Synthesis of 1-methyleneindenes via palladium-catalyzed tandem reactions

Article abstract of DOI:10.1039/b909178e

Palladium-catalyzed tandem reactions of 2-alkenylphenyl-acetylenes with CuCl₂ or CuBr₂ afforded 3-chloro- or 3-bromo-1- methyleneindenes in good yields; these compounds could be further elaborated via palladium-catalyzed coupling rea

Full text of DOI:10.1039/b909178e

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Synthesis of 1-methyleneindenes via palladium-catalyzed tandem
reactionswz
Shengqing Ye,a Ke Gao,a Haibo Zhou,a Xiaodi Yangb and Jie Wu*ac
Received (in Cambridge, UK) 8th May 2009, Accepted 17th July 2009
First published as an Advance Article on the web 4th August 2009
DOI: 10.1039/b909178e
Palladium-catalyzed tandem reactions of 2-alkenylphenyl-
acetylenes with CuCl2 or CuBr2 afforded 3-chloro- or
3-bromo-1-methyleneindenes in good yields; these compounds
could be further elaborated via palladium-catalyzed coupling
reactions.
Scheme 1 Initial studies of the Pd-catalyzed reaction of 1a.
As a privileged scaffold, the indene core has been found in
many drug candidates with remarkable biological activities.1
in the presence of a suitable transition metal catalyst
(Fig. 1, B). Herein, we disclose that 2-alkenylphenylacetylenes
1 undergo Pd-catalyzed tandem reactions in the presence of a
copper(II) halide, leading to 3-halo-1-methyleneindenes. These
compounds could be further elaborated via Pd-catalyzed
cross-coupling reactions to generate highly functionalized
1-methyleneindenes.
Moreover, indenes have been attractive in metallocene
complexes, which are utilized as catalysts in olefin polymerization.2
In addition, applications of these molecules have been
discovered in materials science.3 Thus, the importance of
indenes has stimulated the development of a number of
approaches for the synthesis of the indene ring system.4–7
However, less attention has been paid to 1-methyleneindenes,8
which are easily transformed into functionalized indenes. It
is well-established that tandem C–C bond formations are
powerful methods for the generation of molecular complexity
from relatively simple starting materials in a convergent
way.9–11 Recently, we have developed efficient tandem
reactions for the expeditious synthesis of biologically-relevant
heterocyclic compounds.12 Based on these results, we have
also investigated the tandem reaction of 2-(2-(alkynyl)-
benzylidene)malonate with indole.13 In this process, the
reaction was initiated via nucleophilic addition of a nucleophile
to the a,b-unsaturated system (Fig. 1, A). Prompted by the
advancement of halopalladation chemistry,14,15 we conceived
that during the process, the tandem cyclization reaction might
be initiated via nucleophilic attack of the triple bond motif
Initial studies were performed using (E)-ethyl-3-(2-(2-phenyl-
ethynyl)phenyl)acrylate (1a) as a model substrate (Scheme 1).
This compound could be easily synthesized starting from
2-alkynylbenzaldehyde. At the outset, the reaction was
catalyzed by PdCl2 (10 mol%) in the presence of CuCl2
(2.0 equiv.) in DMAc at 120 1C. Gratifyingly, the desired
3-chloroindene, 2a, was generated in 40% yield. Decreasing
the temperature to 80 1C did not affect the reaction efficiency.
However, the reaction was retarded at lower temperatures. We
then examined other solvents in this reaction, and DMAc was
demonstrated to be the best choice. The yield increased to 57%
when 4.0 equiv. of CuCl2 was employed in the reaction.
However, the result could not be improved when the amount
of copper(II) chloride was increased to 6.0 equiv. A blank
experiment indicated that no reaction occurred in the absence
of the palladium catalyst. The reaction also failed without the
addition of the copper salt. A similar result was observed
when 5 mol% of PdCl2 was utilized in the reaction. Further
screening of palladium catalysts revealed that Pd(OAc)2 was
the best for this transformation (66% yield), and only 3 h was
necessary for completion of the reaction. An inferior result
was displayed when the amount of Pd(OAc)2 was decreased to
2 mol% (for details, see the ESIz).
Fig. 1 Tandem cyclization of 2-alkenylphenylacetylene 1.
Next, the scope of the Pd-catalyzed tandem cyclization
reaction of 2-alkenylphenylacetylenes 1 were investigated
under the optimized conditions (Pd(OAc)2 (5 mol%), CuCl2
(4.0 equiv.), DMAc, 80 1C) and the results are shown in
Table 1. From Table 1, it is found that for all cases, the
Pd-catalyzed tandem cyclization reactions of 2-alkenylphenyl-
acetylenes 1 furnish the corresponding 3-chloro-1-methylene-
indenes 2 in moderate to good yields. For instance, when
(E)-1-phenyl-3-(2-(2-phenylethynyl)-phenyl)prop-2-en-1-ones
1c or 1d were utilized in the reaction under the standard
conditions, the desired products 2c or 2d were obtained in
90 and 71% yield, respectively (Table 1, entries 3 and 4).
a Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
Fax: +86 21 6510 2412; Tel: +86 21 5566 4619
b Laboratory of Advanced Materials, Fudan University,
220 Handan Road, Shanghai 200433, China
c State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
w This paper is dedicated to Professor Li-Xin Dai on the occasion of
his 85th birthday.
z Electronic supplementary information (ESI) available: Further
experimental and characterisation data. CCDC 731568. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b909178e
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Table 1 The Pd-catalyzed reaction of 2-alkenylphenylacetylenes 1 in
the presence of CuCl2
Entry Substrate 1
Product 2
Yield (%)a
1
66
Scheme 2 The possible reaction mechanism.
Dimethyl 2-benzylidenemalonate 1e also worked well, leading
to 3-chloro-1-methyleneindene 2e in 95% yield (Table 1, entry 5).
Substrates 1f–1j were also examined, and the reactions
proceeded smoothly to generate the desire products (Table 1,
entries 6–10). Additionally, we have proposed a possible
mechanism (Scheme 2) that is generally explained by a
nucleophilic addition of chloride onto the Pd(II)-activated
CRC triple bond. This Pd(II) complex renders the CRC
triple bond moiety electrophilic, so triggering the inter-
molecular attack of chloride, giving rise to corresponding
intermediate A. Insertion into the double bond and subsequent
b-hydrogen elimination leads to the generation of desired
product 2 and concomitant formation of Pd(0) in the presence
of base, which then oxidizes it to Pd(II)15a,16 so as to re-enter
the catalytic cycle.
2
3
60
90
4
71
We also tested the Pd-catalyzed reactions of 2-alkenyl-
phenylacetylene 1 in the presence of copper(II) bromide
(Scheme 3). These reactions also proceeded well to afford
bromo-containing indenes 3 in good yields.
5
6
95
54
After the successful generation of 3-chloro- and 3-bromo-1-
methyleneindenes, we considered the introduction of more
diversity into the indene scaffold via Pd-catalyzed cross-coupling
reactions. Thus, the Suzuki reaction was investigated. After
optimization, we identified that the combination of Pd(OAc)2
and S-Phos showed high efficiency as a catalyst for the
reaction of 3-chloro-1-methyleneindene (2a) with arylboronic
acids (Scheme 4). For example, a 92% yield of product 4a was
obtained when 4-methylphenyl-boronic acid was employed
in a reaction with 3-chloro-1-methyleneindene (2a). The structure
of compound 4a was also verified by X-ray crystallography.y
7
8
9
55
64
72
78
10
a
Scheme 3 The Pd-catalyzed reaction of 2-alkenylphenylacetylenes 1
Isolated yield based on 2-alkenylphenylacetylene 1.
in the presence of CuBr2.
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Financial support from the National Natural Science
Foundation of China (20772018) is gratefully acknowledged.
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5408 | Chem. Commun., 2009, 5406–5408