Selectfluor F-TEDA-BF4 mediated and solvent directed iodination of aryl alkyl ketones using elemental iodine

Article abstract of DOI:10.1039/b200240j

Reactions of aryl alkyl ketones with methanol solution of elemental iodine and 1-fluoro-4-chloromethyl-1,4-diazonia-bicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor F-TEDA-BF₄) result in the formation of corresponding α-iodo ketones, wh

Full text of DOI:10.1039/b200240j

Selectfluor™ F-TEDA-BF4 mediated and solvent directed iodination of
aryl alkyl ketones using elemental iodine†
Stojan Stavber,* Marjan Jereb and Marko Zupan
Laboratory for Organic and Bioorganic Chemistry, ‘Jozˆef Stefan’ Institute and Department of Chemistry,
University of Ljubljana, Jamova 39, 1000 Ljubljana, Slovenia. E-mail: stojan.stavber@ijs.si; Fax: +386 1
477 3811
Received (in Cambridge, UK) 7th January 2002, Accepted 28th January 2002
First published as an Advance Article on the web 8th February 2002
Reactions of aryl alkyl ketones with methanol solution of
elemental iodine and 1-fluoro-4-chloromethyl-1,4-diazonia-
bicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™ F-
TEDA-BF4) result in the formation of corresponding a-iodo
ketones, while switch over of the regioselectivity can be
directed by using acetonitrile as the solvent and selective
iodination of the aromatic site of target molecules is thus
achieved.
The thus established fact that alkyl aryl ketones bearing an
activated aromatic part of the molecule could be regiose-
lectively iodinated at the a-carbonyl position seems at first sight
to be in contrast to our earlier observation that p-methoxy-
acetophenone is exclusively iodinated at the phenyl ring using
I2–F-TEDA-BF4, but in that case MeCN was used as solvent.8
Encouraged by the possibility that the regiochemistry of the
iodination process could be regulated merely by the solvent
used, we further investigated the reactions of a series of hydroxy
and methoxy substituted aryl ketones with the I2–F-TEDA-BF4
system in methanol and in acetonitrile. As follows from the data
collected in Scheme 2, the solvent directed regioselectivity of
the iodofunctionalisation was confirmed. 4A-Hydroxyacetophe-
none was regioselectively and almost quantitatively trans-
formed to 3A-iodo-4A-hydroxyacetophenone 4 when the reaction
was performed in MeCN, while 1-(4-hydroxyphenyl)-2-iodo-
ethanone 5, was exclusively formed in MeOH. The same switch
of regioselectivity was observed in the case of 2A-methoxy,
2A,4A-dimethoxy and 2A,6A-dimethoxy substituted acetophenone
where ring iodinated products 6, 8, and 10 were formed in
MeCN mediated reactions, while a-iodocarbonyl derivatives 7,
9, 11 were formed when MeOH was used as solvent. We further
confirmed this phenomenon of the switch over of regioselectiv-
ity in the case of two methoxy substituted benzocycloalkan-
1-one derivatives. The formation of 7-iodo-4-methoxyindan-
1-one 12 was established when 4-methoxyindan-1-one was
treated with the I2–F-TEDA-BF4 system in MeCN, and 2-iodo-
4-methoxyindan-1-one 13 was formed after reaction in MeOH,
while a mixture of isomeric aryl iodides 14 and 15 was isolated
after MeCN mediated iodination. The a-iodocarbonyl deriva-
tive 16 was regioselectively formed when 6-methoxy-3,4-dihy-
dronaphthalen-1(2H)-one was used as the target molecule and
the reaction performed in MeOH.
Iodo substituted organic molecules are versatile intermediates
in organic synthesis, and above all in carbon–carbon bond
formation. In addition, many iodoorganic compounds are
biologically active molecules often used in medicine as drugs or
diagnostic aids as radioactive labelled markers or contrastors,
and therefore their related chemistry has attracted broad
interest.1 Aryl iodides and a-iodoketones are especially conven-
ient tools for the above mentioned purposes. Direct iodination
of an aromatic ring involving electrophilic iodine as the reactive
species is the most often used synthetic methodology for the
preparation of aryl iodides,1 and some new reagents or related
systems were introduced recently.2 On the other hand, a-
iodoketones are usually prepared indirectly using halogen
interchange reactions or electrophilic iodination of enol acetates
and enol silyl ethers, while there has been very little information
concerning the direct a-iodination of ketones.3 We now report
a new method for direct a-iodination of aryl ketones using
elemental iodine as an iodine atom source and the N–F
compound,
1-fluoro-4-chloromethyl-1,4-diazoniabicyclo-
[2.2.2]octane bis(tetrafluoroborate) (1), known under the com-
mercial name of Selectfluor™ F-TEDA-BF4, as the mediator of
the reaction. Organic molecules bearing a reactive N–F bond are
excellent reagents for selective fluorination of organic com-
pounds under mild reaction conditions4 and F-TEDA-BF4 is
one of the most popular members of this family.5 On the other
hand, the N–F reagents possess moderate to strong oxidative
power,6 but investigations taking advantage of this property are
still scarce.7
Concerning the mechanism of this synthetically useful
reaction, some preliminary observations should be pointed out.
Under the mentioned reaction conditions we did not observe
any reaction between elemental iodine and F-TEDA-BF4. On
the other hand, it is known that F-TEDA-BF4 is a very effective
reagent for the fluorofunctionalisation of activated aromatics as
In a typical experiment‡ a mixture of an acetophenone
derivative (2a–f), iodine and F-TEDA-BF4, dissolved in
methanol, was stirred at room temperature and after a work-up
procedure high to excellent yields of a-iodocarbonyl substituted
products 3a–f were detected in the crude reaction mixture
(Scheme 1). Half of a molar amount of iodine and F-TEDA-BF4
was established to be sufficient for the conversion of a molar
amount of the ketone to its a-iodo carbonyl derivative.
Substituents on the benzene ring had no crucial effect on the
course of reaction. The target phenyl methyl ketone molecules
bearing a deactivated benzene ring (2e, 2f) were also readily
transformed to the a-iodo carbonyl derivatives 3e and 3f, but a
longer reaction at moderately elevated reaction temperatures
(50–60 °C) and an excess of the iodinating reagent (up to 30%)
was necessary. Acetyl substituted polynuclear aromatics (2g–k)
can also be directly transformed to the corresponding iodome-
thyl aryl ketones 3g–k in high yield using the mentioned
reaction protocol.
† Electronic supplementary information (ESI) available: experimental
details. See http://www.rsc.org/suppdata/cc/b2/b200240j/
Scheme 1
488
CHEM. COMMUN., 2002, 488–489
This journal is © The Royal Society of Chemistry 2002

and that a rounded-up electron flow, starting from oxidation of
I2 with F-TEDA-BF4, and proceeding with attack of the thus
formed electrophilic iodine species at the most reactive position
on the target aryl alkyl ketone, is the driving force of the
reaction. A detailed mechanistic study based on extended
experimental data, including kinetic and thermodynamic
parameters of the reaction, is in progress and will be published
in our forthcoming report.
In conclusion, we can stress the following comparative
advantages of the new method for direct and selective
iodination of aryl ketones. The reaction protocol is easy to
perform and in elemental iodine, as a cost effective source of
iodine, both iodine atoms are involved in the iodination process.
Further, the method can also be used for aryl ketones bearing a
highly activated aromatic ring, while the a-iodocarbonyl vs.
iodoaryl regioselectivity of the reaction can be regulated by the
solvent.
The authors are grateful to the Ministry of Education, Science
and Sport of the Republic of Slovenia for financial support, and
to T. Stipanovic and Professor B. Stanovnik for elemental
combustion analysis.
Notes and references
‡ To a solution of 2 mmol of substituted acetophenone derivative (2) in
MeCN (20 mL), 254 mg (1 mmol) of elemental iodine and 354 mg (1 mmol)
of F-TEDA-BF4 (1) were added and the reaction solution stirred at room
temperature until the red colour of the reaction mixture disappeared (1–24
h). The solvent was removed under reduced pressure and the crude reaction
mixture dissolved in 50 mL of CH2Cl2, insoluble material filtered off, the
solution washed with aqueous sodium thiosulfate pentahydrate (5%, 20 mL)
and water (20 mL), and dried over anhydrous Na2SO4. The solvent was
evaporated, the crude reaction mixtures analysed by 1H NMR, MS and TLC
and amounts of crude products were determined from 1H NMR spectra of
reaction mixture using 1,1-diphenylethene as internal standard while pure
products were obtained after flash chromatography over SiO2 or by
preparative TLC. The physico-chemical and spectroscopic characteristics of
already known a-iodoketones were compared with published data, while
new compounds were validated as stated in the ESI† and their purity
confirmed by elemental analysis.
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Scheme 2
well as of ketones,4,5 but for these transformations a tem-
perature much higher (60–80 °C) than rt was necessary. Since
no significant reaction between aryl methyl ketones 2 and F-
TEDA-BF4 could be observed under the reaction conditions
given below, it seems that a three-component reaction system
I2–F-TEDA-BF4–ketone is necessary for the iodination process
CHEM. COMMUN., 2002, 488–489
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