Synthesis of diaryliodonium triflates using environmentally benign oxidizing agents

Article abstract of DOI:10.1055/s-0029-1217723

A range of symmetric and unsymmetric diaryliodonium triflates have been prepared employing urea-hydrogen peroxide as the oxidizing agent. The use of aqueous hydrogen peroxide and catalytic systems with methylrhenium trioxide in the oxidation of iodoarenes

Full text of DOI:10.1055/s-0029-1217723

LETTER
2277
Synthesis of Diaryliodonium Triflates Using Environmentally Benign
Oxidizing Agents
Synthesis of
D
ia
l
ryliod
e
onium Trifl
a
ates
U
sing
n
H
ydrogen Pe
o
roxide r A. Merritt, Joel Malmgren, Felix J. Klinke, Berit Olofsson*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Fax +46(8)154908; E-mail: berit@organ.su.se
Received 20 May 2009
The initial investigation focused on replacing mCPBA
(Scheme 1, method A) with either 30% aqueous H2O2 or
UHP (Scheme 1, method B). This approach proved large-
ly unsuccessful, furnishing diphenyliodonium triflate (1a)
with a maximum yield of 11%, even after heating and pro-
longed reaction times.
Abstract: A range of symmetric and unsymmetric diaryliodonium
triflates have been prepared employing urea–hydrogen peroxide as
the oxidizing agent. The use of aqueous hydrogen peroxide and cat-
alytic systems with methylrhenium trioxide in the oxidation of
iodoarenes has also been investigated.
Key words: hypervalent iodine, diaryliodonium salts, oxidation,
arenes, green chemistry
–OTf
+
I
I
[O]
+
TfOH
In recent years hypervalent iodine reagents have received
considerable attention befitting their use as non-toxic and
mild reagents in many areas of organic synthesis.1,2 Di-
aryliodonium salts have found applications in many reac-
tions which traditionally employ transition metals, such as
a-arylation of carbonyl compounds3 and cross-coupling
reactions,2,4 as iodine(III) reagents bearing two carbon
ligands display similar properties to metals such as Pd, Hg
and Pb. Replacement of heavy metals with diaryliodoni-
um salts is highly beneficial from an environmental stand-
point, providing a means to reduce both the cost and
toxicity of these processes.
1a
method A: 92%
method B: 11%
Scheme 1 Synthesis of 1a. Reagents and conditions: Method A:6
mCPBA (1.1 equiv), TfOH (3 equiv), CH2Cl2, r.t., 10 min; Method B:
urea–H2O2 (1.1 equiv), TfOH (3 equiv), CH2Cl2, 40 °C, 3 h.
As both Wirth11 and Kita12 have employed trifluoroacetic
anhydride (TFAA) in the synthesis of iodine(III) reagents
using hydrogen peroxide, the reaction was repeated with
the addition of 2.5 equivalents of TFAA, improving the
yield to 29% and demonstrating the need for activation of
the peroxide prior to oxidation of the iodine. The proce-
dure was then simplified to use only triflic anhydride
(Tf2O) in place of the TfOH–TFAA mixture, in the hope
that Tf2O would react with UHP to form triflic peroxide
(2) in situ and that this reagent would be capable of effi-
ciently oxidizing iodoarenes (Scheme 2). The intermedi-
ate iodine(III) compound would subsequently react with
the arene by electrophilic aromatic substitution (EAS),
forming diaryliodonium triflate 1 without need for an an-
ion exchange. An intermediate similar to 2 was proposed
by Kita and co-workers for the reaction between TFAA
and hydrogen peroxide12 and such perfluoroacyl perox-
ides have been observed and characterized by NMR stud-
ies.13
Diaryliodonium salts have the potential to render process-
es that currently employ heavy metals environmentally
benign, provided that the synthesis of the salts themselves
is sufficiently ‘green’. Whilst efficient and operationally
simple methodology for the preparation of such com-
pounds has recently been developed within our laboratory
(Scheme 1, method A),5,6 use of stoichiometric m-chlo-
roperbenzoic acid (mCPBA) as oxidizing agent and the
concomitant production of m-chlorobenzoic acid as waste
make these protocols less desirable on an industrial scale.
Other methods for the preparation of diaryliodonium salts
have been reported, but they suffer from drawbacks such
as the need to preform an iodine(III) species,7 extended re-
action times,8 excess reagents9 or toxic chromium com-
pounds.10
The reaction was first conducted using Kita’s anhydride–
peroxide ratio of 8:2. The solvent of choice was 2,2,2-tri-
fluoroethanol (TFE),12 which has been demonstrated to
Encouraged by the previously reported use of urea–hydro-
gen peroxide (UHP) in the synthesis of iodine(III) re-
agents,11 an investigation into the use of environmentally
benign oxidizing agents in the synthesis of diaryliodoni-
um triflates was undertaken. Triflate was the counterion
of choice due to its poor nucleophilicity and the ease of
purification by precipitation of the salts.
O
F3C
O
Tf2O (2 equiv)
H
O
S
O
O
H
O
S
O
CF3
O
2
Ar1
I
Ar2H
EAS
–OTf
Ar2
+
–OTf
OTf
Ar1
I
Ar1
I
1
SYNLETT 2009, No. 14, pp 2277–2280
x
x
.x
x
.2
0
0
9
Advanced online publication: 31.07.2009
DOI: 10.1055/s-0029-1217723; Art ID: G17709ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Possible reaction intermediates in the synthesis of salts 1
with hydrogen peroxide and triflic anhydride

2278
E. A. Merritt et al.
LETTER
greatly enhance the yield of diaryliodonium salts prepared 2:1 mixture of dichloromethane and TFE (entry 9). As
from preformed iodine(III) reagents.14 The reaction dichloromethane was then the major component of the
proved to be successful, furnishing the product in 24% solvent, the reaction temperature was reduced to 40 °C to
yield after 24 hours at room temperature (Table 1, entry circumvent the need for sealed tube reaction vessels. Grat-
1). Fortunately, isolation of 1a was straightforward also in ifyingly, this did not have a major adverse effect on the
the presence of urea; trituration of the concentrated crude yield of the reaction (entry 10).
mixture with diethyl ether afforded 1a as a colorless solid,
The use of a 3:1 ratio of CH2Cl2–TFE afforded the prod-
with the residual urea remaining in solution in the diethyl
uct, albeit contaminated with residual urea from the UHP
ether washings.
(entry 11). Further alterations of reaction time or stoichio-
Subsequent optimization of the procedure is shown in metry resulted in lower yields (entries 12–14).
Table 1. Increasing the temperature to 80 °C improved the
In the absence of TFE, no reaction was observed and the
yield to 62%. The reaction time could be decreased to
unreacted iodobenzene was recovered (entry 15). Re-
three hours without decreasing the yield (entry 4). Keen to
placement of TFE with ethanol or hexafluoroisopropanol
improve upon the ‘green chemistry’ potential of the reac-
(HFIP) also led to the reisolation of iodobenzene and no
tion, the Tf2O loading was reduced to four equivalents,
formation of 1a (entries 16 and 17) was observed. This
finding shows that TFE plays a vital role in this reaction,
further improving the yield of the reaction (entry 5). Con-
tinued reduction of the reagent amounts drastically re-
likely due to its capability of stabilizing the cationic inter-
duced the yield of 1a (entries 6 and 7). Running the
mediate obtained in the EAS reaction, although other
reaction in a 1:1 mixture of dichloromethane and TFE
mechanistic pathways cannot be excluded (vide infra).14,15
yielded 1a in 69% yield (entry 8), which rose to 82% in a
An alternative system for hydrogen peroxide activation
Table 1 Optimization of the Synthesis of Salt 1a
was subsequently investigated to see whether triflic anhy-
dride could be replaced. Methylrhenium trioxide (MTO)
is widely used in conjunction with hydrogen peroxide in a
range of oxidation and epoxidation processes.16 Unfortu-
nately, all reactions employing MTO with either UHP or
30% aqueous H2O2 failed, both in the presence and in the
absence of triflic acid, universally returning iodobenzene.
Addition of MTO to reactions containing triflic anhydride
resulted in the formation of the characteristic yellow
MTO–H2O2 complex, but no improvement in the yield
was observed compared to reactions without MTO.
–OTf
I+
I
urea–H2O2
Tf2O
+
1 equiv
2 equiv
1a
Entry UHP Tf2O Solvent
(equiv) (equiv)
T
Time Yield
(°C) (h)
(%)a
24
62
50
61
72
37
38
69
82
76
90b
22
65
60c
0
1
2
2
8
8
8
8
4
3
2
4
4
4
4
4
4
4
4
4
4
TFE
r.t.
80
80
80
80
80
80
80
80
40
40
40
40
40
40
40
40
24
24
1
2
TFE
With an optimized method for the synthesis of 1a
(Table 1, entry 10) in hand, the scope of the reaction was
investigated by testing the compatibility of a range of sub-
stituted arenes and iodoarenes.
3
2
TFE
4
2
TFE
3
5
2
TFE
3
The synthesis of (4-iodophenyl)(phenyl)iodonium triflate
(1b) proceeded smoothly under the standard reaction con-
ditions, furnishing the desired product in 73% yield
(Table 2, entry 2). The fluoro analogue 1c was formed in
56% yield (entry 3), which surprisingly decreased to 46%
after six hours. Reaction of iodobenzene with either bro-
mobenzene (entry 4) or chlorobenzene (entry 6) resulted
in formation of the desired product (1d and 1e, respective-
ly), contaminated with 1b. This is likely due to the lower
EAS reactivity of bromo- and chlorobenzene relative to
iodobenzene, combined with the slow oxidation of iodo-
benzene, thus formation of 1b competes with formation of
the desired products.
6
1.5
1.1
2
TFE
3
7
TFE
3
8
CH2Cl2–TFE (1:1)
CH2Cl2–TFE (2:1)
CH2Cl2–TFE (2:1)
CH2Cl2–TFE (3:1)
CH2Cl2–TFE (2:1)
CH2Cl2–TFE (2:1)
CH2Cl2–TFE (2:1)
CH2Cl2
3
9
2
3
10
11
12
13
14
15
16
17
2
3
2
3
2
2
2
6
2
3
In order to overcome this difficulty, the reactions were
conducted using the relevant 4-haloiodobenzene and ben-
zene. Contrary to the results obtained for salt 1c, longer
reaction times considerably improved the yields, giving
1d and 1e in 86% and 83% yield, respectively (entries 5
and 7). Symmetrical halogen-substituted salts 1f and 1g
could also be prepared in high yields with prolonged reac-
tion times (entries 8 and 9).
2
3
2
CH2Cl2–EtOH (2:1)
CH2Cl2–HFIPd (2:1)
3
0
2
3
0
a Isolated yield.
b Product was contaminated with urea.
c Benzene (1.1 equiv) was used.
d HFIP = hexafluoroisopropanol.
Synlett 2009, No. 14, 2277–2280 © Thieme Stuttgart · New York

LETTER
Synthesis of Diaryliodonium Triflates Using Hydrogen Peroxide
2279
Electron-rich arenes could also be successfully employed,
giving salts 1h–n (entries 10–16). The yields were as good
or better when the reaction was performed at room tem-
perature, which is in accordance with the reactivity pat-
tern in electrophilic aromatic substitution reactions. The
only exception was symmetric bis(p-tolyl) salt 1n, which
was obtained in moderate yield upon heating and a poor
yield (4%) was obtained at room temperature (entry 16).
All attempts to employ very electron-rich or electron-poor
arenes and iodoarenes, as well as heterocycles, failed to
yield identifiable products (entries 17–20).
Table 2 Synthesis of Substituted Diaryliodonium Salts
urea–H2O2 (2 equiv)
I
–OTf
Ar
I+
Tf2O (4 equiv)
+
Ar
H
CH2Cl2–TFE (2:1)
40 °C, 3 h
R1
R1
1 equiv
2 equiv
1a–n
Yield (%)b
76c
Entry R1
Arene (Ar–H)
benzene
PhI
Producta
1
2
H
1a
1b
1c
H
73c
3
H
PhF
56
In all cases, only the para-substituted product was ob-
served. Removal of the residual urea by an aqueous work-
up proved to be necessary to precipitate some of the
substituted salts.
4
H
PhBr
1d/1b (3:1) 46
5
Br
H
benzene
PhCl
1d
86 (59)d
6
1e/1b (4:1) 41
Preliminary investigations on the reaction mechanism
were initiated after the observation of the comparatively
poor yield of symmetrical tert-butyl salt 1m (entry 15),
since this product has been obtained in good yield with the
previously developed mCPBA protocol.6
7
Cl
Br
Cl
H
benzene
PhBr
1e
1f
1g
1h
1i
83 (64)d
8
81 (45)d
81 (60)d
76 (76)e
74 (64)e
72 (64)e
61 (55)e
65 (56)e
46 (27)e
42
9
PhCl
We decided to examine whether a free radical process
could be involved, either in formation of the product or in
competing pathways leading to byproducts. Such a mech-
anism would also explain the vital influence of TFE,
which is known to stabilize radical cation intermediates.14
Thus, the synthesis of 1a was repeated with exclusion of
light, which made no significant difference. When the
reaction was run in the presence of TEMPO (1 equiv) as a
radical scavenger the salt was formed cleanly. Analysis of
the crude reaction mixture by NMR spectroscopy and
mass spectrometry showed that no additional aromatic
byproducts were formed. Furthermore, products of side
reactions between TEMPO and any triflate species could
not be detected. This finding implies that a free-radical
pathway is not operative in this reaction.
10
11
12
13
14
15
16
17
18
19
20
toluene
Pht-Bu
p-xylene
H
H
1j
H
1,4-di-tert-butylbenzene 1k
H
mesitylene
1l
1m
1n
–
t-Bu Pht-Bu
Me
H
toluene
PhNO2
benzene
PhOMe
pyridine
0f
NO2
H
–
0f
–
0f
In summary, we have investigated the use of environmen-
tally benign oxidizing agents in the synthesis of diaryl-
iodonium salts17 and found that a range of both symmetric
and unsymmetric salts can be prepared in good yields us-
H
–
0g
a Only the para isomer was observed for monosubstituted arenes.
b Isolated yield after aqueous workup, followed by trituration with di-
ing urea–hydrogen peroxide, a safe and green reagent. ethyl ether.
c Aqueous workup was omitted.
The reaction is insensitive to air and moisture, and product
isolation is straightforward, which makes this methodolo-
gy easily applicable in large-scale reactions.
d Reaction time was 6 h; yield for 3 h reaction time is given in brack-
ets.
e Reaction was run at r.t.; yield at 40 °C is given in brackets.
f No identifiable product was obtained.
g Only the N-oxidation of pyridine was observed.
Acknowledgment
This work was financially supported by the Swedish Research
Council, the Wenner-Gren Foundations, the Carl Trygger Founda-
tion, the Royal Swedish Academy of Sciences and the K & A Wal-
lenberg Foundation.
(2) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593.
(3) (a) Beringer, F. M.; Daniel, W. J.; Galton, S. A.; Rubin, G.
J. Org. Chem. 1966, 31, 4315. (b) Gao, P.; Portoghese, P. S.
J. Org. Chem. 1995, 60, 2276. (c) Ryan, J. H.; Stang, P. J.
Tetrahedron Lett. 1997, 38, 5061. (d) Aggarwal, V. K.;
Olofsson, B. Angew. Chem. Int. Ed. 2005, 44, 5516.
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Soc. 2005, 127, 7330.
References and Notes
(1) (a) Wirth, T. Angew. Chem. Int. Ed. 2005, 44, 3656.
(b) Stang, P. J. J. Org. Chem. 2003, 68, 2997. (c)Zhdankin,
V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (d) Topics
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Heidelberg, 2003.
(5) (a) Zhu, M.; Jalalian, N.; Olofsson, B. Synlett 2008, 592.
(b) Bielawski, M.; Olofsson, B. Chem. Commun. 2007,
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E. A. Merritt et al.
LETTER
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2008, 73, 4602.
(6) Bielawski, M.; Zhu, M.; Olofsson, B. Adv. Synth. Catal.
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(17) Diphenyliodonium Triflate (1a): A stirred mixture of
CH2Cl2 and TFE (2:1, 1 mL) was cooled to 0 °C and UHP
(47 mg, 0.50 mmol) was added. Tf2O (168 mL, 1.00 mmol)
was added dropwise to the suspension and the mixture was
stirred for 30 min at 0 °C. Iodobenzene (28 mL, 0.25 mmol)
was added, followed by benzene (45 mL, 0.50 mmol) and the
solution was warmed to r.t., then heated at 40 °C for 3 h. The
mixture was allowed to cool to r.t., evaporated in vacuo and
the residue was purified by trituration with Et2O (3 × 2 mL),
then dried in vacuo to afford the title compound (82 mg,
76%) as an off-white amorphous solid, spectroscopically
identical with literature data.6
(p-Tolyl)(phenyl)iodonium Triflate (1h): Prepared
according to the above procedure. The crude reaction
mixture was allowed to cool to r.t., evaporated in vacuo and
the residue was partitioned between CH2Cl2 (5 mL) and H2O
(5 mL). The aqueous layer was further extracted with
CH2Cl2 (5 mL) and the organic extracts were combined and
evaporated in vacuo. The residue was purified by trituration
with Et2O (3 × 2 mL) and dried in vacuo to afford the title
compound (84 mg, 76%) as an off-white amorphous solid,
spectroscopically identical with literature data.6
(13) Krasutsky, P. A.; Kolomitsyn, I. V.; Carlson, R. M. Org.
Lett. 2001, 3, 2997.
Synlett 2009, No. 14, 2277–2280 © Thieme Stuttgart · New York