Xing Li*,
Dongjun Li,
Yingjun Li,
Honghong Chang,
Wenchao Gao and
Wenlong Wei*
Department of Chemistry and Chemical Engineering, Taiyuan University of Technology, 79 West Yingze Street, Taiyuan 030024, People's Republic of China. E-mail: lixing@tyut.edu.cn
First published on 8th September 2016
Five efficient processes for the homo-coupling of various Grignard reagents including aryl, heteroaryl and aliphatic ones in the presence of I2, Pd(OAc)2, Ni(OAc)2, CuI, and nano-Fe3O4 were developed, respectively.
First, when phenylmagnesium bromide was treated with 0.2 equiv. of I2 in toluene at 110 °C, the desired product was obtained in 37% yield (Table 1, entry 1). The yield was improved greatly by increasing the amount of I2 and the highest yield was provided when 0.8 equiv. I2 was used (Table 1, entry 4 vs. 2, 3 and 5).
With the promising results, the scope of Grignard reagents was next investigated and the results are shown in Table 2. The results indicated that a variety of Grignard reagents could also be quickly transformed into the corresponding products in the presence of I2. Grignard reagents having electron-poor or -rich groups on benzene ring underwent smoothly transformation to give products in good to high yields (Table 2, entries 1–7). The benzylmagnesium bromide could afford the corresponding product in 54% yield, although a longer time and higher temperature was required (Table 2, entry 8). Heteroaryl Grignard reagents such as pyridylmagnesium bromide and thienylmagnesium bromide were found be suitable substrates to give the homo-coupled products in good yields (Table 2, entries 9–11). Homo-couplings of arylmagnesium chloride also proceeded well under similar conditions (Table 2, entries 12–14). Excitedly, 1,4-diphenylbuta-1,3-diyne was provided in 62% yield when (phenylethynyl)magnesium bromide was used as a substrate (Table 2, entry 15). However, no product was detected for styrylmagnesium bromide (Table 2, entry 16).
Entry | Grignard reagent | Product | t (h) | Yieldb (%) |
---|---|---|---|---|
a Reaction conditions: Grignard reagent (0.3 mmol), I2 (0.8 equiv.), toluene (1.5 mL), temperature (110 °C).b Isolated yield.c 140 °C was used.d N.D. = not detected. | ||||
1 | ![]() |
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48 | 96 |
2 | ![]() |
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50 | 83 |
3 | ![]() |
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48 | 88 |
4 | ![]() |
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48 | 92 |
5 | ![]() |
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48 | 86 |
6 | ![]() |
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50 | 84 |
7 | ![]() |
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50 | 91 |
8 | ![]() |
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48 | 54c |
9 | ![]() |
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48 | 82 |
10 | ![]() |
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48 | 76 |
11 | ![]() |
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48 | 81 |
12 | ![]() |
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48 | 89 |
13 | ![]() |
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50 | 82 |
14 | ![]() |
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48 | 87 |
15 | ![]() |
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48 | 62 |
16 | ![]() |
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48 | N.D.d |
Subsequently, our studies focused on the Pd-catalyzed homo-coupling of various types of Grignard reagents. It was found that through the use of Pd(OAc)2,15 a wide range of Grignard reagents, including arylmagnesium bromide, heteroarylmagnesium bromide, and arylmagnesium chloride could be effectively transformed in good to excellent yields in the presence of LiClO4 (Table 3, entries 1–7 and 9–14).16 Finally, benzylmagnesium bromide also represented a compatible substrate under the reflux conditions (Table 3, entry 8).
Entry | Grignard reagent | Product | t (h) | Yieldb (%) |
---|---|---|---|---|
a Reaction conditions: Grignard reagent (0.3 mmol), Pd(OAc)2 (10 mol%), LiClO4 (0.3 mmol, 1.0 equiv.), toluene (2.0 mL), temperature (100 °C).b Isolated yield.c 120 °C was used. | ||||
1 | ![]() |
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15 | 98 |
2 | ![]() |
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17 | 87 |
3 | ![]() |
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15 | 93 |
4 | ![]() |
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15 | 96 |
5 | ![]() |
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15 | 87 |
6 | ![]() |
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17 | 86 |
7 | ![]() |
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15 | 98 |
8 | ![]() |
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24 | 61c |
9 | ![]() |
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15 | 86 |
10 | ![]() |
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15 | 85 |
11 | ![]() |
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15 | 88 |
12 | ![]() |
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15 | 92 |
13 | ![]() |
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16 | 86 |
14 | ![]() |
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15 | 89 |
To prove the generality of Ni(OAc)2 as a catalyst in the homo-coupling of Grignard reagents, various substrates were investigated. Optimized reaction conditions17 were next applied to prepare a variety of homo-coupled products. For the aryl Grignard reagents having electron-poor or -rich groups on benzene ring (Table 4, entries 2–7), the coupling reactions provided high yields (85–97%). The steric hindrance also played an important role (Table 4, entries 4 vs. 2 and 7 vs. 6). The longer reaction time was required for the reaction with benzylmagnesium bromide, giving relatively low yields (58%) (Table 4, entry 8). Heteroarylmagnesium bromide with Ni(OAc)2 as a catalyst provided somewhat lower yields than that with Pd(OAc)2 (Table 4, entries 9–11). Similar yields were obtained with arylmagnesium chloride (Table 4, entries 12–14).
Entry | Grignard reagent | Product | t (h) | Yieldb (%) |
---|---|---|---|---|
a Reaction conditions: Grignard reagent (0.3 mmol), Ni(OAc)2 (10 mol%), Ag2O (0.3 mmol, 1.0 equiv.), CH2Cl2 (1.5 mL), temperature (25 °C).b Isolated yield.c 13% yield was obtained in the absence of Ni(OAc)2. | ||||
1 | ![]() |
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18 | 95c |
2 | ![]() |
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20 | 90 |
3 | ![]() |
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18 | 93 |
4 | ![]() |
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18 | 97 |
5 | ![]() |
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17 | 90 |
6 | ![]() |
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20 | 85 |
7 | ![]() |
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18 | 92 |
8 | ![]() |
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24 | 58 |
9 | ![]() |
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18 | 82 |
10 | ![]() |
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18 | 77 |
11 | ![]() |
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18 | 81 |
12 | ![]() |
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18 | 83 |
13 | ![]() |
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18 | 86 |
14 | ![]() |
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18 | 90 |
To demonstrate the efficiency and scope of the method with CuI as a catalyst,18 we applied the catalytic system to a variety of Grignard reagents (Table 5). Various substrates including arylmagnesium bromide possessing methyl, methoxy and fluro groups, heteroarylmagnesium bromide, and arylmagnesium chloride were smoothly converted to the desired products in good to excellent yields (Table 5, entries 1–7 and 9–14). Treatment of benzylmagnesium bromide also provided 57% yield at 120 °C (Table 5, entry 8).
Entry | Grignard reagent | Product | t (h) | Yieldb (%) |
---|---|---|---|---|
a Reaction conditions: Grignard reagent (0.3 mmol), CuI (15 mol%), toluene (2.0 mL), temperature (100 °C), air.b Isolated yield.c 120 °C was used. | ||||
1 | ![]() |
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15 | 95 |
2 | ![]() |
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18 | 95 |
3 | ![]() |
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15 | 95 |
4 | ![]() |
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15 | 96 |
5 | ![]() |
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15 | 95 |
6 | ![]() |
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18 | 86 |
7 | ![]() |
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18 | 98 |
8 | ![]() |
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24 | 57c |
9 | ![]() |
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15 | 88 |
10 | ![]() |
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15 | 82 |
11 | ![]() |
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15 | 87 |
12 | ![]() |
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15 | 89 |
13 | ![]() |
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16 | 79 |
14 | ![]() |
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16 | 84 |
Nano Fe3O4 was also found to be a good catalyst.19 Various Grignard reagents turned out to be suitable substrates and worked well (Table 6, entries 1–5 and 9–14) even though the materials bearing electron-withdrawing groups (Table 6, entries 6 and 7). Benzylmagnesium bromide could afford the corresponding product in 50% yield (Table 6, entry 8).
Entry | Grignard reagent | Product | t (h) | Yieldb (%) |
---|---|---|---|---|
a Reaction conditions: Grignard reagent (0.3 mmol), nano-sized Fe3O4 (10 mol%), AgNO3 (0.36 mmol, 1.2 equiv.), toluene (2.0 mL), temperature (100 °C).b Isolated yield.c 9% yield was obtained in the absence of Nano-Fe3O4.d 120 °C was used. | ||||
1 | ![]() |
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20 | 93c |
2 | ![]() |
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24 | 87 |
3 | ![]() |
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20 | 89 |
4 | ![]() |
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20 | 94 |
5 | ![]() |
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20 | 90 |
6 | ![]() |
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18 | 76 |
7 | ![]() |
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18 | 83 |
8 | ![]() |
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24 | 50d |
9 | ![]() |
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18 | 80 |
10 | ![]() |
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20 | 77 |
11 | ![]() |
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20 | 83 |
12 | ![]() |
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20 | 86 |
13 | ![]() |
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20 | 82 |
14 | ![]() |
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20 | 87 |
To clarify the possible reaction mechanism I2-promoted, the homocoupling of iodobenzene with the I2/toluene system, cross coupling of iodobenzene with phenyl magnesium bromide in the presence of I2, and phenyl magnesium bromide with PhI(OAc)2/toluene system were carried out (Scheme 1). The experimental results showed that the reaction process may not involve the generation of an iodobenzene (eqn (1) and (2)). The fact that biphenyl was observed in 57% yield when PhI(OAc)2 was used instead of I2 indicated that hypervalent iodine may play an important role in this process, which suggested that iodine serves not only as the promoter but also as the oxidant (eqn (3)). On the basis of the observations and reported literatures,20 a possible mechanism is postulated as follows (Scheme 2): partial iodine may be first transformed into some hypervalent iodine A in the reaction system. Then a low-valent iodine species B is formed through reduction of A using the Grignard reagent as a strong reducing agent. Subsequently, the species B reacts with the Grignard reagent in the presence of I2 as an oxidant to generate intermediate C, which gives the homo-coupling product D by reductive elimination and releases A.
In conclusion, we have described the homo-coupling reactions of various Grignard reagents in the presence of Pd(OAc)2, Ni(OAC)2, CuI, nano-Fe3O4, and I2, respectively. The five synthetic methods worked very well and were applicable to the homo-coupling of various aryl and heteroaryl Grignard reagents. Similar good yields were obtained regarding nano-Fe3O4, and I2. Pd-, Ni-, and Cu-based catalyst systems provided higher yields than them. Notably, the first two systems are more green.
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra17859f |
This journal is © The Royal Society of Chemistry 2016 |