Catalysis Communications 9 (2008) 2154–2157
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Simple, efficient copper-free Sonogashira coupling of haloaryl carboxylic acids or unactivated aryl bromides with terminal alkynes Zheng Gu a, Zhizhang Li b, Zhichang Liu a, Ying Wang a, Chengbin Liu a, Jiannan Xiang a,* a College of Chemistry and Chemical Engineering, Biomedical Engineering Center and State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, Hunan Province 410082, PR China b Department of Chemistry, Hunan University of Science and Engineering, Yongzhou 425100, PR China
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Article history: Received 4 December 2007 Received in revised form 24 March 2008 Accepted 30 March 2008 Available online 13 May 2008 Keywords: Sonogashira Coupling Alkynes Catalysis Palladium
a b s t r a c t In the absence of Cu(I), the catalytic coupling of haloaryl carboxylic acids or unactivated aryl bromides with terminal alkynes are shown to occur in the presence of 10 equiv. piperidine at 85 °C within 20 min using PdCl2(PPh3)2 as catalyst in good to excellent yields. This procedure avoids the carboxy group protection/deprotection steps and enhances the total yield to simplify the synthesis of acetylenic retinoids. It is noteworthy that this protocol employs direct, mild and efficient copper-free reaction conditions. Ó 2008 Published by Elsevier B.V.
1. Introduction The Sonogashira coupling is one of the straightforward and powerful methods for formation of C(sp2)–C(sp) bonds and has been used in numerous synthetic ventures [1,2]. In order to simplify the Sonogashira reaction protocol, several important aspects have to be improved [3–6]. There remained, however, a need to develop reaction conditions for the coupling of haloaryl carboxylic acids with terminal alkynes. Additionally, substrates containing carboxy group and acetylene group, which are present in many pharmaceutically interesting compounds, may be transformed, obviating the need for additional protection/deprotection steps [7–11]. Furthermore, the presence of CuI can result in the formation of some Cu(I) acetylides in situ that can readily undergo oxidative homocoupling reaction of alkynes. To overcome these drawbacks, many examples have been reported concerning palladium catalyzed Sonogashira coupling of aryl halides bearing carboxy group with terminal alkynes using copper-free reaction conditions [12–15]. In 1992, Genêt et al. [16] reported the first copper-free cross-coupling of alkynes with aryl or vinyl iodides using a water soluble Pd-catalyst. Several sulfonated phosphine derivatives have been prepared and used in the cross-coupling reactions conducted in water or water/organic biphasic solvent systems [17]. * Corresponding author. Tel./fax: +86 731 8821740. E-mail address:
[email protected] (J. Xiang). 1566-7367/$ - see front matter Ó 2008 Published by Elsevier B.V. doi:10.1016/j.catcom.2008.03.056
The intensive application of Sonogashira reaction in the chemical industry depends on the development of new copper-free palladium catalysts. A copper-free coupling of aryl iodides with terminal alkynes has also been reported using an ionic liquid as a solvent [18]. The use of a dendritic material to support the homogeneous [Pd{t-Bu2PCH2N(CH2Ph)CH2Pt-Bu2} (OAc)2] complex [19] and the heterogeneous [Pd(NH3)4]–NaY catalyst [20] is recently reported. These examples contributed the efficient, stable and recyclable catalyst for the copper-free Sonogashira cross-coupling of aryl halides with terminal alkynes, especially for the less reactive electron-withdrawing aryl bromides. So, we assumed that it would be more efficient and simpler, if the phenylacetylene could be coupled directly to the free haloaryl acid unit. To our best knowledge, the direct coupling between phenylacetylene and the free haloaryl carboxylic acid is unworkable under classic Sonogashira coupling condition [21,22]. As previously reported, protection or deprotection of the carboxy group was a need for Sonogashira cross-coupling between terminal acetylene and the carboxylic acid moiety, which requests high temperature and gives the copper-favoured side reaction of the terminal acetylenes [23]. Now, an easy, quick and aerial copper-free methodology for the Sonogashira reaction using readily available palladium complexes as catalyst has been reported [24–26]. It is possible that the Sonogashira cross-coupling of haloaryl carboxylic acids and unactivated aryl bromides with terminal alkynes will be achieved by the methodology above.
Z. Gu et al. / Catalysis Communications 9 (2008) 2154–2157
2. Results and discussion To obtain the optimized reaction conditions, we designed a typical coupling reaction between phenylacetylene and 4-bromobenzoic acid using PdCl2(PPh3)2 as a catalyst (Table 1). When the temperature was low as 25 °C, no product was obtained (Table 1, entry 1), and increasing the reaction temperature from 70 °C to 85 °C, the yield increased 1.5 times (Table 1, entry 4 vs. 5). It indicated that the reaction temperature was an important effect upon the Sonogashira coupling. The yields increased a little with increasing the quantity of catalyst (Table 1, entry 2 vs. 3) or base (Table 1, entry 3 vs. 4) at the same temperature as 70 °C, while the yields obviously decreased when increasing the quantity of piperidine base from 10 to 20 or 50 equiv. (Table 1, entries 6, 8 and 9). By comparison to the reaction time of 10 and 30 min, the reaction time of 20 min gave a highest yield of 99% (Table 1, entries 5–7). Considering the effects of bases, other bases including triethylamine, di-isopropylamine and inorganic sodium carbonate (Table 1, entries 10–12) were examined. The two organic bases of both triethylamine and di-isopropylamine gave good yields as high as 90% and 93%, respectively, while inorganic sodium carbonate gave no product. The results demonstrated clearly the applicability of the conditions in the Sonogashira cross-coupling. Having optimized the reaction conditions for phenylacetylene and 4-bromobenzoic acid, we designed and carried some new Sonogashira cross-couplings of haloaryl carboxylic acids or unactivated aryl bromides with phenylacetylene, and then wanted to expand the methodology for use with aliphatic alkynes so screened as examples 2-methylbut-3-yn-2-ol shown in Table 2. By comparison to the coupling reaction using aryl bromides, the coupling reactions using 3-iodobenzoic acid and ethyl 3-iodobenzoate in the catalysis of 2 mol% of PdCl2(PPh3)2 at 70 °C for 10 min gave a high yield of 99% (Table 2, entries 1, 2 vs. 7). When using 10 equiv. of piperidine as a base in the catalysis of 4 mol% of PdCl2(PPh3)2 at 85 °C, we focused on the coupling of varied aryl bromides and investigated the effects of the substituents. For the more reactive electron-withdrawing 4-bromobenzoic acid and 6-bromo-2-naphthoic acid, gave good yields in the range of 94–99% within 20 min (Table 2, entries 3–6). Under the same conditions as above, the cross-coupling reactions of 2-adamantyl-4-bromoanisole and
Table 1 Screening of conditions for the Sonogashira coupling of 4-bromobenzoic acid with phenylacetylenea
+ Br
Ph
COOH
PdCl2(PPh3)2
Ph
COOH
Entry
Catalyst (mol%)
Base (equiv.)
Time (min)
Temperature (°C)b
Yield (%)c
1 2 3 4 5 6 7 8 9 10 11 12
4 2 4 4 4 4 4 4 4 4 4 4
Piperidine (5) Piperidine (5) Piperidine (5) Piperidine (10) Piperidine (10) Piperidine (10) Piperidine (10) Piperidine (20) Piperidine (50) Et3N (10) (i-pr)2NH (10) Na2CO3(10)
24 h 10 10 10 10 20 30 20 20 20 20 20
25 70 70 70 85 85 85 85 85 85 85 85
0 33 40 46 70 99 97 72 55 90 93 0
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2-(4-bromophenyl)-2-hydroxyacetic acid and ethyl 2-(4-bromophenyl)-2-hydroxyacetate, it also showed good functional group compatibility (Table 2, entries 8–12). All the cross-coupling reactions were performed under very convenient copper-free conditions and used reagents without the further purification. The mechanism of the reaction is suggested as in Scheme 1. As a palladium source, PdCl2(PPh3)2 in amines is used commonly, where a catalytically active, co-ordinatively unsaturated complex is produced by reductive elimination of Pd-acetylide complex generated from PdCl2(PPh3)2 and a terminal alkyne [27]. Although the reaction certainly follows the normal oxidative addition-reductive elimination process common to the Pd-catalyzed C–C bond forming reactions, the exact mechanism for the reaction is not known. The first step is the oxidative addition of Pd0(PPh3)2 with aryl halide. The second step is the activation of the terminal alkyne. Because no copper salt is employed, a transmetalation step could be excluded. The terminal alkyne C–H bond activation is accomplished by the co-ordination of the alkyne to the alkynylpalladium(II) derivatives, which undergoes reductive elimination to afford the required coupled products and regenerates the active Pd-catalyst. The results implied that the methodology was feasible to a range of aryl iodide and aryl bromide substrates with good product yields being obtained. By addition of 10 equiv. of piperidine and the iodoaryl acid had higher activity and much more suitable than the bromoaryl acid, in accord with previously reported results [28]. Therefore, we had adopted the direct coupling of substituted phenylacetylene with 4-bromobenzoic acid as the key step of the strategy towards 1. With these, we found that the same conditions were required in order for the reaction to reach completion with a similar yield. Excellent conversions were observed for all substrates studied with good yields. 3. Experimental 3.1. General All reactions and manipulations were run under nitrogen atmosphere using 25 mL Schelenk-type reactor. 1H NMR, and 13C NMR were recorded on a 400 MHz and 100 MHz spectrometer, respectively. Chemical shifts were reported in ppm downfield from tetramethylsilane with the solvent resonance as the internal standard. Column chromatography was performed using EM Silica gel 60 (300–400 mesh). PdCl2 was purchased form Acros Organics, and PdCl2(PPh3)2 was prepared according to the literature [29]. Aryl bromides were used directly as obtained commercially unless otherwise noted. Other chemicals were purchased from local company as analytical reagents and used without further purification. 3.2. A representative procedure for the Sonogashira coupling reaction
a Unless otherwise indicated, the reaction conditions were as follows: 4-bromobenzoic acid (1 mmol), phenylacetylene (1 mmol) and base. b The reaction mixture was placed in an oil bath at stated temperature and held there for the allotted time. c Isolated yield based on 4-bromobenzoic acid.
3.2.1. Synthesis of 4-(phenylethynyl)benzoic acid (1c) In a 25 mL round bottom flask was placed 4-bromobenzoic acid (5.0 mmol), ethynylbenzene (5.0 mmol), piperidine (50.0 mmol), PdCl2(PPh3)2 (0.2 mmol) and a magnetic stir bar. The flask was placed in an oil bath pre-heated to 85 °C and held there for 20 min. After this time, the resulting complex was poured into a separating funnel and the flask washed with acid (15% v/v HCl) and water and then with ether, these washings being added to the separating funnel. Further water and diethyl ether (20 mL of each) were added and the organic material extracted and then washed with until the washings were acidic. The organic layer was again washed with water (40 mL) before being dried over MgSO4 and the ether removed under vacuum leaving the crude product.
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Z. Gu et al. / Catalysis Communications 9 (2008) 2154–2157
Table 2 Screening of conditions for the copper-free Sonogashira coupling of terminal alkynes with aryl halides
+ X Ar
R
PdCl2(PPh3)2
Ar
R 1
Entry
Aryl halide
1
I
COOH
I
COOEt
2 3
Br
Catalyst (mol%)
Temperature (°C)a
Time (min)
Product number
Yield (%)b
2
70
10
1a
99
2
70
10
1b
99
4
85
20
1c
99
4
85
20
1d
97
HO
4
85
20
1e
95
HO
4
85
20
1f
94
HO
2
70
10
1g
99
4
85
20
1h
75
4
85
20
1i
80
HO
4
85
20
1j
81
HO
4
85
20
1k
76
HO
4
85
20
1l
66
Alkyne
COOH COOH
4 Br
5
Br
COOH COOH
6 Br I
7
COOH
8 Br
OCH 3
COOEt
9
Br OH
10 Br
OCH 3
COOEt
11
Br OH
COOH
12
Br OH
a Reactions were run using 1 mmol aryl halides, 1 mmol terminal alkynes and 10 mmol base. The reaction mixture was placed in an oil bath at stated temperature and held there for the allotted time. b Isolated yield based on ArX.
Acknowledgements
2R'C CH
Ph3P Cl Pd II Cl Ph3P ii
X Ph3P PdII Ph3P R
RX
R'C CH
i ii
2HCl-amine CR' Ph3P C Ph3P iii PdII Pd0 Ph3P C Ph3P CR' R'C CC CR'
HX-amine CR'
Ph3P C PdII Ph3P R
We are grateful for the Project (No. 20472018) supported by the National Natural Science Foundation of China, Project (No. 20060532022) supported by Doctoral Fund of Ministry of Education of China, Project (No. 200520) supported by the State Key Laboratory of Chem/Biosensing and Chemometrics of Hunan University and Key Project (No. 200610) supported by the Science and Technology Bureau of Yongzhou, China.
iii
References R'C CR i: Oxidative Addition; ii:Ligand Exchange; iii: Reductive Elimination. Scheme 1. Outline of the reaction scheme for copper-free Sonogashira coupling of sp2-C halides with terminal acetylenes.
4. Conclusion In conclusion, this procedure avoids the carboxy group protection/deprotection steps and enhances the overall yield. The methodology has the advantage of short reaction times, ease of reaction and the use of a readily available palladium. Further studies of extending the methodology to other substrates and understanding the mechanism of the process are currently under investigation in our group.
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