A Palladium- and Copper-Catalyzed Synthesis of Dihydro[1,2-b]indenoindole-9-ol and Benzofuro[3,2-b]indolines: Metal-Controlled Intramolecular C-C and C-O Bond-Forming Reactions

Article abstract of DOI:10.1002/chem.201503210

A palladium- and copper-catalyzed synthesis of dihydro[1,2-b]indenoindole-9-ol and benzofuro[3,2-b]indolines has been developed, whereby the same starting material is employed for the synthesis of both heterocyclic scaffolds and the selectivity of the pro

Full text of DOI:10.1002/chem.201503210

DOI: 10.1002/chem.201503210
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Synthetic Methods |Hot Paper|
A Palladium- and Copper-Catalyzed Synthesis of Dihydro[1,2-
b]indenoindole-9-ol and Benzofuro[3,2-b]indolines: Metal-
Controlled Intramolecular CÀC and CÀO Bond-Forming Reactions
Siva Senthil Kumar Boominathan and Jeh-Jeng Wang*[a]
Abstract: A palladium- and copper-catalyzed synthesis of di-
hydro[1,2-b]indenoindole-9-ol and benzofuro[3,2-b]indolines
has been developed, whereby the same starting material is
employed for the synthesis of both heterocyclic scaffolds
and the selectivity of the product is controlled by switching
the choice of metal. Salient features of these cascade reac-
tions include wide-ranging functional group tolerance,
simple reaction conditions, and moderate to high yields.
ings,[4a,b] anticancer properties,[4c] inhibition of protein kina-
ses,[4d] antioxidant properties,[4e,f] carbonic anhydrase inhibi-
tion,[4g] regulation of gene battery enzymes,[4h] and membrane
stabilization.[4i,j] Furthermore, these p-conjugated structures
have also found applications in optoelectronics and advanced
materials due to the structure’s unique electronic properties.[5]
Although considerable efforts have been made to synthesize
these heterocycles,[6] the development of operationally simple
procedures with improved efficiency and substrate scope re-
mains highly desirable.
Introduction
Indole-fused polycyclic heterocycles are prevalent structural
motifs present in many natural products, pharmaceuticals, and
bioactive molecules.[1] In particular, the indenoindoles[2] and
benzofuroindolines[3] are embedded in many naturally occur-
ring compounds, such as paspaline, yuehchukene, paxilline,
phalarine, and azonazine (Figure 1). These indole-fused scaf-
folds exhibit wide range of biological and pharmacological
properties, such as activation of potassium channel open-
Palladium-catalyzed a-arylation of alkyl or aryl ketones with
suitable aryl halides provides an efficient means of preparing
valuable synthetic intermediates in organic synthesis.[7] After
the seminal work published by Buchwald and co-workers, the
palladium-catalyzed a-arylation of carbonyl moieties with aryl
halides has made rapid progress and significant efforts have
since been devoted to various applications.[8] Of particular im-
portance, intramolecular a-arylation reactions are of interesting
for the construction of polycyclic compounds.[9] Although such
intramolecular reactions have been well explored for small size
rings, larger rings have been less studied and, probably owing
to difficulties in the formation of large-size palladacycle inter-
mediates. We envisioned that if larger rings could be synthe-
sized by a-arylation, the carbonyl group, intact in the ring,
could be subsequently captured with a suitable nucleophile in
a cascade manner to construct fused heterocycles.
Moreover, copper-catalyzed Ullmann-type C(aryl)ÀN, C(aryl)À
O, and C(aryl)ÀC bond-forming reactions have proven an effi-
cient method in organic synthesis for more than 100 years.[10]
Recently, these reactions have become an attractive synthetic
tool towards the construction of various heterocycles.[11] In
comparison with palladium, copper-catalyzed cascade reac-
tions have been less explored and there is a lot of scope to in-
vestigate in this area. We presumed that involving the Ullman
reactions in a cascade sequence could lead to the generation
of useful heterocycles.
Figure 1. Representative bioactive natural products.
[a] S. S. K. Boominathan, Prof. Dr. J.-J. Wang
Department of Medicinal and Applied Chemistry
Kaohsiung Medical University
100 Shih-Chuan 1st Road, Kaohsiung 80708 (Taiwan)
E-mail: jjwang@kmu.edu.tw
During the last decade, transition metal-catalyzed cascade
reactions have emerged as an important synthetic route to
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503210.
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build complex heterocycles, as well as natural products.[12] Evi-
dently, cascade reactions have distinct advantages, such as
atom and time economy, effective multistep one-pot reactions,
and reductions in waste and labor. In light of these facts and
our ongoing research interest in the development of transition
metal-catalyzed synthetic methodologies,[13] we report herein
a palladium-catalyzed intramolecular a-arylation followed by
nucleophilic addition with ketones to synthesize dihydro[1,2-
b]indenoindole scaffolds [Scheme 1, Eq. (1)]. In addition, we
Having established the optimized reaction conditions, we
moved to examine the scope and limitation of the cascade
process for the synthesis of compound 4 (Scheme 2). With aryl
substituent R1 as either electron-donating (4a–e) or electron-
withdrawing groups (4 f and g), the reaction generally worked
well and the desired products were isolated in high yields. No-
tably, substrates in which R1 was an aryl or heteroaryl group
were also suitable for this process (4h and i). The reaction also
proceeded smoothly with the other aryl substituent R2 as vari-
ous groups including naphthyl,
methoxy, methyl and chloro at
different positions (4j–m), pro-
ducing the expected products in
moderate to good yields. How-
ever, substrate S14 (R2 =nitro)
failed to give the expected prod-
uct (4n). Instead, the benzo-
furo[3,2-b]indoline
compound
5n was formed in 40% yield.
The probable reason may be
that the highly electron-with-
drawing nature of the nitro
Scheme 1. Proposed reaction strategy.
have also discovered a copper-catalyzed intramolecular cas-
cade approach to benzofuro[3,2-b]indolines by nucleophilic ad-
dition with ketones followed by Ullman-type CÀO bond forma-
tion [Scheme 1, Eq. (2)]. By switching the catalyst between pal-
ladium and copper, a divergent synthesis of two different het-
erocycles from the same starting material has been developed.
Table 1. Optimization studies for dihydro [2,3-b]indenoindoles.
Results and Discussion
To realize the hypothesis, we prepared the starting materials
S1–S20 from sulfonylation of 2-amino acetophenone deriva-
tives followed by N-alkylation with 2-halo benzylbromides (see
the Supporting Information). Compound S1 was used as the
model substrate for the optimization studies (Table 1). Initially,
we used [Pd(PPh3)4] as a catalyst, with which various bases
such as K2CO3, Cs2CO3, KOtBu, KOH and NaOH were screened
using acetonitrile as a solvent at reflux temperature (Table 1,
entries 1–5). To our delight, KOH afforded the desired product
in 69% yield, whereas the other bases were inferior to this.
The identity of compound 4a was unambiguously confirmed
by X-ray analysis.[14] In addition to this, we detected the other
possible benzofuro[3,2-b]indoline (5a) product at trace levels.
To further improve the reaction yield, various palladium(0), pal-
ladium(II), and nickel(0) catalysts (Table 1, entries 6–11) were
screened, but none of them provided a better yield than
[Pd(PPh3)4] (entry 4). Solvent studies revealed that acetonitrile
was crucial for this transformation and other solvents were un-
favorable (Table 1, entries 11–15). When we increased the
equivalents of base, the reaction yield was further improved to
77% (Table 1, entry 16). Altering the catalyst loading in either
directions from the optimized quantity had little effect on the
reaction yield (Table 1, entries 18 and 19). Finally, we identified
the conditions outlined for entry 16 as optimum for the syn-
thesis of dihydro[1,2-b]indenoindole-9-ol.
Entry
Catalyst
Base
Solvent
t [h]
Yield of 4a/5a [%]
1
2
3
4
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
Pd(OAc)2
K2CO3
Cs2CO3
KOtBu
KOH
NaOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
DMSO
toluene
dioxane 24
MeCN
MeCN
MeCN
MeCN
24
24
24
24
24
24
24
24
24
24
24
24
24
24
–/–
–/–
–/20
69/trace
30/trace
–/–
5
6[b]
7[b]
8
PdCl2
–/–
[Pd(dba)3]
[Pd2(dba)3]
[PdCl2(PPh3)2]
[Ni(cod)2]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
[Pd(PPh3)4]
62/trace
65/trace
–
–
–
9
10
11
12
13
14[c]
15[c]
16[d]
17[e]
18[f]
19[g]
–
25/trace
trace/trace
77/trace
55/–
78/trace
70/trace
16
12
16
20
[a] Reaction conditions (unless otherwise stated): Compound S1 (200 mg),
catalyst (10 mol%), base (3 equiv) in solvent (3 mL) at 808C for given
time. [b] 20 mol% of PPh3 was added. [c] Reaction performed at 110 8C.
[d] 4 equiv of base was used. [e] 6 equiv of base was used. [f] 20 mol% of
catalyst was used. [g] 5 mol% of catalyst was used; dba=dibenzylidenea-
cetone, cod=1,5-cyclooctadiene.
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Scheme 3. Further transformation of compound 4. Reaction conditions:
Compound 4 (75 mg) and conc. H2SO4 (20 mol%) in toluene (3 mL) at reflux
for 30 min.
The synthetic utility of 4 was demonstrated by its conversion
into tetrahydroindeno[1,2-b]indoles under acid catalysis
(Scheme 3). A few representative examples were smoothly con-
verted into the corresponding dehydrated products, 6a, f, and
j, in excellent yields with the aid of a catalytic amount of sulfu-
ric acid in toluene.
During the optimization studies of compound 4, we ob-
served traces of benzo[3,2-b]furoindolines (5) and this prompt-
ed us to think whether a copper catalyst system could be de-
veloped to achieve this product exclusively by nucleophilic ad-
dition followed by CÀO bond formation [Scheme 1, Eq. (2)]. To
test our hypothesis, we commenced optimization studies
(Table 2). In our initial investigation, S1 was used as a model
substrate and various copper salts (Table 2, entries 1–6) were
screened using 1,2-cyclohexanediamine (mixture of cis and
trans) (L2) as the ligand and KOtBu as a base in aceteonitrile
and DMF at 808C. Among these, Cu(OTf)2 provided the maxi-
mum yield of 55% and was thus chosen as the catalyst for fur-
ther studies. The influence of ligands (L1–L5) was then
screened and 1,10-phenanthroline (L5) proved most efficient
(Table 2, entries 7–10). The reaction was studied with various
bases, such as K2CO3, Cs2CO3, LiOtBu, NaOH, but none of them
led to an improved reaction yield (Table 2, entries 11–15) in
comparison to KOtBu. From the solvent studies, we found
DMF to be superior to the other solvents (Table 2, entries 16–
18). Either increasing or decreasing the reaction temperature
also led to reduced yields (Table 2, entries 19 and 20). When
we increased the amount of catalyst, the yield was not im-
proved (Table 2, entry 21). Finally, the conditions outlined in
entry 10 were identified as the optimized reaction conditions
for benzofuro[3,2-b]indoline synthesis.
Scheme 2. Substrate scope for synthesis of indeno[1,2-b]indole-9-ol products
4. Reaction conditions: Substrate S (200 mg), [Pd(PPh3)4] (10 mol%), and
KOH (4 equiv) in MeCN (3 mL) at reflux for 16 h. [a] Instead of 4n, 5n was
formed in 40% yield.
group disfavors the a-arylation process and the competitive
nucleophilic addition reaction dominates. With regards to the
ketone substituent R3, the reaction of substrate S15 (R3 =ethyl)
proceeded well to give the corresponding product 4o, which
suggests that this protocol is suitable for various substituted
ketones. Moreover, substrate S16, in which the nitrogen sub-
stituent R4 was benzenesulfonyl rather than toluenesulfonyl,
was also tolerated under the optimized reaction conditions.
However, when the iodo substituent of compound S1 was re-
placed with bromo, the reaction was failed to proceed. The
structures of 4a and 4d were determined by X-ray analysis
(see the Supporting Information).[14]
The optimized reaction conditions were then employed to
investigate the substrate scope of the copper-catalyzed cas-
cade synthesis of compound 5 (Scheme 4). Various electron-
donating (5a–e), halide (5 f, 5g), aryl (5h), and heteroaryl (5i)
substituents were tested as R1, with the reaction proceeding
smoothly to give the desired products in moderate to high
yields. Similarly, substrates with R2 as groups such as naphthyl,
methyl, and nitro also afforded the corresponding products
(5j–m). Interestingly, the propyl-substituted compound 5n was
smoothly prepared under the reaction conditions. As the N-
substituent, instead of tosyl, the benzenesulfonyl group was
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Table 2. Optimization studies for benzofuro[3,2-b]indolines.
Entry Catalyst/ligand Base
Solvent
T [oC]/ t [h] Yield [%]
1
2
3
4
5
6
7
8
CuI/L2
CuI/L2
Cu(OAC)2/L2
Cu(OTf)2/L2
CuCl2/L2
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
K2CO3
KOH
Cs2CO3
LiOtBu
NaOH
KOtBu
KOtBu
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
12
12
12
12
12
12
16
16
16
12
24
12
24
16
16
16
16
16
8
22
48
35
55
40
25
40
30
62
80
–
CuBr2/L2
Cu(OTf)2/L1
Cu(OTf)2/L3
Cu(OTf)2/L4
Cu(OTf)2/L5
Cu(OTf)2/L5
Cu(OTf)2/L5
Cu(OTf)2/L5
Cu(OTf)2/L5
Cu(OTf)2/L5
Cu(OTf)2/L5
Cu(OTf)2/L5
Cu(OTf)2/L5
Cu(OTf)2/L5
Cu(OTf)2/L5
Cu(OTf)2/L5
9
10
11
12
13
14
15
16
17
18
19
20
21[b]
30
–
–
–
45
40
45
70
25
50
toluene 110
KOtBu dioxane 100
KOtBu
KOtBu
KOtBu
DMF
DMF
DMF
120
60
80
24
16
[a] Reaction conditions (unless otherwise stated): Compound S1 (200 mg),
catalyst (10 mol%), ligand (20 mol%), base (3 equiv) in solvent (3 mL) at
given temperature and time. [b] 2 equiv of base was used.
also tolerated in the reaction conditions and the respective
compound was isolated in 70% yield. When we switched the
iodo substituent in the precursors for bromo (5a, 5p), the cor-
responding products were obtained, albeit in lower yields
(note that these substrates were incompatible in Scheme 2).
Unfortunately, the oxygen-substituted precursor failed to react
(5q). The reason could be that the methylene group adjacent
to oxygen was less acidic than NTs and the base may not have
been able to deprotonate it. The structures of compound 5a,
5b, 5m, and 5n were confirmed by single crystal X-ray analysis
(see the Supporting Information).[14]
Scheme 4. Substrate scope of benzofuro[3,2-b]indolines. Reaction condi-
tions: Substrate S (200 mg), Cu(OTf)2 (10 mol%), 1, 10-phenanthroline
(20 mol%), and KOtBu (3 equiv) in DMF (3 mL) at 808C for 12 h. [a] Instead
of iodo, bromo was employed in the starting material.
sults establish that the reaction proceeds via a-arylation fol-
lowed by base-mediated nucleophilic substitution.
On the basis of experimental findings and previous litera-
ture, a probable reaction mechanism was proposed for the pal-
ladium-catalyzed synthesis of dihydro[1,2-b]indenoindoles
(Scheme 6). Initially, the Pd0 catalyst undergoes oxidative addi-
tion with compound S1 gives the intermediate A, which is ap-
parently stabilized by internal chelation with nitrogen.[15] Next,
base assisted a-arylation generates the nine-membered palla-
dacycle intermediate B and subsequent reductive elimination
gives intermediate 2 and regenerates Pd0. The intramolecular
nucleophilic addition reaction of intermediate 2 with base
gives the final product 4.
To gain more insights into the mechanism for the palladium-
catalyzed cascade process, we performed some control experi-
ments (Scheme 5). The progress of the reaction with 1e under
optimized reaction condition was stopped after 8 hand the
eight-membered a-arylated intermediate 2e was isolated
[Scheme 5, Eq. (3)]. In addition, the structure was unambigu-
ously confirmed by X-ray analysis.[14] Compound 2e could be
smoothly converted into final product under basic conditions
[Scheme 5, Eq. (4)]. However, the isolation of the intermediate
was only successful with compound 2e and other such inter-
mediates were rapidly converted into final product. These re-
The tentative mechanism for the copper-catalyzed formation
benzo[3,2-b]furoindolines is outlined in Scheme 7. The reaction
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Experimental Section
General information and meth-
ods: All reagents and solvents
were purchased from commercial
sources and used without further
purification. 1H and 13C NMR spec-
tra were recorded with a Varian
(400 MHz) and a JEOL (400 MHz)
spectrometer. HRMS were ob-
tained with a Micromass Q-TOF
spectrometer using electrospray
ionization technique. Column chro-
matography was performed with
silica gel (100–200 mesh) as sta-
tionary phase and hexane/ethyl
acetate as eluent. All reactions
were monitored by thin-layer chro-
matography (Merck aluminum
plates coated with silica gel). Melt-
ing points were measured with
a MelTemp melting point appara-
tus. Full characterization data are
included in the Supporting Infor-
mation.
Scheme 5. Intermediate isolation and control experiment.
General procedure for the syn-
thesis of dihydro[1,2-b]indenoin-
doles (4a–p): To an oven-dried
sealed
tube
containing
S1
(200 mg, 0.39 mmol) in acetonitrile
(3 mL) was added [Pd(PPh3)4]
(45.7 mg, 10 mol%) and KOH
(88 mg, 4 equiv) and the mixture
was heated at reflux with stirring
for 16 h. After the reaction was
completed (monitored by TLC), the
mixture was poured into ice-cold
water (20 mL) and extracted with
EtOAc (2x25 mL). The combined
organic layer was washed with
brine solution (20 mL), dried, and
Scheme 6. Proposed mechanism for formation of compound 4.
proceeds by a base-assisted intramolecular nucleophilic addi-
tion of compound S1 to give alcohol intermediate 3, which
subsequently undergoes Ullman-type CÀO coupling[16] to
afford the desired compound 5.
Conclusions
In summary, we have developed a simple approach to access
dihydroindeno[1,2-b]indole-9-ol derivatives by palladium-cata-
lyzed tandem a-arylation/nucleophilic addition. In addition,
a copper-catalyzed cascade approach to benzofuro[3,2-b]indo-
lines was also developed by nucleophilic addition/Ullmann-
type CÀO coupling. Importantly, the same precursor was uti-
lized for the synthesis of both heterocyclic scaffolds and the
product selectivity was solely determined by employing either
palladium or copper as the catalyst. This protocol displays
a wide substrate scope, good functional group tolerance, and
provides moderate to high chemical yields. Efforts toward the
biological screening of the synthesized compounds and exten-
sion of the strategy to other heterocycles are underway in our
laboratory.
Scheme 7. Proposed mechanism for formation of compound 5.
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68–73; h) R. M. Liu, V. Vasiliou, H. Zhu, J. L. Duh, M. W. Tabor, A. Puga,
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the solvent removed under reduced pressure. The crude residue
was purified by flash column chromatography to afford compound
4a as an off-white solid (114 mg, 77% yield).
General procedure for the synthesis of benzofuro[3, 2-b]indo-
lines (5a–r): To an oven-dried round-bottom flask containing S1
(200 mg, 0.39 mmol) in DMF (2 mL) was added Cu(OTf)2 (14 mg,
10 mol%), 1,10-phenanthroline (14 mg, 20 mol%), and KOtBu
(133 mg, 3 equiv). The resultant mixture was heated at 808C for
12 h or until the starting material was consumed. After reaction
was completed (monitored by TLC), the mixture was poured in to
ice-cold water (20 mL) and extracted with EtOAc (2x25 mL). The
combined organic layer was washed with aqueous ammonium
chloride solution (20 mL), dried, and the solvent removed under re-
duced pressure. The crude residue was purified by flash column
chromatography to afford compound 5a as a beige solid (80%
yield).
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We gratefully acknowledge financial support from the Ministry
of Science and Technology (MOST), Taiwan, and the Centre for
Research Resources and Development of Kaohsiung Medical
University for 400 MHz NMR analyses.
Keywords: cascade synthesis
· copper · heterocycles ·
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[14] CCDC 1417171 (5b),
1417172 (2e),
1417173 (5a),
1417174 (4d),
1417175 (5n), 1417176 (4a), and 1717177 (5m) contain the supplemen-
tary crystallographic data for this paper. These data are provided free of
charge by The Cambridge Crystallographic Data Centre.
Chem. Eur. J. 2015, 21, 17044 – 17050
www.chemeurj.org
17049
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
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Received: August 14, 2015
Published online on October 7, 2015
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