Synthesis of indeno[1,2-b]indole derivatives through one-pot sequential or two-step iodine-catalyzed c-o activation and palladium-catalyzed C-H functionalization

Article abstract of DOI:10.1002/ejoc.201200876

An efficient route for the synthesis of indeno[1,2-b]indoles as tetracyclic derivatives of indole bearing 2-oxo-1-pyrrolidine moieties through one-pot sequential or two-step iodine-catalyzed C-O activation and palladium-catalyzed C-H functionalization is

Full text of DOI:10.1002/ejoc.201200876

Job/Unit: O20876
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Date: 28-08-12 16:56:10
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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200876
Synthesis of Indeno[1,2-b]indole Derivatives through One-Pot Sequential or
Two-Step Iodine-Catalyzed C–O Activation and Palladium-Catalyzed C–H
Functionalization
Hai-Yan Xu,[a] Xiao-Ping Xu,[a] Shun-Yi Wang,*[a] and Shun-Jun Ji*[a]
Keywords: Nitrogen heterocycles / Palladium / Fused-ring systems / C–O activation / C–H functionalization
An efficient route for the synthesis of indeno[1,2-b]indoles as
tetracyclic derivatives of indole bearing 2-oxo-1-pyrrolidine
moieties through one-pot sequential or two-step iodine-cata-
lyzed C–O activation and palladium-catalyzed C–H function-
alization is reported.
Introduction
Indeno[1,2-b]indole derivatives, such as compounds 1
and 2, have received increasing attention in view of their
biological and pharmacological activities.[1] Tetracyclic
5,10-dihydroindeno[1,2-b]indol-1-ol (3) containing both in-
dole and phenolic units shows antioxidant activity and radi-
cal scavenging activity,[2] and 5,10-dihydroindeno[1,2-b]ind-
ole (4) bearing an indole unit acts as an important inter-
mediate for the preparation of the BARAC-Fluor reagent
(5).[3] Meanwhile, terpendole E (6) bearing a indeno[1,2-b]-
indole skeleton shows KSP inhibitory activity and other
bioactivities (Figure 1).[4] On this basis, the discovery of
new synthetic methodologies for the establishment of a
pharmaceutical library is highly desirable.
Figure 1. Structures of tetracyclic derivatives of indole.
Two strategies are possible to access the C/D rings of
tetracyclic indole derivatives: construction of two new C–C
bonds by employing Fisher indole synthesis following func-
tionalization (Scheme 1) or a cross-coupling reaction. The
first strategy was reported by Okamoto and co-workers in
1970[5] and involves the use of phenyl hydrazine (8) and 1-
indanone (9a). However, this approach is limited by the
need for further functionalization of the tetracyclic indole
derivatives. The second strategy involves the coupling reac-
tion of easily prepared pyrrolidin-2-one derivatives 11 and
commercially available indoles 10 and is herein described.
The 2-oxo-1-pyrrolidine moiety is a ubiquitous structural
constituent in a wide variety of pharmacologically and bio-
logically active compounds.[6] As a continuation of our
work on 2-oxo-1-pyrrolidine[7] and the synthesis of poten-
tially pharmacologically and biologically active molecules
bearing the indole framework,[8] we herein describe the syn-
thesis of tetracyclic indeno[1,2-b]indole derivatives bearing
2-oxo-1-pyrrolidine moieties through one-pot sequential or
two-step iodine-catalyzed C–O activation and palladium-
catalyzed C–H functionalization.
Results and Discussion
Owing to the synthetic importance of tetracyclic deriva-
tives, we investigated the synthesis of indoles bearing 2-oxo-
1-pyrrolidine moieties. Initially, 1-[ethoxy(4-nitrophenyl)-
methyl]pyrrolidin-2-one (13a) and indole (10a) were se-
lected as model substrates to optimize the reaction condi-
tions (Table 1). On the basis of our previous work,[7] it was
found that the model reaction proceeded well in the pres-
ence of a catalytic amount of iodine (10 mol-%). After heat-
ing at reflux for 2 h in CH2Cl2 (monitored by TLC), 1-[(1H-
indol-3-yl)(4-nitrophenyl)methyl]pyrrolidin-2-one (3aa) was
obtained in 78% yield (Table 1, entry 1). When various
[a] Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials
Science, Soochow University,
Suzhou, 215123, People’s Republic of China
Fax: +86-512-65880307
E-mail: shunyi@suda.edu.cn
chemjsj@suda.edu.cn
Homepage: http://chemistry.suda.edu.cn/index.aspx?lanmuid=
69&sublanmuid=603&id=53
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200876.
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H.-Y. Xu, X.-P. Xu, S.-Y. Wang, S.-J. Ji
SHORT COMMUNICATION
Scheme 1. Strategies for the preparation of tetracyclic indole derivatives.
other solvents were screened, the yields of the desired prod- tion. Various indoles bearing electron-donating groups,
uct decreased dramatically (Table 1, entries 2–7). Interest-
ingly, it was found that 5 mol-% of I2 was powerful enough
to catalyze the reaction to afford the desired product in
90% yield (Table 1, entry 9). A decrease in the catalyst load-
ing to 1 mol-% or a decrease in the reaction temperature to
ambient temperature resulted in a decrease in the yield of
the desired product (Table 1, entries 10 and 11).
such as methyl and methoxy, reacted smoothly with 13a to
provide the desired products within several hours in good
to excellent yield (Table 2, entries 2–5, 7–9). To our delight,
strongly electron-deficient indole 10f also underwent the re-
action to afford desired product 10af in 67% yield (Table 2,
entry 6).
Furthermore, the scope of the amidoalkylation reagents
was also explored by using indole (10a; Table 3, entries 1–
12). By varying the substituent at the aryl (Ar) function-
ality, it was found that substrates 13 bearing strong elec-
tron-withdrawing groups, such as nitro, cyano, and methyl-
sulfonyl, efficiently underwent reactions with 10a to afford
desired products 14ba–da in 90–94% yield (Table 3, en-
tries 1–3). At the same time, the majority of the substrates
bearing electron-donating groups, such as methoxy and di-
methylamino, gave the expected results within a short reac-
tion time (Table 3, entries 4–7). Unexpectedly, when sub-
strate 13g was subjected to the optimized reaction condi-
tions, a relatively low yield of target product 14ga was ob-
tained, which might be due to the competitive formation of
bis(indole) as a byproduct. Halogens in the Ar functionality
were well tolerated both in the para and ortho positions
(Table 3, entries 8 and 9). It was unexpected that no reac-
tion was observed when 2-pyridinyl was used as the Ar sub-
stituent under identical conditions (Table 3, entry 10). The
presence of a strong coordinative and basic nitrogen atom
may account for this failure.[9] When thiophen-2-yl was in-
troduced instead of 2-pyridinyl, its reaction with indole
went very well to generate the corresponding product in
excellent yield (Table 3, entry 11). Additionally, naphth-
alene-2-yl was also a good candidate for this reaction
(Table 3, entry 12). The influence of other leaving groups
on the amidoalkylation of indoles was investigated as well.
Table 1. Optimization of the reaction conditions.[a]
Entry Catalyst
(mol-%)
Time
[h]
Solvent
T
[°C]
Yield
[%][b]
1
2
3
4
5
6
7
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (5)
2
6
6
6
6
6
6
2
2
4
4
CH2Cl2
EtOH
THF
40
78
65
80
80
80
80
40
40
25
40
78
55
71
64
59
61
42
84
90
38
58
toluene
CH3NO2
CH3CN
H2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8[c]
9[c]
10[c]
11[c]
I2 (5)
I2 (1)
[a] General conditions: compound 13a (0.4 mmol), 10a (0.4 mmol).
[b] Isolated yield. [c] Molar ratio: 13a/10a = 1:1.5; 13a was the lim-
iting reagent.
With the optimized reaction conditions in hand, the It was found that methoxy and isopropoxy substituents ex-
scope of the amidoalkylation of indoles was evaluated. Sub- hibited comparable reactivity to the ethoxy group, furnish-
strate 13a was firstly selected as a precursor for this reac- ing the expected products in 90 and 93% yield, respectively
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Synthesis of Indeno[1,2-b]indole Derivatives
Table 2. I2-catalyzed C–O activation of 1-[ethoxy(4-nitrophenyl)methyl]pyrrolidin-2-one (13a) with indoles.[a]
[a] General conditions: Compound 13a (0.4 mmol), 10 (0.6 mmol), and I2 (5 mol-%) in CH2Cl2 at 40 °C. [b] Isolated yield based on 13a
as the limiting reagent.
(Table 3, entries 13 and 14). On the basis of these results
With the 2-bromophenenyl-pyrrolidin-2-one derivatives
and our previous work,[7] we propose that the reaction pro- in hand, we studied the C–H functionalization of 12 to
ceeds through the formation of a six-membered intermedi- form indeno[1,2-b]indole derivative (Table 5). Conversion of
ate by a SN2 reaction process.[10]
12aa into the corresponding polycyclic derivative through a
To further investigate the preparation of indeno[1,2-b]- Pd-catalyzed intramolecular annulation reaction[11] leading
indoles, we focused on the reaction of 11 and 10 to synthe- to the formation of the C/D rings of the tetracyclic indole
size of the important intermediate 12. To our delight, a derivatives was investigated. Desired product 15a was ob-
series of 12 could be obtained in good to excellent yield by tained in 87% yield (Table 5, entry 1). To further explore
reaction of 11 and 10 catalyzed by I2 (5 mol-%) in refluxing the utility of this method, analogous annulations of dif-
CH2Cl2. The results are demonstrated in Table 4.
ferently substituted indoles, including NMe, and 5-OMe-
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H.-Y. Xu, X.-P. Xu, S.-Y. Wang, S.-J. Ji
SHORT COMMUNICATION
Table 3. Study of the substrate scope.[a]
Table 4. I2-catalyzed C–O bond activation of 2-bromophenenyl-
pyrrolidin-2-one derivatives with indoles.[a]
[a] General conditions: Compound 13 (0.4 mmol), 10a (0.6 mmol),
and I2 (5 mol-%) in CH2Cl2 at 40 °C. [b] Isolated yield based on 13
as the limiting reagent. [c] Molar ratio 13g/10a = 1:1.
[a] General conditions: Compound 11 (0.4 mmol), 10 (0.6 mmol),
and I2 (5 mol-%) in CH2Cl2 at 40 °C. [b] Isolated yield based on 11
as the limiting reagent.
substituted indoles, were also examined (Table 5, entries 2–
7). Different substituents on the Ar ring were also well tol-
erated (Table 5, entries 8 and 9). As a demand for green
Conclusions
In summary, we have reported an efficient route for the
chemistry, we next examined the scope of the one-pot trans- synthesis of indeno[1,2-b]indole derivatives as tetracyclic in-
formation of 13 with 10 to construct fused polycyclic com- dole derivatives bearing 2-oxo-1-pyrrolidine moieties
pounds possessing C/D rings. To our delight, the one-pot through one-pot sequential or two-step iodine-catalyzed C–
protocol also worked well to give the corresponding prod- O activation and palladium-catalyzed C–H functionaliza-
ucts in good yield (Table 5, path B). In addition, the struc- tion. Evaluation of the bioactivity of the indeno[1,2-b]-
ture of representative compound 15b was confirmed by X- indole derivatives is underway and will be reported in due
ray single crystal diffraction (Figure 2).[12]
course.
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Synthesis of Indeno[1,2-b]indole Derivatives
Table 5. Synthesis of heterocycles by intramolecular cyclization of
1-[(2-bromophenyl)(1H-indol-3-yl)methyl]pyrrolidin-2-one deriva-
tives.[a]
Figure 2. Crystal structure of 15b.
Experimental Section
Typical Procedure for Iodine-Catalyzed C–O Activation of 1-
[Ethoxy(phenyl)methyl]pyrrolidin-2-one Derivatives: The indole
(0.6 mmol), I2 (0.02 mmol, 5 mol-%), the 1-[ethoxy(phenyl)methyl]-
pyrrolidin-2-one derivative (0.4 mmol), and CH2Cl2 (2 mL) were
added into a flask. The mixture was then vigorously stirred at 40 °C
until 1-[ethoxy(phenyl)methyl]pyrrolidin-2-one derivatives was
completely consumed as indicated by TLC analysis. After comple-
tion of the reaction, the pure product was obtained after purifica-
tion of the residue by column chromatography (silica gel, ethyl
acetate/petroleum ether).
General Procedure for the Palladium-Catalyzed Intramolecular An-
nulation Reaction of 1-[(2-Bromophenyl)(1H-indol-3-yl)methyl]pyr-
rolidin-2-one: 1-[(2-Bromophenyl)(1H-indol-3-yl)methyl]pyrrolidin-
2-one (1 mmol), PdCl2(CH3CN)2 (5 mol-%), PPh3 (10 mol-%),
CsOAc (2 equiv.), and 1 m DMA (N,N-dimethylacetamide) were
added into a flask under an inert atmosphere. The reaction mixture
was stirred at 110 °C until the staring indole derivative was fully
consumed (4–10 h). Upon completion of the reaction, the resulting
solution was diluted with water (2 mL) and extracted with EtOAc
(3ϫ5 mL). The combined organic extracts were dried with sodium
sulfate and concentrated under reduced pressure. The pure product
was obtained after purification of the residue by column
chromatography (silica gel, ethyl acetate/petroleum ether).
General Procedure for the Palladium-Catalyzed Intramolecular
Annulation Reaction in One Pot: The indole (0.6 mmol), I2
(0.02 mmol, 5 mol-%), the 1-[ethoxy(phenyl)methyl]pyrrolidin-2-
one derivative (0.4 mmol), and CH2Cl2 (2 mL) were added into a
flask. The mixture was then vigorously stirred at 40 °C until the 1-
[ethoxy(phenyl)methyl]pyrrolidin-2-one derivative was completely
consumed as indicated by TLC analysis. After completion of the
reaction, the residue was evaporated to dryness. Subsequently,
PdCl2(CH3CN)2 (5 mol-%), PPh3 (10 mol-%), CsOAc (2 equiv.),
and 1 m DMA were added into a flask under an inert atmosphere.
The reaction was stirred at 110 °C until the starting indole deriva-
tive was fully consumed (10–12 h). Upon completion of the reac-
tion, the resulting solution was diluted with water (2 mL) and ex-
tracted with EtOAc (3ϫ5 mL). The combined organic extracts
were dried with sodium sulfate and concentrated under reduced
pressure. The pure product was obtained after purification of the
residue by column chromatography (silica gel, ethyl acetate/petro-
leum ether).
[a] General conditions for path A: Pd(OAc)2 (5 mol-%), PPh3
(10 mol-%), CsOAc (2 equiv.), 1 m DMA, 110 °C, 10 h. General
conditions for path B: I2 (5 mol-%), 1 m CH2Cl2, 40 °C, 5 h. When
the reaction was complete, the resulting solution was evaporated to
dryness and then path A was followed. [b] Isolated yield for path A
is given first and the isolated yield for path b is given in parenthe-
ses.
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SHORT COMMUNICATION
[10] To better understand the mechanism of this reaction, the 13C
NMR spectra of 13a and 13a with added I2 (1:1) were studied,
respectively. It was found that there was no obvious difference
between the spectra indicating that the EtO–C bond was not
cleaved in the presence of I2. On the basis of our previous re-
sults, we propose that the reaction proceeds through the forma-
tion of a six-membered intermediate by a SN2 reaction process.
First, the C–O bond is polarized and activated by molecular
iodine. Subsequently, indole attacks the activated C–O bond to
form a new C–C bond. Finally, the coordinating iodine mole-
cule leaves the carbonyl group to offer the final product.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, characterization data, and copies of
1
the H NMR and 13C NMR spectra.
Acknowledgments
The work was partially supported by the National Natural Science
Foundation of China (No. 21042007, 21172162, 21202111), Natu-
ral Science Basic Research of Jiangsu Province for Higher Educa-
tion (No. 10KJB150016), a Research Grant from the Innovation
Project for Graduate Student of Jiangsu Province (CX10B-033Z),
Innovation Project for Undergraduate Student-State Level (No.
101028514), and Key Project in Science & Technology Innovation
Cultivation Program of Soochow University.
[11] a) C. Natalia, T. David, L. Zhou, G. Vladimir, Chem. Commun.
2010, 46, 150–152; b) C. Natalia, T. David, L. Zhou, G. Vladi-
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www.ccdc.cam.ac.uk/data_request/cif. Structural parameters
for product 15b: Data collection: Rigaku Mercury CCD area
detector; crystal size: 0.15ϫ0.10ϫ0.3 mm3, C20H18N2O, Mr =
302.36, monoclinic, space group P21/c, a = 10.250(2) Å, b =
11.3649(19) Å, c = 14.355(3) Å, α = 93.549°, β = 106.698(5)°,
γ = 92.775°, V = 1594.9(5) Å3, Z = 4, Dcalcd. = 1.259 gcm–3, R
[IϾ2σ(I)] = 0.0533, wR[IϾ2σ(I)] = 0.1646.
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[9] To the model reaction was added pyridine (1 equiv.), and the
resulting mixture was stirred for 2 h under standard conditions;
no reaction was observed.
Received: July 3, 2012
Published Online: ᭿
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Synthesis of Indeno[1,2-b]indole Derivatives
Polycycles
H.-Y. Xu, X.-P. Xu, S.-Y. Wang,*
S.-J. Ji* ............................................ 1–7
Synthesis of Indeno[1,2-b]indole Deriva-
tives through One-Pot Sequential or Two-
Step Iodine-Catalyzed C–O Activation and
Palladium-Catalyzed C–H Functionaliz-
ation
An efficient route for the synthesis of in-
deno[1,2-b]indoles as tetracyclic derivatives
of indole bearing 2-oxo-1-pyrrolidine moi-
eties through one-pot sequential or two-
step iodine-catalyzed C–O activation and
palladium-catalyzed C–H functionalization
is reported.
Keywords: Nitrogen heterocycles
ladium / Fused-ring systems / C–O acti-
vation / C–H functionalization
/ Pal-
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