Lewis acid catalyzed highly selective halogenation of aromatic compounds

Article abstract of DOI:10.1055/s-2005-918919

A simple and efficient procedure for the halogenation of aromatic compounds with NCS, NBS, NIS and NFSI in the presence of catalytic amount of ZrCl ₄ is described. Chlorination, bromination, iodination and fluorination of various aromatic compounds are performed with high selectivity under mild reaction conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-918919

LETTER
2837
Lewis Acid Catalyzed Highly Selective Halogenation of Aromatic Compounds
L
ewis Acid Cataly
a
zed Efficie
n
nt
H
alogenat
h
ion of
A
roma
u
tic
C
ompou
a
nds Zhang, Kazutaka Shibatomi, Hisashi Yamamoto*
Department of Chemistry, The University of Chicago, 5735 S. Ellis Avenue, Chicago, IL 60637, USA
Fax +1(773)7020805; E-mail: yamamoto@uchicago.edu
Received 7 July 2005
Dedicated to the memory of Dr. Anne Ghosez-Giese.
First, the bromination using NBS was investigated. Ini-
Abstract: A simple and efficient procedure for the halogenation of
aromatic compounds with NCS, NBS, NIS and NFSI in the pres-
ence of catalytic amount of ZrCl4 is described. Chlorination, bromi-
nation, iodination and fluorination of various aromatic compounds
tially, we found anisole can be brominated by use of one
equivalent of NBS in the presence of 5 mol% of ZrCl4 at
–78 °C to afford p-bromoanisole in 98% yield as sole
are performed with high selectivity under mild reaction conditions. product. Screening of various Lewis acid catalysts7 re-
vealed not only ZrCl4 but also FeCl3 and AlCl3 gave sim-
ilar results. However, HfCl4, TiCl4 and ZnCl2 indicated
poor reactivity. Further study on the reaction of 1-amino-
naphthalene and NBS in the presence of 5 mol% of Lewis
acid showed the superiority of ZrCl4 in the selectivity of
product (Table 1, entry 4). Obviously, ZrCl4 is the choice
of reagent in regard to efficiency and selectivity of the
reaction. It is reasonable that the reaction in the absence of
ZrCl4 does not proceed well even at room temperature
(Table 1, entry 1). The results of ZrCl4-catalyzed bromi-
nation of various substrates using NBS are summarized in
Table 1. All the substrates were brominated to give the
corresponding monobromo product in excellent yield, as
well as the regioselectivity. In most cases, the reaction can
proceed at very low temperature and no further purifica-
tion is necessary. Compared to previous methods,8 which
can lead to separation difficulties and unacceptable levels
of toxic and corrosive waste, our method was quite simple
and efficient.
Key words: halogenation, aromatic compounds, N-halo reagents,
zirconium tetrachloride, Lewis acid catalysis
Halogenation of aromatic compounds is a highly useful
reaction for providing the precursors to a number of orga-
nometallic species applicable in the synthesis of natural
products and pharmaceutically important compounds.1 In
particular, aryl bromides and iodides are of importance in
organic syntheses because of their utility to transition-
metal-catalyzed cross coupling reactions to furnish com-
plex functionality.2 Many established methods for the di-
rect introduction of halogen atom into aromatic molecules
have been reported.3 Classical reagents for this reaction
are bromine and chlorine, but the reaction suffers from a
major drawback that only half of the halogen is consumed
and the toxicity of the reagent is problematic.4 In terms of
easy handling, N-bromo- (NBS), N-iodo- (NIS) and N-
chlorosuccinimide (NCS) are superior halogenating re-
agents.5 In previous studies severe reaction conditions
were usually used to activate or enhance the halogenating
ability of NXS (X = Br, Cl, I), such as a considerably
acidic solution,5a a large amount of catalyst5b or a high
temperature.5c Recently we reported ZrCl4 mediated the
asymmetric chlorination of silyl enolate with a,a-dichlo-
rinated 1,3-dicarbonyl compound.6 On the basis of this re-
sult, we developed a simple and efficient procedure for the
halogenation of aromatic compounds with NCS, NBS and
NIS catalyzed by ZrCl4 (Scheme 1). Furthermore, fluori-
nation reactions also occur by using N-fluorobenzene-sul-
fonimide (NFSI) as a fluorine source under similar mild
reaction conditions.
Next, the chlorination reaction with this method was in-
vestigated and the results are shown in Table 2. All the
substrates treated with one equivalent of NCS and 5 mol%
of ZrCl4 afforded the corresponding chlorinated com-
pounds. Although the chlorination reaction is relatively
slower than the bromination reaction, the reaction at room
temperature afforded a high yield of chlorinated product
with high regioselectivity. In some cases, a small amount
of regioisomers (entry 3) or dichlorinated products (entry
4 and 5) was observed.
Our method can also be applied to iodination of aromatic
compounds. NIS activated by Brønsted acids in catalytic
or stoichiometric quantities has been found to be useful
for electrophilic iodination.9 The catalyst we select here is
a unique Lewis acid – ZrCl4, which is known for its low
toxicity.10 As shown in Table 3, both the reactivity and the
regioselectivity of iodination reaction are as good as
bromination reaction. In entry 2, only trace diiodinated
products were observed.
NXS (X = Cl, Br or I) or NFSI
X
ZrCl4 (5 or 20 mol%)
R
R
CH2Cl2
1
2 (X = Cl, Br, I or F)
Scheme 1
Finally, we conducted a brief investigation of fluorination
(Table 4), which is one of the most difficult operations in
organic synthesis. A mild fluorinating reagent, N-fluoro-
benzenesulfonimide (NFSI), was selected as fluorine
source. The reactions of 1-/2-methoxylnaphthalene and
SYNLETT 2005, No. 18, pp 2837–2842
0
3
.1
1
.2
0
0
5
Advanced online publication: 10.10.2005
DOI: 10.1055/s-2005-918919; Art ID: Y06405ST
© Georg Thieme Verlag Stuttgart · New York

2838
Y. Zhang et al.
LETTER
Table 1 ZrCl4-Catalyzed Bromination of Aromatic Compounds by NBSa
Entry
1
Substrate
Product
Temp (°C)
Time (h)
Conversion (%)b
–78
r.t.
5
1
98
OMe
OMe
96
r.t.c
12c
<1c
Br
2
3
Br
–78
r.t.
2
2
>99
>99
OMe
OMe
–78
0
r.t.
1.5
2
2
81
91
95
OMe
OMe
Br
4
–78
1.5
93
NH2
NH2
Br
2-Br:4-Br
(92:8)b
(81:19)b,d
(70:30)b,e
5
6
0
r.t.
4
4
>99
>99
H
H
N
N
Br
Br
–78
0
r.t.
3
2
2
>99
>99
>99
OH
OH
7
r.t.
1
>99
Br
O
O
a Reaction conditions: substrate (0.5 mmol), NBS (0.5 mmol), ZrCl4 (5 mol%), CH2Cl2 (4 mL).
b Determined by 1H NMR.
c In the absence of ZrCl4.
d FeCl3 as the catalyst with 93% yield.
e AlCl3 as the catalyst with 92% yield.
pyrrole with NFSI catalyzed by ZrCl4 gave corresponding
fluorinated products in moderate yields. As shown in
entry 1, the use of a large amount of catalyst increased the
yield of fluorinated product; but the amount of some un-
known by-products also increased.
Zr
O
N
X
O
OMe
The exact reaction mechanism for the above results is not
yet clear. A plausible explanation for the success of this
reaction may involve preferential coordination of the
Lewis acid (ZrCl4) with the carbonyl oxygen to increase
the reactivity of halogen atom as implied in Figure 1.
Figure 1 Hypothetical mechanism
FeCl3 or AlCl3 with almost the same reactivity as that of
ZrCl4. Although the exact radical chain is not quite clear,
the reaction seems to proceed by a radical mechanism. In
fact, the reaction does not proceed at all in the presence of
a radical inhibitor.
Surprisingly, the reaction of NBS and toluene in the
presence of 5 mol% of ZrCl4 does not give the expected
nuclear substituted products, but benzyl bromide almost
exclusively. Table 5 shows some additional examples.
The reaction also proceeded smoothly in the presence of
Synlett 2005, No. 18, 2837–2842 © Thieme Stuttgart · New York

LETTER
Lewis Acid Catalyzed Efficient Halogenation of Aromatic Compounds
2839
Table 2 ZrCl4-Catalyzed Chlorination of Aromatic Compounds by NCSa
Entry
1
Substrate
Product
Temp (°C)
r.t.
Time (h)
12
Conversion (%)b
OMe
OMe
92
Cl
2
3
r.t.
r.t.
12
12
97
94
OMe
Cl
OMe
OMe
OMe
Cl
2-Cl:4-Cl
(13:87)b
4
5
r.t.
0
6
6
92
83
H
H
N
N
Cl
2-Cl:2,5-di-Cl
(83:17)b
OH
OH
Cl
4-Cl:2,4-di-Cl
(75:25)b
Cl
6
7
0
r.t.
6
6
>99
>99
OH
OH
r.t.
12
92
Cl
O
O
a Reaction conditions: substrate (0.5 mmol), NCS (0.5 mmol), ZrCl4 (5 mol%), CH2Cl2 (4 mL).
b Determined by 1H NMR.
CH3
CH2Br
CHBr2
CBr3
Next, dibromination and tribromination of toluene in the
NBS (10 equiv), ZrCl4 (5 mol%)
CH2Cl2, reflux, 22 h
presence of an excess amount of NBS were tested. The
optimum reaction conditions to obtain either as the major
brominated product are shown in Equation 1 and
Equation 2, respectively. Thus, by utilizing suitable
Lewis acid catalyst, we can control the generation of
different brominated products at will.
+
+
(< 1%)
(13%)
(87%)
Equation 2
In conclusion, we have developed a practical and efficient
method for halogenation of aromatic compounds using
readily available N-haloimides and ZrCl4 as Lewis acid
catalyst. This method can be applicable to a wide range of
aromatic compounds and any halogen atom can be direct-
ly introduced to the substrate with high regioselectivity.
The mild reaction condition, easy work-up procedure and
simple operation make our method valuable from an en-
vironmental and preparative point of view.
CH3
CH2Br
CHBr2
CBr3
NBS (6 equiv), AlCl3 (5 mol%)
CH2Cl2, r.t., 22 h
+
+
(2%)
(88%)
(10%)
Equation 1
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2840
Y. Zhang et al.
LETTER
Table 3 ZrCl4-Catalyzed Iodination of Aromatic Compounds by NISa
Entry
1
Substrate
Product
Temp (°C)
r.t.
Time (h)
12
Conversion (%)b
OMe
OMe
95
I
2
0
0
2
6
>99
NH2
NH2
I
4-I:2,4-di-I
(99:1)b
3
4
96
OMe
I
OMe
–78
0
r.t.
6
6
6
93
>99
>99
OMe
OMe
I
5
6
–78
–78
6
6
65
69
NH2
NH2
I
4-I:2,4-di-I
(36:64)b
I
OH
OH
a Reaction conditions: substrate (0.5 mmol), NIS (0.5 mmol), ZrCl4 (5 mol%), CH2Cl2 (4 mL).
b Determined by 1H NMR.
Table 4 ZrCl4-Catalyzed Fluorination of Aromatic Compounds by NFSIa
Entry
1
Substrate
Product
Time (h)
Conversion (%)b
70c
43d
28e
OMe
6
F
OMe
2
3
12
31e
OMe
OMe
F
2-F:4-F (43:57)b
12
53e
H
N
H
N
F
a Reaction conditions: substrate (0.5 mmol), NFSI (0.5 mmol), CH2Cl2 (4 mL), r.t.
b Determined by 1H NMR.
c With 1 equiv of ZrCl4.
d With 50 mol% of ZrCl4.
e With 20 mol% of ZrCl4.
Synlett 2005, No. 18, 2837–2842 © Thieme Stuttgart · New York

LETTER
Lewis Acid Catalyzed Efficient Halogenation of Aromatic Compounds
2841
Table 5 ZrCl4-Catalyzed Radical Bromination of Aromatic Compounds by NBSa
Entry
1
Substrate
Product
Temp (°C)
r.t.
Time (h)
24
Conversion (%)b
89
CH3
CH2Br
2
3
0
6
>99
CHBrCH3
CH2CH3
0
r.t.
5
2
85
88
CH3
CH2Br
4
5
0
r.t.
5
2
80
91
CH2Br
CH3
CH2Br
CH2Br
0
0
6
94
CH3
CH3
Br
Br
6
7
6
89c
Cl
Cl
Cl
Cl
0
6
91c
CH2Br
CH3
F
F
F
F
a Reaction conditions: substrate (0.5 mmol), NBS (0.5 mmol), ZrCl4 (5 mol%), CH2Cl2 (4 mL).
b Determined by 1H NMR.
c Contain trace dibromination product (<4%).
Typical Experimental Procedure11
To a solution of NBS (10.0 mmol, 1.78 g) in CH2Cl2 (80.0 mL)
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Acknowledgment
This work was supported by the Japan Science and Technology
Agency (JST) and the University of Chicago.
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2842
Y. Zhang et al.
LETTER
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Synlett 2005, No. 18, 2837–2842 © Thieme Stuttgart · New York