devised. Incorporating a leaving group on the Micha-
amine 9 was synthesized by reaction of butadiene monox- el-accepting pyridone was evaluated. From the synthesis
ide 8 with excess allylamine and catalytic amounts of wa- of angucyclinones it is known that the phthalide annula-
ter, followed by N-protection with BocON, according to tion reaction is not harmed by the introduction of a g-
the method of Evans et al.12 Vinylketones are highly reac- methoxy group on the accepting compound.15 Furyl sul-
tive which made us decide firstly to perfom the ring-clos- fonamides 17 are useful substrates as they readily undergo
ing metathesis and subsequently to oxidize the alcohol, the aza-Achmatowicz reaction, a reaction defined as the
instead of choosing the inverse reaction sequence. The conversion of furyl amides 17 into 1,6-dihydro-2H-pyri-
ring-closing metathesis always resulted in an almost din-3-ones 18a–g.16 This novel rearrangement has mainly
50:50 mixture of the starting material and the desired tert- been used for the synthesis of azasaccharides.17 The furyl
butyl 3-hydroxy-1,2,3,6-tetrahydropyridinecarboxylate sulfonamides 17 prove to be difficult to synthesize by
(10). Reported yields are in the order of 85%.12 The start- Grignard addition onto the imino carbon of imines 16. A
ing material could easily be recovered by means of flash competition between Grignard addition and reduction
chromatography and reused to increase the yield. A PCC takes place. The best results were obtained performing the
oxidation was used to oxidize the alcohol into the corre- reaction in diethyl ether using freshly prepared Grignard
sponding ketone in an acceptable yield of 65%. The pyri- reagents. After the aza-Achmatowicz reaction the hydrox-
done 11 is rather unstable and should be used within two yl moiety was protected as its methyl ether using trimethyl
weeks (Scheme 3).
orthoformate and boron(III) fluoride. Padwa et al. proved
the applicability of this strategy by the synthesis of 6-
methoxy-2-methyl-1-(toluene-4-sulfonyl)-1,6-dihydro-
2H-pyridin-3-one (19a).18 Now, this strategy is extended
to the synthesis of several 2-alkyl-pyridin-3-ones 19a–g
(Scheme 5).
Boc OH
N
1) 3 equiv allylamine, H2O (cat.),
10 min,15 °C, then 6 h, 100 °C
O
2) BocON, Et3N, DMAP (cat.)
9, 53%
8
Grubbs' II
Ru catalyst
O
OH
O
CH2Cl2
3 equiv LiOt-Bu
LiCl (cat.)
O
11
+
NBoc
THF, –78 °C, 4 h,
r.t., 16 h
O
OH
CN
OH
12, 88%
6
1.2 equiv PCC
CH2Cl2
N
N
5 equiv K2CO3
2.2 equiv Me2SO4
acetone, ∆, 2 h
Boc
Boc
11, 65%
10, 54%
OMe OH
Scheme 3
OMe O
TFA, CH2Cl2
r.t., 2 h
N
With the desired Michael acceptor in hands, it was possi-
ble to accomplish the phthalide annulation step.13 Depro-
tonation
NBoc
OMe
OMe
14, 23%
by
t-BuOLi
and
reaction
with
13, 41%
tetrahydropyridinone derivative 11, resulted in the synthe-
sis of tert-butyl 5,10-dihydroxy-4-oxo-3,4-dihydro-1H-
benzo[g]isoquinoline-2-carboxylate (12). This compound
is relatively insoluble in organic solvents like the corre-
sponding oxygen analogue used in the synthesis of
pentalongin3 and other phthalide annulation products
which are reported to have solubility problems.14 In order
to overcome these dramatic solubility problems the naph-
thalenediol 12 was protected as its double methyl ether 13
3 equiv CAN,
MeCN–H2O, 0 °C,
30 min
O
O
OH
N
15
Scheme 4
Synlett 2007, No. 5, 741–744 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Aza-1-cyano-4-hydroxyanthraquinones
743
NTs
but upon standing on magnesium sulfate the color faded to
yellow. Surprisingly, instead of having the expected 2-
aza-4-hydroxyanthraquinone, structure elucidation by
NMR spectroscopy showed the absence of the H-4 proton
and IR revealed the existence of a cyanide. Apparently,
the cyanide of the 3-cyanophthalide 6 was introduced in
the compound. Having a MS peak of 264 g/mol for com-
pound 19a, the isolated product proved to be 2-aza-1-cy-
ano-4-hydroxy-anthraquinone 26a (Table 1).
O
RMgX, Et2O,
0 °C, 2 h
NHTs
R
O
16
17a 57%, 17b 38%
17c 37%, 17d 41%
17e 41%, 17f 30%
NaBH4, MeOH
0 °C, 2 h
NHTs
H
O
MCPBA,
CH2Cl2, 0 °C, 2 h
Table 1 Comparison of Calculated Parameters
17g 81%
Substrate HOMO
(eV)
LUMO
(eV)
C-10
O-2
log P
O
O
CH(OMe)3, BF3·Et2O,
R
26a
26b
26c
26d
26e
27
–9.85
–9.83
–9.87
–9.87
–10.00
–9.61
–9.62
–9.15
–1.91
–1.89
–1.90
–1.91
–1.96
–1.79
–1.80
–1.72
0.4045
0.4048
0.4047
0.4045
0.4047
0.3611
0.4004
0.3634
–0.3423
–0.3428
–0.3417
–0.3420
–0.3421
–0.2956
–0.3501
–0.2778
0.06
0.55
0.95
1.38
0.44
0.10
0.10
–0.29
R
CH2Cl2, r.t., 3 h
NTs
NTs
OH
18a 97%, 18b 51%
18c 36%, 18d 49%
18e 78%, 18f 69%
18g 90%
OMe
a R = Me, b R = Et,
c R = i-Pr, d R = n-Bu,
e R = n-Pr, f R =i-Bu , g R = H
19a–g >95%
Scheme 5
Subsequently, the phthalide annulation reaction was en-
visaged. Deprotonation of compound 6 was performed us-
ing 3 equivalents t-BuOLi, in THF at –60 °C. The reaction
was kept for 3 hours at –60 °C and then allowed to stir at
room temperature for 16 hours. The reaction was
quenched with 4 N HCl and extracted with ethyl acetate.
The color of the combined organic layers was burgundy,
28
29
These products 26b–f were also found for other deriva-
tives 19b–f. A plausible mechanism for this transforma-
tion is presented in Scheme 6. The reaction between
O
O
O
O
R
R
3 equiv LiOt-Bu
THF, –60 °C, 3 h,
O
a R = Me
b R = Et
O
+
NTs
OMe
19a–g
NTs
c R = i-Pr
d R = n-Bu
e R = n-Pr
f R = i-Bu
g R = H
CN
then r.t., 16 h
NC
OMe
6
20a–g
CN
O
O
O
OH
O
OH
O
O
R
R
R
NTs
OMe
NTs
NTs
OH OMe
22a–g
21a–g
CN
23a–g
OH
O
O
OH
OH OH
H
R
NTs
OH CN
R
R
O2 from air
N
N
H
O
CN
OH CN
25a–g
24a–g
26a 84%, 26b 71%
26c 43%, 26d 69%
26e 70%, 26f 64%
26g complex reaction mixture
Scheme 6
Synlett 2007, No. 5, 741–744 © Thieme Stuttgart · New York

744
S. Claessens et al.
LETTER
OH
OH
O
O
References
OH
O
O
N
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N
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O
OH
28
O
27
29
Figure 1
phthalide 6 and pyridone 19g gave a complex mixture,
from which the 2-aza-anthraquinone could not be isolated.
Furthermore, some electronic properties and the Ghose–
Crippen log P of these compounds 26a–e were calculated
using the PM3 method.10,11 Changing the alkyl group will
not influence much the electronic properties but has a
great influence on the log P value. Comparison with com-
pounds known to have very good physiological activities
27–29 (Figure 1)10,11 shows that our compounds are prom-
ising. The charges at the carbonyl (C-10 and O-2) show
comparable behavior for anti-EBV-EA. Compound 26a
shows a very promising octanol–water partition coeffi-
cient (log P) for antimicrobial activity. Therefore, further
research is going on in order to investigate the bioactivi-
ties of these compounds.
Acknowledgment
This work was financially supported by the Flemish Institute for the
Promotion of Scientific-Technological Research in Industry (IWT)
and the Research Foundation – Flanders (FWO – Vlaanderen).
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Synlett 2007, No. 5, 741–744 © Thieme Stuttgart · New York

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