Highly Selective Pd-Catalyzed Reductive Coupling of Substituted Haloarenes with Supported Phase-Transfer Catalyst using Zn as the Reducing Agent

Article abstract of DOI:10.1002/1615-4169(200212)344:10<1079::AID-ADSC1079>3.0.CO;2-K

Highly selective reductive coupling of substituted haloarenes to biaryls is accomplished by Zn in N,N-dimethylformamide (DMF) and in the presence of a catalytic amount of PdCl₂, PPh₃, and a carbon-supported phase-transfer catalyst (PTC). Selectivity as high as 100% is achieved with chlorotoluenes. It is realized that the supported PTC has a predominant role in minimizing the rate of the hydrodehalogenation reaction. The reaction is found to be selective only when homogeneous PdCl₂ is applied as the catalyst, whereas heterogeneous Pd/C-catalyst selectively reduces chloroarenes to arenes under similar conditions. The role of PPh₃ is discussed and the effects of different process parameters such as temperature, PdCl₂ loading, PPh₃ to PdCl₂ ratio, amount of supported PTC, and solvents have been examined. A mechanism is proposed which is in good agreement with the experimental results obtained.

Full text of DOI:10.1002/1615-4169(200212)344:10<1079::AID-ADSC1079>3.0.CO;2-K

FULL PAPERS
Highly Selective Pd-Catalyzed Reductive Coupling of Substituted
Haloarenes with Supported Phase-Transfer Catalyst using Zn as
the Reducing Agent
Nida Qafisheh,a Sudip Mukhopadhyay,b,* Yoel Sassona,*
a
Casali Institute of Applied Chemistry, Hebrew University of Jerusalem, Jerusalem 91904, Israel
Fax: ( ‡ 972)-26528250; e-mail: ysasson@huji.ac.il
b
Chemical Engineering Department, University of California, Berkeley , CA 94720, U.S.A
Fax: ( ‡ 1)-510-642 4778; e-mail: sudip@uclink2.berkeley.edu
Received: February 23, 2002; Received revised August 23, 2002; Accepted: September 13, 2002
Abstract: Highly selective reductive coupling of catalyst selectively reduces chloroarenes to arenes
substituted haloarenes to biaryls is accomplished by under similar conditions. The role of PPh3 is discussed
Zn in N,N-dimethylformamide (DMF) and in the and the effects of different process parameters such as
presence of a catalytic amount of PdCl2, PPh3, and a temperature, PdCl2 loading, PPh3 to PdCl2 ratio,
carbon-supported phase-transfer catalyst (PTC). Se- amount of supported PTC, and solvents have been
lectivity as high as 100% is achieved with chloroto- examined. A mechanism is proposed which is in good
luenes. It is realized that the supported PTC has a agreement with the experimental results obtained.
predominant role in minimizing the rate of the
hydrodehalogenation reaction. The reaction is found
to be selective only when homogeneous PdCl2 is Keywords: biaryls; C À C coupling; haloarenes; Pd;
applied as the catalyst, whereas heterogeneous Pd/C- reduction; Zn
Introduction
selectivity in heterogeneous Pd-catalyzed reductive
couplings of haloarenes using formate salts as the
The syntheses and utilization of biaryl compounds is a reducing agents. High selectivity to the respective
subject of considerable contemporary interest as they biphenyls was achieved with unsubstituted haloben-
represent important building blocks[1] for numerous zenes; however, the same process scheme failed to
agrochemicals, pharmaceuticals, and for a large number achieve the desired selectivity with 4-chlorotoluene and
of natural products of varied structure, biological 4-chlorobenzaldehyde as the substrate.
activity, and biosynthetic origins.[2] Also, biaryls are
In this communication, we show that the PdCl2-cata-
the structural units of the chiral skeleton of many of the lyzed reductive coupling method can be employed to
asymmetric catalysts.[3] Besides stoichiometric classic selectivelysynthesize biphenyls fromhaloarenes, namely,
general Ullmann,[4a, b] Suzuki,[4cÀf] and Stille[4g] coupling 4-chlorotoluene in the presence of an activated carbon-
reactions, Pd-catalyzed reductive coupling of haloar- supported phase-transfer catalyst, a ligand (PPh3), and a
enes[5] has attracted the attention of many researchers. reducing agent such as zinc in anhydrous N,N-dimethyl-
The reductive coupling of haloarenes benefits from formamide (DMF). Similar attempts have been made
simple reactor design, easy catalyst separation, and before to utilize PdCl2 as the catalyst. However, only low
recycling. Unfortunately, the product selectivity is often reactivity was observed with chloroarenes, whereas
low due to the competing reduction reaction.[6] We bromo- and iodoarenes have reacted to give coupling
successfully explored[7aÀc] the reductive coupling of products.[9] In fact, NiCl2 has been employed[10] success-
haloarenes; however, the goal to diminish side reac- fully as a catalyst in similar coupling reactions; however,
tions, namely, reduction of haloarenes to arenes, and to the need for extremely toxic solvents[10] such as pyridine
utilize substrates of industrial importance viz., 4- orquinolineinvalidatestheutilityofsuchprocesses. Also,
chlorotoluene and 4-chlorobenzaldehyde was still un- Jutand and Mosleh[11] have been reported Pd- and Ni-
attained. Moreover, the role of a phase-transfer catalyst catalyzed synthesis of biaryls from aryl triflates in the
(PTC) in these reactions is not understood. However, presence of Zn powder. Thus, in this work, for the first
the strong impact of a PTC on the coupling product time, we will show that 4-chlorotoluene is coupled with
selectivity was realized. Recently, we reported[8] the almost 100% selectivity by PdCl2 catalyst under mild
effectiveness of carbon-supported PTC on the coupling conditions using carbon-supported PTC in DMF.
Adv. Synth. Catal. 2002, 344, No. 10
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/02/34410-1079 1083 $ 17.50+.50/0
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Nida Qafisheh et al.
FULL PAPERS
Nevertheless, a 100% selectivity to the coupling
product was obtained with 2-chlorotoluene as the
starting material. 4-Chlorotoluene was used as a model
compound for process parameters and kinetic studies.
With each one of the substrates in Table 1, the reactions
were found to be 100% selective within the reaction
time period of 4 5 h. Unfortunately, the rate of reaction
was very low. Thus, the reaction time was optimized at
10 h with 4-chlorotoluene as the substrate. It was
observed that the reaction followed first-order kinetics.
The reaction temperature proved to be one of the key
process parameters to control selective homocou-
pling.[7b] Initially, with an increase in temperature from
60 to 70 8C, the reaction rate and selectivity were
increased, however, a further increase in temperature
above 70 8C was deleterious to the product selectivity
(Table 2, entries 1 6).
R
R
R
PdCl2, PTC/C
R1
R1
2
+
Zn
+
ZnX2
R1
PPh3, DMF, 70 °C
6 – 12 h
X
2
1
1a, 2a: R = CH3, R1 = H, where X= Cl
1b, 2b: R = H, R1 = CH3, where X= Cl
1c, 2c: R = CF3, R1 = H, where X= Cl
1d, 2d: R = CHO, R1 = H, where X= Cl
1e, 2e: R = H, R1 = H, where X= Cl
1f, 2f: R = H, R1 = H, where X= Br
Scheme 1. Pd-catalyzed reductive coupling.
Carbon was selected as the support for PTC over other
A set of experiments was performed with various
common supporting materials[12aÀc] such as poly- amounts of PdCl2. The conversion and selectivity both
mers[12a, b], alumina, or silica gel[12c], because of its high increased marginally when the amount of PdCl2 was
surface area, insolubility in acidic or basic solution, high raised to 2.0 mmol (Table 2, entries 7 10). However,
porosity, as well as its high selectivity as a support the coupling of 4-chlorotoluene was optimized at a
towards our previously studied heterogeneous Pd- 1.4 mmol PdCl2 catalyst loading.
catalyzed reductive coupling reactions.[7]
Table 2. Effect of different process parameters on the
coupling reaction.[a]
Results and Discussion
Entry Parameters
% Con- % Cou- % Re-
version
pling,
Ar-Ar
duction,
ArH
In a typical reaction (see Experimental Section), 1 was
coupled to form 2 with Zn as the reducing agent in the
presence of a catalytic amount of PdCl2, PPh3, and the
carbon-supported PTC in anhydrous DMF at 70 8C
(Scheme 1). Excellent selectivity ( > 91%) was achieved
with each one of the substrates, 1a f as shown in
Table 1. With 4-chlorotoluene (1a), 96% selectivity was
achieved to the corresponding biaryl. Bromobenzene
(1f) appeared to be the most reactive among the
substrates under these conditions, whereas 2-chloroto-
luene had reacted minimally. Also, with 4-chloroben-
zaldehyde (1d), 97% selectivity to the coupling product
was achieved.
1
2
3
4
5
6
7
8
temp, 60 8C
70 8C
70 8C
70 8C
80 8C
42
26[b]
73
92[c]
79
93
0
41
73
78
0
43
56[d]
73
79
43
73
78
83
92
100
96
82
92
83
0
83
96
98
0
99
98
96
84
58
96
76
65
96
96
97
8
0
4
18
8
17
0
17
4
2
0
1
90 8C
PdCl2, 0 mmol
0.7 mmol
1.4 mmol
2.0 mmol
Zn, 0 mmol
15 mmol
19 mmol
19 mmol
23 mmol
PTC[e], 0 g
0.5 g
9
10
11
12
13
14
15
16
17
18
19
20
21
22
2
4
10
42
4
24
35
4
Table 1. Reductive coupling of different substrates.[a]
Entry
Halo-
arene
t [h]
% Con-
version
% Selectivity,
Ar-Ar
0.8 g
1.0 g
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
10
6
10
6
12
12
73
33
65
36
81
84
96
100
98
97
91
PPh3/PdCl2 ˆ 1.35 73
PPh3/PdCl2 ˆ 1.8
PPh3/PdCl2 ˆ 2.1
84
96
4
3
[a]
Reaction conditions: 4-chlorotoluene, 7.9 mmol; PPh3,
1.9 mmol; solvent, anhydrous DMF (total volume
20 mL); reaction time, 10 h.
98
[a]
[b]
[c]
[d]
[e]
Reaction conditions: substrate, 7.9 mmol; PdCl2,
1.4 mmol; Zn, 19 mmol; PPh3, 1.9 mmol; carbon-support-
ed TBAB, 0.5 g; solvent, 20 mL of anhydrous DMF,
temperature 70 8C.
Reaction time: 5 h.
Reaction time: 20 h.
Reaction time: 8 h.
The amount of carbon-supported PTC used.
1080
Adv. Synth. Catal. 2002, 344, 1079 1083

Highly Selective Pd-Catalyzed Reductive Coupling of Substituted Haloarenes
FULL PAPERS
Primarily, Zn was used as the reducing agent.[13] The
rate of reaction was found to be a function of Zn loading
(Table 2, entries 11 15). When the Zn loading was
increased up to 19 mmol, the conversion of halobenzene
increased upto 73% and selectivityincreased up to96%.
However, when Zn loading was increased above
19 mmol, the coupling selectivity decreased.
Also, a different set of reactions was performed to
study the effect of the amount of carbon-supported PTC
on the rate and selectivity. The reaction rate and
selectivity were found to be functions of the amount of
carbon-supported PTC (see Experimental Section) used
in these reactions (Table 2, entries 16 19). It was
observed that the reaction rate varied in direct propor-
tion to the amount of supported PTC above a 0.5 g
Table 3. Effect of solvent on the homocoupling of 4-
chlorotoluene.[a]
Entry
Solvent
t [h]
% Con-
version
% Selectivity,
coupling
1
2
3
4
5
DMF
10
48
8
8
2
73
80
23
0
100
96
10
100
0
Dioxane
DMSO
Toluene
Water
10
[a]
Reaction conditions: 4-chlorotoluene, 7.9 mmol; PdCl2,
1.4 mmol; Zn, 19 mmol; PPh3, 1.9 mmol; carbon-support-
ed TBAB, 0.5 g, temperature, 70 8C.
loading, whereas, the selectivity to 4,4'-dimethylbiphen- Amatore and coworkers.[15] Also, it has been shown
yl varied in inverse proportion to the amount of carbon- elsewhere[16] that Zn can reduce water to H2 in the
supported PTC. Attempts to replace carbon by Al2O3, presence of a catalytic amount of Pd0 or Pd2‡. Thus,
BaSO4, or fused silica did not pay off. The ratio of PdCl2 reactions were executed in anhydrous DMF (0.02 wt. %
to PPh3 was also studied and the reaction was optimized water) to achieve higher coupling selectivity. Interest-
at a ratio of 1:2.1 (Table 2, entries 20 22).
ingly, the product selectivity gradually decreased with
To examine the effect of different types of PTC such as time of reaction progress, while performing the reaction
tetrabutylammonium bromide (TBAB), cetyltrimethyl- in an open glass reactor. This problem was solved when
ammonium bromide, and PEG-400, a set of reactions the reaction was performed in a closed vessel. In fact,
was performed. TBAB was found to be the best PTC when the reaction was performed in a 300-mL Parr
under these reaction conditions. With cetyltrimethyl- autoclave[17], 100% conversion and 97% selectivity to
ammonium bromide, the rate obtained was similar to 4,4'-dimethylbipenyl were achieved in 48 h. Even after
that of TBAB, but the coupling selectivity was 78% and standard drying of DMF (see Experimental Section),
with PEG-400, the selectivity obtained was only 69%. 0.02% water (analyzed by Karl Fischer titration) still
Thus, in subsequent reactions carbon-supported TBAB remained in the solvent. This may be the reason (steps
was used as the PTC. While preparing the supported 3 5) for getting 3 4% dehydrohalogenation products
PTC, the weight ratio of TBAB to the activated carbon even underthe bestreaction conditions in a closed vessel
was kept at 1:5. In fact, upon increasing this ratio to 2:5, a with 4-chlorotoluene as the substrate.
decrease in selectivity to the coupling product was
With an increase in PdCl2 loading, the active concen-
observed. Needless to say that the conversion increased tration of anionic Pd0 species is increasing; thus, we
minimally.
observe an increase in the rate of coupling reaction.
The role of the PTC could be explained if we consider
Table 3 shows the effect of different solvents such as
DMSO, dioxane, toluene, DMF, and water on the rate the solution stability of the anionic species,[14]
and product selectivity. Toluene was found to be Pd0Cl(PPh3)2ClÀ, in the presence of a PTC. Here, the
completely inactive and dioxane and water were found PTC (except PEG-400) is nothing but Q XÀ. Thus, the
‡
to be significantly less effective. DMSO was moderately stability of the anionic Pd(0) species should be increased
‡
effective, and DMF was found to be the most effective due to the counter ion stabilization by Q . In the case of
solvent medium with respect to the conversion and PEG-400, the lone pair of oxygen might be providing the
selectivity to the coupling products.
same stabilization. However, the role of the carbon
The experimental results can be interpreted in terms support is not understood. While performing a reaction
of the mechanism previously proposed by Amatore and without the carbon support, only 69% selectivity to
Jutand.[14] Thus, the reaction proceeds via (1) formation biphenyl was obtained.
of the PdCl2(PPh3)2 complex by the reaction of PdCl2
and PPh3, (2) reduction of PdCl2(PPh3)2 to the of PPh3
On the other hand, it is understood that the presence
[18,19]
is very essential to form the
Pd0(PPh3)2ClÀ species, (3) oxidative addition of ArCl to Pd0Cl(PPh3)2ClÀ. Certainly, the active species might
an anionic Pd0(PPh3)2ClÀ species to form an Ar-PdIICl- not be stabilized in a ligand-free atmosphere. In fact, in
(PPh3)2ClÀ species, (4) reduction of the later complex by the absence of PPh3, a very slow rate and low coupling
Zn to form an anionic Ar-Pd0(PPh3)2ClÀ species, (5) a selectivity were achieved.[20] Clearly, this reaction is built
second oxidative addition of ArCl to the resulting upon homogeneous liquid phase chemistry, thus when
species followed by reductive elimination of the biaryl.
homogeneous PdCl2 was replaced by a heterogeneous
However, the Ar-Pd0(PPh3)2ClÀ species can react with Pd/C, only 3% coupling selectivity was achieved after
an electrophile such as water to form ArH as reported by 10 h at a bromobenzene conversion of 42%. The major
Adv. Synth. Catal. 2002, 344, 1079 1083
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Nida Qafisheh et al.
FULL PAPERS
pounds were then recovered by distilling off the dichloro-
methane and subsequent crystallization in ethanol.
product was benzene. PPh3 is an effective ligand and has
been employed by many researchers[18,19] in similar types
of coupling reactions. However, considering its toxicity
and the hazards associated with handling PPh3 from
large-scale manufacturing perspectives, we performed a
set of reactions with various ligands such as acetylace-
tone, 2,6-pyridinedicarboxylate, and pyridine in place of
PPh3. However, the reaction was found to be selective
only when PPh3 is used as the ligand. The ratio of PPh3 to
PdCl2 is another essential parameter in terms of
selectivity. We observed that a ratio higher than 2.1 is
good for higher conversion and selectivity.
Preparation of Carbon-Supported Phase Transfer
Catalyst
3 mmol of a phase transfer catalyst (any one of TBAB,
cetyltrimethylammonium bromide, or polyethylene glycol-
400) were mixed with 5 g of activated charcoal and then added
in to 50 mL H2O. The mixture was then stirred for 2 h. The
water was then evaporated in a rota-vapor to complete dryness
under 60 torr vacuum at 60 8C bath temperature. The residual
solid was then again dried in the oven at 60 8C for 72 h, then
ultimately cooled and ground to give a finely divided powder.
Portions of this were then taken for the reactions.
Conclusions
Drying Procedure of DMF
In conclusion, a new method for the selective biphenyl
synthesis is developed. Use of the carbon-supported
PTC, and a ligand such as PPh3, can minimize the
occurrence of hydrodehalogenation, thus, making this
PdCl2-catalyzed reductive coupling process attractive
from the selectivity point of view. The isolation of
products from the reaction mixture is also straightfor-
ward.
DMF with a 1.02 wt. % water content (analyzed by Karl
Fischer method) was distilled and dried over molecular sieves
(500 g/L) over a three-day time period. After this period of
time, the water content was lowered to 0.02%. The DMF thus
obtained was stored under N2 gas and used subsequently in the
reactions.
Acknowledgements
We thank Mr. Dmitry Karshtedt and Mr. Ian Drake of UC
Berkeley for their valuable comments on this manuscript.
Experimental Section
Melting points were measured in glass capillaries using an
Electrothermal 9100 instrument. 1H NMR spectra were
measured on a Bruker AMX 300 instrument at 300.13 MHz.
GC and GCMS analyses were performed using an HP-5890 gas
chromatograph with a 50% diphenyl-50% dimethylpolysilox-
ane packed column (25 m/0.53 mm). Chemicals were pur-
chased from commercial sources ( > 99% pure) and used
without further purification. Products were either isolated and
identified by comparison of their 1H NMR spectra to standard
samples, or identified by MS data and comparison of their GC
retention times with previously isolated reference samples in
our laboratory.
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General Procedure for Coupling of Haloarenes:
In a 100-mL glass reactor equipped with a reflux condenser, 1 g
of 4-chlorotoluene (7.9 mmol), 1.25 g of zinc (19 mmol), 0.5 g
PPh3 (1.9 mmol), 0.25 g of PdCl2 (1.4 mmol), 0.5 g of the
supported TBAB on carbon, and 20 mL of DMF were mixed
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stipulated period of time the solids were filtered off and then
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Adv. Synth. Catal. 2002, 344, 1079 1083

Highly Selective Pd-Catalyzed Reductive Coupling of Substituted Haloarenes
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Adv. Synth. Catal. 2002, 344, 1079 1083
1083