Facile and convenient syntheses of 6,11-dihydro-5H-indeno[1,2-c] isoquinolin-5-ones and 6,11-dihydro-5H-indolo[3,2-c]isoquinolin-5-one

Article abstract of DOI:10.1021/ol050331m

(Chemical Equation Presented) The synthesis of 6,11-dihydro-5H-indeno[1,2- c]isoquinolin-5-ones from the base-promoted condensation reaction of homophthalic anhydride and 2-(bromomethyl)-benzonitrile and a convenient method for the synthesis of indolo[3,2-c]isoquinolinones are described.

Full text of DOI:10.1021/ol050331m

ORGANIC
LETTERS
2005
Vol. 7, No. 9
1753-1756
Facile and Convenient Syntheses of
6,11-Dihydro-5H-indeno[1,2-c]isoquinolin-
5-ones and
6,11-Dihydro-5H-indolo[3,2-c]isoquinolin-5-one
Prakash G. Jagtap,* Erkan Baloglu, Garry Southan, William Williams, Aloka Roy,
Alexander Nivorozhkin, Nelson Landrau, Kevin Desisto, Andrew L. Salzman, and
Csaba Szabo´
Inotek Pharmaceuticals Corporation, 100 Cummings Center,
BeVerly, Massachusetts 01915
pjagtap@inotekcorp.com
Received February 16, 2005
ABSTRACT
The synthesis of 6,11-dihydro-5H-indeno[1,2-c]isoquinolin-5-ones from the base-promoted condensation reaction of homophthalic anhydride
and 2-(bromomethyl)-benzonitrile and a convenient method for the synthesis of indolo[3,2-c]isoquinolinones are described.
The therapeutic importance of poly(ADP-ribose)poly-
merase-1 (PARP-1) inhibitors1 has generated much interest
in the discovery of new classes of heterocyclic PARP
scaffolds. The structure-activity relationships (SAR) studies
of these new heterocycles have identified several novel tri-
and tetracyclic PARP-1 inhibitors.2 The PARP-1 drug
discovery that has been carried out during the past few years
has led to various new approaches for the design of mainly
cyclic benzamide inhibitors of the nuclear enzyme PARP-
1.2 There is continued interest in the discovery of new
PARP-1 inhibitors, which is reflected by several recent
publications and reviews.2
1(2H)-one,3 quinazolin-4(3H)-one,3 and [5H]-phenanthridin-
6-one.3,4 The tetracyclic compounds indeno[1,2-c]-, indolo-
[3,2-c]-, and benzofuro[3,2-c]isoquinolinone (1-3) and their
derivatives have never been evaluated for their PARP-1
activity. Thus, due to the structural similarity of indeno[1,2-
c]-, indolo[3,2-c]-, and benzofuro[3,2-c]isoquinolinones (Fig-
ure 1) with the known inhibitors isoquinolin-1(2H)-one3 and
While searching for the new scaffolds that can be used
for the SAR studies we aimed to synthesize new lactams
whose modified derivatives would likely be inhibitors of
PARP-1. The classes of recently synthesized PARP-1 inhibi-
tors2 that have displayed potent PARP-1 inhibitory activity
are derived from the prototypical inhibitors, isoquinolin-
Figure 1. Structures of indeno[1,2-c]-, indolo[3,2-c]-, and benzo-
furo[3,2-c]isoquinolinones (1-3).
[5H]-phenanthridin-6-one,3,4 these tetracycles appeared as
attractive target molecules for synthesis and biological
evaluation.
(1) Virag, L.; Szabo´, C. Pharmacol ReV. 2002, 54, 375-429.
(2) (a) Jagtap, P.; Szabo´, C. Nat. ReV. Drug. DiscoVery 2005 (in press).
(b) Southan, G. J.; Szabo´, C. Curr. Med. Chem. 2003, 10, 321-340. (c)
Peukert, S.; Schwahn, U. Expert Opin. Ther. Pat. 2004, 14, 1531-1551.
10.1021/ol050331m CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/02/2005

The only difference in the structures of the tetracycles 1,
2, and 3 is in the five-membered ring. There are a limited
number of methods available for the synthesis of 1,5 2,6 and
3.7 Cushman et al. have reported a series of indenoisoquino-
linones starting from 11-keto tetracyclic lactone benz[d]-
indeno[1,2-b]pyran-5,11-dione.5a In this study, the indenoiso-
quinolinones were prepared by reacting the corresponding
lactones with an amine followed by the reduction of the keto
group using a diborane. Hiremath et al.6 and Yamaguchi et
al.7 have reported the syntheses of indolo[3,2-c]isoquinoli-
none (2) and benzofuro[3,2-c]isoquinolinone (3), respec-
tively. Previous synthesis of 2 involves multistep reactions
starting from the 2-phenylindole.6 Yamaguchi et al.7 have
described two synthetic pathways for the unsubstituted
benzofuro[3,2-c]isoquinolinone 3 that involve the condensa-
tion reaction of diethyl-R-bromohomophthalate (8) with
salicylonitrile (9) or methyl salicylate. The lack of com-
mercial availability of the benz[d]indeno[1,2-b]pyran-5,11-
dione and the low yielding synthesis of 26 led us to develop
alternative syntheses for the tetracycles 1 and 2. Here, we
report efficient synthetic approaches for 1 and 2 and a
proposed mechanism for the formation of these compounds
by using Yamaguchi’s synthesis of 3.
Scheme 1. Synthesis of Indeno[1,2-c]isoquinolinone 1a
was also carried out using acetonitrile and triethylamine. Our
Our initial efforts to synthesize 1 and 2 by extending
Yamaguchi’s method7 for the synthesis of 3 were unsuc-
cessful. The condensation reactions were tried using various
combinations of starting materials in the presence of a base:
(1) reaction of diethyl R-bromohomophthalate6 (8a) with
2-methylbenzonitrile, (2) reaction of diethyl homophthalate
with 2-(bromomethyl)-benzonitrile (4a), (3) reaction of
homophthalic acid with 4a, and (4) reaction of 8a with
anthranilonitrile.
initial efforts to prepare 2 from the condensation reaction of
Scheme 2. Synthesis of Indeno[1,2-c]isoquinolinones 1b-e
However, the reaction of homophthalic anhydride (5) and
2-(bromomethyl)benzonitrile (4a) in acetonitrile using tri-
ethylamine provided 1a as the major product along with 6
and 7 (Scheme 1). The desired product 1a was insoluble in
acetonitrile, and it was easily isolated from other byproducts
by filtration. Products 6 and 7 were separated from the filtrate
by column chromatograph. This synthetic approach was
further used for the synthesis of substituted indeno[1,2-c]-
isoquinolinones 1b-e, which were obtained in 24-42%
yield (Scheme 2).
Following Yamaguchi’s method,7 compound 3 was pre-
pared by condensation of 2-cyanophenol (9) and bromo-
diester 8a7b in acetone and in the presence of potassium
carbonate. A similar condensation reaction using 8b and 9
anthralinonitrile and 8b in the presence of potassium carbon-
ate were not successful. However, treatment of the N-ethyl
carbamate derivative 108a with 8b in the presence of sodium
hydride8b in toluene provided the desired product 11 in 45%
yield. Hydrazinolysis of 11 (NH2NH2‚H2O, EtOH) yielded
indolo[3,2-c]isoquinolinone (2)6 in 88% yield (Scheme 3).
We were unable to isolate the conjugate acid of 13a from
the reaction of 5 and 4a as shown in Scheme 5. The relative
electrophilicity of benzonitrile and bezylbromide, using
homophthalic anhydride as nucleophile, was studied by
reacting a mixture of homophthalic anhydride (5), 3-ni-
trobenzyl bromide (15), and 4-nitrobenzonitrile (16) with a
solution of triethylamine in acetonitrile at room temperature.
The reaction was completed immediately after the addition
of triethylamine. TLC analysis showed the consumption of
(3) Banasik, M.; Komura, H.; Shimoyama, M.; Ueda, K. J. Biol. Chem.
1992, 267, 1569-1575.
(4) Garcia Soriano, F.; Virag, L.; Jagtap, P.; Szabo´, E.; Mabley, J.;
Liaudet, L.; Marton, A.; Hoyt, D. G.; Murthy, K. G.; Salzman, A. L.;
Southan, G. J.; Szabo´, C. Nat. Med. 2001, 7, 108-113.
(5) (a) Cushman, M.; Jayaraman, M.; Vroman, J. A.; Fukunaga, A. K.;
Fox, B. M.; Kohlhagen, G.; Strumberg, D.; Pommier, Y. J. Med. Chem.
2000, 43, 3688-3698. (b) Chatterjea, J. N.; Mukherjee, H. J. Indian Chem.
Soc. 1960, 37, 379-391.
(6) (a) Hiremath, S. P.; Saundane, A. R.; Mruthyunjayaswamy, B. H.
M. Orient. J. Chem. 1997, 13, 173-176. (b) Soundane, A. R.; Rudresh,
K.; Satyanarayan, N. D.; Hiremath, S. P. Indian J. Pharm. Sci. 1998, 60,
379-383.
(7) (a) Yamaguchi, S.; Uchiuzoh, Y.; Sanada, K. J. Heterocycl. Chem.
1995, 32, 419-423. (b) Yamaguchi, S.; Yoshida, K.; Miyajima, I.; Araki,
T.; Hirai, Y. J. Heterocycl. Chem. 1995, 32, 1517-1519.
(8) (a) Radl, S.; Konvicka, P.; Vachal, P. J. Heterocycl. Chem. 2000,
37, 855-862. (b) Garcia, E. E.; Benjamin, L. E.; Fryer, R. I. J. Heterocycl.
Chem. 1973, 10, 51-53.
1754
Org. Lett., Vol. 7, No. 9, 2005

anthracyclinone precursors were prepared by strong base
induced cycloaddition reaction of 5 with various dienophiles.
The isoquinolinones were prepared by condensation of 5 with
Schiff bases. The formation of the dimer 7 from the reaction
of homophthalic anhydride with a base has been previously
reported.11 Here, we propose a mechanism for the formation
of tetracyclic compounds 1 and 11 that is similar to the
mechanism in the previous synthesis of 3.7 In all three cases,
the initial reaction is the displacement of the bromine, which
leads to the formation of the intermediates 13a, 12a, and
12c (Scheme 5). The benzylic anion of diester (12a and 12c)
Scheme 3. Synthesis of Indolo[3,2-c]- and
Benzofuro[3,2-c]isoquinolinones
Scheme 5. Proposed Mechanism for the Formation of 1a,
3, and 11
5 and 15, and after separation of the crude products, the R,R-
di(3-nitrobenzyl)-homophthalic anhydride (17) appeared as
the major product along with a minimal amount of homo-
phthalic anhydride dimer 7. The 4-nitrobenzonitrile remained
unreactive under the above-mentioned reaction conditions.
Although we were not able to isolate the intermediate 13a,
the formation of dibenzylated adducts 6 (Scheme 1) and 17
(Scheme 4) support the proposed mechanism, where inter-
Scheme 4. Reaction of Homophthalic Anhydride with
15 and 16
or anhydride (13a) then attacks to the nitrile group to form
the intermediates 13b, 12b, and 12d respectively. Further
cyclization produces the intermediate 14. In the case of
diethyl homophthalate, the ester hydrolysis of 12b and 12d
gives an intermediate 14. Decarboxylation in intermediate
14 then produces the tetracyclic compounds 1a, 3, and 11.
mediate 13a may have formed from the reaction of homo-
phthalic anhydride (5) and 2-(bromomethyl)benzonitrile (4a).
In conclusion, we have synthesized indeno[1,2-c] and
indolo[3,2-c]isoquinolinones (1 and 2) by modifying Yamagu-
chi’s synthesis of 3. The current method provides an easy
access to the synthesis of tetracyclic compound 1a, using
readily available reagents 5 and 4a. In addition, these
There is published evidence for the formation of the
reactive benzylic enolate form of homophthalic anhydride.
Earlier, homophthalic anhydride has been used for the
synthesis of anthracyclinones9 and isoquinolones.10 The
(9) Tamura, Y.; Sasho, M.; Nakagawa, K.; Tsugoshi, T.; Kita, Y. J. Org.
Chem. 1984, 49, 473-478.
(10) (a) Cushman, M.; Madaj, E. J. J. Org. Chem. 1987, 52, 907-915.
(b) Azizian, J.; Mohammadi, A. A.; Karimi, A. R.; Mohammadizadeh, M.
R. J. Org. Chem. 2005, 70, 350-352.
(11) (a) Ayyangar, N. R.; Srinivasan, K. V. Indian J. Chem. 1983, 22B,
1108-1115. (b) Sinha, N. K.; Sahay, L. K.; Prasad, K.; Srivastava, J. N.
Indian J. Heterocycl. Chem. 1992, 1, 235-240. (c) Bauta, W. E.; Lovett,
D. P.; Cantrell, Jr., W. R.; Burke, B. D. J. Org. Chem. 2003, 68, 5967-
5973.
Org. Lett., Vol. 7, No. 9, 2005
1755

processes opened route for the modification of the core
structures 1 and 2.12 The reaction mechanisms were suggested
by analogy with that in the synthesis of 3. The SAR studies
of this series of compounds are still underway. The in vitro
and in vivo experimental results of our lead compound, which
is based on scaffold 1 will be published elsewhere.
Acknowledgment. This work was supported by grants
from the National Institutes of Health (R44DK054099 and
R44GM058986).
Supporting Information Available: Experimental pro-
cedures and 1H NMR and 13C NMR spectra for the new and
known products. This material is available free of charge
via the Internet at http://pubs.acs.org.
(12) Jagtap, P.; Baloglu, E.; van Duzer, J. H.; Szabo´, C.; Salzman, A.;
Roy, A.; Williams, W.; Nivorozhkin, A. U.S. Patent Appl. 0039009A1,
2004.
OL050331M
1756
Org. Lett., Vol. 7, No. 9, 2005