July, 1999 number 104

Contribution
Utilization of Iodine Resources
Syntheses & Reactions of Hypervalent Organoiodanes

Masahito Ochiai, Professor,

Faculty of Pharmaceutical Sciences,
University of Tokushima

As Japan is not blessed with abundant natural resources, the Japanese are dependent on the
importation of the majority of our raw materials from overseas. However, Japan can be proud for its
production of iodine, where it is a leading manufacturer in the world. Fossil seawater obtained from
underground is the material for producing industrial iodine. More than 80% of the produced iodine is
exported to various countries of the world. However, we have to rely on the United States and Europe for
importation of the majority of the products into which iodine is incorporated, for instance, an X-ray contrast
medium or a photosensitive agent for photographic film. Because of this, our iodine resource is not fully
utilized. Accordingly, it becomes very important to develop an effective method for utilization of iodine to
its full extent by producing high value organoiodane. Our attention has been directed to trivalence
hypervalent organoiodanes (λ3-organoiodane) with low toxicity and we are making a study of its full use in
the synthetic organic chemistry.
Iodine is large-sized halogen element, easily polarizable and low in electronegativity. It forms
hypervalent organoiodanes beyond the octet theory by readily extending its valence.
The representative λ3-organoiodanes are iodosylbenzene (polymer) 1, (diacetoxyiodo)benzene 2,
[bis(trifluoroacetoxy)iodo]benzene 3, [hydroxy(tosyloxy)iodo]benzene (Koser reagent) 4, o-iodosylbenzoic
acid 5. They have been widely used as oxidants for active methylene groups, double and triple bonds,
alcoholic and phenolic hydroxyl groups, sulphur and amino compounds 1) . More than twenty kinds of λ3-
organoiodanes including the above-noted iodanes, are available from Tokyo Kasei Kogyo Co. Ltd.

I O X I X HO I OTs HO I O t-BuOO I O
n
O O

1 2: X = OAc 4 5 6
3: X = OCOCF3

The λ3-organoiodane which contains an alkylperoxy group as a ligand has not been synthesized
probably because of its high tendency to decompose. We have recently found 2) that the Lewis acid-
catalyzed ligand exchange of 1-hydroxy-1,2-benziodoxol-3(1H)-one 5 with tert-butyl hydroperoxide affords
the crystalline peroxyiodane 6. The peroxyiodane 6 is very stable in the solid state, no decomposition
whatever is found, and its cystalline form stores well at room temperature for over one year. This product
is an interesting compound since it contains tert-butylperoxy group and a trivalent iodine atom, in the same
molecule, both of which are powerful oxidants. The purpose of this review is to describe the usefulness of
λ3-peroxyiodanes and their wide applications as radical oxidants.

1. Syntheses & Reactions of Alkenyliodanes and Alkynyliodanes

In 1985 it was found that when iodosylbenzene 1 was activated with BF3 in dichloromethane, and
is reacted with vinylsilane or vinylstannane, the silicon or tin is replaced with trivalent iodine and λ3-alkeny-
liodane 7 can be synthesized in good yield (Figure 1) 3). The generation of λ3-alkenyliodane is stereospecific
and the stereochemistry of vinylsilane or vinylstannane is maintained. The λ3-alkenyliodane 7 can also be
obtained through boron-iodine exchange reaction, employing vinylboronic acid as a substrate 4).

R1 SiMe3 PhIO 1 R1 I(Ph)BF4

R2 BF3-Et2O R2
7

Fig.1

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The trivalent iodine group exhibits very high leaving group ability and, therefore, nucleophilic
substitution reactions of alkenyliodane 7 at vinylic carbons proceed at room temperature under mild
conditions. Enolate anions, R2CuLi, CuCN, ArSNa, n -Bu4 NCl, etc. act as good nucleophiles in these
reactions. Especially, an SN2 reaction at vinylic carbons accompanied by the stereochemical inversion of
configuration, which was regarded as not to proceed before, is made possible through use of alkenyliodane
7. In alkenyliodane 7, the acidity of α -hydrogens is high enough for the α-elimination to take place followed
by reductive elimination of iodobenzene, in the presence of a base, leading to the generation of an alkylidene
carbene in good yield 5).

In a similar way as the synthesis of alkenyliodanes, alkynyliodane 8 can be synthesized from

alkynylsilane and stannane (Figure 2). Synthesis of alkynyliodanes can also be performed directly from
the terminal alkyne 5). The Michael addition reaction of the alkynyliodane 8 with enolate anions, leads to
the formation of cyclopentene skeletons. As shown in Figure 2, the alkynyliodane 8 (R=H) is a good
ethynylation reagent 6) and available from Tokyo Kasei. The alkylidene carbene is a reaction intermediate
and an ethynylated product can be obtained via 1,2-hydrogen rearrangement of the α-hydrogen.

PhIO 1
R MR3 R I(Ph)
BF3-Et2O BF4
M = Si, Ge, Sn
8

O
n-Bu
O O H O
O O O O
8 n-Bu n-Bu
t-BuOK
R=H O O O O

Fig.2

2. Generation of Allenyliodanes & Their Reductive Iodonio-Claisen Rearrangement

The application of the silicone-iodane exchange reaction to propargylsilane leads to the generation
of λ3-allenyliodane via an SE 2' reaction. When (diacetoxyiodo)benzene 2 was treated with propargylsilane
9 in the presence of BF3, the propargyl group was introduced at the ortho-position of iodobenzene and o-
propargyliodobenzene 10 was obtained in high yields 7) (Figure 3). After a number of other reactions were
studied, the followiing observations were made:
1) The trivalent iodine is always reduced to univalent iodide.
2) Regioselective propargylation occurs at the ortho-position of iodoarenes.
3) The new carbon-carbon bond is formed regioselectively at the α−carbon of the propargyl group.
4) The reaction proceeds at a low temperature.
5) Propargylgermane and stannane can also be used.
6) Hydroxy- and acetoxy-propargylsilanes can be used.

AcO I OAc I
SiMe3
BF3-Et2O
+ R
CH2Cl2, -20°C R
10
2 9
AcOH
R
AcO I H AcO I
•
H • H
R
9 [3, 3]
R
11 12
OAc

Fig.3

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July, 1999 number 104

The reaction mechanism, taking into account the above observations, is shown in Figure 3. Reactions
of propargylsilane with electrophiles, such as halogens and acyl chlorides, are known to proceed via SE 2'
process. To start with, the reaction affords λ 3-allenyliodane 11. Subsequently, a propargyl group is
introduced regioselectively at the ortho-position via intramolecular [3,3]sigmatropic rearrangement, and
acetic acid is then released by means of the subsequent reductive elimination of 12 with the formation of
the o-propargyliodobenzene 10. Intramolecular nature for the rearrangement of λ3-allenyliodane 11 is
strongly supported by the cross reaction in the presence of univalent iodoarene. Although heating at 150-
250°C is required for ordinary Claisen rearrangement reactions, the reductive iodonio-Claisen rearrange-
ment proceeds at a low temperature. The rate determining step of the reaction is presumed to be a
[3,3]sigmatropic rearrangement of the λ3-allenyliodane 11. The lower activation energy associated with
the iodonio-Claisen rearrangement of 11 can be interpreted in terms of the small bond energy needed to
break the apical carbon-iodine(III) bond. In general, aryliodanes ArIX 2 adopt a T-shaped geometry, the
hypervalent I(III)-X bonds being well overlapped with the aromatic π bond. This favorable orbital interaction
could facilitate the rearrangement of 11.
In the above reductive iodine(III) Claisen rearrangememt reaction, we had no direct evidence for
the generation of λ3-allenyliodane 11, which has been considered to be an intermediate. Therefore, we
have carried out the reaction of dimethylpropargylsilane 13 with hydroxyiodane 5 in order to isolate or
detect the intermediate, allenyliodane 14 (Figure 4). It seems reasonable to assume that the [3,3]-sigmatropic
rearrangement of allenyliodane 14 proceeds with difficulty, probably because the hypervalent C-I(III) bond
being cleaved during the [3,3]-sigmatropic rearrangement could not overlap with the aromatic π orbitals
and because of the steric hindrance of the terminal two methyl groups and their electronic effects. As
expected, no propargylation at the ortho-position by [3,3] sigmatropic rearrangement was observed. To
our regret, we could not detect the generation of allenyliodane 14. Contrary to our expectation, the present
reaction generated alkylperoxyiodane 15 8). Peroxyiodane 15 has an alkylperoxy group and hypervalent
iodine(III) in a same molecule, both acting as oxidants, but is stable in a solid state. X-ray analysis
revealed that the iodine atom has a typical T-shaped geometry specific to hypervalent compounds with
some distortion in shape.

Me3Si Me
HO I O SiMe3 Me
Me3Si Me I O OO I O
Me
13 •
O
BF3 Me O O
CH2Cl2 Me Me3Si
5 14 15

Fig.4

3. Synthesis of tert-Butylperoxyiodanes
Hypervalent λ3−organoiodanes having an alkylperoxy group as a ligand are very unstable. In 1968
Milas and Plesnicar reported that reaction of iodosylbenzene 1 with tert-butylhydroperoxide in methylene
chloride at -80°C generated tert-butylperoxy radical and iodobenzene . It was assumed that in this reaction,
an initial ligand exchange on the iodine atom afforded bis(alkylperoxy)iodane, which was so unstable,
resulting in homolytic bond cleavage of the hypervalent O-I bond, even at -80°C, to give a tert-butylperoxy
radical. Accordingly, isolation of alkylperoxyiodane 15 is very interesting because it is stable even at room
temperature. This is attributed to fixation of both the apical heteroatom ligands and equatorial aromatic
ligand in the same plane by the formation of five-membered heterocycles. This arrangement to form an
iodoxolone leads to enhanced stability of the alkylperoxyiodanes 15 because orbital interaction between
the easily cleaved I-O bond and π-orbitals of phenyl group is not feasible.
The alkylperoxyiodanes with unique structure were expected to be utilized as new oxidants in
organic synthesis. Hereby, iodane 6, in which the tert-butylperoxy group was introduced, was designed
as a representative compound and its synthesis attempted. Reaction of hydroxyiodane 5 with tert-butyl-
hydroperoxide did not take place at room temperature and hydroxyiodane was recovered because of its
poor reactivity. However, on addition of Lewis acid to the reaction mixture, the desired ligand exchange on
the iodine atom proceeded effectively to afford peroxyiodane 6 in good yield (Figure 5) 2). Coordination of
BF3 on the oxygen atoms of hydroxyiodanes 5 causes activation. The product tert-butylperoxyiodane 6 is
stable in the solid state and no decomposition is seen when the crystalline form is stored over a year at
room temperature.

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HO I O t-BuOO I O Cl I O

BF3 CDCl3
O + t-BuOOH O O
CHCl3, 0 oC rt

5 6

I I I
•I O
I CO2H
140 oC
6 t-BuOO • O + + + MeCOMe

16

Fig.5

The peroxyiodane 6, though stable in the solid state, is readily decomposed in solution. When the
peroxyiodane 6 is dissolved in chloroform and allowed to stand at room temperature, a ligand exchange
takes place to give chloroiodane, and the half life of 6 is about 4 days. Heating crystalline peroxyiodane at
140°C causes it to decompose explosively to generate 1,2-diiodobenzene (46%), iodobenzene (6%), o -
iodobenzoic acid (14%) and acetone (43%). In this thermal decomposition reaction, the decomposition is
considered to take place via the generation of tert-butylperoxy radical and 9-I-2 σ-iodanyl radical 16 due to
cleavage of the weak hypervalent bond between the oxygen of the peroxy group and iodine atom.

4. Benzylic Oxidation Reaction by tert-Butylperoxyiodane 9)

tert-Butylperoxyiodane 6 is effective for the oxidation of the benzylic methylene group of benzyl
ethers 17, to form esters of benzoic acid 18. Reactions are performed at room temperature under a
nitrogen atmosphere using a rubber balloon. The yields of esters are highly dependent upon the dielectric
constant of the solvents and the best results were obtained in benzene which has a small dielectric constant,
although, the reaction at room temperature was very slow. However, the reaction in benzene was
considerably accelerated with the addition of alkali metal carbonates (K2CO3, Cs2CO3 etc.).
The benzyl group is frequently used as a protecting group for alcohols in organic synthesis. Since
esters are readily hydrolized to alcohols, peroxyiodane 6 provides an oxidative deprotection method for
the benzyl group. One of the common problems associated with deprotection reactions is their
chemoselectivity. Chemoselective oxidation at the benzylic site proceeds even in the presence of MOM
group, silyl group, acetyl group or tetrahydropyranyl group. The allyl group is used as a protecting group
for alcohols and peroxyiodane 6 is useful for the oxidation of allyl ether to the corresponding α,β-unsaturated
esters. Furthermore, the benzylic oxidations of other hydrocarbons also proceed readily and indan,
tetrahydronaphthalene, dihydroanthracene, fluorene,etc. are efficiently oxidized. The results of these
reactions are partly shown in Table 1.
Radical inhibitors such as α -tocopherol and galvinoxyl inhibit the oxidation of the benzylic methylene
group, which suggests the involvement of radical species. To verify that radicals are generated at the
benzylic positions, 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO), which reacts very rapidly with carbon
radicals, was used as a trap for any benzylic radicals. The substituent effect on the oxidation reaction of
benzyl butyl ethers 17a was investigated (Figure 6). The introduction of electron-withdrawing chlorine in
p- or m-position decreased the rate of the reaction, while introduction of p-MeO group or p-Me group
accelerated the reaction. Hammett correlation was established between the relative reaction rate and
substituent constant σ+ with ρ = -0.30. This ρ value appears to be comparable to ρ = -0.65 for benzylic
hydrogen abstractions from dibenzyl ethers by benzoyloxy radical. An examination of the deuterium
primary isotope effect resulted in a very large value (KH/KD =12-14). This large isotope effect also strongly
indicated that the cleavage of the benzylic C-H bond is involved in the rate-determining step.
The effect of molecular oxygen on this reaction was also investigated. Very interestingly, in the
presence of a large excess of benzyl butyl ether 17a relative to the peroxyiodane 6, the prolonged reactions
(410 h) under nitrogen rubber balloons afforded more than stoichiometric amounts of benzoate ester 18a
(ca. 600%), while the reaction in the absence of oxygen (a degassed argon tube experiment) gave 24% of
benzoate ester 18a and 72% of peroxyacetal 19, which has tert-butylperoxy group at the benzylic position.
This result would indicate the formation of two kinds of reaction intermediates: the peroxyacetal 19 and
hydroperoxyacetal 20 derived from the reaction with molecular oxygen. It is assumed that both of these
intermediates are converted into esters of benzoic acid. The reaction mechanism is shown in Figure 7.

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Table 1. Oxidation of Benzyl, Allyl, and Propargyl Ethers 17 with the Peroxyiodane 6

Fig.6

Initially, the weak hypervalent bond between the oxygen atom of the peroxy group and the iodine atom of
the peroxyiodane 6 is cleaved to generate tert -butylperoxy radical and 9-I-2 σ- iodanyl radical 16. The
benzylic radical 21 is generated when the electrophilic iodanyl radical 16 abstracts the benzylic hydrogen
of the benzyl ether 17a. The benzylic radical 21 further reacts with the peroxyiodane 6 to yield tert-
butylperoxyacetal 19, which decomposes to the corresponding ester 18a. On the other hand, in the
presence of molecular oxygen in the reaction system, the reaction of the benzylic radical 21 with oxygen
yields the peroxy radical 22. The peroxy radical 22 further abstracts the benzylic hydrogen of 17a to yield
hydroperoxyacetal 20 and the benzylic radical 21 is regenerated as well. The hydroperoxyacetal 20 is
converted to the corresponding ester 18a under reaction conditions.

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 July, 1999 number 104

t-BuOO I O

O
6

t-BuOO •
•I O I O•

O O
O 6 OOtBu
PhCH2OnBu
Ph OnBu M2CO3 Ph OnBu 16 17a
18a 19 [9-I-2]

I
CO2H
6 H
•
O 6 OOH Ph OnBu
21
Ph OnBu M2CO3 Ph OnBu O2
18a 20

17a H OO•
Ph OnBu
22

Fig.7

5. Oxidation of Sulfides by tert-Butylperoxyiodane 10)

tert-Butylperoxyiodane 6 oxidizes sulfides to sulfoxides. Dialkyl sulfides and alkyl aryl sulfides are
converted to sulfoxides in good yields in aqueous acetonitrile (method A). Diaryl sulfides are converted in
good yields to sulfoxides in dichloromethane (method C). Addition of BF3-Et2O (method B) to aqueous
acetonitrile accelerated the reaction (Figure 8).

iodane 6
R1 S R2 R1 S(O) R2
A) CH3CN-H2O (5:1) / 50 °C
B) CH3CN-H2O (5:1) / BF3-Et2O (0.3) / 25 °C
C) CH2Cl2/25 °C / N2

n-BuSBn, i-BuSBn, s-BuSBn, BnSBn, Me(CH2)4SPh,

CH2=CHCH2SPh, p-MeOC6H4SMe, p-MeC6H4SMe,

p-ClC6H4SMe, PhSCH2P(O)(OEt)2, PhSPh, (p-ClC6H4)2S

Fig.8

Our studies on the substituent effects for the reaction of substituted thioanisoles in aqueous aceto-
nitrile exhibited a large negative ρ value (-3.35) toward the substituent constants σ. The corresponding
BF3-Et2O mediated reaction exhibited the ρ value -2.23, with a better correlation toward the substituent
constants σ+ . It seems reasonable to assume that the reaction in aqueous acetonitrile is an ionic reaction
from the following observations.
1) An equilibrium is in existence between the peroxyiodane 6 and hydroxyiodane 5.
2) Use of either the hydroxyiodane 5 or the tert-butyl hydroperoxide as an oxidant by itself causes no
reaction to occur, but the use of both in together allows the reaction to proceed almost quantitatively.
3) In addition, the effect of the added galvinoxyl which is a radical scavenger, is small.

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July, 1999 number 104

Furthermore, it is strongly suggests that tert-butylperoxyiodane 6 is the active species and that a reactive
intermediate with a considrable positive charge on the sulfur atom is generated . On the other hand, the
reaction in dichloromethane (method C) is completely inhibited by the addition of galvinoxyl indicating that
the reaction takes place by a radical mechanism.
Oxidative deprotection of dithioacetals also takes place. Treatment of dithioacetals with peroxyiodane
6 in aqueous acetonitrile reacts completely in several minutes with the generation of parent ketones in
high yields. The peroxyiodane 6 is useful for the oxidation of selenides to selenoxides and phosphines to
phosphine oxides. Furthermore, the peroxyiodane 6 oxidizes 2 mol of triphenylphosphines to the
corresponding oxides.

6. Oxidation of Amines by tert-Butylperoxyiodane 11)

The tert-butylperoxyiodane 6 is effective for the oxidation of amines. The reaction of secondary
amines with the tert-butylperoxyiodane 6 causes dehydration to occur, yielding imines. Addition of K2CO3
accelerates the reaction. In the oxidation of tetrahydroisoquinoline, dihydroisoquinoline is obtained in high
yeild. When an excess amount of peroxyiodane 6 is used, isoquinoline is produced. The reaction with
tertiary amines generates peroxy amino acetals with the peroxy group being introduced on the α -carbon
atom of the amines (Figure 9).

iodane 6 , K2CO3
NH PhH N

OOtBu
iodane 6
NMe2 N
CH2Cl2
Me

Fig.9

7. Radical Oxidation Reaction of Phenols by tert-Butylperoxyiodane 12)

In reactions with p-alkyl substituted phenols, 4-(tert -butylperoxy)cyclohexadienone is produced.
Treatment of p-substituted phenols with peroxyiodane 6, in the presence of tert-butyl hydroperoxide, gives
tert-butylperoxycyclohexadienones in good yield under mild conditions (ethyl acetate/50°C). It seems
reasonable to assume that this reaction is a radical reaction because the oxidation reaction in the presence
of galvinoxyl was almost completely inhibited and a small amount of a dimer of tert-butylperoxycyclohexa-
dienone was obtained as a by-product. The phenoxy radical, stabilized by resonance, is an intermediate,
and its coupling with the tert-butylperoxy radical yields tert-butylperoxycyclohexadienone.

iodane 6
HO O
t-BuOOH

n AcOEt, 50 n
OOtBu
n = 0, 1

Fig.10

8. Conclusion
In tert-butylperoxyiodane 6, the tert-butylperoxy group and the trivalent iodine atom are bonded by
a hypervalent bond. An intensive survey of its structure leads us to expect its high reactivity but makes us
worry about its potential for explosion. It is likely that a limited number of chemists would actually try to
synthesize this compound by themselves. On the contrary, the crystalline tert-butylperoxyiodane 6 is a
surprisingly stable compound and no decomposition occurs at room temperature. Furthermore, no radical
cleavage of the hypervalent bond occurs until it is made into a solution in which case the reaction proceeds
slowly. Generally, the reaction is carried out at less than 50°C and no attempts have been made beyond

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 July, 1999 number 104

that temperature.
As discussed in the above, the developement of tert-butylperoxyiodane has been attributed to our
concentrated efforts to seek for new potential utilization of iodine. The results have been generated by
many careful experiments carried out by Dr. Takao Ito (Nippon Tobacco Industry K.K. Laboratory). The
author wish to extend heartfelt thanks toward many of the students, for their contributions, whose names
are listed in the reference literature involved in these studies.

References
1) a)G, F. Koser, in “The Chemistry of Functional Groups, Supplement D2”; Ed. by S. Patai and Z. Rappoport,
Wiley, New York (1995); Chapters 21. b) A. Varvoglis, “The Organic Chemistry of Polycoordinated Iodine”,
VCH, New York (1992).
2) M. Ochiai, T. Ito, Y. Masaki, M. Shiro, J. Am. Chem. Soc., 114, 6269 (1992).
3) M. Ochiai, Kagaku Sosetsu, “Hypervalent Organic Compounds”, 34, 181 (1998).
4) M. Ochiai, M. Toyonari, T. Nagaoka, D.-W. Chen, M. Kida, Tetrahedron Lett., 38, 6709 (1997).
5) M. Ochiai, in “Chemistry in Hypervalent Compounds”; Ed. by K. Akiba, Wiley-VCH, New York (1999); Chapters
12.
6) M. Ochiai, T. Ito, Y. Takaoka, Y. Masaki, M. Kunishima, S. Tani, Y. Nagao, J. Chem. Soc., Chem. Commun.,
1990, 118.
7) M. Ochiai, T. Ito, Y. Takaoka, Y. Masaki, J. Am. Chem. Soc., 113, 1319 (1991).
8) M. Ochiai, T. Ito, M. Shiro, J. Chem. Soc., Chem. Commun. , 1993, 218.
9) M. Ochiai, T. Ito, H. Takahashi, A. Nakanishi, M. Toyonari, T. Sueda, S. Goto, M. Shiro, J. Am. Chem. Soc., 118,
7716 (1996).
10) M. Ochiai, A. Nakanishi, T. Ito, J. Org. Chem., 62, 4253 (1997).
11) M. Ochiai, D. Kajishima, T. Sueda, Heterocycles , 46, 71 (1997).
12) M. Ochiai, A. Nakanishi, A. Yamada, Tetrahedron Lett., 38, 3927 (1997).

○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○

Hypervalent Organoiodanes

I O R=H
n R C C I BF4
Ethynyl(phenyl)iodonium
Iodosobenzene Tetrafluoroborate
5g JPYen9,300 (I0072) 1g JPYen 10,100 (E0467)
R=Me3Si
Trimethylsilylethynyl(phenyl)iodonium
Tetrafluoroborate
1g JPYen 6,850 (P1239)

X I X X=OAc tBuOO I O
Iodobenzene Diacetate 1-(tert -Butylperoxy)-1,2-benziodoxol-
25g JPYen7,650 10g JPYen3,900
O 3(1H)-one
(I0330) 1g JPYen 23,800 (B2121)
X=OCOCF3
[Bis(trifluoroacetoxy)iodo]benzene
25g JPYen 12,800 10g JPYen7,350
(B1175)

HO I OTs HO I O
[Hydroxy(tosyloxy)iodo]benzene
o-Iodosobenzoic Acid
25g JPYen 14,500 5g JPYen 5,550 O 10g JPYen 16,300 (I0073)
(P1015)