Synthesis of functionalized 3-bromoindenes via Pd(II)-catalyzed tandem reactions of o-(alkynyl)styrenes: Taking dioxygen as sole oxidant

Article abstract of DOI:10.1246/cl.150756

This paper introduced an economic and environmental approach to 3-bromoindenes from simple and readily available o-(alkynyl)styrenes via a Pd-catalyzed cascade cyclization including bromopalladation/Heck cross-coupling/β-H elimination. With O₂

Full text of DOI:10.1246/cl.150756

Received: August 11, 2015 | Accepted: September 6, 2015 | Web Released: September 12, 2015
CL-150756
Synthesis of Functionalized 3-Bromoindenes via Pd(II)-catalyzed Tandem Reactions
of o-(Alkynyl)styrenes: Taking Dioxygen as Sole Oxidant
Peng Zhou,* Weibing Liu, and Huihua Qiu
School of Chemical Engineering, Guangdong University of Petrochemical Technology,
2 Guangdu Road, Maoming 525000, P. R. China
(E-mail: wanghlu@mail2.sysu.edu.cn)
This paper introduced an economic and environmental
approach to 3-bromoindenes from simple and readily available
o-(alkynyl)styrenes via a Pd-catalyzed cascade cyclization
including bromopalladation/Heck cross-coupling/β-H elimina-
tion. With O2 as the sole oxidant and KBr as bromide source, a
series of poly-substituted 3-bromoindenes were synthesized with
high chemoselectivity avoiding the use of CuBr2.
bromopalladation/Heck cross-coupling/β-H elimination using
dioxygen as the sole oxidant and KBr as the bromide source.
In order to obtain the best reaction conditions, (E)-1-phenyl-
3-[2-(phenylethynyl)phenyl]prop-2-en-1-one (1a) was reacted in
the presence of different catalysts, bromide sources, oxidants,
and solvents, as shown in Table 1. Initially, we focused on the
direct synthesis of the desired product 2a in the presence of
Pd(OAc)2 and LiBr in CH3CN under 1 atm of O2. However, the
desired cascade reaction did not occur and no expected indene
was obtained under these conditions (Table 1, Entry 1). Gratify-
ingly, the yields of 2a dramatically increased to 86% when a
mixture of CH3CN and CH3COOH was used as the solvent. In
the aerobic transformation, CH3COOH, used as a proton shuttle,
was beneficial for the regeneration of the active palladium(II)
species (Table 1, Entry 2).10 When CH3COOH was replaced by
other organic acids like PhCOOH or PivOH (pivalic acid), the
reactions occurred but with lower efficiencies (Table 1, Entries 3
and 4). Subsequently, various bromide sources like KBr and
tetrabutylammonium bromide (TBAB) were screened and the
results showed that KBr was the best choice (Table 1, Entries 5
and 6). Additional studies focused on the efficiencies of other
Cascade cyclizations through nucleopalladation of alkynes
like halopalladation,1 acetoxypalladation,2 oxypalladation,3 etc.
are important and useful tools to carry out the difunctionaliza-
tion of C¸C triple bonds in one transformation that has attracted
widespread interest during the past decade. In particular,
bromopalladation of alkynes is one of the more efficient and
atom-economic methods for the construction of both the C-C
and C-Br bonds.4 According to the mechanism of literatures
mentioned above, a versatile reactive σ-vinylpalladium inter-
mediate A, which would be produced after a nucleophilic
addition of bromide onto the Pd(II)-activated C¸C triple bond
(Scheme 1), plays an important role in the reactions triggered
by bromopalladation. In most of these cases, excess CuBr2 was
usually necessary for oxidizing Pd(0) to Pd(II) and as bromide
source, which is neither environmentally nor economically
favorable. Until now, finding green and low-cost oxidants and
bromide sources to replace CuBr2 is challenging. From the
viewpoint of green chemistry, molecular oxygen is undoubtedly
the best oxidant and recently has been well developed in the
field of organic synthesis.5 As for bromide source, KBr is
nontoxic and cheaper than CuBr2.
Table 1. Screening of reaction conditionsa
O
O
Ph
Pd(II) salts (4 mol%)
Ph
Bromo-source
Ph
O
2 (1 atm)
Solvents
Ph
Br
80 °C
1a
2a
Bromide
sources
Yield
/%b
Entry
Catalyst
Solvents
The indene skeleton is found in several biologically active
natural products6 and functional materials.7 Thus, the develop-
ment of new methods for their construction is still a hot topic
in the field of organic synthesis.8 C¸C triple bonds of o-
(alkynyl)styrenes presented excellent activities in cascade
reactions through nucleopalladation and functional polycycles
like indenes were synthesized through these transformations.4a,9
In this paper, we will introduce a new methodology for 3-
bromoindene derivatives from the corresponding o-(alkynyl)-
styrenes via a Pd-catalyzed cascade cyclization including
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
LiBr
LiBr
LiBr
LiBr
KBr
TBAB
KBr
KBr
KBr
KBr
KBr
KBr
KBr
KBr
CuBr2
CH3CN
NR
86
44
49
89
23
73
78
0
<5
NR
<5
NR
84
68
CH3CN/AcOH(4:1)
CH3CN/PhCOOH
CH3CN/PivOH(4:1)
CH3CN/AcOH(4:1)
CH3CN/AcOH(4:1)
CH3CN/AcOH(4:1)
CH3CN/AcOH(4:1)
CH3CN/AcOH(4:1)
DMF/AcOH(4:1)
DMSO/AcOH(4:1)
Toluene/AcOH(4:1)
AcOH
3c
4
5
6
7
8
PdBr2
®
9
10
11d
12
13
14e
15f
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Br-
Bromopalladation of alkyne
Br
CH3CN/AcOH(4:1)
CH3CN/AcOH(4:1)
PdII
Pd(II)
A
aReaction conditions: 1a (0.25 mmol), Pd salts (4 mol %), bromide salts
(1.5 equiv) in solvent (1.5 mL) at 80 °C for 15 h; 1 atmosphere of O2
Previous work:Taking CuBr2 as Oxidant and bromide source.
This work:Taking O2 as Oxidant and KBr as bromide source.
was kept by
a
balloon. bDetermined by GC. cWith PhCOOH
(1.5 equiv). dNR: No reaction. eThe reaction was carried out in a
f
oxygen bomb (pO ¼ 8 atm). With CuBr2 (4 equiv) to replace 1 atm
2
Scheme 1. Bromopalladation of alkyne.
of O2.
Chem. Lett. 2015, 44, 1637–1639 | doi:10.1246/cl.150756
© 2015 The Chemical Society of Japan | 1637

Table 2. Pd-catalyzed cyclization of o-(alkynyl)styrenes to
functional 3-bromoindenesa
palladium catalysts, such as PdCl2 and PdBr2. When these Pd
salts were used, the reaction gave more complicated results
(Table 1, Entries 7-9). The additional studies indicated that
solvent plays an important role in the transformation; only the
mixture of CH3CN and CH3COOH was effective, which may
due to strong coordination between acetonitrile and Pd(II)
(Table 1, Entries 10-13). When the pressure of O2 was increased
to 8 atm, the yield of 2a cannot be improved obviously (Table 1,
Entry 14). As previously described, Cu(II) salts were often
used as oxidants in Pd-catalyzed oxidations. However, the yield
was only 68% when CuBr2 (4 equiv) was employed as both
oxidant and bromide source (Table 1, Entry 15). Thus, the best
conditions for this cascade cyclization were as follows: 4 mol %
Pd(OAc)2, 150 mol % KBr in CH3CN/CH3COOH under 1 atm
of O2 at 80 °C for 15 h.
R2
R2
Pd(OAc)2 (4 mol%)
R3
KBr (1.5 equiv.)
R3
R1
HOAc/CH3CN (1:4)
2 (1 atm)
80 °C
R1
O
Br
1
2
Product
(Yield)b
Product
(Yield)b
Entry
1
Entry
9
O
O
Ph
Ph
Ph
Ph
F
Br
Br
2a (85%)
2i (88%)
Under the optimal reaction conditions, the activity of
different substituted o-(alkynyl)styrenes were tested, which are
summarized in Table 2. We initially examined substrates bearing
electron-rich or electron-poor aryl group at one side of the C¸C
triple bond and corresponding tandem reaction were carried out
successfully (Table 2, Entries 1-5). When substrates bearing
linear or cyclic alkyl groups at one side of C¸C triple bond
were tested, the expected products 2f and 2g were produced in
78% and 80% yields, respectively (Table 2, Entries 6 and 7).
However, when the R1 group was 2-hydroxy-2-propyl, the
desired tandem reaction through bromopalladation/Heck cross-
coupling/β-H elimination did not occur, which might be due
to its steric bulk (Table 2, Entry 8). Subsequently, substrates
with electron-rich or electron-poor R3 substituents underwent
the reaction, leading to fluoro- and methoxy-substituted indenes
in good yields (Table 2, Entries 9 and 10). In addition, the
scope of the cascade cyclization was expanded to a variety of
o-(alkynyl)styrenes bearing alkoxycarbonyl at one side of the
C=C double bond, which furnish the corresponding 3-bromoin-
denes in 85-91% yields (Table 2, Entries 11-15).
Consequently, a possible mechanism was proposed accord-
ing to a previous report on oxygen-promoted halopalladation
chemistry (Scheme 2). Initially, a nucleophilic addition of
bromide onto the Pd(II)-activated C¸C triple bond of substrate
1 affords the reactive σ-vinylpalladium intermediate A.3 The
C=C double bond of A is easily activated by the Pd(II) complex
and an intramolecular carbopalladation reaction occurs subse-
quently to generate the intermediate B.11 Then, the intermediate
B undergoes β-H elimination to give the expected product 2 and
HPdOAc.12 The resulting Pd(0) species is additionally oxidized
to Pd(OAc)2 by the O2/HOAc system to complete this catalytic
cycle and Pd(II) salts enters the next catalytic cycle.5a,13
Furthermore, oxygen plays a key role in inhibiting the proto-
nolysis of the intermediate B and in promoting β-H elimination.
The Suzuki cross-couplings of arylboronic acids and aryl
bromides are widely used to prepare fused polycyclic aromatic
hydrocarbons, which exhibit excellent photoelectric properties
in the field of organic electronics.14 Consequently, the activities
of 2a and 2k in the Suzuki cross coupling were tested and two
kinds of poly-substituted indenes (isolated yield: 3a in a yield
of 89%; 3k in a yield of 92%) were obtained in high yield
(Scheme 3, 2a and 2k).
O
O
H3CO
Ph
H3CO
OCH3
Ph
2
3
4
5
6
7
8
10
11
12
13
14
15
Br
Br
2b (83%)
O
2j (90%)
O
H3CO
O
CH3
Ph
Br
Br
2c (85%)
O
2k (91%)
O
H3CO
O
Cl
Ph
Br
Br
2d (84%)
O
2l (89%)
O
H3CO
O
F
Ph
Br
Br
2e (79%)
2m (89%)
O
O
H3CO
O
Ph
Br
Br
2f (78%)
2n (85%)
O
HO
O
H3CO
O
Ph
Br
Br
2g (80%)
2o (87%)
O
Ph
OH
Br
2h (0)c
aReaction conditions:
1 (0.5 mmol), Pd(OAc)2 (4 mol %), KBr
In conclusion, we have discovered a unique and direct
approach for constructing 3-bromoindenes from simple and
readily available o-(alkynyl)styrenes via a Pd-catalyzed cascade
(1.5 equiv) in AcOH/CH3CN (1.5 mL, the ratio of volume is 1:4)
under 1 atmosphere of O2 at 80 °C for 15 h. bIsolated yield. cNo
reaction.
1638 | Chem. Lett. 2015, 44, 1637–1639 | doi:10.1246/cl.150756
© 2015 The Chemical Society of Japan

R2
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R1
1
Pd(OAc)2
H2O
Bromopalladation
-
Br
O2
R2
HOAc
PdOAc
R1
HPdOAc
Br
A
R2
5
R2
R1
Carbopalladation
PdOAc
R1
β
-H elimination
Br
2
Br
B
6
7
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Scheme 2. Proposed mechanism.
O
O
R1
R1
Ph
MeO
[Pd(PPh3)4] 5 mol%
K2CO3 2equiv
Dioxane
Ph
Ph
+
PhB(OH)2
0.5 mmol
Ph
Ph
50 °C for 8h
Ph
3a 89%
Ph
Br
Ph
3
3k
92%
0.3 mmol
2
Scheme 3. The activity of 2 in the Suzuki cross-coupling.
8
cyclization including bromopalladation/Heck cross-coupling/
β-H elimination. The reaction conditions are mild and atom-
economic in which O2 (1 atm) is used as the sole oxidant and
KBr is used as the bromide source.
We thank the National Natural Science Foundation of China
(No. 21272037), Guangdong Natural Science Foundation (No.
S2013040014944) and Guangdong University of Petrochemical
Technology for financial support of this work.
9
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Supporting Information is available electronically on J-STAGE.
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Chem. Lett. 2015, 44, 1637–1639 | doi:10.1246/cl.150756
© 2015 The Chemical Society of Japan | 1639