Tagged hypervalent iodine reagents: A new purification concept based on ion exchange through SN2 substitution

Article abstract of DOI:10.1021/ol702319p

(Chemical Equation Presented) The preparation of phenylsulfonate-tagged iodine(III) reagents as well as their use in a novel purification strategy for iodine(III)-promoted reactions is described. The concept is based on ion exchange and is initiated by an azide-promoted S_N2-reaction at the alkyl sulfonate followed by trapping of the resulting aryl sulfonate anion with an ion-exchange resin. The concept is successfully proven for Ru-catalyzed oxidations of alcohols, the activation and glycosidatlon of thioglycosides, and the Suarez reaction of pyranoses.

Full text of DOI:10.1021/ol702319p

ORGANIC
LETTERS
2007
Vol. 9, No. 25
5199-5202
Tagged Hypervalent Iodine Reagents: A
New Purification Concept Based on Ion
Exchange through SN2 Substitution
Eike Kunst,† Florian Gallier,†,‡ Gilles Dujardin,‡ Mekhman S. Yusubov,§ and
Andreas Kirschning*,†
Institut fu¨r Organische Chemie der Leibniz UniVersita¨t HannoVer, Schneiderberg 1B,
30167 HannoVer, Germany, and UCO2M, UMR CNRS 6011, UniVersite´ du Maine,
F-72085 Le Mans Cedex 9, France, The Siberian State Medical UniVersity, 2
MoskoVsky trakt, 634050 Tomsk, Russia, and The Tomsk Polytechnic UniVersity, 30
Lenin St., 634050 Tomsk, Russia
andreas.kirschning@oci.uni-hannoVer.de
Received September 24, 2007
ABSTRACT
The preparation of phenylsulfonate-tagged iodine(III) reagents as well as their use in a novel purification strategy for iodine(III)-promoted
reactions is described. The concept is based on ion exchange and is initiated by an azide-promoted SN2-reaction at the alkyl sulfonate followed
by trapping of the resulting aryl sulfonate anion with an ion-exchange resin. The concept is successfully proven for Ru-catalyzed oxidations
of alcohols, the activation and glycosidation of thioglycosides, and the Sua´rez reaction of pyranoses.
The chemistry of hypervalent iodine reagents 1 in the
oxidation state +3 has flourished for more than two decades
due to their rich and diverse oxidative properties.1 Ionic as
well as radical mechanistic pathways have been discussed
for iodine(III)-mediated oxidations. Recently, iodine(III)
chemistry has been extended to catalytic processes.2
phase bound and perfluoro-tagged reagents3 was employed
to iodine(III) reagents,4 which allows easy removal of excess
of hypervalent iodine reagent 1 as well as of the reduction
product 2 (Figure 1).
All of these concepts are based on the covalent attachment
of the iodo moiety to the solid phase or tag. Recycling then
requires the reoxidation of the immobilized or tagged aryl
iodide which is not always a straightforward procedure,
particularly in the case of polymeric backbones which can
be prone to oxidation. An alternative solid-phase-assisted
Iodobenzene 2 is a common byproduct in these oxidations.
It usually has to be removed chromatographically, which
often is a cumbersome task. Therefore, the concept of solid-
† Leibniz University Hannover.
(3) (a) Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew. Chem.,
Int. Ed. 2001, 40, 650-679. (b) Ley, S. V.; Baxendale, I. R.; Bream, R.
N.; Jackson, P. S.; Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
Storer, R. I.; Taylor, S. J. J. Chem. Soc., Perkin Trans. 1 2000, 3815-
4195. (c) Drewry, D. H.; Coe, D. M.; Poon, S. Med. Res. ReV. 1999, 19,
97-148. (d) Ley, S. V.; Baxendale, I. R. Nat. ReV. Drug DiscoVery 2002,
1, 573-586.
(4) Selected examples: (a) Ley, S. V.; Thomas, A. W.; Finch, H. J. Chem.
Soc., Perkin Trans. 1 1999, 669-671. (b) Hossain, Md. D.; Kitamura, T.
Synthesis 2006, 1253-1256.
‡ Universite´ du Maine.
§ The Siberian State Medical University.
(1) Reviews on hypervalent iodine reagents: (a) Zdhankin, V. V.; Stang
P. J. Chem. ReV. 2002, 102, 2523-2584. (b) Ochiai, M. Top. Curr. Chem.
2003, 224, 5-68. (c) Prakash O.; Saini, N.; Sharma, P. K. Synlett, 1994,
221-227. (d) Varvoglis, A. The Chemistry of Polycoordinated Iodine;
VCH: Weinheim, 1992.
(2) Richardson, R. D.; Wirth, T. Angew. Chem., Int. Ed. 2006, 45, 4402-
4404.
10.1021/ol702319p CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/14/2007

Scheme 2. Preparation of Tagged Iodine(III) Reagents 4a-c
Figure 1. Tagged iodine(III) reagents 1 and corresponding
reduction products 2; L ) ligand.
strategy uses scavenger reagents,3 which so far has hardly
found use for iodine(III)-promoted reactions.5,6 In this paper,
we describe a new general scavenging concept, which relies
on a sulfonate ester tag acting as a dormant ion-exchange
group. The scavenging process is initiated by a SN2 step
which liberates a sulfonate anion. This is directly removed
from solution by trapping to an ion-exchange resin. Excess
of the tagged reagent is removed likewise by this method.
The ion-exchange resin initially serves as a source for the
nucleophile that attacks the sulfonate ester. The byproduct
R-Nu formed results from the SN2-displacement and as a
consequence ought to be volatile so that it will be removed
along with the solvent during workup.
the yield for isobutyl sulfonate 4c was 94% after 1.5 h it
dropped to 80% after a reaction time of 12 h. With isobutyl
alcohol as nucleophile the results were likewise and yielded
sulfonate 4b. Prolonged as well as shorter reaction times were
completely inadequate for the esterification with methanol.
However, methyl sulfonate 4a could be prepared in moderate
yield with an alternative procedure using sodium methanolate
and pipsyl chloride 3 in methanol.
At this early stage, we optimized the scavenging protocol
using azide exchange resin 5. We chose the azide ion because
of its good nucleophilic properties. In fact, Hassner and Stern
showed that ion-exchange resin 5 can be used for the
preparation of alkyl azides from sulfonates.7 Scavenging was
promoted under thermal conditions, and not surprisingly, the
reaction time strongly correlated with the size of R (Table
1). While methyl sulfonate 4a was fully removed from
To prove the versatility (efficiency, chemoselectivity) of
this concept, we first applied it to several iodine reagents in
the oxidation state +3 (Scheme 1). We deliberately chose
Scheme 1. Concept of a Dormant Ion-Exchange Scavenging
Systema
Table 1. Scavenging of Alkyl Sulfonates 4a-c in Acetonitrile
Using Ion-Exchange Resin 5
entry
R
time
24 h
24 h
48 h
10 min
3 h
T (°C)
yield (%)
1
2
3
4
5
6
methyl
rt
60
60
>99
>99
>99
22
35
>99
isopropyl
isobutyl
isobutyl
isobutyl
isobutyl
60 (MW, 150 W)
60 (MW, 150 W)
100 (MW, 150 W)
a Key: A ) starting material; B ) product; Nu ) nucleophile.
2 h
important or demanding transformations such as the oxidation
of alcohols, the oxidative activation of thioglycosides, as well
as radical oxidations of carbohydrates (Sua´rez reaction). The
preparation of a set of tagged iodine(III) reagents started from
commercially available p-iodobenzenesulfonyl chloride 3
(pipsyl chloride) which was converted into the corresponding
alkyl sulfonates 4a-c (Scheme 2). Best yields were obtained
for isobutyl alcohol in the presence of pyridine. However,
conversion strongly depended on the reaction time. While
solution at rt within 12 h, isobutyl sulfonate 4c required 48
h at elevated temperature. MW irradiating conditions dra-
matically accelerated (1 h) the scavenging process of 4c.
Acetonitrile turned out to be the best solvent for this purpose
because of its suitability in SN2-reactions and its favorable
MW absorbing property. In DMF, the process proceeded
equally well (1 h, 100 °C, 150 W), but this solvent was
abandoned due to its higher boiling point hampering rapid
workup.
(5) Yusubov, M. S.; Gilmkhanova, M. P.; Zhdankin, V. V.; Kirschning,
A. Synlett 2007, 563-566.
(6) Kirschning, A.; Yusubov, M. S.; Yusubova, R. Ya.; Chi, K.-W.; Park,
J. Y. Beilstein J. Org. Chem. (BJOC) 2007, 3.
(7) Hassner, A.; Stern, M. Angew. Chem. 1986, 98, 479-480; Angew.
Chem., Int. Ed. Engl. 1986, 25, 478-479.
5200
Org. Lett., Vol. 9, No. 25, 2007

Oxidation of the isobutyl 4-iodophenylsulfonate 4c using
the procedure described by Saltzman et al.8 yielded bis-
(acetoxy)iodoarene 7 (Scheme 3). Other oxidizing conditions
Table 2. RuCl3-Catalyzed Oxidation of Alcohols to Carbonyl
Compounds Using Tagged DIB 7
Scheme 3. Preparation of Iodane 711 and Formation of
Tagged Iodine(III) Reagents 8 and 9 from 7
reported (NaBO3,9 CrO3,10a NaIO4,10b or K2S2O810c) failed,
and in no case were we able to isolate iodanes derived from
aryl iodides 4a and 4b, respectively.
This tagged bis(acetoxy)iodane 7 served as the starting
point for the preparation of two other hypervalent iodine
reagents containing the dormant sulfonate anion (Scheme 3).
However, reaction conditions had to be found which do not
result in hydrolysis of the sulfonate group. Saponification
of 7 afforded isobutyl iodosylphenylsulfonate 8 in 80% yield.
Like iodosylbenzene, derivative 8 is insoluble in organic
solvents very likely because of its oligomeric nature. In triflic
anhydride, depolymerization proceeds within several minutes
to afford a highly labile yellow solid (decomposition to
p-iodophenylsulfonic acid occurs within a few hours in the
glove box) which is expected to be the tagged µ-oxo complex
9, an analogue of Zefirov’s reagent.12 In principle, other
tagged iodine(III) reagents can also be prepared from 7 such
as the Koser reagent or alkynyliodonium salts.
a Isolated yield of pure compound. b Mixture of diastereoisomers was
employed. c Method A (Supporting Information), 3.4 equiv of 7. d Method
B (Supporting Information), 3.2 equiv of 7.
Recently, we reported the RuCl3-catalyzed oxidation of
alcohols using (diacetoxyiodo)benzene (DIB) as oxidant.5,13
Evidence was collected that this reaction proceeds via an
initial instantaneous Ru-catalyzed disproportionation of DIB
to iodobenzene and iodylbenzene with the latter acting as
the actual stoichiometric oxidant. We chose this principle
reaction to initiate the synthetic evaluation of tagged DIB 7
(Table 2). In principle, oxidations proceeded under similar
conditions with similar yields as was shown for DIB.13 The
purification protocol using the azide exchange resin 5
afforded pure oxidation products after filtration and removal
of the solvent. In the case of product 18, contamination with
ruthenium was determined to be around 10 ppm as judged
by ICP-MS. It can be expected that resin 5 also serves to
remove ruthenium salts from the reaction mixture.
As iodine(III) reagents are soft electrophiles, we chose
thioglycosides as glycosyl donors in glycosidations.14 In order
to reduce workup to a minimum, not only removal of the
iodoarenes has to be guaranteed but also scavenging of other
byproducts such as traces of TfOH, thiols, disulfides, and
oxygenated disulfides which are formed during the glycosi-
dation process. Fukase and co-workers15 had demonstrated
that efficient activation of thioglycosides can be achieved
by using the reagent system iodosylbenzene and triflic
anhydride.
As is shown in Scheme 4 a set of reagents was required
to cleanly transform 2-deoxy thioglycoside 22 into glycosides
23 and 24. The optimized procedure (Figure 2) is initiated
by first employing the reagent system iodosyl arene/Tf2O
(8) Sharefkin J. G.; Saltzman, H. Organic Syntheses; Wiley: New York,
1973; Collect. Vol. V, p 660; Org. Synth. 1963, 43, 62.
(9) McKillop, A. Kemp, D. Tetrahedron 1989, 45, 3299-3306.
(10) (a) Kaz´mierczak, P. Skulski, L. Synthesis 1998, 1721-1723. (b)
Kaz´mierczak, P.; Skulski, L.; Kraszkiewicz, L. Molecules 2001, 6, 881-
891. (c) Hossain, M. D.; Kitamura, T. Synthesis 2005, 12, 1932-1934.
(11) For details, see the Supporting Information.
(12) Zefirov, N. S.; Zhdankin, V. V.; Dan’kov, V. V.; Koz’min, A. S. J.
Org. Chem. USSR (Engl. Transl.) 1984, 20, 401-403.
(13) Yusubov, M. S.; Chi, K.-W.; Park, J. Y.; Karimov, R.; Zhdankin,
V. V. Tetrahedron Lett. 2006, 47, 6305-6308.
(14) (a) Kirschning, A.; Scho¨nberger, A.; Jesberger, M. Org. Lett. 2001,
3, 3623-3626. (b) Jaunzems, J.; Kashin, D.; Scho¨nberger, A.; Kirschning,
A. Eur. J. Org. Chem. 2004, 3435-3446. (c) Jaunzems, J.; Kashin, D.;
Scho¨nberger, A.; Kirschning, A. Eur. J. Org. Chem. 2004, 3435-3446.
(15) Fukase, K.; Kinoshita, I.; Kanoh, T.; Nakai, Y.; Hasuoka, A.;
Kusumoto, S. Tetrahedron 1996, 52, 3897-3904.
Org. Lett., Vol. 9, No. 25, 2007
5201

acetalic pyranoses (Sua´rez reaction)18 is a very illustrative
example (Scheme 5). Here, we chose tagged bis(acetoxy)-
Scheme 4. Iodine(III)-Promoted Glycosidations of
Thioglycosides and Scavenging Protocol
Scheme 5. Radical â-Fragmentation of Pyranoses
iodoarene 7 as hypervalent iodine reagent. Thus, pyranoses
25 and 27 in the presence of molecular iodine and 7 afforded
formiates 26 and 28, respectively, after a scavenging protocol
which consisted of treatment with thiosulfate exchange resin
29 for removal of the remaining iodine and azide exchange
resin 5 under microwave accelerating conditions. Remark-
ably, formation of the alkyl azide derived from 28 was not
observed.
which serves to promote glycosidation by electrophilic attack
of the iodine(III) species onto the sulfide moiety. Addition
of Amberlyst A-21 removes traces of acidic byproducts,
while borohydride exchange resin16 in 2-propanol is very
effective in removing all thio-based byproducts.17 Finally,
all sulfonate tagged iodine species are scavenged by the azido
In conclusion, we introduced a new concept for scavenging
aryliodo species which result as byproducts from iodine-
(III)-promoted transformations. In principle, the isobutyl-
sulfonyl tag and this scavenging concept are expected to be
of general applicability for purification protocols of reagents
as well as catalysts. Importantly, scavenging exclusivley
relies on ion exchange resins, which allows easy regeneration
by simply washing protocols. We believe that it should be
possible to implement the concept descibed in continuous
flow reactors, as was recently demonstrated for tagged
phosphine reagents.19
Acknowledgment. Support from the Fonds der Chemis-
chen Industrie is gratefully acknowledged. F.G. thanks the
DAAD for a sandwich scholarship (A/04/20592). M.S.Y.
thanks the Russian Ministry of Education and the Deutsche
Akademische Austauschdienst (DAAD) for a scholarship and
RFBR (Grant No. 07-03-00239a).
Figure 2. 1H NMR spectra of crude glycosidation product 23 and
after sequential treatment with scavinging resins.
Supporting Information Available: Descriptions of
experimental procedures for compounds and analytical
characterization including the X-ray structural analysis of
7. This material is available free of charge via the Internet
at http://pubs.acs.org.
exchange resin 5 under microwave irradiation conditions to
yield the glycosidation products 23 and 24, respectively.
Finally, we chose a radical transformation promoted by
iodine(III) reagents for which the â-fragmentation of hemi-
OL702319P
(16) Kirschning, A. J. Prakt. Chem. 2000, 342, 508-511.
(17) (a) Jaunzems, J.; Hofer, E.; Jesberger, M.; Sourkouni-Argirusi, G.;
Kirschning, A. Angew. Chem., Int. Ed. 2003, 42, 1166-1170. (b) Jaunzems,
J.; Sourkouni-Argirusi, G.; Jesberger, M.; Kirschning, A. Tetrahedron Lett.
2003, 44, 637-639.
(18) de Armas, P.; Francisco, C. G.; Sua´rez, E. Angew. Chem. 1992,
104, 746-748; Angew. Chem., Int. Ed. Engl. 1992, 31, 772-774.
(19) Smith, C. D.; Bavendale, I. R. Baxendale, Tranmer, G. K.; Baumann,
M.; Smith, S. C.; Lewthwaite, R. A.; Ley, S. V. Org. Biomol. Chem. 2007,
5, 1562-1568.
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Org. Lett., Vol. 9, No. 25, 2007