Gold(I)-catalyzed iodination of arenes

Article abstract of DOI:10.1055/s-0033-1340321

A wide variety of electron-rich arenes were efficiently converted into the corresponding iodinated compounds via a gold(I)-catalyzed reaction under mild conditions. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340321

LETTER
▌399
letter
Gold(I)-Catalyzed Iodination of Arenes
Gold(I)-Catalyzed Iodination of Arenes
David Leboeuf, Jennifer Ciesielski, Alison J. Frontier*
Department of Chemistry, University of Rochester, Rochester, NY 14627, USA
Fax +1(585)2760205; E-mail: frontier@chem.rochester.edu
Received: 09.10.2013; Accepted after revision: 05.11.2013
its versatility. Herein, we report a novel and efficient
method for the iodination of arenes using the oxophilic
properties of gold catalysts. The reaction does not require
an inert atmosphere and is compatible with a broad range
of functional groups.
Abstract: A wide variety of electron-rich arenes were efficiently
converted into the corresponding iodinated compounds via a
gold(I)-catalyzed reaction under mild conditions.
Key words: gold, homogeneous catalysis, iodination, arenes, elec-
trophilic aromatic substitution
Initially, we focused on the iodination of 2-methoxybenz-
aldehyde (Table 1). We discovered that when this com-
pound was subjected to NIS (1.1 equiv) and Ph3PAuNTf2
(5 mol%) in dichloromethane at room temperature, 5-
iodo-2-methoxybenzaldehyde (1) was produced in 98%
yield (Table 1, entry 8).14 Other Lewis acids, including
AgNO3, AgSbF6, and In(OTf)3, gave only trace quantities
of the aryl iodide (Table 1, entries 2–4), indicating a poor
compatibility of these catalysts with carbonyl functional-
ities. Several other gold complexes were also tested, but
only AuCl3 was able to effect complete conversion after
16 hours (Table 1, entries 5–7). To rule out a Brønsted
acid catalyzed process, we ran the iodination with a cata-
lytic amount of HNTf2. After 24 hours, the reaction had
only proceeded to 80% conversion, indicating that HNTf2
is not solely responsible for the observed iodination when
Aryl iodides are versatile building blocks that provide a
pivotal entry point for the creation of carbon–carbon and
carbon–heteroatom bonds, thus making them key inter-
mediates in the synthesis of biologically active com-
pounds. Furthermore, they are unparalleled in reactivity
as demonstrated by their use in transition-metal-catalyzed
coupling reactions, such as Suzuki, Stille, Sonogashira, or
Heck couplings.1 Despite the widespread use of aryl io-
dides in both natural product synthesis and methodologi-
cal studies, direct arene iodination is still difficult. Several
methods have been developed to circumvent this problem.
However, these methods are fraught with functional group
incompatibility and limited substrate scope.2 Strong Lewis
or Brønsted acids, such as trifluoroacetic acid,3 trifluo-
romethanesulfonic acid,4 or BF3·OEt2–H2O5 have proven
their efficiency with electron-withdrawing groups on the
aromatic ring, but acid-sensitive functional groups may
not tolerate these extreme conditions. Iodination of arenes
can also be achieved using oxidizing agents, such as ceric
ammonium nitrate,6 bismuth(III) nitrate pentahydrate,7
sodium hypochlorite,8 and urea–hydrogen peroxide9 to
generate the iodonium species, but again, the scope is nar-
row due to limited functional group tolerance.10 To date,
one of the mildest methods for iodination of arenes was
reported by Romo, who demonstrated that electron-rich
arenes undergo iodination upon exposure to N-iodosuc-
cinimide (NIS) and a catalytic amount of In(OTf)3 at room
temperature.11
Table 1 Optimization Studiesa
OMe
OMe
catalyst (5.0 mol%)
NIS (1.1 equiv)
O
O
CH2Cl2, r.t.
I
1
Entry
Catalyst
Time (h) Yield (%)
1
2
–
24
24
24
24
16
16
16
12
14
24
no reaction
trace
trace
trace
94
In(OTf)3
3
AgNO3
In the last decade, gold complexes have emerged as a
powerful tool for the creation of new carbon–heteroatom
bonds, due to their unique carbophilic properties.12 Fur-
thermore, the group of Wang has shown that arenes, and
especially electron-deficient arenes, can be halogenated
using AuCl3.13 The reaction is based on the ability of
AuCl3 to achieve dual activation of both the arene ring and
N-bromosuccinimide (NBS). Given the increasing de-
mand for mild methods that allow access to iodinated
arenes, we sought to explore this reaction and demonstrate
4
AgSbF6
5
AuCl3
6
AuClPPh3/AgSbF6
JohnPhosAu(MeCN)SbF6
Ph3PAuNTf2
Ph3PAuNTf2
HNTf2
85b
7
71b
8
98
9
96c
10
80b
a Reaction conditions: arene (1 mmol), catalyst (0.05 mmol), NIS (1.1
mmol) in CH2Cl2 (0.1 M) at r.t. for the indicated time.
b NMR conversion.
SYNLETT 2014, 25, 0399–0402
Advanced online publication: 16.12.2013
DOI: 10.1055/s-0033-1340321; Art ID: ST-2013-R0951-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
c Amount of catalyst used was 0.025 mmol.

400
D. Leboeuf et al.
LETTER
using the gold complex. Finally, the catalyst loading of N-chlorosuccinimide was not a suitable electrophile, and
Ph3PAuNTf2 could be decreased from 5 mol% to 2.5 only starting material was recovered.16
mol% without a significant effect on yield or reaction time
Table 2 Substrate Scopea
(Table 1, entry 8 vs. entry 9).
Ph3PAuNTf2 (2.5 mol%)
NIS (1.1 equiv)
R
R
To further explore this reaction and its capabilities, we
first examined the iodination of monosubstituted arenes
containing various electron-donating groups using
Ph3PAuNTf2 as the catalyst. As shown in Table 2, amines,
alcohols, methoxy, silyl alcohols, and alkyl functional
groups were tolerated under the reaction conditions, pro-
viding the desired iodinated arenes at room temperature in
high yields (Table 2, entries 1–6). Unfortunately, the reac-
tion with bromobenzene did not lead to the formation of
the corresponding iodobromobenzene (Table 2, entry 7),
presumably due to the poor electron-donating aptitude of
the bromide.
I
CH2Cl2 or (CH2Cl)2
r.t. or reflux
Entry Substrate
Temp (°C)
Product
Yield (%)
R
R
I
1
2
3
4
5
6
R = NH2
R = NMe2
R = OH
20
20
20
20
20
20
2
3
4
5
6
7
93
92
96
98
97
We next examined the scope of this method for iodination
of disubstituted arenes, as shown in Table 2. We began
with arenes bearing an electron-donating group (OH and
OMe) and an ortho-substituent, including electron-donat-
ing and electron-withdrawing groups (Table 2, entries 8–
16). Under the optimized reaction conditions, the iodinat-
ed arenes were obtained in high yields (up to 97%) with
complete control of the regioselectivity. While most of the
reactions were carried out at room temperature, in the
presence of a strong electron-withdrawing group the reac-
tion required heating in 1,2-dichloroethane under reflux
(Table 2, entry 16). High yields were also obtained in the
iodination of arenes containing an electron-donating
group (OMe) with meta-substitution (Table 2, entries 17–
19). In general, iodination occurred preferentially at the
carbon para to the methoxy group. The decrease in regi-
oselectivity (Table 2, entries 17 and 18) can be attributed
to an increase of the steric hindrance at the meta position.
The final class of substrates examined was comprised of
arenes possessing an electron-donating group (OMe and
NH2) with para-substitution (Table 2, entries 20–33). The
iodination occurred smoothly in the presence of a wide
range of functional groups. Overall, the iodinated arenes
were obtained at room temperature in high yields (up to
97%), installing the iodine in the ortho position relative to
the electron-donating group. Again, arenes bearing a
strong electron-withdrawing group (i.e. CF3 and NO2) re-
quired heating in 1,2-dichloroethane under reflux (Table
2, entries 32 and 33).
R = OMe
R = OTIPS
R = Me
59
(p-/o- = 2.4:1)
7
R = Br
HO
20
8
no reaction
HO
R
R
I
8
9
R = Me
20
20
20
40
9
97
94
98
85
R = CHO
R = C(O)Me
R = CO2H
10
11
12
10
11
MeO
MeO
R
R
I
12
13
14
15
16
R = Me
20
20
40
20
85
13
14
15
16
17
97
92
88
91
97
R = Br
R = CO2H
R = CO2Me
R = NO2
When anisole was exposed to the gold catalyst and NBS
rather than NIS, bromoanisole was obtained in 86% yield
(Equation 1), demonstrating that this reaction can also be
employed to generate aryl bromides.15 Unfortunately,
MeO
MeO
R
R
I
OMe
OMe
17
18
R = Me
20
40
18
88
Ph3PAuNTf2 (2.5 mol%)
NXS (1.1 equiv)
(p-/o- = 5:1)
CH2Cl2, r.t.
R = Br
19
98
(p-/o- = 1:1)
X
36, X= Br, 86%
37, X = Cl, no reaction
19
20
R = CHO
R = Me
85
20
20
21
75
89
Equation 1
Synlett 2014, 25, 399–402
© Georg Thieme Verlag Stuttgart · New York

LETTER
Gold(I)-Catalyzed Iodination of Arenes
401
Table 2 Substrate Scopea (continued)
OMe
OMe
Ph3PAuNTf2 (1.0 equiv)
Ph3PAuNTf2 (2.5 mol%)
NIS (1.1 equiv)
R
R
X
I
CH2Cl2, r.t.
CH2Cl2 or (CH2Cl)2
r.t. or reflux
AuPPh3
Equation 2
Entry Substrate
Temp (°C)
Product
Yield (%)
21
22
23
24
25
26
27
28
R = Br
20
40
85
40
20
40
85
85
22
23
24
25
26
27
28
29
96
94
85
88
89
91
80
88
In summary, we have developed a mild and efficient
method for the iodination of arenes.18 There are several
advantages to this method. First, multihalogenated arenes
can be synthesized, which offers the possibility of further
functionalization of the arenes via cross-coupling strate-
gies. Second, the method was demonstrated to have broad
substrate scope. Notably, carbonyl substituents were sta-
ble under the reaction conditions: arene iodination oc-
curred in good to high yield in the presence of carboxylic
acids, esters, amides, ketones and aldehydes.
R = F
R = CHO
R = C(O)Me
R = CO2H
R = CO2Me
R = CONH2
R = CN
H2N
MeO
Acknowledgment
We thank National Institutes of Health (NIGMS R01 GM079364)
and the National Science Foundation (Grant CHE-1152725) for
funding this work.
R
R = Me
I
29
30
31
32
33
20
20
20
85
85
30
31
32
33
34
94
91
90
89
97
Supporting Information for this article is available online at
R = Cl
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
R = CO2Me
R = CF3
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R = NO2
MeO
MeO
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a Reaction conditions: arene (1 mmol), Ph3PAuNTf2 (0.025 mmol),
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of the aromatic ring and NIS by the gold catalyst, accord-
ing to the mechanism presented by Wang et al.;13 or (ii) a
simple electrophilic aromatic substitution resulting from
the activation of NIS by the gold catalyst. In order to
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one equivalent of Ph3PAuNTf2 in the absence of NIS, in
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no reaction was observed (Equation 2). This result sug-
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Crafts-type mechanism in which Ph3PAuNTf2 activates
the NIS and enhances its reactivity.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 399–402

402
D. Leboeuf et al.
LETTER
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(1 mmol) in CH2Cl2 or (CH2Cl)2 (0.1 M) were added
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toluene, 2:1) followed by N-iodosuccinimide (1.1 mmol, 248
mg). The resulting solution was stirred at r.t. or under reflux
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5-Iodo-2-methoxynitrobenzene (17): compound 17 was
prepared in 97% yield according to the general procedure;
yellow solid; mp 96–98 °C. 1H NMR (400 MHz, CDCl3):
δ = 8.09 (d, J = 2.0 Hz, 1 H), 7.79 (dd, J = 8.8, 2.0 Hz, 1 H),
6.86 (d, J = 8.8 Hz, 1 H), 3.93 (s, 3 H). 13C NMR (100 MHz,
CDCl3): δ = 152.8, 142.7, 140.3, 133.9, 115.6, 80.6, 56.6. IR
(neat): 3109, 3078, 2943, 2851, 1597, 1562, 1512, 1481,
1442, 1343, 1269, 1254, 1188, 1165, 1095, 1015 cm–1.
HRMS (EI+): m/z calcd for C7H6O3IN: 278.9392; found:
278.9383.
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Synlett 2014, 25, 399–402
© Georg Thieme Verlag Stuttgart · New York