Rapid aerobic iodination of arenes mediated by hypervalent iodine in fluorinated solvents

Article abstract of DOI:10.1016/j.tetlet.2017.01.003

Arenes are rapidly converted to the corresponding iodides by aerobic oxidative iodination at room temperature by treatment with iodine and catalytic quantities of nitrous acid in a fluorinated solvent. Dichloroiodic acid is proposed as the actual iodination reagent.

Full text of DOI:10.1016/j.tetlet.2017.01.003

Accepted Manuscript
Rapid aerobic iodination of arenes mediated by hypervalent iodine in fluorinated
solvents
Jernej Iskra, S. Shaun Murphree
PII:
S0040-4039(17)30005-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.003
TETL 48506
Reference:
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
2 December 2016
21 December 2016
2 January 2017
Please cite this article as: Iskra, J., Shaun Murphree, S., Rapid aerobic iodination of arenes mediated by hypervalent
iodine in fluorinated solvents, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.003
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Tetrahedron Letters
Rapid aerobic iodination of arenes mediated by hypervalent iodine in fluorinated
solvents
a,b,
c
Jernej Iskra  and S. Shaun Murphree
a
Laboratory for Organic and Bioorganic Chemistry, “Jožef Stefan” Institute, Jamova 39, 1000 Ljubljana, Slovenia
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
Department of Chemistry, Allegheny College, 520 North Main Street, Meadville, PA, USA
b
c
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Arenes are rapidly converted to the corresponding iodides by aerobic oxidative iodination at room
temperature by treatment with iodine and catalytic quantities of nitrous acid in a fluorinated
solvent. Dichloroiodic acid is proposed as the actual iodination reagent.
2
009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
aromatic substitution
hypervalent compounds
iodination
fluorinated solvents
1,2
Iodoarenes are valuable synthetic intermediates for the
construction of complex organic targets, since they serve as
3,4
convenient precursors for Grignard reagents and as electrophilic
5,6
substrates for various cross-coupling methodologies.
Consequently, the preparation of iodoarenes continues to
7
command attention within the synthetic community. Recently
Scheme 1. Electrophilic aromatic iodination catalyzed by
nitrous acid generated in situ.
reported innovations include the use of N-iodosuccinimide
8
9
10
activated by iron(III), gold(I), or rhodium(III) catalysts;
11
hydrogen iodide in DMSO, and molecular iodine in the
presence of a sulfated ceria-zirconia catalyst in ethylene glycol
12
16
Prior work in our laboratory had demonstrated the efficacy of
13
or potassium 4-iodylbenzenesulfonate in acetonitrile. With this
backdrop, in connection with our ongoing program investigating
the catalytic activation of iodine or iodide toward electrophilic
aromatic substitution using environmentally benign terminal
nitrite catalysis in aromatic iodination, and there was evidence
that fluorinated solvents could further facilitate the reaction.
Thus, we surveyed a variety of reaction media (Table 1) for the
17
aerobic oxidative iodination of anisole using
a sodium
14–18
oxidants,
we wish to disclose our findings with respect to
nitrite/hydrochloric acid system. After 90 min, the reaction did
not show appreciable progress in seven solvents, including protic
electrophilic aromatic iodination (Scheme 1) using elemental
iodine in the presence of a substoichiometric amount of nitrous
acid, which mediates the in situ generation of a hypervalent
iodine reagent via aerobic oxidation.
(ethanol), moderately polar (ether, ethyl acetate, dichloromethane,
and acetone), and polar aprotic (DMF and DMSO) types.
However, good to excellent results were observed in the
fluorinated solvents hexafluoroisopropanol (HFIP), trifluoroacetic
acid (TFA), and trifluoroethanol (TFE). Mixtures of fluorinated
and non-fluorinated solvents were ineffective, as illustrated by the
absence of reactivity in a 1:1 ethanol/TFE medium (entry 17).
—
——

Corresponding author. Tel.: +386-1-4773631; fax: +386-1-4773822; e-mail: jernej.iskra@ijs.si

2
Tetrahedron Letters
The pronounced effect of these solvents is interesting, as
fluorinated alcohols are known to accelerate certain reactions
A plausible mechanism for this reaction is shown in Scheme
2. Nitrosyl chloride is known to be produced by the reaction of
19,20
22
(such as epoxidation) through template catalysis.
Inasmuch
sodium nitrite with hydrochloric acid. When molecular iodine
as TFE dissolves iodine better than HFIP, the effective activation
is greater in TFE for this particular system. While somewhat
more expensive than conventional reaction media, these
fluorinated solvents can be easily recovered in larger-scale
is present, these conditions lead to the subsequent formation of
23
iodine chloride through a process that likely liberates the
24
byproduct nitrosyl iodide, a transient species that is rapidly
25
hydrolyzed to nitrous acid and hydroiodic acid. In the closely
related peroxide-iodine system, spectroscopic and kinetic studies
21
reactions.
pointed to dichloroiodic(I) acid (HICl ) as the relevant iodinating
2
a)
Table 1. Iodination of anisole in various solvents.
17
reagent responsible for the rapid conversions, and comparable
rates observed in the present study suggest a similar pathway.
This would explain the need for excess hydrochloric acid (i.e.,
over and above the amount required to neutralize nitrite) to
Entry
Solvent
EtOH
Conv. (%)
1
2
3
4
5
6
7
8
9
0
0
CH Cl
2
2
convert the initially formed iodine chloride to HICl to maintain
2
high conversions.
acetone
0
High atom economy is achieved by the in situ oxidation of HI
2
Et O
0
to I mediated by a nitric oxide/nitrogen dioxide redox couple
2
DMF
1
26
derived from the aqueous decomposition of nitrous acid. The
increased activity in trifluoroethanol is consistent with DFT
studies suggesting coordination of the solvent with the active
DMSO
EtOAc
CHCl3
MeCN
CCl4
2
2
27
electrophile; however, in this case there is no evidence of the
14
20
29
32
56
70
75
86
99
0
concomitant oxidation of choride to Cl , since no organochlorine
2
products are observed.
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
hexane
AcOH
C6F14
HFIP
TFA
TFE
EtOH/TFE (1:1)
a)
2 2
Reactions were run using 0.5 eq I , 5 mol% NaNO , and 15
mol% HCl. Conversion was determined by HPLC at 90 min.
Scheme 2. Proposed mechanism for nitrous acid-
catalyzed iodination.
Using TFE as a solvent, the loadings of hydrochloric acid and
sodium nitrite were subsequently explored (Table 2). Nitrite is
essential for the protocol—no discernible conversion is observed
in its absence (entry 1). At a loading of 5 mol%, however,
anisole is fully iodinated within 90 min (entry 3); reduced levels
provide concomitantly lower conversions (entry 2). Examining
the influence of hydrochloric acid (entries 5-9) reveals the need
for two equivalents of acid vs. nitrite for satisfactory results (entry
To explore the scope of the reaction, several arenes were
subjected to iodination under the optimized conditions of 5 mol%
sodium nitrite and 15 mol% hydrochloric acid in TFE (Table 3).
For comparison, each reaction was also carried out in two non-
fluorinated solvents (acetonitrile and acetic acid), keeping the
reaction time constant. Highest yields were observed with
moderately nucleophilic arenes, such as durene, anisole, and
mesitylene (entries 5, 7, and 8, respectively), which is in concord
6). The reaction is tolerant to a small excess of acid, but it
28
with a similar study conducted by Wang and co-workers. In the
case of anisole, iodination yielded a 95:5 mixture of para- and
responds negatively to stoichiometric quantities (entries 8 & 9).
a)
Table 2. Influence of catalytic parameters on conversion.
ortho-iodinated products.
For slightly less electron-rich
substrates, such as 4-bromoanisole (entry 3) and 4-tert-
butyltoluene (entry 4), reactivity could be enhanced by shifting
from trifluoroethanol to trifluoroacetic acid. However, the
electron-poor arenes p-nitrotoluene (entry 1) and methyl p-toluate
Entry
eq HCl
0.15
0.15
0.15
0.15
0.05
0.10
0.20
1.0
eq NaNO
2
Conv. (%)
1
2
3
4
5
6
7
8
9
0
0
0.02
0.05
0.10
0.05
0.05
0.05
0.05
0.05
61
99
99
70
98
97
87
78
(entry 2) were resistant to iodination even in TFA for extended
reaction times.
2.0
a)
Reactions were run using 0.5 eq I
2 2
, 5 mol% NaNO , and 15
mol% HCl. Conversion was determined by HPLC at 90 min.

4
Tetrahedron
Table 3. Nitrite-mediated aerobic iodination of arenes.
a)
b)
Entry
Substrate
Product
Solvent
Time
h)
Yield
(%)
Conversion (%) in
(
MeCN
0
AcOH
0
1
TFA
TFA
TFA
TFA
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
72
65
16
4
0
2
3
4
5
6
7
8
9
< 1
95
94
< 1
< 1
< 1
3
< 1
< 1
< 1
5
c)
3
93
3
92
33
56
38
96
74
12
< 1
65
d)
1.5
1.5
98
69
92
90
81
61
12
84
e)
1
100
74
e)
1
1
1
0
1
2
1
e)
1
20
e)
1
< 1
a
isolated yield
b
NMR conversion for the same reaction time
c
used 5 mL of solvent
d
isolated as an inseparable mixture of para- and ortho-isomers (95:5 ratio)
(0.025 eq at a time) was added at 10 min intervals
e
supplemental NaNO
2

At the other end of the nucleophilicity spectrum, highly
electron-rich substrates required a slight modification to the
conditions. Thus, when using di- and trimethoxybenzene
derivatives as substrates (entries 9-12), it was necessary to add
small aliquots of nitrite periodically throughout the iodination;
otherwise, the reaction tended to stall. While dimethylresorcinol
and 1,3,5-trimethoxybenzene (entries 9 and 10, respectively) gave
excellent yields using this technique, the iodination of veratrole
References and notes
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Dohi, T.; Kita, Y.; in Iodine Chem. Appl. (Ed.: Kaiho, T.), John
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Li, J.J.; in Name React., Springer, 2014, pp. 291–292.
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formation of 4-nitro-1,2-dimethoxybenzene. An even more
pronounced anomaly occurred in the case of p-dimethoxybenzene
(entry 12), which provided the iodination product (2m) in only
8
.
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12% yield. Moreover, NMR analysis of the crude reaction
mixture indicated that 2-nitro-1,4-dimethoxybenzene was actually
the major product (molar ratio of nitration to iodination = ca.
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2
1.5:1).
2
It is noteworthy that the iodination efficiency of these highly
electron-rich substrates correlates strongly with their oxidation
2
9
potentials.
trimethoxybenzene are well behaved and also have the highest
redox potentials (E = 1.55 and 1.54 V, respectively); veratrole
= 1.42 V) provides moderate yield; and p-dimethoxybenzene
= 1.28 V) gives the poorest iodination result. In the latter
Thus,
dimethylresorcinol
and
1,3,5-
½
1
1
1
4. Iskra, J.; Stavber, S.; Zupan, M. Synthesis (Stuttg). 2004, 2004,
(
(
E
E
½
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869–1873.
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008, 350, 2921–2929.
½
two cases, it appears that the arene substrate intercepts the
nitrosonium cation in an SET process (as shown in Scheme 3)
2
6. Iskra, J.; Stavber, S.; Zupan, M. Tetrahedron Lett. 2008, 49, 893–
30
through a well-established pathway. The formation of this by-
product has the collateral disadvantage of depleting the
nitrosonium catalyst, essentially shutting down the iodination
reaction. Notably, this competing nitration pathway for very
895.
17. Bedrač, L.; Iskra, J. Adv. Synth. Catal. 2013, 355, 1243–1248.
1
1
2
2
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Chem. Soc. 2006, 128, 8421–8426.
4
28
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2
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In summary, we have shown that molecular iodine in the
presence of catalytic quantities of nitrite and hydrochloric acid in
fluorinated solvent represents a convenient and efficient means
for the aerobic oxidative iodination of moderately electron-rich
aromatic substrates. We continue to study this interesting system
with respect to mechanistic detail, as well as additional
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3
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Acknowledgments
The authors gratefully acknowledge the Fulbright Scholar
Program (Grant No. 48131678), the Slovenian Research Agency
(Program P1-0134 and Bilateral Project BI-US/15-16-083), and
the Slovene Human Resources Development and Scholarship
Fund for their financial support of this work.

6
Tetrahedron
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Rapid aerobic iodination of arenes mediated
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Jernej Iskra* and S. Shaun Murphree

Rapid aerobic iodination of arenes mediated by hypervalent iodine in fluorinated solvents
Jernej Iskra and S. Shaun Murphree
Highlights



Moderately electron-rich arenes are the most suitable substrates for iodination.
A catalytic mechanism involving dichloroiodic acid is proposed.
Competitive formation of nitroarenes is observed in highly electron-rich substrates.