Mild silver(I)-mediated regioselective iodination and bromination of arylboronic acids

Article abstract of DOI:10.1021/ol100537x

A convenient and regioselective silver(I)-mediated electrophilic iodination and bromination reaction of arylboronic acids has been developed. The boronic acid does not require protection prior to the reaction, which can be performed on a multigram scale with moderate to excellent yields. A mild, simple, and effective method is disclosed to provide ortho-haloarylboronic acids that can be used as useful intermediates in selective sequential Suzuki-Miyaura cross-coupling reactions to provide ortho-triaryl derivatives in good yields.

Full text of DOI:10.1021/ol100537x

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2480-2483
Mild Silver(I)-Mediated Regioselective
Iodination and Bromination of
Arylboronic Acids
Raed M. Al-Zoubi and Dennis G. Hall*
Department of Chemistry, Gunning-Lemieux Chemistry Centre, UniVersity of Alberta,
Edmonton, Alberta, T6G 2G2, Canada
dennis.hall@ualberta.ca
Received March 4, 2010
ABSTRACT
A convenient and regioselective silver(I)-mediated electrophilic iodination and bromination reaction of arylboronic acids has been developed.
The boronic acid does not require protection prior to the reaction, which can be performed on a multigram scale with moderate to excellent
yields. A mild, simple, and effective method is disclosed to provide ortho-haloarylboronic acids that can be used as useful intermediates in
selective sequential Suzuki-Miyaura cross-coupling reactions to provide ortho-triaryl derivatives in good yields.
Boronic acids have become an increasingly important class
of compounds for biological and synthetic applications1 due
to: (1) their interconvertibility between the sp2 and sp3 forms,
(2) their strong interaction with diol-containing compounds,
(3) their Lewis acidity, (4) their relatively low toxicity2
[phenylboronic acid: LD50, oral-rat ) 740 mg/kg], and (5)
their stability and commercial availability.
For these unique properties, boronic acids have been used
as pharmaceuticals,1-3 receptors in carbohydrate recogni-
tion,1,2 boron neutron capture therapy agents,1,2 catalysts,4
and synthetic reagents.5
For instance, AN-2690 (1, Figure 1) is a fluoroarene
boroxole-based broad-spectrum antifungal agent developed
specifically for the treatment of onychomycosis, a fungal
infection that affects fingers and toes, causing the nails to
become brittle and discolored with soreness of the surround-
ing skin.6a AN-2690 has retention of antifungal activity and
a nail penetration efficiency coefficient 50-fold higher than
that of topical ciclopirox.6b It is currently in phase II/III
clinical trials by the U.S. Food and Drug Administration.
This compound and other boronic acids such as bortezomib
have initiated significant interest in boron-based small
molecules in drug discovery.
Furthermore, boronic acids and their esters have been used
extensively not only as versatile intermediates in organic
synthetic transformations such as Suzuki-Miyaura5,7a and
Chan-Lam7b couplings, allylborations,7c,d and multicom-
ponent reactions for the synthesis of various amino acids7e,f
but also as efficient catalysts for cycloaddition, aldol, and
amidation reactions.4
(1) Hall, D. G., Ed. Boronic Acids; Wiley-VCH: Weinheim, 2005.
(2) Yang, W.; Gao, X.; Wang, B. Med. Res. ReV. 2003, 23, 346–368.
(3) (a) Winum, J. Y.; Innocenti, A.; Scozzafava, A.; Montero, J. L.;
Supuran, C. T. Bioorg. Med. Chem. 2009, 17, 3649–3652. (b) Collins, B. E.;
Sorey, S.; Hargrove, A. E.; Shabbir, S. H.; Lynch, V. M.; Anslyn, E. V. J.
Org. Chem. 2009, 74, 4055–4060. (c) Altamore, T. M.; Barrett, E. S.;
Duggan, P. J.; Sherburn, M. S.; Szydzik, M. L. Org. Lett. 2002, 4, 3489–
3491. (d) Riggs, J. A.; Hossler, K. A.; Smith, B. D.; Karpa, M. J.; Griffin,
G.; Duggan, P. J. Tetrahedron Lett. 1996, 37, 6303–6306
.
(4) (a) Ishihara, K. Tetrahedron 2009, 65, 1085–1109. (b) Georgiou, I.;
Ilyashenko, G.; Whiting, A. Acc. Chem. Res. 2009, 42, 756–768. (c) Al-
Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem., Int. Ed. 2008, 47,
2876–2879. (d) Arnold, K.; Batsanov, A. S.; Davies, B.; Whiting, A. Green
Chem. 2008, 10, 124–134. (e) Ishihara, K.; Yamamoto, H. Eur. J. Org.
Chem. 1999, 527–538. (f) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org.
Chem. 1996, 61, 4196–4197.
Direct amide bond formation is one of the few reactions
catalyzed by boronic acids. A recent survey revealed that
amide bond formation was not only one of the top 15
reactions currently used in the drug discovery industry but
10.1021/ol100537x  2010 American Chemical Society
Published on Web 05/07/2010

not successful. The reaction was hampered by the formation
of HI, which causes cleavage of the B(OH)2 group to provide
the iodoarene. While the halogenation of aromatic compounds
is one of the most widely studied reactions in the literature,14
a practical iodination of arylboronic acids to access iodinated
arylboronic acids has not been reported. Herein, we report a
convenient and effective method for mild and regioselective
iodination and bromination of free arylboronic acids. This
method provides the ortho-halogenated products in moderate
to high yield (43%-95%). The reaction is operationally simple,
requires no heating or cooling, and is easy to workup to provide
crude products in high purity. Moreover, the silver reagent can
easily be recycled from the reaction mixture as AgI or AgBr,
which can be used for other reactions.15
We initiated this project by looking for a mild and
convenient iodination agent. There have been a number of
reports on direct aromatic iodination;16 however, few Lewis
acids have been examined. The most common Lewis acids
are silver and mercuric salts in combination with I2 due to
the fact that silver and mercury can remove iodide efficiently
from solution by precipitation. We decided to explore
conditions with different solvents using 3-methoxyphenyl-
boronic acid as a model substrate. First, a combination of
silver sulfate and iodine was utilized as an iodinating agent
at room temperature. A brief optimization of solvent revealed
that ethanol and 1,2-ethanediol were the most suitable
solvents for the desired transformation. The iodine color
disappeared within a few minutes to provide the desired
product without ipso deboronation side product (Table 1,
entries 4 and 5). All other solvents were found to be
unsuitable for this reaction (Table 1, entries 1-3). Using
ethanol as a solvent, we examined the influence of different
reagents on iodination of 3-methoxyphenylboronic acid to
further establish the reaction conditions. We found that when
a mixture of Hg(OAc)2/I2 was used instead of Ag2SO4/I2 the
yield of ortho-iodination product 3 decreased and formation
of 10-15% of the ipso-iodination was observed (Table 1,
entry 7). Using AgNO3/I2 led to a similar result as Ag2SO4/
I2 (Table 1, entry 6). No ortho-iodination was observed with
NIS (Table 1, entry 8), while NIS in acetonitrile gave only
the ipso-iododeboronation product in excellent yield (Table
1, entry 9). Furthermore, when the reaction times exceed 3
min, further decomposition occurred, and less ortho-iodina-
tion product 3 was observed.
Figure 1. Structure of AN-2690 (5-fluoro-1,3-dihydro-1-hydroxy-
2,1-benzoxaborole) (1) and ortho-iodophenylboronic acid (2).
also identified as a priority research area by the American
Chemical Society (ACS) Green Chemistry Institute (GCI) and
several leading global pharmaceutical corporations.8 Conse-
quently, the development of efficient amidation methods with
high atom economy continues to be an important scientific
pursuit. In 2008, Hall and co-workers described the remarkable
activity of ortho-halophenylboronic acids as very active and
mild catalysts toward cycloaddition reactions and direct amide
bond formation at ambient temperature.4c ortho-Iodophenyl-
boronic acid 2 (Figure 1) is the most active of the ortho-
haloarylboronic acids. With an aim toward optimizing this
catalyst, we sought to develop new methods that would provide
a variety of substituted ortho-iodoarylboronic acids.
Even though arylboronic acids have been available for several
years, are easy to handle, and are relatively stable, they are
susceptible to chemoselectivity issues that render them difficult
to further derivatization after introduction of the boronic acid.
Their Lewis acidic nature makes them prone to react with
commonly used organic reagents such as strong acids, bases,
oxidants, and metal salts. This reactivity typically causes a
simple protodeboronation or an ipso substitution of the boronic
acid group, thus forming other products such as haloarenes,9
amidoarenes,10 and nitroarenes.11 These transformations are
believed to proceed via boron activation followed by an ipso
displacement mechanism. As a result of this reactivity, boronic
acids are rarely left intact after being carried through a number
of synthetic chemical reactions.12 Although direct bromination
and chlorination of arylboronic acids have been reported by
Kuivila and co-workers in 1962,13 their direct iodination was
(5) (a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147–168. (b)
Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457–2483.
(6) (a) Kumar, S.; Kimball, A. B. Expert Opin. InVest. Drugs 2009, 18
(6), 727–734. (b) Baker, S. J.; Zhang, Y. K.; Akama, T.; Lau, A.; Zhou,
H.; Hernandez, V.; Mao, W.; Alley, M. R. K.; Sanders, V.; Plattner, J. J.
J. Med. Chem. 2006, 49, 4447–4450.
(7) (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513. (b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.;
Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941–2944. (c)
Hall, D. G. Synlett 2007, 1644–1655. (d) Lachance, H.; Hall, D. G. Organic
Reactions; Denmark, S. E., Ed.; Wiley: New York, 2009; Vol. 73. (e)
Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445–446. (f)
Beenen, M. A.; Weix, D. J.; Ellman, J. A. J. Am. Chem. Soc. 2006, 128,
6304–6305.
The best yield of ortho-iodination product was obtained
when 1.1 equiv of Ag2SO4 or AgNO3 was used with 1.0
equiv of I2 (Table 1, entry 10). The reaction also worked
well on a multigram scale (Table 1, entry 12). Although the
stoichiometric use of metal salts should be avoided as much
as possible, it is tolerable for transformations that provide
(8) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer Jr, J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.;
Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411–420.
(9) (a) Furuya, T.; Ritter, T. Org. Lett. 2009, 11, 2860–2863. (b) Furuya,
T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed. 2008, 47, 5993–5996.
(c) Cazorla, C.; Me´tay, E.; Andrioletti, B.; Lemaire, M. Terahedron Lett.
2009, 50, 3936–3938. (d) Sniady, A. Synlett 2006, 960–961. (e) Thiebes,
C.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. Synlett 1998, 141–142.
(10) Prakash, G. K. S.; Moran, M. D.; Mathew, T.; Olah, G. A. J.
Fluorine Chem. 2009, 130 (9), 806–809.
(12) For notable exceptions, see: (a) Mothana, S.; Grassot, J.-M.; Hall,
D. G. Angew. Chem., Int. Ed. 2010, 49, 2883–2887. (b) Mothana, S.; Chahal,
N.; Vanneste, S.; Hall, D. G. J. Comb. Chem. 2007, 9, 193–196.
(13) Kuivila, H. G.; Benjamin, L. E.; Murphy, C. J.; Price, A. D.; Polevy,
J. H. J. Org. Chem. 1962, 27, 825–829.
(14) Johnsson, R.; Meijer, A.; Ellervik, U. Tetrahedron 2005, 61, 11657–
11663.
(15) (a) Shen, Z.; Yeo, Y.; Loh, T. J. Org. Chem. 2008, 73, 3922–
3924. (b) Wei, C.; Li, Z.; Li, C. Org. Lett. 2003, 5, 4473–4475.
(16) Merkushev, E. B. Synthesis 1988, 923–937.
(11) Prakash, G. K. S.; Panja, C.; Mathew, T.; Surampudi, V.; Petasis,
N. A.; Olah, G. A. Org. Lett. 2004, 6, 2205–2207.
Org. Lett., Vol. 12, No. 11, 2010
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Table 1. Effect of Different Iodinating Agents in the Direct
ortho-Iodination of 3-Methoxyphenylboronic Acida
Scheme 1
.
Direct ortho-Iodination and Bromination of
Arylboronic Acidsa
entry
solvent
CH2Cl2
iodinating agent t (min) yield (%)b
1
2
3
4
5
6
7
8
Ag2SO4/I2
Ag2SO4/I2
Ag2SO4/I2
Ag2SO4/I2
Ag2SO4/I2
AgNO3/I2
Hg(OAc)2/I2
NIS
2.5
2
2
3
2.5
3
20
>15
2
2.5
0c
0c
THF
CH3CN
HOCH2CH2OH
EtOH
EtOH
EtOH
EtOH
CH3CN
EtOH
EtOH
EtOH
27d
77
79
75
40e
0f
9
NIS
0g
h
10
11
12j
Ag2SO4/I2
81
82
78
i
Ag2SO4/I2
2.5
2.5
h
Ag2SO4/I2
a Conditions: All the reactions were carried out using 1 equiv of
iodinating agent and stirred at 25 °C for the time specified. b Isolated yield.
c No reaction was observed. d Inseparable mixture of regioisomers along
with ipso-iodinated product (∼40%) was isolated. e ipso-Iodinated product
(∼15%) was also isolated. f No desired product was observed. g 97% yield
of ipso-iodinated product. h Ag2SO4 (1.1 equiv of Ag). i Ag2SO4 (1.5 equiv
of Ag). j 5 g scale (32.9 mmol).
products that are difficult or impossible to access by any
other means. In this regard, we evaluated the substrate
scope of the Ag(I)-mediated direct iodinaton of boronic
acids using the optimized reaction conditions (Scheme 1).
Different electron-rich, neutral, and electron-poor aryl-
boronic acids bearing protic, basic, electrophilic, or
nucleophilic functional groups were subjected to the
optimal reaction conditions to provide the ortho-halogen-
taed products without any traces of other regioisomers.
Substrates with electron-donating substituents such as a
methoxy, amido, or amino provided the desired products
in higher yield and shorter reaction times of 2-5 min
(Scheme 1: 3, 4, 7-16), whereas those bearing electron-
withdrawing substituents decreased the reaction efficiency
and increased the required reaction time to 10-15 min
(Scheme 1: 5, 6, and 17). The neutral substrate 3,5-
dimethylphenylboronic acid was also subjected to the same
reaction conditions to provide the desired iodinated
product within 10 min (Scheme 1: 18). Substrates with
methylthio and trifluoromethyl substituents did not provide
the desired products (Scheme 1: 19-22).
Electron-rich substituents with their ability for conjugation
enhance the reactivity of ortho and para positions toward
electrophilic substitution reactions. The iodination of highly
activated aromatic compounds like aniline provides the para-
iodinated product in 66% yield as well as ortho- and para-
diiodinated products in 13% yield at room temperature.14
Using our conditions, the fact that the substitution occurs
only ortho to the B(OH)2 group and para to the electron-
donating group even with multiple electron-donating groups
a Yields are given for isolated compounds (reaction scale: 3.29 mmol).
1.1 equiv of Br2 was used in case of bromination b AgNO3 was used (1
equiv of Ag). c 2 equiv of Br2 was used. An inseparable mixture of
regioisomers was isolated when 1.1 equiv of Br2 was used. d Recovered
starting material in brackets.
(Scheme 1: 9) indicates that electronic effects are not the
only significant factor in these reactions. Indeed, the observed
regioselectivity suggests that a strong ortho directing group
effect from the B(OH)2 is operative. Moreover, when there
are two distinct ortho positions available for iodination, the
site which is the least sterically hindered and para to the
electron-donating group is iodinated (Scheme 1: 3-8,
10-13).
The regiochemistry in these examples is supported by
X-ray crystallographic analyses of several products,17 which
clearly indicate the position of the electrophilic iodination.
For example, the precursor to 2-iodo-3,5-dimethoxyphenyl
boronic acid (Figure 2, 9) has two positions available for
iodination, ortho and para to the boronic acid group. The
ortho position is iodinated exclusively under the optimized
reaction conditions.
(17) CCDC-767421 and 767422 contain the supplementary crystal-
lographic data for compounds 9 and 14, respectively. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
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Org. Lett., Vol. 12, No. 11, 2010

Scheme 3
.
Chemoselective Suzuki-Miyaura Coupling for
ortho-Iodoarylboronic Acid
Figure 2. ORTEP view of 2-iodo-3,5-dimethoxyphenylboronic acid
(9). Thermal Gaussian ellipsoids at the 20% probability level.
Since we have not observed other regioisomers in the
reaction, it is likely that there exists a prominent interaction
between the boronyl group and the active iodonium inter-
mediate as shown in the proposed mechanism (Scheme 2).
Scheme 4. One-Pot Chemoselective Double Suzuki-Miyaura
Coupling of 2-Iodo 5-Methoxyphenylboronic Acid
Scheme 2
.
Proposed Mechanism for Direct ortho-Iodination of
Arylboronic Acid
functional group tolerance, broad substrate scope, and
regioselectivity of the reaction provide a general method for
halogenated arylboronic acids that are difficult to access
otherwise. Remarkably, the resulting ortho-iodoarylboronic
acids can be cross-coupled chemoselectively with other aryl
iodides.
In ethanol, in the presence of anionic species, the formation
of borate intermediate A is likely. Formation of this boronate
anion activates the ring for electrophilic iodination while
fostering electrostatic attraction with the iodonium reagent.
This directing effect leads iodination to occur at the ortho
position to the boronic acid as depicted in intermediate B.
To demonstrate the utility of these ortho-iodoarylboronic
acids as useful intermediates, different synthetic transforma-
tions were performed. For example, 5-methoxy-2-iodophe-
nylboronic acid 3 was converted into biaryl derivatives by a
highly chemoselective Suzuki-Miyaura coupling reaction
with good to excellent yields (Scheme 3: 23-27). Further-
more, one-pot double Suzuki-Miyaura couplings were also
successful at providing the expected ortho-triaryl derivatives
in good yields (Scheme 4: 28-31).
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council (NSERC) of Canada
(Discovery Grant to D.G.H.) and the University of Alberta
for financial support. R.M.A. thanks the University of Alberta
for a Queen Elizabeth II Scholarship. We thank Dr. R.
McDonald and Dr. M. J. Ferguson at the University of
Alberta for the X-ray crystallographic analyses.
Supporting Information Available: Detailed experimen-
tal procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In conclusion, we have developed the first mild and
regioselective direct iodination of arylboronic acids. The
OL100537X
Org. Lett., Vol. 12, No. 11, 2010
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