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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
arylbenzo[g]isoquinolin-5,10-dione-3-iminium bromides (4) and
octahydrobenzo[j]phenanthridine-7,12-dione derivative 3.
a 1,2,3,4,8,9,10,11-
resulting nicotinic acid with oleum at elevated temperatures,
DOI: 10.1039/C8OB02690D
providing 5 in a total yield of 26%.11 b) A second approach uses a
Diels-Alder reaction between 1,3-cyclohexadiene (7) and
isoquinoline-5,8-dione (8) (Figure 2, path B), followed by oxidation
of the resulting quinol tautomer (structure not depicted) with Ag2O
to the corresponding quinone 10 and subsequent thermal
elimination of ethene, producing 5 in a total yield of 30% (excluding
the synthesis of the starting material).12-13 c) A third approach uses
a phthalide annulation reaction14 (Figure 2, path C) between 3-
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bromopyridine (14) and
temperature to produce benzo[g]isoquinoline-5,10-dione (5) in 65
yield. However, we found this procedure impossible to
a cyanophthalide anion 13 at low
O
N
+
O
%
O
O
reproduce, as the maximum yield of this procedure in our hands
was only 35%. d) Another method using metallation is the reaction
between 3-lithiopyridine (12) and dimethyl phthalate (11) (Figure 2,
path D), which forms an intermediate ester that can be ring closed
via an ortho-lithiation forming 5 in a total yield of 25% starting from
3-bromopyridine.15-17 e) The final and arguably most elegant
method to date for the preparation of benzo[g]isoquinoline-5,10-
dione (5) is based on a Pomeranz-Fritsch type reaction for the ring
closure of a suitable substrate 9 (Figure 2, path E).18 While the
6
O
N
Friedel-Crafts
+
reaction
A
7
8
O
O
O
OMe
N
N
Boc OMe
procedure,
originally
designed
to
prepare
1,2-
O
10
9
E
dihydrobenzo[g]isoquinoline-5,10-diones, was not always able to
yield the target compounds, it was capable of producing 5 in a total
yield of 28% after six steps starting from 1,4-dimethoxy-2-
naphthaldehyde by use of N-Boc protected intermediates. The
major benefit of this approach along with the Diels-Alder reaction
(Figure 2, path B) is that it avoids the use of carbanions at very low
temperatures using strong bases, which is laborious and unsafe on
a larger scale.
B
Pomeranz-Fritsch
type reaction
O
Diels-Alder
reaction
N
Ortho
-lithiation
Phthalide annulation
reaction
O
reaction
D
C
5
O
O
CN
Li
Li
Br
OMe
OMe
N
N
+
O
O
+
Results and discussion
11
12
13
14
For the synthesis of 5 a novel approach was used, starting
from 2-methyl-1,4-naphthoquinone (15) (vitamin K3) (Scheme
1). Following a literature procedure, the starting material was
first reduced with sodium thiosulfate. The resulting
hydroquinone (not depicted) was methylated with dimethyl
sulfate in acetone, to give the dimethoxy compound 16 in
good yield.19 Next, using an improved literature procedure20,
nucleophilic bromination with bromine in DCM provided the
aryl brominated compound (not depicted) in excellent yield.
This compound was subsequently brominated at the CH3-
position in a radical process. The usual solvent for this
reaction20, CCl4, was successfully replaced with the less toxic
EtOAc, and the dibrominated product 17 was obtained in a
93% yield over two steps. Since the dibrominated product 17 is
instable on silica, purification was postponed until the benzyl
bromide was substituted.
Figure 2 Previous approaches to benzo[g]isoquinoline-5,10-dione (5).
In this work we present
a
novel synthesis of the
benzo[g]isoquinoline-5,10-dione (5) core and further explore the
effects of functionalization of the C-ring, by using a chloropyridine
intermediate. The compound library which was obtained was then
evaluated for biological activity and toxicity.
Since the key goal of this research is to synthesize as expeditiously
as possible a wide variety of functionalized compounds and to test
them, we will use benzo[g]isoquinoline-5,10-dione (5) as the central
building block. A summary of the different synthetic routes towards
2-azaanthraquinones has already been reported, partially by our
group, and shows that 5 can be synthesized by a myriad of
methods.10 It is however important to mention that classic methods
for preparing isoquinolines do not necessarily prove to be the
methods of choice for preparing the benzo[g]isoquinoline-5,10-
dione compounds. Since this report, no new methods towards the
unfunctionalized benzo[g]isoquinoline-5,10-dione (5) have been
published. The known syntheses towards 5 can be divided into five
different categories: a) The oldest reported method is a Friedel-
Crafts acylation of benzene with 3,4-pyridinedicarboxylic anhydride
The pyridine ring was constructed using an enamide
intermediate: first the bromomethylated compound
underwent nucleophilic substitution by the anion of N-
vinylformamide (18a). The latter was produced by adding 18a
to a sodium hydride suspension in DMSO.
Calcium hydride was also tested as a base in this reaction, but
no substitution occurred under these conditions. The use of
2 | J. Name., 2012, 00, 1-3
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