Highly Regioselective Iodination of Arenes via Iron(III)-Catalyzed Activation of N-Iodosuccinimide

Article abstract of DOI:10.1021/acs.orglett.5b02345

An iron(III)-catalyzed method for the rapid and highly regioselective iodination of arenes has been developed. Use of the powerful Lewis acid, iron(III) triflimide, generated in situ from iron(III) chloride and a readily available triflimide-based ionic liquid allowed activation of N-iodosuccinimide (NIS) and efficient iodination under mild conditions of a wide range of substrates including biologically active compounds and molecular imaging agents.

Full text of DOI:10.1021/acs.orglett.5b02345

Letter
pubs.acs.org/OrgLett
Highly Regioselective Iodination of Arenes via Iron(III)-Catalyzed
Activation of N‑Iodosuccinimide
†
†
‡
,†
Daugirdas T. Racys, Catherine E. Warrilow, Sally L. Pimlott, and Andrew Sutherland*
†
WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, U.K.
‡
West of Scotland Radionuclide Dispensary, University of Glasgow and North Glasgow University Hospital NHS Trust, Glasgow G11
6NT, U.K.
*
S Supporting Information
ABSTRACT: An iron(III)-catalyzed method for the rapid and highly
regioselective iodination of arenes has been developed. Use of the
powerful Lewis acid, iron(III) triflimide, generated in situ from iron(III)
chloride and a readily available triflimide-based ionic liquid allowed
activation of N-iodosuccinimide (NIS) and efficient iodination under
mild conditions of a wide range of substrates including biologically
active compounds and molecular imaging agents.
ryl halides are highly important intermediates in synthetic
chemistry, used for a wide range of applications including
Although these processes are efficient, many of them require
the use of expensive and toxic late transition metals. The issues
associated with late transition metal catalysts have resulted in the
development of reactions which use first-row transition metals,
such as Fe, Co, and Ni that are much more abundant,
A
cross-coupling reactions, the formation of organometallic
1
reagents, and the generation of free-radical intermediates. The
reactivity and versatility of aryl iodides in particular have made
these important building blocks for total synthesis, medicinal
chemistry, and material science. Radioiodinated aryl compounds
are also becoming increasingly important in medical imaging, in2
understanding diseases associated with neurology and oncology.
For these reasons, significant efforts have been made to
9
,10
inexpensive, and significantly less toxic.
We were interested
in developing an iodination method of arenes that utilized a
nontoxic first row transition metal and that could be extended for
11
the production of iodinated imaging agents. Herein, we report
the use of iron(III) chloride for the rapid iodination of arenes
(
Scheme 1b). As well as demonstrating the use of a triflimide-
3
develop general methods for the synthesis of aryl iodides. These
based ionic liquid to enhance the Lewis acidity of the iron catalyst
and accelerate the reaction, we show this method can be used for
the late stage iodination of medicinally important compounds.
Initial studies focused on the iodination of anisole (1a) with
NIS using a range of first row transition metal catalysts (Table 1,
entries 2−7). While modest conversions were observed after 21 h
for the chloride salts of Mn, Co, Cu, and Zn, the reaction with
include metal-catalyzed halogen exchange reactions from less
4
reactive aryl bromides and substitution reactions using leaving
5
6
groups such as boronic acids and diazonium salts. While these
methods are widely used, they require the installation of a
functional handle and occasionally harsh conditions. More direct
iodination methods using NIS have been reported. Olah et al.
FeCl was complete after 1.5 h and gave an 86% isolated yield of
used BF in water for the efficient iodination of deactivated
3
3
3
a
iodoanisole as a 93:7 mixture of p- and o-isomers, respec-
arenes. Pd(II)- and Ru(0)-catalyzed C−H activation processes
12,13
tively.
To assess the relative activity of FeCl , the reaction
3
have been developed for the synthesis of ortho-iodinated ary7l
was repeated using a range of more traditional electrophilic
aromatic substitution catalysts as well as various late transition
compounds using pyridines and amides as directing groups,
while In(III)- and Au(I)-catalyzed iodination of electron-rich
metal catalysts (entries 8−12). Only AuCl which has been
8
3
arenes have also been described (Scheme 1a).
reported to perform this transformation via a dual activation
process (formation of an arylgold(III) species and coordination
Scheme 1. Iodination of Arenes Using NIS
8a
to NIS) showed similar levels of activity.
Having identified FeCl as a suitable catalyst, we began to
3
examine the scope of the process. Although activated substrates
gave iodinated products in high yield, it became apparent that, for
less active compounds such as 2-methoxybenzaldehyde (1b),
significantly higher catalyst loadings (100 mol %) were required
for an efficient process (Table 2, entry 1). Due to the limited
Received: August 13, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02345
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Activity Screen of Metal Catalysts for Iodination of
, ,
ab c
Anisole (1a)
entry
catalyst
conversion at 1.5 h (%) conversion at 21 h (%)
1
2
3
4
5
6
7
8
9
−
MnCl2
<2
54
100
<2
0
11
55
−
FeCl3
CoCl ·6H O
NiCl2
59
12
63
67
100
83
99
100
−
2
2
CuCl2
0
Figure 1. Iodination of 1a; [BMIM]NTf versus dichloromethane
2
ZnCl2
30
85
4
1
(measured using H NMR spectroscopy).
AlCl3
RuCl3
InCl3
PtCl4
AuCl3
1
1
1
0
1
2
60
34
100
in [BMIM]NTf required only a 5 mol % loading of FeCl and
2 3
gave the 5-iodinated compound 2b as the sole product after 2.5 h
in 88% yield (Table 2, entry 2). To achieve a similar result, using
dichloromethane required a stoichiometric amount of catalyst
and a reaction time of 6 h (entry 1). Thus, the combination of a
more active catalyst, Fe(NTf ) , and the greater cohesive
a
b
Reactions were performed using 1.1 equiv of NIS. Conversions were
measured using H NMR spectroscopy. For all reactions, a ratio of
9:1 was observed in favor of the para-isomer.
1
c
>
2
3
pressure of the ionic liquid resulted in a faster reaction at a
1
9
Table 2. Halogenation of 1b
significantly lower catalyst loading. A study was performed to
compare some of the most active catalysts from Table 1 for the
iodination of 1b using [BMIM]NTf . The harder Lewis acid,
2
Fe(NTf ) , was the most active and gave full conversion of
2
3
iodinated product 2b more quickly than the other catalysts (see
Supporting Information for rate plot). While the focus of this
study was the development of an efficient iodination process of
arenes, it was shown by using 1b that other halogenations can be
performed using the FeCl /[BMIM]NTf system (Table 2).
Bromination using NBS under similarly mild conditions gave 3b
in 88% yield. Chlorination of 1b required a longer reaction time
at a higher temperature, but still gave 4b in 68% yield.
entry
solvent
time (h)
X
yield (%)
a
1
CH Cl2
6
I (2b)
90
88
88
68
2
3
2
2
3
[BMIM]NTf2
2.5
1.5
18
I (2b)
[BMIM]NTf2
[BMIM]NTf2
Br (3b)
Cl (4b)
b
4
a
b
FeCl (100 mol %) was used. Reaction was done at 70 °C and using
3
Following optimization, the scope of the Fe(NTf ) -catalyzed
2
3
MeCN as a cosolvent.
iodination was explored (Scheme 2). The transformation was
found to be compatible and efficient for a wide range of aryl
20
substrate scope, a more active form of Fe(III) was required.
Recently, metal triflimides have received significant attention as
powerful Lewis acids due to the highly delocalized nature of the
compounds with standard activating groups. In nearly all cases,
21
the iodination gave a single regioisomer. Strongly deactivating
groups were also tolerated and gave efficient iodinations. For
example, iodination of 4-nitroaniline (1k) was complete after 2 h
and gave 2k as the sole product in 73% yield. The only limitation
with the procedure was the formation of bis-iodinated products
for particularly active substrates, such as phenols 1c and 1q and
pyrrole 1y. However, under the optimized conditions for these
substrates, the bis-iodinated compounds were only ever formed
in trace amounts and easily removed by column chromatography.
14
triflimide counterion. For example, it has been reported that
iron(III) triflimide salt (formed in situ from FeCl and AgNTf )
3
2
15
is an effective Lewis acid catalyst for addition reactions. An
alternative method of generating Fe(NTf ) which avoids the use
2
3
of late transition metals involves the dissolution of FeCl in the
3
readily available and inexpensive ionic liquid, 1-butyl-3-methyl-
imidazolium bis(trifluoromethylsulfonyl)imide ([BMIM]-
1
6
NTf2). Thus, the combination of an iron catalyst with an air-
stable ionic liquid that has low vapor pressure, has high cohesive
pressure for acceleration of reactions, and can be easily separated
from the product seemed an ideal system for the general
The ionic liquid utilized in this procedure, [BMIM]NTf , has a
2
number of electrochemical applications and, for this reason, is
2
2
relatively inexpensive compared to other ionic liquids.
Nevertheless, we wanted to demonstrate that [BMIM]NTf2
could be easily recovered and reused in subsequent reactions.
Following iodination of anisole (1a), the residual ionic liquid was
washed with water to remove succinimide and dried under high
vacuum. In two successive iodination reactions of 1a using the
recovered ionic liquid, consistent yields of around 90% were
achieved.
17,18
iodination of arenes.
The iodination of anisole (1a) was
repeated using [BMIM]NTf as the solvent. Although similar
2
results were obtained (93:7 ratio of p- and o-isomers in 89%
yield), a significant difference in the rate of reaction was observed
compared to using dichloromethane as the solvent (Figure 1). In
[
BMIM]NTf , complete conversion was achieved in around 0.5
2
h, while over 1.5 h were required for the same conversion in
dichloromethane.
The difference in reactivity was more pronounced with less
reactive substrates. Iodination of 2-methoxybenzaldehyde (1b)
The mechanism of halogenation of arenes using N-
halosuccinimides has been postulated to involve coordination
of the metal to the oxygen carbonyl atom of the succinimide,
which activates halogenation of the aryl ring via an electrophilic
B
DOI: 10.1021/acs.orglett.5b02345
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Organic Letters
Letter
Scheme 2. Scope of Fe(NTf ) -Catalyzed Iodination
coordinating carbonyl group, gave the 5-iodo product 2t in 58%
yield (Scheme 2), along with the 6-iodo regioisomer in 24%
yield. Using the same substituent pattern but carbonyl groups
2
3
(
ester 1u and amide 1v) that bind more strongly to the Fe-NIS
complex switched the outcome of this process to significantly
favor the 6-iodo products 2u and 2v.
Application of this method for the preparation of medicinally
important compounds was next investigated. We were aware that
NIS is incompatible with compounds bearing nucleophilic
groups and so chose particular targets where this would be an
8b
issue. The first target selected was PIMBA (6), a compound
123
used in its [ I]-form for the imaging of human breast cancer
23
tumors. Initial attempts at direct iodination of precursor 5 with
NIS and the FeCl /[BMIM]NTf system gave no iodinated
3
2
product. In these reactions, the solutions were observed to turn
black shortly after addition of NIS. Protection of the nucleophilic
piperidine ring as a salt was then investigated. While the
hydrochloride salt gave the same negative outcome, formation of
the softer tetrafluoroborate salt by treatment of 5 with
tetrafluoroboric acid followed by iodination under the optimized
conditions gave PIMBA (6) in 84% yield over the two steps
24
(
Scheme 3). This approach was then extended to the synthesis
of (−)-IBZM (8), an imaging agent and antagonist of the human
2
5
D receptor, and 8-iodoharmaline (10), a potent monoamine
2
26
oxidase inhibitor. Again, formation of the tetrafluoroborate
salts, followed by reaction with NIS and the in situ generated
Fe(NTf ) , gave the iodinated products in 47% and 73% overall
2
3
27
yield, respectively.
In summary, a highly regioselective, efficient iron(III)-
catalyzed iodination of activated arenes that can be accelerated
using a triflimide based ionic liquid has been developed. The
process requires only a 5 mol % loading of an inexpensive,
nontoxic first row transition metal catalyst, and the ionic liquid
which acts as both the reaction solvent and Fe(III) activator can
be easily recycled after washing with water. This combination
results in faster reactions at lower temperatures compared to
a
b
4
-I isomer was isolated in 21% yield. 6-I isomer was isolated in 24%
c d
8
yield. 5-I isomer was isolated in 7% yield. 5-I isomer was isolated in
% yield.
previous metal-catalyzed methods with NIS, allowing iodination
4
of relatively deactivated compounds such as 2k and 2l.
Furthermore, the process can be used for the late-stage
iodination of medicinally important compounds. In this regard,
the limitations of using NIS for iodination of nucleophilic
substrates were overcome by the identification of tetrafluor-
oborate salts as suitable precursors. Investigation of further
applications of this procedure is currently underway.
8
aromatic substitution process. Halogenation via such a
mechanism is directed by the activating groups. However, during
our studies, it was found that the position of iodination could be
redirected by the use of Fe(III)-complexing substituents. For
example, 2,3-dimethoxybenzaldehyde (1t), which has a weakly
Scheme 3. Synthesis of PIMBA (6), (−)-IBZM (8), and 8-Iodoharmaline (10)
C
DOI: 10.1021/acs.orglett.5b02345
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Hirschman, S. A. Anal. Biochem. 1985, 144, 441. (c) Mason, N. S.; Smith,
H. E.; Danzo, B. J.; Clanton, J. A. J. Labelled Compd. Radiopharm. 1992,
ASSOCIATED CONTENT
Supporting Information
■
*
S
3
1, 729.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02345.
(12) Iodination of anisole, diphenyl ether, and toluene using NIS and
FeCl3 has been reported: Tanemura, K.; Suzuki, T.; Nishida, Y.;
Satsumabayashi, K.; Horaguchi, T. Chem. Lett. 2003, 32, 932.
Experimental details, compound characterization, and
NMR spectra for all compounds (PDF)
(
13) On identifying FeCl as a suitable Lewis acid for iodinations, a
3
solvent screen was performed including polar solvents such as MeCN,
DMSO, and DMA. However, CH Cl was found to give the fastest
2
2
AUTHOR INFORMATION
Corresponding Author
conversion to iodinated anisole using FeCl3.
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2013, 19, 8627.
■
*
(
̃
4
E-mail: Andrew.Sutherland@glasgow.ac.uk.
Notes
(
́
ez, A.; Corma, A. Adv.
ez,
́
The authors declare no competing financial interest.
́
(
́
ACKNOWLEDGMENTS
Financial support from the Scottish Funding Council, EPSRC
EP/K503903/1), and SINAPSE is gratefully acknowledged.
■
(
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̌
c,
̌
(
5
2
(
2
(
(
(
2
absence of FeCl , with NIS in [BMIM]NTf (36 °C), showed no
conversion after 2 h.
(
arenes by N-halosuccinimides (see ref 8), strongly deactivated
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3
2
20) In accordance with other transition metal catalyzed iodinations of
(
1
2
3
(
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(
1
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(
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(
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formation of small quantities of byproducts. For example, like other
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also observed by NMR spectroscopy in the crude reaction mixture.
2
9
(
272.
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D
DOI: 10.1021/acs.orglett.5b02345
Org. Lett. XXXX, XXX, XXX−XXX