Regioselective nitration of N,N-dialkylanilines using cerium(IV) ammonium nitrate in acetonitrile

Article abstract of DOI:10.1016/j.tetlet.2005.10.028

A highly regioselective and inexpensive nitration of N,N-dialkylanilines by cerium(IV) ammonium nitrate (CAN) in acetonitrile under room temperature to yield p-nitryl-N,N-dialkylanilines in good yields was reported.

Full text of DOI:10.1016/j.tetlet.2005.10.028

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8781–8783
Regioselective nitration of N,N-dialkylanilines using
cerium(IV) ammonium nitrate in acetonitrile
Xianghua Yang, Chanjuan Xi* and Yanfeng Jiang
Key Laboratory for Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education),
Department of Chemistry, Tsinghua University, Beijing 100084, China
Received 25 August 2005; revised 8 October 2005; accepted 11 October 2005
Available online 26 October 2005
Abstract—A highly regioselective and inexpensive nitration of N,N-dialkylanilines by cerium(IV) ammonium nitrate (CAN) in aceto-
nitrile under room temperature to yield p-nitryl-N,N-dialkylanilines in good yields was reported.
Ó 2005 Elsevier Ltd. All rights reserved.
The nitroaromatic compounds are widely utilized in the
industry and act as chemical feedstock for a great range
of useful materials such as dyes, pharmaceuticals, per-
fumes, and plastics. Consequently, there is significant
interest in the development of new synthetic methodolo-
gies to access nitroaromatic derivatives in optically pure
form. Conventional procedures for nitration of aromatic
compounds, mainly based on mixed nitric acid and
sulfuric acid,1 are found to be low selective and not
environmental-friendly. Scientists have long been
searching for alternative nitration procedures, especially
for aromatic compounds, and a number of methods
have been reported. Mellor and Mittoo et al.2,3 devel-
oped a nitration system by suspending sulfuric acid on
silica gel following nitration with metal nitrate, in which
the procedure seemed to be complicated and the selectiv-
ity was not very high. Another strategy has been the use
of lanthanide triflates as catalysts in nitric acid, but it
required a strong acid, chlorinated solvents and did
not improve the regioselectivity significantly.4 Other
nitration systems for aromatic compounds, such as
nitration using nitrocyclohexadienones,5 cerium(IV)
ammonium nitrate (CAN) on silica gel,6,7 nitric acid–
acetic anhydride–zeolite b system,8 and similar sys-
tems,9–11 more or less have their limitations for utiliza-
tion. The use of metal nitrates has received much
attention. Recently a vanadium nitrate VO(NO3)3 has
proved to be useful12 in nitration of simple aromatics.
However this nitrate must be prepared from dinitrogen
pentoxide. Earlier, iron,13,14 copper,14 chromium,15
R
R
R1
R1
R2
1eq CAN
CH3CN
N
O2N
N
R2
Scheme 1.
and cerium16 nitrates have been studied but have failed
to be generally useful. Great demand still exists for a
high regioselectivity, inexpensive, and mild nitration sys-
tem. Herein, we would like to report a nitration system
for aromatic substrates, N,N-dialkylanilines, using cer-
ium(IV) ammonium nitrate (CAN) in acetonitrile as
the solvent (Scheme 1).
CAN has been used earlier for many oxidative purposes
including deprotections17 and ultrasound-aided oxida-
tions.18 Recently, we have reported that reaction of
N,N-dialkylanilines with CAN in water afforded
N,N,N0,N0-tetraethylbenzidines in high yields.19 During
the course of our studies, we found that treatment of
N,N-dialkylanilines with CAN in acetonitrile gave
N,N-dialkyl-4-nitroanilines in good yields with high
regioselectivity.
To start with, experiments were carried out to choose
the proper reaction conditions. First of all, a number
of solvents were tried and the results are listed in Table
1. It was interesting to see that nitration tend to hap-
pen only in non-protic and CAN-dissolvable solvents,
such as acetonitrile. Then, the amount of CAN was
varied from 0.5 to 2 equiv. We found 1 equiv of CAN
gave the best results in this reaction.24 Moreover, when
*
Corresponding author. E-mail: cjxi@tsinghua.edu.cn
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.028

8782
X. Yang et al. / Tetrahedron Letters 46 (2005) 8781–8783
N,N-dialkylanilines in water to form N,N,N0,N0-tetra-
ethylbenzidines, in which 2 equiv of CAN was
required.19
Table 1. Effect of solvent and amount of CAN on the nitration of
anilines
Et
Et
Et
Et
CAN
N
O2N
N
solvent, rt. 1 h
The results of a series of N,N-dialkylanilines (1a–h) un-
der the chosen condition were collected and are reported
in Table 2. In most cases, the reaction afforded satisfac-
tory results. The reaction of aniline derivative 1g (entry
7), containing an electron-withdrawing substituted
groupsuch as chloride on the phenyl ring, with 1 equiv
of CAN in acetonitrile gave compound 2g in low yield
accompanied by the dealkylation.20 This result was
probably due to low electron density of phenyl ring. In
other ways, treatment of compound 1h (entry 8) with
CAN in acetonitrile did not give the desired product,
even prolonged the reaction time and increased the reac-
tion temperature. It may be 1h with two methyl groups
on the m-position, which made NO2 groupharder to
attack the para-position. For other N,N-dialkylanilines,
moderate to good yields of p-nitryl-products were
collected.
Entry
Solvent
CAN (equiv)
Yield (%)a
1
2
3
CH2Cl2
CHCl3
CCl4
1
1
1
0
0
0
4
THF
1
0
5
6
7
8
9
10
11
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3OH
1
2
0.5
1.2
1.5
1
65
Complexb
0
41c
10d
Couplinge
Couplinge
CH3OH+CH3CN (1:1)
1
a Isolated yield.
b Starting material disappeared but no major product.
c Another product (N,N,N0,N0-tetraethylbenzidine) was isolated in
31% yield.
d Other two products were isolated: N,N-diethyl-2,4-dinitrobenzen-
amine in 34% yield; N,N,N0,N0-tetraethylbenzidine in 45% yield.
e Major product is N,N,N0,N0-tetraethylbenzidine.
For the nitration reaction it can be noted that the nitro-
groups are introduced in the aromatic nucleus as by
electrophilic nitration. In this work, the CAN acts as a
carrier of nitronium species and the CAN nitration is
similar to that noted with other metal nitrates such as
the nitratocomplexes of TiIV,21 ZrIV, and FeIII.22 The
N,N-diethylaniline was treated with 2 equiv of CAN
in acetonitrile at 0 °C, the reaction did not proceed. It
is different from known CAN-mediated reaction of
Table 2. Nitration of N,N-dialkylanilines with CAN in acetonitrile
Entry
1
Substrate
Time (h)
2
Product
Yield (%)a
65
Et
Et
Et
Et
N
O2N
N
2a
1a
Me
Me
Et
Et
Et
Et
Et
Et
2
Over night
60
N
O2N
O2N
O2N
N
N
1b
1c
2b
2c
2d
3
4
2
2
53
54
N
Me
Me
n-Bu
n-Bu
N
N
1d
Me
Me
Bz
Bz
5
6
Over night
46
40
2e
2f
N
Me
O2N
O2N
N
Me
1e
1f
4
N
N
Cl
Cl
Et
Et
7
Over night
Over night
26
2g
2h
N
1g
O2N
NH
Et
Me
Me
Me
O2N
Et
Et
Et
N
Et
8
Trace
N
1h
Me
a Isolated yield.

X. Yang et al. / Tetrahedron Letters 46 (2005) 8781–8783
8783
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N
R1
R2
N
R1
R2
2-
Ce(OH)(NO3)5
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O2N
R2
Scheme 2.
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behavior of the nitrato-groupas a bidentate ligand has
been indicated to be a condition for the nitration reac-
tion.23 We therefore proposed the mechanism shown
in Scheme 2. The nitration reaction occurred through
a molecular rearrangement within a co-ordination com-
plex of the substrate with a metal-containing species.
In summary, a nitration system using CAN as a nitra-
tion reagent in acetonitrile for N,N-dialkylanilines was
developed. This reaction has several advantages, includ-
ing high regioselectivity, easy handling, and low cost.
´
18. Morey, J.; Saa, J. M. Tetrahedron 1993, 49, 105–112.
19. Xi, C.; Jiang, Y.; Yang, X. Tetrahedron Lett. 2005, 46,
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Acknowledgments
22. Coonbes, R. G.; Russel, L. W. J. Chem. Soc., Sect. B:
Phys. Org. 1971, 2443–2447.
This work was supported by the National Natural Sci-
ence Foundation of China (20372041) (20572058) and
Beijing Department of Education (XK100030514).
23. Addison, C. C.; Garner, C. D.; Simpson, W. B.; Sutton,
D.; Wallwork, S. C. Proc. Chem. Soc. 1964, 367–370.
24. Representative procedure for the nitration of N,N-dialkyl-
anilines. Nitration of N,N-diethylaniline. N,N-Diethylan-
iline (1 mmol) was added dropwise after CAN (1 mmol)
completely dissolved in CH3CN (20 mL), then the reaction
mixture was stirred constantly until N,N-diethylaniline
totally disappeared. The reaction mixture was quenched
with aqueous solution of K2CO3, followed by extraction
of the organic phase with ethyl acetate. The solvent was
evaporated under reduced pressure and product was
isolated by chromatography on neutral Al2O3. The prod-
uct, p-nitryl-N,N-diethylaniline, was isolated (126 mg,
65%) as yellow solid using 1:10 EtOAc/petroleum ether
mixture as eluent. 1H NMR (CDCl3, SiMe4) d 1.23 (t,
J = 7.0 Hz, 6H), 3.44 (q, J = 7.2 Hz, 4H), 6.58 (d, J =
9.6 Hz, 2H), 8.10 (d, J = 9.3 Hz, 2H); 13C NMR (CDCl3,
SiMe4): d 12.5, 45.0, 109.9, 126.6, 136.5, 152.3. ESI-MS:
M+H+ (m/z) 195.
References and notes
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Aromatic Substitution; John Wiley and Sons: Chichester,
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