Palladium-catalyzed ligand-free and efficient Suzuki–Miyaura reaction of heteroaryl halides with MIDA boronates in water

Abstract

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.

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Introduction

Heterobiaryls are common structural motifs in natural products, polymers, and functional materials.¹ Numerous synthetic methodologies for the synthesis of heterobiaryls have been developed in the past decades. Among the methodologies described in the literature, the Suzuki–Miyaura reaction is one of the most practical methods to prepare these compounds.² As nucleophilic coupling partner, organoboronic acids are most often utilized in the Suzuki–Miyaura reactions.³ However, arylboronic acids are sp²-hybridized intermediates, which are not monomeric compounds, but rather exist in equilibrium with dimers and cyclictrimers. Thus, many organoboronic acids are waxy solids that are difficult to purify. Besides, some of useful organoboronic acids are inherently unstable, including 2-heterocyclic derivatives, which significantly limit their storage and/or efficient cross-coupling.^3b,4 Recently, there has been increased interest in the use of N-methyliminodiacetic acid (MIDA) boronates as coupling partners for the Suzuki–Miyaura reaction.⁵ The MIDA boronates, first mentioned in the late 1980s, offer several positive features associated with their use, including air stability and crystallinity, which are highly appealing to the pharmaceutical industry.⁶ In 2007, Burke's group⁷ reported that MIDA could be served as a highly versatile boronic acid protective group, and they also demonstrated how the reactivity was controlled between two different reaction sites in iterative Suzuki–Miyaura reactions of MIDA-protected haloboronic acids. They further found that the MIDA-protected boronates could slowly hydrolyze and release the active boronic acids under mild aqueous basic conditions to take part in the Suzuki–Miyaura reaction.⁸ Since then, the use of MIDA boronates to the Suzuki–Miyaura reaction has been widened by several groups and shown to be remarkably useful in the synthesis of small molecules and natural product.⁹ However, most of the reported approaches involved the use of phosphine ligands which are often air-sensitive, expensive and many reactions require proceeding in a toxic organic solvent with a long reaction time. Therefore, the development of an effective, nontoxic, and environmentally friendly system for the MIDA boronates-mediated Suzuki–Miyaura reaction is still an important goal in synthetic organic chemistry.

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.

Scheme 1 MIDA boronates mediated Suzuki–Miyaura reaction.

Results and discussion

Optimization of reaction conditions

Initially, the cross-coupling between 2-bromopyridine (0.5 mmol) and phenylboronic acid MIDA ester (0.6 mmol) in 1 mL water was chosen as a model reaction for screening base. The results are shown in Table 1. It is clear that the reaction rate was greatly affected by the base used. All of tested inorganic bases such as K₂CO₃, K₃PO₄·3H₂O, which are often used in the Suzuki–Miyaura reaction of arylboronic acids, exhibited low activity in the present protocol (Table 1, entries 1–4). Subsequently, a series of organic bases were examined. Et₃N was the first organic base tested in this system, providing a positive result of a 77% yield of the cross-coupled product in 2 h (Table 1, entry 5). Another base (i-Pr)₂NEt provided a similar result as Et₃N (Table 1, entry 14). The most efficient base in the present catalytic system is (i-Pr)₂NH, which provided a 93% yield in 2 h (Table 1, entry 13). The other tested bases all gave disappointing results (Table 1, entries 6–12). Therefore, the results demonstrate that (i-Pr)₂NH is the preferred base in this catalytic system. The reason for the high efficiency is supposed that (i-Pr)₂NH acts as not only a base, but also a ligand, which has a much higher tendency to coordinate to palladium to form the active species as reported by Boykin and Tao.¹²

Table 1 The effect of base on the Suzuki–Miyaura reaction^a

Entry	Base	Yield^b (%)
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

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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.

Table 2 The effect of palladium species and temperature on the Suzuki–Miyaura reaction^a

Entry	Catalyst	Temperature (°C)	Yield^b (%)
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	64^c
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	61^d

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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).

Table 3 The Suzuki–Miyaura reaction of heteroaryl halides with arylboronic acid MIDA ester^a

Entry	Heteroaryl halides	MIDA boronates	Time (h)	Yield^b
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	80^c
21			4.0	84^c
22			4.0	79^c
23			12	41^c
24			23	Trace^c

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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.

Scheme 2 Gram-scale synthesis of the 2-phenylpyridine. Reaction conditions: 2-bromopyridine (10 mmol), phenylboronic acid MIDA ester (12 mmol), Pd(OAc)₂ (2 mol%), H₂O (10 mL), (i-Pr)₂NH (20 mmol), 100 °C, under air, isolated yield.

Conclusion

In summary, we have developed an efficient and convenient protocol for the palladium-catalyzed Suzuki–Miyaura reaction of heteroaryl halides with arylboronic acid MIDA esters in pure water without any additive. This methodology offers a green, novel alternative way for the synthesis of heteroaryl–aryl based compounds. Further work to explore the exact function of (i-Pr)₂NH in the system is currently under investigation in our laboratory.

Experimental

General remarks

All commercially available reagents (from Acros, Aldrich, Fluka) were used without further purification. N-Methyliminodiacetic acid (MIDA) boronates were prepared from corresponding arylboronic acids following the method reported in the literature.⁷ All reactions were carried out in air. NMR spectra were recorded on a Brucker Advance II 400 spectrometer using TMS as internal standard (400 MHz for ¹H NMR). GC analysis was performed on Agilent GC-7890A with 4-methoxybiphenyl as internal standard. The isolated yield of products were obtained by short chromatography on a silica gel (200–300 mesh) column using petroleum ether (60–90 °C), unless otherwise noted. Compounds described in the literature were characterized by ¹H NMR spectra compared with reported data.

General procedure for the Suzuki–Miyaura reaction

A mixture of aryl bromides (0.5 mmol), N-methyliminodiacetic acid (MIDA) boronates (0.6 mmol), (i-Pr)₂NH (1 mmol), Pd(OAc)₂ (2 mol%), H₂O (1 mL) was stirred at 100 °C in air for the indicated time. The reaction mixture was added to brine (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were concentrated in vacuo and the yield was determined by GC analysis with naphthalene as internal standard, or the product was isolated by short chromatography.

Acknowledgements

The authors thank the financial support from the National Natural Science Foundation of China (21276043, 21076034).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Characterization of cross-coupled products. See DOI: 10.1039/c5ra10001a

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