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Synthesis 2012; 44(10): 1507-1510
DOI: 10.1055/s-0031-1290813
special topic
© Georg Thieme Verlag Stuttgart · New York

Microwave-Assisted Copper-Catalyzed Cross-Coupling Reaction of Alkynes with Aryl Iodides and Vinyl Halides

Wen-Ting Tsai
Department of Chemistry, National Chung Hsing University, Taichung, Taiwan 402, ROC, Fax: +886(4)22862547   Email: cfalee@dragon.nchu.edu.tw
,
Yun-Yung Lin
Department of Chemistry, National Chung Hsing University, Taichung, Taiwan 402, ROC, Fax: +886(4)22862547   Email: cfalee@dragon.nchu.edu.tw
,
Yu-Jen Wang
Department of Chemistry, National Chung Hsing University, Taichung, Taiwan 402, ROC, Fax: +886(4)22862547   Email: cfalee@dragon.nchu.edu.tw
,
Chin-Fa Lee*
Department of Chemistry, National Chung Hsing University, Taichung, Taiwan 402, ROC, Fax: +886(4)22862547   Email: cfalee@dragon.nchu.edu.tw
› Author Affiliations
Further Information

Publication History

Received: 20 February 2012

Accepted: 05 March 2012

Publication Date:
02 April 2012 (online)

 
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Abstract

The microwave-assisted, copper-catalyzed coupling of terminal alkynes with aryl iodides and vinyl halides is reported. In general, the reactions are completed in 10–30 min using 2–5 mol% [CuI(xantphos)] as a catalyst to provide the corresponding alkynes and enynes in good to excellent yields. A broad spectrum of aryl iodides­, vinyl iodides, and bromides are coupled with aryl- and alkyl­ alkynes.


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Key words

microwaves - copper - cross-coupling - alkynes - aryl iodide­

Functional alkynes and enynes are important molecules in organic synthesis and materials science;[ 1 ] as such, many methods have been developed for the synthesis of these compounds.[2] [3] [4] Pioneering work reported by Sonogashira employed palladium and a copper cocatalyst for the coupling of alkynes with aryl halides[ 1b ] and, since this discovery, transition-metal-catalyzed coupling of terminal alkynes with aryl halides and vinyl halides has become an important method for the preparation of alkynes and enynes.[ 3,4 ] More recently, the exclusive use of copper as a catalyst has gained significant attention in the Sonogashira-type reaction owing to the low cost of the copper salts.[ 4 ]

Microwave irradiation has been widely applied in organic synthesis[5] [6] due to the high efficiency of this technique. While microwave-promoted Sonogashira-type reactions are known,[ 7–9 ] such protocols are typically found using Pd/Cu[ 7 ] or Pd[ 8 ] as the catalysts for the coupling of alkynes with aryl halides. Using exclusively copper in the microwave-assisted, copper-catalyzed coupling reaction is known,[9] [10] however, there are some limitations. First, ortho­-substituted aryl halides are not involved in these systems.[ 9a ] Second, the substrates used in these procedures are mainly aryl alkynes.[ 9 ] Recently, Xie and Wan reported the microwave-assisted coupling of aryl- and alkyl alkynes with aryl iodides.[ 10 ] However, some drawbacks remain in these systems. First, high levels of catalyst and ancillary ligand (10 mol% CuI and 20 mol% PPh3) were required. Second, these systems needed excess phase-transfer reagents. Third, 2.4–3.0 equivalents of alkynes are necessary for these couplings.

Recently, we reported the copper-catalyzed coupling reaction of alkynes with aryl iodides[ 4a ] and vinyl halides.[ 4b ] Here, we report a general procedure for the microwave-assisted, copper-catalyzed coupling of alkynes with aryl iodides. Aryl and alkyl substrates both reacted smoothly to provide the corresponding alkynes in good to excellent yields.

Table 1 Optimization of Microwave-Assisted Copper-Catalyzed Coupling of Iodobenzene with Phenylacetylenea

Entry

Base

Solvent

Yield (%)

 1

Cs2CO3

dioxane

22

 2

Cs2CO3

DMSO

95

 3

Cs2CO3

DMSO

–b

 4

Na2CO3

DMSO

43

 5

K3PO4

DMSO

34

 6

K2CO3

DMSO

71

 7

KOt-Bu

DMSO

–

 8

Cs2CO3

DMF

98

 9

Cs2CO3

H2O

63

11

Cs2CO3

THF

trace

12

Cs2CO3

MeCN

85

13

Cs2CO3

NMP

96

14

Cs2CO3

DMF

86c

a Reaction conditions: [CuI(xantphos)] (0.01 mmol, 2 mol%), phenylacetylene (0.75 mmol), iodobenzene (0.5 mmol), base (1.0 mmol), solvent (0.5 mL).

b No catalyst.

c [CuI(xantphos)] (0.005 mmol, 1.0 mol%)

Initially, iodobenzene and phenylacetylene were selected as model substrates to screen for optimal reaction conditions; the results are summarized in Table [1]. A 22% product yield resulted when the reaction was carried out using our previously developed conditions for the coupling of aryl iodides with alkynes under oil bath heating (Table [1, entry] 1).[4a] [b] In general, polar solvents have been shown to enhance the efficiency of microwave irradiation.[ 7–10 ] To our delight, a 95% yield was afforded when the solvent was changed to dimethyl sulfoxide (DMSO; Table [1, entry] 2). No product was observed when the reaction was carried out in the absence of catalyst (Table [1, entry] 3). We then studied the effect of base on the reaction (Table [1, entries] 4–7), and the results showed that Cs2CO3 was optimal for this transformation. Other solvents were examined (Table [1, entries] 8–13) and N,N-dimethylform­amide (DMF) was found to be superior, giving the product in 98% isolated yield (Table [1, entry] 8). Lower catalyst loadings resulted in diminished yield of the desired target (Table [1, entry] 14).

Table 2 Microwave-Assisted Copper-Catalyzed Coupling of Alkynes with Aryl Iodidesa

Entry

R

2

Product

Yield (%)b

 1

Ph

4-MeC6H4I

3b

99

 2

Ph

4-H2NC6H4I

3c

99c

 3

Ph

4-MeOC6H4I

3d

70

 4

Ph

4-ClC6H4I

3e

82

 5

Ph

4-BrC6H4I

3f

87

 6

Ph

2-iodothiophene

3g

53d

 7

Ph

3-iodopyridine

3h

97

 8

4-MeC6H4

PhI

3i

87c

 9

4-MeOC6H4

PhI

3j

67

10

4-F3CC6H4

PhI

3k

99c

11

3-H2NC6H4

PhI

3l

76

12

3-ClC6H4

PhI

3m

99

13

n-Bu

PhI

3n

75c

14

n-Bu

4-MeOC6H4I

3o

75

15

n-Bu

4-H2NC6H4I

3p

99

16

n-Bu

2-Et-6-MeC6H3I

3q

34c

17

n-Bu

4-MeC6H4I

3r

76

18

n-Bu

3-iodopyridine

3s

74

19

n-Bu

2-MeC6H4I

3t

63c

20

n-Bu

4-BrC6H4I

3u

78

21

n-C8H17

PhI

3v

90

22

n-C8H17

4-MeOC6H4I

3w

80

23

n-C8H17

4-MeC6H4I

3x

87

24

n-C8H17

2-MeC6H4I

3y

42c

a Reaction conditions: [CuI(xantphos)] (0.01 mmol, 2 mol% for entries 1–12; 0.025 mmol, 5 mol% for entries 13–24), alkyne (0.75 mmol), aryl iodide (0.5 mmol), base (1.0 mmol), DMF (0.5 mL), 10 min.

b Isolated yield.

c 30 min.

d [CuI(xantphos)] (0.025 mmol, 5 mol%), 10 min.

In order to explore the scope of the system, a variety of aryl alkynes were reacted with aryl iodides (Table [2, entries] 1–12). Functional groups such as free amines (Table [2, entries] 2 and 11), chloro (Table [2, entries] 4 and 12), bromo (Table [2, entry] 5), and sulfur-containing heterocycles (Table [2, entries] 6 and 7) were all tolerated under the reaction conditions. In general, alkyl alkynes were more problematic than aryl alkynes for the copper-catalyzed Sonogashira-type reaction.[ 4a ] Good yields were obtained when the reactions were carried out using 5 mol% catalyst (Table [2, entries] 13–24). Functional group tolerance was evident in cases in which the substrate contained an unprotected amine (Table [2, entry] 2), a bromine (Table [2, entry] 5), or when nitrogen-containing heterocycles were used. More importantly, the sterically demanding 2-iodotoluene could also be used as a coupling partner to provide the products in moderate yields (Table [2, entries] 19 and 24), and a 34% isolated yield was obtained when the reaction was carried out with 2-ethyl-6-methyliodobenzene (Table [2, entry] 16).

We then turned our attention to the coupling of vinyl halides with alkynes, as illustrated in Table [3]. A variety of vinyl iodides reacted with alkynes, giving the corresponding enynes in good to excellent yield. Interestingly, 1-(2-bromovinyl)benzene could also be used as a substrate for this system, giving the enynes in good yields (Table [3, entries] 11 and 12).

Table 3 Microwave-Assisted Copper-Catalyzed Coupling of Alkynes­ with Vinyl Halidesa

Entry

X

Product

Yield (%)

 1

I

5a

57

 2

I

5b

61b

 3

I

5c

43

 4

I

5d

53

 5

I

5e

80

 6

I

5f

48b

 7

I

5g

67

 8

I

5h

56b

 9

Br

5i

40b

10

Br

5j

36b

a Reaction conditions: [CuI(xantphos)] (0.01 mmol, 2 mol% for aryl alkyne; 0.025 mmol, 5 mol% for alkyl alkyne), alkyne (0.75 mmol), vinyl iodide or bromide (0.5 mmol), Cs2CO3 (1.0 mmol), DMF (0.5 mL), 30 min.

b Reaction time: 1 h.

In summary, we have demonstrated that [CuI(xantphos)] is an active catalyst for the microwave-assisted coupling reaction of alkynes with aryl iodides, vinyl iodides and bromides, giving the corresponding internal alkynes and enynes in good to excellent yields.

All products are known compounds, with spectral data agreeing with literature values. See the Supporting Information for details.


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Microwave-Assisted Copper-Catalyzed Coupling of Iodobenzene with Phenylacetylene; General Procedure for Table [1]

A sealable vial equipped with a magnetic stir bar was charged with base (1.0 mmol) and [CuI(xantphos)] (7.7 mg, 0.01 mmol) under a nitrogen atmosphere. The aperture of the vial was then covered with a rubber septum. Under a nitrogen atmosphere, phenylacetylene (1a; 0.083 mL, 0.75 mmol), iodobenzene (2a; 0.056 mL, 0.5 mmol) and solvent (0.5 mL) were added by using a syringe. The septum was then replaced by a screw-cap containing a Teflon-coated septum, and the reaction vessel was placed under microwave irradiation at 135 °C. After stirring at this temperature for 10 min, the heterogeneous mixture was cooled to r.t. and diluted with EtOAc (20 mL). The resulting solution was filtered through a pad of silica gel then washed with EtOAc (20 mL) and concentrated to give the crude material, which was then purified by column chromatography (SiO2, hexane) to yield 3a.


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Microwave-Assisted Copper-Catalyzed Coupling of Alkynes with Aryl Iodides; General Procedure for Table [2]

A sealable vial equipped with a magnetic stir bar was charged with Cs2CO3 (325 mg, 1.0 mmol) and [CuI(xantphos)] (7.69 mg, 0.01 mmol for aryl alkyne; 19.23 mg, 0.025 mmol for alkyl alkyne) under a nitrogen atmosphere. The aperture of the vial was then covered with a rubber septum. Under a nitrogen atmosphere, aryl or alkyl alkyne (1; 0.75 mmol), aryl iodide (2; 0.5 mmol) and DMF (0.5 mL) were added by using a syringe. The septum was then replaced by a screw-cap containing a Teflon-coated septum, and the reaction vessel was placed under microwave irradiation at 135 °C. After stirring at this temperature for 10–30 min, the heterogeneous mixture was cooled to r.t. and diluted with EtOAc (20 mL). The resulting solution was filtered through a pad of silica gel then washed with EtOAc (20 mL) and concentrated to give the crude material, which was then purified by column chromatography (SiO2, hexane or hexane–EtOAc) to yield alkyne 3.


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Microwave-Assisted Copper-Catalyzed Coupling of Alkynes with Vinyl Halides; General Procedure for Table [3]

A 4-mL sealable vial equipped with a magnetic stir bar was charged with Cs2CO3 (325 mg, 1 mmol) and [CuI(xantphos)] (7.69 mg, 0.01 mmol for aryl alkyne; 19.23 mg, 0.025 mmol for alkyl alkyne) under a nitrogen atmosphere. The aperture of the vial was then covered with a rubber septum. Under a nitrogen atmosphere, alkenyl halide (4; 0.5 mmol), aryl or alkyl alkyne (2; 0.75 mmol), and DMF (0.5 mL) were added by using a syringe. The septum was then replaced by a screw-cap containing a Teflon-coated septum, and the reaction vessel was placed under microwave irradiation at 135 °C. After stirring at this temperature for 30–60 min, the heterogeneous mixture was cooled to r.t. The resulting solution was filtered through a pad of silica gel then washed with EtOAc (20 mL) and concentrated to give the crude material, which was then purified by column chromatography (SiO2, hexane) to yield 5.


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Acknowledgment

Financial support by the National Science Council, Taiwan (NSC99-2113-M-005-004-MY2) and the National Chung Hsing University are gratefully acknowledged. We thank Prof. Fung-E Hong for generously sharing his GC-MS instruments. C.F.L. is a Golden-Jade Fellow of Kenda Foundation, Taiwan.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synthesis.
  • Supporting Information


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