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

Article abstract of DOI:10.1039/c4ra02952f

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. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra02952f

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Solvent-free N-arylation of amines with arylboronic
acids under ball milling conditions†
Cite this: RSC Adv., 2014, 4, 22775
*
Xingyi Zhu, Qihong Zhang and Weike Su
Received 3rd April 2014
Accepted 6th May 2014
DOI: 10.1039/c4ra02952f
www.rsc.org/advances
Solvent-free coupling reactions of arylboronic acids with various anilines can be proceeding under ligandless conditions. An
amines were presented under ball milling conditions, achieving the important discovery by Antilla14 has demonstrated that, myristic
aromatic amine coupling products with yields ranging from moderate acid, as an additive, can promote this reaction in good yields.
to good. This type of mechano-chemistry exhibited advantages of This reaction can be carried out by using stoichiometric quan-
solvent-free property, high efficiency, simple work-up procedure and tities of Cu(OAc)2 as catalyst in the presence of various solvents
eco-friendliness.
(e.g., dichloromethane, benzene, toluene) and bases (e.g., Et3N,
pyridine, K2CO3). However, reaction time oen requires more
than 24 h.15 In addition, organic solvents such as dichloro-
methane is oen toxic to researchers' health and environment,
and Cu(OAc)2 is much more expensive than Cu(OAc)2$H2O.
In recent years, the eld of “green chemistry” has grown at a
rapid pace, and solvent-free chemical synthesis is a powerful
methodology as it avoids the use of solvents and efficiently
reduces the production of toxic waste.16 High speed ball milling
(HSBM) is an attractive method for mechanical activation under
solvent-free conditions, which is less harmful to the environ-
ment and efficiently reduces reaction time, and has been
successfully used to promote several solid-state reactions.17
Hereon, we reported the application of HSBM for the
construction of C–N bonds through Cu(OAc)2$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). Aer
carefully screening the catalysts, it was notable that both cop-
per(I) and copper(II) salts could successfully catalyze the reac-
tion. 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).
Aromatic amines are important compounds in the elds of
pharmaceutical and agrochemical industries.1 Among aryl/aryl
C–C bond cross-coupling reactions,2 Suzuki3 and Stille4 reac-
tions 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 oen 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 rstly
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 develop-
ments 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 aryltriuoroborate salts with
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals,
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou
310014, P.R. China. E-mail: pharmlab@zjut.edu.cn; Tel: +86 57188320899
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra02952f
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Table 1 Optimization of the reaction conditionsa
Under the optimized reaction conditions, various aryl-
boronic 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 aryl-
boronic acids. For example, 1a reacting with aromatic amines
afforded the corresponding products in good yields (Table 3,
entries 1–5, 11, 13). The inuence of a monosubstituent group
at the ortho- and para-position of aromatic amines was inves-
tigated to examine the steric effect in the reaction system, and
results were shown in Table 3 (entries 3–10). Notably, aromatic
amines with uoro, chloro and bromo substituents (commonly
used for cross-coupling reactions, Table 3, entries 5–10) were
tolerated under the reaction conditions, and afforded the tar-
geted 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-with-
drawing groups such as triuoromethyl-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.
Entry
Catalyst (equiv.)
Base (equiv.)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
CuCl (1)
CuBr (1)
CuI (1)
CuI (1)
CuSO4$5H2O (1)
CuO (1)
CuCl2$2H2O (1)
Cu(OAc)2$H2O (1)
FeCl3 (1)
Cu(OAc)2$H2O (1)
Cu(OAc)2$H2O (1)
Cu(OAc)2$H2O (1)
Cu(OAc)2$H2O (1)
Cu(OAc)2$H2O (1)
Cu(OAc)2$H2O (2)
Cu(OAc)2$H2O (0.5)
Cu(OAc)2$H2O (1)
Cu(OAc)2$H2O (1)
Cu(OAc)2$H2O (1)
Cu(OAc)2$H2O (1)
Cu(OAc)2$H2O (1)
—
Et3N (2.5)
Et3N (2.5)
Et3N (2.5)
Et3N (2.5)
Et3N (2.5)
Et3N (2.5)
Et3N (2.5)
Et3N (2.5)
Et3N (2.5)
Et3N (2.5)
Na2CO3 (2.5)
Cs2CO3 (2.5)
NaOH (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (4.0)
K2CO3 (1.0)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
—
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
1.5
1.5
1.5
1.5
25
31
39
0c
61
9
42
66
0
74
65
51
72
79
74
54
77
48
80
76d
77e
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Table
3 Copper-promoted coupling of arylboronic acid with
aromatic aminesa
Cu(OAc)2$H2O (1)
21
a
Reaction conditions: 1a (5 mmol), 2a (7 mmol), catalyst (1 equiv.), base
b
c
(2.5 equiv.), silica gel 2.5 g, 1.5 h. Isolated yield. In a nitrogen
atmosphere. With 10 mmol of 1a and 5 mmol of 2a. With 5 mmol
of 1a and 10 mmol of 2a.
d
e
Entry Arylboronic acids Aromatic amines
Product Yieldb (%)
1
2
3
4
5
6
7
8
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
C6H5 (1a)
p-(CH3) (1b)
p-(OCH3) (1c)
p-(CF3) (1d)
o-(CH3) (1e)
p-(Cl) (1f)
p-(CH3) (1b)
p-(OCH3) (1c)
p-(CF3) (1d)
o-(CH3) (1e)
p-(Cl) (1f)
C6H5 (2a)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
86
83
79
74
76
65
50
60
63
55
74
54
79
61
65
63
84
77
81
72
69
79
72
77
61
58
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, a-Al2O3 and g-Al2O3 as
grinding auxiliaries all gave unsatisfactory yields, and KF–Al2O3
relatively performed as a better grinding auxiliary (Table 2,
entries 2–5).
p-(OCH3)C6H4 (2b)
p-(CH3)C6H4 (2c)
o-(CH3)C6H4 (2d)
p-(F)C6H4 (2e)
o-(F)C6H4 (2f)
p-(Cl)C6H4 (2g)
o-(Cl)C6H4 (2h)
p-(Br)C6H4 (2i)
o-(Br)C6H4 (2j)
p-(CF3)C6H4 (2k)
2,4-(F)2C6H3 (2l)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
3aj
3ak
3al
p-(OC2H5)C6H4 (2m) 3am
1-Naphthyl (2n)
o-(C2H5)C6H4 (2o)
3,4,5-(F)3C6H2 (2p)
C6H5 (2a)
C6H5 (2a)
C6H5 (2a)
3an
3ao
3ap
3ba
3ca
3da
3ea
3fa
3bb
3cb
3db
3eb
3
Table 2 Influence of grinding auxiliary on yield of 3aaa
Entry
Grinding auxiliary
Weight (g)
Yieldb (%)
C6H5 (2a)
C6H5 (2a)
1
2
3
4
5
6
—
NaCl
—
55
44
52
45
67
79
2.5
2.5
2.5
2.5
2.5
p-(OCH3)C6H4 (2b)
p-(OCH3)C6H4 (2b)
p-(OCH3)C6H4 (2b)
p-(OCH3)C6H4 (2b)
p-(OCH3)C6H4 (2b)
a-Al2O3 (neutral)
g-Al2O3 (basic)
KF–Al2O3 (37 wt% KF)
Silica gel
a
a
Reaction conditions: 1a (5 mmol), 2a (7 mmol), Cu(OAc)2$H2O
Reaction conditions: 1 (5 mmol), 2 (7 mmol), Cu(OAc)2$H2O (1 equiv.),
b
b
(1 equiv.), K2CO3 (2.5 equiv.), 1.5 h. Isolated yield.
K2CO3 (2.5 equiv.), silica gel 2.5 g, 1.5 h. Isolated yield.
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Table 4 Copper-promoted coupling of phenylboronic acid with
aminesa
Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (Project no. 21176222) for nancial support.
References
Entry
1
Amines
Product
Yieldb (%)
84
1 (a) J. C. Antilla and S. L. Buchwald, Org. Lett., 2001, 3, 2077;
(b) M. Negwer, in Organic-Chemical Drugs and their Synonyms:
(An International SurVey), Akademie Verlag GmbH, Berlin,
7th edn, 1994.
2 D. M. T. Chan, K. L. Monaco, R. P. Wang and M. P. Winters,
Tetrahedron Lett., 1998, 39, 2933.
3 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457.
4 (a) T. N. Mitchell, Synthesis, 1992, 803–815; (b) J. K. Stille,
Angew. Chem., Int. Ed., 1986, 86, 508.
5 T. D. Quach and R. A. Batey, Org. Lett., 2003, 5, 1381.
6 (a) P. S. Herradura, K. A. Pendola and R. K. Guy, Org. Lett.,
2000, 2, 2019; (b) A. Kar, I. A. Sayyed, W. F. Lo,
H. M. Kaiser, M. Beller and M. K. Tse, Org. Lett., 2007, 9,
3405; (c) F. Huang and R. A. Batey, Tetrahedron, 2007, 63,
7667.
2
3
70
55
59
4
5
68
7 (a) B. H. Yang and S. L. Buchwald, J. Organomet. Chem., 1999,
576, 125; (b) J. F. Hartwig, Angew. Chem., Int. Ed., 1998, 37,
2046.
8 (a) F. Ullmann, Ber. Dtsch. Chem.Ges., 1903, 36, 2382; (b)
H. B. Goodbrand and N. X. Hu, J. Org. Chem., 1999, 64,
670; (c) J. Lindley, Tetrahedron, 1984, 40, 1433.
6
Trace
a
Reaction conditions: phenylboronic acid (5 mmol), amines (7 mmol),
Cu(OAc)2$H2O (1 equiv.), K2CO3 (2.5 equiv.), silica gel 2.5 g, 1.5 h.
b
Isolated yield.
9 (a) A. Kiyomori, J. F. Marcoux and S. L. Buchwald,
Tetrahedron Lett., 1999, 40, 2657; (b) M. A. Khan and
J. B. Polya, J. Chem. Soc., 1970, 85; (c) F. Ullmann, Ber.
Dtsch. Chem. Ges., 1903, 36, 2382; (d) H. B. Goodbrand and
N. X. Hu, J. Org. Chem., 1999, 64, 670.
On the other hand, various electron-withdrawing and elec-
tron-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, triuoromethyl
substituents at the para-position or ortho-position of arylbor-
onic acids gave good yields. It was well known that, 3da, 3fa, 3db
and 3 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 alkyl-
amines with arylboronic acids was also briey 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).
10 (a) D. M. T. Chan, K. L. Monaca, R. P. Wanag and
M. P. Winters, Tetrahedron Lett., 1998, 39, 2933; (b)
P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams,
M. P. Winters, D. M. T. Chan and A. Combs, Tetrahedron
Lett., 1998, 39, 2941; (c) A. P. Combs, S. Saubern,
M. Rafalski and P. Y. S. Lam, Tetrahedron Lett., 1999, 40,
1623; (d) P. Y. S. Lam, S. Deudon, K. M. Averill, R. Li,
M. Y. He, P. DeShong and C. G. Clark, J. Am. Chem. Soc.,
2000, 122, 7600; (e) P. Y. S. Lam, C. G. Clark, S. Subern,
J. Adams, K. M. Averill, D. M. T. Chan and A. Combs,
Synlett, 2000, 674; (f) D. M. T. Chan, K. L. Monaco, R. Li,
D. Bonne, C. G. Clark and P. Y. S. Lam, Tetrahedron Lett.,
2003, 44, 3863; (g) P. Y. S. Lam, G. Vincent, D. Bonne and
C. G. Clark, Tetrahedron Lett., 2003, 44, 4927.
11 D. S. Raghuvanshi, A. K. Gupta and K. N. Singh, Org. Lett.,
2012, 14, 4326.
12 M. L. Kantam, G. T. Venkanna, C. Sridhar, B. Sreedhar and
B. M. Choudary, J. Org. Chem., 2006, 71, 9522.
Conclusions
In summary, we have rst developed a copper-promoted
coupling of arylboronic acids with aromatic amines under 13 T. D. Quach and R. A. Batey, Org. Lett., 2003, 5, 4397.
mechanically activated conditions, affording target products 14 J. C. Antilla and S. L. Buchwald, Org. Lett., 2001, 3, 2077.
with moderate to good yields. This method exhibits good 15 P. Y. S. Lam, G. Vincent, D. Bonne and C. G. Clark,
substrate generality and proceeds smoothly under mild condi-
Tetrahedron Lett., 2002, 43, 3091.
tions without using any relatively toxic solvent, and reaction 16 (a) V. Declerck, P. Nun, J. Martinez and F. Lamaty, Angew.
time is signicantly reduced to 1.5 h.
Chem., Int. Ed., 2009, 48, 9318; (b) X. Y. Zhu, Z. H. Li,
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C. Jin, L. Xu, Q. Q. Wu and W. K. Su, Green Chem., 2009, 11,
163.
Chem. Soc. Rev., 2013, 42, 7719; (f) A. L. Garay, A. Pichon
and S. L. James, Chem. Soc. Rev., 2007, 36, 846; (g) A. Stolle
and B. Ondruschka, Pure Appl. Chem., 2011, 83, 1343; (h)
C. J. Li, Acc. Chem. Res., 2009, 42, 335; (i) R. Thorwirth,
A. Stolle, B. Ondruschka, A. Wild and U. S. Schubert,
Chem. Commun., 2011, 47, 4370; (j) R. Schmidt,
R. Thorwirth, T. Szuppa, A. Stolle, B. Ondruschka and
H. Hopf, Chem.–Eur. J., 2011, 17, 8129.
17 (a) A. Stolle, T. Szuppa, S. E. S. Leonhardt and
B. Ondruschka, Chem. Soc. Rev., 2011, 40, 2317; (b)
S. L. James, C. J. Adams, C. Bolm, D. Braga and P. Collier,
Chem. Soc. Rev., 2012, 41, 413; (c) G. W. Wang, Chem. Soc.
Rev., 2013, 42, 766; (d) P. Chauhan and S. S. Chimni,
Beilstein J. Org. Chem., 2012, 8, 2132; (e) E. Boldyreva,
22778 | RSC Adv., 2014, 4, 22775–22778
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