Unexpected and powerful effect of chlorobenzene in direct palladium-catalyzed cascade Sonogashira-hydroarylation reaction

Article abstract of DOI:10.1039/c4ra13979h

A ubiquitous accelerating effect of chlorobenzene (PhCl) was observed unexpectedly in the Pd-catalyzed cascade Sonogashira-hydroarylation reaction. This new type of carbon-carbon bond forming cross-coupling reaction was efficiently catalysed by Pd₂(dba)₃ in the presence of a catalytic amount of PhCl, which provides a facile and direct approach to the synthesis of trisubstituted olefins.

Full text of DOI:10.1039/c4ra13979h

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Unexpected and Powerful Effect of Chlorobenzene in
Direct Palladium-Catalyzed Cascade Sonogashira-
hydroarylation Reaction
Cite this: DOI: 10.1039/x0xx00000x
Bo Yu, a Wei Xu, a Huaming Sun, a Binxun Yu, a Guofang Zhang, a LiꢀWen Xu, a,b
Weiqiang Zhang*a, Ziwei Gao*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
crossꢀcoupling reaction are still highly desirable for the practical
organic synthesis.
Abstract: Ubiquitous accelerating effect of chlorobenzene
(PhCl) was observed unexpectedly in Pd-catalyzed cascade
Sonogashira-hydroarylation reaction. This new type of
carbon-carbon bond forming cross-coupling reaction was
efficiently catalysed by the Pd2(dba)3 in the presence of
catalytic amount of PhCl, which provide a facile and direct
approach to the synthesis of trisubstituted olefins.
Palladiumꢀcatalyzed crossꢀcoupling reaction is one of the most
important transformations in organic synthesis.1 With the
development of Pd catalysis, various carbonꢀcarbon bond forming
reactions have been developed successfully except classic Suzuki
reaction, Sonogashira reaction, and others. For example, the
palladiumꢀcatalyzed hydroarylation of diarylacetylenes with aryl
halides,2 Heck diarylation of arylvinylenes,3 and double Suzukiꢀ
Miyaura couplings of 1,1′ꢀdihaloꢀ2ꢀarylꢀethenes4 have been applied
Scheme 1. The preliminary results on the Pd(OAc)2ꢀcatalyzed
cascade Sonogashiraꢀhydroarylation reactions of PhCCH and PhI.
Reaction conditions of experiments 1a/1b/1c: phenylacetylene, 0.5
mmol; iodobenzene, 1.5 mmol; K2CO3, 2 equiv; additive, 10 mol%;
5 mL ethanol at 70 °C for 10 h.
to synthesize trisubstituted olefins. Recently,
a
sequential
Sonogashira coupling and hydroarylation reaction provided a
concise twoꢀstep synthesis of triarylethylenes from simple starting
materials, aryl iodides and terminal alkynes.5 Notably, triarylethene
subunits are valuable building blocks in organic synthesis for various
functional compounds.6 As chemotherapeutic agents, Tamoxifen and
Clomiphene have been applied for the treatment of breast cancer and
infertility, respectively.7 Because of their unique extended πꢀ
conjugated system, triarylethene compounds are also of great interest
as molecular photomaterials such as 4,4′ꢀbis(2,2ꢀdiphenylvinyl)ꢀ1,1′ꢀ
biphenyl (DPVBi), 4′,4′′ꢀ(2ꢀPhenylꢀetheneꢀ1,1ꢀdiyl) dibiphenylꢀ4ꢀ
amine (TriPEDA), aggregation induced emission (AIE) materials,
and conjugated dendrimers.8
Inspired by previous works in the catalytic synthesis of
trisubstituted olefins, herein, we report an unexpected finding that
the reactivity of the Pd catalyst was significantly accelerated by the
chlorobenzene and tuned by varying the Pd loading. The phosphineꢀ
free Pd catalyst system featured a catalytic amount of chlorobenzene
as the additive for the direct preparation of triarylethenes from aryl
iodides and aryl acetylenes. It should be noted that, while phosphine
ligands play crucial roles in classical Pdꢀcatalyzed organic
transformations, phosphineꢀfree and direct palladiumꢀcatalyzed
In the preliminary experiment, chlorobenzene dramatically
changed the products distribution of oneꢀpot reactions of
iodobenzene and threeꢀfold of phenylacetylene. To determine
whether PhCl was responsible for selective formation of
triphenylethylene 4, three parallel experiments were conducted in
ethanol with K2CO3 as the base (Scheme 1). In experiment 1a, the
Pd(OAc)2/PPh3 system catalyzed the crossꢀcoupling of iodobenzene
with phenylacetylene to afford the crossꢀcoupling product 3 in 79%
yield and the sequential hydroarylation product 4 in only 8% yield.
Interestingly, the reaction course dramatically changed when the
phosphine ligand was not used. Experiment 1b afforded 3 in 10%
yield, while the yield of 4 increased to 28%. The results indicate that
PPh3 accelerated the Pdꢀcatalyzed Sonogashira coupling, but
inhibited further Pdꢀcatalyzed hydroarylation.9 To our delight, in the
presence of 10 mol% PhCl, experiment 1c afforded 4 in 45%
isolated yield. These experiments clearly demonstrated that PhCl can
accelerate not only Sonogashira coupling but also hydroarylation
reactions.
To optimize the reaction conditions, iodobenzene and
phenylacetylene were selected as the substrates. The tandem
reactions were conducted in the presence of PhX (X = F, Cl, and Br)
under suitable reaction conditions (Table 1). After screening several
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DOI: 10.1039/C4RA13979H
catalyst systems, the PhCl/Pd2(dba)3 system was found to exhibit the lower reactivity. The ratios of triarylethene regioisomers were
best catalytic activity. In the presence of Pd2(dba)3 (5 mol%) and determined by comparing the integration of the corresponding
methyl protons.11 In these reactions, gem- and trans- isomers were
PhCl (10 mol%), the tandem reaction of 1 with 2 occurred at 70 °C,
formed equally, indicating that the steric bulkiness of these
substituents are too close for any significant regioselectivity. To
further illustrate the regioselectivity of this method, the reaction of
1ꢀhexyne with iodobenzene was investigated. To our delight, the two
regioisomers could be separated by column chromatography (Fig.
S9). Trans-isomer 4m was isolated in 38% yield, while only a trace
amount of gem-isomer 4m (12%) was isolated, indicating that the
hydroarylation of the internal alkyne intermediate preferentially
occurred with a less sterically congested trans-configuration.
and the product was obtained in 80% yield (Table 1, entry 4). The
reaction has the same outcome as Nꢀheterocyclic carbene (NHC)/Pdꢀ
catalyzed Sonogashira/hydroarylation sequential reactions. However,
the reaction is mild and clean in the absence of HOOCCF3.5 The
course of the reaction was monitored by gas chromatographyꢀmass
spectrometry (Figure 1 and see Supporting Information), indicating
the importance of PhCl in this reaction. PhF and PhBr also
accelerated the formation of 4 but with inferior activity (65% and
62% yields respectively, see Table 1, entries 5 and 6). In the blank
experiment (without PhCl), 4 was isolated in only 58% yield along
with 2% unconverted diphenylacetylene 3 (Table 1, entry 7). To our
surprise, the reactivity of PhCl/Pd system is dependent on the
catalyst loading, in which the use of 0.01 mol% Pd2(dba)3 led to
promote efficiently the Sonogashira coupling of iodobenzene with
100
80
60
40
20
0
phenylacetylene
selectively,
and
no
hydroarylation
of
diphenylacetylene was observed (Table 1, entry 8). Higher catalyst
loading significantly accelerated the hydroarylation process. When
>1 mol% catalyst was used, the hydroarylation process dominated,
and 60% product was obtained using 3 mol% Pd (Table 1, entries 10
and 11). However, a further increase in the catalyst decreased the
yield of 4 (Table 1, entries 12 and 13). Notably, when the amount of
PhCl was decreased to 1 mol% or 5 mol%, the yield of the desired
product 4 was not good (50%ꢀ55%, Table 1, entries 14 and 15). It
further suggested that 10 mol% of PhCl was necessary to give
significant effect on the catalytic activity of Pd2(dba)3.
1
2
3
4
5
6
7
8
9
10 11 12
chlorobenzene
phenylacetylene
diphenylacetylene
triphenylethylene
Figure 1. The kinetic effect of PhCl on Pdꢀcatalyzed cascade
Sonogashiraꢀhydroarylation reaction of PhCCH and PhI
Table 2. Substrate scope for the synthesis of trisubstituted olefinsa, b
Table 1. PhCl accelerated Pdꢀcatalyzed cascade Sonogashiraꢀ
hydroarylation reaction of PhCCH and PhI a
Entry
Catalyst (mol%)
Additive
3 [% yield] b
4 [% yield] b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
PdCl2 (5%)
Pd(PPh3)2Cl2 (5%)
Pd(PPh3)4(5%)
Pd2(dba)3 (5%)
Pd2(dba)3 (5%)
Pd2(dba)3 (5%)
Pd2(dba)3 (5%)
Pd2(dba)3 (0.01%)
Pd2(dba)3 (0.1%)
Pd2(dba)3 (1%)
Pd2(dba)3 (3%)
Pd2(dba)3 (8%)
Pd2(dba)3 (10%)
Pd2(dba)3 (5%)
Pd2(dba)3 (5%)
PhCl
PhCl
PhCl
PhCl
PhF
5
1
95
0
3
7
52
56
0
80
65
62
58
0
13
54
60
57
43
55%
50%
PhBr
ꢀ
2
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl d
PhCl e
78 c
75
22
0
5
8
trace
trace
a
Reaction conditions: phenylacetylene, 0.5 mmol; iodobenzene, 1.5 mmol;
K2CO3, 2 equiv; additive, 10 mol%; 5 mL ethanol at 70 °C for 2 h. b Isolated
yield. c 12 h. d PhCl 1 mol%. e PhCl 5 mol%.
The substrate scope and limitations of these new methods were
then investigated with various aryl iodides and alkynes. For
symmetrical trisubstituted olefins, product 4b with paraꢀmethoxy
substituents was obtained in 72% yield, whereas the products with
methyl groups at the para- (4c) and meta- (4d) positions were
obtained in moderate yields. ParaꢀBr (4e) substituent was well
tolerated, offering the potential for further orthogonal
functionalization.10 Unsymmetrical triarylethenes were prepared by
varying aryliodides or arylacetylenes. Alkynes with strong electronꢀ
donating substituents afforded acceptable yields. The methyl groups
at para- (4h and 4l) and meta- (4i, 4j, and 4k) positions resulted in
a Reaction conditions: alkynes 0.5 mmol; aryl iodide 1.5 mmol; Pd2(dba)3 (Pd
5 mol%); K2CO3 2 equiv; chlorobenzene 10 mol%; 5 mL EtOH at 70 oC, 12 h.
Isolated yield. 2ꢀbis(4ꢀbromophenyl)ethyne 0.08 mmol. Determined by
1H NMR.
b
c
d
2 | J. Name., 2012, 00, 1-3
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The combined PhCl/Pd catalyst systems were successfully applied
for the construction of extended πꢀconjugated systems (Scheme 2).
Starting from 1,3ꢀdiiodobenzene (5), mono- (8) and di- (7) acetylide
benzenes were obtained in 22% and 58% yields using 0.1 mol% Pd
and 10 mol% PhCl. The hydroarylation of 7 catalysed by 5 mol% Pd
and 10 mol% PhCl afforded two triaryl conjugated structures, trans-
(9) and gem- (10) isomers, in 62% and <5% yields, respectively. 3ꢀ
Alkyne biphenyl (11) was prepared in 95% yield by Suzuki–Miyaura
crossꢀcoupling using 1 mol% Pd and 10 mol% PhCl. Next, the
hydroarylation reaction of 11 afforded trans-aryl ethene (12) and
gem-isomer (13) in 57% and 13% yields, respectively. The low yield
of 13 can be attributed to the steric factor during the insertion of the
substituted internal alkyne intermediate into the Pd–Ar bond.
synthesis of symmetrical and unsymmetrical trisubstituted
olefins in moderateꢀtoꢀgood yields. In addition, two extensive
πꢀconjugated systems were constructed from 1,3ꢀdiiodobenzene
via the Pdꢀcatalyzed Sonogashira coupling, sequential Suzukiꢀ
Miyaura coupling, and hydroarylation reactions with the aid of
catalytic amount of PhCl. Although the true mechanistic
procedure of PhClꢀaccelerated Pdꢀcatalyzed Sonogashiraꢀ
hydroarylation was not clear at present, this work provided a
facile and practical approach for the synthesis of
multisubstituted and conjugated olefins.
Notes and references
a
Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of
Education, School of Chemistry & Chemical Engineering, Shaanxi
Normal University, 199 South Chang’an Road, Xi'an, China. Eꢀmail:
zwgao@snnu.edu.cn zwq@snnu.edu.cn.
b
Key Laboratory of Organosilicon Chemistry and Material Technology
of Ministry of Education, Hangzhou Normal University, Hangzhou
310012, P. R. China. Eꢀmail: liwenxu@hznu.edu.cn
General Procedure for Pd/PhCl Catalyzed Direct Preparation of
Trisubstituted Olefins. Under the protection of N2, 5 mL EtOH was
cannula transferred into Schlenk tubes containing Pd2(dba)3 (0.0114 g,
0.0125 mmol) and K2CO3 (0.138 g, 1 mmol). Alkyne (0.5 mmol), aryl
iodine (1.5 mmol), chlorobenzene (5uL, 0.05mmol) were added by
syringe. The reaction mixture was stirred at 70 °C for 12 h. After the
reaction cooled down to room temperature, the solvent was removed
under vacuum and the crude products were filtered off and purified by
column chromatography on silica gel using dichloromethane/petroleum
ether as eluent. All products were identified by comparing their spectral
data with those of authentic samples.
Scheme 2. The construction of extensive πꢀconjugated systems on
the basis of PhClꢀaccelerated Pdꢀcatalyzed Sonogashiraꢀ
hydroarylation reaction
To identify the origin of the vinyl proton in the product, a
deuterium labelling experiment was conducted in CD3OH. In the 1H
NMR spectrum of the isolated triphenylethylene (Fig. S10), the vinyl
proton was exchanged by the deuterium of CD3OH, indicating that
the proton may originate from the methyl group of the alcoholic
solvent. Therefore, the βꢀH elimination of coordinated ethoxide in
was proposed to rationalize the formation of Pd species, finally
This work was supported by the 111 Project (B14041), Innovative
Research Team in University of China (IRT1070), National Natural
Science Foundation of China (21171112, 21271124, 21371112),
Fundamental Doctoral Fund of Ministry of Education of China
(20120202120005), Shaanxi Innovative Team of Key Science and
Technology (2013KCTꢀ17), Natural Science Basic Research Plan in
Shaanxi Province of China (2012JM2006).
affording triphenylethylene product
4 through the reductive
elimination. On the basis of experimental results as well as previous
reports, the effect of PhCl on the palladiumꢀcatalyzed cascade
Sonogashiraꢀhydroarylation was quite interesting. Although the true
role of PhCl was not clear, we suggested that the PhCl could
possibly act as an electronꢀdeficient π ligand to promote the
reductive elimination in this cascade Sonogashiraꢀhydroarylation
reaction. In other words, the role of PhCl in this palladiumꢀcatalyzed
cascade Sonogashiraꢀhydroarylation reaction might be similarly to
that of dibenzylideneacetone (bda). Further studies on the PhClꢀ
assisted palladiumꢀcatalyzed cascade Sonogashiraꢀhydroarylation
reaction will be carried out and reported in the near future.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/c000000x/
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In summary, we reported an unexpected PhClꢀaccelerated
Pdꢀcatalyzed Sonogashiraꢀhydroarylation reaction for direct
synthesis of trisubstituted olefins. A catalytic amount of PhCl
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