Practical and metal-free electrophilic aromatic halogenation by interhalogen compounds generated in situ from N-halosuccinimide and catalytic TMSCL

Article abstract of DOI:10.1055/s-0034-1378225

Halomonochloride compounds (ClCl, BrCl, ICl) generated in situ from N-halosuccinimide and catalytic chlorotrimethylsilane (TMSCl, 0.1 equiv) can efficiently halogenate aromatic compounds to give halogenated products in good to excellent yields and selectivities. The reaction can be carried out at room temperature or at lower temperatures, requires only one hour, is practical to apply to a wide range of substrates, and provides a simple access to a variety of haloarene compounds. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0034-1378225

LETTER
▌1769
letter
Practical and Metal-Free Electrophilic Aromatic Halogenation by Inter-
halogen Compounds Generated In Situ from N-Halosuccinimide and Catalytic
TMSCl
Practical and Metal-Free Electrophilic Aromatic Halogenation
Tapanee Maibunkaew,a Charnsak Thongsornkleeb,*a,b Jumreang Tummatorn,b Anon Bunrit,b Somsak Ruchirawata,b
a
Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology, CHE,
Ministry of Education, 54 Kampang Phet 6, Laksi, Bangkok 10210, Thailand
b
Chulabhorn Research Institute, 54 Kampang Phet 6, Laksi, Bangkok 10210, Thailand
Fax +66(2)5538545; E-mail: charnsak@cri.or.th
Received: 28.03.2014; Accepted after revision: 01.05.2014
A number of examples have shown the utility of the clas-
Abstract: Halomonochloride compounds (ClCl, BrCl, ICl) gener-
sical electrophilic aromatic halogenation for the installa-
ated in situ from N-halosuccinimide and catalytic chlorotrimethyl-
tion of a halogen atom. Several procedures employ Cl2,
Br2, I2, and interhalogen compounds (ICl and IBr) as the
silane (TMSCl, 0.1 equiv) can efficiently halogenate aromatic
compounds to give halogenated products in good to excellent yields
and selectivities. The reaction can be carried out at room tempera- electrophilic halogenating reagents. However, N-chloro-
ture or at lower temperatures, requires only one hour, is practical to
apply to a wide range of substrates, and provides a simple access to
a variety of haloarene compounds.
succinimide (NCS), N-bromosuccinimide (NBS), and
N-iodosuccinimide (NIS) have become more common
and convenient alternatives, especially to Cl2, Br2, and in-
terhalogens, which are toxic and more difficult to handle.
Key words: interhalogens, electrophilic aromatic halogenation,
isocryptolepine, chlorotrimethylsilane, N-halosuccinimide
For some unreactive substrates, the employment of cata-
lysts is necessary to promote the halogenation reaction.
These catalysts include Lewis acids, such as AlCl3,4
ZrCl4,5 AuCl3,6 and FeCl3 and protic acids, namely TFA,8
AcOH,9 p-TsOH,10 and HClO4.11 Moreover, heat and/or
stoichiometric amounts of promoters may be needed un-
der certain conditions.12 For reactions utilizing metal
Lewis acids, trace amounts of metal may remain in the
product, which can be an important concern especially in
the pharmaceutical industry where final products with the
complete absence of trace metal are extremely important.
Due to these restrictions and limitations, a mild, practical,
and metal-free electrophilic aromatic halogenation is still
actively investigated and remain a highly desirable proto-
col.
7
Halogen-substituted aromatic compounds are of major in-
terest because they find many applications as important
building blocks for the preparation of organometallic
reagents1 and as substrates for various cross-coupling re-
actions.2 In addition, halogenated aromatic compounds
display properties which may find various uses in the
pharmaceutical, agrochemical, and medicinal industries.3
In fact, several well-known and important drugs contain
halogen atoms as the crucial part of their structures (Fig-
ure 1).
As mentioned previously, protic acids are known to acti-
vate N-halosuccinimides (NXSs) in aromatic halogena-
tions. Recently, Shi13 and Mahajan14 have shown that
halide ions from metal halide salts (LiBr and NaCl) can
react with NBS or NCS to generate Br2 or Cl2 in situ. In-
spired by our recent work using a chlorotrimethylsilane
(TMSCl)–LiBr combination in wet MeCN for the in situ
production of HBr,15 we envisioned that TMSCl in wet
solvent could provide protons and chloride ions (as HCl),
which in the presence of NXS may generate interhalogen
XCl in situ for electrophilic aromatic halogenations as
shown in Scheme 1.
N
Cl
I
O
H
N
Cl
HO
I
I
OH
NH2
O
I
O
N
O
H
(S)-thyroxine
(thyroid hormone)
aripiprazole
(anti-psychotic)
CO2Me
N
Cl
S
To examine the possibility of the proposed reaction,
4-bromoanisole (1a) was selected as the substrate for
screening with NCS as the halogenating agent(Table 1).
clopidogrel
(antiplatelet agent)
Figure 1 Examples of halogen-containing drugs
As seen in Table 1, we found that indeed the electrophilic
aromatic chlorination could be effected using TMSCl and
NCS. Both CH2Cl2 and DCE were found inefficient for
the chlorination (entries 1 and 2). The reaction was less ef-
SYNLETT 2014, 25, 1769–1775
Advanced online publication: 05.06.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378225; Art ID: st-2014-u0267-l
© Georg Thieme Verlag Stuttgart · New York

1770
T. Maibunkaew et al.
LETTER
O
X
R
H
N
O
R
or TMSCl
X
trace HCl
(from hydrolysis
of TMSCl)
N
O
X
direct electrophilic
aromatic halogenation
O
Cl
(from HCl)
electrophilic
aromatic halogenation
X
Cl
interhalogen
Scheme 1 Proposed generation of interhalogens from TMSCl
ficient when conducted in ethereal solvents, including di- further when performed in solvents such as MeNO2 and
ethyl ether and THF (entries 3 and 4). When a non-polar MeCN which provided a range of noticeably better con-
solvent such as hexane was employed, the reaction gave versions (entries 7–11). In these solvents, the reactions
no conversion at all (entry 5). The reaction became more proceeded well even at 0 °C using one equivalent of NCS
efficient when conducted in EtOH (entry 6), which pro- with conversions up to 97% in as little as 30 minutes. In
vided a 56% conversion. The reaction could be improved addition, the amount of TMSCl could be reduced to only
0.1 equivalent, resulting in up to 96% conversion when
conducting the reaction in MeCN at room temperature for
one hour (entry 11). When anhydrous MeCN was used,
the conversion was lower (47%), indicating that the pres-
Table 1 Optimization of Chlorination of 4-Bromoanisole
OMe
OMe
Cl
ence of water was crucial for an efficient reaction (entry
12). In the absence of TMSCl, no conversion was ob-
served (entry 13), which proved that it was necessary for
the reaction. In addition to TMSCl, tert-butyldimethyl-
silyl chloride (TBSCl) was also attempted and found to ef-
fect a lower conversion (entry 14), which may be
attributed to the slower rate of hydrolysis due to steric hin-
drance, hence lowering the effective concentration of
HCl. We next attempted the reaction with 0.1 equivalent
of concd HCl which was found to give 73% conversion
(entry 15). This result seemed to confirm the necessary
role of HCl (Scheme 1) in our halogenation with NCS.
Other protic acids were also attempted for comparison
(entry 16) and their efficiency was found to be inferior to
TMSCl, giving conversions ranging from 4% to 29%.
NCS (1.0 equiv), R3SiCl
conditions
Br
Br
1a
2a-Cl
Entry Solventa
Acid (Equiv)
Temp Time Conversionb
(°C) (min) (%)
1
2
CH2Cl2
DCE
TMSCl (1.0)
TMSCl (1.0)
TMSCl (1.0)
TMSCl (1.0)
TMSCl (1.0)
TMSCl (1.0)
TMSCl (1.0)
TMSCl (1.0)
TMSCl (1.0)
TMSCl (1.0)
TMSCl (0.1)
TMSCl (0.1)
−
0
30
30
30
30
30
30
30
30
30
30
60
60
60
60
60
60
20
12
0
0
3
Et2O
0
4
THF
0
9
5
hexane
EtOH
0
0
6
0
56
80
97
75
95
96
47
0
In general, the reaction was equally efficient in both
MeNO2 and MeCN, however the latter is preferred for be-
ing more easily removable, promoting the practicality of
the reaction. Therefore, MeCN was chosen as the solvent
for our optimized conditions with 0.1 equivalent of
TMSCl and 1.0 equivalent of halogenating agent (NCS,
NBS or NIS) at room temperature for one hour.
7
MeNO2
MeNO2
MeCN
MeCN
MeCN
MeCNc
MeCN
MeCN
MeCNc
MeCN
0
8
r.t.
0
9
10
11
12
13
14
15
16
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
We next investigated the scope of the reaction, and the re-
sults are summarized in Table 2. Several substrates could
be easily and effectively halogenated with NCS, NBS, and
NIS under the general and optimized conditions. In all
cases, the reactions were conducted at room temperature
and in most cases they were complete within one hour.
For 4-bromoanisole, the reaction proceeded readily to
give 2a-Cl or 2a-Br in excellent yields (entry 1). For an-
isole, the reaction proceeded readily with NCS or NBS to
give the desired products in excellent yields as regioiso-
meric mixtures with preference for the p-halogenated
products (entry 2). Propargylic ether 1c could be haloge-
nated with NCS or NBS to give the desired products in
excellent yields and regioselectivities (entry 3). It is espe-
TBSCl (0.1)
HCl (0.1)d
53
73
protic acidse (0.1) r.t.
4–29
a Analytical reagent grade solvents were used except where indicated.
b Determined by 1H NMR.
c Anhyd MeCN was used.
d Concd HCl was used.
e Protic acids were employed: Si-TsOH (conversion 15%), p-TsOH
(conversion 10%), TfOH (conversion 29%) and TFA (conversion
4%).
Synlett 2014, 25, 1769–1775
© Georg Thieme Verlag Stuttgart · New York

LETTER
Practical and Metal-Free Electrophilic Aromatic Halogenation
1771
cially noteworthy that no addition of the interhalogen to For aniline derivatives (entries 13–15), the reactions pro-
the alkyne was observed with NCS or NBS. However, for ceeded as expected to give the desired products in all cas-
4-iodoanisole (1d), only NBS provided the desired prod- es. For the unprotected N-methylaniline, the reaction with
uct in 77% yield, whereas no conversion was observed NCS gave only 21% of the expected p-chloro product
with NCS. As for multiply oxygenated substrates, the re- (2m-Cl) along with other unidentified by-products, possi-
actions generally proceeded smoothly and provided the bly a mixture of overchlorinated compounds. For the re-
expected products in good to excellent yields and excel- action with NBS, p-bromo product 2m-Br was obtained
lent regioselectivities (entries 5–11). It is worth to men- in 66% yield as well as 6% of dibrominated product 2m-
tion that for the highly electron-rich 1,3,5- diBr and other inseparable unidentified by-products (en-
trimethoxybenzene (1j), we also conducted the reaction try 13). For anilines 1n and 1o, the reactions proceeded
without TMSCl for comparison. We found that the reac- smoothly to furnish the desired halogenated products in
tion with TMSCl proceeded to a full conversion within excellent overall yields as regioisomeric mixtures (entries
one hour to give the monochlorinated and dichlorinated 14 and 15). For both N-protected homoveratrylamine de-
products in 93% and 4% yields (Table 2, entry 10), while rivatives 1p and 1q, the reactions were smooth to give the
for the reaction without TMSCl we observed 88% conver- corresponding chloro- and iodo products in good to excel-
sion within the same amount of time. These results dem- lent yields for 1p (entry 16) and good yields of the corre-
onstrated the effect of TMSCl in accelerating the reaction sponding chloro- and bromo products for 1q (entry 17). It
to a full conversion. For toluene, the reaction proceeded should be noted that the acid-labile Boc group could with-
uneventfully to give the desired products in moderate stand our conditions, and we observed very clean conver-
yields as regioisomeric mixtures with some remaining sions in the crude reaction mixtures.
starting material (entry 12).
Table 2 Scope of TMSCl-Catalyzed Halogenation
NXS, TMSCl
R
R
MeCN, r.t.
X
1
2
Entry
1
Substrates (1)
Products (2)/Yieldsa
OMe
OMe
B
X = Cl: 2a-Cl; A = Br, B = Cl; 88%
2a-diCl; A = B = Cl; 11%
X = Br: 2a-Br; A = B = Br; 95%
Br
A
A
1a
X = Cl: 2b-p-Cl; A = Cl, B = H; 86%
2b-o-Cl; A = H, B = Cl; 11%
X = Br: 2b-p-Br; A = Br, B = H; 81%
2b-o-Br; A = H, B = Br; 2%
OMe
OMe
B
2
1b
2b-diBr; A = B = Br; 9%
O
B
X = Cl: 2c-p-Cl; A = Cl, B = H; 88%
2c-o-Cl; A = H, B = Cl; 7%
O
3
4
X = Br: 2c-p-Br; A = Br, B = H; 91%
2c-o-Br; A = H, B = Br; 4%
A
A
1c
OMe
OMe
B
X = Cl: 2d-Cl; A = I, B = Cl; NR
X = Br: 2d-Br; A = I, B = Br; 77%
2d-diBr; A = B = Br; 8%
I
1d
MeO
OH
MeO
MeO
OH
X = Cl: 2e-Cl; A = Cl; 91%
X = Br: 2e-Br; A = Br; 70%
5
6
MeO
A
1e
B
MeO
OMe
X = Cl: 2f-Cl; A = Cl, B = H; 64%
2f-diCl; A = B = Cl; 5%
X = Br: 2f-Br; A = Br, B = H; 77%
MeO
A
OMe
1f
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1769–1775

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T. Maibunkaew et al.
LETTER
Table 2 Scope of TMSCl-Catalyzed Halogenation (continued)
NXS, TMSCl
R
R
MeCN, r.t.
X
1
2
Entry
7
Substrates (1)
Products (2)/Yieldsa
MeO
Br
MeO
MeO
Br
A
X = Cl: 2g-Cl; A = Cl; 99%
X = Br: 2g-Br; A = Br; ≤99%
X = I: 2g-I; A = I; 86%
1g; 9%
MeO
1g
MeO
OMe
OMe
OMe
MeO
A
OMe
B
X = Cl: 2h-Cl; A = Cl, B = H; 73%
X = Br: 2h-Br; A = Br, B = H; 82%
X = I: 2h-I; A = I, B = H; 62%
2h-diI; A = B = I; 7%
8
9
Cl
Cl
1h
MeO
MeO
A
OMe
B
X = Cl: 2i-Cl; A = Cl, B = H; 75%
X = Br: 2i-Br; A = Br, B = H; 89%
X = I: 2i-I; A = I, B = H; 59%
2i-diI; A = B = I; 6%
Br
Br
1i
MeO
MeO
A
OMe
B
X = Cl: 2j-Cl; A = Cl, B = H; 93%
2j-diCl; A = B = Cl; 4%
X = Br: 2j-Br; A = Br, B = H; 58%
2j-diBr; A = B = Br; 6%
10
11
OMe
OMe
1j
X = Cl: 2k-Cl; A = Cl, B = H; 73%
2k-diCl; A = B = Cl; 15%
1k; 2%
A
B
O
O
O
O
X = Br: 2k-Br; A = Br, B = H; 76%
2k-diBr; A = B = Br; 16%
1k
X = Cl: 2l-p-Cl; A = Cl, B = H; 33%
2l-o-Cl; A = H, B = Cl; 22%
1l; 43%
X = Br: 2l-p-Br; A = Br, B = H; 57%
2l-o-Br; A = H, B = Br; 24%
1l; 11%
Me
Me
12b
A
B
1l
NHMe
NHMe
B
X = Cl: 2m-Cl; A = Cl, B = H; 21%
X = Br: 2m-Br; A = Br, B = H; 66%
2m-diBr; A = B = Br; 6%
13
14
A
A
1m
NHAc
X = Cl: 2n-p-Cl; A = Cl, B = H; 75%
2n-o-Cl; A = H, B = Cl; 24%
X = Br: 2n-p-Br; A = Br, B = H; 94%
2n-o-Br; A = H, B = Br; 4%
NHAc
B
1n
NHTs
X = Cl: 2o-p-Cl; A = Cl, B = H; 79%
2o-o-Cl; A = H, B = Cl; 14%
X = Br: 2o-p-Br; A = Br, B = H; 79%
1o; 12%
NHTs
B
15
16
A
1o
MeO
MeO
MeO
X = Cl: 2p-Cl; A = Cl; 76%
X = I: 2p-I; A = I; 91%
NHCO2Et
MeO
NHCO2Et
A
1p
Synlett 2014, 25, 1769–1775
© Georg Thieme Verlag Stuttgart · New York

LETTER
Practical and Metal-Free Electrophilic Aromatic Halogenation
1773
Table 2 Scope of TMSCl-Catalyzed Halogenation (continued)
NXS, TMSCl
R
R
MeCN, r.t.
X
1
2
Entry
17
Substrates (1)
Products (2)/Yieldsa
MeO
MeO
X = Cl: 2q-Cl; A = Cl; 74%
NHBoc
X = Br: 2q-Br; A = Br; 75%
MeO
NHBoc
MeO
A
1q
OMe
O
OMe
H
X = Cl: 2r-Cl; A = Cl, B = CHO; 87%
2r-diCl; A = B = Cl; 2%
X = Br: 2r-Br; A = Br, B = CHO; 99%
A
B
18
19
MeO
OMe
MeO
OMe
O
1r
O
A
X = Cl: 2s-Cl; A = Cl; complex mixture
X = Br: 2s-Br; A = Br; 87%
1s; 7%
MeO
MeO
1s
Br
A
Br
X = Cl: 2t-Cl; A = Cl; 98%
N
20
21
X = Br: 2t-Br; A = Br; complex mixture
H
N
H
1t
O2N
A
O2N
X = Cl: 2u-Cl; A = Cl; 83%
X = Br: 2u-Br; A = Br; complex mixture
N
H
N
H
1u
NH
B
NH
X = Cl: 2v-p-Cl; A = Cl, B = H; 56%
2v-o-Cl; A = H, B = Cl; 16%
X = Br: 2v-p-Br; A = Br, B = H; 79%
2v-diBr; A = B = Br; 15%
X = I: 2v-p-I; A = I, B = H; 90%
22
N
N
PhO2S
PhO2S
A
1v
a Isolated yield.
b Regioselectivities and yields were determined by GC using p-anisaldehyde as the internal standard.
For compound 1r (2,4,6-trimethoxybenzaldehyde, entry Finally, we attempted our halogenation with compound
18), we found the reaction to proceed cleanly to give both 1v which has been used as a synthetic precursor to
chloro- and bromo products in excellent efficiencies. For isocryptolepine analogues,16 compounds possessing anti-
the reaction with NCS, however, a trace amount (ca. 2%) malarial and anticancer activities17 (entry 22). As seen in
of chlorodeformylation product, which is the same com- Table 2, the chlorination of 1v with NCS afforded two iso-
pound as 2j-diCl, was also obtained. As for compound 1s, meric products 2v-p-Cl (56%) and 2v-o-Cl (16%). The re-
the reaction with NCS afforded a complex mixture, while action of 1v with NBS afforded the desired 2v-p-Br in
the reaction with NBS gave 95% yield of the desired prod- good yield (79%) along with dibrominated product 2v-
uct 2s-Br (entry 19). Our halogenation conditions could diBr in 15% yield. The reaction of compound 1v with NIS
be applied to heterocycles as shown in entries 20 and 21. proceeded smoothly to provide only 2v-p-I as the single
For indole 1t, we found the reactions proceeded normally product in 90% yield. These examples highlight the con-
with NCS to give indole 2t-Cl in 98% yield (entry 20). venience and efficiency of our halogenation procedure in
However, the reaction with NBS only showed decompo- installing halogen atoms onto compounds of advanced
sition. The same was also observed with indole 1u, where structures, which will be useful in preparing compounds
we could obtain the desired indole 2u-Cl in excellent for biological activity studies. Specifically, isocrypto-
yield while decomposition was observed with NBS (entry lepine analogues containing halogen atoms at various po-
21).
sitions in the structures have been evaluated for their
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1769–1775

1774
T. Maibunkaew et al.
LETTER
activities against both drug-sensitive and drug-resistant which make this procedure a very robust and attractive
strains recently.17e
method for halogenating aromatic compounds.
Further practicality of this procedure is shown in Scheme
2; anisole could be halogenated sequentially in one pot by
controlling the order of addition of NXS to give the de-
sired dihalogenated 2b-Cl-Br with high regiocontrol in
90% yield based on 1H NMR using 1,3,5-trimethoxyben-
zene as the internal standard.
Acknowledgment
This work was supported by the Chulabhorn Research Institute
(CRI), the Chulabhorn Graduate Institute (CGI), and the Center of
Excellence on Environmental Health and Toxicology (EHT), Mini-
stry of Education, for which we are grateful.
NCS (1 equiv), TMSCl (0.1 equiv)
OMe
OMe
Supporting Information for this article is available online
MeCN, r.t., 1 h
at
http://www.thieme-connect.com/products/ejournals/journal/
then NBS (1 equiv), r.t., 1 h
10.1055/s-00000083.SunogIpimrfiantoSuIpg
n
fonirtat
ori
Cl
Br
90% in one pot
2b-Cl-Br
1b
References and Notes
Scheme 2 Sequential halogenation of anisole
(1) (a) Davis, S. G. In Organotransition Metal Chemistry:
Applications to Organic Synthesis; Pergamon Press: Oxford,
UK, 1982. (b) Cannon, K. C.; Krow, G. R. In Handbook of
Grignard Reagents; Dekker: New York, 1996.
(2) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000,
100, 3009. (c) Meijere, A.; Meyer, F. E. Angew. Chem., Int.
Ed. 1994, 33, 2379.
(3) Hernandes, M. Z.; Cavalcanti, S. M. T.; Moreira, D. R. M.;
de Azevedo, Jr. W. F.; Leite, A. C. L. Curr. Drug Targets
2010, 11, 303.
(4) Kamigata, N.; Satoh, T.; Yoshida, M.; Matsuyama, H.;
Kameyama, M. Bull. Chem. Soc. Jpn. 1988, 61, 2226.
(5) (a) Zhang, Y.; Shibatomi, K.; Yamamoto, H. Synlett 2005,
2837. (b) Zhang, Y.; Yamamoto, H. Eur. Patent 1928599B1,
2006.
As proposed in Scheme 1, we set out to prove the exis-
tence of interhalogen compounds (XCl) generated in situ
from NXS and TMSCl by performing a reaction with al-
cohol 3, which we have shown previously that it could be
converted into furan 4 using ICl.18 In the current reaction,
we subjected compound 3 to ICl generated from NIS (2.0
equiv) and TMSCl (2.0 equiv) in CHCl3 at room temper-
ature, and we obtained the expected iodofuran 4 in 37%
yield unoptimized (Scheme 3).
O
OH
NIS (2.0 equiv)
Cl
TMSCl (2.0 equiv)
CHCl3, r.t., 2 h
37%
(6) (a) Mo, F.; Yan, J. M.; Qiu, D.; Li, F.; Zhang, Y.; Wang, J.
Angew. Chem. Int. Ed. 2010, 49, 2028. (b) Qiu, D.; Mo, F.;
Zheng, Z.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 5474.
(7) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.;
Horaguchi, T. Chem. Lett. 2003, 32, 932.
I
3
4
Scheme 3 ICl-promoted cyclization of 3 with NIS and TMSCl
(8) Castanet, A.-S.; Colobert, F.; Broutin, P.-E. Tetrahedron
Lett. 2002, 43, 5047.
Additionally in the beginning of the reaction, the solution
of alcohol 3 and NIS appeared light orange. Once TMSCl
was added to the reaction, it immediately turned dark
brown. Upon completion, the reaction was quenched with
aqueous sodium metabisulfite (Na2S2O5), causing the col-
or to disappear and indicating that the interhalogen spe-
cies was reduced. All of these observations support our
proposal that interhalogen species are generated during
the reaction.
(9) Yu, G.; Mason, H. J.; Wu, X.; Endo, M.; Douglas, J.;
Macora, J. E. Tetrahedron Lett. 2001, 42, 3247.
(10) Bovonsombat, P.; Ali, R.; Khan, C.; Leykajarakul, J.;
Pla-on, K.; Aphimanchindakul, S.; Pungcharoenpong, N.;
Timsuea, N.; Arunrat, A.; Punpongjareorn, N. Tetrahedron
2010, 66, 6928.
(11) Goldberg, Y.; Alper, H. J. Org. Chem. 1993, 58, 3072.
(12) Schmid, H. Helv. Chim. Acta 1946, 29, 1144.
(13) Shao, L.-X.; Shi, M. Synlett 2006, 1269.
(14) Mahajan, T.; Kumar, L.; Dwivedi, K.; Agarwal, D. D.
Ind. Eng. Chem. Res. 2012, 51, 3881.
(15) Bunrit, A.; Ruchirawat, S.; Thongsornkleeb, C. Tetrahedron
Lett. 2011, 52, 3124.
In conclusion, we have demonstrated that TMSCl could
be used as a universal and powerful catalyst which in
combination with N-halosuccinimide (NXS) leads to the
formation of interhalogen compounds (XCl) in MeCN.19
The interhalogens generated by this innovative combina-
tion can be used to efficiently halogenate aromatic com-
pounds to give the desired haloarenes free of metal
contaminant in good to excellent efficiencies. The current
procedure presents a significant improvement for electro-
philic aromatic halogenations, which is highlighted by the
practicality in conducting the reaction, the widely avail-
able reagents (NCS, NBS, NIS) and catalyst (TMSCl),
and the applicability to a wide range of substrates, all of
(16) Tummatorn, J.; Thongsornkleeb, C.; Ruchirawat, S.
Tetrahedron 2012, 68, 4732.
(17) (a) Sharaf, M. H. M.; Schiff, Jr. P. L.; Tackie, A. N.; Phoebe,
Jr. C. H.; Martin, G. E. J. Heterocycl. Chem. 1996, 33, 239.
(b) Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.;
Vlietinck, A. Tetrahedron Lett. 1996, 37, 1703. (c) Grellier,
P.; Ramiaramanana, L.; Millerioux, V.; Deharo, E.;
Schrével, J.; Frapper, F.; Trigalo, F.; Bodo, B.; Pousset, J.-L.
Phytother. Res. 1996, 10, 317. (d) Baelen, G. V.; Hostyn, S.;
Dhooghe, L.; Tapolcsányi, P.; Mátyus, P.; Lemière, G.;
Dommisse, R.; Kaiser, M.; Brun, R.; Cos, P.; Maes, L.;
Hajós, G.; Riedl, Z.; Nagy, I.; Maes, B. U. W.; Pieters, L.
Bioorg. Med. Chem. 2009, 17, 7209. (e) Whittell, L. R.;
Synlett 2014, 25, 1769–1775
© Georg Thieme Verlag Stuttgart · New York

LETTER
Practical and Metal-Free Electrophilic Aromatic Halogenation
1775
Batty, K. T.; Wong, R. P. M.; Bolitho, E. M.; Fox, S. A.;
Davis, T. M. E.; Murray, P. E. Bioorg. Med. Chem. 2011, 19,
7519.
washed with sat. aq NaCl, dried over Na2SO4 and
concentrated. The crude material was purified by flash SiO2
column eluted with 5–10% EtOAc–hexane to give a mixture
of 4-bromo-2-chloro-1-methoxybenzene (2a-Cl) and 2,4-
dichloro-1-methoxybenzene (2a-diCl): 237.0 mg yield
(88% of 2a-Cl and 11% of 2a-diCl, based on NMR ratio 2a-
Cl/2a-diCl = 7.1:1.0; as a pale yellow solid). IR (neat):
2854, 1288, 1222, 1028 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 7.49 (d, J = 2.4 Hz, 1 H), 7.36 (d, J = 2.4 Hz, 0.15 H,
minor), 7.32 (dd, J = 8.7, 2.4 Hz, 1 H), 7.19 (dd, J = 9.0, 2.7
Hz, 0.14 H, minor), 6.84 (d, J = 8.7 Hz, 0.15 H, minor), 6.79
(d, J = 8.7 Hz, 1 H), 3.87 (s, 3 H). 13C NMR (75 MHz,
CDCl3): δ = 154.4, 132.6, 130.5, 129.9 (minor), 127.6
(minor), 123.6, 113.3, 112.8 (minor), 112.5, 56.34, 56.28
(minor).
(18) Thongsornkleeb, C.; Rabten, W.; Bunrit, A.; Tummatorn, J.;
Ruchirawat, S. Tetrahedron Lett. 2012, 53, 6615.
(19) General Procedure for the Electrophilic Aromatic
Halogenation; 4-Bromo-2-chloro-1-methoxybenzene
(2a-Cl) and 2,4-Dichloro-1-methoxybenzene (2a-diCl;
Ref 20): To a solution of 4-bromoanisole (1a; 200.8 mg,
1.09 mmol, 1.0 equiv) in MeCN (2 mL) was added N-
chlorosuccinimide (NCS; 158.3 mg, 1.19 mmol, 1.1 equiv)
at r.t. to give a slightly cloudy mixture. Chlorotrimethyl-
silane (TMSCl; 14 μL, 0.11 mmol, 0.1 equiv) was then
added dropwise to the reaction mixture. Within a few
minutes, the reaction mixture became clear pale yellow
solution. The mixture was stirred continuously at r.t. for 1 h
and H2O was added to it. The separated aqueous layer was
extracted with EtOAc. The combined organic phases were
(20) Garcia, P.; Lau, Y. Y.; Perry, M. R.; Schafer, L. L. Angew.
Chem. Int. Ed. 2013, 52, 9144.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1769–1775

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