Copper-catalyzed nitration of arylboronic acids with nitrite salts under mild conditions: An efficient synthesis of nitroaromatics

Article abstract of DOI:10.2174/157017812800221717

Copper-catalyzed nitration of arylboronic acids has been developed with nitrite salts as nitrating agent under mild conditions. This process provides an efficient and practical method for the synthesis of nitro aromatics, due to its simple experimental procedure and its use of convenient and inexpensive copper catalyst.

Full text of DOI:10.2174/157017812800221717

Letters in Organic Chemistry, 2012, 9, 133-137
133
Copper-Catalyzed Nitration of Arylboronic Acids with Nitrite Salts Under
Mild Conditions: An Efficient Synthesis of Nitroaromatics
Guobing Yan*, Ling Zhang and Jian Yu
Department of Chemistry, Lishui University, Lishui 323000，P. R. China
Received June 16, 2011: Revised September 22, 2011: Accepted November 01, 2011
Abstract: Copper-catalyzed nitration of arylboronic acids has been developed with nitrite salts as nitrating agent under
mild conditions. This process provides an efficient and practical method for the synthesis of nitro aromatics, due to its
simple experimental procedure and its use of convenient and inexpensive copper catalyst.
Keywords: Arylboronic acids, copper catalyst, nitration.
INTRODUCTION
C-O, C-S, C-X and C-P coupling protocols of arylboronic acids
with nucleophiles [9]. Here, we report a more convenient and
inexpensive copper-catalyzed method for the synthesis of
nitroaromatics under mild conditions.
Aromatic nitro compounds have found widespread
applications as pharmaceuticals, dyes, industrial materials,
and so on [1]. They are also versatile building blocks in
organic synthesis [2]. Traditional methods for the synthesis
of nitroaromatics are via direct electrophilic aromatic
substitution in the presence of an excess of nitric acid or a
mixture of nitric acid and sulfuric acid [2]. These classic
methods, although still widely used in the industry as well as
in the laboratory, suffer from issues of poor regioselectivity
and arrow functional group compatibility. Moreover, these
nitrating agents are also good oxidants, the nitrated
compounds are often accompanied by oxidation products. In
2000, Prakash and co-workers firstly reported the ipso-
nitration of arylboronic acids with Crivello’s reagent [3a].
The same group in 2004 made further modifications to the
nitration protocol by using inorganic nitrate salt and
chlorotrimethylsilane, which acted as a selective and
efficient ipso-nitrating agent [3b]. Recently, transition-metal-
catalyzed nitration of aromatic halide has emerged as a more
attractive method to synthesize aromatic nitro compounds. In
2005, Saito and co-workers disclosed a method for the
transformation of aryl iodides and bromides to
nitroaromatics catalyzed by copper in the presence of N, N-
dimethylethylenediamine [4]. Buchwald and co-workers in
RESULTS AND DISCUSSION
On the outset of this investigation, we used 4-
methylphenylboronic acid 1a as model substrate with n-
Bu4NNO2 to screen suitable reaction conditions and the
results are summarized in Table 1. When Cu2O was used
catalyst, the nitration of 1a indeed took place in methanol at
room temperature under open air, albeit in low yield (entry
1). Encouraged by this initial result, we proceeded to
optimize the proposed reaction. To our delight, the nitration
product 2a was obtained with 61% yield in MeCN (entry 2).
Other solvents, such as CH2Cl2, THF, dioxane, DMF and
DMSO, were unsuitable for this reaction (entries 3-7). Various
copper sources were further tested. It was found that the
reaction afforded the desired product with lower yields under
Cu(I) or Cu(II) catalysts, except for CuO (entries 8-13). The
yield of the reaction was significantly improved by increasing
the amount of 1a, due to the competing side reaction of the
formation of 4,4'-dimethylbiphenyl and 4-methylphenol (entry
14). Finally, for comparison the reaction was carried out in the
absence of Cu2O, no product 2a could be detected (entry 15).
2009 developed
a very efficient palladation-nitration
protocol for the regioselective ipso-nitration of aryl
Under the optimized conditions, the substrate scope of
this reaction was investigated and the results are summarized
in Table 2. It was observed that the reaction was marginally
affected by electronic effects of the substituents of
arylboronic acids. The reaction with ortho-, meta-, and para-
electron-donating substituted arylboronic acids proceeded
smoothly and afforded the corresponding nitro compounds in
excellent yields (2a, c-g). Higher reactivity was observed for
4-tert-butylphenylboronic acid and 2-naphthylboronic acid
(2f, 2i). The substituted arylboronic acids bearing electron-
deficient groups showed slightly lower reactivity than those
bearing electron-rich or neutral groups (2j-o). It is
particularly noteworthy that bromo and chloro substituents
are tolerated in the reaction conditions, which is
advantageous for further transformations (2j, 2k). The
reaction tolerated a wide range of functional groups, such as
chlorides, triflates and nonaflates with sodium nitrite [5].
The transition-metal-catalyzed functionalization of
arylboronic acids is the most powerful tool for the formation
of carbon–carbon and carbon–heteroatom bonds in modern
organic synthesis [6]. Apart from the well-known Suzuki-
Miyaura cross-coupling [7], there has been a significant
development in copper-mediated oxidative coupling of
arylboronic acids with heteroatom nucleophiles reported by
Chan and Lam [8]. These pioneering reports spurred recent
numerous investigations into the copper-catalyzed C-C, C-N,
*Address correspondence to this author at the Department of Chemistry,
Lishui University, Xueyuan Road, Lishui City 323000, Zhejiang Province,
P. R. China; Tel: +86 578 2271308; Fax: +86 578 2271 308;
E–mail: gbyan@lsu.edu.cn
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

134 Letters in Organic Chemistry, 2012, Vol. 9, No. 2
Yan et al.
a
Table 1. Optimization of Copper-Catalyzed Nitration of 1a with n-Bu4NNO2
Cu Cat.
NO2
n-Bu4NNO2
+
B(OH)2
Solvent
2a
1a
Entry
Cu Cat.
Solvent
Yield(%)b
1
2
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuI
MeOH
MeCN
CH2Cl2
THF
35
61
3
15
4
18
5
Dioxane
DMF
Trace
Trace
Trace
31
6
7
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
8
9
CuBr
CuCl
CuO
37
10
11
12
13
14c
15d
40
/
Cu(OAc)2
Cu(OTf)2
Cu2O
/
21
26
75
/
aUnless otherwise noted, the reaction conditions are as follows: 4-methylphenylboronic acid 1a (1.5 equiv), n-Bu4NNO2 (0.3 mmol), Cu Cat. (20 mol %), in anhydrous solvent (2
mL), at room temperature, under open air. bIsolated yield. c4-methylphenylboronic acid 1a (2 equiv). dThe reaction was carried out in the absence of Cu2O.
a
Table 2. Copper-Catalyzed Nitration of Arylboronic Acids 1a-p with n-Bu4NNO2
Cu2O (20 mol %)
ArB(OH)2
n-Bu4NNO2
ArNO2
+
MeCN, Air, RT
1a-p
2a-p
Entry
ArB(OH)2 (1)
Product (2)
Yield (%)b
1
2
p-MeC6H4 1a
C6H5 1b
2a
2b
2c
2d
2e
2f
75
61
3
o-MeC6H4 1c
m-MeC6H4 1d
3,5-Me2C6H3 1e
p-tBuC6H4 1f
p-MeOC6H4 1g
70
4
72
5
80
6
87
7
2g
2h
2i
78
8
4-Me-1-naphthyl 1h
2-naphthyl 1i
p-BrC6H4 1j
65
9
88
10
11
12
13
14
15
16
2j
51
p-ClC6H4 1k
2k
2l
57
m-CNC6H4 1l
p-CHOC6H4 1m
p-MeO2CC6H4 1n
p-CF3C6H4 1o
2-thiophyl 1p
48
2m
2n
2o
2p
60
53
30
Trace
aUnless otherwise noted, the reaction conditions are as follows: arylboronic acid 1a-p (2.0 equiv), n-Bu4NNO2 (0.3 mmol), Cu2O (20 mol %), MeCN (2 mL), at room temperature,
under open air. bIsolated yield.

An Efficient Synthesis of Nitroaromatics
Letters in Organic Chemistry, 2012, Vol. 9, No. 2
135
Table 3. Copper-Catalyzed Nitration of Arylboronic Acids with Sodium Nitritea
Cu2O (20 mol %)
pyridine (3 equiv)
NaNO2
ArNO2
ArB(OH)2
1
+
MeCN, Air, RT
2
Entry
ArB(OH)2 (1)
Product (2)
Yield (%)b
1
2
p-MeC6H4 1a
C6H5 1b
2a
2b
2c
2d
2f
81
68
72
78
88
80
55
60
50
68
3
o-MeC6H4 1c
m-MeC6H4 1d
p-tBuC6H4 1f
p-MeOC6H4 1g
p-BrC6H4 1j
p-ClC6H4 1k
m-CNC6H4 1l
p-CHOC6H4 1m
4
5
6
2g
2j
7
8
2k
2l
9
10
2m
aUnless otherwise noted, the reaction conditions are as follows: arylboronic acid 1 (2.0 equiv), NaNO2 (0.3 mmol), Cu2O (20 mol %), Pyridine(3.0 equiv), MeCN (2 mL), at room
temperature, under open air. bIsolated yield.
bromo, chloro, cyano, aldehyde, ester, and trifluoromethyl
groups (2j-o). However, the application of this process is
problematic for the nitration of sulfur-containing
heteroaromatic boronic acid (2p). The reason for the failure
of the reaction is less clear.
or pyridine (71.1 mg, 3.0 equiv), and dry MeCN (2 mL). The
mixture was kept stirring at room temperature for 8-12 h.
After completion of the reaction, removal of the solvent
under reduced pressure gave a crude product, which was
purified on silica gel (Petroleum ether/EtOAc) to afford the
products.
Next, we preceeded to apply sodium nitrite as nitrating
agent, which is genernally low solubility in organic solvents.
Under the optimized conditions, the nitration product 2a of
4-methylphenylboronic acid 1a was obtained with 62% yield.
As we all know, base could promote the transmetalation of
arylboronic acids. Pyridine was found the most suitable base
to promote the reaction with 81% yield, while the addition of
inorganic bases, such as K2CO3, Cs2CO3 and K3PO4,
inhibited the reactivity of the substrate. A series of
arylboronic acids were then subjected to this optimized
reaction conditions. As shown in Table 3, the reaction also
gave cross coupling products in moderate to good yields.
Spectral Data for the Products
1-methyl-4-nitrobenzene 2a, [10] (Table 2, entry 1)
1H NMR (300 MHz, CDCl3) ꢀ = 8.08 (d, J = 9.0 Hz, 2H),
7.28 (d, J = 9.0 Hz, 2H), 2.43 (s, 3H). 13C NMR (75 MHz,
CDCl3) ꢀ = 146.0, 144.5, 129.8, 123.5, 21.6.
1-nitrobenzene 2b, [11] (Table 2, entry 2)
1H NMR (300 MHz, CDCl3) ꢀ = 8.18 (d, J = 9.0 Hz, 2H),
7.68 (t, J = 9.0 Hz, 1H), 7.51 (t, J = 9.0 Hz, 2H). 13C NMR
(75 MHz, CDCl3) ꢀ =146.5, 134.6, 129.3, 123.4.
1-methyl-2-nitrobenzene 2c, [12] (Table 2, entry 3)
EXPERIMENTAL
1H NMR (300 MHz, CDCl3) ꢀ = 7.95 (d, J = 9.0 Hz, 1H),
7.47 (d, J = 9.0 Hz, 1H), 7.32 (t, J = 3.0 Hz, 2H), 2.59 (s,
3H). 13C NMR (75 MHz, CDCl3) ꢀ = 149.1, 133.6, 133.0,
132.7, 126.9, 124.6, 20.4.
Copper catalysts and arylboronic acids were purchased
from Accela ChemBio Co. Ltd. Chloroform-d was purchased
from Cambridge Isotope Laboratories. All solvents were
distilled prior to use. For chromatography, 200-300 mesh
1
silica gel (Qingdao, China) was employed. H NMR (300
1-methyl-3-nitrobenzene 2d, [13] (Table 2, entry 4)
MHz) and 13C NMR (75 MHz) spectra were measure on
Bruker 300 M spectrometers. CDCl3 was used as solvent
with tetramethylsilane (TMS) as internal standard.
1H NMR (300 MHz, CDCl3) ꢀ = 8.00 (d, J = 6.0 Hz, 2H),
7.47 (d, J = 6.0 Hz, 1H), 7.40 (d, J = 6.0 Hz, 1H), 2.44 (s,
3H). 13C NMR (75 MHz, CDCl3) ꢀ = 148.3, 139.7, 135.3,
129.0, 123.9, 123.8, 120.6, 21.2.
General Procedure for the Nitration of Arylboronic
Acids
1,3-dimethyl-5-nitrobenzene 2e, [5] (Table 2, entry 5)
1H NMR (300 MHz, CDCl3) ꢀ = 7.81 (s, 2H), 7.28 (s,
1H), 2.39 (s, 6H). 13C NMR (75 MHz, CDCl3) ꢀ = 148.2,
139.4, 136.2, 121.1, 21.1.
Under open air, a reaction tube was charged with
arylboronic acids (2.0 equiv), NaNO2 (20.7 mg, 0.3 mmol) or
n-Bu4NNO2 (84.6mg, 0.3 mmol), Cu2O (8.64 mg, 20 mol %),

136 Letters in Organic Chemistry, 2012, Vol. 9, No. 2
Yan et al.
1-tert-butyl-4-nitrobenzene 2f, [5] (Table 2, entry 6)
under mild conditions. This process provides an attractive
alternative to the traditional nitration protocol. Further
investigation of the detailed mechanism and the scope of
substrates is currently underway in our lab.
1H NMR (300 MHz, CDCl3) ꢀ = 8.13 (d, J = 9.0 Hz, 2H),
7.51 (d, J = 9.0 Hz, 2H), 1.34 (s, 9H). 13C NMR (75 MHz,
CDCl3) ꢀ = 158.8, 146.1, 126.2, 123.3, 35.4, 31.0.
1-methoxy-4-nitrobenzene 2g, [14] (Table 2, entry 7)
ACKNOWLEDGEMENT
1H NMR (300 MHz, CDCl3) ꢀ = 8.18 (d, J = 9.0 Hz, 2H),
6.93 (d, J = 9.0 Hz, 2H), 3.88 (s, 3H). 13C NMR (75 MHz,
CDCl3) ꢀ = 164.5, 141.5, 125.9, 114.0, 55.9.
We are grateful for the financial support by Lishui
University Opening Foundation for advanced talents.
1-methyl-4-nitronaphthalene 2h, [15] (Table 2, entry 8)
1H NMR (300 MHz, CDCl3) ꢀ = 8.66 (d, J = 9.0 Hz, 1H),
8.15 (q, J = 9.0 Hz, 2H), 7.77~7.65 (m, 2H), 7.40 (d, J = 9.0
Hz, 1H), 2.81(s, 3H). 13C NMR (75 MHz, CDCl3) ꢀ = 142.3,
133.1, 128.9, 127.1, 125.1, 125.0, 124.7, 124.2, 123.9, 123.6,
20.2.
CONFLICT OF INTEREST
Declared none.
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In summary, we have developed a new, simple, efficient
approach to the synthesis of nitroaromatics by copper-
catalyzed coupling of arylboronic acids with nitrite salts

An Efficient Synthesis of Nitroaromatics
Letters in Organic Chemistry, 2012, Vol. 9, No. 2
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