Cobalt-Catalyzed Dual Annulation of o-Halobenzaldimine with Alkyne: A Powerful Route toward Bioactive Indenoisoquinolinones

Article abstract of DOI:10.1002/chem.201501152

A cobalt-catalyzed dual annulation reaction for the synthesis of variously substituted indenoisoquinolinones from 2-bromobenzaldehydes, amines, and methyl 2-(ethynyl)benzoates has been developed. This method could also be applied to the synthesis of an ar

Full text of DOI:10.1002/chem.201501152

DOI: 10.1002/chem.201501152
Full Paper
&
Cobalt Catalysis
Cobalt-Catalyzed Dual Annulation of o-Halobenzaldimine with
Alkyne: A Powerful Route toward Bioactive
Indenoisoquinolinones
Chuan-Che Liu,[a] Jen-Chieh Hsieh,*[b] Rajendra Prasad Korivi,[a] and Chien-Hong Cheng*[a]
Abstract: A cobalt-catalyzed dual annulation reaction for the
synthesis of variously substituted indenoisoquinolinones
from 2-bromobenzaldehydes, amines, and methyl 2-(ethy-
nyl)benzoates has been developed. This method could also
be applied to the synthesis of an array of highly functional-
ized bioactive indenoisoquinolinones and their derivatives. A
possible mechanism of the cobalt catalysis is proposed, in-
volving imine formation from bromobenzaldehyde and the
amine, followed by a series of oxidative addition, alkyne in-
sertion, cyclization reactions, and carbon–carbon double-
bond migration. The regioselective alkyne insertion plays an
important role for the success of the second annulation.
was removed.[1] Recently, several indenoisoquinoline-diones
have shown a similar DNA cleavage pattern with good chemi-
cal stability and resistance to reversal after the drug was re-
moved (NSC 706744, NSC 314622 etc).[2] In addition, indenoiso-
quinolinones were found to be useful in treating inflammatory
diseases as well. Previous reports for the synthesis of indenoi-
soquinoline-diones mainly relied on the condensation reaction
between the homophthalic anhydride and the imine to pre-
pare a 3,4-disubstituted isoquinolinone-carboxylic acid and this
was later converted to the indenoisoquinolinone by a cycliza-
tion reaction.[3] Unfortunately, this method gave a mixture of
cis and trans isomers, but only the cis isomer is suitable for the
cyclization reaction. Moreover, the preparation of substrates is
tortuous and a multistep synthesis is required.[3] Cyclization of
the lithiated toluamide with nitriles was also reported to be
a strategy for the synthesis of indenoisoquinoline-diones; how-
ever, the process is still complicated with limitation of the sub-
strate scope.[3f] Also, there is no direct procedure for the syn-
thesis of indenoisoquinolinones, which were generally pre-
pared by a reduction of the corresponding indenoisoquinoline-
dione followed by a dehydration reaction by using triethylsi-
lane and trifluoroacetic acid.[3c]
Introduction
Camptothecin (CPT) and its analogues (Scheme 1) are impor-
tant DNA topoisomerase I (Top I) inhibitors, which display
marked cytotoxic properties and are FDA-approved medication
for cancer treatment.[1] However, some problems associated
with their usage have been found. For example, the binding
complex (DNA–CPT–Top I) formed is reversible after the drug
Scheme 1. Camptothecin and its analogues, bioactive indenoisoquinoline-
diones, and indenoisoquinolinones.
Results and Discussion
Recently, we observed the cyclization of o-halobenzaldimines
with alkynes in the presence of cobalt complexes to give in-
denamine products, regioselectively.[4a] The Indenamine deriva-
tive I was obtained if the loaded alkyne did not contain an
electron-withdrawing group. On the other hand, the indena-
mine II with a double-bond migration was found if the alkyne
had a strong electron-withdrawing substituent (R4 = strong
electron-withdrawing group (SEWG), Scheme 2).
[a] Dr. C.-C. Liu, Dr. R. P. Korivi, Prof. Dr. C.-H. Cheng
Department of Chemistry
National Tsing Hua University
Hsinchu 30013 (Taiwan)
E-mail: chcheng@mx.nthu.edu.tw
[b] Prof. Dr. J.-C. Hsieh
Department of Chemistry
Tamkang University
New Taipei City, 25137 (Taiwan)
E-mail: jchsieh@mail.tku.edu.tw
The results are in sharp contrast to the nickel-,[4b–d] palladi-
um-,[4e–h] and rhodium-catalyzed[4i–k] formation of isoquinolini-
um salts from o-halobenzaldimines and alkynes. The formation
Supporting information for this article is available on the WWW under
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Table 1. Optimization studies for the synthesis of indenoisoquinolinone
4a.[a]
Entry Catalyst/ligand (1:1) Additive Solvent (ratio)
Yield [%][b]
1[c]
[CoCl2(dppe)]/none
[CoCl2(dppe)]/acac
[CoCl2(dppe)]/dppe
[CoCl2(dppe)]/dppe
[CoI2(dppf)]/dppf
[CoI2(dppf)]/dppf
[CoI2(dppf)]/dppf
[CoI2(dppf)]/dppf
[CoI2(dppf)]/dppf
[CoI2(dppf)]/dppf
none
none
none
ZnCl2
ZnCl2
none
ZnCl2
ZnCl2
ZnCl2
ZnCl2
CH3CN/THF (1:1)
CH3CN/THF (8:2)
9
0
2[c]
3[c]
CH3CN/THF (8:2) 13
CH3CN/THF (1:1) 22
CH3CN/THF (1:1) 23
CH3CN/THF (1:1) 12
CH3CN/THF (1:1) 68
CH3CN/THF (1/1) 75
4[c,e]
5[c,e]
6[d]
Scheme 2. Metal-selective syntheses of indenamines and isoquinolines from
the azacomplex A. dppe=1,2-bis(diphenylphosphino)ethane.
7[d,e]
8[d,f]
9[d,f]
10[d,g]
of indenamine II prompted us to explore the possibility for the
application of this cobalt catalysis to the synthesis of indenoi-
soquinolinones. Herein, we report a one-pot synthesis of in-
denoisoquinolinones from o-halobenzaldimines by using
cobalt complexes as catalysts. This catalytic reaction demon-
strates a new tandem nucleophilic addition of vinylcobalt spe-
cies to imine and carbonyl groups. The method can be applied
to the synthesis of biologically active indenoisoquinoline deriv-
atives with much shorter synthetic steps compared to previous
reports.[3]
CH3CN
CH3CN
92
60
[a] Reaction conditions: o-bromobenzaldehyde, p-toluidine, alkyne, cobalt
complex (0.021 mmol), ligand (0.021 mmol), and Zn (0.6 mmol) in solvent
(1 mL) at 1008C for 20 h. [b] NMR spectroscopic yields by using mesity-
lene as an internal standard. [c] Ratio of reactants: 1a/2a/3a=
0.3:0.3:0.6 mmol. [d] Ratio of reactants: 1a/2a/3a=0.6:0.6:0.3 mmol.
[e] ZnCl2: 0.3 mmol. [f] ZnCl2: 0.6 mmol. [g] ZnCl2: 0.9 mmol.
We envisioned that, in the cobalt-catalyzed synthesis of in-
denamine derivative, if the alkyne used has an ester group at
the ortho position of the aryl substituent, further reaction of
the coordinated amide group with the ester group is likely to
provide a unique access to substituted indenoisoquinolinones
(see the mechanism for details). To test this possibility, we pre-
pared substrate 3a through a Sonogashira coupling reaction
of trimethylsilylacetylene with methyl o-iodobenzoate. The re-
action of o-bromobenzaldehyde (1a) and p-tolylamine (2a)
with compound 3a in the presence of [CoCl2(dppe)] and zinc
metal powder gave the expected indenoisoquinolinone deriva-
tive 4a in very low yield (Table 1, entry 1). We then examined
the effect of various cobalt complexes, ligands, and Lewis acid
additives. It was found that the reaction was completely inhib-
ited when extra acetylacetonate (acac) was loaded to the solu-
tion. The desired product 4a was obtained in slightly better
yield when [CoCl2(dppe)] was used along with extra dppe and
further improvement was observed when ZnCl2 was added
into the reaction mixture (Table 1, entries 3 and 4).
of the indenoisoquinolinone 4a involves three tandem steps:
cobalt-catalyzed formation of the indenamine core, formation
of the CÀN bond, carbon–carbon double-bond migration, and
removal of the trimethylsilyl (TMS) group under the present re-
action conditions.
The cobalt-catalyzed cyclization reaction for the synthesis of
substituted indenoisoquinolinones was successfully extended
to various substrates and the results are listed in Scheme 3. As
indicated, reactions for substrates 3 with TMS substitution on
the ethynal moiety afforded the corresponding desilylated in-
denoisoquinolinones 4b–4m in moderate to good yields. Re-
actions for substituted o-bromobenzaldehyde with both elec-
tron-donating and electron-withdrawing groups were well-tol-
erated and provided the corresponding indenoisoquinolinones
4b, 4c, and 4 f in 61, 87, and 42% yields, respectively. Reac-
tions for substrate 3 bearing electron-withdrawing or electron-
donating groups were also compatible and afforded the corre-
sponding products 4d and 4e in 65 and 85% yield, respective-
ly. A variety of amines, including an aromatic amine with an
electron-donating group, p-methoxybenzyl amine (PMB), and
alkyl amines, are all reactive and the corresponding products
4g–4m were obtained in moderate to good yields. When the
TMS group on the ethynyl moiety of compound 3 was re-
placed by phenyl or n-butyl groups, the catalytic reactions still
proceeded very well and the corresponding products 4n–4q
were provided in good to excellent yields. Apart from the NMR
spectroscopic analysis, the structure of compound 4n
(Figure 1) was further verified by single-crystal X-ray diffraction.
The indenoisoquinolinones 4 could further be oxidized by
SeO2 to give the corresponding indenoisoquinoline-diones 5,
which were also known to be DNA topoisomerase I inhibitors.
Thus, some selected indenoisoquinolinones were converted to
their corresponding indenoisoquinoline-diones in nearly quan-
Under the same reaction conditions, using [CoI2(dppf)]
(dppf=1,1’-bis(diphenylphosphino)ferrocene) as the catalyst,
the reaction provided product 4a in 23% yield; however, com-
pared to [CoI2(dppe)], the crude NMR spectrum of the reaction
mixture revealed that no other side products were formed.
Hence, [CoI2(dppf)] was chosen for further investigations. Sig-
nificant improvement was realized when the quantity of the
imine components 1a and 2a were increased with respect to
the alkyne (1a/2a/3a=2:2:1, Table 1, entry 7). The addition of
200 mol% of ZnCl2 led to further improvement and a much
better result was realized when the reaction was carried out in
CH3CN (Table 1, entries 8 and 9). However, when 300 mol% of
ZnCl2 were used, a lower yield of compound 4a was observed
(Table 1, entry 10). It is interesting to note that the formation
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Scheme 4. Synthesis of the indenoisoquinoline-diones 5. Reactions were per-
formed with compounds 4 (0.30 mmol) and SeO2 (2.40 mmol) in 1,4-dioxane
(10 mL) at 1008C for 48 h.
In order to extend the applications of this cobalt-catalyzed
dual annulation reaction, two important pharmaceutical com-
pounds 4r and 7 were synthesized (Scheme 5). Compound 4r
was synthesized according to our developed protocol, which is
known to enhance the differentiation of human myeloid leuke-
mia cells when combined with all-trans retinoic acid (ATRA).[6]
Compound 7 was prepared from compound 5j using standard
procedures, with further reduction of the carbonyl group and
subsequent etherification with iBuOH. Compound 7 was re-
ported to demonstrate significant cytotoxicity effects against
four different tumor cell lines as well as Top 1 inhibitory activi-
ty.[3d] It is noteworthy that the syntheses of both compounds
4r and 7 by using the present cobalt-catalyzed method ap-
pears to have the highest overall yields with the shortest syn-
thetic steps.[1g,h]
Scheme 3. Scope of the indenoisoquinolinones synthesis. Reaction condi-
tions: compound 1 (0.6 mmol), compound 2 (0.6 mmol), compound 3
(0.3 mmol), [CoI2(dppf)] (0.021 mmol, 7 mol%), dppf (0.021 mmol, 7 mol%),
Zn (0.6 mmol), and ZnCl2 (0.6 mmol) in MeCN (1 mL) at 1008C for 20 h. Iso-
lated yields are given in parenthesis. [a] Reactions were performed by using
o-bromobenzaldimines.
A possible mechanism for the cobalt-catalyzed synthesis of
indenoisoquinolinones 4 through a dual annulation reaction is
shown in Scheme 6. The reaction is initiated by the reduction
of CoII to CoI by zinc powder. Chelation-assisted oxidative in-
sertion of CoI into the arylÀbromine bond of o-bromobenzaldi-
mine forms a five-membered ring, that is, the aza-cobaltacyle
A. Coordination of alkyne 3 followed by regioselective inser-
tion into the CoÀC bond results in the formation of the aza-co-
baltacycle C,[5,7] which is likely stabilized by the coordination of
the carbonyl group. With the dppf ligand, this step is found to
be crucial to give a single regioisomer product (see Scheme 6
for details). The regiochemistry for the insertion of alkyne in
structure B in the present process is similar to that of the
alkyne insertion to the five-membered azametallacycle inter-
mediates in the reductive coupling reactions by using an imine
and an alkyne.[8] In both cases, the aryl substituents of the aryl
acetylenes are adjacent to the metal in the azametallacycle. A
subsequently intramolecular nucleophilic addition to the imine
group occurs to give intermediate D. Further nucleophilic addi-
tion of the NÀCo bond to the ester group in the aza-cobalt
complex D followed by elimination of the methoxyl group and
a carbon–carbon double-bond migration in the indene core af-
fords the final indenoisoquinolinone 4. A similar acylation pro-
cess with metal alkoxide elimination was proposed in the rho-
Figure 1. X-ray structure of compound 4n. Ellipsoids are drawn at the 30%
probability level.
titative yields (Scheme 4). The reaction was carried out by
using SeO2 as the oxidant in 1,4-dioxane at 1008C for 48 h to
provide the desired indenoisoquinoline-diones.[5] This oxidation
reaction cannot proceed at room temperature.
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positive charge compared with
the other three metal ions.
Hence, the electrophilic inser-
tion of an imine into the CÀCo
bond in the azametallacycle is
more facile than to the other
CÀM bonds. It should be noted
that all of the cobalt, nickel, pal-
ladium and rhodium metalÀ
carbon bonds undergo 1,2-addi-
tion to the carbonyl group
of aldehydes, ketones, or esters
in carbocyclization reactions
(Scheme 7).[10]
To understand the role and
coordination ability of the ester
group in the formation of inter-
mediate C (Scheme 6), we ex-
Scheme 5. Preparation of the biologically active indenoisoquinolinone derivatives 4r and 7.
Scheme 7. Electrophilic insertion of the carbonyl group to the vinylÀmetal
bond in carbocyclization reactions (M=Ni, Co, Pd, and Rh).
amined the product of the reaction of methyl 5-phenylpent-4-
ynoate (3h) with imine 1aa by using the different cobalt com-
plexes [CoI2(dppf)] and [CoI2(dppe)]. Treatment of compound
1aa with compound 3h in the presence of [CoI2(dppf)], dppf,
Zn, and ZnCl2 regioselectively gave the indenamine VI as the
sole product in 70% yield. Product VI is likely formed by a reg-
ular addition of the MÀC bond to the alkyne (Michael-type,
Scheme 8). On the other hand, when [CoI2(dppe)] was used as
the catalyst, product 4t was obtained in 58% yield. The regio-
selectivity of the alkyne insertion in the formation of com-
pound 4t is opposite to that of the general observation; that
Scheme 6. Proposed mechanism for the formation of indenoisoquinolinones
4.
dium- and cobalt-catalyzed nucleophilic addition reactions in-
volving ester and vinyl methoxide groups.[9] Formation of CoI
through reduction of methoxycobalt(III) with zinc powder com-
pletes the catalytic cycle. Alternatively, intermediate D may be
protonated to give indenamine III, which then undergoes
a Lewis acid (ZnCl2) assisted intramolecular lactamization to
afford the final product 4.
The unique behavior of the present cobalt-catalyzed reac-
tion is interesting in view of the observation of the rhodium-,
palladium-, nickel-, and ruthenium-mediated formation of iso-
quinoline or isoquinolinium salts from aza-metal complex A
and an alkyne (Scheme 2).[3] Although rhodium and cobalt
metals are in the same family and likely have the same oxida-
tion state in the catalytic reaction, the resulting products are
entirely different. A possible reason for the observed difference
in the product formation of CoIII from the other metal catalysts
is the acidity of CoIII. We expect that CoIII is a stronger Lewis
acid than RhIII, PdII, and NiII due to its smaller size or higher
Scheme 8. Reactions between compounds 1aa and 3h under various reac-
tion conditions. a) [CoI2(dppe)], dppe, Zn, ZnCl2, CH3CN, 1008C.
b) [CoI2(dppf)], dppf, Zn, ZnCl2, CH3CN, 1008C.
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is, the electron-withdrawing substituent of the unsymmetrical
alkyne should be situated next to the metal. This indicates that
product 4t might have arisen from an alkyne insertion induced
by the sigma coordination of the ester group rather than an
alkyne insertion based on the nature of the substituents. In the
presence of the dppf ligand purely regioselective insertion of
alkynes into azametallacycle A takes place, based on the
alkyne polarity (intermediate E). The bulkiness of the dppf
ligand seems to prevent the ester coordination. For dppe, the
alkyne coordination is probably accompanied by ester coordi-
nation (intermediate F) leading to the formation of compound
4t. For the catalytic reaction of methyl 2-ethynylbenzoate de-
rivatives 3 with o-halobenzaldimine by using [CoI2(dppf)] and
dppf as the catalyst, intermediate G similar to intermediate F is
likely involved during the catalytic reaction, in view of the ob-
served product 4t from compounds 1aa and 3h catalyzed by
the same cobalt complex.
Keywords: azametallacycles · cobalt · indenes · isoquinoline ·
zinc
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Conclusion
We have developed a new and efficient method for the syn-
thesis of indenoisoquinolinones through a cobalt-catalyzed an-
nulation reaction of methyl o-ethnylbenzoates with o-haloben-
zaldimines. It is a rare example of a catalytic tandem reaction
involving a highly regioselective alkyne insertion followed by
an intramolecular nucleophilic addition. Moreover, this method
appears to provide the shortest synthetic route for the prepa-
ration of indenoisoquinolinones, and it is now possible to syn-
thesize a series of structural analogues of bioactive indenoiso-
quinolinones with potentially medicinal properties.
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Experimental Section
Synthesis of indenoisoquinolinone 4a: To a screw-caped seal
tube, 2-bromobenzaldehyde 1a (101 mg, 0.60 mmol) and p-tolui-
dine 2a (64 mg, 0.60 mmol) were added and the mixture was
stirred at room temperature for 10 min. Then, to the reaction mix-
ture were added [CoI2(dppf)] (18 mg, 0.021 mmol), dppf (11.4 mg,
0.021 mmol), zinc (40 mg, 0.60 mmol), and zinc chloride (82 mg,
0.6 mmol) and the aperture of the seal tube was closed with
a rubber septum. The tube was evacuated and purged three times
with nitrogen gas. Methyl 2-((trimethylsilyl)ethynyl)benzoate 3a
(68 mg, 0.30 mmol) and freshly distilled acetonitrile (1.0 mL) were
added to the mixture through a syringe. The septum was quickly
exchanged for a screw cap and the reaction mixture was stirred at
1008C for 20 h. At the end of the reaction, the reaction mixture
was diluted with ethyl acetate and then filtered through a Celite-
gel pad by using ethyl acetate as the eluent (ꢀ20 mL). The com-
bined filtrate was concentrated in vacuum and the residue was
separated on a silica gel column by using a mixture of n-hexane
and ethyl acetate as eluent to afford the desired pure white solid
4a in 91% yield.
Acknowledgements
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We thank the Ministry of Science and Technology of Republic
of China (MOST, 102-2633M-007-002) for financial support of
this research.
Chem. Eur. J. 2015, 21, 9544 – 9549
www.chemeurj.org
9548
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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Received: March 24, 2015
Published online on May 18, 2015
Chem. Eur. J. 2015, 21, 9544 – 9549
www.chemeurj.org
9549
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim