Highly efficient Pd/tetraphosphine catalytic system for copper-free sonogashira reactions of aryl bromides with terminal alkynes

Article abstract of DOI:10.1007/s10562-012-0796-2

In this study, an easily synthesized polydentate ligand N,N,N',N'-tetra(diphenylphosphinomethyl)-1,2-ethylenediamine (1) in combination with [Pd(C₃H₅)Cl]₂ was found to be an active catalyst in copper-free Sonogashira reactions. Most substrates, including steric hindered phenyl bromides and heteroaryl bromides, could couple efficiently with terminal alkynes in the presence of low catalyst loading (0.1 mol%) and this catalytic system showed excellent functional group tolerance. The influence of water in this system was also preliminarily investigated via 31P NMR in situ; that is, appropriate water favors the reaction while excess hindered this reaction.

Full text of DOI:10.1007/s10562-012-0796-2

Catal Lett (2012) 142:594–600
DOI 10.1007/s10562-012-0796-2
Highly Efficient Pd/Tetraphosphine Catalytic System for Copper-
Free Sonogashira Reactions of Aryl Bromides with Terminal
Alkynes
•
Tao Yi Min Mo Hai-Yan Fu Rui-Xiang Li
•
•
•
•
Hua Chen Xian-Jun Li
Received: 15 November 2011 / Accepted: 1 March 2012 / Published online: 27 March 2012
Ó Springer Science+Business Media, LLC 2012
Abstract In this study, an easily synthesized polydentate
ligand N,N,N’,N’-tetra(diphenylphosphinomethyl)-1,2-eth-
ylenediamine (1) in combination with [Pd(C3H5)Cl]2 was
found to be an active catalyst in copper-free Sonogashira
reactions. Most substrates, including steric hindered phenyl
bromides and heteroaryl bromides, could couple efficiently
with terminal alkynes in the presence of low catalyst
loading (0.1 mol%) and this catalytic system showed
excellent functional group tolerance. The influence of
water in this system was also preliminarily investigated via
31P NMR in situ; that is, appropriate water favors the
reaction while excess hindered this reaction.
dimerization (Glaser coupling) and make the product dif-
ficult to isolate [8]. Recently, palladacycles and ionic liq-
uids systems have been applied in the copper-free
´
reactions. C. Najera and I. Błaszczyk groups utilized pal-
ladacycle catalysts in the coupling of iodobenzene and its
derivatives [9, 10]. I. Ryu and A. Trzeciak employed
PdCl2(PPh3)2 and PdCl2[P(OPh)3]2 as catalyst precursors
and [BMIm][PF6] as reaction medium for the coupling of
aryl iodides [11, 12]. Meanwhile, Hierso et al. [13]
reported a [BMIM][BF4]-[Pd(C3H5)Cl]2-dppf system for
the coupling of aryl bromides under copper-free condition.
Additives (silver or zinc salts) were alternative choice to
promote the reaction but might cause the catalytic system
more complicated [14–17]. Herein simple copper-free
protocols without those salts were published later. How-
ever it was noteworthy that high catalyst loading
(1–5 mol%) was commonly needed in these methodologies
for the active species cannot be fully stabilized by ligands
[18–23].
Keywords Palladium ꢀ Tetraphosphine ꢀ Copper-free ꢀ
Sonogashira reaction ꢀ Aryl bromides
1 Introduction
Palladium-catalyzed Sonogashira cross-coupling of aryl
halides with terminal alkynes is among the most powerful
and straightforward strategies for the formation of C(sp2)–
C(sp) bonds [1–3]. Due to its good functional group
tolerance, this reaction has been widely utilized in total
synthesis [4] and pharmaceuticals [5]. In the past decades,
much effort has been devoted to the design of new ligands
and the exploration of catalytic methods, and one of the
fields was elimination of copper salt from the reaction
[6, 7], as the presence of copper might lead to alkyne
Polydentate phosphines such as cis,cis,cis-1,2,3,4-tetra-
kis(diphenylphosphinomethyl)cyclopentane (Tedicyp) [24]
and 1,2-bis(diphenylphosphino)-10-(diisopropylphosphino)-
4-tert-butylferrocene [Fc(P)t2Bu(PiPr)] [25] were success-
fully used in Sonogashira reactions to reduce the catalyst
loading. Tedicyp in combination with [Pd(C3H5)Cl]2 could
lower the catalyst loading to 10-5 mol% with 4-Tri-
fluoromethylbromobenzene as substrate [26–30], and the
use of [Fc(P)t2Bu(PiPr)] decreased the amount of catalyst to
10-4 mol% for the coupling of 4-bromoacetophenone.
However, the long synthetic routes of these two ligands may
limit their applications, and catalytic amount of CuI
(5 mol%) was still required in both systems.
T. Yi ꢀ M. Mo ꢀ H.-Y. Fu ꢀ R.-X. Li (&) ꢀ H. Chen ꢀ X.-J. Li
Key Laboratory of Green Chemistry and Technology of the
Ministry of Education, College of Chemistry, Sichuan
University, Chengdu 610064, People’s Republic of China
e-mail: liruixiang@scu.edu.cn
We have recently reported the successful application of
a simple tetraphosphine N,N,N’,N’-tetra(diphenylphosphi-
nomethyl)-1,2-ethylenediamine (1) (Fig. 1) in Heck
123

Highly Efficient Pd/Tetraphosphine Catalytic
595
reaction [31]. In this paper we tried to report the efficiency
of this structurally simple and easily synthesized ligand for
the Sonogashira coupling of aryl bromides with terminal
alkynes in the absence of copper (Scheme 1).
Table 1 Screening of solvents and bases in Sonogashira reactions of
phenyl bromide with phenylacetylene
Entry
Solvents
Base
Conversion (%)a
1
DMF
K2CO3
K3PO4
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
K3PO4
NaHCO3
NaOAc
KOH
68
2
DMF
74
3
DMA
54
2 Results and Discussion
4
DMA
81
5
Xylene
60
72b
Our work began with the screening of catalyst precursors
for the coupling of phenyl bromide with phenylacetylene as
the nature of Pd source is critical for the Sonogashira
reactions [32]. By monitoring the reaction, [Pd(C3H5)Cl]2
was proved to be the most efficient catalyst precursor. In
our previous research, it was observed that 1 only played
the role of tetradentate phosphine under the reaction con-
dition for 31P NMR spectra of 1 with [Pd(C3H5)Cl]2 in situ
did not show any evidence to prove the coordination of
nitrogen atom with Pd [31]. We next examined the effect of
base and solvent on the Sonogashira reaction in the pres-
ence of 1(0.1 mol%)-[Pd(C3H5)Cl]2(0.05 mol%). Both
polar (DMF and DMA) and apolar solvents (xylene)
showed moderate activity, so did the ether solvents (DME
and 1,2-diethoxylethane) (Table 1, entries 1–7). It was
concluded that moderate polar aprotic solvents in combi-
nation with inorganic base was useful [33]. 1,4-dioxane in
combination with K2CO3 or K3PO4 were tested in the
reaction, resulting that not only the conversion of phenyl
bromide increased, but also high selectivity was observed
(Table 1, entries 8, 9). In contrast, neither weak nor strong
inorganic bases could fully promote the reaction (Table 1,
entries 10–12). Likewise, the associations of 1,4-dioxane to
organic bases were less efficient for the reaction (Table 1,
entries 13, 14). Increasing the reaction temperature and
extending the reaction time, the conversion was up to 96 %
in the presence of K3PO4 (Table 1, entry 15).
6
DME
7
1,2-Diethoxylethane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
73
8
81
9
84
10
11
12
13
14
15
6
10
65
NEt3
9
DMAP
K3PO4
Trace
96c, 10d
Reaction condition: [Pd(C3H5)Cl]2 (0.05 mol%), 1 (0.1 mol%), phe-
nyl bromide (1 mmol), phenylacetylene (1.2 eq.), base (2 eq.), sol-
vent (3 mL), 100 °C, 15 h
a
Conversions according to GC based on the amount of phenyl bro-
mide used
b
85 °C
105 °C, 20 h
c
d
0.01 mol% of catalyst loading, 105 °C, 20 h
PPh2
PPh2
Ph2P
Ph2P
N
N
1
Fig. 2 Relationship between reaction conversion and ratio of 1 to
[Pd]
Fig. 1 Ligand 1
Scheme 1 Copper-free
Sonogashira reactions of
phenyl/heteroaryl bromides
with terminal alkynes
Br
[Pd]/ 1, copper-free
R
R'
R'
R
+
R'
Base, Solvent
Heteroaryl-Br
Heteroaryl
R = H, CF3, CHO, COCH3, CN, CH3, OCH3
R' = H, OCH3, NO2
Heteroaryl = pyridine, quinoline, pyrimidine
123

596
T. Yi et al.
The change of 1:[Pd] ratio was further investigated
reaction [31]. Regardless of increasing or decreasing the
ratio of 1 to [Pd], the concentration of g4-Pd complex was
reduced, leading to lower conversion.
(Fig. 2). Being free of ligand, nearly no coupling product
was detected; it is essential for the existence of ligand in
the reaction. The highest conversion of 96 % (Table 1,
entry 15) was obtained under the 1:1 ratio of 1 to [Pd]. As
reported before, a possible g4-Pd complex was formed
under this ratio (1:1) and performed high activity in
On the basis of previous research, we subsequently
moved our focus to expanding the scope of aryl bro-
mides. Under the optimized condition, the reaction of
both electron-withdrawing (Table 2, entries 1–10) and
Table 2 Scope of Sonogashira reactions of aryl bromides with terminal alkynes
Terminal
Alkyne
Entry
Aryl Bomide
Product
Yield (%)a
123

Highly Efficient Pd/Tetraphosphine Catalytic
597
Table 2 continued
Terminal
Alkyne
Entry
Aryl Bomide
Product
Yield (%)a
Reaction conditions: [Pd(C3H5)Cl]2 (0.05 mol%), 1 (0.1 mol%), aryl bromide (1 mmol), terminal alkyne (1.2 eq.), K3PO4 (2 eq.), 1,4-dioxane
(3 mL), 105 °C, 20 h
a
Isolated yields based on aryl bromides. Data in parentheses are GC yields
b
0.01 mol% of catalyst loading
c
0.001 mol% of catalyst loading
electron-donating (Table 2, entries 11–19) phenyl bromide
derivatives gave desired products in good yields (up to
99 %). To the best of our knowledge, fewer study on the
coupling of o-substituted phenyl bromides with phenyl-
acetylene was reported, relatively contrary to the use of
m- and p-substituted aryl bromides, and higher catalyst
loading was usually required [27], whereas it is found that
the reaction of o-substituted phenyl bromides with phen-
ylacetylene still proceeded smoothly at a low palladium
loading of 0.1 mol% in our system and satisfactory yields
of 88–96% were obtained (Table 2, entries 5, 8, 11, 13 and
15–17). For instance reaction of 2-bromobenzonitrile
afforded isolated yield of 89 % (Table 2, entry 5) while the
literature reported was 22 % [27]. The relatively low yield
of 72 % for 2-bromoanisole (Table 2, entry 17) might be
ascribed to electron-donating effect rather than steric factor
for 4-bromoanisole gave the similarly low yield of 74 % as
well as 2-bromoanisole (Table 2, entry 19).
Compared to phenyl bromide derivatives, only a few
couplings of heteroaryl bromides were reported. Copper-
free protocols were even rarely studied, and they often
required a high catalyst loading (up to 5 mol%) [19, 28, 29,
123

598
T. Yi et al.
Scheme 2 Addition of water to
the catalytic system
[Pd(C3H5)Cl]2 / 1
water, copper-free
Br
+
K3PO4, 1,4-Dioxane
105 or 95 oC, 20h
34–36]. We thereby tried to evaluate this catalyst on the
copper-free coupling of heteroaryl bromides with phenyl-
acetylene. Isolated yields of 95–98 % were obtained with
bromopyridines (Table 2, entries 20, 21), 3-bromoquino-
line (Table 2, entry 22) and 5-bromopyrimidine (Table 2,
entry 23). When the catalyst loading was further decreased
to 0.01 mol%, 2-bromopyridine still coupled efficiently
with phenylacetylene to give yield of 81 %, and the yield of
31 % could be obtained with 0.001 mol% of catalyst
(Table 2, entry 20). For 2-bromothiophen (Table 2, entry
24) and 2-bromothiazole (Table 2, entry 25), unfortunately,
yields of only 16–12 % were obtained, respectively. The
active species might be poisoned by the sulfur atom. In the
end, the scope of terminal alkynes was also broadened.
Induction of electron-donating group (–OCH3) on phenyl-
acetylene obviously accelerated the reaction, giving yield
of 96 and 83 % with 4-bromobenzotrifluoride and 4-bromo-
anisole, respectively (Table 2, entries 26, 27). Contrarily,
electron-withdrawing group (–NO2) slowed down the
reaction (Table 2, entry 28).
It was once reported that the addition of water could
promote the coupling reaction [9]. Can water always ben-
efit the reaction? We preliminarily investigated the influ-
ence of water on the reaction (Scheme 2) and concluded
that appropriate water may promote the reaction while
excess would hinder it (Fig. 3). In the absence of water,
31P NMR experiment (Fig. 4) indicated that the species
represented a fluxional behavior that displayed broad peaks
on the spectrum. Therefore we assumed that P-Pd bond in
g4-Pd complexes bearing tetraphosphine was weak and the
labile suffered a fast coordination-dissociation process
[30, 31, 37, 38]. However, this process may be slowed
down in the presence of excess water. As a result, splitted
and sharp 31P NMR peaks appeared at 26.1, 6.6, 4.4 and
-15.1 ppm. Obviously, the addition of water changed the
coordination microenvironment of Pd, and resulted in the
structural transformation of the active species. Although it
is not explicit that how water interacts with the Pd species,
Santelli et al. had proved that the rapid structure transfor-
mation of Pd species bearing tetraphosphine was the key
reason that Pd-Tedicyp system performed with highly
Fig. 3 Relationship between the conversion and mole ratio of H2O to
[Pd]
Fig. 4 31P NMR spectra of
catalysts in situ
123

Highly Efficient Pd/Tetraphosphine Catalytic
599
catalytic activity [30, 38]. In this case, the introduction of
water in this system restrained the structural transformation
of Pd species, but the appropriate amount of water pro-
moted the catalytic activity. It was reasonable to suggest
that the improvement of base solubility in solvent would
led to the acceleration of the reaction. Finally the influence
of water with the presence of a strong base KOH (Fig. 3)
was investigated, and it was found that the promotional
role of KOH was obviously stronger than K3PO4, espe-
cially in high ratio of water to Pd. The results proved that
appropriate water improved the solubility of base and
accelerated the reaction.
d: -28.4 (s). 1H NMR (400 MHZ, CDCl3) d: 7.37–7.23 (m,
40H), 3.50 (d, 8H), 2.88 (s, 4H).
4.2 General Procedure for Sonogashira Reaction
(Table 2, entry 2)
K3PO4 (424 mg, 2 mmol), 4-bromobenzotrifluoride (138 lL,
1 mmol) and phenylacetylene (130 lL, 1.2 eq.) were suc-
cessively added into a dried Schlenk tube with a magnetic bar.
Then DMF solution (0.1 mL) involved [Pd(C3H5)Cl]2
(0.05 mol%)-1 (0.1 mol%), and 1,4-dioxane (3 mL) was
introducedthroughsyringe.Themixturewasheatedto105 °C
and vigorously stirred for 20 h. At the end of the reaction, the
mixture was quenched with water (5 mL) and extracted with
ethyl acetate (3 9 5 mL). The organic layer was dried over
MgSO4(s), concentrated under vacuum and purified by silica
gel column chromatography to yield the product in 94 %.
3 Conclusion
In summary, the tetraphosphine 1 in combination with
[Pd(C3H5)Cl]2 has been used in copper-free Sonogashira
reactions. The highly efficient coupling reaction was car-
ried out under optimized condition in the presence of a low
catalyst loading and the excellent functional group toler-
ance was shown in this protocol. It was sightworthy that
couplings of o-substituted phenyl and heteroaryl bromides
performed smoothly in good yields. In addition, the coor-
dination microenvironment of Pd might be changed by
addition of water, and appropriate amount of water bene-
fited, while excess water was unfavorable for the reaction.
4.3 Investigation of the Ratio of 1 to [Pd] (Fig. 2)
Reagents: phenyl bromide (105 lL, 1 mmol), phenylacet-
ylene (130 lL, 1.2 eq.), K3PO4 (424 mg, 2 eq.), DMF
solution [0.1 mL, 1-[Pd(C3H5)Cl]2(0.05 mol%)] and
1,4-dioxane (3 mL). 105 °C, 20 h. Conversions are calcu-
lated according to GC based on the amount of phenyl
bromide used.
4.4 Influence of Water Addition on the Reaction
(Fig. 3)
4 Experimental
Reagents: phenyl bromide (105 lL, 1 mmol), phenylacety-
lene (130 lL, 1.2 eq.), K3PO4 (424 mg, 2 eq.), DMF solu-
tion [0.1 mL, 1(0.1 mol%)-[Pd(C3H5)Cl]2(0.05 mol%)],
1,4-dioxane (3 mL) and water. 105 or 95 °C, 20 h. Con-
versions are calculated according to GC based on the amount
of phenyl bromide used.
All catalytic reactions were carried out under the argon
atmosphere. Solvents were purified by standard procedures
and distilled prior to use. All starting materials were
commercially available and were directly used without
further purification. Catalyst precursors and 1 were pre-
1
pared following reported methods. 31P NMR and H NMR
spectra were recorded on Bruker AV II-400 MHz.
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