Toluenee Amination

ISSN 20799780, Review Journal of Chemistry, 2011, Vol. 1, No. 4, pp. 359384. Pleiades Publishing, Ltd., 2011.
Original Russian Text A.V. Aksenov, N.A. Aksenov, O.N. Nadein, Yu.I. Smushkevich, 2011, published in Obzornyi Zhurnal po Khimii, 2011, Vol. 1, No. 4,
pp. 350375.
Methods for the Amination of Arenes

A. V. Aksenova #, N. A. Aksenova, O. N. Nadeina, and Yu. I. Smushkevichb
b
a
Stavropol State University, ul. Pushkina 1a, Stavropol, 355009 Russia
Mendeleev University of Chemical Technology of Russia, Miusskaya pl. 9, Moscow, 125820 Russia
#email: alexaks05@rambler.ru; smu@muctr.edu.ru
Received January 25, 2011; in final form July 4, 2011
AbstractThis review covers literature data on the amination of arenes and considers both multistep
methods for the introduction of an amino group in the aromatic ring and the direct amination (ami
dation) of aromatic hydrocarbons. The main attention is drawn to the electrophilic amination (ami
dation) of aromatic hydrocarbons because of the lack of comprehensive reviews on recent advances in
this area.
Keywords: direct electrophilic amination and amidation, aromatic amines, anilides, arenes, methods
of functionalization.
DOI: 10.1134/S2079978011040017
CONTENTS
1. Introduction
2. Twostep Methods For Amination
3. Nucleophilic Amination of Arenes
4. Direct Electrophilic Amination of Arenes
4.1. Electrophilic Amination of Arenes with Hydroxylamine and Its Derivatives
4.2. Electrophilic Amination of Arenes with Haloamines
4.3. Electrophilic Amination of Arenes with Hydrazoic Acid and Azides
4.4. Other Reagents for the Electrophilic Amination of Arenes
5. Conclusions
1. INTRODUCTION
Amines are important intermediates in the synthesis of different substances widely used in diverse areas
of human activity. These are pharmaceuticals, for example, paracetamol, acetophenetidine, and acetoac
etanilide, as well as various dyes and pigments [14]. This review is therefore dedicated to methods for the
synthesis of these compounds, with the main attention devoted to direct electrophilic amination.
2. TWOSTEP METHODS FOR AMINATION
The substitution of a hydrogen atom in the aromatic ring by an amino group is usually a twostep pro
cess that includes the introduction of an intermediate functional group or atom [57]. The classical vari
ant of these processes is provided by a nitrationreduction sequence (Scheme 1).
ArH
HNO3
H2SO4
ArNO2
[H]
ArNH2
Scheme 1.
At present, there is a great number of systems for nitration, which are not considered in this review,
because many of them are included in textbooks on organic chemistry.
A large number of different systems was also suggested for reduction. Among them are metals in acidic
medium, for example, [810]; metals in neutral medium, for example, ZnCaCl2EtOH [11, 12]; metals
in alkaline medium, for example, ZnNaOHEtOH [13]; metal salts in alkaline medium, for example,
FeSO4NH4OH [14]; hydrazine hydrate, for example, [15]; and others.
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AKSENOV et al.
In many cases, an acylation of the amino group occurs in the course of reduction, for example, [8, 9,
16, 17] (Scheme 2).
O
[H]
ArNO2
Ar N
H
RCOX
X = OH, Cl;
Scheme 2.
Metals in the presence of acids or acid chlorides [8, 9], formic esters [16], thioacids [17], and other
reagents were used in these reactions.
Another twostage reaction sequence includes azo coupling and the reduction of the resulting azo
compound, for example, [18] (Scheme 3).
NH2 NH2
Ph N N
NH2
PhN2
SnCl2
HCl
NH2 NH2
NH2
NH2 86%
96%
+
PhN2
NH2 NH2
Ph N N
NH2
Ph N N
NH2
SnCl2
HCl
NH2 NH2
94%
31%
Scheme 3.
One more variant of the twostep process is the sequence of the acylation reaction and the Schmidt
(Beckmann, Lossen, and other) rearrangements. We will consider these reactions in more detail, because
they are the most akin to the onestep reactions under consideration. It should be noted that the low reac
tivity of acylating agents is the disadvantage of this method. Therefore, the scope of this method is limited
to the area of application of the acylation reaction.
Carboxylic acids and their derivatives are used as acylating agents: mixed anhydrides, anhydrides,
esters, and nitriles. Lewis acids, polyphosphoric acid (PPA), and Broensted acids are employed as cata
lysts. The acylation reaction is reversible; therefore, its regioselectivity is dependent on the type of reagent,
catalyst, and reaction conditions, for example [1923].
The second stage of the method is the Schmidt or Beckmann rearrangement or related reaction. These
have been studied rather well [24, 25]. The mechanism of the Schmidt reaction for unsymmetrical ketones
seems to be more complex than that for symmetrical ones on account of the presence of isomeric forms.
In this case, the preferable product has a structure where a migrating hydrocarbon substituent occupies
the anti position toward the diazo group [24, 25] (Scheme 4).
N+ N
N
HN3
N2
H+
O
RL
O
L
RS
HN3
N N+
H+
RL
N2
N
RS
N
RS
H
major
RL
N
H
minor
RS
Scheme 4.
The authors failed to reveal a clear relationship between migratory aptitude and the electronic effect of
the substituent in the benzene ring (Scheme 5) [26].
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METHODS FOR THE AMINATION OF ARENES
O
NaN3 (3 equiv)
H2SO4 (3.6 equiv)
Cl3CCOOH
5060C
361
H
N
N
H
+
O
A
59
51
54
61
52
X = Cl
NO2
Me
OMe
Ph
B
41
49
46
39
48
Scheme 5.
The dependence on the sterical hindrances of the substituent is more clear. The migratory aptitude of
alkyl substituent R relative to the phenyl group increases with size; however, the best yields were obtained
in the case of phenyl group migration (Scheme 6).
O
R
H
N
NaN3 (3 equiv)
H2SO4 (3.6 equiv)
Cl3CCOOH
5060C
N
H
O
A
A:B
Yield, %
Me
Et
iPr
tBu
95 : 5
85 : 15
51 : 49
0 : 100
81
80
57
11
Scheme 6.
The possibility of formation of amides from ketones through their reaction with hydroxylamine and
oxalic acid was demonstrated in [27]. The authors considered the possibility of the reaction course via
alternative mechanisms (Scheme 7).
NH2OH*HCI
(CO2H)2
O
R
R'
100C
412 h
OCOCO2H
OCOCO2H
R'
NH
or
HO
R'
O
R'
N R
H
6096%
Scheme 7.
The Schmidt reaction with aldehydes and ketones leads simultaneously to nitriles and formamides.
The yield of the latter rises with molar concentration of H2SO4 in the reaction mixture [28] (Scheme 8).
O
R
HN3
H2SO4
RCN +
H
N
6096%
Scheme 8.
The conditions of the Schmidt and Beckmann reactions are close to those of the acylation reaction
[2931], and they can therefore be combined. The tandem of the acylationBeckmann rearrangement
was realized in [32] (Scheme 9). The corresponding acetanilides were obtained in 4595% yield.
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AKSENOV et al.
H
N
1) AcOH/PPA
2) NH2OH
MeO
4595%
H
N
1) AcOH/PPA
2) NH2OH
O 72%
MeO
Scheme 9.
A onepot process using the sequence of the Schmidt and acylation reactions is exemplified in the work
[33] (Scheme 10).
O
NH
1) AcOH/PPA
quantitative
yield
2) NaN3
3) H2O
HN
NH
Scheme 10.
Another approach to electrophilic amination consists in the transformation of the initial arene into an
organometallic compound followed by reaction with an Nelectrophile [3439]. Arylsulfonylhydroxy
lamines were used as such electrophiles in [3436] (Scheme 11).
MgBr
NR2
ArSO3NR2
R
Li
3791%
NEt2
ArSO3NEt2
42%
Scheme 11.
Another reagent based on hydroxylamine is N,Obis(trimethylsilyl)hydroxylamine, which is used in
combination with lithium cyanocuprates [37] (Scheme 12).
NH2
Si O
CuCNLi2 +
N Si
H
MeO
MeO
70%
Si O
CuCNLi2 +
S
2
N Si
H
NH2
S
58%
Scheme 12.
There are reagents for such an amination on the basis of phosphorus compounds [38], for example,
hydroxylamine 1 (Scheme 13). Phosphorus reagents are less efficient than compounds based on sulfur or
silicon, so amination products form in a lower yield.
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MgBr(Li)
+
363
NH2
O
P
R
O NH2
2235%
Li+ +
NH2
O
P
O NH2
37%
Scheme 13.
Diphenoxyphosphoryl azide provides an example of a reagent based on organic azide [39]. In this case,
aryl halides are used as initial compounds. The onepot process initially leads to an organomagnesium
compound that then produces phosphorylated triazene 2 in a yield up to 91%. Hydrochloric acid hydrol
ysis of the latter results in amine salt (Scheme 14).
Br
H
N N
1) Mg
2) (PhO)2P(O)N3
R
2
HN N
Br
1) Mg
N
P(O)(OPh) 2
NH3
R
Cl
3351%
+
NH3
N
P(O)(OPh) 2
2) (PhO)2P(O)N3
HCl
MeOH
HCl
MeOH
Cl
28%
Scheme 14.
3. NUCLEOPHILIC AMINATION OF ARENES
Nucleophilic amination of arenes containing electronwithdrawing substituents and deficient
hetarenes and their salts is a well studied process. A.E. Chichibabin first reported such processes almost
100 years ago, and at present this reaction is named after the discoverer [4042] (Scheme 15).
HetArH
1) NaNH2
2) H2O
1) NaNH2
HetArNH2 for example
N
NH2
2) H2O
N
58%
Scheme 15.
The disadvantage of the method is the use of rather severe reaction conditions that substantially con
fined the scope of its application.
About 30 years ago, van der Plas proposed a method of homogeneous oxidative amination with a
RNH2NH3KMnO4 system, which at present is widely used in organic synthesis, especially for the
functionalization of heterocyclic compounds. This method provides an opportunity to carry out reactions
under mild conditions and to involve compounds containing labile groups as substrates. This reaction is
exemplified by the amination of pyridazine reported in the work [45] (Scheme 16). Previously, it was
shown by NMR in [46] that the reaction proceeds through the intermediate formation of 3,4dihydropy
ridazine 3.
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AKSENOV et al.
KNH2
NH3
NH2
NH2
KMnO4
N
H
3
N
N
91%
Scheme 16.
When an additional electronwithdrawing group is present in the molecule of the heterocyclic com
pound, the amination can be carried out in the absence of metal amide [47] (Scheme 17).
NO2
NO2
R
R'
NH3
KMnO4
H2N
R'
9398%
Scheme 17.
Air oxygen can act as an oxidizing agent in this reaction, for example, [48] (Scheme 18).
R
N
R'
N
R
N
N
RR'NH
O2
3060%
Scheme 18.
At present, the AgPy2MnO4 complex is the most efficient oxidizing agent for such reactions. For exam
ple, this complex provides even the diamination of 6,8dimethylpyrimido[4,5c]pyridazine5,7(6,8)
dione 4 [49] (Scheme 19).
N
O
HN
H
N
RNH2
AgPy2MnO4
N
7377%
Scheme 19.
Vicarious substitution is one more variant of nucleophilic amination. As a rule, hydroxylamine and,
less frequently, hydrazine are used as aminating reagents in these reactions [48, 50] (Scheme 20).
NH2
NO2
N
NO2
NH2OH
[50]
50%
NH2
N
N
NH2OH
[48]
48%
Scheme 20.
Examples of amination by vicarious substitution followed by the closure of the imidazole ring were
reported in [51] (Scheme 21).
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NH2OH
AcOH
AcONa
quantitative
yield
X
N
Br
365
Scheme 21.
Hydrazine is used in these reactions much less frequently. An example of this type of transformation is
the reaction of pyridazinones with hydrazine hydrate [52], which results in a mixture of isomeric amines
(Scheme 22).
R
R
N
N
N
N
N2H4
H2N
R'
R'
1537%
Scheme 22.
4. DIRECT ELECTROPHILIC AMINATION OF ARENES
As shown above, the substitution of the hydrogen atom in the aromatic ring by an amino group is usu
ally a twostep process that requires the preliminary introduction of a functional group or atom. Excep
tions are azines, azoles, and aromatic compounds with strong electronwithdrawing substituents that can
be aminated by the nucleophilic substitution of a hydrogen atom. Therefore, in recent years there has been
growing interest in the study of reactions of direct electrophilic amination of arenes. These reactions have
been known for more than 100 years (see, for example, [5, 5355]). Over this time, different reagents and
their combinations have been used, but no universal and truly efficient method has been designed to date.
4.1. Electrophilic Amination of Arenes with the Use of Hydroxylamine and Its Derivatives
One of the first works in this direction is the paper by Grabe published in 1901 [55] (Scheme 23). This
work describes the amination of benzene and alkylbenzenes with hydroxylamine in the presence of alumi
num chloride. Toluene forms a mixture of p and otoluidines in a 9 : 1 ratio in 2% yield. orthoXylene
afforded a yield of 7%.
R
NH2
NH2OH
AlCl3
27%
Scheme 23.
The effect of the nature of hydroxylamine salt on the yield and regioselectivity of toluene amination
was studied in [56]. Hydroxylamine sulfate in the presence of a 10% excess of aluminum chloride proved
to be the most efficient salt for this purpose.
Other derivatives of hydroxylamine such as alkylhydroxylamine [57] and hydroxylaminesulfonic
acid [5860] were successfully used for electrophilic amination.
Thus, the amination of toluene with hydroxylaminesulfonic acid was reported to result in a mixture
of p and toluidines in a 40% yield toward the aminating reagent [58, 60]. The yield toward initial tolu
ene was about 4% (Scheme 24). It was noted in [58, 59] that the content of the para isomer in the toluidine
mixture is about 96%. It was later shown that these data were erroneous [60]. A more detailed study of the
reaction (catalyst amount, reaction time, solvent) showed the formation of mtoluidine in 1113% yield
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AKSENOV et al.
along with p and toluidines formed in approximately equal amounts or with a slight predominance of
the ortho isomer.
R
NH2
NH2OSO3H
AlCl3
240%
Scheme 24.
The application of alkylhydroxylamines allowed the direct introduction of the amino and dialkylamino
group into the arene molecule [57] (Scheme 25). Similarly to the reaction of hydroxylaminesulfonic
acid, toluene forms a mixture of all isomers but with the predominance of the para isomer. In certain
instances, its content in the reaction mixture reaches 60%.
R
NR2
NR2OR'
AlCl3
242%
Scheme 25.
There are papers in which Nphenylhydroxylamine with PPA or trifluoroacetic anhydride in trifluoro
acetic acid was used as the aminating reagent, for example, [61] (Scheme 26).
NH2
HN
OH
R
PPA/TFA
or TFAA/TFA
H
N
+
NH2
R
R = H, Me;
total yield is 7865%
Scheme 26.
In this case, along with the amination product, a mixture of products of arylation at the ortho and para
positions relative to the amino group is also formed. Amination product prevails in the case of benzene
and pxylene. Its yield in the reaction with benzene is 25% for PPA and 45% for trifluoroacetic anhydride.
In the reaction with pxylene, the yields under the same conditions were 47 and 66%, respectively.
ArylNbenzoylhydroxylamines undergo intramolecular electrophilic amination under the action
of aluminum chloride in methylene chloride [62] (Scheme 27). The products of electrophilic amination
at the ortho position form in 2285% yield.
O
H
N
O
Ph
OH
AlCl3
CH2Cl2
H
N
2285%
Ph
Scheme 27.
The authors postulate a reaction mechanism that involves the coordination of the catalyst at the oxygen
atom of the hydroxylamine group at the first stage of the process [62] (Scheme 28).
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H
N
Cl3Al
H
N
AlCl3
Ph
Ph
CH2Cl2
Cl3Al
Cl3Al
AlCl2
AlCl3
HCl
367
AlCl2
N
R
Ph
O
Ph
HCl
Cl2Al
OH
H
N
AlCl2
H2O
N
R
Ph
O
Ph
Scheme 28.
In some cases, this reaction leads to side reactions: substitution of the hydroxy group and halogenation
when a halogen is present in the para position, as well as the displacement of a halogen at the ortho position
and chlorination (Scheme 29).
O
H
N
Cl
AlCl3
Ph
H
N
CH2Cl2
19%
Ph
Cl
Cl
Al(OH)Cl2
AlCl3
O
Ph
Cl
Cl
Cl
O
Ph
Cl
Cl Al
Al + NH
Cl Al +
Cl
O H
O
O
NH
N
H
H
O
F
Cl
Cl
H
N
O
Ph
Ph
Cl
Cl
Cl
OH
AlCl3
CH2Cl2
Br
H
N
O
Ph 46%
Br
Cl
AlCl3
H2O
O
Ph
Cl
Cl
Cl
Cl
O
Cl
Ph
Al +
Al
Al +
Al + NH
Cl
Cl
Cl
O
O
O
Cl
O
H
NH
N
Ph +
F
F
H
F
O
Br
Br
Br
Br
H Cl
Cl
Cl
H
N
Scheme 29.
In our opinion, these side processes involve chemical reactions shown in Scheme 29.
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O
368
AKSENOV et al.
There are examples of acetamination of arenes with the use of hydroxylamine derivatives, namely,
hydroxamic acids [63, 64] (Scheme 30).
OR
OR
O
+
R'
PPA
OH
N
H
R'
863%
NH
6
Scheme 30.
The yield of acetanilides 6 was from 8 to 63%. The lowest yield of the product is observed for com
pounds with electronwithdrawing substituents like iodine or a carbonyl group.
The intramolecular reaction of electrophilic amination with participation of hydroxylamine deriva
tives, namely oximes, has been used many times in the synthesis of quinoline derivatives (Scheme 31) [64].
PPA
OH
N
H
57%
N
H
Scheme 31.
A thermal cyclization of methylated oximes into quinolines was reported in [65] (Scheme 32).
O
N
PhMe
reflux
93%
Scheme 32.
Chemical and photochemical variants of such transformations are possible for acylated oximes [55,
67] (Scheme 33).
O
O
Ph
Et2N
Ar
NEt2
[66]
9660%
Ar
Ph
Ph
O
O
Ph
[67]
52%
Ph
Ph
Scheme 33.
The reaction reported in [68] may provide an example for the use of ketoxime with a saturated side
chain for the synthesis of quinoline (Scheme 34).
N
O
OH
Bu4NReO4
CF3SO3H
chloranil,
dichloroethane
O
75%
Scheme 34.
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369
4.2. Electrophilic Amination of Arenes with the Use of Haloamines

Another type of reagents used for direct electrophilic amination is bromo and chloroamines [54, 69
77]. Preparative procedures have been developed on their basis in many instances.
The amination of benzene with Nchloropiperidine was the first use of haloamines [70] (Scheme 35).
A small amount of Nphenylpiperidine was detected among the reaction products.
+
N
Ph
N
Cl
traces
Scheme 35.
The amination of phenol with chloroamine, which led to small amounts of paminophenol along with
4,4'dihydroxydiphenylamine, was studied later [71] (Scheme 36).
OH
+
NH2
NH2 + HO
HO
Cl
OH + ...
N
H
Scheme 36.
The amination of 2,5disubstituted phenols with chloroamine is accompanied by ring expansion [72,
73]. The suggested mechanism of this reaction involves the ipso attack by chloroamine on the substituted
phenols to form intermediate 7, whose oxo group then undergoes intramolecular nucleophilic attack by
the amino group. The resulting bicyclic compound 8 undergoes expansion of the sixmembered ring via
pericyclic reaction (Scheme 37).
O
R
O
R
NH2Cl
NH2
R
OH H
N
R
OH
R
NH
R
7
5055%
Scheme 37.
The preparatively significant methods of amination with the use of haloamines are presented in the
works [7477] (Scheme 38).
NR2
ClNR2
Cl
+R
R
1938%
ClNR2
NR2
21%
Scheme 38.
The reaction of chloroamines with toluene was shown to result mainly in a para isomer along with
smaller amounts of ortho and meta isomers. The latter prevails in the presence of iron salts. In this case,
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AKSENOV et al.
there is no byproduct of arene halogenation, which is present when other systems are used, except for the
reactions carried out in nitromethane and nitrobenzene, the best solvents for this process. The effect of
acid nature was also studied. Sulfuric acid proved to be more efficient than aluminum chloride. The effect
of acid concentration and metal ion was also shown. A conclusion was drawn on the possibility of reaction
course via a freeradical mechanism.
4.3. Electrophilic Amination of Arenes with Hydrazoic Acid and Azides
Another system long used for direct electrophilic amination is hydrazoic acid in the presence of differ
ent catalysts: Lewis and Broensted acids. The paper by Schmidt [78] published in 1924 was one of the first
works that addressed amination with the use of this reagent. It describes the amination of benzene with
hydrazoic acid in the presence of sulfuric acid. Aniline was obtained in this reaction in a low yield (Scheme
39).
NH2
NH3
H2SO4
Scheme 39.
Hydrazoic acid proved to be one of the most promising reagents for direct electrophilic amination.
Thus, HN3 in the presence of aluminum chloride is more efficient for toluene amination than hydroxy
laminesulfonic acid [58]. Since toluene was used as a solvent, the yield of isomeric toluidines toward
toluene does not exceed 5%. The reaction leads to a mixture of ortho and para isomers with considerable
predominance of the latter (Scheme 40).
NH3
NH2
NH2
+
AlCl3
40% (with respect to the aminating agent)
Scheme 40.
The authors of [79] reported the direct electrophilic amination of mesitylene with hydrazoic acid in
concentrated sulfuric acid. They described the formation of three amines in this reaction: mesidine,
diaminomesitylene, and 3amino2,4,6trimethylbenzenesulfonic acid (Scheme 41). The main reaction
product is 3amino2,4,6trimethylbenzenesulfonic acid formed in 42% yield.
HN3
H2SO4
NH2 HO3S
+
NH2
+
NH2
NH2
42%
Scheme 41.
A number of works deal with the thermal decomposition of hydrazoic acid or its ammonium salt in aro
matic hydrocarbons, for example, [80]. The decomposition was carried out in benzene and pxylene in a
bomb at 220260 to give the corresponding amines in a low yield.
The results of comparison for the reaction of hydrazoic acid with toluene in the presence of sulfuric
acid and aluminum chloride are described in [81]. In all cases, the reaction leads to a mixture of three pos
sible isomers with the predominance of the ortho isomer. The total yield in the presence of aluminum chlo
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371
ride as catalyst is higher than in the presence of sulfuric acid. The reaction of hydrazoic acid with chlo
robenzene in the presence of aluminum chloride was also studied; the para isomer prevailed in this case.
G. Olah and colleagues studied the electrophilic amination of benzene and its derivatives in a NaN3
AlCl3HCl system [82]. The authors suggested the reaction mechanism shown in Scheme 42 [82].
NaN3 + AlCl3
AlCl2N3 + NaCl
AlCl2N3 + 2HCl
NH2N2+ AlCl4
NH2AlCl4 + N2
H2N
NH2
H
H+
N2
N
N
+
H2N H
H2N N N
H
+
Scheme 42.
Study of the solvent effect showed that the best result was achieved when an excess of the aromatic
compound was used. Its replacement with hexane leads to reduction in the yield of amines, while in the
authors opinion 1,2dichloroethane and nitromethane are inappropriate solvents on account of strong
complexation with the Lewis acid. However, it was shown in [83] that the amination of mesitylene with a
NaN3AlCl3HCl system in hexane and 1,2dichloroethane as solvents provided moderate (40%) and
high (86%) yields of mesidine, respectively.
The same authors performed an elaborate study on the effect of solvent and crown ether additives on
the yield and regioselectivity of amination of xylene, mesitylene, durene, and pentamethylbenzene in a
NaN3AlCl3HCl system [84] (Scheme 43).
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AKSENOV et al.
NH2
HN3
AlCl3/HCl
NH2
HN3
NH2
+
AlCl3/HCl
NH2
HN3
AlCl3/HCl
NH2
HN3
AlCl3/HCl
Scheme 43.
According to the data of this work, methylene chloride and 1,2dichloroethane are the most efficient
solvents for these processes. Upon oxylene amination, the ratio of 2,3 and 3,4dimethylanilines vary
depending on solvent nature from 0.56 to 0.9. In all cases, the 3,4isomer is the main reaction product.
Crown ethers have little effect on the amination of arenes [84]. The amination of solid arenes, durene and
pentamethylbenzene, was also reported in [84]. The yield of 2,3,5,6tetramethylaniline and pentamethy
laniline in methylene chloride was 30 and 52%, respectively.
The effect of Lewis acid nature on the amination of mesitylene with a NaN3MHlgnHCl system was
studied in [85]. The following Lewis acids were used: GaCl3, ZrCl4, AlCl3, AlBr3, FeCl3, SbCl5, SnCl4,
TiCl4, SbCl3, and GeCl4. The use of SnCl4 and TiCl4 leads to very low conversion of the initial arene, while
no reaction was observed with SbCl3 and GeCl4. Such Lewis acids as AlBr3, FeCl3, and SbCl5 show mod
erate activity, while GaCl3, ZrCl4, and AlCl3 are the most efficient.
In [86], the authors described the use of ionic liquid ([bmim]Cl) in the amination reaction of and
mxylene and mesitylene in a NaN3AlCl3HCl system. Xylene produces a mixture of isomeric dimeth
ylanilines in 65% total yield for xylene and 78% for mxylene. Mesitylene under these conditions gives
mesidine in 76% yield.
G. Olah and colleagues proposed the use of trimethylsilyl azide in trifluoromethanesulfonic acid for
direct electrophilic amination [87]. This reagent allows preparation of corresponding anilines from alkyl
and halobenzenes in 73 to 95% yield with respect to the aminating reagent (Scheme 44). The disadvan
tages of the method are the use of an excess of aromatic substrate as a solvent and low regioselectivity for
monosubstituted benzenes.
H2NN2+ O3SCF3 + Me3SiOSO2CF3
Me3SiN3 + 2F3CSO3H
+ H2NN2+ O3SCF3
N2
NH2
H O3SCF3
NH2
CF3SO3H
R
7396%
Scheme 44.
It proved very efficient to use a N3CF3COOHCF3SO3H system for direct electrophilic amination
[88]. The system allows the amination of a large number of alkyl and halobenzenes, diphenyl, naphtha
lene, and phenanthrene. The total yield of anilines toward hydrazoic acid was from 15 to 100%. As in the
Vol. 1
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373
previous case, the excess of aromatic compound and low reaction regioselectivity are the drawbacks of the
method.
The amination of mesitylene can be accomplished without trifluoroacetic acid in a NaN3CF3SO3H
system [89]. The yield of mesidine in this case was 72%.
A method of direct electrophilic amination of arenes with a sodium azidePPA system was developed
recently in our laboratory. The method was found to be applicable for the amination of arenes containing
electrondonating substituents [90], including crown ethers with an aromatic ring [93], naphthalene [90],
and naphthalenes with electrondonating substituents such as pyrimidine [91, 92] (Scheme 45).
RO
1) NaN3/PPA
RO
7486%
2) H2O
NH2
R = H, Me;
MeO
1) NaN3/PPA
MeO
2) H2O
MeO
MeO
NH2
78%
OMe
MeO
1) NaN3/PPA
2) H2O
OMe
NH2
OMe
74%
NH2
1) NaN3/PPA
31%
2) H2O
NH2
NH2
1) NaN3/PPA
2) H2O
NH
HN
6276%
NH
HN
N
R
6276%
O
O
NaN3
NH2
PPA
61%
Scheme 45.
The advantage of this system consists in regioselectivity close to 100% at sufficiently high yields of 18
86% [9093]. We assume that such a selectivity is explained by a reaction mechanism that includes the
azo coupling stage shown in Scheme 46.
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AKSENOV et al.
NaN3
PPA
O a
b
...O P N N+ N
OH
PPA
O
...O P N N+ N
H
HO
O
...O P N N+ NH
HO
A
ArH
A
PPA
O
...O P N N N Ar
H
HO
O
...O P N N N Ar
H
HO
HO
HO
+
OH P N N N Ar
H2
H O
H2O
H+
N2
H3PO4
H+
ArNH2
Scheme 46.
Another advantage of this system is the possibility to combine it with other reactions. An example of
cascade transformation shown in [95] includes the Schmidt reaction, electrophilic amination, and het
erocyclization (Scheme 47).
R'
R'
NaN3
PPA
NH
R
R
3144%
Scheme 47.
The probable mechanism of this reaction according to [94] is shown in Scheme 48.
PPA
N
O
N
NH HN
R'
R'
HN
R'
NaN3
NaN3
PPA
PPA
NH
NH
N
R
PPA
R'
N
R'
N
NH
O2
R'
HO
N N
NH
NH
PPA
N2
N
R
NH
R
Scheme 48.
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375
Other examples of tandem reactions with participation of sodium azide in PPA are given in [93, 95,
96]. In these papers, the system of reagents is used cooperatively with 1,3,5triazines. The reaction with
benzene or naphthalene derivatives as initial arenes results in the orthoannelation of the pyrimidine ring
[93, 95] (Scheme 49).
R''
RO
RO
1) NaN3/PPA
2)
R'
R''
R''
R'
N
R''
R = H, Me;
R' = H, OMe;
4954%
R''
R'' = H, Me, Ph;
R
N
1) NaN3/PPA
2)
N
N
N
R
R = H, Me, Ph;
2226%
Scheme 49.
The mechanism of the transformation is shown in Scheme 50 and includes the stages of electrophilic
addition of phosphoryl azide to initial triazine, followed by the opening of the threemembered ring and
closure of the pyrimidine ring [93, 95] (Scheme 50).
R
O
...O P N N N Ar + R
H
HO
N
R
N
N
NH
R
RN
H+
H+
R
N
H+
NH2
N
R
Scheme 50.
In the reaction of pyrimidines, a periannelation occurs [96] (Scheme 51).
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2011
NH2
HN=CRNH2
N
H
N
H
RN
R
H
N R
N Ar
N H
PPA
NH2
HN=CHNH2
N2
N
O
+
...O P N N N Ar
H
HO
N
R
N Ar
N H
R
376
AKSENOV et al.
R
HN
HN
1) NaN3/PPA
2)
N
R1
N
H
R1
7279%
NH
1
NH R
R1
H2O
HN
R1
R1
NH
O
3847%
Scheme 51.
The mechanism of the transformation is close to that shown in Scheme 50. It is confirmed by the fact
that the reaction leads to corresponding amides if the reaction mixture is kept for 2 h at 7080C and
treated with water after the addition of triazines.
Alkyl and arylamination of aromatic compounds with the use of alkyl and aryl azides is described in a
number of papers.
One of the first such works dealt with the decomposition of aryl azides in the presence of phenol and
aniline [97, 98]. The authors reported on the formation of phydroxy(amino)diphenylamines in these
reactions. The series of aryl azides and arenes involved in the reactions was extended in later work [99].
Later, the reaction of aryl azides with arenes was carried out in the presence of trifluoroacetic acid
(TFA) [100, 101] and trifluoromethanesulfonic acid, which provided an opportunity to increase substan
tially the yield of amination products (Scheme 52). The reaction was found to result in a complex mixture
of amination and arylation products.
NH2
N3
R
+
TFA
H
N
H
N
+
R
or TFSA
73%
8%
N3
+
NH2
8%
NHPh
TFA
or TFSA
82%
Scheme 52.
Several papers reported on the introduction of a sulfonamido group in arenes upon decomposition of
arylsulfonyl azides in the presence of an aromatic compound [103105]. The reaction of substituted ben
zenes leads to a mixture of sulfonamidation products at the ortho, meta, and para positions (Scheme 53).
Considerable amounts of the meta substitution product form only when an electronwithdrawing substit
uent is present in the substrate molecule. The reactions of intramolecular amination with azides are the
most interesting; these lead, as a rule, to different heterocyclic compounds in a good yield.
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2011
SO2Ar
NH
+
ArSO2N3
SO2Ar
NH
+
377
SO2Ar
NH
R
R
655%
Scheme 53.
A large number of works is dedicated to the synthesis of indoles. There is a report on the synthesis of
imides of indole2,3dicarboxylic acids [106] (Scheme 54).
O
O
R
N
NaN3
O
Cl
N
H
N3
40%
Scheme 54.
A large number of reports is devoted to the synthesis of indoles from the products of condensation of
benzaldehydes with azidoacetic acid ester [107115] (Scheme 55).
R
R'
O
O
KOH
R'
N3
R'
N3
N
H
O
40%
Scheme 55.
This is associated with the high availability of the initial azides and the biological importance of hard
toaccess 4substituted indoles.
In addition to indoles, electrophilic amination with azides provides the preparation of other heterocy
clic compounds. Thus, the conversion of 2azidobiphenyl into carbazole in quantitative yield was
described in [116] (Scheme 56).
decalin
reflux
N
H
N3
97%
Scheme 56.
The synthesis of phenanthridines is described in [117]. It is likely that cations 9 form at the first stage
and then react with hydrazoic acid to give intermediate compound 10. The latter eliminates a nitrogen
molecule and undergoes ring expansion to yield phenanthridines (Scheme 57).
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378
AKSENOV et al.
HN3
H2SO4
OH
H+
94%
H2O
HN3
N2
X
X
HN
N+
H
11
N+ N
10
Scheme 57.
4.4. Other Reagents for the Electrophilic Amination of Arenes
+
Electrophilic species NH 2 can be generated upon decomposition of Naminoazines. This approach

was used in the development of a series of methods for direct electrophilic amination [118123]. The elec
trophilic species was produced by the photolysis or thermolysis of salts. The reaction with monosubsti
tuted arenes results in a mixture of all isomeric substituted anilines (Scheme 58). This transformation has
theoretical rather than practical significance.
R'
R'
N
R''
NH2
N
NH2
N
R'
NH2
NH2
A or B or
hv or t
+
NH2
NH2
1720%
810%
414%
Scheme 58.
A method of direct electrophilic amination of arenes with the use of a XeF2Me3SiNCOCF3SO3H
system was suggested recently [124] (Scheme 59). The yield of amination products is 3545%, and mono
substituted benzenes form a mixture of ortho and para isomers in approximately equal amounts.
R
R
R'
R'
XeF2/Me3SiNCO
CF3SO3H
R
NH2
R'
+
NH2
3445%
Scheme 59.
There are several reports on electrochemical methods of electrophilic amination, for example, [125,
126] (Scheme 60). A method of electrochemical amination of arenes with hydroxylamine in sulfuric acid
in the presence of transition metal ions was described in [126]. The authors believe that the reaction occurs
with the participation of cation radicals by a chain mechanism. The current efficiency in the case of ben
zene is up to 147%.
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H
N
+
H2O
[125]
N
H
NH2
Pt/MeCN
379
1124%
1854%
NH2
NH2OH
NH2
+
Ti(IV)
NH2
[126]
H2N
27%
72%
Scheme 60.
An interesting method of electrophilic amination of arenes under the action of azidodicarboxylic esters
and related azo compounds was published recently [127, 128]. The reaction proceeds in the presence of
InCl3 on SiO2 as a catalyst under conditions of thermal or microwave activation [127] (Scheme 61). Ben
zene and naphthalene derivatives with electrondonating substituents were involved in the reaction. The
yield was 6080% with thermal activation and 6892% with microwave activation.
+ EtO2C N
CO2Et
N
CO2Et
N
H
InCl3/SiO2
N CO2Et
t or mw
6092%
EtO2C
H
N CO2Et
O
InCl3/SiO2
t or mw
90%
Scheme 61.
The reaction of halosubstituted phenols with a halogen in the para position results in the migration of
the halogen to a free ortho position on account of the ipso attack at the para position [128] (Scheme 62).
OH
Hal
O
OH
O
+
N
R
Hal'
O
N
R
Hal
O
Hal
N
N
H
ZrCl4
CH2Cl2
Hal'
583%
R
+
N
N
H
HO
Hal'
086%
Scheme 62.
Nitrenes produced in situ from nitro [129] and nitroso compounds [130] and triethyl phosphite were
used as electrophilic aminating reagents (Scheme 63).
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380
AKSENOV et al.
P(OEt)3
[129]
NO2
N
H
5070%
N
Me
N
Me
H
N
O2N
P(OEt)3
[129]
N
Me
N
Me
5070%
H
N
O2N
P(OEt)3
[130]
76%
Scheme 63.
The last method considered in this review was developed recently in our laboratory. The method is based on
the acetamination of aromatic compounds with nitroalkanes in PPA [131, 132] (Scheme 64). The reaction can
be carried out with benzene and its derivatives with electrondonating substituents. Monosubstituted benzenes
produce only amination products at the para position, which is explained by the thermodynamic control of the
acylation stage. The yield of acetanilides is from 60 to 92%. The corresponding amines can be obtained if the
reaction mixture is refluxed after treatment with water [131]. Dibenzo18crown6 under these conditions pro
duces a mixture of mono and diacetamination products [132].
H
N
R'CH2NO2
PPA
[131]
O
6392%
R'
O
O
CH3CH2NO2
NH
PPA
[132]
54%
H
N
O
O
O
O
NH
O
O
O
O
+
H
N
33%
O
O
O
O
O
O
N
H
Scheme 64.
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381
The reaction of pyrimidines with nitroethane in PPA leads to corresponding acetamides [133] or, at a
higher temperature, the products of the peri annelation of the pyrrole ring [134] (Scheme 65).
R
N
NH
Me
HN
CH3CH2NO2
HN
t
PPA
NH
R
N
R
4654%
Scheme 65.
5. CONCLUSIONS
Thus, the literature currently comprises both multistep methods for the introduction of an amino
group into the aromatic ring and the direct amination (amidation) of aromatic compounds. The multistep
methods that include nitration and reduction, azo coupling and reduction, acylation and the Schmidt
reaction, and acylation and the Beckmann rearrangement are well studied from the theoretical and prac
tical viewpoint. One can expect that further progress in this field will be associated with the introduction
of new nitrating agents into practice.
The methods of direct amination (amidation) of aromatic compounds are relatively less studied both
theoretically and preparatively. A substantial disadvantage of these methods is their low regioselectivity.
One can expect that further progress in this area will be associated with the introduction of novel aminat
ing (amidating) electrophilic reagents into practice.
ACKNOWLEDGMENTS
This work was supported by the Federal Targeted Program Scientific and Academic Brainpower of
Innovative Russia for 20092013 (Grant no. 16.740.11.0162).
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2011

Toluenee Amination

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ISSN 20799780, Review Journal of Chemistry, 2011, Vol. 1, No. 4, pp. 359384. Pleiades Publishing, Ltd., 2011.

Methods for the Amination of Arenes

Received January 25, 2011; in final form July 4, 2011

METHODS FOR THE AMINATION OF ARENES

METHODS FOR THE AMINATION OF ARENES

HetArNH2 for example

METHODS FOR THE AMINATION OF ARENES

total yield is 7865%

METHODS FOR THE AMINATION OF ARENES

METHODS FOR THE AMINATION OF ARENES

4.2. Electrophilic Amination of Arenes with the Use of Haloamines

40% (with respect to the aminating agent)

METHODS FOR THE AMINATION OF ARENES

METHODS FOR THE AMINATION OF ARENES

METHODS FOR THE AMINATION OF ARENES

R'' = H, Me, Ph;

METHODS FOR THE AMINATION OF ARENES

Electrophilic species NH 2 can be generated upon decomposition of Naminoazines. This approach

METHODS FOR THE AMINATION OF ARENES

METHODS FOR THE AMINATION OF ARENES

METHODS FOR THE AMINATION OF ARENES

REVIEW JOURNAL OF CHEMISTRY

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