Chapter Six Synthetic Applications of a Novel...
Transcript of Chapter Six Synthetic Applications of a Novel...
Synthetic Applications of a Novel Pd(OAc)2/DABCO/Hydrotrope Combined Catalyst at Room Temperature
166
Chapter Six
Synthetic Applications of a Novel Pd(OAc)2/DABCO/Hydrotrope
Combined Catalyst at Room Temperature
6.1 Introduction
Coupling reactions are widely used routes for the formation of carbon-
carbon bonds and carbon–hetero atom bonds particular for the synthesis of
biaryl compounds. For Suzuki–Miyaura cross coupling reaction, the most often
used polar aprotic solvents are DMF, toluene, acetonitrile, THF and dioxane
because they allow best solubility of both the substrates and the catalyst.
Therefore, high conversions can be obtained in short reaction times, under mild
conditions with higher selectivities. But many of these solvents are toxic or
they are not easy to remove from the product because of high boiling points.
These solvents are the main reason for a non satisfying E factor (environmental
factor) especially in the pharmaceutical industry. The results of their use are
emissions to atmosphere and water pollution. Now a days, new solvents like
ionic liquids, supercritical fluids, fluorous solvents as support for homogeneous
catalysts are widely used in organic synthesis [1]. However, these alternative
reaction media are currently of considerable interest due to increasing emphasis
on making organic processes ‘greener’ by minimizing organic waste in the
form of organic solvents. The most likely alternative among the various choices
available, in terms of potential generality, is reaction in water.
SM reaction is generally carried out at high reaction temperature, which
has its drawback in lower selectivity, deactivation of catalyst and mass transfer
limitations. These disadvantages limit the SM reaction at high temperature,
hence the reaction at room temperature is highly desirable. The reaction was
mostly carried out by homogeneous catalytic systems, because of their high
reactivity, high turnover numbers and milder reaction conditions. However, the
efficient separation and subsequent recycling of homogeneous Pd catalyst
remains a scientific challenge and an aspect of economical relevance. Research
on recycling of the catalyst attracts interest but is rarely established in industry.
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In a biphasic solvent mixture, substrates and product are, dissolved in one
solvent whereas the catalyst is dissolved in the other, and hence a catalyst
recycling can be accomplished by easy decantation.
1,4-Diazabicyclo [2.2.2] octane (DABCO), a cage-like compound (Fig.
6.1), is a small diazabicyclic molecule with medium-hindrance. It is used to
regulate the reaction rate in flexplay time-limited DVDs by adjusting pH.
Antioxidants, like DABCO, are used to improve the lifetime of dyes. This
makes DABCO useful in dye lasers and in mounting samples for fluorescence
microscopy [2].
Fig. 6.1 DABCO has received considerable attention as an inexpensive,
eco‐friendly, high reactive, easy to handle and non‐toxic base catalyst for
various organic transformations, affording the corresponding products in
excellent yields with high selectivity Fig. 6.2. The reactions are environmental
friendly and the catalyst can be recycled in some cases. Applications of
DABCO in synthetic chemistry have been reviewed by Bita Baghernejad [3].
Fig. 6.2
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Morita–Baylis–Hillman reaction (MBH) is an organic reaction of an
aldehyde and an α, β-unsaturated compound containing electron-withdrawing
group to give an allylic alcohol in presence of DABCO as a catalyst (Scheme
6.1). The MBH reaction, in the present day version, is an atom-economic
carbon-carbon bond formation reaction [4].
R1
CHO
+ EWG
DABCO
R1
OH
EWG
Scheme 6.1
Luque and Macquarrie [5] have developed a metal-free DABCO
catalyst for Sonogashira coupling with or without microwave (Scheme 6.2).
DABCO
I
F CF3
Ph +
F
F3C
Ph
n-decane, heat
Scheme 6.2 Choe and Lee [6] demonstrated stereoselective DABCO-catalyzed
synthesis of (E)-α-Ethynyl-α,β-unsaturated esters (Scheme 6.3) from allenyl
acetates.
R
OAc
COOEt
. R
COOEtDABCO
DMF, rt
Scheme 6.3
Sarlo and co-workers [7] demonstrated DABCO as an efficient reagent
for the synthesis of isoxazole derivatives (Scheme 6.4) from primary nitro
compounds and dipolarophiles.
R NO2
R2R1
+
DABCO
CHCl3O
N
R1
R2
R
Scheme 6.4
Li and co-workers [8] have extensively studied the phosphine-free C-C
bond forming reactions using DABCO as a ligand under various reaction
conditions and are reviewed in Table 6.1.
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Table 6: Reported application of Pd(OAc)2/DABCO system in cross coupling
reactions.
X B(OH)2
R1 R2
+N
N
Pd-cat, base, solvent
R1
R2
Sr. No Reaction Solvent Temperature (ºC) Reference
1 Suzuki Acetone 110 [8a]
2 Suzuki DMF 110 [8b]
3 Suzuki PEG-400 110 [8c]
4 Stille Dioxane 100 [8d]
5 Sonogashira CH3CN MW [8e]
6 Sonogashira - Ball Milling [8f]
7 Sonogashira CH3CN RT [8g]
About many decades chemists began to retrieve the benefits of water as a
lovely substitute to the conventional organic solvents, not only due to the
availability and economical concern but also its greenness [9]. Traditionally
water is not proper solvent for organic transformations because of the limited
solubility of many organic substrates and reagents and functional group
tolerance, which causes the catalyst decomposition and deactivations.
Though recently effective methodologies are reported in literature for SM
reaction at room temperature in various organic solvents and in water with
heating, to the best of our knowledge very few data is available related to this
reaction in water at ambient temperature. Hence, to carry out SM reaction in
water at room temperature is highly desirable (Fig. 6.3).
Fig. 6.3
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In literature a variety of SM reactions has been carried out and outlined
bellow:
6.1.1 Suzuki-Miyaura reaction at room temperature in organic solvents.
6.1.2 Suzuki-Miyaura reaction at high temperature in water
6.1.3 Suzuki-Miyaura reaction at room temperature in water.
6.1.1 Suzuki-Miyaura reaction at room temperature in organic solvents:
Chun Liu et al. [10] developed a convenient, effective and mild protocol
for the palladium-catalyzed ligand-free Suzuki-Miyaura reaction in aqueous
DMF in presence of PdCl2 at room temperature.
Zhang and co-workers [11] developed a highly efficient
Pd(OAc)2/guanidine/ethanol:water system for the room temperature SM cross-
coupling reaction (Scheme 6.5).
Scheme 6.5
Saito and Fu [12] developed Ni-catalyzed SM cross-coupling of
unactivated alkyl electrophiles with alkylboranes at room temperature using
commercially available trans-N,N'-dimethyl-1,2-cyclohexanediamine ligand in
dioxane (Scheme 6.6).
R X
R1
NBB-9 NiCl2 glyme ligand
dioxane, rtR
R1
NH2
NH2
Ligand
+
Scheme 6.6
A versatile method was developed by Kirchhoff and co-workers [13]
for the cross-coupling of boronic acids with unactivated alkyl electrophiles at
room temperature using Pd(P(t-Bu)2Me)2 in t-amyl alcohol.
Rahimi and Schmidt [14] demonstrated 3,3'-[3,4-
Bis(dichloromethylene)cyclobut-1-ene-1,2-diyl]bis(1-methyl-1H-imidazolium)
bis(tetrafluoroborate), palladium(II)acetate catalyzed SM reactions (Scheme
6.7) in toluene.
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Scheme 6.7
Nolan et al. [15] developed (NHC)Pd(R-allyl)Cl complexes for Suzuki-
Miyaura reaction (Scheme 6.8) at room temperature in isopropanol.
Scheme 6.8
Yang, Li and Wang [16] introduced a recyclable Merrifield resin
immobilized phenanthroline-palladium(II) complex for SM reaction (Scheme
6.9) under mild reaction conditions.
Scheme 6.9
Zhang and co-workers [17] developed a highly active, air- and moisture-
stable and easily recoverable magnetic-nanoparticle-supported Pd catalyst
(Scheme 6.10) for SM reaction in ethanol.
Scheme 6.10
6.1.2 Suzuki-Miyaura reaction at high temperature in water:
Chao-Jun Li [18] demonstrated that Suzuki-Miyaura reaction in high-
temperature water without transition metals (Scheme 6.11).
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B(OH)2
+
Z
Br
TBAB, Na2CO3
Water, 150 oCZ
Z = Me, Ome, Cl, NH2, NO2 etc Scheme 6.11
Major modification is made available by use of soluble catalyst or
ligands [19] with this regard organoaqueous media which uses the water
soluble ligand has been emerged as a new way to carry out reactions in water.
As a part of a biphasic reaction mixture with the catalyst in the aqueous phase
and the product dissolved in the organic phase, easy product separation and
catalyst recycling is possible. This newly developed catalytic system that can
promote SM reaction in aqueous medium under mild reaction conditions using
a highly accessible and cheap ligand system would be extremely advantageous.
Liu and co-workers [20] developed oxygen-promoted PdCl2-catalyzed
ligand-free SM reaction in aqueous media.
Savignac et al. [21] described SM cross-coupling reactions between a
range of aryl bromides and boronic acids using a water-soluble Pd(0)/TPPTS
catalyst (Scheme 6.12) under mild conditions with high efficiency.
B(OH)2
+
R
Br
5 % Pd(OAc)2
15 %TPPTS
WaterR
Scheme 6.12
Shaughnessy and Booth [22] described sterically demanding, water-
soluble alkylphosphines (Fig. 6.4) in SM coupling in aqueous solvents.
3
SO3Na
P
1
2 3
Bu3P
NMe3
+
Cl-NMe3PR2
+
Cl-
Fig. 6.4
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Thermo regulated solvents, which are applied to enhance the
recyclability and because of environmental aspects, solvents, which are toxic or
non-volatile should be replaced with the aim of waste prevention rather than
waste treatment. Therefore, several research groups working in these areas
focused on different ideas. Liu et al. [23] developed an efficient and recyclable
protocol for the SM reaction in water based on the cloud point of thermo
regulated ligand Ph2P(CH2CH2O)nCH3 (Fig. 6.5).
Fig. 6.5
Jin and co-workers [24] introduced water-soluble imidazolium salts
bearing poly(ethylene glycol) moieties directly attached to N-atom of
imidazole which could be served as NHC precursors for the Pd-catalyzed SM
reaction in water (Fig. 6.6).
Fig. 6.6
Fleckenstein and Plenio [25] developed the highly active Pd complex of
the new disulfonated 9-(3-phenylpropyl)-9-PCy2-fluorene ligand (Fig. 6.7) in
aqueous SM coupling reactions.
Fig. 6.7
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The use of microwave ovens in organic synthesis is well acknowledged,
which is another alternative green technology in heating. The heating effect
utilized in microwave-assisted organic transformations is due to the dielectric
constant of the solvent. It is particularly convenient that, qualitatively, the
larger the dielectric constant of the reaction medium, greater is the absorption
of microwaves. With its high dielectric constant, water is also potentially a very
useful solvent for microwave-assisted organic synthesis.
There are various reports in literature [26] which uses MW assisted Pd
catalyzed reactions in water. Leadbeater and Marco [27] showed that the
Suzuki-type coupling of boronic acids and aryl halides is possible without the
need for a transition-metal catalyst under MW in water in presence of TBAB as
additive.
Yu and co-workers [28] demonstrated microwave-promoted SM
coupling reaction of aryl chlorides with boronic acids performed in an aqueous
media using air- and moisture-stable catalyst POPd2 (dihydrogen di-µ-
chlorodichlorobis(di-tert-butylphosphinito-κP)dipalladate) (Fig. 6.8).
Fig. 6.8
6.1.3 Suzuki-Miyaura reaction at room temperature in water (Use of
amphiphiles):
Peng and co-workers [29] disclosed an efficient catalytic system for the
ligand-free Suzuki–Miyaura reaction in water at room temperature, using
Stilbazo (Fig. 6.9) as a surfactant.
Fig. 6.9
Das and co-workers [30] described in situ generated catalytic system
based on PdCl2 and primary amine-based ligand (Fig. 6.10) in the SM reaction
of arylhalides in water, at room temperature, without any additive.
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Fig. 6.10
Suzuki-Miyaura reaction at room temperature in water has been
generally carried out in the presence of additives, which increases the solubility
of substrates in water. The diverse set of amphiphiles is reported in literature.
Yamamoto [31] has recently developed transition metal-catalyzed aryl
C–H bond activation reactions which provide an especially direct and atom
economical approach for functionalizing aromatic rings using Brij surfactant.
Zhang et al. [32] have shown that Pd(OAc)2, in combination with PEG,
can be used as a highly efficient catalyst for the SM coupling reaction in water.
Palladium-catalyzed Suzuki cross-coupling reaction in presence of
catalytic amount of quaternary ammonium salts Aliquat 336
(tricaprilylmethylammonium chloride) was described by Colobert and co-
workers [33].
Arcadi and his group [34] described palladium-catalyzed
Suzuki−Miyaura cross coupling reaction in various aqueous surfactants under
mild conditions.
Palladium on activated carbon (Pd/C) is also used as catalyst with the
advantages in recovery, refining of the palladium, the better performance at
higher temperatures without the need of expensive phosphine ligands and it
shows a low metal contamination of the products. The used carbon is
inexpensive and its large surface area (~1000 m2/g) allows Pd to disperse
widely on its surface. Carbon as support material is more stable to basic and
acidic conditions than alumina or silica. Recent reports have demonstrated the
applications of Pd/C for the Suzuki-Miyaura coupling as a convenient and
phosphine-free catalyst [35].
Lipshutz et al. [36] have published a series of papers demonstrating the
use of PTS (Polyoxyethanyl-α-Tocopheryl Succinate) surfactant derivative
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(Fig. 6.11) in number of palladium- and ruthenium-catalyzed reactions in water
at room temperature.
Fig. 6.11
Unlike many amphiphile PTS is an unsymmetrical diester containing
three components: a dicarboxylic acid (Sebacic acid), a lipophilic portion in
vitamin E (or α-Tocopherol), and a hydrophilic subsection based on PEG-600
(Scheme 6.13).
B(OH)2
+
R2
Br
PTS
Water, RTR2
R1
R1
Scheme 6.13
Lipshutz and co-workers [37] have recently developed a second
generation surfactants based on the polyoxyethanyl-α-tocopheryl succinate
derivative, TPGS-750-M (Fig. 6.12).
Fig. 6.12
It is an effective nano micelle-forming diester species composed of
racemic α-tocopherol, MPEG- 750, and succinic acid, and has been readily
prepared and used in metal-catalyzed cross-coupling reactions like Heck,
Suzuki-Miyaura, Sonogashira, and Negishi, in water.
Hence, this chapter focuses on the application of Pd/DABCO catalyst, in
which a hydrpotrope enables the Nobel prize award-winning Suzuki-Miyaura
coupling reaction to be run in water at room temperature which is not been
reported in literature yet. Within the frame a parallel work of other coupling
reactions is processing in our laboratory.
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6.2. Present work
Recently highly effective methodologies are reported in literature for
Suzuki-Miyaura reaction at room temperature. Major modification is
forthcoming by use of soluble catalyst or ligands. Although these approaches
lead to water soluble catalysts, a sequence of steps is required in each
preparation. Hence very simple protocol for affecting the water solubilization
at room temperature in absence of co-solvent and without recourse to
alterations in substrate/commercial catalyst design is of prime importance.
To engender solubility most reactions in water were performed using a
co-solvent or some co-solutes such as PTC, surfactants etc [38]. Another
approach towards increasing the potential of water for organic synthesis to
compete with organic solvents is hydrotropism [39] similar to miceller catalysis
[40]. Thus hydrotropes are small amphiphilic molecules with hydrophilic
character having ability to increase solubility of organic compounds many fold
excess in water. As such hydrotropes are of great industrial interest, notably
their applications in drug solubilization in pharmaceuticals, separation sciences,
nanocarriers, and organic transformations.
There is large number of reports available, which uses the phosphine
ligands, as they show high activity in Suzuki-Miyaura reaction. But major
obstacle by use of phosphines is their toxicity, air sensitivity and difficulty in
reusability due to the formation oxide having high environmental concern.
Hence, development of phosphine-free Pd catalysis is emerged as new catalytic
tool in transition metal catalyzed reactions [41]. In this regard amine ligands
are emerging as good alternatives in many Pd catalyzed reactions [42], because
of ease of tuning their electronic characters, less toxicity and easy availability.
Recently DABCO was found to act as useful ligand in many Pd catalyzed
phosphine-free cross coupling reactions.
Very recently, we have demonstrated hydrotrope as efficient, green,
recyclable reaction medium for various organic transformations. Hence we
expected that this medium might help to improve the Pd(OAC)2/DABCO
mediated cross-coupling reactions at ambient temperature. Here, we report the
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detail study of Pd(OAC)2/DABCO/Hydrotrope combined catalyst for SM
reaction in aqueous medium at room temperature. Our motivation is to develop
aqueous reaction medium for Pd catalyzed C-C bond forming reactions with
high activity to compete with the homogeneous catalysts.
6.3 Results and discussion
In search of more economically, commercially available, functionally
viable amphiphilic hydrotropic agents like Sodium p-Toluene Sulphonate
(NaPTS), Sodium Xylene Sulphonate (NaXS), Sodium Benzene Sulphonate
(NaBS) and Sodium Salicylate (NaS) found immense importance. At the
outset, 4-bromobenzophenone 1 and phenyl boronic acid 2 were employed as
the reaction partners to optimize the various reaction conditions in aqueous
hydrotropic solution (Scheme 6.14) at room temperature.
O
Br
BOHOH
+
O
K 2CO 3
aq.hydrotropic solution
Pd(OAc) 2 , DABCO
1 23
Scheme 6.14 Pd(OAc)2/DABCO/Hydrotrope combined catalyst for
Suzuki-Miyaura coupling reaction.
The key focus of the use of hydrotropes as a reaction media depends on
the nature of the hydrotrope used and its minimum hydrotropic concentration
(MHC). MHC of NaXS hydrotrope is 0.012 M aqueous solution [43], this
concentration was first chosen to study its effect for Suzuki-Miyaura reaction
in water. It was observed that only 50 % conversion was obtained at room
temperature after stirring the reaction mixture for prolonged reaction time
(Table 6.2, entry 1).
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Table 6.2: Optimization of hydrotrope concentration in Suzuki–Miyaura
coupling reactiona
Entry Concentration
(w/v %)
Time
(h)
Yieldb (%)
1 0.012M 25 50
2 10 20 50
3 20 16 60
4 30 5 97
5 40 2.5 96
6 50 4.0 96
7 60 1.0 96
8 70 1.25 97
9 80 5 90
aReaction conditions: arylhalide (1.0 mmol), arylboronic acid (1.1 mmol), Pd(OAc)2 (1 mol
%), DABCO (10 mol %), K2CO3 (2.0 mmol) and aq. hydrotropic solution (5.0 mL), room
temperature under air. bIsolated yields after purification.
With this result in hand, we have determined the optimum amount of
hydrotrope in water to obtain maximum conversion of substrates in minimum
time. Hence various wt % solutions from 10-80 % of NaXS were screened. It
was observed that 60 % NaXS concentration in water appeared to be more
effective. Reactivity maxima are frequently observed for many reactions
reported in hydrotrope aggregates, which leads to the conclusion that there
must be an optimal reaction site in aggregate where the rate of reaction is
maximum.
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Table 6.3: Optimization of catalyst and ligand loading in Suzuki–Miyaura
coupling reactiona
Entry Pd(OAc)2
(mol %)
DABCO
(mol %)
Time
(h)
Yieldb (%)
1 0.25 10 10 20
2 0.5 10 4.5 90
3 1.0 10 1.0 96
4 2.0 10 1.0 97
5 1.0 5 1.0 96
6 1.0 10 1.0 96
8 1.0 20 1.0 96
9 1.0 - 12 70
10 1.0 TPP
(10 mol%)
16 10
aReaction conditions: arylhalide (1.0 mmol), arylboronic acid (1.1 mmol), Pd(OAc)2 (0.25-
1mol %), DABCO (5-20 mol %), K2CO3 (2.0 mmol) and 60 % aq. hydrotropic solution (5.0
mL), rt under air. bIsolated yields after purification.
The use of hydrotrope is advantageous as it is commercially available,
very least expensive and can be recycled many times with simple reaction
workup.
As hydrotropes increase the solubility of reactants in many fold excess,
the product precipitates on dilution with water from hydrotropic solution,
which leads to the product formation in crystalline form with an improved
purity, and the mother liquor can be used to concentrate the hydrotrope for
recycling. After the completion of reaction as monitored by TLC, the reaction
mixture is quenched with water and the crude products were either filtered
directly or extracted with diethyl ether. The addition of diethyl ether facilitates
the phase separation, which makes the separation of product facile.
When model reaction was carried in absence of NaXS, under identical
conditions, gave trace amount of the product. This observation suggests that the
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181
hydrotrope is presumably providing micro-environment for substrate or reagent
or catalyst accumulation in which the coupling takes place.
Next, optimization of Pd catalyst and DABCO ligand was done. After
various experimentations 1 mol % Pd(OAc)2 and 10 mol % DABCO was found
to be best for maximum conversion in minimum time at ambient temperature
(Table 6.3). Without any ligand, only a 70 % yield of the corresponding
product 3 was obtained in the presence of 1 mol % Pd(OAc)2 and 2 equivalent
K2CO3 (Table 6.3, entry 9), whereas the yield was increased to 96 % when 10
mol % DABCO was added. No increase in yield was observed, with increase in
amount of DABCO (Table 6.3, entry 8). When same reaction was carried in
presence of 10 mol % TPP the yield decreased to 10 % in 16 h indicate that
DABCO is far more effective than phosphines (Table 6.3, entry 10).
After the optimization of Pd, DABCO and hydrotropic concentration, a
series of hydrotropes such as, NaPTS, NaBS, NaS were used along with
Pd(OAc)2 and DABCO for model reaction with 60 % concentration. Results
revealed that NaXS is more active as compared to NaPTS, NaBS and NaS
(Table 6.4).
Table 6.4: Screening of the various hydrotropes for Suzuki–Miyaura coupling
reactiona
Entry Hydrotrope Hydrotropic
concentration (% w/v)
Time
(min)
Yieldb
(%)
1 NaPTS 60 1.5 95
2 NaXS 60 1 96
3 NaBS 60 2.5 93
4 NaS 60 5 92
aReaction conditions: arylhalide (1.0 mmol), arylboronic acid (1.1 mmol), Pd(OAc)2 (0.25-
1mol %), DABCO (5-20 mol %), K2CO3 (2.0 mmol) and 60 % aq. hydrotropic solution (5.0
mL), rt under air. bIsolated yields after purification.
We next investigated the scope of this reaction using different bromo
compounds with various aryl boronic acids in 60 % aqueous NaXS solution
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182
with 1 mol% Pd(OAc)2 and 10 mol% DABCO (Table 6.5) at ambient
temperature.
Table 6.5: The Suzuki-Miyaura reaction of various aryl halides and
arylboronic acidsa
Entry Aryl halide Arylboronic
acid Product
b
Time
(h)
Yieldc
(%)
1
O
Br
BOH)2
O
1 96
2
BOH)2
F
O
F
1 96
3 B(OH) 2
O
1 93
4 CH3
O
Br
BOH)2
O
0.75 96
5 B(OH) 2
CH3
O
0.75 95
6 CH3
O
Cl
BOH)2
CH3
O 24 20
7 H
O
Br
BOH)2
H
O 1 95
8 B(OH) 2
H
O
1 94
9
Br
BOH)2
12 40
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10 NBr Br
BOH)2
N
0.5 96
11
B(OH)2
Et
N
CH3 CH3
1 95
12
Br
BOH)2
18 50
aReaction conditions: arylhalide (1.0 mmol), arylboronic acid (1.1 mmol), Pd(OAc)2 (1 mol
%), DABCO (10 mol %), K2CO3 (2.0 mmol) and 60 % aq. hydrotropic solution (5.0 mL),
room temperature under air. bAll products were analyzed by
1H NMR,
13C NMR, and Mass spectroscopy.
cIsolated yields after purification.
4-Chloro acetophenone gave very less desired product even on
extending the reaction time to 24 h (Table 6.5, entry 6), as compared to aryl
bromides. Very less yield of the corresponding product was observed, when the
reaction of 2-bromofluorene, 4-bromobiphenyl, with phenyl boronic acid
(Table 6.5, entry 9 and 12), and this point indicated that the catalytic system is
highly selective towards the nature of the substrates used. In general
Pd(OAC)2/DABCO/Hydrotrope combined catalytic system was the carrier of
choice for a wide range of aryl boronic acids, but not good for range of aryl
halides.
Another striking feature of catalyst was easy recovery from the reaction
mixture. As hydrotrope are more soluble in water than in organic solvents,
almost 100 % of catalyst was quite easily recovered from the aqueous solution
after the reaction was completed. The reaction mixture was quenched with
water and the precipitated product was simply separated by extraction with
diethyl ether. The catalyst was in the aqueous layer and only removal of water
gave the catalyst which could be used in the next reaction. To assess the
reusability of catalyst, recycling experiments were carried out with 4-
bromobenzophenone and phenylboronic acid as substrates over the four
reaction cycles. After each experiment, the aqueous solution of catalyst was
recovered by extraction, washed thoroughly with diethyl ether, concentrated
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184
and then subjected to a new run with fresh reactants under identical reaction
conditions. The results showed in Table. 6.6 indicated that catalyst could be
reused for at least five runs and yield of the product decreases continuously
with increasing reaction time.
Table 6.6: Recycling of Pd(OAC)2/DABCO/Hydrotrope combined catalyst in
Suzuki-Miyaura coupling reaction
Cycle Aryl halide Time (h) Yield (%)
1 1 96
2 26 90
3 48 50
4 48 30
5
O
Br
48 15
Characterization of products:
4-(naphthalen-5-yl)benzaldehyde (Table 6.5, entry 8): The 1H NMR
spectrum (Fig. 6.15) of the compound showed multiplet for four Hd protons
present on naphthalene ring at δ 7.42-7.57 ppm, while another multiplet at δ
7.89-7.93 ppm for two He protons (Fig. 6.13). One deshielded dd signal at δ
8.02 ppm is for two Ha protons of benzene ring and coupled to Hb proton of
same ring which showed doublet at 7.69 ppm. One Hc proton of naphthalene
ring resonated as doublet at 7.84 ppm having J = 8.4 Hz. Spectrum also showed
one sharp singlet at δ 10.13 ppm of aldehydes proton. 13
C NMR spectrum (Fig.
6.16) of same compound exhibited thirteen signals in the aromatic region from
δ 125.2 to 147.1 ppm, while signal at δ 191.1 ppm represent aldehyde carbon.
Synthetic Applications of a Novel Pd(OAc)2/DABCO/Hydrotrope Combined Catalyst at Room Temperature
185
Fig. 6.13
6.4 Conclusion
The conclusion from this study was that hydrotrope was essential for
SM reaction in water at room temperature. The procedure is very simple like
‘dump and stir’ in water. The reagents and reaction medium (hydrotrope and
water) are readily available. No special precautions are needed in terms of
solvent degassing or protection of reactions from air. Isolation of products
involves simple filtration/extraction of reaction mixtures. No modifications of
catalyst/substrate were required to enhance their water solubility, nor any
special techniques involved. Easy recovery of product and possible reuse of
hydrotropic solutions makes this protocol the most attractive, particularly at
industrial levels. Hydrotropy technique is unique technique that eliminates the
costly organic solvents and energy normally involved in the conventional
organic transformations.
6.5 Experimental section
1H NMR and
13C NMR spectra were recorded on a Brucker AC (300
MHz for 1H NMR and 75 MHz for
13C NMR) spectrometer using CDCl3 as
solvent and tetramethylsilane (TMS) as an internal standard. Infrared spectra
were recorded on a Perkin-Elimer FTIR spectrometer. The samples were
examined as KBr discs ~ 5 % w/w. Melting points were determined with a
DBK melting point apparatus and are uncorrected. All the chemicals were
Synthetic Applications of a Novel Pd(OAc)2/DABCO/Hydrotrope Combined Catalyst at Room Temperature
186
obtained from Aldrich, Spectrochem and were used without further
purification.
Typical experimental procedure for the Suzuki-Miyaura reaction
Arylbromide (1.0 mmol) and aryl boronic acid (1.1 mmol) was added to
a round bottom flask containing aqueous hydrotropic solution (5 mL). The
reaction mixture was stirred at room temperature and Pd(OAc)2 (1 mol %),
DABCO (10 mol %), and K2CO3 (2.0 mmol) were added to a flask and allowed
to stir until completion of reaction as determined by TLC. The resulting
reaction mixture was poured into water (15 mL), extracted with diethyl ether
(3×10 mL), and dried over anhydrous Na2SO4. Crude product was isolated and
purified by column chromatography from n-hexane-ethyl acetate.
Spectral data for representative compounds:
Biphenyl-4-carboxaldehyde (Table 6.5, entry 8): Low melting solid. IR
(KBr): υ = 3039, 2900, 2842, 1706 (C=O), 1608, 1390, 1200, 1166, 1018, 837,
805, 775, 689 cm-1
. 1H NMR (CDCl3, 300 MHz): δH (ppm): 7.30-7.35 (m, 3H),
7.60 (d, 2H, J = 7.6 Hz), 7.72 (d, 2H, J = 8.2 Hz), 7.89-7.91 (m, 2H), 10.00, (s,
1H). 13
C NMR (CDCl3, 75 MHz): δC (ppm) 191.3, 147.5, 141.0, 135.6, 130.7,
130.0, 128.9, 128.0, 127.8.
2,6-diphenylpyridine (Table 6.5, entry 10): White solid, observed mp 73–75
°C. IR (KBr): υ = 3055, 3030, 1585, 1485, 1421, 1389, 1333, 1242, 1071,
1010, 927, 818 cm-1
. 1H NMR (CDCl3, 300 MHz): δH (ppm): 7.50–7.59 (m,
6H), 7.70–7.86 (m, 3H), 8.19-8.25 (m, 4H). 13
C NMR (CDCl3, 75 MHz): δC
(ppm) 118.4, 127.0, 128.5, 128.9, 137.2, 139.4, 156.8.
2,6-bis(4-ethylphenyl)pyridine (Table 6.5, entry 11): White solid, observed
mp 106-108 °C. IR (KBr): υ = 2963, 2923, 2868, 1651, 1572, 1412, 1187,
1163, 1120, 1042, 1015, 802, 743 cm-1
. 1H NMR (CDCl3, 300 MHz): δH
(ppm): 1.30 (6H, t), 2.71 (4H, q), 7.27-7.54 (4H, m), 7.64-7.94 (4H, m), 8.06-
8.10 (3H, m). 13
C NMR (CDCl3, 75 MHz): δC (ppm) 15.5, 28.7, 118.0, 126.9,
128.2, 128.3, 137.3, 139.0, 145.2, 157.0.
Synthetic Applications of a Novel Pd(OAc)2/DABCO/Hydrotrope Combined Catalyst at Room
Temperature
194
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6.6 Spectra
Fig. 6.14 IR spectrum of 4-(naphthalen-5-yl)benzaldehyde
188
Fig. 6.15 1H NMR spectrum of 4-(naphthalen-5-yl)benzaldehyde
189
Fig. 6.16 13
C NMR spectrum of 4-(naphthalen-5-yl)benzaldehyde
190
Fig. 6.17 1H NMR spectrum of (4-(naphthalen-4-yl)phenyl)(phenyl)methanone
191
Fig. 6.18 13
C NMR spectrum of (4-(naphthalen-4-yl)phenyl)(phenyl)methanone
192
Fig. 6.19 1H NMR spectrum of 1-(4-(naphthalen-5-yl)phenyl)ethanone
193
Fig. 6.20 13
C NMR spectrum of 1-(4-(naphthalen-5-yl)phenyl)ethanone