Palladium-catalyzed reaction of 2-alkynylhalobenzene with 2-alkynylbenzamide: An efficient approach to indeno[1,2-c]azepin-3(2H)-ones

Article abstract of DOI:10.1039/c1cc14480d

A novel and efficient route for rapid access to indeno[1,2-c]azepin-3(2H)- ones is described, which proceeds through a palladium-catalyzed tandem reaction of 2-alkynylhalobenzene with 2-alkynylbenzamide in the presence of PPh ₃ or PCy₃. The indeno[1,2-c]azepin-3(2H)-ones which incorporate both indene and unsaturated seven-membered ring lactam skeletons are obtained in good to excellent yields.

Full text of DOI:10.1039/c1cc14480d

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COMMUNICATION
Palladium-catalyzed reaction of 2-alkynylhalobenzene with
2-alkynylbenzamide: an efficient approach to indeno[1,2-c]azepin-3(2H)-onesw
Yong Luoa and Jie Wu*ab
Received 23rd July 2011, Accepted 25th August 2011
DOI: 10.1039/c1cc14480d
A novel and efficient route for rapid access to indeno[1,2-c]-
azepin-3(2H)-ones is described, which proceeds through
lactam and indene, we conceived that indeno[1,2-c]azepin-3(2H)-
one (Scheme 1) could be regarded as a privileged scaffold as well,
which incorporated both indene and unsaturated seven-membered
ring lactam skeletons. We expected that interesting biological
a
palladium-catalyzed tandem reaction of 2-alkynylhalobenzene
with 2-alkynylbenzamide in the presence of PPh3 or PCy3. The
indeno[1,2-c]azepin-3(2H)-ones which incorporate both indene and
unsaturated seven-membered ring lactam skeletons are obtained in
good to excellent yields.
activities would be displayed from
a focused library of
indeno[1,2-c]azepin-3(2H)-ones. With the above consideration in
mind, we started to explore the possibility for efficient assembly of
indeno[1,2-c]azepin-3(2H)-ones.
Intense interest has been directed toward the tandem reaction
due to its high efficiency and other attractive advantages.13,14
Recently, we described a novel method for the generation of
structurally complex molecules via a palladium-catalyzed
tandem reaction of 2-alkynylhalobenzene.12c,e Encouraged
by this result, we envisioned that indeno[1,2-c]azepin-3(2H)-
one could be constructed starting from 2-alkynylhalobenzene 1
as well (Scheme 1). We reasoned that the intermediate A would
be formed via oxidative addition of Pd(0) to 2-alkynyl-
halobenzene 1. This Pd(II) complex would coordinate with the
triple bond of 2-alkynylbenzamide 2, followed by insertion of the
triple bond to afford an intermediate B. Subsequently an intra-
molecular CRC insertion and C–N bond formation occurred to
It is well recognized that a medium-sized unsaturated lactam is
the core structure of natural products that possess impor-
tant biological properties, including antibiotic, antitumor,
antihelminthic1,2 and insecticidal activity.3 These compounds
find wide applications in organic synthesis.4 Moreover, they
serve as a basis of the peptidomimetic scaffold, which is utilized
to define and stabilize the biologically active conformations of
peptides and proteins.5 So far, methods for the formation of simple
monocyclic lactams have been developed, including ring expansion,
cycloaddition, ring closure, and fragmentation reactions.1
Transition metal catalyzed approaches such as palladium-catalyzed
carbonylation reactions have been successfully applied for the
preparation of medium-sized lactams as well.6,7 The indene is
another kind of privileged fragment, which can be discovered in
many drug candidates with remarkable biological activities.8
Additionally, these compounds have found applications in materials
science9 as well as in olefin polymerization as catalysts.10
Currently, a good deal of effort has centered on diversity-oriented
synthesis for the generation of small molecules in the field of
chemical genetics.11 The development of efficient and concise
pathways for rapid construction of molecular complexity is a
major concern of the synthetic organic chemical community.
Strategies that allow multiple transformations in a single-pot
process with high selectivity and efficiency are especially attractive.
Recently, we have been involved in this field for rapid access to
natural product-like compounds with privileged scaffolds.12
Inspired by the core structures of medium-sized unsaturated
a Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: jie_wu@fudan.edu.cn;
Fax: +86 21 6564 1740; Tel: +86 21 6510 2412
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, China
w Electronic supplementary information (ESI) available: Experimental
procedure, characterization data, 1H and 13C NMR spectra of com-
pound 3. CCDC 836855. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc14480d
Scheme 1 Indeno[1,2-c]azepin-3(2H)-ones generation via a Pd-catalyzed
reaction of 2-alkynylhalobenzene 1 with 2-alkynylbenzamide 2.
c
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Chem. Commun., 2011, 47, 11137–11139 11137

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Table 1 Initial studies for the palladium-catalyzed reaction of 1-bromo-
2-(phenylethynyl)benzene 1a with 2-(2-phenylethynyl)benzamide 2a
Table 2 Synthesis of indeno[1,2-c]azepin-3(2H)-ones via a Pd-catalyzed
reaction of 2-alkynylbromobenzene 1 with 2-alkynylbenzamide 2a
Entry
Ligand
Base
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
PPh3
PPh3
PPh3
PPh3
—
PCy3
Xantphos
DPEphos
DPPP
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
NaOtBu
NaOCH3
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
DMF
nr
nr
nr
94
60
91
91
90
60
96
82
Trace
Trace
51
9
10
11
12
13
14
15b
K2CO3
K2CO3
K2CO3
K2CO3
DMSO
Toluene
1,4-Dioxane
79
a
b
Isolated yield based on 2-(2-phenylethynyl)benzamide 2a. The
reaction occurred at 80 1C.
generate the desired indeno[1,2-c]azepin-3(2H)-one 3. Herein, we
wish to disclose our preliminary results for this transformation.
We selected 1-bromo-2-(phenylethynyl)benzene 1a and
2-(2-phenylethynyl)benzamide 2a as the model substrates for
reaction development. The preliminary screening results are
presented in Table 1. Initially, no reaction occurred when the
reaction was catalyzed by Pd(OAc)2 in the presence of PPh3
and NaOtBu in 1,4-dioxane under reflux conditions (entry 1).
The same results were observed when the base was changed to
NaOCH3 or Na2CO3 (entries 2 and 3). Interestingly, the
desired indeno[1,2-c]azepin-3(2H)-one 3a was obtained in
good yield when Cs2CO3 was employed as a base in the
reaction (94% yield, entry 4). In the meantime, the structure of
product 3a was unambiguously illustrated by X-ray diffraction
analysis (see the ESIw). A control experiment without the addition
of phosphine ligand indicated that the reactivity was diminished
(entry 5). Further screening of ligands revealed that PCy3,
Xantphos, and DPEphos were all good choices (entries 6–8).
Considering the easy availability, PPh3 was selected for the
further development. An excellent yield was afforded when the
reaction was performed in the presence of K2CO3 as a base
(entry 10). The reaction occurred in other solvents leading to
inferior results (entries 12–14). The yield was decreased with
prolonged reaction time when the reaction took place at 80 1C
(entry 15).
a
b
Isolated yield based on 2-alkynylbenzamide 2. PPh3 was used as
c
the ligand. PCy3 was used as the ligand.
Additionally, the substrates with electron-donating or electron-
withdrawing groups attached to the aromatic ring were good
partners for the generation of indeno[1,2-c]azepin-3(2H)-ones.
In some cases, the yields were not satisfied, which was due to
the existence of the un-reacted starting materials. The reaction
time could not be prolonged since the products would be
hydrolyzed slowly under the basic reaction conditions.
We further investigated the reactions of 2-alkynylbromobenzene
1 and 2-alkynylbenzamide 2 with substitutions in the amide group
under the standard conditions shown in Table 2 (Table 3).
Table
3
Palladium-catalyzed reaction of alkynylbromobenzene
1 with 2-alkynylbenzamide 2a
With the optimized conditions in hand [Pd(OAc)2 (5 mol%),
PPh3 (10 mol%), K2CO3, 1,4-dioxane, 105 1C], we started to
explore the scope of the palladium-catalyzed cascade reaction
of 2-alkynylhalobenzene 1 with 2-alkynylbenzamide 2, and the
results are shown in Table 2. We found in some cases better
results were afforded when PCy3 was utilized instead of
PPh3. All the reactions worked well to afford a variety of
indeno[1,2-c]azepin-3(2H)-ones 3 in good to excellent yields.
Various substitutions including aryl and alkyl groups attached
to the triple bond were all tolerated in the transformations.
a
Isolated yield based on 2-alkynylbenzamide 2.
c
11138 Chem. Commun., 2011, 47, 11137–11139
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Scheme 2 Pd-catalyzed reaction of 2-alkynylchlorobenzene 4 with
2-alkynylbenzamide 2.
It is noteworthy that the yields of this conversion are very
sensitive to the substrates. For example, the reaction proceeded
smoothly when R5 was an ester substituted phenyl group.
However, no product was formed when the 4-methoxyphenyl
group was attached to the amide. We reasoned that it might be
due to the acidity of the amide (N–H) in the substrate.
Moreover, the reactions of 1-chloro-2-(2-phenylethynyl)-
benzene 4 with 2-alkynylbenzamides were explored (Scheme 2).
The corresponding products could be obtained as well under the
standard conditions. From these results, we are convinced that
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In summary, we have presented a novel and efficient route for
the generation of indeno[1,2-c]azepin-3(2H)-ones through a
palladium-catalyzed tandem reaction of 2-alkynylhalobenzene
with 2-alkynylbenzamide. The indeno[1,2-c]azepin-3(2H)-ones
which incorporates both indene and unsaturated seven-membered
ring lactam skeletons are obtained in good to excellent yields.
Investigation of 2-alkynylhalobenzenes in other transformations
is currently underway.
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Financial support from National Natural Science Foundation
of China (No. 21032007 and 21172038) is gratefully
acknowledged.
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 11137–11139 11139