An efficient protocol for copper- and amine-free Sonogashira reactions catalyzed by mononuclear palladacycle complexes containing bidentate phosphine ligands

Article abstract of DOI:10.1016/j.catcom.2013.03.028

An efficient protocol for copper- and amine-free Sonogashira coupling of aryl halides with phenylacetylene in mild reaction conditions under air is reported using moisture/air-stable and robust palladacycle phosphine complexes as catalyst precursors. The use of 0.001 mol% catalysts in the presence of Cs₂CO₃ allows the coupling reaction to proceed with moderate to good yields. Also, ³¹P NMR studies showed that palladacycle 1 can be reduced to zerovalent palladium in methanol, by forming dppe dioxide.

Full text of DOI:10.1016/j.catcom.2013.03.028

An efficient protocol for copper- and amine-free Sonogashira reactions
catalyzed by mononuclear palladacycle complexes containing bidentate
phosphine ligands
Seyyed Javad Sabounchei, Mohsen Ahmadi
PII:
DOI:
Reference:
S1566-7367(13)00111-8
doi: 10.1016/j.catcom.2013.03.028
CATCOM 3453
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
17 December 2012
21 March 2013
25 March 2013
Please cite this article as: Seyyed Javad Sabounchei, Mohsen Ahmadi, An efficient pro-
tocol for copper- and amine-free Sonogashira reactions catalyzed by mononuclear pal-
ladacycle complexes containing bidentate phosphine ligands, Catalysis Communications
(2013), doi: 10.1016/j.catcom.2013.03.028
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

ACCEPTED MANUSCRIPT
An efficient protocol for copper- and amine-free Sonogashira
reactions catalyzed by mononuclear palladacycle complexes
containing bidentate phosphine ligands
Seyyed Javad Sabounchei, Mohsen Ahmadi
Faculty of Chemistry, Bu-Ali Sina University, Hamedan, 65174, Iran
Abstract
An efficient protocol for copper- and amine-free Sonogashira coupling of aryl halides with
phenylacetylene in mild reaction conditions under air are reported using moisture/air-stable and
robust palladacycle phosphine complexes as catalyst precursors. The use of 0.001 mol%
catalysts in the presence of Cs2CO3 allows the coupling reaction to proceed with moderate
to good yields. Also, 31P NMR studies showed that palladacycle 1 can be reduced to zerovalent
palladium in methanol, by forming dppe dioxide.
Keywords
Palladacycle phosphine complexes
Copper- and amine-free Sonogashira cross-coupling
Mild reaction condition
Efficient protocol
31P NMR spectroscopic investigations
 Corresponding author. Tel.: +98 8118272072; fax: +98 8118273231.
E-mail address: jsabounchei@yahoo.co.uk (S.J. Sabounchei).
1

ACCEPTED MANUSCRIPT
1. Introduction
Sonogashira coupling reaction of phenylacetylene with aryl halides catalyzed with Pd
complexes in the presence of copper reagent is one of the most powerful tools in organic
synthesis and has been widely applied to various areas such as natural product synthesis,
biologically active molecules and material science [1,2]. In the Sonogashira coupling reaction,
copper salts usually play a significant role in transmetalation. The original Sonogashira reaction
generally proceeds in the presence of large amount of homogeneous palladium catalyst
containing copper as co-catalyst under inert conditions. It has been well-documented that the
Sonogashira coupling often suffers from the Glaser-type oxidative dimerization of the alkyne
substrate [3] as a side-reaction in the presence of a Cu(I) co-catalyst. The other limitation of
Sonogashira reactions arises from the usage of not so environment friendly amines [4] such as
piperidine or triethylamine, as solvent [5], which also are used as bases in the coupling reactions [6].
All copper-free methodologies are usually called copper-free Sonogashira couplings. Frequently,
these copper-free processes involve the use of excess amine something that diminishes to some
extent the environmental and economical advantages of the methodology. Thus, the development
of methods which allow the elimination of ligand, copper and amine in the Sonogashira cross-
coupling has been pursued in the past few years [6-10]. In addition, there are few catalytic
systems to be carried out the Sonogashira coupling reactions under air in low catalyst loading.
Therefore, the development of a convenient method in mild conditions is an important objective
in this effort. Herein, we report the copper-free, homogeneous Sonogashira reactions catalyzed
under air, in methanol by two palladacycle phosphine complexes that we recently developed
[11,12]. In these Palladacycle complexes, the phosphorus ylide as a ligand coordinated to the
palladium atom via terminal phosphorus atom and methene group and 1,2-
2

ACCEPTED MANUSCRIPT
bis(diphenylphosphino)ethane (dppe) via phosphorus atoms to form two five membered chelate
rings (Fig. 1).
Insert Figure 1
2. Results and discussion
It is well established that palladium complexes containing phosphorus ylides, which
combine both good donor strength and π-accepting capacity, always have a high catalytic activity
[11,13]. In this communication, we attempted to use our palladium (II) complexes as catalyst
precursors in Sonogashira reaction. The rate of coupling is dependent on a variety of parameters
such as solvent, base and catalyst loading. Preliminary experiments showed that the protocol
which we reported recently was not directly applicable to the Sonogashira cross-coupling
reaction [13]. Hence, we investigated the effects of different reaction parameters on the catalytic
activity in order to optimize the protocol for Sonogashira coupling. In the first, we chose the
cross-coupling of 4-bromobenzaldehyde with phenylacetylene as model reaction, and the effects
of the catalyst loading were examined. The results were summarized in Table 1. The ability to
use small amounts of catalysts and still achieve high yields is a great concern in cross coupling
reactions due to the high cost of metals and ligands. Catalyst loading tests were performed to
determine the catalytic efficiency of the catalysts 1 and 2 in the presence of methanol and
Cs2CO3. A control experiment indicated that the coupling reaction did not occur in the absence
of 1 and 2. Good yields were obtained from catalyst loads down to a level of 0.1 and 0.01 mol%
(without homo-coupling products). A moderate yield was obtained even at catalyst loading as
low as 0.0005 mol%. Various catalyst concentrations were also tested and 0.001 mol% gave the
best result (Table 1, entry 4, 85% and entry 8, 87%).
Insert Table 1
3

ACCEPTED MANUSCRIPT
During the course of our further optimization of the reaction conditions, we examined
several different solvents and bases for the Sonogashira coupling reactions. In order to optimize
the reaction conditions, the coupling of 4-bromobenzaldehyde with phenylacetylene carried out
using 0.001 mol% of palladacycle complexes 1 and 2 under air in the undried solvent, as shown
in Table 2. In the present study, non-polar solvents at 110 °C gave moderate yield (entry 1, 56%,
entry 5, 52%), whereas polar solvents such as NMP or DMF are found to be more efficient for
generating coupling products to 70% and 69% yield, respectively (Table 2, entries 2, 3). On the
other hand, polar aprotic solvent at 80 °C (entry 4) gave comparatively good yield. The highest
isolated yield was obtained with methanol as solvent at 60 °C (Table 2, entry 6, 85% Cat.1 and
87% Cat. 2). After selecting Methanol as the optimal solvent, we investigated the influence of
various bases on the copper-free Sonogashira reaction. The bases including Cs2CO3, K2CO3,
Na2CO3, NaOAc, NaF, and Et3N were investigated, as shown in Table 2. The addition of organic
bases such as Et3N resulted in poor yield (entry 11). It was clear from the results that inorganic
bases (entries 6-10) were much better than organic ones (Table 2, entry 11). Among the bases
tested, the Cs2CO3 proved to be the most efficient and gave the good isolated yield (entry 6). The
yield of product from reaction with phenylacetylene approached 85% for palladacycle 1 as
catalyst whereas the same product has been isolated with the yield of 87% for the catalyst 2. So,
based on the above results, we selected Cs2CO3 as the base and methanol as the solvent in the
presence of 0.001 mol% of the catalysts at 60 °C as the best conditions for the Sonogashira reactions.
Insert Table 2
Under the determined reaction conditions, a wide range of aryl halides bearing electron-
donating and electron-withdrawing groups coupled with phenylacetylene, affording the coupling
products in moderate to good yields. The results are summarized in Table 3.
4

ACCEPTED MANUSCRIPT
Insert Table 3
In palladium catalyzed C-C bond formation reactions, it is commonly believed that better
yields are achieved for aryl halides with electron-withdrawing rather than electron-donating
substituent [14]. This fact is more appropriate for aryl halides with electron-withdrawing
substituent in which the reaction rate of the coupling is faster than the reoxidation of Pd(0). But
with electron-rich halides, the corresponding coupling reactions are rather slower. The electron-
neutral, electron-rich and electron-poor aryl iodides are reacted with phenylacetylene to generate
the corresponding cross-coupling products in good yields (Table 3, entries 1, 4 and 7). For
instance, by using 4-iodoacetophenone as activated aryl compound, it was not surprising to
obtain good yields with the catalytic loading of 0.001 mol % in 24 h (Table 3, entry 7).
Interestingly, the Sonogashira coupling of phenylacetylene with aryl bromide bearing electron-
donating and electron-withdrawing groups gave the corresponding biarylacetylenes in good
yields (Table 3, entries 5, 10 and 12). In the other reaction, 1-methyl-4-(2-
phenylethynyl)benzene was isolated in good yield for deactivated aryl bromide substrate with
this system (entry 5). The electronically neutral bromobenzene (entry 2) produced good amount
of desired product. Trying to apply 2-bromothiophene and 1-bromonaphthalene as efficient
substrate were successful (Table 3, entries 14 and 16). As can be seen in Table 3, we observed
that in all cross-coupling reactions, catalyst 1 and 2 had approximately same catalytic activities
and similar yields. To extend the scope of our work, we next investigated the coupling of various
aryl chlorides with phenylacetylene. The aryl chlorides with electron-withdrawing groups
reacted smoothly, and the corresponding products were obtained in good yields. The coupling
products of 4-chloroacetophenone, 4-chlorobenzaldehyde and 4-chloronitrobenzene with
phenylacetylene were obtained in good yields by using 0.001 mol% of both catalysts. However,
5

ACCEPTED MANUSCRIPT
for chlorobenzene, catalyst 1 and 2 showed low activity under the same conditions (Table 3,
entry 3). For 4-methylchlorobenzene with electron-donating group, lower yield was observed
(Table 3, entry 6). Increasing the catalyst loading to 0.1 mol % gave moderate yield (Table 3,
entry 6 (72 %, Cat. 1, 75% cat. 2)) without addition of CuI as a co-catalyst. The stronger C–Cl
bond is in fact responsible of the slower reaction rate of aryl halides, because the oxidative
addition step was suggested being the rate determining step in cross-coupling catalytic cycles [6].
In all the reactions of aryl halides, the color of the reaction mixture changed very fast (~30
seconds) from light brown to black. Thus, it can be inferred that the reaction mechanism starts
with a pre-dissociation and/or reduction step [6]. Furthermore, coupling of 2-chlorothiphene with
phenylacetylene using 0.001 mol% of catalyst 1 and 2 afforded the product in 69-73 % yields.
A number of recent studies have paid attention to the mechanism of the Sonogashira
reaction, particularly to the simplest copper- and amine-free process; this reaction is still far of
being clearly understood. It seems that different catalytic cycles can operate depending on
substrates, bases and catalyst precursors [15]. Some of observations made us think about a
mechanism being similar to copper-free Sonogashira cross-coupling reactions [15]. There have
been few attempts to elucidate the composition of the active species present in the C-C catalytic
cycle. Published studies have been limited to the use of electrochemical techniques [16], anionic
detection (ESI-MS, EXAFS) [17] together with detailed kinetic studies [18], NMR detections
[19] and theoretical study [20].
Several reports on the existence of highly active soluble palladium(0) colloids
(nanoparticles) has established the function of palladacycles as plain Pd(0) reservoirs in high
temperature applications like Heck and Sonogashira couplings [21]. The reduction of palladium
occurs via insertion into the Pd-C bond followed by a reductive elimination to reduce Pd(II) into
6

ACCEPTED MANUSCRIPT
Pd(0), but this is generally followed by formation of Pd(0) nanoparticles. The homogeneous
nature of the catalysis was checked by classical mercury test [22]. Addition of a drop of mercury
to the reaction mixture did not affect the yield of the reaction (no significant reduction in the
reaction yield in presence of mercury under analogous conditions) which suggests that the
catalysis is homogeneous in nature, since heterogeneous catalysts would form an amalgam, there
by poisoning it (supporting information; Table S1). The fact that metallic Hg does not kill the
catalysis is a good point that no metallic Pd is being produced. Electrochemistry is indeed one of
the most convenient techniques to detect Pd(0) complexes that are generated in situ from Pd(II)
complexes [23]. In the other way, we previously showed that Pd(II) in this palladacycle was
reduced to Pd(0) by cyclic voltamnetry [12]. In addition, we investigated the activation of
31
palladacycle phosphine complex 1 to produce active Pd(0) spices with P NMR spectroscopy
under the same reaction conditions.
31P NMR studies of palladacycle 1 in methanol at various temperatures under air were
31
recorded. P NMR study does not show any dissociation of 1 in methanol even after 4 hours in
25 °C, but after 2 hours in 60 °C we observed a singlet in 34.7 ppm due to dppe dioxide and two
doublets in 14.2 and 37.1 ppm (due to Pa and Pb, respectively) that can be assigned to
unsaturated species A1 (path I) (Scheme 1 and Fig. 2). We also previously showed that the
interaction energy between the phosphorus ylide and [Pd(dppe)]2+ fragment is more than that
between dppe and [Pd(ylide)]2+. The interaction energy of Pd2+ ion and ylide is larger than that
with dppe, and both are significantly larger than those between the ylide and [Pd(dppe)]2+
fragment [12]. Other peaks seen in the spectrum (signal of Pc at 29.3 ppm, Pd at 39.6 ppm, Pe at
53.2 ppm and Pf at 32.4 ppm) can be related to spices A2 with zero oxidation state (path II)
7

ACCEPTED MANUSCRIPT
(Scheme 1 and Fig. 2) [24,25]. Thus, the chemical shifts of observed signals confirm that Pd(II)
centre is reduced to Pd(0) in initiated catalytic cycle.
Insert figure 2
Based on above observations and evidences, we proposed that the formation of active
pd(0) catalyst can be done through two possible ways: (i) path I may operate through the
dechelation of one arm giving a palladacycle bearing a certain structural similarity, that can be
concerns the distorted square planer geometry of palladacycle 1 [12], bulkiness of ligands and
some of strain in ring like to Herrmann’s palladacycles [19]. We expected that by increasing the
temperature up to 60 °C, further dechelation of another arm of dppe is done which is
accompanied by the reduction of palladium to its zerovalent state and formation of dppe dioxide
in aerobic condition. (ii) Path II can be done by dechelation of one arm of dppe and also
dechelation of P-coordinated arm of phosphorus ylide which is resulted to the formation of active
pd(0) catalyst [24,26].
Proposed catalytic cycle for copper-free Sonogashira reaction is presented in Scheme 1.
Although the reaction certainly follows the normal oxidative addition-reductive elimination
process common to the Pd-catalyzed C–C bond forming reactions, but exact mechanism for the
reaction is not known. Two different mechanisms have been proposed for the copper-free
Sonogashira reaction: (i) deprotonation mechanism [27] and (ii) carbopalladation mechanism
[28]. The main catalyst precursor formed cis and trans coordinatively unsaturated 14 electron
species (Scheme 2, intermediate A1 (path I) and A2 (path II)) [11,12,24,26]. A highly reactive
Pd(0) species does undergo an oxidative addition with ArX (intermediate B1 and B2). Loss of
the dppe creates a vacant coordination site for subsequent ligation of the alkyne, generating the
intermediate C (π-coordination of the alkyne produces an alkyne–Pd(II) complex containing
8

ACCEPTED MANUSCRIPT
phosphorus ylide as a C-coordinated accompanied by the dangling ylide) [29]. Because no
copper salt was employed, a transmetalation step could be excluded. Both pathways share to
form of intermediate C. At this point, the two reaction mechanisms differ in the next steps
leading to the final coupled product. In the case of the deprotonation mechanism (Scheme 1) the
intermediate D can then facilitate deprotonation of the alkyne proton with the leaving group X.
Reductive elimination of intermediate D with coupling of the aryl halides and alkyne gives the
coupling product and regenerates the Pd(0) catalyst A1 [30]. Alternatively, in the
carbopalladation mechanism (Scheme 1) intermediate C undergoes addition of the organic group
Ar to the terminal alkyne and produces intermediate E. This followed by the coordination of the
P atom of phosphorus ylide to the Pd center to form intermediate F. Subsequent base-mediated
reductive elimination also gives the C-C product and A1 species.
Insert Scheme 1
For further studies, we investigated the catalytic activity of precursor complex
[Pd(dppe)(OTf)2] (3) (see ref. [12]) in comparison with palladacycle complexes in Sonogashira
coupling reactions. It seems that the precursor complex 3 can also be used to behave as an active
resource for producing Pd(0). We used this complex as main catalyst under identical conditions.
As can be seen in Table 4, the activity of catalyst 3, with an 'easy' set of substrates (entries 1-3)
and a 'difficult' set of substrates (entries 4-6) were tested. The electron-neutral, electron-rich and
electron-poor aryl iodides reacted with phenylacetylene in the presence of different loading of
catalyst 3 to generate the corresponding cross-coupling products in moderate yields (Table 4,
entries 1-3). The Sonogashira coupling of phenylacetylene with aryl chlorides bearing electron-
neutral, electron-donating and electron-withdrawing groups gave the corresponding
biarylacetylenes in low yields (Table 4, entries 4-6). In the reaction of aryl iodides with
9

ACCEPTED MANUSCRIPT
phenylacetylene, we found that increasing the catalyst loading from 0.001 to 0.1 mol% could
give good results (Table 4, entries 1-3). Reduction in the amount of the catalyst led to a gradual
decrease in the yields under the same reaction conditions (Table 4, entry 1, 70 to 37%).
Therefore, the activities of the catalyst 1 and 2 are found to be superior compared with the
catalyst 3.
Insert Table 4
The comparison data presented in Table 5 show the efficiency of these new classes of
catalysts towards the copper- and amine-free Sonogashira coupling reactions. From an industrial
view point, the low catalyst loading, low temperature, aerobic reaction condition, and stable
phosphine ligands provide an indisputable advantage than the other catalytic systems.
Insert Table 5
Although several catalytic systems have been reported to support Sonogashira C-C
coupling reaction, a homogeneous catalyst of this type is novel for its P donor of dppe as ligand
and P and CH of phosphorus ylide environment. Although acetylene homocoupling reactions are
generally useful in synthetic and application point of view [34], formation of homo-coupling
products while targeting cross-coupling is undesirable. This is because the terminal acetylene is
either very expensive or synthesized through several steps. Therefore, the formation of dimer is
considered wasteful. In this protocol, no copper salt was used; the undesired formation of
oxidative homocoupling diyne products was avoided. Also, the ease of preparation of the
complexes as homogeneous catalysts, its high solubility in organic solvents, low catalyst loading,
and stability toward air make their ideal complexes for Sonogashira coupling. This method
proved successful in most cases to give the product in >99% purity. In all of the successful
10

ACCEPTED MANUSCRIPT
1
13
reactions, the H and C NMR data of the products indicated no homocoupling diyne products.
The NMR spectra of the C-C products are given in supporting information.
3. Experimental
3.1. Materials and instruments
The required chemicals were of analytical reagent grade and were purchased from Merck and
Alderich. Melting points were measured on a SMPI apparatus and are reported without
correction. NMR Spectra were recorded on a 90 MHz Jeol spectrometer (1H at 89.60 MHz and
31P at 36.26 MHz) or 400 MHz Bruker spectrometer (13C at 100.62 MHz) in CDCl3 as solvent at
1
31
13
25 °C. The splitting of proton resonances in the H, P and C NMR spectra are shown as, s =
singlet, d = doublet, t = triplet and m = multiplet.
3.2. Characterization of possible Pd–P species in this system
General procedure: To a round-bottom flask equipped with a magnetic stirring bar were added
palladacycle 1 (0.04 g) in methanol (2 ml) under air at 60 °C. The mixture was heated for 2 h and
recorded 31P NMR in room temperature. 31P NMR (CDCl3): δ (ppm) 14.2 (d, 2JPP= 30.3 Hz, Pa),
2
37.1 (d, 2JPP= 31.0 Hz, Pb), 34.7 (s, dppe oxide), 29.3 (d, 2JPP= 45.8 Hz, Pc), 32.4 (d, JPP= 34.7
Hz, Pf), 39.6 (dd, 2JPP= 32.5 Hz, 3JPP= 17.9 Hz, Pd), 53.2 (dd, 3JPP= 25.1 Hz, 3JPP= 16.6 Hz, Pe).
3.3. Typical procedure for the copper- and amine-free Sonogashira reactions
General procedure: A mixture of an aryl halide (1 mmol), phenylacetylene (1.3 mmol), Cat.
(0.001 mol%), Cs2CO3 (2.5 mmol), and methanol (3 ml) was heated to 60 °C for 24 hour. The
reaction mixture was then cooled to room temperature and the solvent was removed under
11

ACCEPTED MANUSCRIPT
reduced pressure. The combined organic extracts were washed with brine and dried over CaCl2
and MgSO4. The solvent was evaporated and coupling product was obtained. The liquid residues
were purified by silica gel column chromatography (n-hexane:EtOAc, 80:20) and The solid
residues were purified by re-crystallization from ethanol and water.
3.4. Characterization of cross-coupling products
3.4.1. 1,2-diphenylethyne (Table 3, entries 1, 2, 3)
White solid, m.p.: 54-55 oC, 1H NMR (ppm): δ = 7.26–8.73 (m, 4H, phenyl), 6.75–7.23 (m, 6H,
phenyl). 13C NMR: δ = 88.72, 122.54, 128.38, 128.57, 132.49 [35,36].
3.4.2. 1-methyl-4-(2-phenylethynyl)benzene (Table 3, entries 4, 5, 6)
White solid, m.p.: 71-73 oC, 1H NMR (ppm): δ = 6.55–7.82 (m, 9H, Phneyl), 2.40 (s, 3H, CH3).
13C NMR (ppm): δ = 21.93, 88.80, 89.12, 121.16, 122.76, 128.38, 128.86, 129.89, 130.40,
131.34, 138.53 [35,36].
3.4.3. 1-(4-(2-phenylethynyl)phenyl)ethanone (Table 3, entries 7, 8, 9)
Pale yellow solid, m.p.: 97-99 0C, 1H NMR (ppm): δ = 7.84-7.93 (m, 2H, phenyl), 7.31-7.66 (m,
13
7H, phenyl), 2.57 (s, 3H, CH3). C NMR (ppm): δ = 197.69, 136.56, 132.29, 132.05, 129.51,
128.82, 128.37, 128.22, 123.09, 92.94, 88.91, 27.04 [35,36].
3.4.4. 4-(2-phenylethynyl)benzaldehyde (Table 3, entries 10, 11)
1
Pale yellow liquid, H NMR (ppm): δ = 6.61 (d, 1H, J = 5.3 Hz, phenyl), 7.01-8.04 (m, 8H,
phenyl), 9.34 (s, 1H, CHO). 13C NMR (ppm): δ = 190.45, 134.34, 131.95, 131.07, 132.76,
128.57, 127.95, 127.81, 126.16, 92.42, 87.48. [35].
12

ACCEPTED MANUSCRIPT
3.4.5. 1-nitro-4-(2-phenylethynyl)benzene (Table 3, entries 12, 13)
1
Pale yellow solid, m.p. 112–114 °C, H NMR (ppm): δ = 8.04–8.13 (m, 2H, phenyl), 7.07-7.92
(m, 7H, phenyl). 13C NMR (ppm): δ = 87.60, 94.75, 122.11, 123.66, 128.58, 129.32, 130.27,
131.87, 132.29, 146.96 [35].
3.4.6. 2-(2-phenylethynyl)thiophene (Table 3, entries 14, 15)
1
Colorless oil, H NMR (ppm): δ = 7.01-8.05 (m, 8H, phenyl). 13C NMR (ppm): δ = 131.92,
131.43, 128.44, 128.39, 127.28, 127.12, 123.31, 122.92, 93.03, 82.61 [35].
3.4.7. 1-(2-phenylethynyl)naphthalene (Table 3, entry 16)
Pale brown liquid, 1H NMR (ppm): δ = 8.46 (d, 1H, J = 8.6 Hz, phenyl), 7.26–7.91 (m, 11H,
phenyl and naphthyl). 13C NMR (ppm): δ = 130.57, 129.29, 127.71, 127.38, 127.35, 127.25,
125.73, 125.38, 125.09, 124.22, 122.883, 122.26, 93.28, 86.46 [31].
4. Conclusion
We used palladacycle complexes containing bidentate phosphine ligands as an efficient
and well-defined catalyst for the Sonogashira coupling of various aryl halides. Also, we have
developed a clean and safe protocol for copper- and amine-free Sonogashira reactions catalyzed
by palladacycle complexes under aerobic conditions. The catalyst shows not only high catalytic
activity, but also offers many practical advantages such as low catalyst loading and air stability.
13

ACCEPTED MANUSCRIPT
Acknowledgments
We gratefully acknowledge the funding support received for this project from the Bu-Ali
Sina University, I. R. Iran. Our gratitude also goes to Dr. Abdoli and Mr. Zebarjadian for all
cooperation.
References
[1] K. Sonogashira, Metal-Catalyzed Cross- Coupling Reactions, Wiley-VCH, New York,
NY, 1998.
[2] I. Paterson, R.D.M. Davies, R. Marquez, Angewandte Chemie International Edition 40
(2001) 603–607.
[3] C. Glaser, Berichte der Deutschen Chemischen Gesellschaft 2 (1869) 422–424.
[4] H. Greim, D. Bury, H.-J. Klimisch, M. Oeben-Negele, K. Ziegler-Skylakakis,
Chemosphere 36 (1998) 271–295.
[5] D. Méry, K. Heuzé, D. Astruc, Chemical Communications 15 (2003) 1934–1935.
[6] R. Chinchilla, C. Najera, Chemical Reviews 107 (2007) 874–922.
[7] T. He, L.L. Wu, X. L. Fu, H.Y. Fu, H. Chen, R.X. Li, Chinese Chemical Letters 22
(2011) 1175–1178.
[8] S. Inomata, H. Hiroki, T. Terashima, K. Ogata, S.-ichi Fukuzawa, Tetrahedron 67 (2011)
7263–7267.
[9] Y. Liang, Y.-X. Xie, J.-H. Li, The Journal of Organic Chemistry 71 (2006) 379–381.
14

ACCEPTED MANUSCRIPT
[10] C. Dash, M.M. Shaikh, P. Ghosh, European Journal of Organic Chemistry (2009) 1608–
1618.
[11] S.J. Sabounchei, M. Ahmadi, Z. Nasri, Journal of Coordination Chemistry 66 (2013)
411–423.
[12] S.J. Sabounchei, M. Ahmadi, Z. Nasri, E. Shams, S. Salehzadeh, Y. Gholiee, R.
Karamian, M. Asadbegy, S. Samiee, Comptes Rendus Chimie (2012) DOI:
10.1016/j.crci.2012.10.006.
[13] S.J. Sabounchei, M. Panahimehr, M. Ahmadi, Z. Nasri, H.R. Khavasi, Journal of
Organometallic Chemistry 723 (2013) 207–213.
[14] A.N. Marziale, J. Schlüter, J. Eppinger, Tetrahedron Letter 52 (2011) 6355–6358.
[15] M. Schilz, H. Plenio, The Journal of Organic Chemistry 77 (2012) 2798−2807.
[16] A. Tougerti, S. Negri, A. Jutand, Chemistry - A European Journal 13 (2007) 666–676.
[17] C.D. Buarque, V.D. Pinho, B. Gontijo Vaz, M.N. Eberlin, A.J.M. da Silva, P.R.R. Costa,
Journal of Organometallic Chemistry 695 (2010) 2062–2067.
[18] C. Amatore, S. Bensalem, S. Ghalem, A. Jutand, Y. Medjour, European Journal of
Organic Chemistry (2004) 366–371.
[19] W.A. Herrmann, C. Brossmer, K. Öfele, C.-P. Reisinger, T. Priermeier, M. Beller, H.
Fischer, Angewandte Chemie International Edition in English 34 (1995) 1844–1848.
[20] L. Sikk, J. Tammiku-Taul, P. Burk, Organometallics 30 (2011) 5656–5664.
[21] B.J. Borah, D.K. Dutta, Journal of Molecular Catalysis A: Chemical 366 (2013) 202–209.
[22] K. Inamoto, J. Kuroda, K. Hiroya, Y. Noda, M.Watanabe, T. Sakamoto, Organometallics
25 (2006) 3095–3098.
[23] C. Amatore, E. Carré, A. Jutand, M.A. M’Barki, Organometallics 14 (1995) 1818–1826.
15

ACCEPTED MANUSCRIPT
[24] Y. Ben-David, M. Portnoy, M. Gozin, D. Milstein, Organometallics 11 (1992) 1995–
1996.
[25] Z. Csákai, R. Skoda-Földes, L. Kollár, Inorganica Chimica Acta 286 (1999) 93–97.
[26] M. Portnoy, Y. Ben-David, I. Rousso, D. Milstein, Organomettalics 13 (1994) 3465–
3479.
[27] T. Ljungdahl, T. Bennur, A. Dallas, H. Emtenäs, J. Mårtensson Organometallics 27
(2008) 2490–2498.
[28] F. Heck, H.A. Dieck, Journal of Organometallic Chemistry 93 (1975) 259–263.
[29] X. Moreau, J. M. Campagne, G. Meyer, A. Jutand, European Journal of Organic
Chemistry (2005) 3749–3760.
[30] R. Chinchilla, C. Nájera, Chemical Society Reviews 40 (2011) 5084–5121.
[31] A. Arques, D. Auńon, P. Molina, Tetrahedron Letter 45 (2004) 4337–4340.
[32] B.-S. Zhang, C. Wang, J.-F. Gong, M.-P. Song, Journal of Organometallic Chemistry 694
(2009) 2555–2561.
[33] J. L. Bolliger, C. M. Frech, Advanced Synthesis & Catalysis 351 (2009) 891–902.
[34] J.-H. Li, Y. Liang, Y.-X. Xie, The Journal of Organic Chemistry 70 (2005) 4393–4396.
[35] A. Komáromi, Z. Novák, Chemical Communications 40 (2008) 4968–4970.
16

ACCEPTED MANUSCRIPT
Figure Captions
Figure 1. Structure of Palladacycle phosphine complexes (Catalyst 1 and 2).
Figure 2. 31P NMR spectrum of Pd (0) species.
Scheme 1. Proposed mechanism for copper-free Sonogashira reaction.
17

ACCEPTED MANUSCRIPT
Figure 1
18

ACCEPTED MANUSCRIPT
P(O)
P(O)
Path II
Path I
e
d
a
b
c
f
Figure 2
19

ACCEPTED MANUSCRIPT
Scheme 1
20

ACCEPTED MANUSCRIPT
Table 1
Optimization of catalyst concentrations a
Entry
Catalyst (mol %)
Isolated
yield (%)
NRb
85
80
85
48
83
82
87
1
2
3
4
5
6
7
8
9
None
1 (0.1)
1 (0.01)
1 (0.001)
1 (0.0005)
2 (0.1)
2 (0.01)
2 (0.001)
2 (0.0005)
45
a Reaction conditions: 4-bromobenzaldehyde (1 mmol), phenylacetylene
(1.3 mmol), Cs2CO3 (2.5 mmol), CH3OH (3 ml), 24 h, 60 °C .
b No reaction
21

ACCEPTED MANUSCRIPT
Table 2
Optimization of base and solvent for Sonogashira cross-coupling reactions of 4-
bromobenzaldehyde with phenylacetylene.a
Entry
1
Base
Cs2CO3
Solvent
Dioxane
Temp. (°C) Catalyst (Yield %)b
110
110
110
80
1 (56)
2 (55)
1 (70)
2 (68)
1 (69)
2 (72)
1 (73)
2 (72)
1 (52)
2 (56)
1 (85)
2 (87)
1 (71)
2 (63)
1 (65)
2 (59)
1 (55)
2 (58)
1 (55)
2 (63)
1 (47)
2 (52)
2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
NaOAc
NaF
NMP
3
DMF
4
CH3CN
Toluene
Methanol
Methanol
Methanol
Methanol
Methanol
Methanol
5
110
60
6
7
60
8
60
9
60
10
11
60
Et3N
60
a Reaction conditions: 4-bromobenzaldehyde (1 mmol), phenylacetylene (1.3 mmol), base (2.5 mmol), solvent (3 ml), 24 h, 60 °C , under air.
b Isolated yield.
22

ACCEPTED MANUSCRIPT
Table 3. copper- free Sonogashira cross-coupling reaction of aryl halides with phenylacetylene
catalyzed by Pd complex 1 and 2.a
Entry
1
Ar-X
Product
Catalystb (Yield %)c
1 (84)
2 (86)
I
Ph
Ph
Ph
2
3
4
1 (85)
2 (81)
Br
Cl
1 (65)
2 (68)
1 (79)
2 (78)
I
H3C
H3C
Ph
Ph
Ph
Ph
H3C
H3C
5
6
7
1 (75)
2 (75)
Br
Cl
1 72d(54)
2 75d(59)
H3C
O
H3C
O
1 (88)
2 (87)
I
H3C
O
H3C
O
8
1 (85)
2 (88)
Ph
Ph
Br
H3C
O
H3C
O
9
1 (79)
2 (77)
Cl
H3C
O
H3C
O
10
1 (85)
2 (87)
Ph
Ph
Br
H
O
H
O
11
12
13
14
1 (80)
2 (79)
Cl
H
H
1 (86)
2 (85)
Br
Cl
O2N
Ph
O2N
1 (81)
2 (80)
O2N
Ph
O2N
1 (74)
2 (78)
Br
Cl
Ph
Ph
S
S
S
S
15
16
1 (69)
2 (73)
1 (74)
2 (74)
Ph
Br
a Reaction conditions: aryl halides (1 mmol), phenylacetylene (1.3 mmol), Cs2CO3 (2.5 mmol), CH3OH (3 ml), 24 h, 60 °C , under air.
b Catalyst loading (0.001 mol%)
c
Isolated yield.
23

ACCEPTED MANUSCRIPT
d Using 0.1 mol% catalysts.
Table 4
The copper-free Sonogashira coupling of aryl halides with phenylacetylene catalyzed by precursor
complex 3.a
Entry
1
Ar-X
Product
Catalyst loading b (Yield %)c
0.1 (70)
I
Ph
0.01 (53)
0.001 (37)
0.1 (62)
0.01 (50)
0.001 (32)
0.1 (75)
2
3
I
H3C
O
Ph
Ph
H3C
O
I
0.01 (64)
H3C
0.001 (48)
H3C
4
5
6
0.1 (51)
0.01 (40)
0.001 (23)
0.1 (41)
0.01 (32)
0.001 (10)
0.1 (52)
0.01 (47)
0.001 (29)
Cl
Ph
Cl
H3C
O
Ph
Ph
H3C
O
Cl
H3C
H3C
a Reaction conditions: aryl halides (1 mmol), phenylacetylene (1.3 mmol), catalyst precursor [Pd(dppe)(OTf)2] (ref. [12] ), Cs2CO3 (2.5 mmol), CH3OH (3
ml), 24 h, 60 °C , under air.
b mol%
c Isolated yield.
24

ACCEPTED MANUSCRIPT
Table 5
Comparison catalytic activity of some palladacycles complexes that promote the copper- and amine-free Sonogashira
coupling between phenylacetylene and aryl halides.
Entry Ar-X
Pd catalyst
[Pd]
mol%
1
2
3
1
0.1
1
Base
Solvent
Conditions
Yield
(%)
40
Ref.
1
2
3
4
5
6
7
8
Ph-Br
Pd-NHC complex
Pd-diphosphane complex
Pd-NHC complex
CsOAc
K2CO3
Cs2CO3
Et3N
TBAOAc
Cs2CO3
K3PO4
DMA
DMF
100 oC, in air, 15 h
[8]
[7]
[10]
[14]
[31]
[32]
[33]
This work
This work
4-MePhBr
4-NO2PhBr
4-MePhBr
4-MePhBr
4-MePhBr
Ph-Br
130 oC, in argon, 20 h 97
DMF/H2O 90 oC, in air, 1 h
58
48
99
39
71
85
75
Pd-phosphinite complex
Pd-phosphine imine complex
PCN pincer Pd complexes
H2O
NMP
MeOH
Glycol b
MeOH
MeOH
40 oC, in argon, 4 h
110 oC, in air, 1 h
70 oC, in air, 12 h
140 °C, in N2, 3 h
60 oC, in air, 24 h
60 oC, in air, 24 h
Pd-aminophosphine complexes a 0.005
Ph-Br
Pd-phosphine ylide complex c
Pd-phosphine ylide complex
0.001
0.001
Cs2CO3
Cs2CO3
9
4-MePhBr
Catalyst added in solution (dioxane).
a
b
Ethylene glycol.
c Using catalyst 1.
25

ACCEPTED MANUSCRIPT
Graphical Abstract
An efficient protocol copper- and amine-free palladium-catalyzed Sonogashira reaction of
various aryl halides with phenylacetylene in mild reaction condition has been developed. Various
aryl halides were coupled with phenylacetylene under air in the presence of 0.001 mol% of the
moisture-stable and homogeneous catalysts to afford corresponding C-C products in moderate to
good yields. 31P NMR studies showed that palladacycle 1 can be reduced to zerovalent palladium
in methanol, by forming dppe dioxide.
26

ACCEPTED MANUSCRIPT
Highlights
 New classes of homogenous catalysts for the Sonogashira reactions were used for the first
time.
 The reactions carried out under aerobic and copper- and amine-free conditions.
 The ease of preparation of the complexes and low catalyst loading make their ideal
complexes for Sonogashira reaction.
 Proposed catalytic cycle for copper-free Sonogashira reaction is presented.
27