Copper-catalyzed halogenation of arylboronic acids

Article abstract of DOI:10.1016/j.tetlet.2011.02.075

In this Letter, a copper-catalyzed halogenation of arylboronic acids was described. This reaction tolerates a variety of functional groups, providing aromatic halides with good yields. It represents a facile and mild procedure to aryl halides.

Full text of DOI:10.1016/j.tetlet.2011.02.075

Tetrahedron Letters 52 (2011) 1993–1995
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Tetrahedron Letters
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Copper-catalyzed halogenation of arylboronic acids
Guangyou Zhang a, Guanglei Lv a, Liping Li a, Fan Chen a, , Jiang Cheng a,b,
⇑
⇑
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325027, PR China
b State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter, a copper-catalyzed halogenation of arylboronic acids was described. This reaction tolerates
a variety of functional groups, providing aromatic halides with good yields. It represents a facile and mild
procedure to aryl halides.
Received 31 December 2010
Revised 13 February 2011
Accepted 18 February 2011
Available online 22 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Aryl halides are important synthetic intermediates that have
been used extensively in various carbon–carbon and carbon–het-
eroatom bond-forming reactions.1 The traditional aromatic haloge-
nation includes electrophilic aromatic substitution and conversion
of an amine into a halide via the diazonium salt (i.e., the Sandmey-
er reaction).2 Although the electrophilic aromatic halogenation
works well for the preparation of chloroarenes and bromoarenes,
the direct iodination of arenes with iodine is generally not feasible.
The alkenyl boronic acids can be converted into alkenyl halides by
reaction with N-halosuccinimides.3–6 However, examples on such
transformation for arylboronic acids were less reported. In 1982,
Kabalka et al. developed halogenation involving the reaction of
organoboranes with halide ions in the presence of chloramine-T.7
In 1998, Prakash and co-workers described the preparation of halo-
arenes by ipso-substitution of arylboronic acids with N-halosuccin-
imides in moderate to good yields.3 In 2003, Szumigala, Jr.
demonstrated the halodeboronation of arylboronic acids by 1,3-di-
bromo-5,5-dimethylhydantoin (DBDMH).8 Recently, John Hynes
and Wu reported chlorination of arylboronic acids by NCS.6 Re-
cently, cyanation, trifluoromethylation, and carboxylated of aryl-
boron also received attention due to its inherent nature.9 From
the synthetic point of view, the employing of simple halogen salts
in the halogenation of arylboronic acids would be attractive. Here-
in, we reported our study on such transformation using KI and KBr.
We initiated our investigation by examining 4-methoxy-
phenylboronic acid (0.3 mmol) with potassium iodide (0.2 mmol)
as the model reaction. Fortunately, the product 1-iodo-4-methoxy-
benzene (3a) was formed in 43% yield (Table 1, entry 1), along with
homocoupling byproduct 4,40-dimethoxybiphenyl in 24% yield.8 To
improve the yield of 3a, different Cu sources were further screened
(Table 1, entries 1–6) and CuBr2 was the best (Table 1, entry 6).
Moreover, the solvent and the ligand played a significant role on
the reaction (Table 1, entries 7–17). Other common solvents (e.g.,
THF, DMSO, NMP, toluene, and 1,4-dioxane) decreased the reaction
efficiency. To our delight, in DMF, the yield of 3a increased to 79%
and 85% of 3a was isolated when the reaction was conducted under
oxygen (Table 1, entry 12). Among the ligands we tested (scheme
1), L1 was the best (Table 1, entries 12–17). The yield of 3a was
dramatically decreased in the absence of CuBr2 or L1 (Table 1, en-
tries 18 and 19).
Finally, the optimal reaction conditions are: CuBr2 (10 mol %)
and 1,10-phenanthroline (20 mol %) in DMF at 80 °C for 20 h under
oxygen. The scope and functional-group tolerance of this
transformation were tested, as summarized in Table 2. Arylboronic
Table 1
Selected results of screening the optimal conditions
copper source
+
K I
MeO
B(OH)2
MeO
I
ligand, solvent
2a
1a
3a
Entry
Cu source
Ligand
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
CuI
CuBr
CuCl
LI
LI
LI
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
DMSO
NMP
toluene
1,4-Dioxane
DMF
DMF
DMF
DMF
43
56
30
46
CuCl2
Cu(acac)2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
—
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
—
59
70 (56)b
10
72 (47)b
<5
6
<5
79 (85)b
<5b
60b
62b
64b
<5b
<5b
58b
DMF
DMF
DMF
DMF
CuBr2
a
All reactions were run with potassium iodide (0.2 mmol), 4-meth-
⇑
Corresponding authors.
E-mail addresses: fanchen@wzu.edu.cn (F. Chen), jiangcheng@wzu.edu.cn
oxyphenylboronic acid (0.3 mmol), Cu source (10 mol %), ligand (20 mol %), dry
solvent (2 mL), air, 80 °C, 20 h. Isolated yield.
b
Under O2.
(J. Cheng).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.075

1994
G. Zhang et al. / Tetrahedron Letters 52 (2011) 1993–1995
Table 2 (continued)
Entry
Boronic acid 1
Product 3
Yieldb (%)
82
N
N
N
N
N
N
NC
B(OH)2
1l
L1
L4
12
3l
L3
L2
L5
B(OH)2
1m
13
14
3m
3n
76
73
O
O
N
N
N
N
N
N
B(OH)2
L6
H
1n
Scheme 1. Ligands for screening.
B(OH)2
15
3o
89
1o
Table 2
CuBr2-catalyzed iodination of arylboronic acids by KIa
16
17
3p
3q
87
53
CuBr2 (10 mol %)
L1 (20 mol %)
B(OH)2
ArB(OH)2
+
KI
ArI
1p
O2, DMF
2a
3
1
B(OH)2
1q
Entry
1
Boronic acid 1
Product 3
Yieldb (%)
85
N
a
Reaction conditions:
(20 mol %), dry DMF (2 mL), O2, 80 °C, 20 h.
1
(0.3 mmol), 2a (0.2 mmol), CuBr2 (10 mol %), L1
MeO
B(OH)2
3a
3b
1a
b
Isolated yield.
B(OH)2
1b
2
3
63
75
acids with electron-donating group on the phenyl ring as well as
those with electron-neutral analogues underwent iodidation
smoothly with good yields (Table 2, entries 2–6). Steric hindrance
on the phenyl ring of arylboronic acid had no obvious effect on the
reaction. For example, 85% of 3a was isolated, while 3c and 3g were
formed in 75% and 70% yields, respectively (Table 2, entries 1 vs 3
and 7). The reaction tolerated a variety of substituents, such as
methylthio, methoxycarbonyl, cyano, nitro, acetyl, and formyl
groups (Table 2, entries 7–14). Notably, the heteroaromatic boronic
acid, such as pyridin-3-ylboronic acid, proved to be competent
substrates, providing the corresponding heteroaromatic iodide
with 53% yield (Table 2, entry 17).
3c
B(OH)2
1c
4
5
3d
3e
74
73
B(OH)2
1d
B(OH)2
1e
6
3f
77
B(OH)2
Table 3
1f
CuBr2-catalyzed bromination of arylboronic acids by KBra
OMe
CuBr2 (10 mol %)
L1 (20 mol %)
7
8
3g
3h
70
95
B(OH)2
1g
ArB(OH)2
+
KBr
ArBr
O2, DMF
2b
1
4
Yieldb (%)
MeS
B(OH)2
Entry
Boronic acid 1
Product 4
1
2
3
1a
1e
1f
4a
4e
4f
70 (20)c
68
1h
NO2
71
4
5
6
7
8
9
10
1g
1h
1j
1k
1l
4g
4h
4j
4k
4l
67
82
74
77
74
78
80
9
3i
86
B(OH)2
1i
O2N
MeO
1m
1n
4m
4n
10
11
3j
90
88
B(OH)2
1j
B(OH)2
11
4r
78
1r
B(OH)2
1k
3k
O
a
Reaction conditions:
1 (0.3 mmol), 2b (0.2 mmol), CuBr2 (10 mol %), L1
(20 mol %), dry DMF (2 mL), O2, 130 °C, 20 h.
b
Isolated yield.
80 °C
c

G. Zhang et al. / Tetrahedron Letters 52 (2011) 1993–1995
1995
To enhance the synthetic utility of this protocol, the reaction
References and notes
of arylboronic acids with potassium bromide was also investi-
gated, as shown in Table 3. It was found that 4-meth-
oxyphenylboronic acid and KBr were subjected to the standard
conditions; 1-bromo-4-methoxybenzene (4a) was obtained in
only 20% yield. Fortunately, the yield increased to 70% in 130 °C
(Table 3, entry 1). Under the optimized conditions, electron-
donating (Table 3, entries 1–5) as well as electron-withdrawing
analogues (Table 3, entries 6–10) all gave the products in moder-
ate yields. Disappointingly, KCl failed to provide the halogenation
product under this catalytic system.10
In summary, we have developed an efficient copper-catalyzed
halogenation reaction between arylboronic acids and halogen salts
under oxygen atmosphere, affording ArX (X = I, Br) in moderate to
good yields. The reaction showed remarkably broad substrate
scope and good functional group tolerance. Furthermore, the use
of inexpensive copper catalysts and O2 as the terminal oxidant
1. (a) Hudlicky, M.; Hudlicky, T. Formation of Carbon–Halogen Bonds In
Supplement D: The Chemistry of Halides, Pseudohalides and Azides; Patai, S.,
Rappoport, Z., Eds.: The Chemistry of Functional Groups; Wiley Sons: Chichester,
U.K., 1983; pp 1021–1172. Chapter 22; (b) Sasson, Y. Formation of Carbon–
Halogen Bonds (Cl, Br, I) In Supplement D: The Chemistry of Halides,
Pseudohalides and Azides; Patai, S., Rappoport, Z., Eds.: The Chemistry of
Functional Groups; Wiley Sons: Chichester, U.K., 1995; pp 535–628. Chapter 11.
2. Urch, C. J. Vinyl and Aryl Halides In Comprehensive Organic Functional Group
Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Ley, S. V., Eds.;
Elsevier: Oxford, U.K., 1995; 2, pp 605–633.
3. Thiebes, C.; Prakash, G. K. S.; Petasis, N.; Olah, G. A. Synlett 1998, 141.
4. Clough, J. M.; Diorazio, L. J.; Widdowson, D. A. Synlett 1990, 761.
5. Petasis, N. A.; Zavialov, I. A. Tetrahedron Lett. 1996, 37, 567.
6. Wu, H.; Hynes, J., Jr. Org. Lett. 2010, 12, 1192.
7. Kabalka, G. W.; Sastry, K. A. R.; Sastry, U.; Somayaji, V. Org. Prep. Proced. Int.
1982, 14, 359.
8. Szumigala, R. H., Jr.; Devine, P. N.; Gauthier, D. R., Jr.; Volante, R. P. J. Org. Chem.
2004, 69, 566.
9. For selected examples, please see: (a) Zhang, Z. H.; Liebeskind, L. S. Org. Lett.
2006, 8, 4331; (b) Liskey, C. W.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2010,
132, 11389; (c) Chu, L. L.; Qing, F.-L. Org. Lett. 2010, 12, 5060; (d) Takaya, J.;
Tadami, S.; Ukai, K.; Iwasawa, N. Org. Lett. 2008, 10, 2697; (e) Ukai, K.; Aoki, M.;
Takaya, J.; Iwasawa, N. J. Am. Chem. Soc. 2006, 128, 8706.
provides
a
significant and practical advantage for this
transformation.11
10. The chlorination of arylboron, see Refs. 6, and 8 and: Murphy, J. M.; Liao, X.;
Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 15434.
Acknowledgments
11. General procedure: under oxygen, a sealed reaction tube was charged with KX
(X = I, Br) (0.2 mmol), arylboronic acid (0.3 mmol), CuBr2 (4.5 mg, 10 mol %),
1,10-phen (7.2 mg, 20 mol %) and DMF (2 mL). The mixture was stirred at 80 or
130 °C. After the completion of the reaction, the solvent was evaporated under
reduced pressure and the residue was purified by flash column
chromatography on silica gel to give the product.
We thank the National Natural Science Foundation of China
(No. 20504023) and the Key Project of Chinese Ministry of Educa-
tion (No. 209054) for financial support.