Solvent-free N-arylation of amines with arylboronic acids under ball milling conditions

Abstract

Solvent-free coupling reactions of arylboronic acids with various amines were presented under ball milling conditions, achieving the aromatic amine coupling products with yields ranging from moderate to good. This type of mechano-chemistry exhibited advantages of solvent-free property, high efficiency, simple work-up procedure and eco-friendliness.

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Aromatic amines are important compounds in the fields of pharmaceutical and agrochemical industries.¹ Among aryl/aryl C–C bond cross-coupling reactions,² Suzuki³ and Stille⁴ reactions are important methodologies in organic synthesis. In modern times, people's cognition of C–C coupling is much higher than that of carbon–heteroatom coupling. However, organic synthesis and drug preparation often involve C–N, C–O,⁵ and C–S⁶ coupling, and C–N coupling is particularly important. In formation of C–N bonds, palladium or nickel has been successfully utilized to catalyze the coupling of amines with aryl halides.⁷ Copper catalyzed or mediated systems for the coupling of amines with aryl halides are typically performed under Ullmann-type conditions.⁸ However, Ullmann reaction conditions are usually harsh, requiring high temperature and giving variable yields.⁹ Chan, Evans and Lam have firstly reported Cu-mediated oxidative amination of arylboronic acids with amines and other nucleophiles, developing a valuable alternative to traditional cross-couplings of carbon–heteroatom bonds.¹⁰ This reaction can be smoothly proceeded under mild condition, affording excellent yields at room temperature and making up for the Suzuki reaction. A recent series of developments for this reaction have been reported, including the innovation of catalytic system, substrate scope and reaction procedure.^11,12 Quach¹³ has found that the cross-coupling of arylboronic acids and potassium aryltrifluoroborate salts with anilines can be proceeding under ligandless conditions. An important discovery by Antilla¹⁴ has demonstrated that, myristic acid, as an additive, can promote this reaction in good yields. This reaction can be carried out by using stoichiometric quantities of Cu(OAc)₂ as catalyst in the presence of various solvents (e.g., dichloromethane, benzene, toluene) and bases (e.g., Et₃N, pyridine, K₂CO₃). However, reaction time often requires more than 24 h.¹⁵ In addition, organic solvents such as dichloromethane is often toxic to researchers' health and environment, and Cu(OAc)₂ is much more expensive than Cu(OAc)₂·H₂O.

In recent years, the field of “green chemistry” has grown at a rapid pace, and solvent-free chemical synthesis is a powerful methodology as it avoids the use of solvents and efficiently reduces the production of toxic waste.¹⁶ High speed ball milling (HSBM) is an attractive method for mechanical activation under solvent-free conditions, which is less harmful to the environment and efficiently reduces reaction time, and has been successfully used to promote several solid-state reactions.¹⁷ Hereon, we reported the application of HSBM for the construction of C–N bonds through Cu(OAc)₂·H₂O-promoted Chan–Lam coupling reaction, with reaction time reduced to 1.5 h and without using any solvent.

In this paper, we initially chose the coupling reaction of phenylboronic acid (1a) with p-methylaniline (2a) as the model system to optimize the reaction parameters (Table 1). After carefully screening the catalysts, it was notable that both copper(I) and copper(II) salts could successfully catalyze the reaction. However, copper(II) salts could promote the reaction better than copper(I) salts, with a 66% yield of desired product by employing Cu(OAc)₂·H₂O (Table 1, entries 1–8). However, under nitrogen atmosphere, the catalytic activity of copper(I) salts was sharply decreased and no desired product was obtained (Table 1, entry 4). When the reaction was performed in various bases, K₂CO₃ gave the best yield among the common bases such as Et₃N, Na₂CO₃, NaOH and Cs₂CO₃ (Table 1, entries 11–14). No reaction occurred when the procedure was carried out in the absence of catalyst, and 21% yield was achieved when no base was added (Table 1, entries 22 and 23).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst (equiv.)	Base (equiv.)	Time (h)	Yield^b (%)
a Reaction conditions: 1a (5 mmol), 2a (7 mmol), catalyst (1 equiv.), base (2.5 equiv.), silica gel 2.5 g, 1.5 h.b Isolated yield.c In a nitrogen atmosphere.d With 10 mmol of 1a and 5 mmol of 2a.e With 5 mmol of 1a and 10 mmol of 2a.
1	CuCl (1)	Et3N (2.5)	1.0	25
2	CuBr (1)	Et3N (2.5)	1.0	31
3	CuI (1)	Et3N (2.5)	1.0	39
4	CuI (1)	Et3N (2.5)	1.0	0^c
5	CuSO4·5H2O (1)	Et3N (2.5)	1.0	61
6	CuO (1)	Et3N (2.5)	1.0	9
7	CuCl2·2H2O (1)	Et3N (2.5)	1.0	42
8	Cu(OAc)2·H2O (1)	Et3N (2.5)	1.0	66
9	FeCl3 (1)	Et3N (2.5)	1.0	0
10	Cu(OAc)2·H2O (1)	Et3N (2.5)	1.5	74
11	Cu(OAc)2·H2O (1)	Na2CO3 (2.5)	1.5	65
12	Cu(OAc)2·H2O (1)	Cs2CO3 (2.5)	1.5	51
13	Cu(OAc)2·H2O (1)	NaOH (2.5)	1.5	72
14	Cu(OAc)2·H2O (1)	K2CO3 (2.5)	1.5	79
15	Cu(OAc)2·H2O (2)	K2CO3 (2.5)	1.5	74
16	Cu(OAc)2·H2O (0.5)	K2CO3 (2.5)	1.5	54
17	Cu(OAc)2·H2O (1)	K2CO3 (4.0)	1.5	77
18	Cu(OAc)2·H2O (1)	K2CO3 (1.0)	1.5	48
19	Cu(OAc)2·H2O (1)	K2CO3 (2.5)	3.0	80
20	Cu(OAc)2·H2O (1)	K2CO3 (2.5)	1.5	76^d
21	Cu(OAc)2·H2O (1)	K2CO3 (2.5)	1.5	77^e
22	—	K2CO3 (2.5)	1.5	0
23	Cu(OAc)2·H2O (1)	—	1.5	21

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To further study the effect of the grinding auxiliary, various grinding auxiliaries were examined respectively. Silica gel was found to be the most effective among those grinding auxiliaries (Table 2, entry 6). It might act as both the grinding-aid agent and adsorbent in the reaction. In the absence of grinding auxiliary, substrates could not be mixed efficiently, leading to the poor yield (Table 2, entry 1). NaCl, α-Al₂O₃ and γ-Al₂O₃ as grinding auxiliaries all gave unsatisfactory yields, and KF–Al₂O₃ relatively performed as a better grinding auxiliary (Table 2, entries 2–5).

Table 2 Influence of grinding auxiliary on yield of 3aa^a

Entry	Grinding auxiliary	Weight (g)	Yield^b (%)
a Reaction conditions: 1a (5 mmol), 2a (7 mmol), Cu(OAc)2·H2O (1 equiv.), K2CO3 (2.5 equiv.), 1.5 h.b Isolated yield.
1	—	—	55
2	NaCl	2.5	44
3	α-Al2O3 (neutral)	2.5	52
4	γ-Al2O3 (basic)	2.5	45
5	KF–Al2O3 (37 wt% KF)	2.5	67
6	Silica gel	2.5	79

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Under the optimized reaction conditions, various arylboronic acids and aromatic amines were examined to explore the scope and generality of this coupling reaction. As shown in Table 3, both electron-withdrawing and electron-donating substituted aromatic amines were successfully coupled to arylboronic acids. For example, 1a reacting with aromatic amines afforded the corresponding products in good yields (Table 3, entries 1–5, 11, 13). The influence of a monosubstituent group at the ortho- and para-position of aromatic amines was investigated to examine the steric effect in the reaction system, and results were shown in Table 3 (entries 3–10). Notably, aromatic amines with fluoro, chloro and bromo substituents (commonly used for cross-coupling reactions, Table 3, entries 5–10) were tolerated under the reaction conditions, and afforded the targeted products in poor to good yields, making possible the construction of aryl/aryl C–N bonds. Nevertheless, the reaction became sluggish by using aromatic amines with electron-withdrawing groups such as trifluoromethyl-group at the para-position (3ak). It was noteworthy that, 3ak was difficult to prepare from the corresponding aryl halides via Ullmann coupling reaction, since the electron-withdrawing groups on the aromatic ring would decrease the migratory rate.

Table 3 Copper-promoted coupling of arylboronic acid with aromatic amines^a

Entry	Arylboronic acids	Aromatic amines	Product	Yield^b (%)
a Reaction conditions: 1 (5 mmol), 2 (7 mmol), Cu(OAc)2·H2O (1 equiv.), K2CO3 (2.5 equiv.), silica gel 2.5 g, 1.5 h.b Isolated yield.
1	C6H5 (1a)	C6H5 (2a)	3aa	86
2	C6H5 (1a)	p-(OCH3)C6H4 (2b)	3ab	83
3	C6H5 (1a)	p-(CH3)C6H4 (2c)	3ac	79
4	C6H5 (1a)	o-(CH3)C6H4 (2d)	3ad	74
5	C6H5 (1a)	p-(F)C6H4 (2e)	3ae	76
6	C6H5 (1a)	o-(F)C6H4 (2f)	3af	65
7	C6H5 (1a)	p-(Cl)C6H4 (2g)	3ag	50
8	C6H5 (1a)	o-(Cl)C6H4 (2h)	3ah	60
9	C6H5 (1a)	p-(Br)C6H4 (2i)	3ai	63
10	C6H5 (1a)	o-(Br)C6H4 (2j)	3aj	55
11	C6H5 (1a)	p-(CF3)C6H4 (2k)	3ak	74
12	C6H5 (1a)	2,4-(F)2C6H3 (2l)	3al	54
13	C6H5 (1a)	p-(OC2H5)C6H4 (2m)	3am	79
14	C6H5 (1a)	1-Naphthyl (2n)	3an	61
15	C6H5 (1a)	o-(C2H5)C6H4 (2o)	3ao	65
16	C6H5 (1a)	3,4,5-(F)3C6H2 (2p)	3ap	63
17	p-(CH3) (1b)	C6H5 (2a)	3ba	84
18	p-(OCH3) (1c)	C6H5 (2a)	3ca	77
19	p-(CF3) (1d)	C6H5 (2a)	3da	81
20	o-(CH3) (1e)	C6H5 (2a)	3ea	72
21	p-(Cl) (1f)	C6H5 (2a)	3fa	69
22	p-(CH3) (1b)	p-(OCH3)C6H4 (2b)	3bb	79
23	p-(OCH3) (1c)	p-(OCH3)C6H4 (2b)	3cb	72
24	p-(CF3) (1d)	p-(OCH3)C6H4 (2b)	3db	77
25	o-(CH3) (1e)	p-(OCH3)C6H4 (2b)	3eb	61
26	p-(Cl) (1f)	p-(OCH3)C6H4 (2b)	3fb	58

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On the other hand, various electron-withdrawing and electron-donating groups on the phenyl ring of arylboronic acids were examined. Results were shown in Table 3 (entries 17–26). To our delight, methyl, methoxy, chloro, trifluoromethyl substituents at the para-position or ortho-position of arylboronic acids gave good yields. It was well known that, 3da, 3fa, 3db and 3fb were hard to prepare due to their strong electron-withdrawing effect. Hereon, we provided an efficient and alternative method to obtain those compounds.

The application of this reaction to the coupling of alkylamines with arylboronic acids was also briefly explored, affording desired N-alkyl aniline products in moderate yield, as depicted in Table 4. Heterocyclic amines, primary and secondary amines as substrates were all smoothly coupled with phenylboronic acid, and gave good yields (entries 1–5). And due to steric effect, diethylamine could not be successfully coupled with phenylboronic acid (entry 6).

Table 4 Copper-promoted coupling of phenylboronic acid with amines^a

Entry	Amines	Product	Yield^b (%)
a Reaction conditions: phenylboronic acid (5 mmol), amines (7 mmol), Cu(OAc)2·H2O (1 equiv.), K2CO3 (2.5 equiv.), silica gel 2.5 g, 1.5 h.b Isolated yield.
1			84
2			70
3			55
4			59
5			68
6			Trace

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Conclusions

In summary, we have first developed a copper-promoted coupling of arylboronic acids with aromatic amines under mechanically activated conditions, affording target products with moderate to good yields. This method exhibits good substrate generality and proceeds smoothly under mild conditions without using any relatively toxic solvent, and reaction time is significantly reduced to 1.5 h.

Acknowledgements

We gratefully acknowledge the National Natural Science Foundation of China (Project no. 21176222) for financial support.

References

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra02952f

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