Chlorosulfonic acid-mediated cyclization of 4-phenyl-3-isocoumarincarboxylic acids and 4-phenyl-3-isoquinolinonecarboxylic acids: an efficient synthesis of 3-oxoindeno[2,1-c]isocoumarins and 3-oxoindeno[2,1-c]isoquinolinones

Article abstract of DOI:10.1016/j.tetlet.2009.02.089

A highly efficient and clean method has been developed for the synthesis of 3-oxoindeno[2,1-c]isocoumarins and 3-oxoindeno[2,1-c]isoquinolinones from 4-phenyl-3-isocoumarincarboxylic acids and 4-phenyl-3-isoquinolinonecarboxylic acids, respectively.

Full text of DOI:10.1016/j.tetlet.2009.02.089

Tetrahedron Letters 50 (2009) 2057–2059
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chlorosulfonic acid-mediated cyclization of 4-phenyl-3-isocoumarincarboxylic
acids and 4-phenyl-3-isoquinolinonecarboxylic acids: an efficient synthesis
of 3-oxoindeno[2,1-c]isocoumarins and 3-oxoindeno[2,1-c]isoquinolinones
*
Prakash G. Jagtap , Zhiyu Chen, Garry J. Southan
Inotek Pharmaceuticals Corporation, 33 Hayden Avenue, Lexington, MA 02421, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient and clean method has been developed for the synthesis of 3-oxoindeno[2,1-c]isocouma-
rins and 3-oxoindeno[2,1-c]isoquinolinones from 4-phenyl-3-isocoumarincarboxylic acids and 4-phenyl-
3-isoquinolinonecarboxylic acids, respectively.
Received 24 December 2008
Revised 10 February 2009
Accepted 11 February 2009
Available online 15 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Isoquinolinones and compounds possessing an isoquinolinone-
pharmacophore are well known for their important therapeutic
potential.1–7 Some isoquinolinone derivatives exhibit prominent
biological effects such as antitumor,1,6,7 cytotoxic antibiotic,2 and
cardiovascular activities.3 The tetracyclic isoquinolinone, 11-oxo-
indeno[1,2-c]isoquinoline (1a), has been known for several years.8
Formation of its derivative was initially reported while synthesiz-
ing nitidine chloride6a,b which was later identified as a potential
topoisomerase I (top1) inhibitor, NSC 314622.6c Recently, we have
reported the results from structure–activity relationship (SAR)
studies9 of poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors,10
which are based on the indeno[1,2-c]isoquinolinone scaffold (1b).
The recent reports11,12 on new syntheses of indenoisoquinolinone
and benz[d]indeno[1,2-b]pyran-5,11-dione derivatives (1a–d) as
the top1 and PARP-1 inhibitors justify the reevaluation of this class
of tetracyclic scaffolds (Fig. 1).
and lactams. Herein, we present an efficient method for the rapid
construction of 3-oxoindeno[2,1-c]isocoumarins (6) and 3-oxoin-
deno[2,1-c]isoquinolinones (2) from 4-phenyl-3-isocoumarincarb-
oxylic acids (5) and 4-phenyl-3-isoquinolinonecarboxylic acids (7),
respectively (Schemes 1 and 2).
The syntheses of 3-oxoindeno[2,1-c]isocoumarin (6) and 3-oxo-
indeno[2,1-c]isoquinoline (2) were performed as depicted in
Scheme 1. Using the literature method,15 the commercially avail-
able 2-benzoylbenzoic acids (4a–d) were converted to 4-phenyl-
3-isocoumarincarboxylic acids (5a–d). Cyclization of 5a using neat
polyphosphoric acid (PPA)7,16 resulted in poor yield. A similar
cyclization reaction with PPA in xylene17 produced 6a but the
workup procedure to isolate the product in pure form was compli-
cated. However, our further attempts to cyclize 5a using chlorosul-
fonic acid produced isocoumarin 6a in excellent yield. Cyclization
was completed in less than 30 min and as a result of its simple
workup procedure, the product was readily isolated from the reac-
tion mixture. Additionally, we have not seen any aromatic chloro-
sulfonylated byproducts under these conditions. The potential of
this intramolecular cyclization was studied with isocoumarin
derivatives 5b, 5c, and 5d. Their reaction with chlorosulfonic acid
was immediate and produced 6b, 6c, and 6d in excellent yield.
As shown in Scheme 1, the 4-phenyl-3-isoquinolinonecarboxylic
acids (7a–d) were prepared from isocoumarin derivatives (5a–d)
using ammonia. Similarly, under the above mentioned reaction con-
ditions, treatment of 7a with chlorosulfonic acid at 0 °C produced
exclusively indenoisoquinolinone 2a in excellent yield (Table 1).
Indenoisoquinolinone derivatives 2b, 2c, and 2d were also obtained
in excellent yield from the cyclization of 7b, 7c, and 7d, respectively.
However, the treatment of chlorosulfonic acid with nitro derivative
7e (Scheme 2) did not produce the desired tetracyclic product. The
4-nitro-compound 7e remained unreactive under the above men-
tioned reaction conditions.
We were interested in the synthesis13 of indeno[2,1-c]isoquin-
olinones (2 and 3) due to their structural similarity with inde-
no[1,2-c]isoquinolinones analogues (1) that we investigated
recently as PARP-1 inhibitors.9 There are a limited number of liter-
ature methods7,14 available for the synthesis of lactams 2 and 3.
Patented method7 for the synthesis of 2a from 7a requires harsh
reaction conditions (i.e., PPA at 100 °C). As a result of its tedious
workup procedure, we were unable to isolate the product as re-
ported. Additionally, the treatment of 2-O-benzoylindanone with
90% H2SO4 did not produce even a trace of the desired product 8
by following the literature methods (Fig. 2).14 Due to the above
mentioned reasons, it was imperative to investigate new synthetic
methods that will give an easy access to these tetracyclic lactones
* Corresponding author. Tel.: +1 781 676 2118; fax: +1 781 676 2155.
E-mail address: pjagtap@inotekcorp.com (P.G. Jagtap).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.089

2058
P. G. Jagtap et al. / Tetrahedron Letters 50 (2009) 2057–2059
O
O
O
O
O
NH
NH
NH
NH
NH
O
X
O
1a
1b
1c: X = O
1d: X = NH
3
2
Figure 1. Structures of tetracyclic lactam scaffolds 5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione (1a), 6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-one (1b), benzofuro[3,2-
c]isoquinolin-5(6H)-one (1c), 6,11-dihydro-5H-indolo[3,2-c]isoquinolin-5-one (1d), 5H-indeno[2,1-c]isoquinoline-5,7(6H)-dione (2), and 6,7-dihydro-5H-indeno[2,1-c]iso-
quinolin-5-one (3).
O
1. H2SO4, MeOH, reflux, 72%
2. H2SO , KNO3, 44%
3. KOH,4MeOH, 81%
O
O
O
90% H2SO4
Ref. 14
O
O
NH
NH
O
O
O
OH
OH
NO2
2-O-Benzoylindanone
8
7a
7e
Figure 2. Attempts to make 8 using the literature method.14
Scheme 2. Synthesis of 7e.
reaction of insoluble lactam derivative 2a. Indenoisoquinolinone
3 was ultimately obtained from the reaction of 8 with ammonia
in MeOH.
Since our attempts to make an intermediate 8 using literature
methods14 were fruitless, we selected compound 6a as a starting
material for the synthesis of 3. It was reacted with TFA and trieth-
ylsilane at room temperature,9 which provided a mixture of prod-
ucts. The desired product 8 was then separated from the mixture
using silica gel column chromatography. However, the reaction
of 2a with TFA and triethylsilane produced a mixture of 3 along
with several other non-separable byproducts. The product ob-
tained from the reduction of 6a was more easily purified by col-
umn chromatography than the product obtained from the
In summary, an efficient method has been developed for the
synthesis of 3-oxoindeno[2,1-c]isocoumarins and 3-oxoinde-
no[2,1-c]isoquinolinone using chlorosulfonic acid as cyclizing
agent. These new routes allow practical and reproducible synthe-
ses of tetracyclic compounds 2, 3, 6, and 8, and gave an easy access
to them as compared to the literature methods.7,14 The in vitro and
in vivo experimental results of lead compounds from scaffolds 2
and 3 will be published elsewhere.
O
O
BrCH(CO2Et)2,
K2CO3, DMF;
thenHCl/AcOH
O
O
ClSO3H, 0 oC - rt
TFA, Et3SiH, rt, 35%
OH
O
O
O
O
O
O
OH
R
R
R
8
4a-d
5a-d
NH3, reflux; then dil. HCl
6a-d
NH3-MeOH, reflux, 50%
O
O
O
NH
NH
ClSO3H, 0 oC - rt
NH
O
O
OH
R
R
7a-d
2a-d
3
Scheme 1. Synthesis of 3-oxoindeno[2,1-c]isocoumarins (6a–d) and 3-oxoindeno[2,1-c]isoquinolinones (2a–d).

P. G. Jagtap et al. / Tetrahedron Letters 50 (2009) 2057–2059
2059
Table 1
Indenoisocoumarin and indenoisoquinolinone derivatives and intermediates produced via Scheme 1
Entry
Starting compound
Reagent
Product
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4a (R = H)
BrCH(CO2Et)2
BrCH(CO2Et)2
BrCH(CO2Et)2
BrCH(CO2Et)2
ClSO3H
ClSO3H
ClSO3H
ClSO3H
ClSO3H
ClSO3H
ClSO3H
ClSO3H
ClSO3H
TFA-Et3SiH
NH3-MeOH
5a (R = H)15b
5b (R = Me)16
5c (R = (CH2)3COOH)19
5d (R = Cl)19
6a (R = H)18
89
92
80
66
95
89
88
96
96
94
95
93
0
4b (R = Me)
4c (R = (CH2)3COOH)
4d (R = Cl)
5a (R = H)15b
5b (R = Me)16
5c (R = (CH2)3COOH)
5d (R = Cl)
6b (R = Me)16
6c (R = (CH2)3COOH)19
6d (R = Cl)19
2a (R = H)18
7a (R = H)15a
7b (R = Me)15c
7c (R = (CH2)3COOH)
7d (R = Cl)
2b (R = Me)19
2c (R = (CH2)3COOH)19
2d (R = Cl)19
2e (R = NO2)
819
7e (R = NO2)15a
6a
8
35
50
319
See Refs. 18 and 19 for the general cyclization procedure of 6a and 2a, and spectral data of 6a, 5c–d, 2a–d, 7c–d, 8, and 3.
18. Typical procedure for the cyclization of 4-phenyl-3-isocoumarincarboxylic
acids (5) and 4-phenyl-3-isoquinolinonecarboxylic acids (7) using
chlorosulfonic acid: Acid 5a (5 g, 18.79 mmol) was slowly added to
chlorosulfonic acid (50 ml) over 5 min. at 0 °C and vigorously stirred for
5 min. Then, the ice bath was removed and the reaction mixture was stirred at
rt for additional 10 min. The mixture was slowly poured on the ice. The orange
colored solid precipitated out was filtered and washed thoroughly with water.
It was then dried under vacuum to provide cyclized product 6a (4.440 g, 95%).
1H NMR (DMSO-d6): d 7.30–7.35 (dd, J = 8.1 and 7.2 Hz, 1H), 7.44–7.49 (dd,
J = 8.1 and 7.5 Hz, 1H), 7.51–7.56 (t, J = 7.5 Hz, 1H), 7.80–7.85 (t, J = 7.5 Hz, 1H),
7.96 (d, J = 7.2 Hz, 1H), 7.99–8.04 (dd, J = 7.5 and 7.8 Hz, 1H), 8.31 (d, J = 7.8 Hz,
1H), 8.36 (d, J = 7.8 Hz, 1H). 13C NMR d 123.08 (2 ArC), 124.26, 125.72, 129.01,
129.52, 131.02, 131.68, 132.14, 135.77, 136.10, 136.67 (2 ArC), 139.36, 166.39,
180.20.
Acknowledgments
This work was supported by grants from the National Institutes
of Health (R44DK054099 and R44GM058986).
References and notes
1. Cheon, S. H.; Park, J. S.; Lee, J. Y.; Yi, H.; Chung, B. H.; Choi, B. G.; Cho, W. J.; Choi,
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19. 1H and 13C NMR data of 5c–d, 7c–d, 2a–d, 8, and 3 (300 MHz, DMSO-d6):
Compound 5c 1H NMR d 1.80–1.90 (m, 2H), 2.23–2.28 (dd, J = 7.2 and 7.5 Hz,
2H), 2.65 (t, J = 7.5 Hz, 2H), 7.02 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H), 7.28
(d, J = 8.1 Hz, 2H), 7.69–7.84 (m, 2H), 8.27 (d, J = 7.8 Hz, 1H), 12.20 (bs, 1H),
13.42 (bs, 1H). Compound 5d 1H NMR d 6.99 (d, J = 8.1 Hz, 1H), 7.33 (d,
J = 8.1 Hz, 2H), 7.53 (d, J = 8.7 HZ, 2H), 7.70–7.75 (dd, J = 7.2 and 7.5 Hz, 1H),
7.80–7.84 (dd, J = 7.2 and 6.9 Hz, 1H), 8.27 (d, J = 7.2 Hz, 1H), 13.58 (s, 1H).
Compound 7c 1H NMR d 1.93–2.03 (m, 2H), 2.31–2.36 (dd, J = 7.2 and 7.5 Hz,
2H), 2.71–2.76 (dd, J = 7.8 and 7.2 Hz, 2H), 7.12 (d, J = 8.1 Hz, 1H), 7.20 (d,
J = 7.8 Hz, 2H), 7.29 (d, J = 7.5 Hz, 2H), 7.61–7.74 (m, 2H), 8.33 (d, J = 7.5 Hz,
1H), 12.35 (s, 1H). Compound 7d 1H NMR d 6.99 (d, J = 8.4 Hz, 1H), 7.15 (d,
J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.45 (t, J = 6.9 Hz, 1H), 7.56 (t, J = 6.9 Hz,
1H), 8.23 (d, J = 7.5 Hz, 1H), 10.23 (s, 1H, NH). Compound 2a 1H NMR d 7.22–
7.27 (dd, J = 7.2 and 7.5 Hz, 1H), 7.48 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 7.5 Hz, 1H),
7.71–7.76 (dd, J = 7.5 and 7.8 Hz, 1H), 7.89–7.95 (m, 2H), 8.36 (d, J = 9.0 Hz,
1H), 8.40 (d, J = 9.3 Hz, 1H), 12.18 (bs, 1H). 13C NMR d 122.17, 124.15, 124.41,
125.41, 128.13, 129.28 (2 ArC), 129.98, 130.88, 132.76, 134.20, 134.43, 135.89,
142.99, 161.88 (lactam CO), 188.68 (keto CO). Compound 2b 1H NMR d 2.30 (s,
3H), 7.29 (s, 1H), 7.70–7.75 (dd, J = 7.2 and 7.8 Hz, 2H), 7.78–7.80 (dd, J = 8.1
and 6.9 Hz, 1H), 7.88–7.92 (dd, J = 7.5 and 6.9 Hz, 1H), 8.34 (d, J = 7.8 Hz, 2H),
12.13 (s, 1H). Compound 2c 1H NMR d 2.07–2.11 (dd, J = 5.4 and 6.6 Hz, 2H),
2.61–2.65 (t, J = 6.3 Hz, 2H), 2.99–3.03 (dd, J = 5.4 and 5.7 Hz, 2H), 7.02 (d,
J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.57–7.69 (m, 4H), 8.28–8.31 (dd, J = 1.2 and 7.8 Hz,
1H), 11.10 (s, 1H); MS (ES+): m/z 334.1616 (M+1). Compound 2d 1H NMR d 7.45
(s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.70–7.75 (dd, J = 8.1 and 7.2 Hz, 1H), 7.88(d,
J = 7.8 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 8.35 (d, J = 8.4 Hz, 2H), 12.25 (s, 1H).
Compound 8: d 3.94 (s, 2H), 7.26–7.31 (dd, J = 7.2 and 7.5 Hz, 1H), 7.40–7.45
(dd, J = 7.2 and 7.8 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.63–7.68 (dd, J = 7.5 and
7.8 Hz, 1H), 7.95–8.00 (dd, J = 7.8 and 7.5 Hz, 1H), 8.08 (d, 7.5 Hz, 1H), 8.27 (d,
J = 8.4 Hz, 1H), 8.33 (d, 8.4 Hz, 1H). 13C NMR d 36.29, 114.26, 120.02, 121.28,
123.50, 125.16, 125.66, 127.80, 128.64, 131.18, 134.59, 136.48 (2 ArC), 137.40,
139.30, 166.37. Compound 3: d 3.85 (s, 2H), 7.16–7.21 (dd, J = 7.2 and 7.5 Hz,
1H), 7.35–7.40 (dd, J = 7.5 and 7.8 Hz, 1H), 7.51–7.57 (m, 2H), 7.82–7.88 (dd,
J = 7.5 and 7.8 Hz, 1H), 8.05 (d, J = 7.5 Hz, 1H), 8.33 (d, J = 8.1 Hz, 1H), 8.38 (d,
J = 8.1 Hz, 1H), 12.16 (s, 1H). 13C NMR d 36.13 (CH2), 113.84, 120.37, 123.35,
124.37, 125.06, 125.63, 126.32, 127.70, 128.83, 133.65, 134.87, 139.12, 141.52,
147.13, 162.50.
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