An expeditious and environmentally benign preparation of aryl halides from aryl amines by solvent-free grinding

Article abstract of DOI:10.1016/j.tetlet.2010.10.099

An efficient solvent-free methodology for conversion of various aryl amines into bromides and chlorides via arenediazonium tosylate salts under grinding conditions is disclosed. This new methodology not only avoids the use of strong acids and expensive reagents for diazotization-halogenation reactions, but also decreases the amount of organic waste from the reaction process.

Full text of DOI:10.1016/j.tetlet.2010.10.099

Tetrahedron Letters 51 (2010) 6769–6771
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An expeditious and environmentally benign preparation of aryl halides from
aryl amines by solvent-free grinding
Mi Eun Moon a, Younghwa Choi a, Young Min Lee a, Vaishali Vajpayee a, Marina Trusova b,
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:
An efficient solvent-free methodology for conversion of various aryl amines into bromides and chlorides
via arenediazonium tosylate salts under grinding conditions is disclosed. This new methodology not only
avoids the use of strong acids and expensive reagents for diazotization-halogenation reactions, but also
decreases the amount of organic waste from the reaction process.
Received 13 September 2010
Revised 16 October 2010
Accepted 20 October 2010
Available online 26 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Arenediazonium tosylate salt
Solvent-free grinding
Halogenation
The versatile applicability of diazonium salts for Matsuda–Heck
coupling, Sandmeyer and other cross-coupling reactions has been
well-established.1,2 Taking into account the numerous applications
of arenediazonium salts, we recently reported a facile synthesis
and isolation of pure and unusually stable arenediazonium tosyl-
ate salts in excellent yields.3 The exceptional stability of these salts
can be rationalized on the basis of close and multiple contacts be-
tween the nitrogen atom of the diazonium cation and the oxygen
atoms of the tosylate moiety. Most other diazonium salts have
drawbacks, such as difficulty in isolation, air and thermal sensitiv-
ity, tedious preparation, or further work-up of precursors.4 The
easy synthesis of pure and thermally stable arenediazonium tosyl-
ate salts is advantageous for their use in various reactions. Further-
more, we have been interested in exploring the application of
these tosylate salts in organic synthesis, and in this context we
have published a couple of reports on efficient and economical
diazotization-iodination reaction which could be accomplished
with or without solvent.5–7 In addition, these tosylate salts were
efficiently employed in bromination and chlorination reactions un-
der solvent conditions.8 There is copious literature demonstrating
the importance of aryl halides for various organic transformations,
including substitution reactions9 that produce compounds con-
taining new carbon–carbon10 or carbon–heteroatom11 bonds in
high yields.
A number of methods have been reported for the synthesis of
aryl halides, either by the Sandmeyer reaction involving the use
of an equimolar amount of Cu salt or by the direct halogenation;12
however, all of the procedures reported to date have potentially
serious environmental concerns as they involve directly or indi-
rectly toxic reagents, use expensive catalysts, or require tedious
purification processes. Considering the wide range of aryl halide
applications, it is worthwhile to develop a practical, cost-effective,
simple, fast, and environmentally benign protocol for the synthesis
of aryl bromides and chlorides. It is known that, the high redox
potentials of chloride and bromide anions make chlorination and
bromination reactions more challenging and demanding than
iodination reactions. In this context, the reaction conditions for
the effective bromination and chlorination of aryl amines make
this report noteworthy.
Herein, we wish to report for the first time, a solvent-free grind-
ing process for the fast and efficient conversion of aryl amines into
aryl bromides and chlorides via arenediazonium tosylate salts. The
one-pot sequential diazotization-halogenation reaction for the
synthesis of aryl bromides and chlorides involves a solvent-free
reaction of various anilines with halogenating reagent, tert-butyl
nitrite, p-TsOH, and a catalytic amount of a copper(II) salt (Scheme
1) and avoids the isolation of intermediate diazonium tosylate
salts. Unlike the corresponding solution reactions, this solid-phase
synthesis is not only clean and fast, but also avoids the formation
of organic wastes.
The main features of this protocol include an easy solvent-
free process and use of only a catalytic amount of Cu(II) halides
for the conversion under grinding conditions, thus offering an
⇑
Corresponding authors. Tel.: +82 52 259 2344; fax: +82 52 259 2348 (K.-W.C.).
E-mail addresses: filimonov@tpu.ru (V.D. Filimonov), kwchi@ulsan.ac.kr (K.-W.
Chi).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.099

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M. E. Moon et al. / Tetrahedron Letters 51 (2010) 6769–6771
tert-BuONO(1.2 eq.)
p-TsOH(1.2 eq.)
Ar-NH2 + M X
Ar-X
Cu Halide (1 mol %)
3,4
2
1
1,3,4: a, Ar =2-NO2-C6H4 ; b,Ar = 3-NO2C6H4; c,Ar =4-NO2C6H4 ; d,Ar = 2-CNC6H4;e,Ar= 4-CNC6H4;
f,Ar = 4-IC6H4; g,Ar = 4-BrC6H4;h,Ar = 4-ClC6H4; i,Ar = 2-OCH3C6H4; j, Ar = 4-OCH3C6H4;
k, Ar = 4-NO2-2-OCH3C6H3; l,Ar = 2-NO2-4-OCH3C6H3
2: benzyltriethylammonium chloride(BTAC),sodium bromide, tertabutylammonium bromide(TBAB)
3: X = Br, 4: X = Cl
Scheme 1. Synthesis of aryl bromides and chlorides by diazotization–halogenation of aryl amines.
environmentally and economically favourable alternative over
other reported protocols that employ organic solvents, a desir-
able goal for current green synthetic chemistry methodologies.
The reaction of various anilines with sodium bromide in the
presence of a catalytic amount of Cu(II) bromide, tert-butyl nitrite,
p-TsOH and a few drops of water produced aryl bromides in mod-
erate yields (Table 1) after 15–20 min of grinding. A limitation of
the aniline substrate, that it requires a strong electron-withdraw-
ing group, was observed. To overcome this drawback, we used tet-
rabutylammonium bromide (TBAB) as the bromide source in the
absence of water; the desired products were obtained in less than
20 min in higher yields (Table 1) after grinding in a quartz mor-
tar.13 This variation works well with electron-donating as well as
electron-withdrawing substituents. The p-TsOH also plays signifi-
cant role in facilitating the reaction since no conversion was ob-
served in the absence of p-TsOH.
Similarly, aryl chlorides (Table 2) were synthesized in good
yields by treatment of anilines with benzyltriethylammonium
chloride (BTAC) in the presence of CuCl2 as a catalyst via diazonium
tosylate salts.14 The comparatively lower yield of aryl chlorides to
aryl bromides can be explained in terms of the lower nucleophilic-
ity or the difficult electron transfer of chloride anions, as compared
to bromide anions as a result of their higher redox potential.
In summary, we have presented a simple, environmentally be-
nign, cost-effective, and practical method for the synthesis of aryl
bromides and chlorides from aryl amines via arenediazonium tos-
ylate salts by a simple solvent-free process. This methodology pro-
vides an efficient alternative to existing methods for the synthesis
of aryl bromides and chlorides.
Table 1
Acknowledgement
Solvent-free bromination of various aryl amines
Entry Substrate
Yield (%) of 3 Yield (%) of 3 Mp (°C)
by method 1 by method 2
This work was financially supported by the 2010 Research Fund
of the University of Ulsan, Ulsan, Republic of Korea.
1
2
3
2-NO2C6H4(1a)
3-NO2C6H4(1b)
4-NO2C6H4(1c)
55
58
65
71
77
87
38–39.5 (40a)
51–52 (52a)
123–124
(124a)
References and notes
1. (a) Zollinger, H. In The Chemistry of Amino, Nitroso, Nitro and Related Groups;
Patai, S., Ed.; Wiley & Sons: New York, 1996; pp 636–637; (b) Moro, A. V.;
Cardoso, F. S. P.; Correia, C. R. D. Tetrahedron Lett. 2008, 49, 5668; (c) Roglans,
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Heinrich, M. R.; Blank, O.; Ullrich, D.; Kirschstein, M. J. Org. Chem. 2007, 72,
9609; (e) Kikukawa, K.; Kono, K.; Wada, F.; Matsuda, T. J. Org. Chem. 1983, 48,
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A. H. L.; Correia, C. R. D.; Eberlin, M. N. Angew. Chem., Int. Ed. 2004, 43, 4389; (c)
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4
5
2-CNC6H4(1d)
4-CNC6H4(1e)
42
54
68
82
52–54
(53–57a)
109–111
(110a)
6
7
8
4-IC6H4(1f)
4-BrC6H4(1g)
4-ClC6H4(1h)
30
16
10
64
60
46
87–89 (89a)
82–84 (83a)
64–66
(64–67a)
Oil (2a)
9
10
11
2-MeOC6H4(1i)
4-MeOC6H4(1j)
4-NO2-2-MeOC6H3
(1k)
2-NO2-4-
MeOC6H3(1l)
0
0
24
44
45
80
Oil (9a)
101–102
12
25
78
31–33
(32–33a)
3. Filimonov, V. D.; Trusova, M.; Postnikov, P.; Krasnokutskaya, E. A.; Lee, Y. M.;
Hwang, H. Y.; Kim, H.; Chi, K. W. Org. Lett. 2008, 10, 3961.
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Galli, C. Chem. Rev. 1988, 88, 765; (c) Barbero, M.; Crisma, M.; Degani, I.; Fochi,
R.; Perracino, P. Synthesis 1998, 1171.
Method 1: tert-BuONO, p-TsOH, Cu(II) bromide, NaBr, a few drops of water.
Method 2: tert-BuONO, p-TsOH, Cu(II) bromide, TBAB.
a
Reference mp (Aldrich Handbook of Fine Chemicals).
5. Gorlushko, D. A.; Filimonov, V. D.; Krasnokutskaya, E. A.; Semenishcheva, N. I.;
Go, B. S.; Hwang, H. Y.; Cha, E. H.; Chi, K. W. Tetrahedron Lett. 2008, 49, 1080.
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Table 2
Solvent-free chlorination of various aryl amines
7. Gorlushko, D. A.; Filimonov, V. D.; Semenishcheva, N. I.; Krasnokutskaya, E. A.;
Tret’yakov, A. N.; Go, B. S.; Hwang, H. Y.; Cha, E. H.; Chi, K. W. Russ. J. Org. Chem.
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2010, 66, 7418.
9. (a) Han, X.; Weng, Z.; Andy Hor, T. S. J. Organomet. Chem. 2007, 692, 5690; (b)
Manolikakes, G.; Hernandez, C. M.; Schade, M. A.; Metzger, A.; Knochel, P. J. Org.
Chem. 2008, 73, 8422; (c) Ye, Z.-W.; Yi, W.-B. J. Fluorine Chem. 2008, 129, 1124;
(d) Farina, V. In Comprehensive Organometallic Chemistry II; Abel, E. W., Stone, F.
G. A., Wilkinson, G., Eds.; Pergamon Press: Oxford, 1995; Vol. 12, pp 161–240;
(e) Soderbegr, B. C. G. Coord. Chem. Rev. 2004, 248, 1085.
Entry
Substrate
Yield (%) of 4 by method 3
Mp (°C)
Oil (33a)
1
2
3
4
5
6
7
8
2-NO2C6H4(1a)
3-NO2C6H4(1b)
4-NO2C6H4(1c)
2-CNC6H4(1d)
4-CNC6H4(1e)
4-MeOC6H4(1j)
4-NO2-2-MeOC6H3(1k)
2-NO2-4-MeOC6H3(1l)
53
65
70
33
54
54
65
69
46–47 (47a)
80–81 (81a)
41–43 (43a)
90–92 (91a)
87–89 (89a)
76–80
38–41 (41a)
10. (a) Phan, N. T. S.; Styring, P. Green Chem. 2008, 10, 1055; (b) Lehmann, U.;
Awasthi, S.; Minehan, T. Org. Lett. 2003, 5, 2405; (c) Milton, E. J.; Clarke, M. L.
Method 3: tert-BuONO, p-TsOH, Cu(II) chloride, BTAC.
a
Reference mp (Aldrich Handbook of Fine Chemicals).

M. E. Moon et al. / Tetrahedron Letters 51 (2010) 6769–6771
6771
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Chem. 2010, 12, 985.
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Gupte, S. P.; Chaudhari, R. V. Appl. Catal. A: General 2010, 372, 73; (c) Benyahya,
S.; Monnier, F.; Man, M. W. C.; Bied, C.; Ouazzani, F.; Taillefer, M. Green Chem.
2009, 11, 1121.
TLC), the solid was washed with water and extracted with CH2Cl2.The resulting
solution was dried with anhydrous MgSO4, and the solvent was removed in a
rotary evaporator under reduced pressure. Further purification of the product
was performed by column chromatography using hexane: dichloromethane as
eluting solvents. All physical and 1H NMR data of the products were identical
to those from commercially available samples of analytical purity.
12. (a) Sandmeyer, T. Chem. Ber. 1884, 17, 1633; (b) Hodgson, H. H. Chem. Rev.
1947, 40, 251; (c) Zollinger, H. Azo and Diazo Chemistry; Interscience: NY, 1961;
(d) Doyle, M. P.; Siegfried, B., Jr.; Dellaria, J. F. J. Org. Chem. 1977, 42, 2426; (e)
Doyle, M. P.; Van Lente, M. A.; Mowat, R.; Fobare, W. F. J. Org. Chem. 1980, 45,
2570; (f) Barbero, M.; Degani, I.; Dughero, S.; Fochi, R. J. Org. Chem. 1999, 64,
3448.
13. Grinding method for diazotization–halogenation of aryl bromides: into an
agate mortar, aniline (1.0 equiv), p-TsOH (1.2 equiv), tert-butyl nitrite
(1.2 equiv), TBAB (1.2 equiv), and a catalytic amount of copper(II) bromide
(1 mol %) were added, and the mixture was ground vigorously. An immediate
evolution of N2 was observed. After completion of the reaction (confirmed by
14. Grinding method for diazotization–halogenation of aryl chlorides: p-TsOH
(1.2 equiv), tert-butyl nitrite (1.2 equiv), benzyltriethylammonium chloride
(1.2 equiv) and a catalytic amount of copper salt (1 mol %) were combined in
an agate mortar-containing aniline (1.0 equiv) and the mixture was vigorously
ground for 15–20 min, until the evolution of N2 completely stopped. After
completion of the reaction (confirmed by TLC), the crude residue was worked
up, as described for the aryl bromide reaction, and was purified by column
chromatography using hexane: dichloromethane as eluting solvents. All
physical and 1H NMR data of the products were identical to those from
commercially available samples of analytical purity.