A copper- and amine-free Sonogashira reaction employing chlorophosphine as new and efficient ligand

Article abstract of DOI:10.1016/j.cclet.2011.11.007

An efficient palladium-catalyzed copper- and amine-free Sonogashira coupling reaction of aryl bromides and chlorides was studied using a sterically hindered monooxychlorophosphine as new ligand. The use of 2 mol% Pd(OAc) ₂ in the presence of K₂CO₃ allows the coupling reaction to proceed at mild condition with good to excellent yields.

Full text of DOI:10.1016/j.cclet.2011.11.007

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 185–188
www.elsevier.com/locate/cclet
A copper- and amine-free Sonogashira reaction employing
chlorophosphine as new and efficient ligand
*
Wen Peng Mai , Jin Wei Yuan, Zhi Cheng Li, Gang Chun Sun
Chemistry and Chemical Engineering School, Henan University of Technology, Zhengzhou 450001, China
Received 29 August 2011
Available online 22 December 2011
Abstract
An efficient palladium-catalyzed copper- and amine-free Sonogashira coupling reaction of aryl bromides and chlorides was
studied using a sterically hindered monooxychlorophosphine as new ligand. The use of 2 mol% Pd(OAc)2 in the presence of K2CO3
allows the coupling reaction to proceed at mild condition with good to excellent yields.
# 2011 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
Keywords: Palladium; Copper-free; Coupling; Sonogashira reaction; Chlorophosphine
Palladium-catalyzed cross-coupling reactions are extremely useful synthetic tools [1,2]. The Sonogashira reaction
provides a powerful tool for C–C bond formation, which has been widely applied to natural products, a wide range of
industrial intermediates, pharmaceuticals and agrochemicals, and molecular materials for optics and electronics [3,4].
Although a lot of modifications have been reported for the coupling, including phase-transfer reaction conditions and
aqueous, and solvent-free, a copper cocatalyst was still needed [5–7]. However, the presence of CuI can induce
homocoupling reactions (Glaser-type reaction) of terminal alkynes to diynes in the presence of oxygen. It has been
reported that CuI had a deleterious effect on the Sonogashira cross-coupling reaction [8]. Amines, another additive, are
not eco-friendly reagent which has bad smell. Though copper-free Sonogashira reaction has been reported, in most
case, aryl iodide must be used or high temperature even under MW conditions [9–12]. Several examples have
described copper-free methodologies; amines such as piperidine, pyrrolidine and DABCO were still required [13,14].
For these reasons, eliminating the use of copper (I) iodide as cocatalyst and avoiding the use of the amine have been
applied to simplify the catalyst system.
Ackermann [15,16] have reported a diaminochlorophosphine as new and high efficient ligand in Suzuki reaction
and Buchwald–Hartwig amination and Wolf [17] reported Stille cross-coupling reactions using PXPd (X = Cl) as
catalyst. Though chlorophosphine compounds are comparatively unstable in moisture air, they have high activities
because oxidative addition of chlorophosphine to low-valent palladium species could give a phosphenium cation
which is isolable to N-heterocyclic singlet carbenes.
* Corresponding author.
E-mail address: wpmai@yahoo.com.cn (W.P. Mai).
1001-8417/$ – see front matter # 2011 Published by Elsevier B.V. on behalf of Chinese Chemical Society.
doi:10.1016/j.cclet.2011.11.007

186
W.P. Mai et al. / Chinese Chemical Letters 23 (2012) 185–188
Results and discussion
Herein we wish to report a new comparatively air-stable monooxychlorophosphine L1 [18] (Scheme 1) as novel and
efficient ligand for palladium-catalyzed Sonogashira cross-couplings of aryl bromides and chlorides as our continuous
work in coupling reactions.
We first selected 1-bromo-4-methoxybenzene (1a) and phenylacetylene (2a) as substrates and L1–3 as ligands
(Scheme 2) to develop the Sonogashira reaction in the absence of copper and amine. L2 is commercially available and
L3 is Zhang’s ligand [19] for copper- and amine-free Sonogashira reaction. The reaction conditions and results were
summarized in Table 1.
Treatment of a mixture of 1a (374 mg, 2.0 mmol), 2a (0.24 mL, 2.2 mmol), Pd(OAc)2 (8.9 mg, 0.04 mmol), L1
(13.6 mg, 0.04 mmol)in5 mL CH3CN at50 8C underN2 atmosphere for10 h gavethedesiredcoupling product 3 in78%
isolated yield (Table 1, entry 1). This is good result in the absence of copper salt and amine. We next tested different
solvents, bases and ligands under thesame conditions. As shown in Table 1, good to excellentyieldswere obtained for the
coupling reaction when using L1 as theligand and DABCO or K2CO3 as base (Table 1, entries 1, 4, 5, 6 and 10). But using
Et3N as base and THF as solvent, the product yield was only 57% in the presence of L1 (Table 1, entry 9). L2 is analog to
L1, but only very low product yields were obtained in the presence of organic or inorganic bases (Table 1, entries 2, 7 and
11). The reason maybe the bulk of L2 is smaller than L1 based on the mechanism of the coupling reactions. L3 has been
tested in copper- and amine-free Sonogashira reaction in previous study [19] and it was effective in the reaction under our
condition but was not the most efficient (Table 1, entries 3, 8 and 12). THF as solvent was better than CH3CN under our
conditions. For example, the yield of product 3 decreased from 93% to 78% when using CH3CN under the same
conditions (Table 1, entries 1 and 10).
t
PCl , Et N
2.5equiv BuMgCl
3
3
OH
O
P(Cl)
O P
2
o
toluene, 0~100
70%
Et O, rt~reflux
2
C
Cl
L1
83%
Scheme 1. Synthesis of L1.
N
N
P
N
O
P
P
Cl
Cl
L1
L2
L3
Scheme 2. Ligands tested in this work.
Table 1
Effect of solvents, bases and ligands in the Sonogashira cross-coupling reaction.a
Entry
Solvent
Base
Ligand
Yield (%)b
1
2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
K2CO3
K2CO3
K2CO3
DABCO
Et3N
L1
L2
L3
L1
L1
L1
L2
L3
L1
L1
L2
L3
78
26
66
72
80
83
18
55
57
93
20
77
3
4
5
6
DABCO
DABCO
DABCO
Et3N
7
THF
8
THF
9
THF
10
11
12
THF
K2CO3
K2CO3
K2CO3
THF
THF
a
Pd(OAc)2 (2.0 mol%), p-bromoanisole (2 mmol), phemylacetylene (2.2 mmol) and ligand (2.0 mol%) in 5 mL of the indicated solvent at 50 8C
for 10 h.
b
Isolated yield.

W.P. Mai et al. / Chinese Chemical Letters 23 (2012) 185–188
187
Table 2
Pd(OAc)2-catalyzed Sonogashira cross-coupling of aryl halides (1) with alkynes (2)a. .
Pd(OAc)2/L1
+
R
Ar
R
ArX
K2CO3, THF
o
8-18h
50 C,
1a-1n
2a-2b
3-16
Entry
ArX
R
Time (h)
Products
Yield (%)b
1
2
4-BrC6H4OMe/1a
4-BrC6H4Me/1b
2-BrC6H4Me/1c
1-Bromonaphthalene/1d
BrC6H5/1e
H/2a
H
10
10
10
8
3
4
93
90
3
H
5
87
4
H
6
94
5
H
8
7
90
6
4-BrC6H4CHO/1f
4-BrC6H4COCH3/1g
2-Bromomesitylene/1h
2-Bromopyridine/1i
3-Bromopyridine/1j
BrC6H5/1e
H
8
8
91
7
H
8
9
84
8
H
10
8
10
11
12
8
72
9
H
89
10
11
12
13
14
15
16
H
8
93
CHO/2b
CHO
H
8
85
2-BrC6H4Me/1c
ClC6H5/1k
10
18
18
18
18
13
7
76
46c
52c
38c
Tracec
4-ClC6H4COCH3/1l
ClC6H5/1k
4-ClC6H4C6H5/1m
H
9
CHO
CHO
8
16
a
Reaction conditions: ArX (2.0 mmol), aryl alkynes (2.2 mmol), K2CO3 (4.0 mmol), Pd(OAc)2 (0.04 mmol), L1 (0.04 mmol), THF (5 mL),
50 8C, 8–18 h.
Isolated yield.
b
c
At 90 8C.
Under the optimized reaction conditions, the coupling reactions between a variety of aryl bromides (1a–1j) and
chlorides (1k–1m) and two aryl alkynes (2a–2b) were carried out and the results were summarized in Table 2. As shown
inTable 2, both electron-poorandelectron-rich aryl bromides(1a–1j) wereefficientlycoupled with phenylacetylene(2a)
and 4-ethynylbenzaldehyde (2b) to give products in excellent yields (72–94%). For aryl bromides which have ortho
substituentgroups such as2-bromotoluene(1c) and2-bromomesitylene(1h), 72%and87%productyieldswere obtained
respectively (Table 2, entries 3 and 8). This indicated that the ortho group in the aryl bromides had little effect in the
reaction under our conditions. On one hand, for aryl bromides, there was no great difference in product yield between
Pd(OAc)2
O
P
O
P
O P
_
OAc
PdCl2
Cl
OAc
1
1'
1''
ArX
Ar
R
PdCl2
Pd(0)L2
I
III
L
Ar
L
Pd
O
P
Cl
Pd
ArPd(II)L2X
R
Cl
P O
II
Base-HX
ArPd(II)L2X
R
R
H
Base
Scheme 3. Probable mechanism.

188
W.P. Mai et al. / Chinese Chemical Letters 23 (2012) 185–188
those electron-deficient and elecron-rich substrates (Table 2, entries 1, 2 and entries 6, 7). On the other hand, for aryl
alkynes, it could be observed obviously that the same aryl bromides coupled with phenylacetylene (2a) could obtain a
little higher yield than those they coupled with 4-ethynyl-benzaldehyde (2b) (Table 2, entries 2, 3, 5, 8, 11 and 12). For
example, treatment of 2-bromotoluene (1c) with alkynes 2a and 2b gave 87% and 76% isolated yields (Table 2, entries 3
and 12). The heterocyclic bromides 3-bromopyridine (1i) and 2-bromopyridine (1j) were likewise converted smoothly to
the coupled products with phenylacetylene (2a) in 89% and 93% yields respectively (Table 2, entries 9 and 10).
According to our earlier report, ligand L1 was efficient in the Suzuki–Miyaura cross-coupling reaction of aryl chlorides,
[18] however, L1 gave only middle yields in the Sonogashira cross-coupling reaction of aryl chlorides (Table 2, entries
13–15). Treatment of chlorobenzene (1k) with 2a and 2b could only produced coupled products 7 and 8 in 46% and 38%
yields (Table 2, entries 13 and 15). A little higher yield (52%) could be obtained when using more activated 4-
chloroacetophenone (1l) as substrate coupled with 2a (Table 2, entry 14). However, when using inactivated 4-
chlorobiphenyl (1m) and inactivated alkyne 2b as substrates at the same time, almost no product could be produced
(Table 2, entry 16). The reason that L1 was not efficient for Sonogashira reaction of aryl chlorides was not clear.
The use of phosphenium ions as ligands for transition metals has also been investigated [20], but its application in
cross-coupling reaction had few reports. We tried to explain its high efficiency in cross-coupling reactions. Aworking
mechanism as outlined in Scheme 3 was proposed on the basis of the earlier report [20]. As shown in Scheme 3, we
considered that the intermediate (10) was real ligand coordinated with palladium. Phosphenium ion which lack
electrons is isoelectronic analog to N-heterocyclic carbene, so its electron-rich property make the Pd-P bond very
strong and stabilize the metal. This could make the step I (oxidative step) more easier. The large bulk of intermediate
(10) could accelerate the step (III) (reductive elimination). So we thought the electron-rich and bulky intermediate (10)
might play key roles in the Sonogashira cross-coupling reactions.
Conclusion
In summary, we have developed an efficient, copper- and amine-free Sonogashira cross-coupling reaction using
novel and air-stable chlorophosphine as ligand. A variety of aryl bromides including electron-deficient and electron-
rich bromides were reacted with aryl alkynes smoothly in good yields under mild conditions. Several aryl chlorides
were tested under the conditions and gave the middle yields.
Acknowledgment
We gratefully acknowledge Henan University of Technology for financial support (The Introduction of Talent Fund).
References
[1] J.P. Corbet, G. Mignani, Chem. Rev. 106 (2006) 2651.
¨
[2] M. Magerlein, A.F. Indolese, M. Beller, Angew. Chem. Int. Ed. 40 (2001) 2856.
[3] J.C. Hierso, H. Doucet, Angew. Chem. Int. Ed. 46 (2007) 834.
´
[4] R. Chinchilla, C. Najera, Chem. Rev. 107 (2007) 874.
[5] S. Bhattacharya, S. Sengupta, Tetrahedron Lett. 45 (2004) 8733.
´
[6] M. Erdelyi, A. Gogoll, J. Org. Chem. 68 (2003) 6431.
[7] D.S. Kim, J. Ham, Org. Lett. 12 (2010) 1092.
[8] D. Gelman, S.L. Buchwald, Angew. Chem. Int. Ed. 42 (2003) 5993.
[9] B.C. Carnavalet, A. Archambeau, C. Meyer, et al. Org. Lett. 13 (2011) 956.
[10] T. He, L.L. Wu, X.L. Fu, et al. Chin. Chem. Lett. 22 (2011) 1175.
[11] M. Bakherad, A. Keivanloo, B. Bahramian, et al. Tetrahedron Lett. 50 (2009) 1557.
´
[12] M. Cordoba, M.L. Lzquierdo, J. Alvarez-Builla, Tetrahedron Lett. 52 (2011) 1738.
[13] J.H. Li, Y. Liang, Y.X. Xie, J. Org. Chem. 70 (2005) 4393.
[14] B. Liang, M.J. Dai, J.H. Chen, et al. J. Org. Chem. 70 (2005) 391.
[15] L. Ackermann, J. Spatz, G.J. Gschrei, et al. Angew. Chem. Int. Ed. 45 (2006) 7627.
[16] L. Ackermann, R. Born, Angew. Chem. Int. Ed. 44 (2005) 2444.
[17] R. Lerebours, A.C. Soto, C. Wolf, J. Org. Chem. 70 (2005) 8601.
[18] W.P. Mai, G.H. Lv, L.X. Gao, Synlett 14 (2007) 2247.
[19] J. Cheng, Y.H. Sun, F. Wang, et al. J. Org. Chem. 69 (2004) 5428.
[20] M.B. Abrams, B.L. Scott, R.T. Baker, Organometallics 19 (2000) 4944.