Palladium(ii)-catalyzed synthesis of functionalized indenones via oxidation and cyclization of 2-(2-arylethynylphenyl)acetonitriles

Article abstract of DOI:10.1039/c3ob40103k

A one-pot two-step synthesis of versatile indenones has been developed. This palladium(ii)-catalyzed transformation involves generation and condensation of ortho-functionalized 1,2-benzils from 2-(2-arylethynylphenyl)acetonitriles using Ph₂SO as the oxidant. The resulting 3-cyanoindenones can be converted to various valuable molecules.

Full text of DOI:10.1039/c3ob40103k

Organic &
Biomolecular Chemistry
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Palladium(II)-catalyzed synthesis of functionalized
indenones via oxidation and cyclization of
2-(2-arylethynylphenyl)acetonitriles†
Cite this: Org. Biomol. Chem., 2013, 11,
2582
Received 18th January 2013,
Accepted 24th February 2013
Xuxing Chen, Qian He, Yuyuan Xie and Chunhao Yang*
DOI: 10.1039/c3ob40103k
www.rsc.org/obc
A one-pot two-step synthesis of versatile indenones has been made to date, novel methods for the synthesis of diverse inde-
developed. This palladium(II)-catalyzed transformation involves nones are still highly desirable.
generation and condensation of ortho-functionalized 1,2-benzils
We envisioned that ortho-functionalized 1,2-benzils which
from 2-(2-arylethynylphenyl)acetonitriles using Ph2SO as the could be obtained via direct oxidation of internal alkynes
oxidant. The resulting 3-cyanoindenones can be converted to undergo intramolecular aldol condensation to afford inde-
various valuable molecules.
nones (Scheme 1). During the past few years, several trans-
formations from alkynes to 1,2-dicarbonyl compounds have
been reported.14 Among these cases, transition-metal-catalyzed
oxidations of alkynes using sulfoxides as very mild oxidants
attracted our attention. Recently, Li and co-workers described
a gold-catalyzed protocol to oxidize 1,2-diarylacetylenes to
benzil derivatives using diphenyl sulfoxide as the oxidant,
while ortho-highly congested substrates were not involved.14h
And palladium-catalyzed oxidations of internal alkynes in
DMSO usually require high temperature or a long time.14a,e,i
Inspired by these reports, we believed that it is feasible to con-
struct indenones via oxidation and cyclization of ortho-substi-
tuted 1,2-diarylacetylenes under mild conditions.
Initially, 2-(2-(phenylethynyl)phenyl)acetonitrile 1a was
treated under Chi–Yusubov’s condition (10 mol% PdCl2,
DMSO, 140 °C, 15 h).14a As a result, the desired product 2a was
obtained in 65% NMR yield (ESI, Table S1,† entry 1). In order
to lower the reaction temperature, AgSbF6 was added and
diphenyl sulfoxide was used as the external oxidant instead of
DMSO. To our delight, when 1,2-dichloroethane (DCE) was
used as the solvent, the starting material 1a disappeared at
100 °C in 1 h and the identified 1,2-dicarbonyl compound 3a
was observed (98% NMR yield) (Table S1,† entry 3). We found
that 3a could be easily converted to 2a in the presence of
Cs2CO3. Attempts to produce 2a via cyclization of 3a in a
Substituted indenones play an important role in medicinal
chemistry because of their extraordinary biological and
pharmaceutical properties. They have been employed as fluor-
escent binding agents of estrogen receptor,1 peroxisome prolif-
erator-activated receptor
γ
(PPARγ) agonists,2 selective
inhibitors of cyclooxygenase-2 (COX-2),3 topoisomerase
I
(Top I) inhibitors,4 and so on.5 In addition, indenones and
their derivatives also serve as key precursors and intermediates
in the synthesis of bioactive natural products6 and pharma-
ceuticals.7
Due to the importance of indenones, various synthetic
methodologies for their synthesis have been reported. Tra-
ditional methods to yield indenones include intramolecular
Friedel–Crafts acylations8 and Grignard reactions9 usually
require multiple steps or have limited scope. Recently, tran-
sition metal-mediated syntheses of indenones have been devel-
oped. One of these strategies towards their synthesis involves
generation of aryl and vinyl metal complexes and insertion of
a coordinated CO.10 The preparation of 2,3-disubstituted inde-
nones has been achieved from ortho-functionalized benzal-
dehydes, benzonitriles or benzoates by Heck–Larock
annulation11 and related processes.12 And ortho-inert benz-
aldehydes, benzamides, benzoyl chlorides and phenylmethan-
imines have also been used for synthesis of indenones via C–H
bond activation.13 Although significant advances have been
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China.
E-mail: chyang@simm.ac.cn
†Electronic supplementary information (ESI) available: The experimental pro-
cedures, and characterization data of compounds. CCDC 917397. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob40103k
Scheme 1 New synthetic strategy to afford indenones.
2582 | Org. Biomol. Chem., 2013, 11, 2582–2585
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Table 1 Optimization of reaction conditions for synthesis of indenones in a
one-pot two-step processa
Table 2 Reaction scope for the synthesis of indenonesa
Temp
(°C)
Time
(h)
Yieldb
(%)
Entry
Catalysts (mol%)
1
2
3
4
5
6
7
8
PdCl2 (5)/AgSbF6 (10)
PdCl2 (5)/AgSbF6 (10)
PdCl2 (5)/AgSbF6 (10)
PdCl2 (5)/AgSbF6 (10)
PdCl2 (5)
PdCl2 (5)/AgSbF6 (5)
PdCl2 (2)/AgSbF6 (4)
AgSbF6 (10)
PdCl2 (5)/AgSbF6 (10)
Pd(PPh3)2Cl2 (5)/AgSbF6 (10)
PdCl2 (5)/AgSbF6 (10)
PdCl2 (5)/AgSbF6 (10)
100
80
60
40
60
60
60
60
60
60
60
60
2.5
2.5
3
10
10
10
10
10
3
90
91
99(97)c
56
0
88
68
0
Trace
Trace
99
9d
10
11e
12f
3
3
3
89
a Standard reaction conditions: 1 (0.23 mmol), Ph2SO (0.69 mmol),
PdCl2 (5 mol%), AgSbF6 (10 mol%), dry DCE (1 mL), heated at 60 °C
for the specified time, then Cs2CO3 (0.28 mmol) was added, stirred for
an additional 20–120 min. b Isolated yields. c PdCl2 (10 mol%) and
AgSbF6 (20 mol%) were used.
a Reaction conditions: a mixture of 1a (0.23 mmol), Ph2SO, catalysts in
dry DCE (1 mL), heated at the indicated temperature under air for the
specified time, then Cs2CO3 was added, heated for an additional
30 min. b Determined by 1H NMR analysis of the crude product using
CH2Br2 as an internal standard. c The isolated yield is given in
parentheses. d H2O (1.15 mmol) was added. e The reaction was carried
out under a N2 atmosphere. f The reaction was carried out on the scale
of 7.6 mmol of 1a.
the ortho position of the arylethynyl group could also furnish
the corresponding indenones (2d, h). When R2 was a formyl or
cascade process were not successful (Table S1†). Therefore, we cyano group on the phenylacetylene moiety, higher loading of
next turned our attention toward screening of reaction con- catalysts was required for the reaction to occur (2j, m). In
ditions for synthesis of indenones in a one-pot two-step addition, naphthalen-1-ylethynyl substituted phenylaceto-
process (Table 1). After complete conversion of 1a, Cs2CO3 nitrile proceeded smoothly too, and provided 2s in 57% yield.
(1.2 equiv.) was added, and 2a was formed in 90% NMR yield It is noteworthy that multisubstituted indenone was also easily
(Table 1, entry 1). The reaction temperature (entries 1–4) and accessible by the oxidation and cyclization process (2r). The
effect of the loading of catalysts (entries 3, 6, 7) were also inves- structure of 2d was further confirmed by X-ray diffraction
tigated. When the reaction was conducted at 60 °C in DCE for analysis.15
3 h with PdCl2 (5 mol%) and AgSbF6 (10 mol%), then Cs2CO3
After the above reaction was achieved, the synthetic utility
(1.2 equiv.) was added, stirred for an additional 30 min, 2a was of 3-cyanoindenones was demonstrated. As illustrated in
produced in nearly quantitative yield (entry 3). Notably, the Scheme 2, 2a could react with either amines or H2O through
reaction could also afford 2a in 89% NMR yield on gram scale a Michael addition/elimination process, to give 3-amino-
(entry 12). Conversion into the desired product 2a was not indenones 4, 5 and 1,3-indandione 6, respectively. It should be
observed when either PdCl2 or AgSbF6 alone were used at noted that a number of compounds containing 3-aminoinde-
60 °C (entries 5 and 8), which suggests that a cationic Pd(II) none frameworks display various biological properties4,5 and
species is preferred for this functionalization process at lower 1,3-indandiones are important building blocks in the synthesis
temperature. Because similar yields were achieved when the of pharmaceutically important compounds.1b,9c,16 When
reaction was conducted either in air or in a nitrogen atmos- EtMgBr was used as the nucleophile, 1,2-addition product 7
phere (entries 3, 11), diphenyl sulfoxide should be the oxi- was observed. Interestingly, when 2h was reacted with hydra-
dizing reagent.
zine monohydrochloride, Cs2CO3 and CuCl2 in dioxane at
With the optimal reaction conditions in hand, the reaction 90 °C for 20 h, indeno[1,2-c]cinnolinone 8 was formed in 93%
scope was then examined (Table 2). Both electron-rich (2b–e, yield. This procedure involved two new C–N bond and one new
n–q) and electron-deficient (2f–m) arylethynyl substituted phe- N–N bond formations, one C–C bond and one C–F bond clea-
nylacetonitriles could be transformed into the desired pro- vages, removal of two hydrogen atoms in one manipulation.
ducts with moderate to excellent yields. The positions of the
A mechanistic proposal for these 3-cyanoindenones synth-
substituent at the phenylethynyl group have no significant eses is depicted in Scheme 3. The oxygen atom from sulfoxide
influence on this transformation (2b–d, f–h, n–o). Even rela- attacked alkynes mediated by Pd(II) species, and gave palla-
tively more sterically hindered substrates with a substituent at dium vinyl intermediate
A bearing a positively-charged
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sulfoxide as the oxidant and gives various 3-cyanoindenones in
moderate to excellent yields. And the method with a PdCl2/
AgSbF6/Ph2SO system is also a novel and facile pathway to 1,2-
diketones via directly oxidizing internal alkynes. Furthermore,
the 3-cyanoindenones can be converted to various valuable
molecules. Application of this method to the synthesis of more
drug-like compounds and their biological evaluation is cur-
rently under investigation.
This work was supported by the “Interdisciplinary
Cooperation Team” Program for Science and Technology Inno-
vation of the Chinese Academy of Sciences, and the National
Natural Science Foundation of China (21072205) and
SIMM1203ZZ-0103.
Notes and references
Scheme 2 Transformations of 3-cyanoindenones. All of the reactions were not
optimized. Isolated yields. Reaction conditions: (a) 2a (0.13 mmol), butyl amine
(0.39 mmol), Cs2CO3 (0.39 mmol), 1,4-dioxane (2 mL), 60 °C, 1 h; (b) 2a
(0.13 mmol), morpholine (0.39 mmol), Cs2CO3 (0.39 mmol), 1,4-dioxane (2 mL),
60 °C, 1 h; (c) 2a (0.13 mmol), Cs2CO3 (0.26 mmol), H2O (1 mL), 1,4-dioxane
(1 mL), 80 °C, 4 h; (d) 2a (0.13 mmol), EtMgBr (0.16 mmol), THF (2 mL), −20 °C,
5 min; (e) 2h (0.13 mmol), hydrazine monohydrochloride (0.26 mmol), CuCl2
(10 mol%), 1,4-dioxane (2 mL), air, 90 °C, 20 h.
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Scheme 3 Proposed reaction mechanism.
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