Facile syntheses of 7,9-dimethoxypyrrolo[3,2,1-ij]quinolin-6-ones

Article abstract of DOI:10.1016/j.tetlet.2011.10.089

The activated dimethoxypyrrolo[3,2,1-ij]quinolin-6-one ring system was synthesized via two approaches, starting from an indole and quinolin-4-one, respectively. Subsequent demethylation led to both monohydroxy- and dihydroxypyrrolo[3,2,1-ij]quinolin-6-one

Full text of DOI:10.1016/j.tetlet.2011.10.089

Tetrahedron Letters 52 (2011) 7095–7098
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Tetrahedron Letters
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Facile syntheses of 7,9-dimethoxypyrrolo[3,2,1-ij]quinolin-6-ones
⇑
Santosh Rajput, Chao-wei Leu, Kasey Wood, David StC Black, Naresh Kumar
School of Chemistry, The University of New South Wales, Sydney, NSW 2052, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The activated dimethoxypyrrolo[3,2,1-ij]quinolin-6-one ring system was synthesized via two approaches,
starting from an indole and quinolin-4-one, respectively. Subsequent demethylation led to both monohy-
droxy- and dihydroxypyrrolo[3,2,1-ij]quinolin-6-ones.
Received 19 August 2011
Revised 4 October 2011
Accepted 17 October 2011
Available online 29 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolo[3,2,1-ij]quinoline
Indole
Isoflavonoid
Phytoestrogen
The pyrrolo[3,2,1-ij]quinoline system is an important heterocy-
clic scaffold that has been investigated for potential therapeutic
use.1 Pyrrolo[3,2,1-ij]quinolines possess a range of biological activ-
ities including analgesic, anti-pyretic, anti-inflammatory, and anti-
convulsant. They also exist in a variety of oxidised forms which
show a range of medicinal effects.2 For example, 1,2,5,6-tetrahy-
dropyrrolo[3,2,1-ij]quinolin-4-one (4-lilolidone),3 2-lilolidone,4
and their derivatives show effective fungicidal activity against
microbes causing rice blast disease.5
However, there have been no reports of the isolation or activity of
any naturally occurring pyrroloquinolin-6-ones. Hence the chemis-
try and potential bioactivity of these compounds remains relatively
unexplored. Moreover, pyrroloquinolin-6-ones are structurally re-
lated to the natural isoflavones, which are known to have a wide
range of medicinal properties. In particular, the 5-phenylpyrrolo
[3,2,1-ij]quinolin-6-one scaffold 1 was selected for this study on
the basis of its structural similarity and related oxygenation pattern
to the isoflavone genistein (2), which has anti-tumour activity.6
Herein we describe two alternate strategies for preparing the
target system 1. The first approach starts with an indole 3 and
entails the construction of the six-membered pyridone ring
between C7 and N1. The second route begins with quinolin-
4-one 4 and involves formation of the corresponding pyrrole ring
(Scheme 1).
Our group has previously investigated the reactivity of several
3-aryl and 2,3-disubstituted 4,6-dimethoxyindoles towards
electrophilic substitution reactions and established routes for the
synthesis of a variety of C7 and C2 substituted heterocyclic
compounds.2,7 It was therefore anticipated that the pyrroloquino-
lin-6-one nucleus 1 could be synthesized by C7 acylation of
4,6-dimethoxyindoles 3 followed by cyclisation of the resulting
7-indolyldeoxybenzoins 6 with a suitable one carbon reagent; a
route used extensively for the preparation of isoflavones.8,9
R1
OMe
R2
N
R1
R2
R2
N
R1
N
MeO
MeO
HO
O
H
MeO
3
H
N
OMe O
MeO
OH
O
R3
OH
OMe O
2
R3
1
1
OMe O
R3
4
⇑
Corresponding author. Tel.: +61 293854698; fax: +61 293856141.
E-mail address: n.kumar@unsw.edu.au (N. Kumar).
Scheme 1. Synthetic strategies for 7,9-dimethoxypyrrolo[3,2,1-ij]quinolin-6-ones.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.089

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S. Rajput et al. / Tetrahedron Letters 52 (2011) 7095–7098
Table 1
Friedel–Crafts acylation of 4,6-dimethoxy-3-phenylindole (3a)
Synthesis of 7- and 2-indolyldeoxybenzoins
with 4-methoxyphenylacetyl chloride and stannic chloride
afforded only poor yields of 7-indolyldeoxybenzoin 6b and 2-ind-
olyldeoxybenzoin 7b, with the undesired 2-isomer 7b as the major
product. Reaction optimisation was performed, however, it
appeared that the indole nucleus complexed with tin salts, thus
hindering the acylium ion from reacting at C7 as desired.
Entry
R1
R2
R3
6
Yield (%)
7
Yield (%)
1
2
3
4
5
6
Ph
Ph
4-BrC6H4
4-BrC6H4
Ph
H
H
H
H
Ph
Ph
H
MeO
H
MeO
H
MeO
6a
6b
6c
6d
6e
6f
40
15
39
24
85
65
7a
7b
7c
7d
—
2
trace
47
16
—
Vilsmeier–Haack conditions were subsequently examined in
order to overcome this lack of regiochemical control, with 3-aryl-
4,6-dimethoxyindoles 3a and 3b being reacted with N,N-dimethy-
larylacetamides 5 in phosphoryl chloride, initially at 0 °C and then
with heating at 70 °C for 1 h. 7-Indolyldeoxybenzoins 6 and
2-indolyldeoxybenzoins 7 were obtained in only low yields, which
was attributed to decomposition of the acid sensitive 3-aryl-4,6-
dimethoxyindoles under these concentrated conditions. However,
the use of halogenated solvents such as dichloromethane or chlo-
roform was found to facilitate the reactions and generally
improved the yields, though the ratio of 7-indolyldeoxybenzoins
6 to 2-indolyldeoxybenzoins 7 varied (Scheme 2, Table 1, entries
1–4). In contrast, the 2,3-disubstituted indole system 3c reacted
exclusively at the 7-position, producing an 85% and 65% yield of
7-indolyldeoxybenzoins 6e and 6f, respectively, in the presence
of a chlorinated solvent (Table 1, entries 5 and 6).
Ph
—
—
R2
R2
NH
R1
R1
MeO
N
MeO
OMe O
OMe O
R3
R3
6
1
Scheme 3. Reaction conditions: DMF-DMA, anhyd THF, 160 °C, 24 h, pressure
tube.10
Table 2
The synthesis of isoflavones from deoxybenzoins has been
efficiently achieved upon treatment with boron trifluoride diethyl
etherate and methanesulfonyl chloride in DMF.9 However, the
Cyclisation of 7-indolyldeoxybenzoins 6
Entry
R1
R2
R3
Product
Yield (%)
1
2
3
4
5
Ph
H
H
H
Ph
Ph
H
H
MeO
H
MeO
1a
1b
1c
1d
1e
51
92
62
91
97
analogous cyclisation of 7-indolyldeoxybenzoins
6 to pyrrol-
4-BrC6H4
4-BrC6H4
Ph
o[3,2,1-ij]quinolin-6-ones 1 using these reagents gave poor results,
possibly due to a competing formylation reaction at the indole C2
position. Efficient cyclisation was instead achieved through
treatment of 7-indolyldeoxybenzoins 6 with N,N-dimethylformam-
ide-dimethyl acetal (DMF-DMA) at 160 °C for 24 h in toluene or
tetrahydrofuran in a pressure tube. The resulting pyrrolo[3,2,
1-ij]quinolin-6-ones 1 were afforded in good yields and purity
(Scheme 3, Table 2).10
The structures of pyrroloquinolin-6-ones 1 were elucidated
through a combination of analytical techniques. The 1H NMR spec-
tra of compounds 1a–e displayed characteristic singlets at d 6.5
and d 7.9 which corresponded to H8 and H4, respectively. The
3-substituted analogues 1a–c also displayed a characteristic H2
singlet at d 7.2. The carbonyl carbon was observed between d
175 and 179 ppm in the 13C NMR spectra, which is consistent with
other pyrroloquinolin-6-one examples. Formation of the pyrrol-
o[3,2,1-ij]quinolin-6-one nucleus was also confirmed by the X-
ray crystal structure of compound 1d (Fig. 1).
Ph
Treatment of 5,7-dimethoxy-3-aryl-quinolin-4-ones 4a,b for
4 h at room temperature with substituted -bromoacetophenones
a
8 in DMF and in the presence of potassium carbonate afforded the
desired quinolinoketones 9 in good yields of 60–68% (Scheme 4,
Table 3). Interestingly, reaction of the less activated quinolinone
4b afforded a much lower yield of 34%. The ensuing cyclisation
reaction was performed at reflux for 1 h using polyphosphoric acid
(PPA) and generated the pyrroloquinoline analogues 1 in good
yields.
In comparison to the first investigated approach, this second
synthetic route beginning from a quinolin-4-one proved to be a
more versatile and efficient method of preparing pyrrolo[3,2,1-
ij]quinolin-6-ones, though less activated analogues gave poorer
yields across both steps.
In general, the phenolic isoflavones have far greater biological
efficacy compared to their methylated analogues12 and therefore
the demethylation of these pyrroloquinolin-6-one systems was
also of interest. Selective demethylation of the C7-methoxy group
was performed by stirring pyrrolo[3,2,1-ij]quinolin-6-ones 1 at
room temperature for 18 h with 4 equiv of boron tribromide,
affording monohydroxy compounds 10a–c in low 18–23% yields
Overall, this strategy led to the successful preparation of the
target pyrrolo[3,2,1-ij]quinolin-6-ones 1, however, the poor yields
and selectivity observed in the first step led to subsequent exami-
nation of an alternative approach.
It was anticipated that 5,7-dimethoxy-3-aryl-quinolin-4-ones 4
could undergo N-acylation with suitable
a-bromoacetophenones
to give quinolinoketones that could then undergo acid-catalysed
cyclisation to generate pyrrolo[3,2,1-ij]quinolin-6-ones 1.
R1
OMe
R1
OMe
R1
OMe
O
NMe2
+
R2
O
+
R2
R3
N
R3
MeO
N
MeO
H
N
MeO
H
H
6
7
O
3a R1 = Ph, R2 = H
5a R3 = H
3b R1 = 4-BrC6H4, R2 = H
3c R1 = Ph, R2 = Ph
5b R3 = OMe
R3
Scheme 2. Reaction conditions: POCl3, halogenated solvent,
D
, 1–2 h.

S. Rajput et al. / Tetrahedron Letters 52 (2011) 7095–7098
7097
Figure 1. ORTEP diagram of compound 1d.11
O
R1
R1
H
N
MeO
N
MeO
O
MeO
N
a
b
+
Br
R1
OMe O
OMe O
R3
OMe O
R3
R3
R3 = H
3 = Br
4a
4b
8
9
1
R
Scheme 4. Reaction conditions: (a) K2CO3, DMF, rt, 4 h; (b) PPA, reflux, 1 h.
Table 3
Synthesis of pyrrolo[3,2,1-ij]quinolin-6-ones 1
Table 4
Demethylation of pyrrolo[3,2,1-ij]quinolin-6-ones 1
Entry
R1
R3
9
Yield (%)
1
Yield (%)
Entry
R1
R2
10
Yield (%)
11
Yield (%)
1
2
3
4
5
Ph
H
H
H
H
Br
9a
9b
9c
9d
9e
68
66
64
60
34
1a
1b
1f
1g
1h
58
56
56
54
30
1
2
3
4
5
6
7
8
9
Ph
H
H
H
H
H
H
H
H
Ph
10a
10b
10c
10b
10c
10b
10b
10b
10d
18
21
23
40
48
20
10
—
11a
11b
11c
11b
11c
11b
11b
11b
11d
—
—
—
—
—
—
5
4-BrC6H4
4-FC6H4
4-ClC6H4
4-FC6H4
4-BrC6H4
4-FC6H4
4-BrC6H4
4-FC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
Ph
10
53
R2
N
40
R2
N
R1
R2
N
R1
R1
2918 cmÀ1, was indicative of hydrogen bonding to the adjacent
carbonyl moiety.
HO
MeO
MeO
+
Synthesis of the corresponding dihydroxypyrroloquinolin-6-
ones 11 proved to be more problematic. Heating pyrroloquinolin-
6-one 10b with 3 equiv of aluminium trichloride in chlorobenzene
for 1 h returned only the monohydroxy compound 10b in 20% yield
(Table 4, entry 6). Extending the reaction time to 3 h led to a mix-
ture of the monohydroxy and dihydroxy compounds 10b and 11b
being produced (Table 4, entry 7), while heating at reflux for 8 h
led to exclusive formation of the dihydroxy compound 11b, though
only a low yield of 10% was obtained (Table 4, entry 8). Both the
methoxy resonances were absent from the 1H NMR spectrum of
compound 11b, and the presence of a broad IR peak at 3297
cmÀ1 confirmed the presence of free hydroxy groups.
OH
O
OH
10
O
OMe O
1
11
Scheme 5. Reaction conditions: (a) BBr3, CH2Cl2, rt, 18 h; (b) CeCl3.7H2O, NaI,
MeCN, reflux, 8 h; (c) AlCl3, chlorobenzene, reflux; (d) 48% HBr, AcOH, reflux, 72 h.
(Scheme 5, Table 4, entries 1–3). Alternatively, heating pyrrolo-
quinolin-6-ones 1 at reflux with cerium trichloride and sodium
iodide in acetonitrile for 8 h resulted in the monohydroxy com-
pounds 10b and 10c being produced in higher yields of 40% and
48%, respectively (Table 4, entries 4 and 5). The 1H NMR spectrum
of compound 10b showed the single methoxy resonance at d 4.01
and the new hydroxy resonance at d 12.55. The high chemical shift
of the hydroxy group, coupled with the IR stretching frequency at
Demethylation of the 1,2-disubstituted analogue 1d was found
to be more robust than the corresponding 1-substituted com-
pounds, with a 40% yield of the monohydroxypyrroloquinolin-6-

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S. Rajput et al. / Tetrahedron Letters 52 (2011) 7095–7098
6. (a) Magee, P. J.; Rowland, I. R. Br. J. Nutr. 2004, 91, 513–531; (b) Limer, J. L.;
Speirs, V. Breast Cancer Res. 2004, 6, 119–127; (c) Ren, M. Q.; Kuhn, G.; Wegner,
J.; Chen, J. Eur. J. Nutr. 2001, 40, 135–146.
7. (a) Black, D. StC.; Bowyer, M. C.; Ivory, A. J.; Jolliffe, K. A.; Kumar, N. Tetrahedron
1996, 52, 4687–4696; (b) Black, D. StC.; Kumar, N.; McConnell, D. B. Tetrahedron
1996, 52, 8925–8936; (c) Black, D. StC.; Ivory, A. J.; Kumar, N. Tetrahedron 1996,
52, 7003–7012; (d) Black, D. StC.; Bowyer, M. C.; Catalano, M. M.; Ivory, A. J.;
Keller, P. A.; Kumar, N.; Nugent, S. J. Tetrahedron 1994, 50, 10497–10508.
8. Pelter, A.; Foot, S. Synthesis 1976, 326.
one 10d and 53% yield of the dihydroxypyrroloquinolin-6-one 11d
being obtained upon treatment with 48% hydrobromic acid in gla-
cial acetic acid (Table 4, entry 9). In general, the dihydroxypyrrolo-
quinolin-6-ones 11 were found to be difficult to isolate and purify
due to their low stability and susceptibility to degradation.
In conclusion, 7,9-dimethoxypyrrolo[3,2,1-ij]quinolin-6-ones 5
were prepared in two steps from both indole and quinolin-4-one
starting materials. Demethylation of these 7,9-dimethoxypyrrol-
9. Bass, R. J. J. Chem. Soc., Chem. Commun. 1976, 2, 78–79.
10. Representative procedure for the synthesis of pyrrolo[3,2,1-ij]quinolin-6-ones
o[3,2,1-ij]quinolin-6-ones
1
was performed, with selective
1:
A mixture of 7-indolyldeoxybenzoin 6e (0.400 g, 0.88 mmol) and N,N-
C7-demethylation being achieved in the presence of cerium
trichloride and the dihydroxy analogues being obtained upon
treatment with aluminium trichloride.
dimethylformamide-dimethyl acetal (2 mL) in THF (2 mL) was heated in a
pressure tube at 160 °C for 24 h. The resulting solid was filtered and washed with
H2O to afford 1b as a yellow solid (0.347 g, 92%). Mp 306–307 °C (from CHCl3/
MeOH). Found: C, 65.04; H, 4.05; N, 2.96%. C25H18BrNO3 requires: C, 65.23; H,
3.94; N, 3.04%. 1H NMR (300 MHz, CDCl3): d 3.96 (s, 3H, OMe), 4.08 (s, 3H, OMe),
6.50 (s, 1H, H8), 7.23 (s, 1H, H2), 7.35–7.42 (m, 3H, ArH), 7.54 (s, 4H, ArH), 7.60 (d,
J = 8.7 Hz, 2H, ArH), 7.95 (s, 1H, H4). 13C NMR (75 MHz, CDCl3): d 55.6, 56.6, 91.5,
107.5, 107.9, 120.2, 121.3, 124.2, 127.5, 127.9, 129.0, 129.2, 130.5, 131.1, 132.4,
Acknowledgments
We thank the University of New South Wales and the Australian
Research Council for their financial support.
134.9, 136.8, 159.2, 162.1, 175.6. IR (Nujol):
mmax 1643, 1622, 1595, 1537, 1460,
1434, 1377, 1354, 1322, 1309, 1295, 1213, 1178, 1138, 1093, 1051, 1005, 807,
767 cmÀ1. UV (MeOH): kmax 206 nm ( 61121 cmÀ1 MÀ1), 259 (53618), 345
e
(20508), 368 (19641). MS (ESI): m/z 482, [M+Na]+ (35%).
References and notes
11. Crystallographic data for the structure of 1d reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre as Supplementary
Publication No. CCDC 823849. X-ray crystal structures were obtained by Don
Craig, Crystallography Laboratory, UNSW Analytical Centre, Sydney, Australia.
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