Mild preparation of haloarenes by ipso-substitution of arylboronic acids with N-halosuccinimides

Article abstract of DOI:10.1055/s-1998-1614

Aryl and heteroaryl boronic acids react with N-iodosuccinimide and N-bromosuccinimide to give the corresponding iodo-and bromo- arenes in good to excellent yields. The reaction is usually highly regioselective and yields only the ipso-substituted product. Esters of arylboronic acids react similarly, but less readily.

Full text of DOI:10.1055/s-1998-1614

February 1998
SYNLETT
141
Mild Preparation of Haloarenes by Ipso-Substitution of Arylboronic Acids with
N-Halosuccinimides
Christoph Thiebes, G. K. Surya Prakash,* Nicos A. Petasis,* George A. Olah*
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1661, USA
Received 20 October 1997
Abstract: Aryl and heteroaryl boronic acids react with N-iodo-
succinimide and N-bromosuccinimide to give the corresponding iodo-
and bromo- arenes in good to excellent yields. The reaction is usually
highly regioselective and yields only the ipso-substituted product. Esters
of arylboronic acids react similarly, but less readily.
NIS. The formation of NIS is rapid and an excess of sodium iodide is
not needed. The fact that sodium iodide can be employed is important,
since it is the most common source for radioactive iodine.
It was recently reported that alkenyl boronic acids can be converted into
1
alkenyl halides by reaction with N-halosuccinimides. The reaction is
believed to proceed via a boron activation / direct displacement
mechanism, affording geometrically pure products with retention of
configuration. Herein we report the analogous conversion of arylboronic
2
acids to the corresponding haloarenes. Arylboronic acids are readily
available and easy to handle compounds, which have recently become
important substrates in organic synthesis as aryl group donors in the
3
Suzuki coupling reaction. They are generally less reactive than alkenyl
boronic acids and are not expected to react with N-halosuccinimides via
an addition / elimination mechanism.
Haloarenes are valuable synthetic intermediates and various methods
for their preparation have been developed. While electrophilic aromatic
halogenation works well for the preparation of chloroarenes and
bromoarenes, the direct iodination of arenes with iodine is generally not
4
feasible and a number of different methods for the preparation of
5
iodoarenes have been developed. These include: (a) the use of strong
6
oxidizing reagents to activate the halogens, (b) various methods
7
involving the use of highly reactive and toxic aromatic mercury and
8
9
thallium compounds, and (c) the Sandmeyer reaction, involving the
regioselective introduction of chlorine, bromine and iodine via aryl
diazonium ions under acidic conditions.
The procedure reported herein, involving the use of N-halosuccinimides
as sources of electrophilic halogen, is milder and complementary to the
above methods and may be applied when harsh reaction conditions must
be avoided. In certain cases the preparation of haloarenes from aryl
boronic acids may not be useful since the aryl boronic acids themselves
are prepared from haloarenes. However, a number of substituted
10
Reaction temperatures and times reflect the reactivity of arylboronic
acids. Although the reaction was typically performed under reflux
conditions, activated and mildly deactivated substrates reacted well
even at room temperature. Where side reactions such as
polyhalogenation were possible, reactions were carried out at room
temperature and with equimolar amounts of NIS. However, for 1f, it
was not possible to avoid the formation of the 3,4-disubstituted anisole,
due to ring activation.
arylboronic acids are available via a directed metallation approach. In
addition, the boronic acid functionality could serve as a protecting group
for haloarenes, which can be easily regenerated under mild conditions
by the reaction with N-halosuccinimides. This process may be
particularly useful for the preparation of radiolabelled iodoarenes,
which have found many applications as research tools and as
11
components of diagnostic and therapeutic agents. Typically, the
preparation of these compounds require the efficient and regioselective
introduction of radioactive iodine in one of the final steps of a multi-step
As shown below, several heteroaryl boronic acids were also converted
to the corresponding iodides. These systems were generally more
reactive and the reactions were performed at room temperature. On the
other hand, the corresponding furyl and pyrrole derivatives gave
complex mixture of products.
125
synthesis by using Na I.
Several examples of iodoarenes (2) synthesized from aryl boronic acids
12
(1) using N-iodosuccinimide (NIS) in acetonitrile are shown below.
Generally, only the ipso-substituted iodoarenes were observed as
products, irrespective of the influence of directing groups on the
aromatic ring. The method tolerates various functionalities and affords
the product in good to excellent yields except for the strongly
deactivated 3-nitrophenylboronic acid (1g). NIS can also be generated
in situ by reacting sodium iodide with N-chlorosuccinimide in
acetonitrile. The yields for this procedure are the same within
experimental error as for the procedure with commercially available
Similarly, reaction of arylboronic acids with NBS gave bromoarenes in
moderate to good yields. The bromination procedure with NBS is
similar to that described for the iodination with NIS. Yields and reaction
times show the same tendency as for the reaction with NIS. However, in
the cases of strongly activated 2- and 3-thienylboronic acids, even at
room temperature and when only one equivalent of NBS was employed,
di- and tri-substituted thiophenes were the major products.

142
LETTERS
SYNLETT
Acknowledgments
We gratefully acknowledge the financial support by the Loker
Hydrocarbon Research Institute, by the National Institutes of Health
(grant GM 45970 to NAP), the donors of the Petroleum Research Fund
administered by the American Chemical Society (grant 30941-AC to
NAP), and by a Konrad-Adenauer Foundation fellowship to CT. We
also thank I. A. Zavialov and A. K. Yudin for their help.
References and Notes
1)
2)
Petasis, N. A.; Zavialov, I. A. Tetrahedron Lett. 1996, 37, 567.
(a) Köster, R., in Houben-Weyl, 4th ed., Köster, R., ed.; Thieme:
Stuttgart, 1982; Vol. E13a, pp 617.
(b) Negishi, E., in Comprehensive Organometallic Chemistry,
Wilkinson, G., Stone, F. G. A. and Abel, E. W., ed.; Pergamon
Press: New York, 1983; Vol. 7, pp 323.
3)
4)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
de la Mare, P. B. D. Electrophilic Halogenation; Cambridge
University Press: Cambridge, 1976.
5)
Olah, G. A.; Wang, Q.; Sandford, G.; Prakash, G. K. S. J. Org.
Chem. 1993, 58, 3194.
6)
7)
8)
Merkushev, E. B. Synthesis 1988, 923.
Fish, R. W.; Rosenblum, M. J. Org. Chem. 1965, 1253.
McKillop, A.; Hunt, J. D.; Zelesko, M. J.; Fowler, J. S.; Taylor, E.
C.; Mc Gillivray, G.; Kienzle, F. J. Am. Chem. Soc. 1971, 93,
4841.
9)
Sandmeyer, T. Chem. Ber. 1884, 1633.
10) Snieckus, V. Chem. Rev. 1990, 90, 879.
11) Dewanjee, M. K. Radioiodination: Theory, Practice, and
Biomedical Applications; Kluwer Academic Publishers: Boston,
1992, pp
12) General Procedure: To a solution of arylboronic acid (1 mmol) in
dry acetonitrile (5 mL) N-iodosuccinimide (1.0-2.0 mmol) (or a
mixture of sodium iodide N-chlorosuccinimide) was added and
the mixture was stirred at the given temperature protected from air
and light until completion of the reaction was confirmed by TLC
(silica gel, hexanes : ethyl acetate = 1 : 1). After the reaction was
completed, the reaction mixture was extracted with pentane (3 x
50 ml) and the collected pentane extracts were washed with
The analogous reaction of N-chlorosuccinimide with arylboronic acids
gave only traces of the desired chloroarenes, even when bases were
added to activate the arylboronic acids.
In order to enhance the synthetic utility of the reported method, the
reaction of arylboronic esters with N-halosuccinimides was also
investigated. It was found that 2-phenyl-1,3,2-dioxaborinane reacts with
NIS slowly affording iodobenzene in only moderate yield (30 %). Also,
with NBS, after refluxing for 72 h in acetonitrile only traces of
bromobenzene and dibromobenzene were detected.
distilled water, aqueous NaHSO (1 M), aqueous NaHCO (1 M)
3
3
and distilled water and finally dried over MgSO . The residue
4
obtained by evaporation of the solvent in vacuo was further
purified by column chromatography (silica gel / pentane).
Evaporation of the eluent afforded the pure product. The
spectroscopic data of the products were compared to those of
authentic samples or to literature data.
Overall, the reported procedure is convenient and practical, giving the
ipso-substituted iodo- and bromo- arenes from the corresponding
arylboronic acids, without the use of highly reactive halogens, strong
oxidizing agents or toxic heavy metals. Moreover, it gives further
1
support to a mechanism involving boron-activation / substitution.