Mono-nitration of aromatic compounds via their nitric acid salts

Article abstract of DOI:10.1016/j.tetlet.2007.10.027

Aromatic compounds bearing a basic nitrogen atom can be converted to the corresponding nitric acid salts. Mono-nitration of the compounds can be carried out by adding a dichloromethane solution of the salts to sulfuric acid, or by adding acetyl chloride (or trifluoroacetic anhydride) to a dichloromethane solution of the salts. This protocol provides, among other benefits, the most convenient and reliable way for the prevention of over-/under-nitration and is especially suitable for scale-up.

Full text of DOI:10.1016/j.tetlet.2007.10.027

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8659–8664
Mono-nitration of aromatic compounds via their nitric acid salts
Pingsheng Zhang,* Miall Cedilote, Thomas P. Cleary and Michael E. Pierce
Pharmaceutical Process Development, Roche Carolina Inc., 6173 East Old Marion Highway, Florence, SC 29506, USA
Received 17 September 2007; revised 3 October 2007; accepted 4 October 2007
Available online 9 October 2007
Abstract—Aromatic compounds bearing a basic nitrogen atom can be converted to the corresponding nitric acid salts. Mono-nitra-
tion of the compounds can be carried out by adding a dichloromethane solution of the salts to sulfuric acid, or by adding acetyl
chloride (or trifluoroacetic anhydride) to a dichloromethane solution of the salts. This protocol provides, among other benefits,
the most convenient and reliable way for the prevention of over-/under-nitration and is especially suitable for scale-up.
Ó 2007 Elsevier Ltd. All rights reserved.
Nitration of aromatic nuclei is one of the most basic
reactions in organic synthesis and is widely used in the
pharmaceutical and chemical industries.1 However, this
reaction is notorious for several reasons, such as safety
concerns, over-nitration, formation of regioisomers,
and generation of impurities due to oxidation. These
shortcomings are amplified when a nitration process is
scaled up for commercial manufacturing, where process
safety becomes paramount, precise charge of reagents
cannot be easily achieved, dosing large amount of solids
to a reactor could be technically challenging, the use of
flash column chromatography to remove process impu-
rities becomes impractical, and the disposal of large
amounts of process wastes becomes an environmental
issue and adds to financial cost. On the other hand, these
challenges are the driving forces for the continuing
research on the reaction that has created a large library
of nitration reagents and methods.2 While the creation
of new reagents is important to achieve better results,
the invention of novel process protocols can be equally
effective in resolving critical nitration issues. In the pre-
vious paper3 we disclosed a process for the synthesis of
4-(4-methoxy-3-nitrophenyl)morpholine via nitration of
isolated nitric acid salt of 4-(4-methoxyphenyl)morpho-
line. This approach not only helped us to overcome a
tough technical difficulty of preventing under-/over-
nitration during manufacturing, but also resulted in
the improvement of process safety, 59% increase of
overall yield, 30% increase of capacity, and 40%
decrease of total process wastes, among other benefits.
Here we report that this protocol can be applied to a
variety of aromatic substrates that contain one basic
nitrogen atom in the molecule.
1.0 eq. 70% HNO3
_
NO3
+
TBME/THF, ~0 ˚C
90%
N
H
N
1
2
NO2
1. H2SO4, ~0 ˚C, 1h
2. NH4OH
95%
N
3
The essential of the protocol is exemplified in the
scheme. N,N-dimethyl-p-toluidine (1) was converted to
its nitric acid salt, 2, by reacting with 1.0 equiv of nitric
acid. The salt, precipitated out from solution during acid
addition, was collected and dried. The nitration was
effected by adding a dichloromethane solution of the salt
to concentrated sulfuric acid. Table 1 lists some exam-
ples of arylamines. Good to excellent overall yield was
observed in all the examples. The method applies to
tertiary, secondary, and primary amines. Under the
reaction conditions the protonated amino groups acted
as deactivating groups, and thus activating groups on
the aromatic rings dictated the regioselectivity. In
the cases where there were no other groups (entries 3
and 9) the reactions produced mixtures of meta- and
para-isomers. These results are similar to those observed
when conventional methods were used.4,6
*
Corresponding author. Tel.: +1 843 629 4241; fax: +1 843 629
4128; e-mail: pingsheng.zhang@roche.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.027

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P. Zhang et al. / Tetrahedron Letters 48 (2007) 8659–8664
Table 1. Mono-nitration of arylamines
Entry
1
Substrate
Producta
Yieldb,c (%)
Br
Br
NO2
94
N
N
NO2
2
3
94
N
N
N
NO2
NO2
93 (944)
+
25%
75%
N
N
NO2
4
5
6
93
84
95
(trace
amount)
O2N
N
N
N
NO2
NO2
N
N
NO2
(34%)
(66%)
N
N
N
O
O
NO2
7
92
N
O
NH
O
NO2
NO2
8
9
88 (725)
93 (726)
NH2
NH2
NH2
NO2
NH2
(47%)
(50%)
NH2
(3%)
NO2
NH2
Cl
Cl
O2N
10
92 (507)
NH2
NH2
a Isomeric ratio was estimated using 1H NMR spectra of the crude products.
b Isolated yield.
c Yields in parentheses are the best isolated yield in the literature for the nitration of the same substrates in sulfuric acid.

P. Zhang et al. / Tetrahedron Letters 48 (2007) 8659–8664
8661
The method can also be applied to other substrates with
an aromatic nucleus and a nitrogen atom that is basic
enough to form a salt with nitric acid. Table 2 lists some
aromatic amines in which the amino groups are sepa-
rated from the aromatic rings. Table 3 lists some exam-
ples of substrates with a basic nitrogen atom in a
heterocyclic ring. Again good to excellent yield was
observed in all the cases.
acid/sulfuric acid mixture remains to be the top choice
for commercial scale nitration processes. It is well
accepted that the actual nitrating agent is nitronium
ion and the concentration of the ion in the reaction mix-
ture is a major factor to affect the reaction rate and the
quality of the product. Many practical methods have
been adopted to improve the nitration reaction based
on the assumption of the equilibrium below:
ꢀ
HNO3 þ H2SO4 ¼ H2O þ NO2þ þ HSO4
Nitration of the salts can also be catalyzed by other acids,
often giving different regioselectivity. This is again illus-
trated by the nitration of 2. Some examples are listed in
Table 4. Acetic acid was not strong enough to initiate
the reaction. But in trifluoroacetic acid (TFA) the reac-
tion was completed within 1 h, producing N,N-di-
methyl-2-nitro-p-toluidine (4) in 94% yield. When a
solution of 2 in dichloromethane was added to a mixture
of methanesulfonic acid (MsOH) in dichloromethane at
0 °C the nitration completed within 4 h and a mixture
of 3 (7%) and 4 (93%) was isolated in 92% yield. At
17 °C the reaction was completed in 1 h and the ratio of
3–4 was changed to 2:98. When solid 2 was added to pure
MsOH at 17 °C the reaction produced a mixture of 3 and
4 with a ratio of 25:75 in 91% yield. Also indicated in the
table is that the nitration can be activated with acetyl
chloride and trifluoroacetic anhydride. In both cases, 4
was isolated as the only product in good yield. When ace-
tic anhydride was used no reactions occurred until the
mixture was heated to 40 °C and the product contained
multiple components. Similar results were observed when
methanesulfonic anhydride (Ms2O) was used.
These methods include using fuming nitric acid, using
large excess of concentrated sulfuric acid, and adding
water scavengers to remove water in the reaction mix-
ture. The use of isolated and dried nitric acid salt of a
substrate automatically eliminates the part of water that
would be brought to the reaction mixture if 70% HNO3
is used and makes it possible to reduce sulfuric acid
charge. This was well demonstrated in our process for
the synthesis of 4-(4-methoxy-3-nitrophenyl)morpho-
line, in which we were able to reduce the sulfuric acid
charge by 60% while still maintained the same reaction
rate and product purity.3
The use of isolated nitric acid salts provides an easy and
reliable method to introduce a substrate and nitric acid
into a reaction mixture in a 1:1 molar ratio, and thus
over-/under-nitration could be effectively prevented
and cleaner nitration could be expected. A typical con-
ventional nitration process involves either the addition
of substrates to concentrated sulfuric acid followed by
the addition of a mixture of nitric acid and sulfuric acid,
or the addition of substrates to a mixture of nitric acid
and sulfuric acid. These operations are highly exothermic
Despite the availability of a large variety of nitrating
reagents (mostly various types of nitrate salts8) nitric
Table 2. Mono-nitration of aromatic amines with the amino groups separated from the aromatic nuclei
Entry
Substrate
Producta
Yieldb (%)
N
N
N
1
95
(25%)
(67%)
NO2
NO2
N
NO2
(8%)
NH2
NH2
2
3
89
89
NO2
O
O
NH2
Cl
NH2
NH2
O2N
(55%)
(45%)
Cl
Cl
NO2
a Isomeric ratio was estimated using 1H NMR spectra of the crude products.
b Isolated yield.

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P. Zhang et al. / Tetrahedron Letters 48 (2007) 8659–8664
Table 3. Mono-nitration of aromatics containing a heterocyclic ring
Entry Substrate
Producta
Yieldb (%)
O
N
O
N
1
89
NO2
N
N
2
3
95
82
O2N
N
N
H
N
N
H
H
NO2
N
N
H
N
N
4
95
NO2
N
N
N
N
5
82
O
O
S
S
NO2
O
O
N
N
N
N
N
N
NO2
6
85
(26%)
NO2
(63%)
N
N
(11%)
O2N
O2N
N
N
O
N
7
89
O
O2N
O
(26%)
(74%)
NO2
N
N
8
9
97
85
N
H
N
H
NO2
O
O
N
N
a Isomeric ratio was estimated using 1H NMR spectra of the crude products.
b Isolated yield.

P. Zhang et al. / Tetrahedron Letters 48 (2007) 8659–8664
Table 4. Different conditions to carry out nitration
8663
NO2
Conditions
+
_
NO2
+
N
H
NO3
N
N
2
3
4
Entry
Reagent
Conditions
Producta
Yieldb (%)
1
2
3
4
5d
AcOH
TFA
MsOHc
MsOHc
MsOH
60 °C, 4 h
0 °C, 1 h
0 °C, 4 h
17 °C, 4 h
17 °C, 1 h
No reaction
4
94
92
93
91
4 (93%) + 3 (7%)
4 (98%) + 3 (2%)
4 (75%) + 3 (25%)
6
7
8
9
AcCl
Ac2O
(CF3CO)2O
Ms2O
0 °C, 2 h
4
93
89
40 °C, 16 h
0 °C, 16 h
20 °C, 4 h
Complicated mixture
4
Complicated mixture
a Isomeric ratio was estimated using 1H NMR spectra of the crude products.
b Isolated yield.
c 1:1 (v/v) mixture with CH2Cl2.
d Add solid 2 to pure MsOH.
and cause locally overheating in the reaction mixture
that is not only a major safety concern but also a pri-
mary cause for side reactions. In our protocol the nitra-
tion process can be easily controlled by adjusting the
addition rate of dichloromethane solution of the salts,
and thus those shortcomings can be overcome. This
may explain the high yields observed in all the examples
in this Letter, especially the significantly higher yields
for aniline and its derivatives (Table 1, entries 8–10).
was stirred for 1 h. The mixture was slowly added to
40 mL of cold water and was then basified with 28%
NH4OH solution until pH 10. The mixture was
extracted with dichloromethane. The organic solution
was dried over MgSO4, filtered, and concentrated to give
crude product, which was purified with flash column
chromatography (silica gel, eluting with 1:1 CH2Cl2/
hexane) to afford 4.3 g (95%) of 3.
Preparation of 4: To a solution of 5 g (25.2 mmol) of 2
in 25 mL dichloromethane was slowly added 4 g
(50.4 mmol) acetyl chloride while maintaining batch
temperature at 0 5 °C. After the addition the mixture
was stirred for 2 h. The reaction mixture was basified to
pH 10 by the slow addition of 28% NH4OH solution.
The organic layer was separated and the aqueous layer
was extracted with dichloromethane. The combined
organic solution was washed with brine, dried over
MgSO4, filtered and concentrated to give a crude prod-
uct, which was purified with flash column chromatogra-
phy (silica gel, eluting with 1:1 CH2Cl2/hexane) to afford
4.3 g (93% yield) of 4.
The nitration of 4-substituted arylamines can be con-
trolled at either ortho or meta positions. Typically, in
sulfuric acid the meta-nitration predominates. ortho-
Nitration can be achieved in less acidic media, such
as NaNO2/AcOH,9 HNO3/Ac2O,10 and Tl(NO3)3/
MeCN.11 It is believed that under these conditions the
free base amino groups dictate the regioselectivity. This
is consistent with our observations. For instance, the
nitration of 2 in sulfuric acid afforded only 3 while in
TFA, AcCl, and (CF3CO)2O 4 was the only isolated
product.12 Thus, we provide here a method for the con-
venient control of regioselectivity for properly substi-
tuted arylamines.
Typical experimental procedures
Acknowledgements
Preparation of 2: To a solution of 10 g (74 mmol) N,N-
dimethyl-p-toluidine in a mixed solvent of 50 mL t-butyl
methyl ether (TBME) and 50 mL THF at 0 °C was
slowly added 6.6 g (74 mmol) of 70% nitric acid. After
the addition the mixture was stirred for 1 h. The solid
was filtered, washed with TBME, and dried at 20 °C
under house vacuum overnight to give 13.6 g (90% yield)
of 2.
We thank Drs. Geng-Xian Zhao, Robert Thomas
Williamson, Stephen Chan, Ms. Joni Bishop, and Ms.
Eileen Zhao for their analytical support.
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