Fluorous oxime palladacycle: A precatalyst for carbon-carbon coupling reactions in aqueous and organic medium

Article abstract of DOI:10.1021/jo202482h

To facilitate precatalyst recovery and reuse, we have developed a fluorous, oxime-based palladacycle 1 and demonstrated that it is a very efficient and versatile precatalyst for a wide range of carbon-carbon bond formation reactions (Suzuki-Miyaura, Sonogashira, Stille, Heck, Glaser-type, and Kumada) in either aqueous or organic medium under microwave irradiation. Palladacycle 1 could be recovered through F-SPE in various coupling reactions with recovery ranging from 84 to 95% for the first cycle. Inductively coupled plasma optical emission spectrometry (ICP-OES) analyses of the Pd content in the crude product from each class of transformation indicated extremely low levels of leaching and the palladacycle could be reused four to five times without significant loss of activity.

Full text of DOI:10.1021/jo202482h

Article
pubs.acs.org/joc
Fluorous Oxime Palladacycle: A Precatalyst for Carbon−Carbon
Coupling Reactions in Aqueous and Organic Medium
Woen Susanto,† Chi-Yuan Chu,‡ Wei Jie Ang,† Tzyy-Chao Chou,‡ Lee-Chiang Lo,*,‡ and Yulin Lam*,†
†Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
‡Department of Chemistry, National Taiwan University, No. 1, Sec. 4 Roosevelt Road, Taipei 106, Taiwan
S
* Supporting Information
ABSTRACT: To facilitate precatalyst recovery and reuse, we have
developed a fluorous, oxime-based palladacycle 1 and demonstrated
that it is a very efficient and versatile precatalyst for a wide range of
carbon−carbon bond formation reactions (Suzuki−Miyaura, Sonoga-
shira, Stille, Heck, Glaser-type, and Kumada) in either aqueous or
organic medium under microwave irradiation. Palladacycle 1 could be
recovered through F-SPE in various coupling reactions with recovery
ranging from 84 to 95% for the first cycle. Inductively coupled plasma
optical emission spectrometry (ICP-OES) analyses of the Pd content
in the crude product from each class of transformation indicated
extremely low levels of leaching and the palladacycle could be reused
four to five times without significant loss of activity.
biphasic catalysis, the catalyst contains >60% fluorine by mo-
lecular weight so as to provide good liquid/liquid separation
between the organic and perfluorocarbon solvent. However the
prohibitive cost of the perfluorocarbon solvents makes such
catalysis impractical for industrial purposes. An alternative
method involves “light fluorous” catalysts where the fluorine
content is <50% by molecular weight.7g These catalysts can be
used in conventional organic solvents, recovered and recycled
by fluorous solid-phase extraction (F-SPE) with fluorous silica.8
Recently, we reported the synthesis of a light fluorous,
oxime-based palladacycle 1 (Figure 1) and demonstrated that it
INTRODUCTION
■
Palladium-catalyzed carbon−carbon bond-forming reactions are
one of the most important tools in organic synthesis, having
found applications in the preparation of a wide spectrum of
organic chemicals, materials, and natural products.1 Over the
decades, various homogeneous catalytic systems have been
developed for this transformation.2 This includes the start of
the field on palladacycles as catalysts for cross-coupling re-
actions in 1995 when Herrmann and Beller reported that the
application of cyclopalladated tri-o-tolylphosphane for the Pd-
catalyzed Heck3 and Suzuki4 coupling reactions provided
unparalleled turnover numbers (TONs). Since then, a wide
variety of nitrogen, oxygen, phosphorus, and sulfur pallada-
cycles with high TONs have been developed for different C−C
and C-heteroatom-coupling reactions.5
Although homogeneous catalysts generally have a higher
activity and selectivity as compared to heterogeneous catalysts,
difficulties in separation and recovery of the catalyst and con-
tamination of the products with traces of the heavy metals are
common problems encountered which restrict their applica-
tions in certain industries.6 To circumvent this problem, various
new strategies for transition-metal catalysis have been
developed.7 One of these strategies involves the development
of fluorous-tagged catalyst.7e−g Attaching fluorous groups, such
as perfluorooctyl (−C8F17) groups to organic molecules eases
the separation of the catalyst from the reaction products. In
addition, fluorous tags are inert to chemical reactions and have
little effect on the reactivity of the parent molecule as the
electron-withdrawing fluorines are insulated from the reactive
site of the parent molecule via methylene segments alone or
methyl segments with heteroatoms or phenyl rings. Today,
there are basically two types of fluorous catalysts. In fluorous
Figure 1. Oxime-derived fluorous-tagged palladacycle 1.
is a very active precatalyst for promoting the Suzuki−Miyaura,
Sonogashira and Stille coupling reactions in aqueous medium.9
Palladacycle 1 could be used under microwave irradiation at
high temperatures which shortened the reaction time sig-
nificantly. It could also be recovered and recycled over five runs
in a Suzuki−Miyaura reaction with very low Pd leaching
(0.023−0.033 ppm over five cycles). This amount of Pd leach-
ing is very much lower than that observed from the poly-
mer-supported oxime-based palladacycle analogue10 and three
Received: December 14, 2011
Published: February 16, 2012
© 2012 American Chemical Society
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earlier reported fluorous Pd-catalysts which were applied to
cross-coupling reactions in aqueous medium.11 With these
promising results in hand, we proceeded to examine the general
usefulness of palladacycle 1. Herein, we have expanded the
application of palladacycle 1 to other substrates for the Suzuki-
Miyaura, Sonogashira, and Stille coupling reactions and have
also assessed the precatalytic activity of palladacycle 1 in the
Heck and Kumada reactions.
Table 1. Suzuki−Miyaura Reaction of Arylboronic Acids
with Various Aryl and Benzyl Halides
RESULTS AND DISCUSSION
■
Suzuki−Miyaura Reaction. Palladium-catalyzed cross
coupling reaction of aryl halides and arylboronic acids is a
very versatile and widely used methodology for the con-
struction of biaryls which are important building blocks in
natural products, pharmacophores, and functional materials.12
In our preliminary studies,9 we have demonstrated the Suzuki−
Miyaura reaction between phenylboronic acid with various aryl
and benzyl halides in aqueous medium. To investigate the
general usefulness of palladacycle 1 for the Suzuki−Miyaura re-
action, we extended our studies to different combinations of
halides and boronic acids (Tables 1 and 2). Under the opti-
mized reaction conditions,9 good to excellent yields of the
desired products were achieved in all cases. It was also gratify-
ing to note that our reaction protocol could be applied suc-
cessfully to aryl chlorides (Table 1, entries 4 and 5) as only few
recyclable catalytic systems are known to promote the Suzuki−
Miyaura reaction of chloroarenes in water.13
Since styrene derivatives are often used as key building
blocks in the polymer industry and also for fine chemical syn-
thesis,15 we proceeded to examine the synthesis of styrene
compounds using palladacycle 1 and trivinylboroxine-pyridine
complex 4 as the representative vinylating agent. Treatment of
4 with various aryl halides under the optimized reaction con-
dition9 provided the styrene derivatives in good yields (Table 2,
entries 1−4), indicating that palladacycle 1 is an efficient pre-
catalyst for the installation of a terminal vinyl group.
2
2
Besides Csp −Csp bond formation, we have also applied
2
3
palladacycle 1 to the formation of Csp −Csp bonds through the
cross-coupling between aromatic or heteroaryl halides with
trimethylboroxine (TMB) or butylboronic acid (Table 2,
entries 5−10). In our initial studies, we had attempted to
methylate the aromatic ring by cross-coupling aryl bromides
with methylboronic acid and palladacycle 1 under the opti-
mized reaction conditions. However, with methylboronic acid
(1.5 equiv), the reaction proceeded sluggishly and the yield of
the desired product obtained was much lower as compared to
the yield obtained when the same equivalence of TMB was
used. Increasing the amount of methylboronic acid used re-
sulted in a higher yield of the desired product (Table 2, entry 5).
Since TMB gave a better yield of the desired product and is also
a cheaper reagent than methylboronic acid, it was used as the
methylating agent for our Suzuki-Miyaura reaction.
Sonogashira Reaction. The Sonogashira reaction is a
common reaction used for the formation of biarylacetylenes. In
recent years, active research in green chemistry has resulted in
numerous reports on the use of water as a cosolvent and/or the
use of catalysts containing water-soluble ligands for this re-
action.17 However Sonogashira reactions in neat water and in
the absence of additives18 are rare and often low-yielding
because of the poor solubility or instability of the catalysts and
coupling reagents in aqueous medium.19 In our preliminary
studies, we have demonstrated that palladacycle 1 is a versatile
precatalyst for the copper-free Songashira reaction between
a
b
c
Isolated yield. Refers to 1-naphthylboronic acid. Use of TBAB is
crucial for good conversion to 3b. TBAB is known to be a phase-
transfer catalyst and it also stabilizes the Pd nanoparticles so as to
avoid aggregation.14
phenylacetylene and various aryl bromides and iodides in
water.9 Using the optimized reaction conditions which we have
established in the previous study, we now extend the applica-
tion to other terminal alkynes and aryl halides (Table 3). The
results obtained show that good reactivity was preserved in
both activated and nonactivated aryl halides, indicating that
palladacycle 1 is an efficient precatalyst for the Sonogashira
coupling reaction in aqueous medium.
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undegassed water was used as the solvent.9 This prompted us to
explore the use of palladacycle 1 as a precatalyst for such Glaser-
type homocoupling reactions. In our initial experimentation, we
used undegassed water and the optimized reaction condition for
the Sonogashira reaction. However, this provided the homo-
coupled product in moderate yield (Table 5, entry 1). Addition of
CuI as a cocatalyst not only increased the yield but also slightly
reduced the reaction time. This is because CuI could aid in the
formation of an activated species through its reaction with the
terminal alkyne.22 To demonstrate the generality of this reaction
condition, we carried out the homocoupling reaction on other
terminal alkynes which essentially gave quantitative yields for all
cases (Table 5, entries 2−4).
Table 2. Suzuki−Miyaura Reaction of Trivinylboroxine−
Pyridine Complex 4, Trimethylboroxine, or Butylboronic
Acid with Various Aryl Halides
Stille Coupling Reaction. The Stille coupling reaction is a
versatile C−C bond-forming reaction between stannanes and
halides because of its tolerance toward most functional groups
and also because the organotin reagents are easy to make and
are very stable to oxygen and moisture. In our previous studies,9
we explored the use of palladacycle 1 as a precatalyst for the
Stille reaction. As a model reaction, tributyl(4-methoxyphenyl)-
stannane was coupled to various aryl halides in the presence of
palladacycle 1 (0.005 mol % Pd) and tetra-n-butylammonium
bromide (TBAB) as an additive in water and under microwave
irradiation at 100 °C. The reactions occurred very rapidly and
gave the products in good to excellent yields. To survey the
scope of this reaction, we herein conducted the reaction using
other organostannanes and aryl halides (Table 6). To our
delight, the reactions occurred with ease leading to only the
cross-coupled product for all cases, indicating that palladacycle
1 was generally suitable for CuI-free Stille couplings in water
(CuI was demonstrated to accelerate the coupling reaction25).
To address the recyclability of palladacycle 1 in the Stille
reaction, the leaching of the active Pd species in solution was
examined for the coupling reaction of tributyl(phenyl)stannane
with iodobenzene under the optimized reaction conditions.
The results obtained were gratifying as the yields over five runs
were quantitative and the time required for the reaction to go
to completion remained short (Table 7). In addition, the Pd
leaching was also very low.
Heck Reaction. Previous studies on homogeneous catalysis
have shown that palladacycles, despite their high catalytic
activities,29 are not stable under the Heck reaction conditions
and undergo decomposition via olefin insertion into the C−Pd
bond followed by Pd(II) to Pd(0) reduction.30 To facilitate
recovery and reuse, supported palladacycles, such as the polymer-
supported cyclopalladated Milstein-type imine complex (the
immobilized palladacycle was reported to have completely lost
its activity in the third run)31 and the palladated Kaiser oxime
resin,32 were developed. Since palladacycle 1 has been shown to be
an efficient precatalyst for the Suzuki−Miyaura, Sonogashira,
Glaser-type, and Stille coupling reactions, from a practical point of
view, it was important to study the scope of this palladacycle as a
precatalyst in the Heck reaction.
In our initial studies, the Heck reaction was performed using
N-vinylphthalimide and 4-methoxybromobenzene with Cy2NMe
as base, TBAB as additive, palladacycle 1 (0.5 mol % Pd) as
precatalyst, DMF as solvent, and under microwave irradiation at
160 °C. This gave the E-configuration product 13a in 79% yield
(Table 8, entry 1). Increasing the reaction temperature to
170 and 180 °C resulted in a shortening of the reaction time
(Table 8, entries 2−3). Since the product yield was higher at
170 °C, this reaction temperature was used in our subsequent
studies.
a
b
Isolated yield. Using 4.5 equiv of methylboronic acid instead of 1.5
equiv of TMB. Using polymer-supported oxime-based palladacycle:16
1 mol % of Pd, K2CO3, H2O, TBAB, 100 °C.
c
We have also investigated the possibility of recovering
and recycling palladacycle 1 from the Sonogashira reaction.
4-Nitrobromobenzene and phenylacetylene were used for the
model reaction under the optimized reaction conditions. In this
regard, we found that over 5 runs, the time taken for the re-
action to complete was 5−12 min, and compound 8k was
obtained in 89−93% yields (Table 4). In addition, ICP-OES
analysis of the crude product indicated that the Pd content was
very low (0.063−0.073 ppm over 5 cycles). To our knowledge,
this leaching concentration is significantly lower than the
amounts determined for the recyclable Pd catalysts reported
earlier for the Sonogashira reaction.11,21
Homocoupling Reaction of Terminal Alkynes. During
the optimization of the Sonogashira reaction with phenylacetylene
and various aryl halides, we found that a significant amount of
the homocoupled product was formed as a side-product when
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Table 3. Sonogashira Reaction Using Palladacycle 1
a
b
Isolated yield. Using pincer complexes of palladium: Pd cat. (100 ppm), K3PO4, ethylene glycol, 140 °C.20
Next, we investigated the effects of bases on the reaction. In
addition to Cy2NMe, TEA and Cs2CO3 were examined (Table 8,
entries 2, 4, and 5), and Cy2NMe was found to be the most
effective base for the reaction. The zero conversion obtained
when Cs2CO3 was used as a base could be attributed to the
insolubility of the base in DMF. Solvent was also varied and the
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Table 4. Recycling of Palladacycle 1 in the Sonogashira
Reaction
Table 6. Stille Coupling Reaction Using Palladacycle 1
b
Pd leaching
(ppm)
a
c
cycle
time (min)
yield (%)
recovered 1 (wt %)
1
2
3
4
5
5
7
93
93
91
89
89
0.067
0.063
0.065
0.069
0.073
93
90
92
90
89
8
12
12
a
b
Isolated yield. Determined by ICP-OES of the crude product.
c
Recovered via F-SPE.
Table 5. Glaser-Type Oxidative Homocoupling Using
Palladacycle 1
a
b
c
Isolated yield. In the absence of cocatalyst CuI. Using mesoporous
Pd-MCM-48: Pd catalyst (0.6 mol %), ethanol, refluxed.23 Using
PdCl2(PPh3)2 in ionic liquid: Pd catalyst (2 mol %), piperidine,
25 °C.24
d
experimental data obtained (Table 8, entries 2 and 6−9) in-
dicated that the reaction proceeded most efficiently in DMF.
Using the optimized reaction conditions, we extended the
Heck reaction to both activated and deactivated aryl halides,
which gave good to excellent yields of the desired product
(Table 9). Comparison of palladacycle 1 with its polymer-
supported and solution-phase analogues also showed that the
Heck reaction with palladacycle 1 gave a higher yield of the
product (Table 9, entries 3−6).
Recycling experiments for the Heck reaction were performed
using iodobenzene, N-vinylphthalimide under the optimized
reaction conditions. From the results obtained (Table 10), the
reaction gave 13e in good yields: 93% in 3 min in the first run
to 90% in 30 min in the fourth run. These values are higher
than those obtained via polymer-supported palladacycle17 and
with palladacycle 1, no drastic decrease in the product yield was
observed. Pd leaching was observed in the crude product but
the amount of Pd leached was lower than that from the
polymer-supported palladacycle17 (Table 10, entries 1−3). The
increase in reaction time and lower amount of palladacycle 1
recovered could be due to the formation of the palladium black
at elevated temperature.
a
b
c
Isolated yield. Pd cat. (5 mol %), dioxane, reflux.26 Pd cat.,
CsF, dioxane, rt→100 °C.27 Pd cat. (0.5 mol %), DMF/H2O (9:1),
80 °C.28
d
Encouraged by the results obtained from the Heck reaction
between N-vinylphthalimide and the aryl halides, we proceeded
to explore other coupling partners for this reaction. Pre-
vious works by Cacchi and co-workers34 have shown that under
appropriate reaction conditions and with Pd(OAc)2 as cat-
alyst, cinnamaldehydes 15 and ethyl 3-arylpropionoates 16
could be prepared from acrolein diethyl acetal 14 using the
Heck reaction (Scheme 1). In our study, we initially carried out
the reaction with 14 and 4-chloroiodobenzene employing the
Cacchi condition (K2CO3 as base, tetra-n-butylammonium acetate
(TBAA) and KCl as additives at 120 °C) with palladacycle 1
(0.5 mol % of Pd) as precatalyst. By varying the solvent, we found
that the best yield for cinnamaldehyde 15a was obtained when
DMAc was used as the solvent (Table 11, entries 2, 5, and 7).
Performing the reaction under microwave irradiation although
gave 15a in a similar yield, but the reaction time was very much
shorter and selectivity was high (15a:16a = 97:3). Application of
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Table 7. Recycling of Palladacycle 1 in the Stille Reaction
Table 9. Heck Reaction of N-Vinylphthalimide with Various
Aryl Halides
a
b
c
cycle time (min) yield (%) Pd leaching (ppm) recovered 1 (wt %)
1
2
3
4
5
0.75
0.75
0.75
0.75
0.8
99
99
98
99
97
0.52
0.58
0.56
0.58
0.57
95
96
93
93
91
a
b
Isolated yield. Determined using the crude product, mg Pd/1 L 1%
c
HNO3 aqueous solution. Recovered via F-SPE.
Table 8. Optimization of the Heck Reaction
a
entry temp (°C)
base
solvent
time (min) yield (%)
1
2
3
4
5
6
7
8
9
160
170
180
170
170
120
140
170
170
Cy2NMe
Cy2NMe
Cy2NMe
TEA
DMF
DMF
DMF
DMF
DMF
CH2Cl2
THF
30
20
79
87
72
65
0
b
10
20
Cs2CO3
Cy2NMe
Cy2NMe
Cy2NMe
Cy2NMe
20
150
25
10
72
72
0
CH3CN
H2O
20
20
a
b
Isolated yield. E/Z regioisomeric ratio is >98/2. Using palladacycle
1 (2.5 mol % Pd), the isolated yield was 72%.
a
b
Isolated yield. E/Z regioisomeric ratio is >98/2. Polymer-supported
reaction condition: Cy2NMe, TBAB, DMF, 120 °C.33 Solution-phase
reaction condition: Cy2NMe, TBAB, DMF, M.W., 140 °C.33
c
these reaction conditions to other aryl halides also proceeded well
providing cinnamaldehyde 15 in good yields and high selec-
tivity (Table 12, entries 1 and 2). For the synthesis of ethyl
3-arylpropionoates 16, total selectivity was observed by changing
the base from K2CO3 to Cy2NMe and using DMAc/H2O as sol-
vent. This could be attributed to the similarity in shape of
Cy2NMe and triphenylphosphine which leads to the ease of its
coordination with [Pd(HX)].35a This results in the removal of
HX to form the ammonium salt, which hydrolyzes the ketene
acetal into an ester.35b In addition, ethyl 3-arylpropionoates 16
were obtained in good yields (Table 12, entries 3−6).
d
Solution-phase reaction condition: Cy2NMe, TBAB, DMF, 140 °C.33
Table 10. Recycling Experiments: Heck Reaction of N-
Vinylphthalimide with Iodobenzene
a
Pd leaching
(mg Pd/g product)
recovered
d
b
c
cycle
time (min) yield (%)
1
(wt %)
For studying the recovery and reuse of palladacycle 1 in the
Heck reaction, the experiments were performed using 14 and
4-chloroiodobenzene under the optimized reaction conditions.
The palladacycle 1 recovered from each run (Table 13) was
lower than the amount recovered from the Suzuki−Miyaura,
Sonogashira, and Stille reactions. This could be due to the
formation of Pd black during the reaction. It is nevertheless
worth noting that the recovered palladacycle 1 showed high
activity under the reaction condition and the amount of Pd
leached into the solution of crude product is significantly lower
than that observed from the polymer-supported palladacycle.36
Kumada Cross-Coupling Reaction. The Kumada cross-
coupling reaction is commonly used in the industrial-scale
production of styrene derivatives as it provides an economical
C−C bond-forming transformation through the direct coupling
between Grignard reagents and alkyl, vinyl or aryl halides.
1
2
3
4
3 (14 h)
10 (24 h)
20 (24 h)
30
93 (86)
93 (72)
92 (46)
90
0.24 (0.35)
0.24 (0.35)
0.18 (0.47)
<0.1
70
75
60
51
a
Data within parentheses are the results obtained from polymer-
supported reaction conditions: Pd catalyst, Cy2NMe, TBAB, DMF at
120 °C.17 Isolated yield. Determined in the crude product, mg Pd/1
b
c
d
L 1% HNO3 aqueous solution. Recovered via F-SPE.
Herein we report for the first time the use of an oxime-based
palladacycle to catalyze the Kumada cross-coupling reaction.
Initial studies of the Kumada cross-coupling reaction between
phenylmagnesium bromide (1 M) in THF and 4-bromotoluene
in DMAc under microwave irradiation at 140 °C afforded
4-methylbiphenyl 17a in only 53% yield. By screening through
various solvents (Table 14, entries 1−4), we found that THF
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Scheme 1. Synthesis of Cinnamaldehydes and Ethyl
3-Arylpropionoates Using the Heck Reaction
Table 13. Recycling of Palladacycle 1 in the Heck Reaction
b
c
Pd leaching
(ppm)
recovered 1
(wt %)
a
cycle
time (min)
yield (%)
1
2
3
4
5
1 (2.5 h)
3 (3.5 h)
6 (5.5 h)
10 (9 h)
92 (96)
91 (90)
87 (92)
85 (90)
82 (84)
0.067 (0.51)
0.076 (0.56)
0.048 (0.63)
0.004
84
82
65
63
63
Table 11. Optimization of the Heck Coupling of 14 with 4-
Chloroiodobenzene
22 (14 h)
0.023
a
b
Isolated yield. Determined using the crude product, mg Pd/1 L 1%
HNO3 aqueous solution. Data within parentheses are the results
c
obtained from polymer-supported reaction conditions.36 Recovered
from running through F-SPE.
a
entry
temp (°C)
solvent
DMAc
time (s)
yield (%)
b
c
b
c
explored the possibility of reducing the precatalyst loading to
0.05 mol % Pd. This afforded 17a in 95% yield within a similar
reaction time (Table 14, entry 8). However, further reduction of
the precatalyst loading to 0.005 mol % Pd drastically decreased
the product yield (Table 14, entry 9). Thus a precatalyst loading
of 0.05 mol % Pd was used for our subsequent experiments. With
the optimized reaction condition, we extended the reaction to
different combinations of Grignard reagents and halides which
afforded good yields of the desired product (Table 15). Finally to
determine the stability of palladacycle 1 under the Kumada cross-
coupling reaction conditions, we carried out the recycling
experiment using bromobenzene and phenylmagnesium bromide
for the model study (Table 16). Palladacycle 1 could be reused
over 4 runs with yields ranging from 91 to 63%. The decreasing
1
2
3
4
5
6
7
120
120
150
170
120
120
15 min (3 h )
82 (85 )
DMAc
60
10
5
87
41
77
31
39
37
DMAc
DMAc
DMF
60
90
d
DMAc/H2O
CH3CN
100
90
a
b
c
Isolated yield. With oil bath heating. Polymer-supported reac-
tion conditions: Pd catalyst, K2CO3, TBAA, KCl, DMAc, 120 °C.36
d
DMAc/H2O = 4:1.
gave the best result, providing 17a in 97% yield within 1 min.
Next we varied the reaction temperature and the experimental
data obtained indicated that comparable yield and reaction time
could be achieved at 100 °C (Table 14, entries 5−7). Finally, we
Table 12. Chemoselective Synthesis of 15 and 16 Using Heck Reaction of 14 and Various Aryl Halides
a
b
c
A: 1 (0.5 mol % Pd), K2CO3, TBAA, KCl, DMAc. B: 1 (0.5 mol % Pd), Cy2NMe, TBAB, DMAc/H2O. Isolated yield. Polymer-supported
reaction condition: Pd catalyst, K2CO3, TBAA, KCl, DMAc, 120 °C.36
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Table 14. Optimization of the Kumada Cross-Coupling
Reaction
a
entry
temp (°C)
solvent
time (min)
yield (%)
1
2
3
4
5
6
7
8
9
140
140
140
140
DMAc
CH2Cl2
THF
1
53
76
97
62
53
69
1
1
EtOEt
THF
1
b
rt
8 h
3 h
b
reflux
THF
c
c
100
THF
1 (30 min )
96 (93 )
d
100
THF
1.5
5
95
40
e
100
THF
a
b
Isolated yield. Experiment was not carried out under MW conditions.
c
Experiment was not carried out under MW conditions: Pd(OAc)2
(1 mol %), toluene, rt.37 Using palladacycle 1 (0.05 mol % Pd).
d
e
Using palladacycle 1 (0.005 mol % Pd).
yield could be attributed to the very small amounts of Pd black
formed during the reaction and the comparatively higher Pd
leaching. However this amount of Pd leaching is within the purity
required for active pharmaceutical ingredients (2−20 ppm).40
(1.2 mL), and C8F17I (1.3 mL, 4.8 mmol) and AIBN (65.6 mg,
0.4 mmol) were added. The reaction flask was equipped with a con-
denser, and the apparatus was purged and filled with Ar, stirred at
85 °C for 18 h, and then concentrated to dryness. The desired product 1b
(2.06 g, 74%) was obtained as a pale yellow solid after purification by
column chromatography. 1H NMR (500 MHz, CDCl3): δ 7.80 (d, 8H, J =
8.9 Hz), 6.98 (d, 8H, J = 8.9 Hz), 4.56 (q, 2H, J = 6.4 Hz), 4.38 (q, 2H,
J = 5.0 Hz), 4.28 (q, 2H, J = 6.4 Hz), 3.23−3.12 (m, 2H), 2.91−2.79
(m, 2H). 13C NMR (125 MHz, CDCl3): δ 194.1, 160.8, 132.3, 131.7,
114.3, 72.7, 37.9 (t, J = 21.0 Hz), 12.1. 19F NMR (282 MHz, CDCl3):
δ −80.71 (t, 6F, J = 10.3 Hz), −113.16 to −113.59 (m, 4F), −121.49
to −121.83 (d, 12F), −122.63 (s, 4F), −123.39 (s, 4F), −126.04
(s, 4F). HRMS (ESI): calcd for C35H18O3F34I2Na (M + Na) 1408.8692,
found 1408.8695.
Bis(4-(perfluorooctylpropoxy)phenyl)methanone (1c). Com-
pound 1b (20.8 g, 15.0 mmol) was dissolved in dichloroethane
(80 mL), and Bu3SnH (10.5 mL, 39.0 mmol) and AIBN (0.49 mg,
3.0 mmol) were added. The reaction flask was equipped with a con-
denser, and the apparatus was purged and filled with Ar. The reaction
mixture was stirred at 85 °C for 18 h and then concentrated to dry-
ness. The desired product 1c (15.19 g, 89%) was obtained as a white
solid after purification by column chromatography. 1H NMR (500
MHz, CDCl3): δ 7.79 (d, 8H, J = 8.8 Hz), 6.96 (d, 8H, J = 8.8 Hz),
4.13 (t, 4H, J = 6.3 Hz), 2.39−2.29 (m, 4H), 2.18−2.13 (m, 4H). 13C
NMR (125 MHz, 50 °C, CDCl3): δ 194.1, 161.9, 132.2, 131.4, 114.1,
66.7, 28.1 (t, J = 21.9 Hz), 20.7. 19F NMR (282 MHz, CDCl3):
δ −81.60 (t, 6F, J = 10.3 Hz), −114.73 (t, 4F, J = 14.4 Hz), −122.22 to
−122.43 (d, 12F), −123.25 (s, 4F), −123.98 (s, 4F), −126.71 (s, 4F).
HRMS (ESI): calcd for C35H20O3F34Na (M + Na) 1157.0763, found
1157.0762.
Bis(4-(perfluorooctylpropoxy)phenyl)methanone Oxime (1d).
To a solution of compound 1c (1.26 g, 1.11 mmol) and triethylamine
(1.7 mL, 12.5 mmol) in anhydrous EtOH (10.0 mL) and benzene
(15.0 mL) was added hydroxylamine hydrochloride (575 mg,
8.28 mmol). The mixture was refluxed with a Dean−Stark apparatus
for 16 h and then concentrated to dryness. Citric acid (5%) was added,
and the resulting mixture was extracted with EtOAc. The organic phase
was washed consecutively with 5% citric acid, 5% NaHCO3, H2O, and
brine, dried over anhydrous MgSO4, filtered, and concentrated. The
desired product 1d (1.11 g, 87%) was obtained as a white solid after
purification by column chromatography. 1H NMR (500 MHz, acetone-
d6): δ 10.09 (s, 1H), 7.39 (d, 2H, J = 8.8 Hz), 7.33 (d, 2H, J = 8.8 Hz),
7.04 (d, 4H, J = 8.8 Hz), 6.93 (d, 4H, J = 8.8 Hz), 4.22 (t, 2H, J =
6.3 Hz), 4.17 (t, 2H, J = 5.7 Hz), 2.57−2.42 (m, 4H), 2.19−2.11
CONCLUSION
■
In summary, we have demonstrated that palladacycle 1 is a very
versatile and efficient precatalyst which can be used in a wide
variety of cross-coupling reactions (Suzuki-Miyaura, Sonoga-
shira, Stille, Heck and Kumada), both in organic and aqueous
media. The stability of palladacycle 1 is also remarkable and it
could be reused four to five times without significant loss of
activity. The amount of Pd leaching was also very low.
EXPERIMENTAL SECTION
■
All chemical reagents purchased were used without further
purification. Moisture-sensitive reactions were carried out under
nitrogen with commercially obtained anhydrous solvents. Analytical
thin-layer chromatography (TLC) was carried out on precoated F254
silica plates and visualized with UV light or stained with the
Dragendorff−Munier and Hanessian stain. Column chromatography
was performed with silica (230−400 mesh). NMR spectra (1H and
13C) were recorded at 298 K. Chemical shifts are expressed in terms of
δ (ppm) relative to the internal standard tetramethylsilane (TMS).
Mass spectra were performed under EI mode. Microwave reactions
were performed on the Biotage InitiatorTM microwave synthesizer in
quartz pressure tubes.
Preparation of Palladacycle 1.9 Bis(4-(allyloxy)phenyl)-
methanone (1a). To a solution of 4,4′-dihydroxybenzophenone
(5.0 g, 23.3 mmol) in DMF (50 mL) were added KOH (6.5 g,
116.7 mmol) and allyl bromide (5.1 mL, 58.4 mmol). The
reaction mixture was stirred at room temperature for 24 h,
quenched with H2O (10 mL), and consecutively washed with
EtOAc (100 mL × 3). The organic layers were combined,
washed with brine (50 mL × 3), dried over anhydrous MgSO4,
filtered, and concentrated. The desired product 1a (6.77 g,
99%) was obtained as a white crystal after purification by
column chromatography. 1H NMR (500 MHz, CDCl3): δ 7.77
(d, 8H, J = 8.9 Hz), 6.96 (d, 8H, J = 8.9 Hz), 6.06 (m, 2H),
5.44, (dd, 2H, J1 = 17.1 Hz, J2 = 1.3 Hz), 5.32 (dd, 2H, J1 =
10.7 Hz, J2 = 1.3 Hz), 4.61 (d, 4 H, J = 5.1 Hz). 13C NMR
(125 MHz, CDCl3): δ 194.3, 161.8, 132.6, 132.1, 130.8, 118.1,
114.1, 68.8. HRMS (EI): calcd for C19H18O3 294.1256, found
294.1259.
Bis(4-(perfluorooctyl-2-iodopropoxy)phenyl)methanone (1b).
Compound 1a (0.59 g, 2.0 mmol) was dissolved in dichloroethane
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Palladacycle (1). To a suspension of oxime 1d (2.3 g, 2.0 mmol) in
acetone (26 mL) were added anhydrous sodium acetate (0.165 g,
2.0 mmol) and Li2PdCl4 (0.524 g, 2.0 mmol). The mixture was stirred
under reflux for 1 day, after which water (10 mL) was added and the
precipitate which formed was filtered off and dried under reduced
pressure over P2O5 to give the desired product 1 (2.33 g, 90%) as a
Table 15. Kumada Cross-Coupling Reaction Using
Palladacycle 1
1
brown solid. H NMR (500 MHz, acetone-d6): δ 10.9 (s, 1H), 7.49
(d, 1H, J = 2.5 Hz), 7.42 (d, 4H, J = 8.85 Hz), 7.12 (d, 4H, J = 8.85 Hz),
6.59 (d, 1H, J = 8.15 Hz), 6.49, 6.48 (dd, 1H, J1 = 8.2 Hz, J2 = 2.5 Hz),
4.27 (t, 2H, J = 6.3 Hz), 4.09 (t, 2H, J = 6.3 Hz), 2.57−2.41 (m, 4H),
2.19−2.07 (m, 4H). 13C NMR (125 MHz, acetone-d6): δ 163.7, 160.5,
158.0, 155.0, 137.4, 131.4, 128.0, 123.3, 121.8, 119.9, 115.1, 110.0,
67.3, 66.8, 55.4, 31.7, 28.6−28.0 (m), 21.2. 19F NMR (282 MHz,
CDCl3): δ −81.64 (t, 6F, J = 10.3 Hz), −114.72 (t, 4F, J = 12.4 Hz),
−122.22 to −122.43 (d, 12F), −123.25 (s, 4F), −123.95 (s, 4F),
−126.71 (s, 4F). IR (KBr): v = 3429, 2961, 2762, 1578, 1246, 1206,
1025 cm−1. MALDI HR: calcd for C35H18O3F34NPd (M−H)
1287.9545, found 1287.9540.
General Procedure for the Suzuki−Miyaura Reaction of
Boronic Acids and Various Halides under Microwave Heating.
To a suspension of aryl halide (0.50 mmol), boronic acid/boroxine
(0.75 mmol), TBAB (0.161 g, 0.50 mmol), palladacycle 1 (0.05 mol %
Pd), and water (1.0 mL) in a pressure tube was added a 2 M solution
of K2CO3 (0.5 mL). The reaction mixture was microwave irradiated
(with the heating program starting at 150 W) at 140 °C, and the re-
action was monitored by TLC. When the reaction has completed, the
reaction mixture was cooled to room temperature, poured into EtOAc
(20 mL), and washed successively with water (3 × 10 mL). The
organic layer was dried over anhydrous MgSO4, filtered, and con-
centrated. The crude product was then purified by column chro-
matography. On the basis of the 1H NMR, the purities of compounds
were determined to be ≥96%.
10-(3-Ethoxyphenyl)anthracene (2a). White solid. Mp: 119−
120 °C. 1H NMR (CDCl3, 300 MHz): δ 8.51 (s, 1H), 8.07 (d, 2H, J =
8.5 Hz), 7.78 (d, 2H, J = 14.1 Hz), 7.55−7.47 (m, 3H), 7.42−7.37 (m,
2H), 7.13−7.05 (m, 3H), 4.10 (q, 2H, J = 7.0 Hz), 1.47 (t, 3H, J =
7.0 Hz). 13C NMR (CDCl3, 75 MHz): δ 158.9, 140.1, 136.9, 131.3,
130.1, 129.3, 128.3, 126.9, 126.4, 125.3, 125.1, 123.5, 117.1, 113.8,
63.4, 14.8. HRMS (EI): calcd for C22H18O 298.1358, found 298.1357.
3-(3-Ethoxyphenyl)quinoline (2b). Yellow liquid. 1H NMR
(CDCl3, 300 MHz): δ 9.07 (s, 1H), 8.16 (s, 1H), 8.03 (d, 1H, J =
8.2 Hz), 7.74 (d, 1H, J = 7.9 Hz), 7.63−7.57 (m, 1H), 7.47−7.42 (m,
1H), 7.32−7.28 (m, 1H), 7.17−7.12 (m, 1H), 6.86−6.83 (m, 1H),
4.00 (q, 2H, J = 7.0 Hz), 1.35 (t, 3H, J = 7.0 Hz). 13C NMR (CDCl3,
75 MHz): δ 159.5, 149.8, 147.3, 139.2, 133.6, 133.1, 130.1, 129.3,
129.1, 127.9, 126.9, 119.6, 113.8, 63.5, 14.8. HRMS (EI): calcd for
C17H15ON 249.1154, found 249.1151.
a
b
Isolated yield. Using nanosized MCM-41-supported palladium
bipyridyl complex (0.05 mol % Pd), THF, 50 °C.38 Using silica-
supported phosphine Pd(0) complex (1 mol % Pd), THF, 65 °C.39
c
1
3-Ethoxy-4′-nitrobiphenyl (2c). Yellow solid. Mp: 95−96 °C. H
Table 16. Recycling of Palladacycle 1 in the Kumada Cross-
Coupling Reaction
NMR (CDCl3, 500 MHz): δ 8.28 (d, 2H, J = 8.9 Hz), 7.72 (d, 2H, J =
8.8 Hz), 7.41−7.38 (m, 1H), 7.20−7.14 (m, 2H), 6.97 (d, 1H, J =
8.2 Hz), 4.11 (q, 2H, J = 7.0 Hz), 1.46 (t, 3H, J = 6.9 Hz). 13C NMR
(CDCl3, 125 MHz): δ 159.3, 149.1, 146.8, 142.1, 136.3, 133.1, 130.2,
126.3, 119.8, 119.5, 115.4, 114.0, 63.7, 14.7. HRMS (EI): calcd for
C14H13O3N 243.0895, found 243.0893.
b
3-Ethoxy-2′,4′-dinitrobiphenyl (2d). Orange solid. Mp: 105−
Pd leaching
(ppm)
1
a
c
107 °C. H NMR (CDCl3, 300 MHz): δ 8.68 (s, 1H), 8.45 (d, 1H,
cycle time (min) yield (%)
recovered 1 (wt %)
J = 8.5 Hz), 7.68 (d, 1H, J = 8.5 Hz), 7.39−7.34 (m, 1H), 7.01−6.98
(m, 1H), 6.89−6.84 (m, 2H), 4.05 (q, 2H, J = 7.0 Hz), 1.43 (t, 3H, J =
7.0 Hz). 13C NMR (CDCl3, 75 MHz): δ 159.3, 149.1, 146.8, 142.1,
136.3, 133.1, 130.2, 126.3, 119.8, 119.5, 115.4, 114.0, 63.7, 14.7.
HRMS (EI): calcd for C14H12O5N2 288.0746, found 288.0743.
1
2
3
4
2
91
83
72
63
0.87
0.88
0.88
0.84
90
88
86
81
3.5
4.5
5
a
b
1
Isolated yield. Determined using the crude product, mg Pd/1 L 1%
HNO3 aqueous solution. Recovered from running through F-SPE.
3-Ethoxybiphenyl (2e). H NMR (CDCl3, 500 MHz): δ 7.64 (d,
c
1H, J = 8.2 Hz), 7.49−7.41 (m, 2H), 7.39−7.37 (m, 2H), 7.23−7.18
(m, 2H), 6.95−6.92 (m,1H), 4.13 (q, 2H, J = 6.9 Hz), 1.49 (t, 3H, J =
6.9 Hz). 13C NMR (CDCl3, 125 MHz): δ 159.3, 142.7, 141.1, 129.7,
128.7, 127.3, 127.1, 119.5, 113.5, 113.2, 63.4, 14.9. HRMS (EI): calcd
for C14H14O 198.1045, found 198.1046.
(m, 4H). 13C NMR (125 MHz, acetone-d6): δ 160.3, 159.7, 155.2,
132.8, 131.8, 131.3, 129.8, 127.1, 115.0, 114.7, 67.1, 67.1, 66.5, 28.5−
28.1 (m), 21.3. 19F NMR (282 MHz, CDCl3): δ −80.72 (t, 6F, J =
10.3 Hz), −114.4 to −114.32 (d, 4F), −121.67 to −121.87 (d, 12F),
−122.66 (s, 4F), −123.36 (s, 4F), −126.05 (s, 4F). HRMS (ESI): calcd
for C35H22O3F34N (M + H) 1150.1055; found 1150.1051.
Ethyl 5-(Naphthalen-1-yl)thiophene-2-carboxylate (3a). 1H NMR
(CDCl3, 500 MHz): δ 8.18 (d, 1H, J = 2.6 Hz), 7.92−7.87 (m, 3H),
7.59−7.49 (m, 4H), 7.24 (d, 1H, J = 3.8 Hz), 4.41 (q, 2H, J = 7.0 Hz),
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1.42 (t, 3H, J = 7.0 Hz). 13C NMR (CDCl3, 125 MHz): δ 162.3, 149.0,
133.8, 133.7, 133.4, 131.4, 131.4, 129.3, 128.4, 128.2, 128.0, 126.8,
126.2, 125.3, 125.2, 61.2, 14.4. HRMS (EI): calcd for C17H14O2S
282.0715, found 282.0714.
2.20 (s, 6H). 13C NMR (CDCl3, 125 MHz): δ 167.5, 163.0, 110.1,
23.4. HRMS (EI): calcd for C6H9N31123.0796, found 123.0797.
1-(4-Butylphenyl)ethanone (7a). H NMR (CDCl3, 500 MHz): δ
7.80 (d, 2H, J = 8.2 Hz), 7.19 (d, 2H, J = 8.2 Hz), 2.60 (t, 2H, J =
7.6 Hz), 2.51 (s, 3H), 1.58−1.52 (m, 2H), 1.33−1.27 (m, 2H), 0.86
(t, 3H, J = 7.6 Hz). 13C NMR (CDCl3, 125 MHz): δ 197.8, 148.8,
134.9, 128.6, 128.4,35.7, 33.2, 26.5, 22.3, 13.9. HRMS (EI): calcd for
C12H16O 176.1201, found 176.1203.
1-Benzylnaphthalene (3b). Mp: 53−55 °C (lit.41 mp 54−57 °C).
1H NMR (CDCl3, 500 MHz): δ 7.73−7.66 (m, 3H), 7.57−7.55
(m, 1H), 7.38−7.11 (m, 8H), 4.06 (s, 2H). 13C NMR (CDCl3, 125
MHz): δ 141.0, 138.6, 133.6, 132.0, 129.0, 128.5, 128.1, 127.6, 127.6,
127.5, 127.1, 126.1, 126.0, 125.3, 42.1. HRMS (EI): calcd for C17H14
218.1096, found 218.1093.
10-Butylanthracene (7b). Mp: 45−47 °C (lit.46 mp 49−50 °C). 1H
NMR (CDCl3, 500 MHz): δ 8.36−8.31 (m, 3H), 8.03−8.02 (m, 2H),
7.54−7.46 (m, 4H), 3.64 (t, 2H, J = 8.2 Hz), 1.88−1.82 (m, 2H),
1.68−1.60 (m, 2H), 1.07 (t, 3H, J = 7.6 Hz). 13C NMR (CDCl3,
125 MHz): δ 135.4, 131.6, 129.5, 129.2, 128.6, 128.1, 125.3, 124.5,
33.5, 27.8, 23.4, 14.1. HRMS (EI): calcd for C18H18 234.1409, found
234.1410.
10-(Naphthalen-1-yl)anthracene (3c). 1H NMR (CDCl3,
500 MHz): δ 8.51 (s, 1H), 8.02−7.91 (m, 4H), 7.62−7.59 (m, 2H),
7.45−7.31 (m, 4H), 6.99 (d, 1H, J = 8.9 Hz). 13C NMR (CDCl3,
125 MHz): δ 136.5, 134.9, 133.7, 133.5, 131.4, 131.0, 129.1, 128.4,
128.2, 128.1, 126.9, 126.9, 126.5, 126.2, 125.9, 125.5, 125.5, 125.2.
HRMS (EI): calcd for C24H16 304.1252, found 304.1255.
Naphthalen-1-yl(naphthalen-2-yl)methane (3d). Mp: 89−90 °C
(lit.42 mp 89−91 °C). 1H NMR (CDCl3, 500 MHz): δ 8.07 (d, 1H, J =
8.2 Hz), 7.90−7.72 (m, 5H), 7.63 (s, 1H), 7.51−7.35 (m, 4H), 4.62
(s, 2H). 13C NMR (CDCl3, 125 MHz): δ 138.1, 136.5, 133.9, 133.6,
132.1, 132.1, 128.6, 128.0, 127.8, 127.6, 127.5, 127.4, 127.4, 127.2,
127.0, 126.0, 125.9, 125.8, 125.6, 125.5, 125.3, 39.2. HRMS (EI): calcd
for C21H16 268.1252, found 268.1255.
3-Methyl-6-(naphthalen-1-ylmethyl)pyridin-2-amine (3e). Pale
yellow solid. Mp: 156−158 °C. 1H NMR (CDCl3, 500 MHz): δ
8.15−8.13 (m, 1H), 7.91−7.87 (m, 2H), 7.57−7.47 (m, 4H), 5.59
(s, 2H), 2.41 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 168.2, 167.5,
163.0, 136.7, 133.8, 130.5, 129.5, 128.3, 126.8, 126.5, 126.0, 125.4,
125.1, 111.8, 24.0. HRMS (EI): calcd for C17H16N2 248.1313, found
248.1312.
General Procedure for the Sonogashira Cross-Coupling
Reactions between Terminal Alkynes with Various Aryl
Halides under Microwave Heating. To a suspension of aryl halide
(0.50 mmol), phenylacetylene (0.75 mmol), pyrrolidine (0.161 g,
0.25 mmol), and palladacycle 1 (0.05 mol % Pd) in a pressure tube was
added 1 mL of degassed water. The reaction mixture was microwave
irradiated (with the heating program starting at 150 W) at 140 °C, and
the reaction was monitored by TLC. When the reaction was complete,
the reaction mixture was cooled to room temperature, poured into ether
(20 mL), and washed successively with water (3 × 10 mL). The organic
layer was dried over anhydrous MgSO4, filtered, and concentrated. The
crude product was then purified by column chromatography. On the
basis of the 1H NMR, the purities of compounds were determined to be
≥96%.
3-(2-(4-Chlorophenyl)ethynyl)thiophene (8a). Mp: 102−104 °C.
1H NMR (500 MHz, CDCl3): δ 7.57−7.50 (m, 1H), 7.44 (d, J =
3-Nitro-5-vinylpyridin-2-amine (5a). 1H NMR (CDCl3, 500 MHz):
δ 8.44 (s, 1H), 8.41 (s, 1H), 6.61 (dd, 1H, J = 17.7 Hz and 11.4 Hz),
5.71 (d, 1H, J = 17.7 Hz), 5.29 (d, 1H, J = 11.4 Hz). 13C NMR
(CDCl3, 125 MHz): δ 153.9, 152.6, 131.4, 131.3, 128.0, 124.4, 114.6.
HRMS (EI): calcd for C7H7O2N3 165.0538, found 165.0534.
5-Vinylpyrimidine (5b). 1H NMR (CDCl3, 500 MHz): δ 9.10
(s, 1H), 8.76 (s, 1H), 6.66 (dd, 1H, J = 17.7 Hz and 11.4 Hz), 5.93
(d, 1H, J = 17.7 Hz), 5.51 (d, 1H, J = 11.4 Hz). 13C NMR (CDCl3,
125 MHz): δ 157.6, 154.2, 130.9, 130.1, 118.6. HRMS (EI): calcd for
C6H6N2 106.0531, found 106.0536.
8.4 Hz, 2H), 7.34−7.24 (m, 3H), 7.19 (d, J = 5.1 Hz, 1H). 13C NMR
(CDCl3, 125 MHz): δ 134.2, 132.7, 130.5, 129.8, 128.9, 128.7, 125.5,
122.0, 87.8, 85.4. HRMS (EI): calcd for C12H7ClS 217.9957, found
217.9955.
3-(2-(Thiophene-3-yl)ethynyl)quinoline (8b). Brown solid. Mp:
70−72 °C. 1H NMR (500 MHz, CDCl3): δ 8.99 (d, J = 2.0 Hz, 1H),
8.28 (d, J = 1.8 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 8.2 Hz,
1H), 7.73−7.68 (m, 1H), 7.63−7.53 (m, 2H), 7.35−7.33 (m, 1H),
7.28−7.23 (m, 1H). 13C NMR (126 MHz, CDCl3): δ 152.0, 146.8,
138.1, 130.0, 129.8, 129.4, 129.4, 127.6, 127.3, 125.6, 121.7, 117.4,
88.9, 87.8, 86.2. HRMS (EI): calcd for C15H9SN 235.0456, found
235.0455.
1-Nitro-3-vinylbenzene (5c). 1H NMR (500 MHz, CDCl3): δ 8.27
(s, 1H), 8.12 (dd, J = 8.2, 1.3 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.52
(t, J = 8.0 Hz, 1H), 6.79 (dd, J = 17.6, 10.9 Hz, 1H), 5.92 (d, J =
17.6 Hz, 1H), 5.47 (d, J = 10.9 Hz, 1H). 13C NMR (126 MHz,
CDCl3): δ 148.61, 139.27, 134.74, 132.02, 129.41, 122.38, 120.85,
117.04. HRMS (EI): calcd for C8H7NO2 149.0477, found 149.0475.
Ethyl 5-Vinylthiophene-2-carboxylate (5d). Orange solid. Mp:
3-(2-(4-Nitrophenyl)ethynyl)thiophene (8c). Brown solid. Mp:
1
152−153 °C. H NMR (500 MHz, CDCl3): δ 8.21 (d, J = 8.8 Hz,
2H), 7.67−7.59 (m, 3H), 7.34 (dd, J = 5.0, 2.8 Hz, 1H), 7.22 (d, J =
5.1 Hz, 1H), 1.55 (s, 1H). 13C NMR (126 MHz, CDCl3): δ 147.0,
132.1, 130.3, 130.1, 129.7, 125.8, 123.6, 121.2, 89.9, 87.2. HRMS (EI):
calcd for C12H7SNO2 229.0197, found 229.0197.
1
140−142 °C. H NMR (CDCl3, 500 MHz): δ 7.64 (d, 1H, J = 3.8
Hz), 6.95 (d, 1H, J = 3.8 Hz), 6.77 (dd, 1H, J = 17 Hz and 10.7 Hz),
5.71 (d, 1H, J = 17 Hz), 5.29 (d, 1H, J = 10.7 Hz), 4.34 (q, 2H, J =
7.0 Hz), 1.47 (t, 3H, J = 7.0 Hz). 13C NMR (CDCl3, 125 MHz): δ
162.2, 149.3, 133.6, 132.1, 129.5, 116.3, 61.1, 14.3. HRMS (EI): calcd
for C9H10O2S 182.0402, found 182.0407.
2-(2-(4-tert-Butylphenyl)ethynyl)pyridine (8d). 1H NMR
(500 MHz, CDCl3): δ 8.60 (d, J = 5.1, 1H), 7.67−7.50 (m, 3H),
7.39−7.37 (m, 2H), 7.22 - 7.19 (m, 1H), 1.32 (s, 9H). 13C NMR
(CDCl3, 125 MHz): δ 152.3, 150.0, 143.7, 136.0, 131.8, 127.0, 125.4,
122.5, 119.2, 89.5, 88.1, 34.8, 31.1. HRMS (EI): calcd for C17H17N
235.1361, found 235.1361.
9-Methylanthracene (6a). Mp: 78−81 °C (lit.43 mp 79−80 °C).
1H NMR (CDCl3, 500 MHz): δ 8.36−8.31 (m, 3H), 8.04−8.02
(m, 2H), 7.56−7.49 (m, 4H), 2.43 (s, 3H). 13C NMR (CDCl3,
125 MHz): δ 131.5, 130.1, 129.0, 128.1, 125.3, 125.2, 124.8, 124.6,
13.9. HRMS (EI): calcd for C15H12 192.0939, found 192.0942.
5-Methylfuran-2-carbaldehyde (6b). 1H NMR (CDCl3,
500 MHz): δ 9.40 (s, 1H), 7.08 (d, 1H, J = 3.8 Hz), 6.15 (d, 1H,
J = 4.5 Hz), 2.31 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ 176.6,
159.5, 151.7, 123.5, 109.3, 13.7. HRMS (EI): calcd for C6H6O2
110.0368, found 110.0367.
2-Methoxy-6-(2-(4-(trifluoromethyl)phenyl)ethynyl)naphthalene
(8e). Pale yellow solid. Mp: 151−153 °C. 1H NMR (500 MHz,
CDCl3): δ 8.01 (s, 1H), 7.74−7.55 (m, 7H), 7.19 (dd, J = 9.0, 2.5 Hz,
1H), 7.13 (d, J = 2.4 Hz, 1H), 3.94 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 158.6, 134.4, 131.7, 131.7, 129.9, 129.6, 129.4, 128.8, 128.5,
127.4, 126.9, 125.3, 125.3, 125.2, 125.2, 125.1, 122.9, 119.6, 117.4,
105.9, 92.5, 87.7, 55.3. HRMS (EI): calcd for C20H13F3O 326.0918,
found 326.0914.
2-Methoxy-6-(2-(4-methoxyphenyl)ethynyl)naphthalene (8f).
Mp: 165−166 °C (lit.47 mp 165−167 °C). 1H NMR (500 MHz,
CDCl3): δ 7.96 (s, 1H), 7.70 (t, J = 8.9 Hz, 2H), 7.52 (ddd, J = 8.8,
7.6, 1.7 Hz, 3H), 7.16 (dd, J = 8.9, 2.5 Hz, 1H), 7.12 (d, J = 2.4 Hz,
1H), 6.90 (d, J = 8.7 Hz, 2H), 3.93 (s, 3H), 3.84 (s, 3H). 13C NMR
(CDCl3, 125 MHz): δ 159.5, 158.2, 134.0, 133.0, 130.9, 129.3, 129.0,
2-Methyl-1H-imidazole (6c). Mp: 138−141 °C (lit.44 mp 140−142
°C). 1H NMR (CDCl3, 500 MHz): δ 12.44 (s, 1H), 6.97 (s, 2H), 2.42
(s, 3H). 13C NMR (CDCl3, 125 MHz): δ 144.6, 121.2, 13.7. HRMS
(EI): calcd for C4H6N2 82.0531, found 82.0532.
4,6-Dimethylpyrimidin-2-amine (6d). Mp: 150−153 °C (lit.45 mp
1
153 °C). H NMR (CDCl3, 500 MHz): δ 6.27 (s, 1H), 5.68 (s, 2H),
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128.6, 126.8, 119.3, 118.5, 115.6, 114.0, 105.9, 89.0, 88.6, 55.3, 55.3.
HRMS (EI): calcd for C20H16O2 288.1150, found 288.1151.
5-(2-(6-Methoxynaphthalen-2-yl)ethynyl)pyrimidine (8g). Yellow
solid. Mp: 196−197 °C. 1H NMR (500 MHz, CDCl3): δ 9.14 (s, 1H),
8.87 (s, 1H), 8.00 (s, 1H), 7.72 (dd, J = 8.7, 2.3 Hz, 2H), 7.53 (dd, J =
8.5, 1.3 Hz, 1H), 7.18 (dd, J = 9.0, 2.4 Hz, 1H), 7.12 (d, J = 2.1 Hz,
1H), 3.92 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 158.8, 158.5,
156.5, 134.7, 131.9, 129.5, 128.6, 128.3, 127.0, 120.1, 119.7, 116.5,
105.9, 97.1, 55.3. HRMS (EI): calcd for C17H12N2O 260.0950, found
260.0950.
2-(2-(4-tert-Butylphenyl)ethynyl)-6-methoxynaphthalene (8h).
Yellow solid. Mp: 140−142 °C. 1H NMR (500 MHz, CDCl3): δ
7.99 (s, 1H), 7.71 (t, J = 9.2 Hz, 2H), 7.59−7.46 (m, 3H), 7.44−7.37
(m, 2H), 7.17 (dd, J = 8.9, 2.5 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 3.93
(s, 3H), 1.35 (s, 9H). 13C NMR (126 MHz, CDCl3): δ 158.2, 151.4,
134.0, 131.3, 131.1, 129.3, 129.1, 128.5, 126.8, 125.3, 120.4, 119.3,
118.4, 89.3, 89.2, 55.3, 34.8, 31.2. HRMS (EI): calcd for C23H22O:
314.1671, found 314.1670.
1,4-Bis(4-tert-butylphenyl)buta-1,3-diyne (9d). 1H NMR (500 MHz,
CDCl3): δ 7.45 (d, J = 8.3 Hz, 4H), 7.36 (d, J = 8.5 Hz, 4H), 1.33
(s, 18H). 13C NMR (CDCl3, 125 MHz): δ 152.1, 131.9, 125.3, 119.1,
83.8, 76.4, 34.8, 31.1. HRMS (EI): calcd for C24H26 314.2035, found
314.2033.
General Procedure for the Stille Cross-Coupling Reaction
between Organostannanes with Aryl Halides under Micro-
wave Heating. To a suspension of aryl halide (0.50 mmol), boronic
acid (0.75 mmol), TBAB (0.161 g, 0.25 mmol), and palladacycle 1
(0.005 mol % Pd) in a pressure tube was added 1 mL of degassed
water. The reaction mixture was microwave irradiated (with the heat-
ing program starting at 150 W) at 100 °C, and the reaction was moni-
tored by TLC. When the reaction has completed, the reaction mixture
was cooled to room temperature, poured into ether (20 mL), and
washed successively with water (3 × 10 mL). The organic layer was
dried over anhydrous MgSO4, filtered, and concentrated. The crude
product was then purified by column chromatography. On the basis
1
of the H NMR, the purities of compounds were determined to be
≥96%.
2-Methoxy-6-(2-(4-nitrophenyl)ethynyl)naphthalene (8i). Mp:
1
3-Ethoxybiphenyl (10a). H NMR (500 MHz, CDCl3): δ 7.67 (d,
1
128−130 °C. H NMR (500 MHz, CDCl3): δ 8.19 (d, J = 8.7 Hz,
J = 7.7 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H),
7.27−7.19 (m, 2H), 6.96 (dd, J = 8.2, 2.4 Hz, 1H), 4.16 (q, J = 7.0 Hz,
2H), 1.52 (t, J = 7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 159.3,
142.7, 141.1, 129.7, 128.7, 127.3, 127.1, 119.5, 113.5, 113.2, 63.4, 14.9.
HRMS (EI): calcd for C14H14O 198.1045, found 198.1041.
4-Fluorobiphenyl (10b). Mp: 71−72 °C (lit.52 mp 72−73 °C).
1H NMR (500 MHz, CDCl3): δ 7.59−7.52 (m, 3H), 7.52−7.41
(m, 13H), 7.39−7.29 (m, 2H), 7.17−7.10 (m, 2H). 13C NMR (125 MHz,
CDCl3): δ 136.5, 128.8, 128.7, 128.6, 128.2, 127.9, 127.2, 127.0, 115.7,
115.5. HRMS (EI): calcd for C12H9F 172.0688, found 172.0687.
4-Chlorobiphenyl (10c). Mp: 72−75 °C (lit.53 mp 74−76 °C).
1H NMR (500 MHz, CDCl3): δ 7.58−7.46, (m, 3H), 7.44−7.42
(m, 4H), 7.39−7.33 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 136.5,
132.7, 128.9, 128.9, 128.4, 127.9, 127.6, 127.0. HRMS (EI): calcd for
C12H9Cl 188.0393, found 188.0390. HRMS (EI): calcd for C12H9Cl
188.0393, found 188.0391.
2H), 8.00 (s, 1H), 7.72 (dd, J = 8.7, 4.1 Hz, 2H), 7.64 (d, J = 8.7 Hz,
2H), 7.54 (dd, J = 8.4, 1.4 Hz, 1H), 7.19 (dd, J = 9.1, 2.4 Hz, 1H), 7.12
(d, J = 2.3 Hz, 1H), 3.93 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ
158.7, 146.7, 134.6, 132.1, 132.0, 130.4, 129.4, 128.7, 128.3, 127.0,
123.6, 119.7, 116.8, 105.9, 95.6, 87.3, 55.3. HRMS (EI): calcd for
C19H13NO3 303.0895, found 303.0890.
Ethyl 5-(2-(6-Methoxynaphthalen-2-yl)ethynyl)thiophene-2-car-
1
boxylate (8j). Yellow solid. Mp: 124−125 °C. H NMR (500 MHz,
CDCl3): δ 7.98 (s, 1H), 7.70 (dd, J = 10.6, 6.0 Hz, 3H), 7.52 (d, J =
8.4 Hz, 1H), 7.23 (d, J = 3.8 Hz, 1H), 7.17 (dd, J = 9.0, 2.2 Hz, 1H),
7.11 (d, J = 1.7 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 1.39
(t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, CDCl3): δ 161.6, 158.6,
134.5, 134.1, 133.1, 131.9, 131.6, 130.1, 129.4, 128.5, 128.4, 127.0,
119.6, 117.0, 105.9, 96.3, 81.8, 61.3, 55.3, 14.3. HRMS (EI): calcd for
C20H16O3S 336.0820, found 336.0818.
4-tert-Butylbiphenyl (10d). Mp: 49−51 °C (lit.54 mp 49−50 °C).
1H NMR (500 MHz, CDCl3): δ 7.61−7.59 (m, 2H), 7.56−7.54 (m,
2H), 7.49−7.42 (m, 4H), 7.34−7.33 (m, 1H), 1.41 (s, 9H). 13C NMR
(125 MHz, CDCl3): δ 150.2, 141.0, 138.3, 136.8, 128.7, 127.0, 127.0,
126.8, 125.7, 31.3, 15.3. HRMS (EI): calcd for C16H18: 210.1409,
found 210.1409.
1-Nitro-4-(2-phenylethynyl)benzene (8k). Mp: 111−112 °C
(lit.48 mp 111−113 °C). H NMR (500 MHz, CDCl3): δ 8.22 (d,
1
J = 8.8 Hz, 2H), 7.67 (d, J = 8.8 Hz, 2H), 7.64−7.53 (m, 2H), 7.52−
7.35 (m, 3H). 13C NMR (CDCl3, 125 MHz): δ 146.9, 132.2, 131.8,
130.2, 129.2, 128.5, 123.6, 122.0, 94.7, 87.5. HRMS (EI): calcd for
C14H9NO2 223.0633, found 223.0630.
Biphenyl (10e). Mp: 66−68 °C (lit.55 mp 66−68 °C). H NMR
General Procedure for Glaser-Type Oxidative Homocou-
pling. To a suspension of the respective terminal alkyne (0.25 mmol),
pyrrolidine (0.041 mL, 0.5 mmol), palladacycle 1 (0.05 mol % Pd),
and CuI (5 mol %) in a pressure tube was added water (1 mL). The
reaction mixture was microwave irradiated (with the heating program
starting at 150 W) at 140 °C, and the reaction was monitored by TLC.
When the reaction has completed, the reaction mixture was cooled to
room temperature, poured into ether (20 mL), and washed suc-
cessively with water (3 × 10 mL). The organic layer was dried over
anhydrous MgSO4, filtered, and concentrated. The crude product was
then purified by column chromatography. On the basis of the 1H
NMR, the purities of compounds were determined to be ≥96%.
1,4-Bis(6-methoxynaphthalen-2-yl)buta-1,3-diyne (9a). Mp:
1
(500 MHz, CDCl3): δ 7.64−7.63 (m, 4H), 7.49−7.46 (m, 4H), 7.40−
7.37 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 141.2, 128.7, 127.2,
127.1. HRMS (EI): calcd for C12H10 154.0783, found 154.0785.
4-(1-Methyl-1H-indol-2-yl)benzonitrile (11a). Mp: 160−161 °C
(lit.56 mp 161−162 °C). 1H NMR (500 MHz, CDCl3): δ 7.68 (d, J =
7.8 Hz, 1H), 7.36−7.28 (m, 1H), 7.20 (t, J = 7.2 Hz, 1H), 6.67 (s,
1H), 3.78 (s, 3H).). 13C NMR (125 MHz, CDCl3): δ 139.2, 139.0,
137.2, 132.3, 129.4, 127.6, 122.7, 120.9, 120.3, 118.7, 111.1, 109.8,
103.5, 31.4. HRMS (EI): calcd for C16H12N2 232.1000, found
232.1007.
2-(4-tert-Butylphenyl)-1-methyl-1H-indole (11b). Yellow solid.
Mp: 115−116 °C. 1H NMR (CDCl3, 500 MHz): δ 7.64 (d, J =
7.6 Hz, 1H), 7.51−7.45 (m, 4H), 7.36 (d, J = 8.2 Hz, 1H), 7.25−7.23
(m, 1H), 7.15−7.13 (m, 1H), 6.55 (s, 1H), 3.79 (s, 3H), 1.39 (s, 9H).
13C NMR (CDCl3, 125 MHz): δ 150.9, 141.6, 138.3, 129.9, 129.0,
128.0, 125.4, 121.5, 120.3, 119.7, 109.5, 101.3, 34.7, 31.3, 31.2. HRMS
(EI): calcd for C19H21N 263.1674, found 263.1677.
235−236 °C (lit.49 mp 237−238 °C). H NMR (500 MHz, CDCl3):
1
δ 8.01 (s, 2H), 7.70 (dd, J = 12.5, 8.7 Hz, 4H), 7.52 (dd, J = 8.5, 1.4 Hz,
2H), 7.18−7.11 (m, 4H), 3.94 (s, 6H). 13C NMR (CDCl3, 125 MHz): δ
158.8, 134.6, 132.8, 129.4, 129.2, 128.4, 127.0, 119.6, 119.1, 105.9, 82.2,
73.9, 55.4. HRMS (EI): calcd for C26H18O2 362.1307, found 362.1307.
3-(4-(Thiophene-3-yl)buta-1,3-diynyl)thiophene (9b). Mp: 110−
1-Methyl-2-(thiophene-2-yl)-1H-indole (11c). Mp: 59−60 °C
112 °C (lit.50 mp 111.5−112.5 °C). H NMR (500 MHz, CDCl3): δ
1
(lit.56 mp 58−59 °C). H NMR (500 MHz, CDCl3): δ 7.64 (d, J =
1
7.60−7.57 (m, 2H), 7.28 (dd, J = 5.0, 2.9 Hz, 2H), 7.17 (dd, J = 5.0,
1.1 Hz, 2H). 13C NMR (CDCl3, 125 MHz): δ 131.2, 130.2, 125.6,
120.9, 76.5, 73.5. HRMS (EI): calcd for C12H6S2 213.9911, found
213.9908.
8.5 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.31(d, J = 8.3 Hz, 1H), 7.23−
7.20 (m, 2H), 7.12−7.06 (m, 2H), 6.64 (s, 1H), 3.89 (s, 3H). 13C
NMR (125 MHz, CDCl3): δ 138.3, 134.1, 133.9, 127.6, 127.6, 126.7,
126.1, 122.0, 120.5, 120.0, 109.5, 102.7, 31.0. HRMS (EI): calcd for
C13H11NS 213.1612, found 213.1619.
1,4-Diphenylbuta-1,3-diyne (9c). Mp: 83−84 °C (lit.51 mp 85 °C).
1H NMR (500 MHz, CDCl3): δ 7.58−7.50 (m, 4H), 7.41−7.31 (m,
6H). 13C NMR (CDCl3, 125 MHz): δ 132.5, 129.2, 128.4, 121.8, 81.5,
73.9, 31.1. HRMS (EI): calcd for C16H10 202.0783, found 202.0779.
3-Methyl-5-(1-methyl-1H-indol-2-yl)pyridin-2-amine (11d). Yel-
low solid. Mp: 115−117 °C. 1H NMR (500 MHz, CDCl3): δ 8.12 (s,
1H), 7.62 (d, J = 8.2 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 8.2 Hz, 1H),
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7.26−7.22 (m, 1H), 7.22−7.12 (m, 1H), 6.50 (s, 1H), 4.60 (br s, 2H),
3.72 (s, 3H), 2.21 (s, 3H) . 13C NMR (126 MHz, CDCl3): δ 156.7,
145.9, 138.8, 138.6, 138.1, 127.9, 121.5, 120.2, 120.0, 119.6, 116.2,
109.5, 101.1, 30.9, 17.1. HRMS (EI): calcd for C15H15N3 237.1266,
found 237.1265.
128.9, 126.1, 123.8, 119.6, 118.6, 26.6. HRMS (EI): calcd for
C18H13O3N 291.0895, found 291.0899.
(E)-2-Styrylisoindoline-1,3-dione (13e). Mp: 187−188 °C
(lit.59 mp 187−189 °C). H NMR (300 MHz, CDCl3): δ 7.91−7.88
1
(m, 2 H), 7.77−7.74 (m, 2 H), 7.65 (d, J = 15.1 Hz, 1 H), 7.47 (d, J =
7.38 Hz, 2 H), 7.38 - 7.33 (m, 3 H), 7.28−7.23 (m, 1H). 13C NMR
(125 MHz, CDCl3): δ 166.4, 136.0, 134.5, 131.7, 128.7, 127.6, 126.2,
123.6, 120.3, 117.6. HRMS (EI): calcd for C16H11O2N 249.0790,
found 249.0795.
1-Methyl-2-(3-nitrophenyl)-1H-indole (11e). Mp: 152−154 °C. 1H
NMR (500 MHz, CDCl3): δ 8.42 (t, J = 1.8 Hz, 1H), 8.31−8.25 (m,
1H), 7.89−7.87 (m, 1H), 7.73−7.65 (m, 2H), 7.46−7.20 (m, 3H),
6.72 (s, 1H), 3.82 (s, 3H). 13C NMR (125 MHz, CDCl3): δ 148.3,
138.7, 138.6, 134.9, 134.5, 129.5, 127.6, 123.7, 122.6, 122.4, 120.9,
120.3, 109.8, 103.2, 31.3. HRMS (EI): calcd for C15H12N2O2
252.0899, found 252.0895.
General Procedure for the Synthesis of Cinnamaldehydes
15 under Microwave Heating. A suspension of the respective aryl
halide (0.25 mmol), acrolein diethyl acetal (0.06 mL, 0.38 mmol),
K2CO3 (51.8 mg, 0.38 mmol), TBAA (151 mg, 0.50 mmol), KCl (18.8 mg,
0.25 mmol), and palladacycle 1 (0.5 mol %Pd) in DMAc (1 mL) was
placed in a pressure tube. The reaction mixture was microwave
irradiated (with the heating program starting at 150 W) at 120 °C, and
the reaction was monitored by TLC. When the reaction has com-
pleted, the reaction mixture was cooled to room temperature, and an
aqueous solution of HCl (2 M, 2.5 mL) was added slowly. The
mixture was stirred at room temperature for 10 min, poured into
EtOAc (5 mL), and then washed successively with HCl (2 M, 5 mL)
and H2O (2 × 5 mL). The organic layer was dried over anhydrous
MgSO4, filtered, and concentrated. The crude product was separated
from the palladacycle 1 using F-SPE and the desired cinnamaldehyde
Ethyl 5-(2-Phenylethynyl)thiophene-2-carboxylate (12a). Brown
solid. Mp: 56−58 °C. 1H NMR (500 MHz, CDCl3): δ 7.68 (d, J = 4.0
Hz, 1H), 7.56−7.50 (m, 2H), 7.47−7.32 (m, 3H), 7.21 (d, J = 3.9 Hz,
1H), 4.35 (q, J = 7.0 Hz, 2H), 1.38 (t, J = 6.7 Hz, 3H). 13C NMR (126
MHz, CDCl3): δ 161.5, 134.3, 133.4, 133.0, 131.5, 130.8, 129.0, 128.4,
122.2, 95.5, 82.0, 61.4, 14.3. HRMS (EI): calcd for C15H12SO2
256.0558, found 256.0555.
1-Methoxy-4-(2-phenylethynyl)benzene (12b). Mp: 59−60 °C
(lit.57 mp 57−61 °C). 1H NMR (500 MHz, CDCl3): δ 7.53−7.49 (m,
2H), 7.47 (d, J = 8.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 3.83 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 159.6, 131.4, 128.3, 127.9, 123.6,
115.4, 114.0, 55.3. HRMS (EI): calcd for C15H12O 208.0888, found
208.0887.
1
10 was purified by column chromatography. On the basis of the H
NMR, the purities of compounds were determined to be ≥96%.
4-Chlorocinnamaldehyde (15a). Mp: 61−62 °C (lit.60 mp 59−
61 °C). 1H NMR (500 MHz, CDCl3): δ 9.70 (d, J = 7.6 Hz, 1 H), 7.50
(d, J = 8.8 Hz, 2 H), 7.41 (d, J = 8.8 Hz, 2 H), 7.43 (d, J = 15.8 Hz,
1 H), 6.69 (dd, J1 = 15.8 Hz, J2 = 7.6 Hz, 1 H). 13C NMR (125 MHz,
CDCl3): δ 193.3, 151.0, 137.3, 132.5, 129.6, 129.4, 129.0. HRMS (EI):
calcd for C9H7OCl 166.0185, found 166.0182.
4-(2-Phenylethynyl)benzonitrile (12c). Mp: 109−110 °C (lit.58 mp
1
110.2−111.4 °C). H NMR (500 MHz, CDCl3): δ 7.67−7.58 (m,
4H), 7.56−7.54 (m, 2H), 7.40−7.38 (m, 3H). 13C NMR (125 MHz,
CDCl3): δ 132.0, 132.0, 131.8, 129.1, 128.5, 128.2, 122.2, 118.5, 111.4,
93.8, 87.7. HRMS (EI): calcd for C15H9N 203.0735, found 203.0733.
General Procedure for the Synthesis of (E)-N-Styrylphthali-
mides 13 via the Heck Reaction and under Microwave Heating.
A mixture of the respective aryl halide (0.51 mmol), N-vinyl-
phthalimide (87.0 mg, 0.50 mmol), Cy2NMe (0.16 mL, 0.75 mmol),
TBAB (161 mg, 0.50 mmol), and the palladacycle 1 (0.5 mol %Pd) in
DMF (0.75 mL) was placed in a pressure tube. The reaction mixture
was microwave irradiated (with the heating program starting at
150 W) at 170 °C, and the reaction was monitored by TLC. When the
reaction was complete, the mixture was cooled to room temperature
and concentrated to dryness. The crude product was separated from
the palladacycle 1 using F-SPE,8 and the desired E-product 13 was
purified by column chromatography. On the basis of the 1H NMR, the
purities of compounds were determined to be ≥96%.
4-Methoxycinnamaldehyde 15b. Mp: 56−57 °C (lit.61 mp 57−
58 °C). 1H NMR (300 MHz, CDCl3): δ 9.65 (d, J = 7.6 Hz, 1 H), 7.50
(d, J = 8.8 Hz, 2 H), 6.95 (d, J = 8.8 Hz, 2 H), 7.42 (d, J = 15.8 Hz,
1 H), 6.61 (dd, J1 = 15.8 Hz, J2 = 7.6 Hz, 1 H), 3.86 (s, 3 H). 13C NMR
(125 MHz, CDCl3): δ 193.6, 152.6, 162.2, 130.3, 126.8, 114.6, 126.6,
55.4. HRMS (EI): calcd for C10H10O2 162.0681, found 162.0681.
4-(Trifluoromethyl)cinnamaldehyde (15c). Mp: 61−63 °C (lit.62
mp 59−61 °C). 1H NMR (500 MHz, CDCl3): δ 9.74 (d, J = 7.6 Hz, 1
H), 7.72−7.64 (m, 4 H), 7.50 (d, J = 15.8 Hz, 1 H), 6.77 (dd, J1 = 15.8
Hz, J2 = 7.6 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ 193.1, 150.2,
137.3, 132.6 (q, J = 32.1 Hz), 130.5, 126.0 (q, J = 3.7 Hz), 123.7
(q, J = 272.2 Hz), 128.3. HRMS (EI): calcd for C10H7OF3 200.0449,
found 200.0446.
(E)-2-(4-Methoxystyryl)isoindoline-1,3-dione (13a). Mp: 162−
163 °C (lit.59 mp 164−166 °C). H NMR (300 MHz, CDCl3): δ
1
General Procedure for the Synthesis of Ethyl 3-Arylpropa-
noates 16 under Microwave Heating. A solution of the respective
aryl halide (0.25 mmol), acrolein diethyl acetal (0.06 mL, 0.38 mmol),
Cy2NMe (0.08 mL, 0.38 mmol), TBAB (80.5 mg, 0.25 mmol), and
palladacycle 1 (0.5 mol % Pd) in DMAc (1 mL) and water (0.25 mL)
was placed in a pressure tube. The reaction mixture was microwave
irradiated (with the heating program starting at 150 W) at 120 °C, and
the reaction was monitored by TLC. When the reaction has com-
pleted, the reaction mixture was cooled to room temperature, poured
into EtOAc (5 mL), and washed successively with HCl (2 M, 2 ×
5 mL) and H2O (5 mL). The organic layer was dried over anhydrous
MgSO4, filtered, and concentrated. The crude product was separat-
ed from the palladacycle 1 using F-SPE, and the desired ethyl 3-
arylpropanoate 16 was purified by column chromatography. On the
7.91−7.88 (m, 2 H), 7.76−7.73 (m, 2 H), 7.60 (d, 1H, J = 15.1 Hz),
7.41 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 15.1 Hz, 1H), 6.90 (d, J = 8.7 Hz,
1H), 3.83 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 166.5, 159.3,
134.4, 131.7, 128.5, 127.4, 123.6, 120.1, 115.9, 114.2, 55.3. HRMS
(EI): calcd for C17H13O3N 279.0895, found 279.0896.
(E)-2-(4-Methylstyryl)isoindoline-1,3-dione (13b). Mp: 171−
173 °C (lit.59 mp 172−174 °C). H NMR (300 MHz, CDCl3): δ
1
7.91−7.88 (m, 2 H), 7.77−7.74 (m, 2 H), 7.62 (d, J = 15.1 Hz, 1H),
7.37 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 15.1 Hz, 1H), 7.16 (d, J =
8.0 Hz, 2 H), 2.36 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ 166.5,
137.5, 134.5, 133.0, 131.7, 129.4, 126.1, 123.6, 120.3, 116.8, 21.2.
HRMS (EI): calcd for C17H13O2N 263.0946, found 263.0949.
(E)-2-[4-(Trifluoromethyl)styryl]isoindoline-1,3-dione (13c). Mp:
202−204 °C (lit.59 mp 205−207 °C). 1H NMR (500 MHz, CDCl3): δ
7.92−7.90 (m, 2 H), 7.79−7.77 (m, 2 H), 7.68 (d, J = 15.15 Hz, 1H),
7.59 (d, 2H, J = 8.85 Hz), 7.55 (d, 2H, J = 8.85 Hz), 7.43 (d, J = 15.15
Hz, 1H). 13C NMR (125 MHz, CDCl3): δ 166.2, 139.7, 134.7, 131.6,
129.5, 126.3, 125.7 (q, J = 0.91 Hz), 123.8, 119.5, 118.4. HRMS (EI):
calcd for C17H10O2NF3 317.0664, found 317.0667.
1
basis of the H NMR, the purities of compounds were determined to
be ≥96%.
Ethyl 3-(4-Nitrophenyl)propanoate (16a). 1H NMR (300 MHz,
CDCl3): δ 8.12 (d, J = 8.6 Hz, 2 H), 7.35 (d, J = 8.6 Hz, 2 H), 4.10
(q, J = 7.1 Hz, 2 H), 3.04 (t, J = 7.4 Hz, 2 H), 2.65 (t, J = 7.6 Hz, 2 H),
1.21 (t, J = 7.2 Hz, 3 H). 13C NMR (75 MHz, CDCl3): δ 172.0, 148.3,
146.6, 129.2, 123.6, 60.6, 35.0, 30.6, 14.1. HRMS (EI): calcd for
C11H13O4N 223.0845, found 223.0846.
(E)-2-(4-Acetylstyryl)isoindoline-1,3-dione (13d). Mp: 188−
189 °C (lit.59 mp 187−189 °C). H NMR (300 MHz, CDCl3): δ
1
Ethyl 3-(4-Methoxyphenyl)propanoate (16b). 1H NMR (500
MHz, CDCl3): δ 7.11 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H),
4.12 (q, J = 7.3 Hz, 2H), 2.91 (t, J = 7.7 Hz, 2H), 2.58 (t, J = 7.7 Hz,
7.95−7.90 (m, 4 H), 7.79−7.76 (m, 2 H), 7.69 (d, J = 15.1 Hz, 1 H),
7.54 (d, J = 8.4 Hz, 2 H), 7.46 (d, 1 H, J = 15.1 Hz), 2.60 (s, 3 H). 13C
NMR (75 MHz, CDCl3): δ 197.4, 166.2, 140.9, 135.9, 134.7, 131.5,
2740
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The Journal of Organic Chemistry
Article
2H), 1.24 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 173.1,
158.2, 132.3, 129.3, 113.9, 60.7, 55.2, 36.3, 30.1, 14.1. HRMS (EI):
calcd for C12H16O3 208.1099, found 208.1097.
AUTHOR INFORMATION
Corresponding Author
*(Y.L.) Tel: (65)-6516-2688. Fax: (65)-6779-1691. E-mail:
chmlamyl@nus.edu.sg. (L.C.L.) Tel: +886-233661669. Fax:
+886-223636359. E-mail: lclo@ntu.edu.tw.
■
General Procedure for the Kumada Cross-Coupling be-
tween Grignard Reagents with Various Halides under Micro-
wave Heating. To a solution of the respective halide (0.25 mmol)
and anhydrous THF (1 mL) in a pressure tube was added palladacycle
1 (0.05 mol %) followed by 1 M Grignard reagent in THF (0.3 mL).
The reaction mixture was microwave irradiated (with the heating
program starting at 150 W) at 100 °C, and the reaction was monitored
by TLC. When the reaction has completed, the reaction mixture was
cooled to room temperature, poured into EtOAc (20 mL), and washed
successively with water (3 × 10 mL). The organic layer was dried over
anhydrous MgSO4, filtered, and concentrated. The crude product
obtained was purified by column chromatography. On the basis of the
1H NMR, the purities of compounds were determined to be ≥96%.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research is supported by grants from the National
University of Singapore (R-143-000-399-112 to Y.L.) and the
National Science Council of Taiwan (NSC 98-2113-M-002-
009-MY3 to L.-C.L.).
4-Methylbiphenyl (17a). Mp: 45−47 °C (lit.63 mp 43−44 °C).
1H NMR (500 MHz, CDCl3): δ 7.63 (d, J = 8.2 Hz, 2H), 7.50−7.44
(m, 2H), 7.42−7.36 (m, 2H), 7.06 (d, J = 8.2 Hz, 2H), 2.32 (s, 3H).
13C NMR (125 MHz, CDCl3): δ 141.2, 136.7, 131.2, 130.8, 128.7,
127.2, 127.1, 119.0, 20.5. HRMS (EI): calcd for C13H12 168.0939,
found 168.0937.
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ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds 1a−d, 1, 2a−e, 3a−e,
5a−d, 6a−d, 7a,b, 8a−k, 9a−d, 10a−e, 11a−e, 12a−c, 13a−e,
15a−c, 16a,b, 17a−e, and 18. 19F NMR spectra of compounds
1b−d and 1. FTIR spectrum of compound 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
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