Suzuki-Miyaura cross-coupling and ring-closing metathesis: A strategic combination to the synthesis of indeno[1,2-c]isoquinolin-5,11-diones

Article abstract of DOI:10.1016/j.tetlet.2011.01.113

A variety of diversely substituted isoindeno[1,2-c]isoquinolin-5,11-diones has been readily assembled through a sequence involving a Suzuki-Miyaura cross-coupling reaction with enol phosphates combined with a ring-closing metathesis (RCM) reaction. Intram

Full text of DOI:10.1016/j.tetlet.2011.01.113

Tetrahedron Letters 52 (2011) 1481–1484
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Suzuki–Miyaura cross-coupling and ring-closing metathesis: a strategic
combination to the synthesis of indeno[1,2-c]isoquinolin-5,11-diones
Stéphane Lebrun a,b, Axel Couture a,c, , Eric Deniau a,b, Pierre Grandclaudon a,b
⇑
a Univ Lille Nord de France, F-59000 Lille, France
b USTL, Laboratoire de Chimie Organique Physique, EA CMF 4478, Bâtiment C3(2), F-59655 Villeneuve d’Ascq, France
c CNRS, UMR 8181 ‘UCCS’, F-59655 Villeneuve d’Ascq, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of diversely substituted isoindeno[1,2-c]isoquinolin-5,11-diones has been readily assembled
through a sequence involving a Suzuki–Miyaura cross-coupling reaction with enol phosphates combined
with a ring-closing metathesis (RCM) reaction. Intramolecular carbocationic annulation reaction and ulti-
mate oxidation of a latent hydroxyl functionality completed the synthesis of the target titled compounds.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 13 December 2010
Revised 19 January 2011
Accepted 24 January 2011
Available online 1 February 2011
Keywords:
Indenoisoquinolinediones
Enol phosphate
Suzuki–Miyaura coupling
Ring-closing metathesis
1. Introduction
leading to molecular complexity in a highly efficient manner is an
area of current interest.
Indenoisoquinolinediones 1 (Scheme 1) are a class of non-cam-
ptothecin topoisomerase I poisons that display marked cytotoxic
properties and for some of them, potent antitumor activities in
xenograft models.1 These highly fused compounds which contain
a planar tetracyclic heteroring system equipped with multifarious
functionalities as exemplified by the lead compound 2 (NCS
314622), indotecan 3 (NCS 724998) and indimitecan 4 (NCS
725776) (Fig. 1) have been demonstrated to inhibit topoisomerase
I enzymes by intercalating between the DNA base pairs and to sta-
bilize a ternary complex consisting of the drug molecule, DNA and
topoisomerase I.2 Additionally they produce a unique pattern of
DNA cleavage sites relative to camptothecins and therefore may
target genes differently, which could result in a different spectrum
of anticancer activity.1,2 During the past decade considerable effort
has been expended to develop constitutionally diverse analogues
and progresses have been made on the improvement of the poten-
cies and pharmacokinetics properties of these indenoisoquinolin-
ediones through structure manipulation of the tetracyclic
molecular scaffold.1f,g,3,4 Preclinical developments of several inden-
oisoquinolinediones as alternatives to camptothecin have recently
begun.2 As a consequence, for the construction of structurally di-
verse models, the development of general synthetic methodologies
For the elaboration of substituted indenoisoquinolinediones
organic chemists have at their disposal a number of synthetic
methods that can be cursorily classified into three main categories
(Scheme 1). The first one hinges upon the condensation of benz[-
d]indeno[1,2-b]pyran-5,11-diones 5 with primary amines (Scheme
1, path a).1c,d,g,5 This technique has been used exclusively for the
assembly of bare models. To accommodate additional substituents
on the two aromatic rings of the indenoisoquinoline system an
alternative synthesis was executed which was based on the con-
densation of Schiff bases 6 with homophthalic anhydrides 7 to af-
ford cis-substituted isoquinolones 8 which were subsequently
subjected to an intramolecular SOCl2-induced Friedel–Crafts reac-
tion (Scheme 1, path b).1f,2,6 At last a synthetic method relying
on chemical manipulation of suitably substituted NH free 3-aryl-
isoquinolones 9 assembled through a dilithiated toluamide 10-
benzonitrile 11 cyclization process has been recently developed
(Scheme 1, path c).1e All these methods generally proceed in satis-
factory yields but they are fraught with difficulties associated with
the elaboration of structurally diverse precursors 5 for the first one,
the requirement of mandatory cis-stereodefined models 8 for the
second approach which turned out to a subject of controversy7
and finally the presence of compromising competing metalation
sites for the last one.
We wish to report in this paper an alternative and conceptually
new synthetic approach to these highly condensed indenoisoqui-
nolinediones 1. This new route, which is depicted in Scheme 1,
⇑
Corresponding author. Tel.: +33 3 20 43 44 32; fax: +33 3 20 33 61 09.
E-mail address: axel.couture@univ-lille1.fr (A. Couture).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.113

1482
S. Lebrun et al. / Tetrahedron Letters 52 (2011) 1481–1484
O
O
O
O
HOOC
D
7
O
C
+
RNH
2
A
B
+
O
N
N
path a
path b
path c
R
R
8
O
O
O
1
5
N
6
R
path d
BnO
OHC
N
N
R
H
O
12
9
O
BnO
Me
NHMe
O
+
N
NC
13
O
10
11
R
O
Scheme 1. Reported and planned synthetic strategies for the construction of titled compounds 1.
O
in THF and subsequent interception of the transient sodium amide
salt with acetyl chloride delivered the N-acetyl-o-vinylbenzamide
derivatives 13a,c,d albeit in modest yields (Scheme 2).8 With rapid
access to these diacylated models established, the focus of the re-
search shifted to the use of these compounds as advanced interme-
diates for the concise and efficient generation of the dienic
aromatic compounds 12a–d. We surmised that these styrene benz-
amides would possess the appropriate functionalities required for
the installation of an additional styrene unit through a palladium-
mediated cross-coupling reaction.
O
O
O
O
O
MeO
MeO
MeO
MeO
O
N
N
N
Me
O
O
3 Indotecan (NCS 724998)
2 (NCS 314622)
O
O
O
Since the pioneering work in 1980 of Oshima et al.,9 who cou-
pled a series of vinyl phosphates with trialkylaluminum species in
the presence of Pd(PPh3)4 catalyst, several groups have success-
fully and elegantly used constitutionally diverse enol phosphates
in a variety of cross-coupling reactions.10 Whereas simple N-
alkylated amides proved not to be effective substrates10b the cou-
pling reaction could however be performed with models
equipped with electron-withdrawing groups on nitrogen atom.
The N-diacylated models 13a,c,d developed in this study fulfill
these stringent structural criterions. We were then pleased to ob-
serve that exposure of compounds 13a,c,d to KHMDS in THF at
À78 °C provided a potassium enolate 16 which was captured by
reaction with diphenyl chlorophosphate. After simple workup
the sensitive vinyl phosphate 17 was used in the next step with-
out further purification. A Pd-catalyzed Suzuki–Miyaura coupling
reaction was subsequently applied under well defined conditions.
For this purpose the vinyl phosphate 17, a suitably (un)substi-
tuted 2-formylboronic acid 18–20, Pd(PPh3)4 as a catalyst, aque-
ous Na2CO3 (2 M), a few drops of EtOH were refluxed in THF.
Under these conditions the expected functionalized distyrene
amides 12a–d, candidates for a planned ring-closing metathesis
reaction were isolated in very satisfactory yields (Scheme 2). Ole-
fin RCM reaction has become a powerful tool in organic synthesis
over the past decades and ranks high in the hierarchy of synthetic
approaches for the elaboration of small, medium and large unsat-
MeO
MeO
N
N
N
O
4 Indimitecan (NCS 725776)
Figure 1. Chemical structures of representative bioactive indenoisoquinoline-
diones.
path d, combines (i) a ring-closing metathesis reaction applied to
12 to secure the creation of the lactam that is ring B in titled com-
pound 1, (ii) a Suzuki–Miyaura cross-coupling reaction involving
enol phosphate deriving from 13 and adequately (or suitably) func-
tionalized boronic acids for the installation of the aromatic unit D,
(iii) and the ultimate creation of the five-membered nucleus C.
2. Results and discussion
The first facet of the synthesis which is depicted in Scheme 2
was the construction of the polyenic benzamides 12a–d. Initially
the o-vinylbenzoic acids 14a,c were efficiently converted into the
corresponding NH free benzamides 15a,c,d via their acid chlorides
and under standard conditions. Deprotonation of 15a,c,d with NaH

S. Lebrun et al. / Tetrahedron Letters 52 (2011) 1481–1484
1. (COCl) , toluene-DMF
1483
2
1. NaH , THF
r.t. , 2 h
r.t. , 2 h
3
3
2. R NH , Et N , CH Cl
O
2
3
2
2
O
R
2. CH COCl
3
2
1
2
1
2
1
COOH
R
R
R
R
R
r.t. , 4 h
-78 °C to r.t. , 5 h
N
3
NHR
O
70-85%
54-66%
R
14a,c
13a,c,d
15a,c,d
1. Pd(PPh ) 5 mol%
3 4
Na CO , H O
2
3
2
5
2.
CHO
R
Cl
4
B(OH)
R
2
P
OPh
3
3
PhO
18-20
O
R
O
THF-H O
reflux , 2 h
R
2
KHMDS
THF , -78 °C
2
1
2
1
R
N
R
N
-78 °C , 20 min
O
O
72-87%
R
P
R
PhO OPh
16
17
nd
3
4
Grubbs' cat. 2 generation
toluene , reflux , 3 h
O
O
R
10% HCl in acetone
r.t. , 24 h
R
3
2
2
1
R
R
R
N
N
5
R
1
81-93%
76-88%
4
R
R
R
OHC
OHC
21a-d
5
R
12a-d
O
O
3
3
2
1
2
PDC , CH Cl
r.t. , 12 h
R
R
1
2
3
4
5
2
2
R
R
R
R
H
H
R
R
H
R
N
N
a
b
c
d
H
H
Me
H
1
R
R
4
4
73-85%
Me OMe
H
R
R
HO
22a-d
O
OMe OMe Me
Bn
H
H
H
5
5
R
R
H
H
OMe
1a-d
Scheme 2. Synthesis of indeno[1,2-c]isoquinolin-5,11-diones.
urated heterocycles.11 It is now routinely applied to ensure the
assembly of cyclic olefins containing multifarious functionalities12
but annulation processes involving styrene compounds are rather
scant.13 We then undertook the RCM experiments on metathesis
precursors 12a–d and after considerable experimentation we
found that Grubbs’ catalyst 2nd generation performed signifi-
cantly better than the 1st generation analogue. The best results
were obtained by employing 5 mol % of catalyst at reflux in tolu-
ene for 3 h and very satisfactory yields of functionalized 3-aryl-
isoquinolones 21a–d were observed by this technique.8
Interestingly the carboxaldehyde functionality was spared upon
this annulation process. The elaboration of the C ring of the tetra-
cyclic core was secured through a carbocationic intramolecular
enamide–aldehyde cyclization triggered by treatment with 10%
HCl in acetone. The hydroxylated cyclization adducts 22a–d were
obtained in fairly good yields (Scheme 2)8 and at this stage, it is
worth mentioning that hydroxyindenoisoquinolinones structur-
ally related to 22a–d are endowed with profound chemothera-
peutic properties.1d,1e,14 Ultimately the hydroxyl functionality of
precursors 22a–d was converted into the required carbonyl group
by oxidation with PDC in CH2Cl2 to provide quite satisfactory
3. Conclusion
In conclusion we have devised a conceptually new synthetic ap-
proach to a variety of indenoisoquinolinediones. This methodology
underpins the synthetic utility of acyclic a-phosporylenamides as
effective, synthetically useful substrates and enriches the reper-
toire of the RCM reactions. The simple protocol developed in the
present study paves the way for the construction of related inden-
oisoquinolinediones for further biological studies.
Acknowledgments
This research was supported by the Centre National de la
Recherche Scientifique, by MENESR and by the Program PRIM
(Région Nord-Pas de Calais).
References and notes
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(Scheme 2).8

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3H, OCH3), 5.45 (s, 1H, CH), 5.57 (br s, 1H, OH), 6.94 (d, J = 6.5 Hz, 1H, Harom),
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H
arom), 8.22 (d, J = 7.0 Hz, 1H, Harom) ppm; 13C NMR (75 MHz, DMSO) d = 31.9
(NCH3), 55.9 (OCH3), 70.9 (CH), 109.6 (CH), 112.5 (CH), 121.3 (C), 124.0 (C),
124.1 (CH), 125.7 (CH), 126.7 (CH), 128.5 (CH), 132.7 (CH), 134.2 (C), 137.4 (C),
140.6 (C), 140.7 (C), 160.0 (C), 162.6 (NC@O) ppm.1a (91%) mp 218–220 °C; 1
H
NMR (300 MHz, DMSO) d = 3.99 (s, 3H, NCH3), 7.49–7.61 (m, 4H, Harom), 7.81 (t,
J = 7.3 Hz, 1H, Harom), 7.92 (d, J = 7.9 Hz, 1H, Harom), 8.21 (d, J = 8.1 Hz, 1H,
H
arom), 8.53 (d, J = 8.1 Hz, 1H, Harom) ppm; 13C NMR (75 MHz, DMSO) d = 32.2
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(NCH3), 106.6 (C), 122.5 (CH), 122.6 (CH), 122.7 (C), 124.4 (CH), 127.0 (CH),
128.1 (CH), 131.3 (CH), 131.7 (C), 133.6 (CH), 134.4 (C), 137.1 (C), 157.2 (C),
162.5 (NC@O), 189.9 (C@O) ppm.
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8. Selected data for compounds: 12d (76%) oil; 1H NMR (300 MHz, CDCl3) d = 3.82
(s, 3H, OCH3), 4.91 (br s, 1H, Hvinyl), 5.05 (s, 2H, NCH2Ph), 5.33 (d, J = 10.9 Hz,
1H, Hvinyl), 5.50 (br s, 1H, Hvinyl), 5.72 (d, J = 17.4 Hz, 1H, Hvinyl), 6.78 (dd,
J = 10.9, 17.4 Hz, 1H, Hvinyl), 7.05–7.36 (m, 11H, Harom), 7.83 (d, J = 7.6 Hz, 1H,
H
arom), 9.81 (br s, 1H, CHO) ppm; 13C NMR (75 MHz, CDCl3): d = 48.1 (NCH2Ph),
55.6 (OCH3), 110.7 (CH), 113.2 (CH), 115.4 (CH), 116.5 (CH2), 116.8 (CH2), 123.7
(C), 125.2 (CH), 127.2 (CH), 127.4 (CH), 127.7 (CH), 128.3 (2 Â CH), 129.4
(2 Â CH), 130.9 (CH), 131.4 (C), 133.8 (CH), 135.2 (C), 137.3 (C), 144.4 (C), 144.8
(C), 159.4 (C), 171.2 (NC@O), 191.1 (CHO) ppm.21c (78%) mp 184–186 °C; 1H
NMR (300 MHz, CDCl3) d = 3.33 (s, 3H, NCH3), 3.96 (s, 3H, OCH3), 4.02 (s, 3H,
OCH3), 6.31 (s, 1H, Hvinyl), 6.83 (s, 1H, Harom), 7.45 (d, J = 7.4 Hz, 1H, Harom), 7.65
(t, J = 7.4 Hz, 1H, Harom), 7.72 (t, J = 7.4 Hz, 1H, Harom), 7.83 (s, 1H, Harom), 8.03
(d, J = 7.4 Hz, 1H, Harom), 9.98 (s, 1H, CHO) ppm; 13C NMR (75 MHz, CDCl3)
d = 33.7 (NCH3), 56.1 (OCH3), 56.3 (OCH3), 105.9 (CH), 107.7 (CH), 108.4 (CH),
119.2 (C), 128.9 (CH), 129.7 (CH), 130.8 (CH), 131.3 (C), 134.1 (CH), 134.4 (C),
14. (a) Jagtap, P. G.; Baloglu, E.; Southan, G. J.; Mabley, J. G.; Li, H.; Zhou, J.; van
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