The Synthesis of Benzofulvenes through Palladium-Catalyzed Sequential Three-Component Reactions

Article abstract of DOI:10.1002/adsc.201801141

An approach for the synthesis of benzofulvenes has been developed through palladium-catalyzed sequential three-component reactions. The reactions likely involve C,C-palladacycles as the key intermediates. The palladacycles are generated through cascade reactions of aryl halides and alkynes, and then reacted with CH₂Br₂ to form benzofulvenes as the final products. (Figure presented.).

Full text of DOI:10.1002/adsc.201801141

Title: Synthesis of Benzofulvenes through Palladium-Catalyzed
Sequential Three-Component Reactions
Authors: Bo Zhou, Zhuo Wu, Weixin Qi, Xueliang Sun, and Yanghui
Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801141
Link to VoR: http://dx.doi.org/10.1002/adsc.201801141

10.1002/adsc.201801141
Advanced Synthesis & Catalysis
Very Important Publication
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
The Synthesis of Benzofulvenes through Palladium-Catalyzed
Sequential Three-Component Reactions
Bo Zhou,a Zhuo Wu,a Weixin Qi,a Xueliang Sun,a Yanghui Zhanga, *
a School of Chemical Science and Engineering, Shanghai Key Laboratory of Chemical Assessment and Sustainability,
Tongji University, 1239 Siping Road, Shanghai 200092, P. R. China
E-mail: zhangyanghui@tongji.edu.cn; Web: http://zhangyhgroup.tongji.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
However, for this method, since C,C-palladacycles
has been developed through palladium-catalyzed sequential are synthesized directly from the Pd-mediated
Abstract: An approach for the synthesis of benzofulvenes
three-component reactions. The reactions likely involve
C,C-palladacycles as the key intermediates. The
palladacycles are generated through cascade reactions of
aryl halides and alkynes, and then reacted with CH2Br2 to
form benzofulvenes the final products.
cyclization of the substrates, the substrates have
complex structures and have to be presynthesized.
Therefore, it is highly desirable to develop new
methods for the synthesis of C,C-palladacycles by
employing simple substrates.
Keywords: C,C-palladacycles; C–H activation; Alkylation;
Palladium; Benzofulvenes.
Benzofulvenes are key privileged scaffolds present
in natural products and bioactive molecules and have
found versatile applications in materials science,
medicinal chemistry and organometallics.[1] In
particular, benzofulvenes are important monomers in
polymer chemistry, and polybenzofulvenes often
show intriguing properties.[1e, 1f] A great number of
methods have been developed for the synthesis of
benzofulvenes.[2] The traditional methods often rely
on the use of structurally complex starting materials.
Notably, the synthesis of benzofulvenes through C-H
activation has also been reported,[3] However, the
reactions are limited to those using aryl ketones as
starting materials. Therefore, continuous efforts
should still be devoted to seeking new reactions for
the synthesis of benzofulvenes.
Scheme 1. Synthesis of Benzofulvenes via Transition-
Metal-Catalyzed C−H Activation.
It has been reported that C,C-palladacycles could
be obtained from aryl halides and alkynes, which
represents
a
straightforward method for the
construction of C,C-palladacycles from relatively
simple precursors.[8] However, the resulting
palladacycles usually underwent intramolecular
cyclization. Although the intermolecular arylation of
C,C-palladacycles formed via reactions of aryl
iodides and alkynes has been developed, the aryl
iodides were also the starting materials forming the
C,C-palladacycles.[9] Actually, this reaction indicates
that it should be quite a challenge to functionalize
such C,C-palladacycles obtained from aryl halides
and alkynes with other external reagents. Since
multiple reactants, intermediates, and steps are
involved in the reactions, each step should proceed in
a well-defined sequence to make the reactions occur
as desired. Herein, we report the alkylation reaction
of C,C-palladacyclic intermediates obtained from aryl
halides and alkynes. The transformation represents a
novel method for the synthesis of benzofulvenes.
As an important class of organometallic
compounds, metallacycles are very common
intermediates in transition-metal catalysis,[4] In
particular
in
transition-metal-catalyzed
C–H
functionalization reactions.[5] In this context, C,C-
palladacycles are particularly attractive.[6] C,C-
palladacycles consist of a C–Pd–C bonding motif and
contain two C–Pd bonds. Due to their unique
structures, C,C-palladacyclic intermediates may
exhibit novel reactivity. More importantly, the
presence of two C–Pd bonds offers opportunities to
develop new transformations. C,C-Palladacycles are
usually obtained by Pd-catalyzed intramolecular C-H
activation of aryl halides as starting materials.[7]
1
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10.1002/adsc.201801141
Advanced Synthesis & Catalysis
8
KOAc / PhCO2K
(7 / 0.8)
PEG / DMA /
i-PrOH
90
(85[b])
(2 / 1 / 0.5 )
[a] The yields were determined by 1H NMR analysis of the
crude reaction mixture using CHCl2CHCl2 as the internal
[b]
standard.
Isolated yield. PEG = poly(ethylene glycol)
400. DMA = N,N-dimethylacetamide.
[a]Yields of the the isolated products.
[b]Observed by GC-MS.
The greatest advantage of C,C-palladacycles is that
they contain two C-Pd bonds. Although the above
alkylation reaction demonstrates the feasibility of
intermolecular functionalization of C,C-palladacycles
obtained from aryl halides and alkynes, only one C-
Pd bond was functionalized. Our aim is to develop
synthetically useful reactions by functionalizing both
C-Pd bonds of C,C-palladacycles. We found that
C,C-palladacycles can react with CH2Br2, affording
fluorenes as the products.[10] Therefore, we turned to
investigate the reaction of the C,C-palladacycles
formed in situ from aryl halides and alkynes with
CH2Br2. Unexpectedly, benzofulvene 6aa was
obtained in the reaction of 1a, 2a, and 5 in the
presence of Pd(OAc)2 and KOAc (Table 1, entry 1).
Spurred by this exciting result, we continued to
optimize the reaction conditions. The addition of
PhCO2K promoted the yield to 21% (entry 2). The
same amount of KOAc was less effective (entry 3).
The yield was improved to 30% when 0.5 mL
isopropanol was added. The isopropanol should act as
a reductant, because the catalytic cycle is expected to
start with Pd(0). Gratefully, a yield of 50% was
obtained by replacing isopropanol with PEG (entry
5).[11] The yield increased when the reaction was
carried out in a mixture of DMA, PEG, and
isopropanol (entries 6 and 7). Finally, benzofulvene
was formed in 90% yield when the amount of KOAc
was enhanced to 7 mmol. While the role of KOAc is
unknown, KOAc is a common base in the C-H
activation reaction of aryl halides and can promote C-
H activation. [12]
Scheme 2. Alkylation of C,C-palladacyclic intermediate
with alkyl iodides.
As it has been demonstrated that C,C-palladacycles
have high reactivity towards alkyl halides,[7n] we first
investigated alkylation reaction of C,C-palladacyclic
intermediates obtained from aryl halides and alkynes.
Therefore, iodobenzene 1a and diphenylacetylene 2a
were selected for constructing C,C-palladacycle, and
n-butyl iodide was used as the alkylating reagent.
After extensive screening, alkylated product 4aaa
was obtained in 52% yield under the conditions as
shown in Scheme 2. An isomer of 4aaa and two
dialkylated products were also observed by GC-MS.
Although the structures of these minor isomers could
not be identified due to insufficient quantities, the
isomer of 4aaa may result from the alkylation of the
alkene moiety (for the mechanism of the alkylation
reaction see the Supporting Information).
Table 1. Optimization of Reaction Conditions for the
Benzofulvene-Forming Reaction.
To gain insight into the mechanism of the
benzofulvene-forming reaction, we first synthesized
2,3-diphenyl-1H-indene. When 2,3-diphenyl-1H-
indene was allowed to react with CH2Br2. 6aa was
obtained in a yield of 70%. Furthermore, a small
amount of 2,3-diphenyl-1H-indene was observed
under some conditions that were tested during the
course of reaction optimization. These outcomes
indicate that 2,3-diphenyl-1H-indene should be
formed as the intermediate in the reaction. The
benzofulvene was formed in good yields when the
reaction was performed in the presence of TEMPO,
which is against a SET process.
Entry
Base
Solvent
(mL)
Yield
(%)[a]
11
(mmol)
1
2
KOAc (2.4)
KOAc / PhCO2K
(2.4 / 0.8)
DMA (2)
DMA
21
(2)
3
4
KOAc (3.2)
KOAc / PhCO2K
(2.4 / 0.8)
DMA (2)
DMA / i-PrOH
(2 / 0.5)
15
30
5
6
KOAc / PhCO2K
(2.4 / 0.8)
DMA / PEG
(2 / 0.5)
50
61
KOAc / PhCO2K
(2.4 / 0.8)
DMA / PEG /
i-PrOH
(2 / 0.5 / 0.5)
DMA / PEG /
i-PrOH
7
KOAc / PhCO2K
(2.4 / 0.8)
72
(1 / 2 / 0.5)
2
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10.1002/adsc.201801141
Advanced Synthesis & Catalysis
Having developed an efficient synthetic protocol
for benzofulvenes, we then investigated the substrate
scope of the method. We first examined the
compatibility of various substituted iodobenzenes. As
shown in Table 2, a variety of functional groups at
the para positions, including methyl, tert-butyl,
methoxy, phenyl, and acetamido, were compatible
(6ba–6fa), and substrates bearing a meta-substituent
were also suitable (6ga and 6ha). The reactivity of
disubstituted iodobenzenes was also investigated. A
range of iodobenzene derivatives were transformed
into the corresponding benzofulvenes in moderate
yields (6ia-6la). It should be mentioned that a trace
amount of isomers were observed by GC-MS in most
of the reactions. However, the structures of the
isomers could not be identified due to insufficient
amount, and they may result from the cis-trans
isomerization of the vinyl palladium complexes (for
the possible structures of the isomers and the
Scheme 3. Mechanistic studies.
On the basis of these experimental results and
previous reports,[9a, 10, 13] a mechanism is proposed as
shown in Scheme 4. The catalytic cycle starts with
the oxidative addition of iodobenzenes to Pd(0). The
resulting arylPd(II) species A undergo migratory
insertion to form vinylPd(II) species B. The
subsequent intramolecular C–H activation generates
C,C-palladacycle C. C may undergo oxidative
addition of CH2Br2 to form Pd(IV) complex D. The
reductive elimination and intramolecular oxidative
addition yield six-membered palladacycle G.
Alternatively, G could also be formed via a carbene
complex F. The reductive elimination of G generates
intermediate 2, 3-diphenyl-1H-indene H and releases
Pd(II), which is reduced to Pd(0) to close the catalytic
cycle. Under the basic conditions, H can react with
CH2Br2 to form alkylated products J. The subsequent
elimination reaction yields final benzofulvene
products 6.
formation
processes
see
the
supporting
information).[9a]
Table 2. Iodobenzene scope of the benzofulvene-forming
reaction.[a]
[a]Yields of the isolated products.
Next, we examined the performance of substituted
diphenylacetylenes.
A
variety of symmetrical
diphenylacetylenes bearing two methyl, tert-butyl,
methoxy, or fluoro groups at the para positions
reacted with iodobenzene and CH2Br2 to afford
various benzofulvene derivatives in moderate or good
yields (Table 3, 6ab-6ae). The meta-substituted
diphenylacetylenes also underwent the cascade
reaction (6af-6ah), and even the substrate bearing
two ortho-fluoro groups was compatible (6ai). The
unsymmetrical alkynes was also examined. 2-Propyl
phenylacetylenes was subjected to the standard
conditions. The indene 6aj was obtained instead of
the expected benzofulvene. The reason might be that
Scheme 4. Proposed mechanism.
3
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10.1002/adsc.201801141
Advanced Synthesis & Catalysis
The work was supported by the National Natural Science
Foundation of China (No.216721626 and No.2137217) and
Shanghai Science and Technology Commission (14DZ2261100).
We thank Prof. Keary M. Engle (The Scripps Research Insitute)
for helpful discussions.
Table 3. Diarylacetylene scope of the benzofulvene-
forming reaction.[a]
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the benzylic C-H bond is less acidic and cannot be
deprotonated under the conditions. It should be noted
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was the sole product.[14]
In conclusion, we have developed a new approach
for the synthesis of benzofulvenes through palladium-
catalyzed sequential three-component reactions. The
reactions involve putative C,C-palladacycles as the
key intermediates. Unlike the common methods for
accessing such species from structurally complex
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Experimental Section
A 35 mL Schlenk-type tube (with a Teflon high pressure
valve and side arm) equipped with a magnetic stir bar was
charged with diphenylacetylenes 2 (0.24 mmol), Pd(OAc)2
(4.5 mg, 0.02 mmol), PhCO2K (128.2 mg, 0.8 mmol) and
KOAc (687.0 mg, 7.0 mmol). Then the mixture was first
stirred at room temperature for 1 minute followed by the
addition of DMA (1 mL), i-PrOH (0.5 mL), aryl iodides 1
(0.2 mmol), CH2Br2 5 (98.2 μL, 1.4 mmol) and PEG (Mn
400, 2 mL). The reaction was frozen with liquid nitrogen,
and the tube was then evacuated and backfilled with
nitrogen (10 times).The reaction was stirred at 75 °C for 12
h. Upon completion, the reaction mixture was cooled to
room temperature, diluted with EtOAc (15 mL) and
washed with brine (2X15 mL). The organic phase was
dried over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by preparative silica gel TLC to afford
the corresponding products.
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Advanced Synthesis & Catalysis
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5
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Advanced Synthesis & Catalysis
COMMUNICATION
The Synthesis of Benzofulvenes through
Palladium-Catalyzed Sequential Three-Component
Reactions
Adv. Synth. Catal. Year, Volume, Page – Page
Bo Zhou, Zhuo Wu, Weixin Qi, Xueliang Sun,
Yanghui Zhang *
6
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