Recyclable palladium catalysts for the heck/sonogashira reaction under microwave-assisted thermomorphic conditions

Article abstract of DOI:10.1002/jccs.201400252

The reaction of allyl palladium(II) chloride dimer and 4,4′-bis(R_fCH₂OCH₂)-2,2′-bpy, 1a-b, in the presence of AgOT_f resulted in the synthesis of cationic palladium complex, [Pd(η³-allyl)(4,4′-bis-(R

Full text of DOI:10.1002/jccs.201400252

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CHEMICAL SOCIETY
Article
Recyclable Palladium Catalysts for the Heck/Sonogashira Reaction under
Microwave-assisted Thermomorphic Conditions
Norman Lu,a,b,* Kwan-Yu Lin,a Chieh-Keng Li,a Chih-Chieh Kung,b Yun-Peng Yeh,a
Yao-Yi Chenga and Ling-Kang Liuc
aInstitute of Organic and Polymeric Materials, National Taipei University of Technology, Taipei 106, Taiwan
bDepartment of Molecular Science and Engineering, National Taipei University of Technology, Taipei 106, Taiwan
cInstitute of Chemistry, Academia Sinica, Taipei 115, Taiwan
(Received: Jun. 16, 2014; Accepted: Sept. 4; Published Online: ??; DOI: 10.1002/jccs.201400252)
The reaction of allyl palladium(II) chloride dimer and 4,4¢-bis(RfCH2OCH2)-2,2¢-bpy, 1a–b, in the pres-
ence of AgOTf resulted in the synthesis of cationic palladium complex, [Pd(h3-allyl)(4,4¢-bis-
(RfCH2OCH2)-2,2¢-bpy)](OTf), 2a–b where Rf = C9F19 (a), C10F21 (b), respectively. The reaction of
[PdCl2(CH3CN)] or K2PdCl4 with 1b, gave rise to the synthesis of [PdCl2(4,4¢-bis-(C10F21CH2OCH2)-
2,2¢-bpy)], 3b. The quantitatively determined solubility curves of 2a-b and 3b in DMF indicated dramatic
increase of solubility for 2a-b and 3b from -40 to 90 °C. The catalyst-recoverable Pd-catalyzed Heck/
Sonogashira reactions were successfully achieved in DMF with microwave-assistance. The cationic
Pd-catalyzed Heck arylation of methyl acrylate was selected to demonstrate the feasibility of recycling
2a-b using DMF as a solvent under microwave-assisted thermomorphic conditions. At the end of each cy-
cle, the product mixtures were cooled, and then the catalysts were recovered by decantation. The Heck
arylation catalyzed by 2b under microwave-assisted mode exhibited good recycling results favoring the
trans product. To our knowledge, this is the first example of cationic Pd-catalyzed Heck arylation under
microwave-assisted thermomorphic conditions. Additionally, recoverable 3b-catalyzed Sonogashira re-
actions were also achieved successfully in DMF. The reactions under microwave-assistance gave much
better results in yield and in efficiency than that under conventional thermal heating.
Keywords: Cationic palladium complex; Heck reaction; Sonogashira reaction; Microwave-assis-
tance; Recoverable; Homogeneous catalyst; Fluorous.
INTRODUCTION
Although organic chemical reactions at present still
aryl halides and arylboronic acids to form biaryls under mi-
crowave-assisted mode.6-7 Fast Pd-catalyzed aminations
have also been achieved by using temperature-controlled
microwave heating, which gave rise to good yields (75-
91%) in a reaction timeframe of only a few minutes.8-10
A homogeneous catalyst, where the catalyst is in the
same phase as the reactants, has advantages of optimizing
the efficiency of catalysis and providing a wide range of
chemoselectivity, regioselectivity and/or stereoselectivity.
This is because not only the catalysts can be modified eas-
ily by ligand design but their structure and reaction path-
ways can be characterized in detail by a range of spectro-
scopic techniques. Nevertheless, due to the difficulties of
separation and recyclization of the catalyst from product
mixture, it may be time consuming and/or environmentally
polluting in practice.11-12 Furthermore, heterogeneous ca-
talysis is a form of catalysis where the phase of the catalyst
differs from that of the reactants, and its advantage is that
take place mainly by thermal heating, microwave-assisted
chemical reactions have gained more popularity for the
past decades because of the rapidness and high efficiency
of reactions.1-4 We have recently synthesized a series of
cationic palladium complexes containing fluorous-pony-
tailed bipyridyl ligands and successfully evaluated them
for Heck arylation under the thermomorphic or fluorous
biphasic conditions.5 Nevertheless, the cationic Pd-cata-
lyzed reactions still take at least 3 h to completion. On the
other hand, it is well-known that microwave-assisted reac-
tions can quickly and directly couple the microwave energy
with the molecules of the entire reaction mixture such that
it leads to faster reaction kinetics to shorten the reaction
time. Additionally, Leadbeater et al. had presented the cou-
pling of phenylboronic acid with 4-bromoaceto-phenone
and also the transition-metal-free Suzuki-type coupling of
* Corresponding author. Email: normanlu@ntut.edu.tw
Supporting information for this article is available on the www under http://dx.doi.org/10.1002/jccs.201400252
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Article
Lu et al.
the catalyst is usually solid or metal and therefore is easier
to separate and recycle. Terasawa et al. prepared the reac-
tion of poly-4-diphenylphosphinomethyl-styrene with pal-
ladium chloride, with hydrazine in ethanol in the presence
of triphenylphosphine.13 Fukuyama et al. performed
[PdCl2(PPh3)2]-catalyzed Sonogashira coupling reaction,
in good to high yields, in an ionic liquid ([BMIm][PF6]) in
the absence of a copper salt.14 Lucas et al. demonstrated
that palladium and tungsten complexes effectively bind to
titanium dioxide nanoparticles (TiO2), which are easy to
separate and recycle after Sonogashira reaction.15 We re-
cently demonstrated that long fluorous-ponytailed Pd com-
plexes can effectively and recyclably catalyze the C-C
forming reactions under thermomorphic conditions.16
Therefore, by combining the advantages of efficiency and
rapidness of microwave-assistance with the advantages of
recoverability and effectiveness of Pd-catalysts under
thermomorphic conditions, we can make the organic reac-
tions more practical, economical and environ-mentally
friendly.
ture in the range from -30 and 10 °C. There was a dramatic
increase at ~10 °C. Similarly for cationic Pd complex 2b,
an onset temperature for solubility was found at approxi-
mately -20 °C and also a significant increase at temperature
slightly over 23 °C. Although complex 2a has a great op-
portunity in the thermomorphic recovery and recycling ap-
plication on Heck/Sonogashira reactions, as judged from
its excellent solubility when the temperature is greater than
10 °C, it is however, more difficult to operate on the cata-
lyst recovery when the temperature has to cool to much
lower than -30 °C. Thus, requiring only to cool down to -20
°C on recovery, the cationic Pd complex 2b was selected
for the subsequent catalytic experiments to investigate the
microwave-assisted, catalyst recyclable Heck/Sonogashira
reactions under thermormorphic conditions. The tempera-
ture dependent solubility curve of neutral palladium com-
plex 3b in DMF was similarly determined.16-17 The solubil-
ity of neutral Pd complex 3b starts at almost zero at 20 °C
and increases by several orders of magnitude when the tem-
perature is raised up to 90 °C.
The fluorous-ponytailed Pd complexes for the Heck
arylation have been reported in our previous studies.16,17
The Pd-catalyzed Heck reaction, discovered by R. F. Heck
(2010 Nobel Prize winner with E. I. Negishi and A.
Suzuki),18 is one of the most reliable and versatile methods
of synthesis in new drug development, manufacture of ac-
tive biological compounds, chemicals and industrial mate-
rials.19 The Pd-catalyzed Sonogashira reaction also gained
much attention for biological, chemical and material appli-
cations. Thus in this study, we focused and demonstrated
the microwave-assisted recoverable Pd-catalyzed Heck/
Sonogashira reaction under thermomorphic conditions.
The thermormorphic property of cationic 2b had al-
ready been utilized in efficient recycling experiments on
2b-catalyzed Heck reactions with conventional thermal
heating for 8 times.17
Microwave-assisted Heck Reaction of Nitroiodoben-
zene (4a) with Methyl Acrylate (5)
As shown in Scheme 1, the Pd-catalyzed Heck
arylation of methyl acrylate with aryl iodides was selected
RESULTS AND DISCUSSION
Figure 1 shows the temperature dependence of solu-
bility of cationic Pd complex 2a-b and of neutral Pd com-
plex 3b in DMF. The dissolution of cationic and neutral Pd
complexes in this polar aprotic solvent increased with in-
crease of temperature. The temperature dependence was
1
measured by H and 19F NMR spectroscopic methods,
where the temperature of NMR samples of Pd complexes
were varied from -40 to 90 °C. The integrated peak area of
aromatic proton signals on 2,2¢-bpy was compared to the
integrated peak area of terminal HCF2 group of
HCF2(CF2)3CH2OH, the internal standard. The cationic Pd
complex 2a started to show NMR signals in DMF at -30 °C.
Its solubility gradually increased with increasing tempera-
Fig. 1. Diagram of solubility of 2a-b and 3b as a func-
tion of temperature. The extent of solubility
change of 2a-b with temperature is greater than
that of 3b.17 Note: 2a-b: [Pd(h3-allyl)(4,4¢-bis-
(RfCH2OCH2)-2,2¢-bpy)](OTf) where Rf = n-
C9F19 (a), n-C10F21 (b), respectively; 3b:
PdCl2[4,4¢-bis-(n-C10F21CH2OCH2)-2,2¢-bpy)].
2
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Microwave-assisted Thermomorphic Conditions
Table 1. Recycling results of microwave-assisted 2b-catalyzed
Heck reaction for 4a with 5 under thermomorphic
conditions
The microwave-assisted 2b,3b-catalyzed
Scheme 1
Heck reaction under thermomorphic condi-
tions
Microwave
Power (W)
Temperature
(°C)
Cycle
Time (h)
Yield (%) TON
1
2
3
4
5
6
7
8
100
150
150
150
150
150
150
150
0.25
0.67
0.67
0.67
0.67
0.67
0.67
0.67
145
145
145
145
145
145
145
145
100
100
100
100
100
100
100
100
1000
1000
1000
1000
1000
1000
1000
1000
to demonstrate the feasibility of recycling usage with 2b or
3b as catalyst using DMF as solvent under the microwave-
assisted mode, at ca 100-150 W for 15-108 min. varying in
each cycle. At the end of each cycle, the product mixtures
were cooled to below -20 °C and centrifuged for recovery
of the catalyst (via decantation). The recovered 2b was
added with DMF, substrates, and base to proceed to the
next microwave-assisted run. The products were quantified
with GC analysis by comparison to the internal standard
(NMP). The results of Heck reaction exhibited a 100% se-
lectivity favoring the trans product in just 40 min. Shown
in Table 1, the Heck reaction of nitroiodobenzene (4a) with
methyl acrylate (5) catalyzed by 2b at 140 °C could be mi-
crowave heated with good recycling results for 8 times
within one hour, keeping the same trans selectivity, with
TON = 1000.
Note: Reaction conditions: DMF (5 mL); 4a (2.54 mmol, 513
mg), 5 (5.08 mmol, 437 mg), NEt3 (7.61 mmol, 1091 mg) or
NiPr3 (7.61 mmol), 2b (4 mg, 0.1 mol %).
Table 2. Recycling results of microwave-assisted 3b-catalyzed
Heck reaction for 4a with 5b under thermomorphic
conditions
Microwave Time Temperature
Cycle
Yield (%) TON
Power (W)
(hr)
(°C)
1
2
3
4
100
150
150
150
0.25
0.72
0.72
0.73
145
145
145
145
100
100
100
100
1000
1000
1000
1000
Note: Reaction conditions: DMF (3 mL); 4a (2.54 mmol, 554
mg), 5 (5.49 mmol, 472 mg), NEt3 (8.23 mmol, 1179 mg), 3b (4
mg, 0.1 mol %).
In Tables 1 and 3, the reaction time of microwave-as-
sisted Heck reactions using 2b were faster than that of ther-
mal heated counterparts reported before.17 For the micro-
wave-assisted reactions, all were completed within one
hour. The microwave power of 100 W was used to start up
the first reaction which usually performed much better than
the other runs, and then it was raised to 150 W and main-
tained at this wattage through the rest of the recycling runs.
To our knowledge, this is the first example of fluorous
cationic Pd-catalyzed Heck reaction under the micro-
wave-assisted mode with high yield and recyclability.
The neutral complex 3b was also used to catalyze the
same Heck reaction with microwave-assistance at 145 °C
under thermomorphic conditions. From the results of Ta-
bles 1 and 2, it is observable that the cationic complex 2b is
similar to the neutral complex 3b in catalyzing the Heck re-
actions using the similar microwave heating for the first
four repeating runs.
different features as shown in Table 3. The results from en-
tries (e.g. 1 & 2) in Table 3 indicate that 2b/3b-catalyzed
Heck reaction at about 140 °C under microwave-assisted
mode is about ten times faster than under thermal heating.17
The Heck reaction of 4b and 5 catalyzed by 2b/3b ex-
hibiting catalytic activity and convenient catalyst recycling
protocol under thermomorphic mode. Our previous studies
showed that after Heck reaction catalyzed by the cationic
catalyst 2b and the neutral catalyst 3b the residual Pd atom
present in the product is ca 3.5% and 0.01%, respectively.5
Microwave-assisted Heck Reaction of Iodoacetophe-
none (4b) with Methyl Acrylate (5)
The replacement of nitroiodobenzene (4a) by less ac-
tivated iodoacetophenone (4b) was attempted. The micro-
wave-assisted 2b/3b-catalyzed Heck reaction of iodoace-
to-phenone 4b with methyl acrylate 5 was studied to dem-
onstrate the feasibility of recycling usage using DMF as the
solvent at 145 °C, each cycle being finished in less than 2 h
reaction time. The results are listed in Table 4 and Table 5
The results from microwave-assisted reactions and
from thermally heated reactions17 for the 2b/3b-catalyzed
Heck reaction under thermomorphic conditions exhibited
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Table 3. Recycling results of 2b,3b-catalyzed Heck reaction of
4a with 5 under thermomorphic conditions
Table 4. Recycling results of microwave-assisted 2b-catalyzed
Heck reaction of 4b with 5 under thermomorphic condi-
tions
Reactants
catalyst
Time Temp
(h) (°C)
Entry
1
Method
Yieldb
Microwave
Power (W)
Temperature Yield
Cycle
Time (h)
TON
(°C)
(%)
(4a,5);2b microwave 0.25-
power 100- 0.67
150 (W)
145 100, 100, 100,
100, 100, 100,
100, 100.
1
2
3
150
150
150
0.25
1.56
1.23
145
145
145
100
91.6
90.3
1000
916
903
2a
(4a,5);2b thermal
3
140 100, 100, 100,
100, 100, 100,
100, 100.
Note: Reaction conditions: DMF (3 mL); 4b (2.54 mmol, 505
mg), 5 (5.08 mmol, 437 mg), Net3 (7.61 mmol, 1090 mg) or NiPr3
(7.61 mmol), 2b (4 mg, 0.1 mol %).
heating
3
(4a,5);3b microwave 0.25-
power 150- 0.73
200 (W)
145 100, 100, 100,
100.
Table 5. Recycling results of microwave-assisted 3b-catalyzed
Heck reaction of 4b with 5 under thermomorphic
conditions
4a
(4a,5);3b thermal
5-7
140 100, 00, 100,
100, 100, 100,
100, 100.
heating
Microwave
Power (W)
Temperature Yield
Cycle
Time (h)
TON
(°C)
(%)
Note: Reaction conditions: DMF (3 mL); 4a (2.54 mmol, 554
mg), 5 (5.49 mmol, 472 mg), NEt3 (8.23 mmol, 1179 mg), 2b or
3b (0.1 mol %). [a] The data (entries 2 & 4) shown here are from
the previous results.5
1
2
3
150
150
200
0.167
0.59
1.66
145
145
145
100
100
75.5
1000
1000
755
Note: Reaction conditions: DMF (3 mL); 4b (2.74 mmol, 546
mg), 5 (5.49 mmol, 472 mg), Net3 (8.23 mmol, 1179 mg), 3b (4
mg, 0.1 mol %).
for the 2b- and 3b-catalyzed Heck reactions, respectively.
Based on these results, it is easily found that when
aryl iodide carries an acetyl functional group on the ring,
the Heck reaction took longer time to completion than a ni-
tro functional group on the ring. In Tables 4 and 5, the mi-
crowave power was set at 150-200 W, the time 10-90 min,
and the temperature 145 °C.
wave-assisted Heck reaction.
Microwave-assisted Heck Reaction of Electron-donat-
ing 4-Iodobenzene Derivatives (4c or 4b) with Methyl
Acrylate (5)
Two more substrates with electron donating groups
have been added. These data are presented in Table 6. As
expected, when the substituents on aryl halides are electron
donating groups, they tend to slow down the reactions.
Although cationic 2b catalyst shows a better thermo-
morphic property than neutral 3b catalyst, the 3b actually
shows slightly better recycling results than 2b in the micro-
Table 6. Recycling results of 3b-catalyzed Heck reaction of methyl acrylate with two
electron-donating iodobenzene derivatives,a 4-X-C6H4-I, (X= CH3 or OCH3)
Reactant
4c or
4da:(when
X=)
Reactant 5b:
Entry Cycleb
Time (h) Temp (°C) Yieldc (%) TON
1
1st
CH3
Methyl acrylate
2
145
100
(99)
84
1000
2
3
2nd
1st
CH3
Methyl acrylate
Methyl acrylate
2
3
145
145
840
OCH3
100
(99)
97
1000
4
2nd
OCH3
Methyl acrylate
3
145
970
a (Reactant =) derivatives of iodobenzene, 4-X-C6H4-I, [X = CH3 (4c) or OCH3 (4d)].
b Reaction conditions: DMF (4 mL); 4-X-C6H4-I, [X = CH3 (4c) or OCH3 (4d)] (0.45 mmol),
methyl acrylate (0.90 mmol, 77.5 mg), Net3 (2.25 mmol, 227.7 mg), 2b (16 mg, 0.1 mol %).
c The yields inside the parentheses are isolated yields which agree well with GC/MS yields.
4
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Microwave-assisted Thermomorphic Conditions
Table 7. Recycling results of microwave-assisted 3b-catalyzed
Sonogashira reaction of nitroiodobenene 4a under
thermomorphic conditions
Thus, when people compare the results in Tables 1, 5 and 6,
this trend can be easily observed.
Microwave-assisted 3b-catalyzed Sonogashira Reac-
tion under Thermomorphic Conditions
Microwave
Power (W)
Temperature Yield
Cycle
Time (h)
TON
(°C)
(%)
When comparing the results from Tables 4 and 5, it
was found that 3b was mostly better than 2b in catalyzing
the Heck reaction under microwave-assisted conditions.
Thus, for the following studies of Pd-catalyzed Sonogashira,
only 3b was selected to study the CuI-free Pd-catalyzed
Sonogashira Reaction under microwave-assisted thermo-
morphic conditions.
1
2
3
4
5
6
7
8
120
120
120
120
120
120
120
120
0.420
0.167
0.167
0.167
0.167
0.250
0.250
0.250
145
140
140
140
140
140
140
140
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
The Pd-catalyzed Sonogashira reactions of phenyl-
acetylene with aryl iodide or aryl bromide were selected to
demonstrate the feasibility of recycling usage with 3b as
the catalyst using DMF as the solvent without using CuI
under microwave assisted mode, at 120 W for 10-25.5 min.
varying in different cycles (see Scheme 2).
Note: Reaction conditions: DMF (3 mL); 4a (0.27 mmol, 68 mg),
phenylacetylene (0.41 mmol, 42 mg), DABCO (0.82 mmol, 92
mg), 3b (4 mg, 1 mol %).
Table 8. Recycling results of microwave-assisted 3b-catalyzed
Sonogashira reaction of 4-nitrobrormobenzene 6a under
thermomorphic conditions
The microwave-assisted 3b-catalyzed Sono-
gashira reaction of aryl halide with phenyl-
acetylene under thermomorphic conditions
Scheme 2
Microwave
Cycle
Time (h) Temp (°C) Yield (%) TON
Power (W)
1
2
3
4
120
120
120
120
0.5
0.5
0.5
0.5
140
140
140
140
100
100
100
100
100
100
100
100
Reaction conditions: DMF (3 mL); 6a (0.27 mmol, 68 mg),
phenylacetylene (0.41 mmol, 42 mg), DABCO (0.82 mmol, 92
mg), 3b (4 mg, 1 mol %), CuI free.
As shown in Table 7, microwave-assisted 3b-cata-
lyzed Sonogashira reaction of 4-nitro-iodobenzene 4a can
be easily carried out and 3b reused for 8 times at 120 W and
at about 140 °C without using CuI under thermomorphic
conditions. Most importantly, the reactions were com-
pleted in less than 30 mins., with a 100% yield.
ing listed in Table 9 and Table 10, respectively.
Both Table 8 and Table 9 gave rise to almost identical
results, suggesting that the NO2 group and the CN group
exert almost identical electronic withdrawing effects on the
aromatic ring and hence the corresponding aryl bromides
proceeded to the CuI-free 3b-catalyzed Sonogashira reac-
tion under microwave-assisted mode in a similar manner.
When the C(O)Me group is on the aromatic ring, its elec-
tronic withdrawing effect is less than that of NO2 group or
CN group, and as shown in Table 10, its reaction rate is
slower accordingly.
Then we investigated the 3b-catalyzed Sonogashira
reaction of less reactive bromobenzene derivatives with
phenylacetylene under thermomorphic conditions with mi-
crowave-assistance. Table 8 shows that the CuI-free 3b-
catalyzed Sonogashira reaction of 4-nitrobromobenzene
(6a) and phenylacetylene under microwave-assisted mode,
led to quick completion, easy recovery, and 4 cycles of rep-
etition while the microwave power was 120 W and temper-
ature 140 °C. In view of this success, reactions with two
other activated bromobenzene derivatives cyanobromo-
benzene (6b) and bromoacetophenone (6c) were also car-
ried out successfully with good yields and the catalyst recy-
cled 4 times without loss of catalytic activity, the results be-
The 3b-catalyzed Sonogashira reaction of activated
bromo-benzene with phenylacetylene under thermomor-
phic conditions by conventional heating was studied previ-
ously20 in our laboratory. When comparing results from
previous studies with those under thermomorphic condi-
tions with microwave-assistance in Tables 8-10, an inter-
esting observation shown in Table 11 was that 3b-catalyzed
Sonogashira reaction, operated under microwave-assis-
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Table 9. Recycling results of microwave-assisted 3b-catalyzed
Sonogashira reaction of 4-cyanobromobenzene, 6b,
under thermomorphic conditions
Table 10. Recycling results of microwave-assisted 3b-catalyzed
Sonogashira reaction of 4-acetophenone, 6c, under
thermomorphic conditions
Microwave
Microwave
Cycle
Time (h) Temp (°C) Yield (%) TON
Cycle
Time (h) Temp (°C) Yield (%) TON
Power (W)
Power (W)
1
2
3
4
120
120
120
120
0.67
0.67
0.83
1
140
140
140
140
100
100
100
>99
100
100
100
>99
1
2
3
120
120
120
1
140
140
140
100
92.6
83.9
100
92.6
83.9
0.83
0.5
Note: Reaction conditions: 6c (0.27 mmol, 55 mg),
Note: Reaction conditions: DMF (3 mL); 6b (0.27 mmol, 50 mg),
phenylacetylene (0.41 mmol, 42 mg), DABCO (0.82 mmol, 92
mg), 3b (4 mg, 1 mol %), CuI free.
phenylacetylene (0.41 mmol, 42 mg), DABCO (0.82 mmol, 92
mg), 3b (4 mg, 1 mol %); DMF (3 mL), CuI free.
heating method there was a need to use 10% CuI for entries
1, 3, 5 in the 3b-catalyzed Sonogashira reaction of bromo-
benzene derivatives.
tance, has several advantages over the simple thermal heat-
ing method. The advantages include the fastness, the effi-
ciency and the greater yields. Using microwave-assistance
the reaction took less than one hour (entries 2, 4, 6) in that
the results show that the reactions with microwave-assis-
tance are essentially 100% completion as opposed to 66 to
93% with their counterparts (entries 1, 3, 5). It is also
clearly shown that under microwave-assisted mode there
was no need to use CuI for entries 2, 4, 6, but under thermal
Microwave-assisted 3b-catalyzed Sonogashira Reac-
tion of 4a with Other Substituted Phenyl Acetylene,
4X-C6H4-Cº C-H [X=CH3 (9b) or F (9c)] under
Thermomorphic Conditions
Two more substituted phenyl acetylenes which were
also selected for Sonogashira reactions. Shown in Table 12,
the results indicate that both two new substrates can also
Table 11. Recycling results of microwave-assisted 3b-catalyzed Sonogashira reaction of
activated bromobenzenes 6a-c with phenylacetylene under thermomorphic conditions
Entry Substrate
Method
Time (h) Temp (°C) 10%CuIa
Yieldb
1c
6a
6a
thermal heating
14
135
w
93, 92, 92, 90
2
microwave-assisted
w/o
100, 100, 100, 100
<1
14
<1
14
<1
140
135
140
135
140
3c
4
5c
6b
6b
6c
6c
thermal heating
microwave-assisted
thermal heating
w
w/o
w
85, 90, 82, 66
100, 100, 100, 100
50, trace
6
microwave-assisted
w/o
100, 93,84
Note: Reaction condition: 1 mol % Pd catalyst 3b (4 mg); DMF (5 mL); CuI-free (for entries 2, 4
& 6) or with 10% CuI (for entries 1, 3 & 5); 6a-c (0.275 mmol), phenylacetylene (0.33 mmol, 34
mg), DABCO: 1.5 equivalents (0.412 mmol, 46 mg); reaction time = 14 h (thermal heating) or <1
h (microwave). [a] w: with, w/o: without; [b] Based on GC yield (internal standard is NMP); [c] Data
of entries 1, 3 and 5 are the previous data from ref. 20.20
Table 12. Recycling results of microwave-assisted 3b-catalyzed Sonogashira Reaction
of 4a with other substituted phenyl acetylene, 4-X-C6H4-CºC-H [X=CH3
(9b) or F (9c)] under thermomorphic conditions
Reactant 9b
Entry Cycleb Reactant
or 9c
Time (h) Temp (°C) Yield (%) TON
(when X=)
1
2
3
4
1st
2nd
1st
4a
4a
4a
4a
CH3
CH3
F
0.5
0.5
0.5
0.5
140
140
140
140
100
100
95
100
100
95
2nd
F
95
95
Note: Reaction conditions: DMF (5 mL); 1-iodo-4-nitrobenzene (0.27 mmol, 67.23 mg),
9b or 9c (0.41 mmol), DABCO (0.82 mmol, 91.9 mg), 3b (4.00 mg, 1 mol %).
6
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CHEMICAL SOCIETY
Microwave-assisted Thermomorphic Conditions
easily undergo the Sonogashira reactions under micro-
wave-assisted reaction in the thermomorphic mode.
a 0.25 mm stationary phase film thickness. The flow rate was 1
mL/min and splitless injection was used. Samples analyzed by
fast atom bombardment (FAB) mass spectroscopy were deter-
mined by the staff of the National Central University (Taiwan)
mass spectrometry laboratory. Infrared spectra were recorded on
a Perkin Elmer RX I FT-IR Spectrometer. NMR spectra were re-
corded using a Bruker AM 500 or AM 300 using 5 mm sample
tubes. D-toluene, deuterated DMF, D-chloroform and deuterated
Me2SO were the references for both 1H and 13C NMR spectra; and
Freon® 11 (CFCl3) was the reference for 19F NMR spectra. Mi-
crowave-assisted reactions were operated on CEM Discovery mi-
crowave synthesis system at 2.5 atm.
CONCLUSIONS
In summary, the cationic Pd complexes (2a-b) con-
taining fluorous ponytailed bipyridyl ligands were synthe-
sized and 2b successfully evaluated for Heck arylation un-
der thermomorphic conditions using microwave-assisted
mode. The Pd complexes 2a-b in our earlier thermal heat-
ing studies showed excellent activity and reusability for 8
runs under thermomorphic conditions.21-25 The ionic nature
of cationic Pd complexes 2a-b gave rise to good thermo-
morphic property, rendering greater solubility in polar sol-
vents at high temperature. The thermomorphic property of
complex 2b gives high efficiency and good recyclability
which is very close to ideally recoverable catalyst.26,27 With
homogeneously catalytic activity at elevated temperature,
complex 2b can be easily precipitated from the product
mixture at less than -20 °C and collected by decantation.
The microwave-assisted Heck arylation of aryl iodide with
methyl acrylate was easily achieved with very high TON
under themomorphic conditions.
Chemicals, reagents and solvents employed were commer-
cially available and used as received. C9F19CH2OH (a) and
C10F21CH2OH (b) were purchased from Aldrich and SynQuest.
Preparation of cationic Pd complexes, 2a-b, and neutral Pd com-
plex, 3b, where Rf = n-C9F19 (a) and n-C10F21 (b). As shown in
Scheme 3, the similar procedure for the synthesis of 2a-b was re-
ported before and was briefly mentioned again below. The reac-
tion of allylpalladium(II) chloride dimer and AgOTf with two
highly fluorinated bipyridine derivatives, 4,4¢-bis(RfCH2OCH2)-
2,2¢-bpy (1a-b) in different reactions were charged into a round
bottomed flask, and CH2Cl2 (3 mL) added as the solvent. After the
solution color changed from red to yellow, the solution was fur-
ther stirred at 60 °C for 24 h before the solvents and volatiles were
removed under vacuum, resulted in the synthesis of cationic com-
plex, [Pd(h3-allyl)(4,4¢-bis-(RfCH2OCH2)-2,2¢-bpy)](OTf) 2a-b,
as the pale yellow solid, where Rf = n-C9F19 (a), n-C10F21 (b), re-
spectively. In addition, the complex 3b, {PdCl2[4,4¢-bis-(n-
C10F21CH2OCH2)-2,2¢-bpy)]}, was synthesized by the reaction of
1b with K2PdCl4 {or [PdCl2(CH3CN)2]; this procedure reported
elsewhere21 under reflux for overnight. After the reaction, the pre-
cipitate solid was collected by filtration and washed with ether
and water for 3 times. The resulting yellow solid was collected as
spectroscopically pure product with 94% yield.
Furthermore, the microwave-assisted, recoverable,
CuI-free 3b-catalyzed Sonogashira reaction of aryl halides,
aryl bromide in particular, has also been successfully
achieved in DMF under thermomorphic conditions. The re-
sults show that 3b-catalyzed Sonogashira reaction oper-
ated under microwave-assisted mode is much better in
yield and in efficiency than under thermal heating.
In short, the catalytic system discussed here has inte-
grated the advantages of the microwave-assisted fast reac-
tion and the thermomorphic catalysis to realize short reac-
tion time, high catalytic activity, easy catalyst re-cycliza-
tion and without significant loss of activity for the Pd-cata-
lyzed Heck/Sonogashira reactions.
EXPERIMENTAL
Scheme 3 Synthesis of 2a-b and 3b
General: Microwave irradiation experiments were con-
ducted in a CEM Discoverer microwave with ramp times mostly
within 60 min, and with 20 min cooling. The reaction mixture was
contained in a sealed tube in the microwave oven and irradiated at
the power specified in all the related tables, which also gives the
solvent, reactants, reaction temperature and the reaction time etc.
Gas chromatographic/mass spectrometric data were carried
out using an Agilent 6890 Series gas chromatograph with a series
5973 mass selective detector. The reaction was monitored with a
HP6890 GC using a 30 m ´0.250 mm HP-1 capillary column with
J. Chin. Chem. Soc. 2014, 61, 000-000
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7

Article
Lu et al.
The purities of cationic Pd complexes 2a-b and neutral Pd
C3H6O2), 102 (M+-C4H6O3) (8a: 4-O2NC6H4CCPh) 1H NMR (300
MHz, CDCl3): d (ppm) 8.19 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8
Hz, 2H), 7.55-7.52 (m, 2H), 7.38-7.36 (m, 3H); 13C NMR (75
MHz, CDCl3) d (ppm): 146, 132, 131, 130, 129, 128, 123, 122, 94,
87; GC/MS (m/z; EI): 223 (M+), 193 (M+-NO), 177 (M+-NO2),
165 (M+-CNO2), 151 (M+-C2H2NO2). (8b: 4-NCC6H4CCPh)1H
NMR (300 MHz, CDCl3) d (ppm): 7.59-7.58 (m, 4H), 7.51-7.54
(m, 2H), 7.37-7.35 (m, 3H); 13C NMR (75 MHz, CDCl3) d
(ppm):132, 131, 131, 129, 128,128, 122, 118, 111, 93, 87; GC/MS
(m/z; EI): 203 (M+), 176 (M+-CHN), 150 (M+-C3H3N), 101 (M+-
C7H4N), 88 (M+- C8H5N), 75 (M+-C9H6N). (8c: 4-CH3C(=O)
C6H4CCPh) 1H NMR (300 MHz, CDCl3) d (ppm): 7.92 (d, J = 8.0
Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.55-7.51 (m, 2H), 7.35 (m, 3H),
2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) d (ppm): 197, 136, 131,
128, 128, 122, 92, 88, 26; GC/MS (m/z; EI): 220 (M+), 205
(M+-CH3), 176 (M+-C2H4O), 151 (M+-C4H5O), 88 (M+-C9H8O).
catalyst 3b were checked by comparing with the literature data.
The analytical data of 2a-b and 3b were listed in ref. 5 and ref. 20,
respectively.5,20 Microwave-assisted Heck reaction recycling
with Pd complex 2b as a catalyst under thermomorphic condi-
tions. In a typical microwave-assisted Pd-catalyzed Heck reac-
tion run, the reaction vessel was charged with DMF (5 mL), 4a,
methyl acrylate (4b), triethylamine or tripropylamine (3 eq.) and
the 0.1 mol % Pd complex 2b (about 4 mg). Then the reaction
mixture was set to react under the microwave-assisted mode at ca
100-150 wattage of power for 15-108 minutes varying in each cy-
cle before GC analysis. After the reaction, the product mixtures
were cooled to -30 °C by the cold bath (for convenient operation,
the -20 °C freezer was frequently used.) and the precipitated cata-
lyst was centrifuged and quickly recovered by decantation at
room temperature after each run. The recovered Pd catalyst was
washed with 2 mL DMF (or CH2Cl2) three times before proceed-
ing to the next microwave-assisted run.
ACKNOWLEDGEMENTS
Microwave-assisted, CuI-free Sonogashira reaction recy-
cling with Pd complex 3b as a catalyst under thermomorphic con-
ditions. In a typical run, the reaction vessel was charged with
DMF (5 mL), 4a (or 6a-c) (0.275 mmol), pheylacetylene, DABCO
(0.825 mmol, 92.4 mg) and the 0.1 mol % Pd complex 3b (4 mg).
Then the reaction mixture was subject to microwave irradiation
for a short period of time while temperature was maintained at ca
145 °C before GC analysis. After the reaction, the product mix-
tures were centrifuged and the precipitated 3b was recovered by
decantation at room temperature after each run. The recovered 3b
was washed with 2 mL DMF (or CH2Cl2) several times before
proceeding to the next microwave-assisted cycle. And the prod-
ucts were analyzed by GC/MS and NMR spectrometer.
The authors thank the National Science Council
(NSC-101-2113-M-027-004-MY3)), Taiwan, for the fi-
nancial support. We would also like to thank Dr. R.
Sobocinski (DuPont) for proofreading the manuscript.
SUPPORTING INFORMATION
The1H NMR, 13C NMR spectra and mass diagrams of
7a, 7b, 8a, 8b and 8c are shown as the supporting informa-
tion.
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