Efficient and economic halogenation of aryl amines via arenediazonium tosylate salts

Article abstract of DOI:10.1016/j.tet.2010.07.005

Arenediazonium tosylate salts have been successfully employed as a new and efficient reagent in halogenation reactions. A novel and economic protocol has been developed for the bromination and chlorination of various anilines using arenediazonium tosylate salts. A wide variety of reaction conditions were studied in acetonitrile at either room temperature or 60 °C in the presence or absence of catalyst with good to excellent yields. A surprising result showed the formation of acetanilides as a major product of aniline and methyl-substituted aniline halogenations in high yields.

Full text of DOI:10.1016/j.tet.2010.07.005

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Tetrahedron 66 (2010) 7418e7422
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Efficient and economic halogenation of aryl amines via arenediazonium
tosylate salts
,
a,
*
Young Min Lee a, Mi Eun Moon a, Vaishali Vajpayee a, Victor D. Filimonov b , Ki-Whan Chi
*
a Department of Chemistry, University of Ulsan, Ulsan 680-749, Republic of Korea
b Department of Organic Chemistry, Tomsk Polytechnic University, Tomsk 634050, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
Arenediazonium tosylate salts have been successfully employed as a new and efficient reagent in
halogenation reactions. A novel and economic protocol has been developed for the bromination and
chlorination of various anilines using arenediazonium tosylate salts. A wide variety of reaction conditions
were studied in acetonitrile at either room temperature or 60 ꢀC in the presence or absence of catalyst
with good to excellent yields. A surprising result showed the formation of acetanilides as a major product
of aniline and methyl-substituted aniline halogenations in high yields.
Received 26 March 2010
Received in revised form 2 July 2010
Accepted 2 July 2010
Available online 21 July 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Arenediazonium tosylate salt
Aniline derivatives
Halogenation
Acetanilide
1. Introduction
traditional Sandmeyer reaction.18e22 Subsequently, a successful
method for the halogenation of aromatic amines by alkyl nitrites in
Arenediazonium salts have gained attention in synthetic
chemistry due to their powerful synthetic as well as industrial
importance.1e3 To broaden the scope of arenediazonium salt appli-
cations, we recently reported the synthesis of new and highly stable
arenediazonium tosylate salts with various applications.4 The close
and multiple contacts between the nitrogen atom in the diazonium
cation and the oxygen atoms of the tosylate anion were accountable
for the unusual stability of these salts, which was supported by X-
ray structure. It is well documented that arenediazonium salts5,6
are very reactive intermediates for various organic conversions.
They electrochemically reduce into radicals or cations that imme-
diately attach covalently to carbon or other substituents. This be-
havior of diazonium salt was explored for the simple and efficient
diazotizationeiodination of aromatic amines.7e10 The diazotization
and halogenation reaction is a one-pot, two-step process that first
includes the diazotization of amines with sodium nitrite or tert-
butyl nitrite in the presence of acid and a subsequent reaction with
a halogenating agent in the presence or absence of copper salt.
It is well known that aromatic halides are important building
blocks in organic transformations, such as the Suzuki cross coupling
and Heck-type reactions11e17, and one of the most renowned
methods for the synthesis of aryl halides by aryl amines is the
the presence of anhydrous copper(II) salts via a substitutive
deamination reaction was reported by Doyle et al.23,24 Recently,
a one-step method for the iodination of aromatic derivatives was
reported using HI/KNO2 in DMSO or KI/NaNO2/p-TsOH in CH3CN.25
A recent publication also reports the synthesis of aryl halides using
various arenediazonium salts.26
This manuscript is an extension of our ongoing interest on the
versatility of arenediazonium tosylate salts. This report clearly dem-
onstrates the synthesis of aryl halides that avoids the use of unstable
diazonium salts. In addition, this method utilizes a complete organic
medium without acids to minimize aqueous waste and to provide
applicable useful, economic, and easyone-pot synthetic procedure for
the synthesis of halo-benzene derivatives. The results of this study
discuss the preparation of aromatic bromides and chlorides by di-
azotization and halogenation of aromatic amines with different ha-
logenating reagents in the presence of p-TsOH in acetonitrile.
2. Results and discussion
The reaction of anilines with halogenating reagents in acetoni-
trile under various reaction conditions resulted in a rapid and
quantitative evolution of nitrogen and the formation of aryl halides
(Table 1e4). The nature of the free halide ion in solution was the
main influence determining the reaction rate; use of the bromide
ion reacted faster than the chloride ion, which was only converted
to aryl chloride after an extended reaction period (Scheme 1).
* Corresponding authors. Fax: þ82 52 259 2348; e-mail addresses: filimonov@
tpu.ru (V.D. Filimonov), kwchi@ulsan.ac.kr (K.-W. Chi).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.005

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Y.M. Lee et al. / Tetrahedron 66 (2010) 7418e7422
p-TsOH (1.2eq), Cu halide(1 mol %)
7419
Ar-NH2
+
X Hal
+
Y NO2
Ar-Hal
acetonitrile
4-5
1
2
3
Here ; 1, 4-5: a, Ar = 4-NO2C6H4; b, Ar = 3-NO2C6H4; c, Ar = 2-NO2-C6H4; d, Ar = 4-CNC6H4;
e, Ar = 2-CNC6H4; f, Ar = 4-IC6H4; g, Ar = 4-BrC6H4;
h, Ar = 4-ClC6H4; i, Ar = 4-OCH3C6H4; j, Ar = 2-OCH3C6H4;
k, Ar = 4-NO2-2-OCH3C6H3; l, Ar = 2-NO2-4-OCH3C6H3; m, Ar = benzothiazol
2 : sodium bromide, tertabutylammonium bromide(TBAB), benzyltriethylammonium chloride(BTAC)
5 : Hal = Cl
3 : t-butyl nitrite, sodium nitrite 4 : Hal = Br
Scheme 1. Diazotizationehalogenation of aniline derivatives.
Table 1
Table 3
Reaction conditions for diazotizationebromination of 4-nitroaniline (1a)
Reaction conditions for diazotizationechlorination of 4-nitroaniline (1a)
t-BuONO (1.2 equiv.)
p-TsOH(1.2 equiv.)
BTAC (2.0 equiv.)
sodium nitrite/t-BuONO (1.2 equiv.)
p-TsOH(1.2 equiv.)
brominating agent (2.0 equiv.)
NH2
Cl
NH2
Br
Cu salt(1 mol %)
CH3CN, rt or 60 °C
Cu salt (1 mol %)
CH3CN, rt-60 °C
NO2
NO2
NO2
NO2
5a
1a
4a
1a
Entry
Catalyst
Temp
Time (h)
Yield (%)
Entry
Method
Catalyst
Temp
rt
Time (h)
Yield (%)
1
2
3
4
5
6
CuCl2
CuCl
d
rt
rt
rt
rt
24
24
24
24
1
76
60
39
1
2
3
4
5
6
7
8
9
1
1
1
2
2
2
2
3
3
3
CuBr
CuBr
CuBr
d
6
3
6
6
2
2
6
4
1
1
62
60 ꢀ
rt
C
59
29a
74
d
Tracea
60
60 ꢀ
60 ꢀ
C
C
rt
rt
rt
rt
rt
rt
rt
CuCl
CuCl2
CuBr
CuBr2
CuBr
d
86
84
1
71
a
In the absence of p-TsOH.
Tracea
78
CuBr
CuBr2
81
86
10
Table 4
Diazotizationechlorination of anilines 1
Method 1: NaNO2, p-TsOH, Cu salt, AcOH, NaBr in CH3CN.
Method 2: t-BuONO, p-TsOH, Cu salt, NaBr in CH3CN.
Method 3: t-BuONO, p-TsOH, Cu salt, TBAB in CH3CN.
t-BuONO (1.2 equiv.)
p-TsOH(1.2 equiv.)
BTAC (2.0 equiv.)
a
In the absence of p-TsOH.
Ar-NH2
Ar-Cl
5
CuCl2 (1 mol %)
CH3CN, rt or 60 °C
1
Entry
Ar
Temp
Time (h)
Yield (%)
Table 2
Diazotizationebromination of anilines 1
1
2
3
4
5
6
3-NO2C6H4(1b)
2-NO2C6H4(1c)
4-CNC6H4(1d)
2-CNC6H4(1e)
4-NO2-2-MeOC6H3(1k)
2-NO2-4-MeOC6H3(1l)
60 ꢀ
rt
rt
rt
60 ꢀ
60 ꢀ
C
1
24
24
24
1
66(5b)
43(5c)
69(5d)
61(5e)
63(5k)
34(5l)
t-BuONO (1.2 equiv.)
p-TsOH(1.2 equiv.)
TBAB (2.0equiv.)
Ar-NH2
C
C
Ar-Br
1
CuBr2 (1 mol %)
CH3CN, rt
4
1
We varied several reaction parameters to optimize the reaction
conditions, including the sodium nitrite or tert-butyl nitrite, the
halogenating agent, the reaction temperature, time, catalyst, the
presence or absence of catalyst, and the presence or absence of
p-TsOH under various methods. It is known that bromination and
chlorination is more challenging as compared with iodination,
simply because of the lower nucleophilicity of bromide and chlo-
ride than iodide. Keeping this in mind we used acetonitrile, a polar
aprotic solvent, for effective bromination and chlorination.
Reaction parameters began with the treatment of sodium nitrite
and sodium bromide with aniline in the presence of p-TsOH using
Cu halide as a catalyst in acetonitrile, and only a satisfactory yield
was achieved with various substituted anilines at room tempera-
ture or 60 ꢀC (method 1).
Entry
Ar
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
3-NO2C6H4(1b)
2-NO2C6H4(1c)
4-CNC6H4(1d)
2-CNC6H4(1e)
4-IC6H4(1f)
4-BrC6H4(1g)
4-ClC6H4(1h)
4-MeOC6H4(1i)
2-MeOC6H4(1j)
4-NO2-2-MeOC6H3(1k)
2-NO2-4-MeOC6H3(1l)
1
1
1
1
1
79(4b)
76(4c)
82(4d)
75(4e)
78(4f)
71(4g)
58(4h)
77(4i)
74(4j)
88(4k)
83(4l)
1
23
23
23
1
9
10
11
1
S
12
(1m)
3
89(4m)
NH2
With the intension to increase the yield, we replaced the sodium
nitrite with tert-butyl nitrite (method 2) and carried out several
N

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7420
Y.M. Lee et al. / Tetrahedron 66 (2010) 7418e7422
Table 5
reactions at room temperature in the presence or absence of Cu(I) and
Cu(II) halides. The observed results showed an increased yield of the
desired product, and the rate of the reaction varied with aniline
substitution. It was hypothesized that the halodediazoniation
followed the homolytic dediazoniation pathway27,28 and an electron
transfer initiated the reaction. The electron-withdrawing substituent
at the para-position led to a fast reaction with a high yield due to the
high electrophilicity of the cation, even without using Cu as the cat-
alyst (Table 1).
The addition of tetrabutylammonium bromide as the bromi-
nating agent (method 3) to the reaction mixture increased the
formation of the desired product up to 89% yield in a shorter re-
action time. Consistently high yields of the bromodediazoniation
products were achieved with a variety of aniline derivatives.
Method 3 proved to be equally applicable for anilines containing
electron-donating as well as electron-withdrawing groups, which
is not the case with method 2 (Table 1 and 2).
The comparatively low yield of chlorodediazoniation products
to bromodediazoniation products can be justified by the redox
potentials of both halide anions. The high redox potential of Clꢁ
reasonably explains its difficulty in electron transfer as compared
with Brꢁ, which is responsible for the compared low yield. Fur-
thermore, varying the Cu(I) and Cu(II) halides showed no signifi-
cant change in yield. It is understood that the Cu(I) salt played an
important role in the Sandmeyer substitution reaction. Also, the
effective use of Cu(II) salt was noticed in the substitution process by
its reduction to Cu(I) during the course of the reaction. We also
observed that both Cu(I) and Cu(II) salts worked effectively for the
generation of aryl halides. It is worth mentioning that only a cata-
lytic amount of Cu salt worked effectively in our reaction conditions
resulting in excellent yields of the desired products.
In most of the cases, it was observed that the rate of the reaction
was increased at 60 ꢀC, and moderate to high yields of the desired
product were achieved in 1 h reaction time. To monitor the role of
p-TsOH salt in the reaction, we carried out some reactions in the
absence of p-TsOH and noticed a very poor yield, confirming the
involvement of diazonium tosylate salt formation during the course
of the reaction.
Diazotizationehalogenation of aniline and methyl-substituted anilines
Entry
Substrate
Product 6
Yield (%)
(method 3)
H3C
NH
78b
87c
O
O
1
NH2
H3C
NH
89a
96c
NH2
CH3
2
CH3
H3C
O
NH2
84a
91c
3
4
NH
H3C
H3C
H3C
NH
H3C
NH
20a
24b
74c
O
H3C
NH2
H3C
38a
45b
83c
O
H3C
H3C
NH2
5
H3C
H3C
a
Room temperature, reaction time (6 h).
Room temperature, reaction time (23 h).
Reaction temperature (60 ꢀC), reaction time (23 h).
b
c
The present reaction pathway may involve the formation of res-
onating structures 7 by an initial dominant attack of the tosylate salt
with the acetonitrilesolvent inplace of thehalogenating agent, which
further leads to the synthesis of acetanilide in the presence of water.
Finally, a very surprising result was observed with the reaction
of aniline and methyl-substituted anilines (Scheme 2). The treat-
p-TsOH(1.2eq),
t-BuONO(1.1eq)
Ar-NHAc
Ar-NH2
CH3CN, TBAB(2eq)
1
6
Here; 1, 6: n, Ar = C6H5; o, Ar=2-CH3C6H4; p, Ar = 3-CH3C6H4; q, Ar = 4-CH3C6H4; r, Ar= 3,4-(CH3)2C6H3
Scheme 2. Reaction of aniline and methyl-substituted anilines.
ment of aniline or methyl-substituted aniline with tert-butyl nitrite
The formation of acetanilide was again confirmed in the absence of
and TBAB in the presence of p-TsOH in acetonitrile yielded the alkyl
acetanilides in high yield and IR, NMR, and GC-MASS data provided
the evidence for the formation of the product. Several conditions
were attempted to generate the desired methyl-substituted aryl
halide, but in all the process variations, we achieved acetanilides in
74e96% yield. After confirming the synthesis of 4-methyl-
acetanilide in the 4-methylaniline reactions, we extended the study
to several different methyl-substituted anilines and the results are
summarized in Table 5.
These results were quite interesting and the synthesis of an
alkylacetanilide with common anilines provides a new tool for
this synthesis; however, this reaction process requires further
modification and a detailed study of the reaction conditions. No
clear evidence is available to explain the reaction pathway;
however a plausible reaction mechanism can be suggested as
follows:
a brominating agent during the course of the reaction (Scheme 3).
3. Conclusion
In conclusion, this research demonstrates the synthesis of aro-
matic halides from various aniline derivatives via an arenediazo-
nium tosylate salt using only catalytic amounts of Cu salt. The
protocol is operationally simple, efficient, and industrially appli-
cable; it does not require special anhydrous conditions and pro-
ceeds with good to high yield in most cases. In addition, the
acetanilide synthesis is also observed with aniline and methyl-
substituted anilines. We believe that this protocol is an effective
compliment to the existing methods for halogenation and also es-
tablishes a wide applicability for the unusually stable arenediazo-
nium tosylate salts. Further investigations are in progress

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Y.M. Lee et al. / Tetrahedron 66 (2010) 7418e7422
7421
CH3
CH3
CH3
CH3
CH3
C
p-TsOH
t-butyl nitrite
H
N
N
O
N
NH2
N2 OTs
H
C
C
CH3
CH3
7
CH3
CH3
CH3
H3C
N
H
H
H3C
H
N
H3C
NH
O
O
H
O
OTs
Scheme 3. Plausible mechanism for acetanilide synthesis.
concerning the application of arenediazonium tosylate salts as
building blocks in various reactions.
chromatography by using hexane/dichloromethane as the eluting
solvent. Physical and 1H NMR data were identical to those of a com-
mercially available sample of analytical purity.29
4. Experimental
4.2.3. Acetanilide. Thereactionmixtureofaniline(1.0 equiv), p-TsOH
(1.2 equiv), tert-butyl nitrite (1.1 equiv), and TBAB (2.0 equiv) in ace-
tonitrile (20 ml) was stirred at the mentioned reaction temperature
and time (Table 5). The progress of reaction was monitored by TLC.
After completion of reaction the solvent was evaporated by rotary
evaporator. The crude solid was purified by column chromatography
using hexane and dichloromethane as eluting solvents. Physical and
1H NMR data were identical to those of a commercially available
sample of analytical purity.29
4.1. Materials and measurements
The melting points were uncorrected. The IR spectra were
recorded on Mattson-5000(UNICAM). The 1H NMR spectra were
recorded in CDCl3 on a Bruker 300 MHz spectrometer. IR spectra
were recorded on Varian 2000 FT-IR spectrometer and CHN anal-
ysis were carried out on varioMICRO V 1.9.4 CHN analyzer. Details
for the reactions and yields of the pure isolated products are listed
in Table 1e5.
4.2.4. 20-Methylacetanilide (6o). White solid, mp: 98e100 ꢀC, 1H
NMR (300 MHz, CDCl3)
d
7.73 (d, 1H, J¼6.0 Hz), 7.18 (t, 2H,
4.2. Conversion of aryl amines to aryl bromides and
chlorides: general procedure
J¼8.4 Hz), 7.06 (t, 1H, J¼6.0 Hz), 2.24 (s, 3H), 2.19 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 168.7, 135.7, 130.6, 129.9, 126.8, 125.6, 123.8, 24.3,
17.9; IR (cmꢁ1) 3292, 3032, 2979, 1653, 1589, 1529, 1457, 756;
found: C, 72.10; H,7.21; N,9.06. C9H11NO requires C, 72.46; H, 7.43;
N, 9.39%; MS m/z 42.9, 76.9, 105.8, 106.8, 107.8, 148.5, 149.7(Mþ).
4.2.1. Aryl bromides. Catalytic amounts of copper bromide (1 mol %)
were added to a solution of aniline (1.0 equiv) in acetonitrile (20 ml),
p-TsOH(1.2 equiv), sodium nitrite or tert-butyl nitrite (1.2 equiv),
and brominating agent (2.0 equiv). The reaction mixture was stirred
at the indicated reaction temperatures and times (Table 1 and 2).
The evolution of N2 was immediately observed. The solvent was
removed by a rotary evaporator after completion of the reaction
4.2.5. 30, 40-Dimethylacetanilide (6r). Ivory solid, mp: 96e98 ꢀC, 1H
NMR (300 MHz, CDCl3)
d
7.26 (d, 1H, J¼3.0 Hz), 7.20 (dd, 1H, J¼3.0,
3.1 Hz), 7.05 (d, 1H, J¼8.4 Hz), 2.21 (s, 3H), 2.19 (s, 3H), 2.13 (s, 3H);
13C NMR (75 MHz, CDCl3)
d
168.8, 137.2, 135.7, 132.8, 130.0, 121.7,
(confirmed by b-naphthol test and TLC). The solid was washed with
117.8, 24.5, 20.0, 19.31; IR (cmꢁ1) 3289, 3125, 2967, 1664,1610,1539,
1444,824; found: C, 73.59; H, 7.78; N, 8.43. C10H13NO requires C,
73.59; H, 8.03; N, 8.58%; MS m/z 42.8, 90.9, 105.8, 107.0, 119.8, 120.8,
121.8, 162.5, 163.7(Mþ).
water and extracted with CH2Cl2. The resulting solution was dried
over anhydrous MgSO4 and the solvent was removed under reduced
pressure. The pure product was then collected by column chroma-
tography using hexane: dichloromethane as eluting solvents.
Physical and 1H NMR data were identical to those of a commercially
available sample of analytical purity.29
Acknowledgements
This work was supported by the 2009 Research Fund of Uni-
versity of Ulsan.
4.2.2. Aryl chlorides. p-TsOH (1.2 equiv), tert-butyl nitrite (2.0 equiv),
benzyltriethylammoniumchloride (2.0 equiv), and catalytic amounts
of copper chloride (1 mol %) were added to an acetonitrile solution
(20 ml) of aniline (1.0 equiv). The reaction mixture was stirred at the
indicated reaction temperatures and times (Table 3 and 4). The
evolution of N2 was immediately observed. The solvent was removed
by rotary evaporator after completion of the reaction (confirmed by
Supplementary data
Supplementary data associated with this article contains NMR,
IR and GCeMS spectra of 20-methylacetanilide (6o) and 30, 40-
dimethylacetanilide (6r), and physical and spectral data for all the
b-naphthol test and TLC). The crude residue was purified via column