Chun
Liu
*,
Xinmin
Li
,
Chao
Liu
,
Xinnan
Wang
and
Jieshan
Qiu
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Linggong Road 2, Dalian 116024, China. E-mail: cliu@dlut.edu.cn; Tel: +86-411-84986182
First published on 15th June 2015
A simple and environment-friendly protocol for the palladium-catalyzed ligand-free Suzuki–Miyaura reaction of heteroaryl halides with N-methyliminodiacetic acid (MIDA) boronates is developed. The reaction is performed in water as the sole medium and allows the preparation of a variety of heterobiaryls in excellent yields.
Water is an abundant, nontoxic, noncorrosive and nonflammable solvent, and the use of water as a sole reaction medium in organic reaction is one of the latest challenges for modern chemists.10 More recently, Lipshutz and co-workers11 reported a room temperature catalytic system for the cross-coupling reactions of aryl halides with aryl/heteroaryl MIDA boronates in water. In the presences of Pd(dtbpf)Cl2 and a polymer phase transfer catalyst TPGS-750-M, the reactions run smoothly with good products yields. Here, we wish to report a simple and aerobic catalytic system for the Suzuki–Miyaura reaction of aryl MIDA boronates with heteroaryl halides in pure water without any additive (Scheme 1). This catalytic system, using Pd(OAc)2 as catalyst, (i-Pr)2NH as base, is highly efficient for various substrates.
Entry | Base | Yieldb (%) |
---|---|---|
a Reaction conditions: 2-bromopyridine (0.5 mmol), phenylboronic acid MIDA ester (0.6 mmol), Pd(OAc)2 (2 mol%), H2O (1 mL), base (1 mmol), 100 °C, under air, 2.0 h. b GC yields. | ||
1 | K2CO3 | 38 |
2 | Cs2CO3 | 36 |
3 | K3PO4·3H2O | 51 |
4 | KOH | 18 |
5 | Et3N | 77 |
6 | Pyridine | 20 |
7 | Aniline | 13 |
8 | CyNH2 | 24 |
9 | Cy2NH | 35 |
10 | 1-Adamantaneamine | 24 |
11 | DBU | 32 |
12 | i-PrNH2 | 34 |
13 | (i-Pr)2NH | 93 |
14 | (i-Pr)2NEt | 74 |
The next investigation was to optimize the conditions including palladium species and temperature in the same model reaction. As shown in Table 2, the palladium sources have dramatic effects on the reaction activity. It was clear that precatalysts with palladium(II) salts such as Pd(OAc)2 and PdCl2 exhibited high catalytic activity (Table 2, entries 1 and 3). Using 2 mol% Pd(OAc)2 as catalyst, a 93% yield of the cross-coupling product could be obtained (Table 2, entry 1). When the loading of Pd(OAc)2 was decreased to 1 mol%, only a 64% yield was obtained in the same reaction (Table 2, entry 2). The catalytic activity was relatively low using zero-valent palladium sources such as Pd2(dba)3 or Pd/C (Table 2, entries 5 and 6). The effect of the temperature on this reaction was evaluated too. The coupling reactions performed at 80 °C and 120 °C provided the cross-coupled product in 68% and 89% yield, respectively (Table 2, entries 7 and 8). However, 26% and 61% yields were obtained using Pd(PPh3)4 as catalyst under air or nitrogen, respectively (Table 2, entries 9 and 10). Thus, the optimum reaction conditions for this cross-coupling were found to be 2 mol% Pd(OAc)2, 2 equiv. of (i-Pr)2NH, 100 °C in water.
Entry | Catalyst | Temperature (°C) | Yieldb (%) |
---|---|---|---|
a Reaction conditions: 2-bromopyridine (0.5 mmol), phenylboronic acid MIDA ester (0.6 mmol), Pd(OAc)2 (2 mol%), H2O (1 mL), (i-Pr)2NH (1 mmol), 100 °C, under air, 2.0 h. b GC yields. c Pd(OAc)2 (1 mol%). d N2 atmosphere. | |||
1 | Pd(OAc)2 | 100 | 93 |
2 | Pd(OAc)2 | 100 | 64c |
3 | PdCl2 | 100 | 88 |
4 | PdCl2(CH3CN)2 | 100 | 85 |
5 | Pd2(dba)3 | 100 | 42 |
6 | Pd/C | 100 | 50 |
7 | Pd(OAc)2 | 80 | 68 |
8 | Pd(OAc)2 | 120 | 89 |
9 | Pd(PPh3)4 | 100 | 26 |
10 | Pd(PPh3)4 | 100 | 61d |
With the optimized conditions in hand, we further explored the generality of the cross-couplings between arylboronic acid MIDA ester with different nitrogen-based heteroaryl halides and the results are shown in Table 3. The cross-coupling of 2-bromo-5-methylpyridine with phenylboronic acid MIDA ester gave 5-methyl-2-phenylpyridine in a 95% yield after 1 h, showing high efficiency (Table 3, entry 2). Using 2-bromo-5-fluoro-pyridine instead of 2-bromo-5-methylpyridine, the cross-coupling was completed in 1.5 h, resulting in a 94% yield (Table 3, entry 3). Furthermore, 6-substituted-2-bromopyridines were also successfully employed in the cross-coupling reactions, providing high yields (Table 3, entries 4–6). For example, 2-bromo-6-methoxypyridine afforded the expected product in 95% yield within 1 h (Table 3, entry 4).
Entry | Heteroaryl halides | MIDA boronates | Time (h) | Yieldb |
---|---|---|---|---|
a Reaction conditions: heteroaryl halides (0.5 mmol), arylboronic acid MIDA ester (0.6 mmol), Pd(OAc)2 (2 mol%), H2O (1 mL), (i-Pr)2NH (1 mmol), 100 °C, under air. b Isolated yields. c Pd(OAc)2 (4 mol%). | ||||
1 |
![]() |
![]() |
2.0 | 93 |
2 |
![]() |
![]() |
1.0 | 95 |
3 |
![]() |
![]() |
1.5 | 94 |
4 |
![]() |
![]() |
1.0 | 95 |
5 |
![]() |
![]() |
1.0 | 92 |
6 |
![]() |
![]() |
1.0 | 94 |
7 |
![]() |
![]() |
1.0 | 94 |
8 |
![]() |
![]() |
1.5 | 93 |
9 |
![]() |
![]() |
1.0 | 95 |
10 |
![]() |
![]() |
2.5 | 93 |
11 |
![]() |
![]() |
1.5 | 94 |
12 |
![]() |
![]() |
1.0 | 91 |
13 |
![]() |
![]() |
1.0 | 95 |
14 |
![]() |
![]() |
2.0 | 92 |
15 |
![]() |
![]() |
1.5 | 95 |
16 |
![]() |
![]() |
1.5 | 96 |
17 |
![]() |
![]() |
1.5 | 94 |
18 |
![]() |
![]() |
3.0 | 91 |
19 |
![]() |
![]() |
2.5 | 92 |
20 |
![]() |
![]() |
4.0 | 80c |
21 |
![]() |
![]() |
4.0 | 84c |
22 |
![]() |
![]() |
4.0 | 79c |
23 |
![]() |
![]() |
12 | 41c |
24 |
![]() |
![]() |
23 | Tracec |
The Suzuki–Miyaura reaction of 3-bromopyridine with phenylboronic acid MIDA ester proceeded smoothly to give the expected product in excellent yield (Table 3, entry 7). In addition, 5-bromo-2-methoxypyridine afforded a satisfactory 93% yield in 1.5 h (Table 3, entry 8). A 93% yield of product was obtained by using 2-bromoquinoline as a coupling partner in 2.5 h (Table 3, entry 10). To further investigate the scope and limitations of this methodology, we carried out the cross-couplings of different nitrogen-based heteroaryl halides with various arylboronic acid MIDA esters under standard conditions. Both electron-rich and electron-poor arylboronic acid MIDA esters performed the cross-coupling reactions smoothly with heteroaryl bromides, affording the corresponding biaryls in high yields (Table 3, entries 11–17). For example, the cross-coupling between 2-bromopyridine and p-tolylboronic acid MIDA ester provided 94% yield in 1.5 h (Table 3, entry 11). 5-Bromopyrimidine afforded the target product in 95% yield after 1 h (Table 3, entry 13). Noticeably, steric hinderance due to the ortho substituent on the arylboronic acid MIDA ester did not affect the reaction progress. The cross-coupling reaction of o-tolylboronic acid MIDA ester with 2-bromopyridine and 5-bromo-2-methoxypyridine afforded 91% and 92% yields, respectively (Table 3, entries 18 and 19). Another noteworthy result was that the cross-coupling between 2-chloropyridine and phenylboronic acid MIDA ester provided an 80% yield after 4 h in the presence of 4.0 mol% Pd(OAc)2 (Table 3, entry 20). The cross-couplings of 2-chloropyrazine with phenylboronic acid MIDA esters could also gave good results in this system (Table 3, entries 21 and 22). The coupling reaction of 6-methoxy-2-pyridylboronic acid MIDA ester and 5-bromopyrimidine was performed in this system, providing a 41% yield of the desired product in 12 h (Table 3, entry 23), while only a trace amount of product was obtained using 2-bromopyridine as substrate (Table 3, entry 24). Additionally, a gram-scale reaction was carried out (Scheme 2), furnishing 1.31 g of the desired product with an isolated yield of 84%. No significant detrimental effect on the yield was observed upon increasing the reaction scale.
Footnote |
† Electronic supplementary information (ESI) available: Characterization of cross-coupled products. See DOI: 10.1039/c5ra10001a |
This journal is © The Royal Society of Chemistry 2015 |