Convenient, metal-free ipso-nitration of arylboronic acids using nitric acid and trifluoroacetic acid

Article abstract of DOI:10.1080/00397911.2016.1244690

A feasible protocol for the direct ipso-nitration of arylboronic acids using trifluoroacetic acid and nitric acid as nitration reagent has been developed. Various aromatic nitro compounds are produced in moderate to good yields under the metal-free conditions. The method is operationally simple and regioselective, and might have potential application in industry.

Full text of DOI:10.1080/00397911.2016.1244690

Convenient metal-free ipso-nitration of arylboronic acids using nitric acid and
trifluoroacetic acid
1
1
2
1
1
Guodong Shen , Lingyu Zhao , Wanxing Liu , Xianqiang Huang , Huina Song , Tongxin
1
Zhang
1
School of Chemistry and Chemical Engineering, School of Pharmacy, Liaocheng
University, Liaocheng, Shandong, China, Department of Chemistry, Liaocheng
2
Chemical Institute of Industrial Science, Liaocheng, Shandong, China
Corresponding author: E-mail: shenguodong33@163.com; E-mail:
xintongzhang123@163.com
Abstract
A feasible protocol for the direct ipso-nitration of arylboronic acids using trifluoroacetic
acid and nitric acid as nitration reagent has been developed. Various aromatic nitro
compounds are produced in moderate to good yields under the metal-free condition. The
method is operationally simple, regioselective, and might have potential application in
industry.
GRAPHICAL ABSTRACT
KEYWORDS: Metal-free, ipso-Nitration, Arylboronic acids, Nitroarenes
1

INTRODUCTION
Nitroarenes are important building blocks for the chemical industry and organic
[
1–9]
synthesis.
Widespread applications have also been found in pharmaceuticals, dyes and
[
10–12]
materials.
The electrophilic ipso-nitration of arenes is one of the most classic
methods, which involves the use of either the mixture of nitric and sulfuric acid, or
[
2]
dinitrogen pentoxide. However, the problem of regioselectivity and functional group
tolerance can not be solved under such drastic reaction conditions. Therefore, the
development of mild and operationally simple methods for regioselective nitration is of
great significance in organic synthesis.
In 2000, Prakash and Olah et al. firstly reported the ipso-nitration of arylboronic acids by
[
13]
using NH
4
NO
3
3
and (CF CO)
2
O as nitration reagent. In 2004, another nitration protocol
was disclosed by applying AgNO
3
and TMSCl as selective and efficient nitrating
[
14]
agents. Due to the requirements of economic and easy operation, more and more
attentions had been paid in the exploring novel methods for the ipso-nitration of
arylboronic acids. Recently, several good methods have been reported, such as tert-butyl
nitrite/dioxane, NaNO
TMSCl/NaNO
2
, Cu
2
O/NH
3
-H
2
O, Bi(NO
3
)
3
/K
2 2 8 3 3
S O /toluene, Bi(NO ) /toluene,
[
15–20]
2
/DCM and others.
However, some methods need to use large amount
of metal salts and harsh reaction conditions, limiting their applications in industry. Here
we proposed an economic, operationally simple, regioselective protocol for the synthesis
of aromatic nitro compounds by direct ipso-nitration of arylboronic acids using
trifluoroacetic acid and commercial available 68% nitric acid aqueous solution.
2

RESULTS AND DISCUSSION
Initially, benzeneboronic acid 1a was selected as the model substrate and the reaction
conditions were systematically evaluated (Table 1). The reaction was firstly carried out in
3
AcOH (1.0 mL) and 92.6 mg of 68% nitric acid aqueous solution (HNO 1.0 mmol) at 80
o
2
C under N atmosphere without metal catalyst. After 24 hours, the reaction was stopped
and the anticipated product 1b was isolated in 10% yield after flash chromatography
Table 1, entry 1). Then 92.6 mg of 68% nitric acid aqueous solution (HNO 1.0 mmol)
was used to repeat the reaction and trace 1b was detected (Table 1, entry 2). When AcOH
was replaced by H PO , the result show that only trace 1b was found (Table 1, entry 3).
(
3
3
4
When CF
3
COOH was used to run the reaction, delivering the target product in 31% yield
o
(
Table 1, entry 4). The reaction was also surveyed at 70 and 85 C, but the reaction
o
worked at 80 C provided the best yield (Table 1, entries 5 and 9). To our delight, When
CF COOH and 68% nitric acid aqueous solution were used to run the reaction under air
atmosphere, the yield rose up to 76% (Table 1, entry 6). From the experiments we can
3
[
8]
conclude that the air has the effect on deborylation or oxidization in this reaction. Then
we increased the amount of nitric acid to 3.0 eq and reduced the reaction time to 18 h, the
yields were not changed (Table 1, entries 7 and 8). From reaction entries 9 and 10, we
can conclude that the reaction temperature, air and trifluoroacetic acid are important to
this reaction. Only using nitric acid aqueous solution in the reaction, we got 1b in 12%
yield (Table 1, entry 11). Obviously, entry 8 represents the best condition. Furthermore,
we also used 20g benzeneboronic acid 1a to repeat the reaction, and obtained the product
1
b in 72% yield (Table 1, entry 12).
3

After the reaction condition was optimized, the scope was explored with various
arylboronic acids a. The results are listed in Table 2. The substituted arylboronic acids
bearing both electron-donating groups (o-Me, m-Me, p-Me, o-OMe, p-OMe) and
electron-withdrawing groups (o-Cl, m-Cl, p-Cl, m-COOMe, p-COOMe and m-CF
able to proceed the reaction and gave the products in moderate to excellent yields (Table
, entries 2-12). The reaction seemed sensitive to the electronic effect and sterical
3
) were
2
hindrance on the arylboronic acids a. The reaction yields of o-tolylboronic acid 2a and
o-chlorophenylboronic acid 5a are relatively lower than p-tolylboronic acid 4a and
p-chlorophenylboronic acid 6a (Table 2, entries 2, 4, 5 and 6). The m-substituted
arylboronic acids have much lower yields due to the electronic effect (Table 2, entries 3,
[
21]
1
4
0 and 11). Because of the electron-donating group -OMe, the main product of
-methoxyphenylboronic acid 7a is 1-methoxy-2,4-dinitrobenzene 7b in high yield
(
Table 2, entry 7), the reaction of 2-methoxyphenylboronic acid 8a got a mixture (Table 2,
entry 8). 3-(Methoxycarbonyl)phenylboronic acid 9a and
-(methoxycarbonyl)phenylboronic acid 10a were also suitable for this reaction and the
4
corresponding hydrolysis products were detected (Table 2, entries 10 and 11). The yield
of 4-(trifluoromethyl)phenylboronic acid 12a with strong electron-withdrawing
functional group only gave 40% yield (Table 2, entry 12). 1,4-Phenylenediboronic acid
1
3a reacted smoothly and 1,4-dinitrobenzene 13b was got (Table 2, entry 13).
Interestingly, the reaction of biphenyl-4-ylboronic acid 14a got the product
2
,4'-dinitrobiphenyl 14b (Table 2, entry 14). However, 3,5-difluorophenylboronic acid
5a did not undergo nitration under the reaction condition (Table 2, entry 15). From the
1
above results we could conclude that the nitration reagent of trifluoroacetic acid and
4

nitric acid is efficient and the corresponding products are got in moderate to excellent
yields under the metal-free condition.
EXPERIMENTAL
Sample procedure for the ipso-nitration of arylboronic acids 2a: An round bottle flask
was charged with a magnetic stir bar, arylboronic acid 2a (0.5 mmol), trifluroacetic acid
1
3
.0 mL and 92.6 mg of 68% nitric acid aqueous solution (HNO 1.0 mmol), then the
o
mixture reacted at 80 C under air atmosphere for 18h. The reaction was stopped and
cooled to room temperature. The reaction mixture was directly passed through Celite and
rinsed with an additional 30 mL of AcOEt. The combined filtrate was washed by 1mol/L
3 2 4
NaHCO , H O, then dried by NaSO . The dried AcOEt solution was concentrated and
purified by column chromatography to give the product 2b (48 mg, 70%) as yellow oil.
1
3
H NMR (400MHz, CDCl /TMS): δ 2.59 (s, 3H), δ 7.38 (t, J = 8.0 Hz, 1H), δ 7.49 (d, J =
13
8
3
.0 Hz, 1H), δ 8.01 (d, J = 8.0 Hz, 1H), δ 8.02 (s, 1H). C NMR (100MHz, CDCl /TMS):
+
2
0.5, 124.7, 127.0, 132.9, 133.1, 133.7, 149.4. MS (EI) m/z (M ) 137.0.
CONCLUSION
In summary, a metal-free methodology for the ipso-nitration of various arylboronic acids
has been established. Notably, using inexpensive trifluoroacetic acid and nitric acid as
nitration reagent, different nitroarenes are produced in moderate to good yields. The
method is operationally simple, regioselective, and might have potential application in
industry.
5

ACKNOWLEDGMENT
This work was financially supported by the National Natural Science Foundation
(21402079 and 20401094).
1
13
Supporting Information: Full experimental detail, H and C NMR spectra. This material
can be found via the “Supplementary Content” section of this article’s webpage.
REFERENCES
[1] Feuer, H.; Nielsen, T. Nitro compounds: Recent Advances in Synthesis and Chemistry,
VCH, New York, 1990.
[2] Ono, N. The Nitro Group in Organic Synthesis, John Wiley-VCH, New York, 2001.
[3] Prakash, G. K. S.; Mathew, T. Angew. Chem., Int. Ed., 2010, 49, 1726-1728.
[4] Byun, E.; Hong, B.; De Castro, K.;A.; Lim, M.; Rhee, H. J. Org. Chem., 2007, 72,
9
815-9817.
5] Zhu, H.; Ke, X.; Yang, X.; Sarina, S.; Liu, H. Angew. Chem., Int. Ed., 2010, 49,
657-9661.
[
9
[
[
[
[
6] Corma, A.; Concepcio′ n, P.; Serna, P. Angew. Chem., Int. Ed., 2007, 46, 7266-7269.
7] Tang, C.; He, L.; Liu, Y.; Cao, Y.; He, H.; Fan, K. Chem. Eur. J., 2011, 17, 7172-7177.
8] Lee, C.; Liu, S. Chem. Commun., 2011, 47, 6981-6983.
9] Peng, Q.; Zhang, Y.; Shi, F.; Deng, Y. Chem. Commun., 2011, 47, 6476-6478.
6

[10] Belciug, M.; Ananthanarayanan, V. S. J. Med. Chem., 1994, 37, 4392-4399.
[11] Muller, W. E. The Benzodiazepine Receptor, Cambridge University Press, New York,
1
988.
12] Fan, F. R. F.; Yao, Y.; Cai, L.; Cheng, L.; Tour, J. M.; Bard, A. J. J. Am. Chem. Soc.,
004, 126, 4035-4042.
13] Salzbrunn, S.; Simon, J.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. Synlett., 2000,
0, 1485-1487.
14] Prakash, G. K. S.; Panja, C.; Mathew, T.; Surampudi, V.; Petasis, N. A.; Olah, G. A.
Org. Lett., 2004, 6, 2205-2207.
15] Wu, X. F.; Schranck, J.; Neumann, H.; Beller, M. Chem. Commun., 2011, 47,
2462-12463.
[
2
[
1
[
[
1
[16] Yang, H.; Li, Y.; Jiang, M.; Wang, J.; Fu, H. Chem. Eur. J. 2011, 17, 5652-5660.
[17] Manna, S.; Maity, S.; Rana, S.; Agasti, S.; Maiti, D. Org. Lett., 2012, 14, 1736-1739.
[18] Yadav, R. R.; Vishwakarma, R. A.; Bharate, S. B. Tetrahedron Lett., 2012, 53,
5
958-5960.
19] Prakash, G. K. S.; Gurung, L.; Schmid, P. C.; Wang, F.; Thomas, T. E.; Panja, C.;
Mathew, T.; Olah, G. A. Tetrahedron Lett., 2014, 55, 1975-1978.
[
[
20] Lanke, S. R.; Bhanage, B. M. Synthetic Communications., 2014, 44, 399-407.
21] Bose, A.; Sanjoto, W. P.; Villarreal, S.; Aguila, H.; Banik, B. K. Tetrahedron Lett.,
[
2
007, 48, 3945-3947.
[22] Rattan, V. K.; Kapoor, S. Asian J. Chem., 2005, 18, 585-591.
7

a
Table 1. Optimization of the reaction conditions
o
b
Entry Catalyst
CH COOH/HNO
HNO (2.0 eq)/N
PO /HNO (2.0 eq)/N
T( C) Time(h) Yield(%)
1
2
3
4
5
6
7
8
9
1
1
3
3
(2.0 eq)/N
2
80
80
80
80
85
24
24
24
24
24
24
24
18
18
24
18
18
10
3
2
TRACE
TRACE
31
H
3
4
3
2
CF
CF
CF
CF
CF
CF
3
COOH/HNO
3
COOH/HNO
3
COOH/HNO
3
COOH/HNO
3
COOH/HNO
3
COOH/HNO
3
3
3
3
3
3
(2.0 eq)/N
(2.0 eq)/N
2
2
30
(2.0 eq)/Air 80
(3.0 eq)/Air 80
(2.0 eq)/Air 80
(2.0 eq)/Air 70
76
75
76
60
0
1
2
CH
HNO
CF COOH/HNO
3
COOH/HNO
3
(2.0 eq)/Air 80
80
15
3
(2.0 eq)/Air
12
c
1
3
3
(2.0 eq)/Air 80
72
a
Reaction conditions: benzeneboronic acid (0.5 mmol), proper acid 1.0 mL and 68%
3 2
nitric acid aqueous solution (HNO 1.0 mmol) under N or air atmosphere.
b
Isolated yield after flash chromatography based on benzeneboronic acid.
c
2
0g of benzeneboronic acid 1a was used.
8

a
Table 2. Nitration of different arylboronic acids
b
Entry Arylboronic acids
Products
Yield(%)
1
2
1a
2a
1b
2b
76
70
3
3a
3b
52
4
5
6
7
8
4a
5a
6a
7a
8a
4b
5b
6b
7b
84
61
95
91
8b/8b’/7b:
8
/20/47
c
9
9a
9b
43
d
1
0
10a
10b 55
1
1
1
1
1
2
3
4
11a
12a
13a
14a
11b 41
12b 40
13b 63
14b 46
9

e
1
5
15a
15b
/
a
Reaction conditions: arylboronic acids (0.5 mmol), trifluroacetic acid 1.0 mL and 68%
o
nitric acid aqueous solution (HNO
3
1.0 mmol) at 80 C under air atmosphere for 18h.
b
Isolated yield after flash chromatography based on arylboronic acids.
Reacted for 12h and 18% 4-nitrobenzoic acid was got.
Reacted for 12h and 10% 3-nitrobenzoic acid was got.
No product was detected
c
d
e
10