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Hypervalent iodine-mediated oxidation of alcohols

Muhammet Uyanik and Kazuaki Ishihara*
Received (in Cambridge, UK) 5th January 2009, Accepted 3rd February 2009
First published as an Advance Article on the web 6th March 2009
DOI: 10.1039/b823399c

Over the past two decades there has been a dramatic increse in the use of hypervalent iodine
compounds in synthetic organic chemistry due to their mild and selective oxidizing properties.
Hypervalent iodine compounds catalyze various oxidation reactions such as the oxidation of
alcohols, a-oxidation of ketones, oxidative spirocyclization of phenols, etc. Very recently, we found
Published on 06 March 2009 on http://pubs.rsc.org | doi:10.1039/B823399C

that 2-iodoxybenzensulfonic acid (IBS, 7a), which was generated from 2-iodobenzenesulfonic acid
in situ, is an extremely active and mild catalyst for the highly chemoselective oxidation of various
alcohols with powdered Oxones to carbonyl compounds such as aldehydes, carboxylic acids,
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ketones and cycloalkenones under non-aqueous conditions. In this review, we focus on the design
of hypervalent iodine catalysts and review the discovery and development of the oxidation of
alcohols with the stoichiometric or catalytic use of hypervalent iodine compounds.

1. Introduction cycloalkanones, lactones or cyclic a,b-enones, etc.) are attrac-

The oxidation of alcohols to the corresponding carbonyl
compounds is one of the most fundamental and important
transformations in synthetic organic chemistry.1 In particular,
selective cascade oxidative transformations of alcohols to
carbonyl compounds (i.e. primary alcohols, aldehydes, car-
boxylic acids; secondary alcohols, ketones, esters, cycloalkanols,
Graduate School of Engineering, Nagoya University,
Furo-choChikusa-ku, Nagoya, 464-8603, Japan.
E-mail: ishihara@cc.nagoya-u.ac.jp; Fax: +81-52-789-3222;
Tel: +81-52-789-3331
tive, since the target molecule can be obtained directly
in a one-pot sequence. Numerous transition metal-catalyzed
oxidations of alcohols using aqueous H2O2 or gaseous O2
as a stoichiometric oxidant have been developed.1,2 Never-
theless, more environmentally benign catalytic and chemo-
selective oxidation methods such as organocatalysis are
needed, especially for pharmaceutical processes.3 Over the
past two decades, hypervalent iodine compounds have been
focus of great attention due to their mild and chemo-
selective oxidizing properties and their environmentally benign
character in contrast to toxic metal reagents (Fig. 1).4 In 2004,
Kita and Tohma reviewed the oxidation of alcohols with

Muhammet Uyanik was born Kazuaki Ishihara was born in

in Samsun, Turkey, in 1981 Aichi, Japan, in 1963, and re-
and received his PhD from ceived his PhD from Nagoya
Nagoya University in 2007 un- University in 1991 under the
der the direction of Professor direction of Professor Hisashi
Kazuaki Ishihara. He was ap- Yamamoto. He had the oppor-
pointed as an Assistant Pro- tunity to work under the direc-
fessor at Nagoya University in tion of Professor Clayton H.
2007. His research interests Heathcock at the University of
include oxidation reactions California, Berkeley, as a vis-
and asymmetric catalysis. iting graduate student for
three months in 1988. He was
a JSPS Fellow under the
Japanese Junior Scientists Pro-
Muhammet Uyanik Kazuaki Ishihara gram from 1989 to 1991. After
completing his postdoctoral
studies with Professor E. J. Corey at Harvard University, he
returned to Japan and joined Professor H. Yamamoto’s group at
Nagoya University as an assistant professor in 1992, and became
an associate professor in 1997. In 2002, he was appointed to his
current position as a full professor at Nagoya University. His
research interests include asymmetric catalysis, biomimetic
catalysis induced by artificial enzymes, dehydrative condensation
catalysis towards green and sustainable chemistry, and acid–base
combination chemistry.

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Fig. 1 Hypervalent iodine(V) reagents for the oxidation of alcohols. Published year is shown in parentheses.

stoichiometric hypervalent iodine compounds and their appli-
cation to natural product synthesis.5 In 2005, Vinod and
co-workers succeeded in the first catalytic use (20–40 mol%)
of 2-iodoxybenzoic acid (IBX, 2a) for the oxidation reaction.6,7,50
Very recently, we found that 2-iodoxybenzenesulfonic acid
(IBS, 7a) was much superior to 2a as an oxidation catalyst.8
The oxidation of various alcohols with Oxones (2KHSO5
KHSO4K2SO4) proceeds quantitatively with even less than
1 mol% catalytic loading of 7a. Here we focus on the design of
hypervalent iodine catalysts and review the discovery and
development of the oxidation of alcohols with the stoichio-
metric or catalytic use of hypervalent iodine compounds.
2. Oxidation of alcohols with the stoichiometric
use of hypervalent iodines
2.1 Iodines(V)
As shown in Fig. 1, various hypervalent iodine(V) reagents
(1–16) have been developed as oxidants or catalysts for alcohol
oxidations.
Martin used 2a for precursor 3.11 The first use of 2a in DMSO
for alcohol oxidation was reported by Santagostino in 1994.12
IBX 2a is especially useful for the oxidation of 1,2-diols such
as glycols to the corresponding a-ketols or a-diketones
(Scheme 1).12,13 In contrast, DMP 3 generally cleaves the
C–C bond of glycol.11,13
According to 1H NMR analysis, the reactions of 3 and 2a
with 1,2-diols give spirobicyclic periodinane adducts and
open-chain iodic monoesters as active intermediates, respec-
tively (Scheme 2).13 Recently, Moorthy demonstrated that 2a
exhibited reactivity akin to 3.14 Strained and sterically
hindered tert,tert-1,2-diols could be oxidatively cleaved under
a higher temperature (70–80 1C) than has been reported
previously13 in DMSO via a 12-I-5 spirobicyclic periodinane

2.1.1 Noncyclic iodine(V) (PhIO2, 1). Iodylbenzene (1) is

the simplest iodylarene reagent and has no functional group
for intramolecular interactions with I(V). Only Barton and Scheme 1 Oxidation of 1,2-diols with IBX 2a and DMP 3.
co-workers have reported 1-mediated oxidation of benzyl alco-
hols to the corresponding aldehydes.9 The reaction rate was
accelerated in a protic solvent such as acetic acid (eqn. (1)).

ð1Þ

2.1.2 Cyclic iodines(V) (2–16)

IBX 2a. The most representative cyclic iodylarenes are
2-iodoxybenzoic acid (IBX, 2a) and Dess–Martin periodinane
(DMP, 3).4 IBX 2a was first synthesized in 1893.10 Dess and Scheme 2 Mechanism of 1,2-diol oxidation.

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as 3 (Scheme 2). The use of trifluoroacetic acid (TFA), a

protonating solvent, promotes the formation of the 12-I-5
intermediate for 1,2-diols of all types (sec,sec,sec,tert and
tert,tert), which lead to efficient oxidative fragmentation.14
In early studies, IBX 2a was synthesized from its precursor
2-iodobenzoic acid (17a) with potassium bromate (KBrO3) in
an aqueous solution of sulfuric acid.11a Although IBX had
been believed to be explosive,15 Dess and Martin reported in
1991 that some bromate or other impurity included in the
samples might be the cause, and IBX itself should be
non-explosive.11b The simple one-step preparation of 2a
from 17a with Oxones, an environmentally safe oxidant,
has made it a popular reagent (eqn (2)).16 Nowadays, 2a is
Published on 06 March 2009 on http://pubs.rsc.org | doi:10.1039/B823399C

considered a mild and selective oxidant, which is a cheaper and

much more stable alternative to 3.4 To date, 2a was used as a
powerful yet selective oxidant that mediates a variety of Scheme 3 Goddard’s hypervalent twisting explanation.
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oxidative transformations such as the oxidation of alcohols,

phenols, and amines, the dehydrogenation of ketones,
aldehydes and N-heterocycles, and the oxidative cleavage of
dithioacetals.4
ð2Þ
However, despite its useful oxidizing properties, the
low solubility of 2a in common organic solvents, except
DMSO, due to the strong intermolecular secondary bonding
to create a three-dimensional polymeric structure, has
restricted its practical application in organic synthesis.4
Several research groups have reported that polymer-supported
IBXs (14) could be used in common organic solvents such as
dichloromethane, tetrahydrofuran, etc.17 Quideau reported
a stabilized formulation of IBX (SIBX) containing benzoic
acid and isophthalic acid, which had some advantages
such as safety, easy work-up, etc.18 Moreover, Finney
demonstrated that primary and secondary alcohols could be
oxidized into the corresponding aldehydes or ketones in good
yields by heating a mixture of alcohols and 2a in organic
solvents other than DMSO (i.e.; ethyl acetate, tetrahydro-
furan, benzene, etc.) followed by the filtration of insoluble
byproducts.19
Several research groups have tried to improve 2a by
structurally modifying it, or by developing polymer-supported
analogs.
Arene-modified IBXs (2b–f). Vinod’s group introduced a
carboxyl group (CO2H) at the 6-position of 2a, which was
called water-soluble IBX (2b).20 Although it was difficult to
prepare, 2b could be used for the selective oxidation of benzyl
alcohols in water.20 Very recently, they reported a two-step
synthesis of 2c, an analogue of 2b, from commercially
available 2-aminoterephthalic acid.21 Both of these reagents
are soluble in water and the latter is also soluble in DMF. 2b
and 2c oxidize alcohols in aqueous solvents via a single
electron transfer (SET) mechanism.
Goddard’s group proposed that 3-Me-IBX (2d) should be
theoretically more active than 2a, and hypervalent twisting
should be the rate-determining step for the oxidation
of alcohols with stoichiometric amounts of 2a.22 According
to his explanation, hypervalent twisting is a coordinated
motion of the ligands attached to iodine driven by the
need to generate a stable and planar form of IBA (18a)
from its precursor alkoxyperiodinane intermediate A
(A - B, Scheme 3).22 After acid-catalyzed water/alcohol
exchange on IBX, alkoxyperiodinane A must twist to its
isomeric structure B to eliminate the carbonyl compound to
form planar compound 18a (Scheme 3). Thus, the 3-methyl
group of 2d would have a lower twisting barrier for steric
repulsion between the alkoxy ligand on A. After Goddard’s
report, Moorthy reported that 2-Me-4-MeO-IBX (2e),
which dissolved in common organic solvents, could oxidize
alcohols and sulfides at room temperature with short reaction
periods.23
Wirth also reported another soluble IBX analogue, 3,4,5,6-
F4-IBX (2f), which was more reactive than 2a in common
organic solvents.24 Notably, in contrast to 2a, 2f can cleave
1,2-diols in acetonitrile at room temperature (eqn (3)).
ð3Þ
Ortho-group-modified IBX analogues (4–12). Zhdankin and
co-workers reported the synthesis and structural analysis of
esters and amides of 2a, IBX-esters (4),25 and IBX-amides
(5),26 which were stable and soluble reagents. According to
X-ray crystal data, these new derivatives of IBX have a
pseudo-benziodoxole structure due to iodine–oxygen secondary
bonding interactions. In comparison with 2a and other
benziodoxoles, pseudo-benziodoxoles are much more soluble,
which is explained by a partial disruption of their polymeric
nature due to the redirection of iodine–oxygen secondary
bonding.4f IBX-esters 4 can oxidize alcohols to the respective
aldehydes or ketones in the presence of trifluoroacetic acid or
boron trifluoride etherate.25b In contrast, the reactivity
of IBX-amides 5 in chloroform is similar to that of 2a
without acid additives.26 Lee and co-workers reported the
preparation of polymer-supported IBX-esters (15) and amides

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Scheme 4 Enantioselective oxidation of racemic alcohols and sulfides
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with NIPA.
(16), which showed excellent oxidative activity toward benzylic
alcohols.27
Recently, Zhdankin’s group reported the design,
preparation, structure and oxidative properties of novel
N-(2-iodylphenyl)acylamides (NIPA, 6), which was the
first reported example of a six-membered pseudo-cyclic
scaffold for iodine(V).28 NIPA 6 can oxidize alcohols
and sulfides, and the reactivity strongly depends on the
substitution pattern on the amide group adjacent to the
iodyl moiety (R1 group). Moderate enantioselectivities
were also observed for the oxidation of racemic alcohols
and sulfides with (S)-proline-derived NIPAs 19 and 20,
respectively (Scheme 4).29 A polymer-supported N-(2-iodyl-
phenyl)acylamide reagent (NIPA resin 20) has also been
developed. With the recyclable reagent 20, a wide range of
alcohols were rapidly oxidized to the corresponding carbonyl
compounds.30
Zhdankin’s group reported the preparation and spectro-
scopic characterization of 2-iodoxybenzenesulfonic acid (IBS,
7a) as a thia-analogue of 2a.31 IBS 7a could be synthesized by
the direct oxidation of 2-iodobenzenesulfonic acid (22a) with
Oxones, such as IBX 2a (method A) or hydrolysis of the
methyl ester of 7a (8, method B) (eqn (4)).
ð4Þ
IBS 7a was thermally unstable in organic solvents such as
acetonitrile, DMSO and methanol. The authors failed to
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investigate its oxidative ability due to its low stability in
organic solvents (eqn (5)).31
ð5Þ
The same research group reported IBS-esters (8) and IBS-
amides (9).32 However, in contrast to 4 and 5, compounds 8
and 9 show relatively low solubility in non-polar organic
solvents such as chloroform and dichloromethane. Although
8 could not oxidize alcohols without acid additives as well as 4,
9 was useful for the oxidation of other organic functional
groups, such as sulfides and secondary amines under reflux
conditions in acetonitrile. The characteristics of the reactivity
of IBS-amides 9 showed are similar to those of 5.
Zhdankin’s group also reported the preparation, structural
characterization, and reactivity of 2-iodylphenol ethers (10),
which are new soluble and non-explosive pentavalent iodine
reagents.33 2-Iodylphenol ethers 10 can selectively oxidize
sulfides to sulfoxides and alcohols to the respective aldehydes
or ketones under reflux conditions in acetonitrile and distilled
chloroform, respectively. They also recently reported new
recyclable polymer-supported iodylphenol ethers 24 and 25
which could selectively oxidize a wide range of alcohols to the
desired carbonyl compounds.34
Martin reported the synthesis and reactivity of 11, as a
benzyloxy analogue of 2,11b,35 which (R = tBu) was stable,
non-explosive and soluble in a wide range of common organic
solvents such as hexanes, ether, dichloromethane, acetone,
acetic acid, and water. The oxidation of primary and
secondary alcohols bearing various non-hydroxy functional
groups such as ethers, thioethers, amino, vinyl and halides
with 11 occurred chemoselectively in dichloromethane at room
temperature.35
Very recently, Zhdankin’s group reported the first prepara-
tion of 2-iodyl-N,N-dialkylaniline oxides (12), which could
selectively oxidize alcohols to the desired carbonyl compounds
under mild conditions in the presence of trifluoroacetic acid.36
Non-aromatic iodine(V). Kawashima and co-workers
reported the first preparation of non-aromatic iodine(V)
reagent 13, which could oxidize alcohols to the desired
carbonyl compounds with moderate to good yields under mild
conditions.37
2.2 Iodine(III)
Iodine(III) reagents are less reactive than iodine(V) reagents for
the oxidation of alcohols. Several successful examples of the
iodine(III) reagents for the oxidation of alcohols are shown
in Fig. 2.
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Fig. 2 Hypervalent iodine(III) reagents for the oxidation of alcohols.
2.2.1 Iodosobenzene (PhIQO, 26). In 1968, Takaya and
co-workers reported the first use of iodosobenzene (26) for the
oxidation of activated alcohols such as benzyl alcohols under
reflux conditions in dry dioxane.38 However, aliphatic alcohols
could not be oxidized under such conditions. This is the only
report on the oxidation of alcohols with 26 without additives.
Kita and co-workers reported that the catalytic use of
potassium bromide (KBr) promoted the oxidation of alcohols
with 26 in water (eqn (6)).39 Primary alcohols are converted to
the carboxylic acids in good yields, whereas secondary
alcohols lead to the corresponding ketones. In addition, the
oxidation of diols with the 26–KBr system affords the corres-
ponding lactones in high yields. The polymer-supported
iodine(III) reagent poly(diacetoxyiodo)styrene (PDAIS, 29)
can also be used for the oxidation of alcohols in this system.
A plausible role of 26 in the oxidation of alcohols is shown in
Scheme 5.
ð6Þ
Paraskevopoulou and co-workers found other oxidation
conditions (26–Ph4PBr–CH2Cl2) which were milder than
26–KBr–H2O (eqn (7)).40 Under these conditions, primary
benzyl alcohols were converted to the corresponding alde-
hydes in good yields. In contrast, the oxidation of secondary
alcohols gave the corresponding ketones in poor yield.
Additionally, primary aliphatic alcohols as well as allylic and
Scheme 5 KBr-catalyzed iodosylbenzene-mediated oxidation of
alcohols in water.
2090 | Chem. Commun., 2009, 2086–2099
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homoallylic alcohols could not be oxidized under these
conditions.
ð7Þ
Togo and co-workers reported an efficient cascade trans-
formation of alcohols to a-tosyloxyaldehydes and a-tosyloxy-
ketones using excess amounts of 26 and pTsOH through the
formation of aldehydes and ketones from alcohols (eqn (8)).41
The active oxidant is 27 (Koser reagent) generated in situ from
26 and TsOH.
ð8Þ
2.2.2 Phenyliodine diacetate (PIDA, 28). Although PIDA
28 (R = H) is one of the most useful iodine(III) reagent, there
have been only a few examples of the oxidation of alcohols
with 28 without activation. Kansara et al. reported that
benzylic alcohols could be oxidized with 28 in aqueous acetic
acid to the corresponding aldehydes.42 Zhao and co-workers
reported that various vicinal diols could be oxidatively cleaved
by PDAIS (29) to the corresponding aldehydes.43
Ochiai and co-workers reported that the combination of 28
(R = NO2) and boron trifluoride etherate increased the
oxidizing power of iodine(III) and aliphatic secondary alcohols
were oxidized efficiently to the ketones.44 The proposed me-
chanism involves a rapid ligand-exchange on the iodine(III)
center of 28 with an excess amount of alcohols to generate
the alkoxyiodane intermediate, followed by rate-limiting
reductive elimination of ArI to produce carbonyl compounds
via a-C–H bond cleavage. Both steps are catalyzed by
BF3 (eqn (9)).
ð9Þ
Zhang and co-workers reported the preparation of the
ion-supported [bis(acyloxy)iodo]arene 30 and its application
to the oxidation of alcohols.45 The oxidation of various
primary and secondary alcohols with 30 in the ionic liquid
[emim]+[BF4] (1-ethyl-3-methylimidazolium tetrafluoro-
borate) in the presence of Br (as impurities of the ionic
liquid) affords selectively the corresponding carbonyl
compounds without overoxidation to carboxylic acids under
mild conditions (eqn (10)). The authors proposed that the Br
in the ionic liquid to be oxidized by 30 to form a highly active
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Scheme 6 Proposed mechanism for the oxidation of alcohols with 30
in the presence of Br.
intermediate Br+, probably in the form of acetyl hypobromite
or the bromate(I) complex, which oxidize alcohols to the
corresponding carbonyl compounds with regeneration of the
Br (Scheme 6).46 Accordingly, in this system the ionic liquid
Published on 06 March 2009 on http://pubs.rsc.org | doi:10.1039/B823399C
plays a very important role in preventing aldehydes from
overoxidation to carboxylic acids.45
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ð10Þ
Kita’s group also developed a novel, nonpolymeric, and
recyclable hypervalent iodine(III) reagent (31), which could be
used for the efficient oxidation of alcohols in the presence of a
catalytic amount of KBr in water, as described above.47 The
key features of that unique iodine(III) reagent are as follows:
(1) high reactivity in a variety of solvents due to their
tetrahedral structure and improved solubility over conven-
tional polymer-supported iodine(III) reagents; (2) high
recyclability without degradation loss; and (3) well-defined
structure and convenient preparation, which make it suitable
for commercialization.
3. Hypervalent iodine-catalyzed alcohol oxidation
The first hypervalent iodine(III)-catalyzed oxidative coupling
reactions were reported by Ochiai’s group48 and Kita’s
group,49 independently, in 2005. In situ-generated iodine(III)
catalyzed the a-acetoxylation of ketone and the sub-
sequent oxidative spirocyclization of phenols in the
presence of mCPBA as a stoichiometric oxidant. Also,
the iodine(V)-catalyzed oxidations of alcohols were
reported by Vinod’s group50 and Liu’s group51 in 2005.
Hypervalent iodine-catalyzed oxidations of alcohols are
described below.
3.1 Iodine(V)-catalyzed oxidations of alcohols with Oxones
In 2005, Vinod and co-workers demonstrated the first catalytic
use of 2a in the presence of Oxones as a co-oxidant for the
oxidation of primary and secondary alcohols in aqueous
acetonitrile (eqn (11)).50 They were inspired by Santagostino’s
finding that 2a was obtained from 17a and Oxones in hot
water.16 Secondary alcohols were oxidized to the corres-
ponding ketones, and this was not accompanied by the
formation of Bayer–Villiger oxidation products due to
the presence of Oxones. Primary alcohols were oxidized to
the corresponding carboxylic acids. However, primary
alcohols could not be selectively oxidized to the corresponding
aldehydes.50 Borhan had reported that aldehydes easily
reacted with water to give hemiacetals, which were oxidized
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Scheme 7 In situ generation of 2a from IBA (18a) or 17a with
Oxones and the catalytic use of 2a for alcohol oxidation.
to carboxylic acids in the presence of Oxones in wet
DMF.52
ð11Þ
The proposed catalytic cycle is shown in Scheme 7.
Several months after Vinod’s report, Shulze and Giannis
reported the in situ-generated 2a-catalyzed oxidation of
alcohols in the presence of tetra-n-butylammonium sulfate
(Bu4NHSO4) as a phase-transfer catalyst for the generation
of tetra-n-butylammonium oxone in an ethyl acetate/
water biphasic solvent system.53 Under these conditions,
primary benzylic alcohols were oxidized to the corres-
ponding aldehydes, which were not further oxidized
(eqn (12)).
ð12Þ
Under Vinod’s and Giannis’ conditions, it was not possible
to oxidize allylic and homoallylic alcohols. In these cases, the
formation of complex reaction mixtures was observed.50,53
Page and co-workers demonstrated that the oxidant tetra-
phenylphosphonium monoperoxysulfate (TPPP), which was
derived from Oxones by simple counterion exchange with
tetraphenylphosphonium chloride (eqn (13)), could act as an
Oxones equivalent in non-aqueous organic solvents.54
ð13Þ
With a catalytic amount of 17a in the presence of TPPP,
several primary and secondary alcohols were oxidized to the
respective aldehydes and ketones under reflux conditions in
acetonitrile or dichloroethane (eqn (14)).55 This catalytic
system allows the oxidation of primary alcohols to the
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corresponding aldehydes without the generation
carboxylic acid.
ð14Þ
Page and co-workers found that TPPP could also promote
the oxidation of alcohols in the absence of 2a.55 Hajipour
reported that benzyltriphenylphosphonium peroxymonosulfate
can be used as an oxidant for the oxidation of alcohols, but a
Lewis acid is required for the reaction to occur.56 In the absence
of 17a, the reaction ran to completion only when more than six
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equivalents of TPPP were used, and even then, the reaction was
substantially slower (10 h) with piperonyl alcohol as a substrate
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(eqn (15)). In contrast, 17a is oxidized to 2a much more rapidly
than alcohols by TPPP, and 2a is formed as an alcohol oxidant
in a catalytic system in the presence of 17a.
ð15Þ
Yakura and Konishi demonstrated a novel catalytic
hypervalent iodine oxidation of phenol derivatives using
catalytic amounts of 4-iodophenoxyacetic acid (32) and
Oxones as a co-oxidant.57 p-Alkoxyphenols were oxidized
to the corresponding p-quinones in aqueous acetonitrile in
excellent yields (eqn (16)). A substituent effect was observed in
the oxidation for the iodobenzene ring; p-alkoxy is the most
effective, in the approximate order p-RO 4 p-Me, o-MeO,
m-MeO 4 H 4 o-CO2H.
ð16Þ
A possible catalytic cycle for this oxidation is shown in
Scheme 8.55 Iodoarene would be oxidized by Oxones to
iodine(III) and iodine(V) species which both react with
p-alkoxyphenol to give p-quinone and iodine(III) and iodo-
arene species. Iodoarenes with electron-donating substituents
such as methoxy and methyl groups may be more easily
Scheme 8 Proposed reaction mechanism for the oxidation of
p-alkoxyphenols with iodoarene and Oxones.
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of oxidized by Oxones to cause rapid reactions, whereas an
electron-withdrawing substituent such as a carboxyl group
may decrease the reactivity of iodoarene against the oxidant.
Recently, the same research group reported that the reaction
of p-dialkoxybenzenes with a catalytic amount of 32 in the
presence of Oxones as a co-oxidant in aqueous 2,2,2-trifluoro-
ethanol gave the corresponding p-quinones in excellent yields
(eqn (17)).58 This procedure was applied to the synthesis of
blattellaquinone,59 the sex pheromone of the German cock-
roach, Blattella germanica.
ð17Þ
To develop a more powerful hypervalent iodine catalyst for
selective alcohol oxidation, we were interested in modification
of the arene moiety of 2a. To date, several arene-modified
IBXs 2b–f and 14 have been developed as stoichiometric
oxidants (Fig. 1). However, there have been no reports on
the catalytic use of modified IBX analogues. Thus, we sought
to develop highly efficient IBX-analogous catalysts for the
oxidation of alcohols with Oxones.8
Oxidation of 5-nonanol (33) with Oxones even in the
presence of 1 mol% of 17a gave 5-nonanone (34) in good
yield under Vinod’s conditions50 (eqn (18)). In sharp contrast,
the oxidation of a sterically hindered alcohol such as
()-menthol (35) was problematic under the known conditions50,53
in our hands (eqn (19)). Byproducts such as Baeyer–Villiger
products were also observed in aqueous acetonitrile. Although
these byproducts were suppressed under Giannis’ condi-
tions,53 large amounts of acetic acid and ethanol were pro-
duced together with ()-menthone (36) through the hydrolysis
of ethyl acetate. Thus, various solvent systems were examined
for the in situ-generated 2a-catalyzed oxidation of 35 with
Oxones, and we found that the oxidation proceeded more
cleanly and more rapidly in non-aqueous nitromethane than in
organic solvent/water biphasic systems including Vinod’s
and Giannis’ conditions,50,53 although Oxones was almost
insoluble in nitromethane (eqn (20)).
ð18Þ
ð19Þ
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Scheme 9 Arene-substituted IBXs 2 generated in situ from 17 with
Oxones.
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Scheme 10 Comparison of efficiencies of catalysts 2 generated in situ
from 17 in non-aqueous nitromethane.
ð20Þ
We investigated the in situ-generated IBX-substituent effect
under our non-aqueous conditions (Scheme 9) and the
order of the catalytic efficiencies is shown in Scheme 10.
Although 3-Me-IBX (2d)22 and 3,4,5,6-F4-IBX (2f)24
have been reported to be more reactive oxidants than 2f,
their catalytic use gave 32 in very low yields. 4-Me-IBX (2g)
showed catalytic activity similar to that of 2a, and electron-
donating group-substituted IBXs such as 5-MeO-IBX (2i),
3-iodoxy-2-naphthalenecarboxylic acid (2n), 4,5-Me2-IBX
(1j) and 5-Me-IBX (2h) were superior to 2a. Electron-
withdrawing group-substituted IBXs such as 4-Cl-IBX (2l)
and 5-NO2-IBX (2m) showed lower reactivity than 2a. The
stability of IBX catalysts was strongly influenced by the
solvents and substituents of IBXs. 3-Me-IBX 2d and
4,5-(MeO)2-IBX (2k) were decomposed under these condi-
tions. In general, iodine(V)-catalyzed oxidation was faster
and cleaner under non-aqueous conditions, although Oxones
was almost insoluble in CH3NO2.
3.2 Iodine(V)-catalyzed oxidations of alcohols with O2
Liu and co-workers developed a hypervalent iodine-catalyzed
oxidation of alcohols using molecular oxygen as a terminal
oxidant.51 The aerobic oxidation of alcohols to aldehydes or
ketones in water was effectively catalyzed by 1 (1 mol%) as the
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Scheme 11 Proposed redox catalytic cycles for the 1-mediated
aerobic oxidation of alcohols.
active oxidant in the presence of catalytic amounts of Br2 and
NaNO2 (eqn (21)).
ð21Þ
A proposed catalytic mechanism for this reaction involves
three redox cycles, similar to that for the TEMPO-mediated
oxidation of alcohols (Scheme 11).51 Iodylbenzene 1 is the
active oxidant that oxidizes the alcohol to the corresponding
carbonyl compound and is reduced to 26. Iodosylbenzene 26 is
reoxidized to 1 with Br2, which is reduced to HBr. Oxidation
of NO by atmospheric oxygen produces NO2 which reoxidizes
HBr to Br2. In addition, HNO3 produced by dissolving NO2 in
water can also oxidize HBr to Br2.60
Another aerobic oxidation of alcohols was developed by Li
and co-workers.61 They developed an effective catalytic
system for the oxidation of alcohols under an oxygen atmo-
sphere using catalytic amounts of 28/TEMPO/KNO2
(eqn (22)). In addition, the use of a catalytic amount of
poly[4-(bis(acetoxy)iodo)]styrene led to yields comparable to
that with the non-supported hypervalent iodine reagent, while
offering the advantage of an efficient recovery and subsequent
recycling of the hypervalent iodine reagent. The reaction was
carried out without the need of any additional solvent or
transition metal catalyst. Primary alcohols can be oxidized to
the corresponding aldehydes in moderate to good yields
without any noticeable overoxidation to the carboxylic acids.
While primary benzyl alcohols were oxidized in good yields,
the oxidation of aliphatic alcohols gave lower yields.
ð22Þ
A proposed mechanism for this catalytic oxidation is shown
in Scheme 12. The oxoammonium cation, which is oxidized
from TEMPO, should be the active oxidant in this reaction.
The role of 28 is to regenerate oxoammonium cation,62 and
subsequently, 28 would also be regenerated from its initial
state by KNO2. The oxidation of NO into NO2 can be carried
out easily with molecular oxygen and the catalytic cycles run
the completion in the absence of any transition metal.
Chem. Commun., 2009, 2086–2099 | 2093

Scheme 12 Proposed mechanism for catalytic use of 28 and the
TEMPO-mediated oxidation of alcohols.
3.3 Iodine(III)-catalyzed oxidations
Published on 06 March 2009 on http://pubs.rsc.org | doi:10.1039/B823399C
Togo and co-workers developed a one-pot procedure for the
catalytic oxidation of alcohols to a-tosyloxy ketones
(eqn (23)).63 They modified Kita’s procedure39 for the KBr-
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catalyzed oxidation of alcohols with stoichiometric amounts
of 26. Secondary alcohols were directly converted to the
corresponding a-tosyloxyketones using mCPBA and catalytic
amounts of iodobenzene and potassium bromide, followed
by treatment with pTsOH in a one-pot manner (eqn (23)).
Poly(4-iodostyrene) could also be used as a recyclable catalyst
instead of iodobenzene, and therefore after the reaction it was
recovered in high yields by simple filtration of the reaction mixture.
ð23Þ
4. IBS-catalyzed oxidation of alcohols with
Oxones
4.1 Investigation of the catalytic efficiency of IBS
To develop an even more powerful catalyst for alcohol
oxidation, we were interested in IBS (7a),31 an analogue of
2a. Although 7a was not stable enough to isolate in pure form
and examine in stoichiometric reactions,31 we envisaged
that 7a, which could be prepared from 22 and Oxones
in situ in the presence of an alcohol substrate, might have
greater catalytic activity than 2, since the Lewis acidity of the
iodine(V) atom in 7a would be higher than that in 2 due to its
strong electron-withdrawing sulfo group.64
We investigated and compared the catalytic efficiencies of
in situ-generated 2a and 7a for the oxidation of 33 (Fig. 3, 7a in
red and 2a in blue). In non-aqueous nitromethane and
acetonitrile, 7a was superior to 2a (red squares and circles
vs. blue open-squares and open circles; in nitromethane,
TOF65 = Z 50 h1 vs. 16 h1, respectively). In sharp contrast,
2a was superior to 7a in aqueous solvent systems (red diamonds vs.
blue open diamonds). Moreover, 7a was sufficiently active in
less polar but more environmentally benign ethyl acetate.
However, the 2a-catalyzed oxidation of alcohols did not give
any products in non-aqueous solvents such as ethyl acetate or
acetonitrile. Sodium 2-iodobenzenesulfonate (22aNa) could
2094 | Chem. Commun., 2009, 2086–2099
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Fig. 3 Catalytic efficiencies of 2a (blue) and 7a (red) generated in situ
from 17a and 22, respectively.
be used as a precatalyst for 7a, and 22aNa at a catalyst
loading of 0.05 mol% was enough for the oxidation of 33
in acetonitrile (20-mmol scale, 32 h, 99% isolated yield,
TON65 Z 2000).
The substituent effect of 7a on the oxidation of alcohols in
non-aqueous nitromethane showed the same tendency as IBX.
Electron-donating group-substituted IBSs such as 5-Me-IBS
(7b) and 4,5-Me2-IBS (7c) were superior to IBS 7a, although
the differences in the catalytic efficiencies were not so large.
The oxidation rates in reactions catalyzed by IBXs 2 and
IBSs 7 were further accelerated by the use of powdered
Oxones due to its increased surface area and/or by the
addition of anhydrous sodium sulfate. TOF65 of 7a was
increased from 63 to 120 h1 with the use of powdered
Oxones.
4.2 IBS-catalyzed selective oxidation of alcohols
Various structurally diverse secondary and primary alcohols
could be oxidized with 7a, which were generated in situ from
22aNa, under optimized conditions (Scheme 13). According
to previous reports,1–3,50–55 it is difficult to selectively oxidize
primary alcohols to the corresponding aldehydes or carboxylic
acids with the same catalyst and reagents. Fortunately, as
shown in Scheme 13, not only primary a,b-unsaturated
alcohols, such as allylic, propargylic and benzylic alcohols,
but also aliphatic alcohols could be selectively oxidized to the
corresponding aldehydes and carboxylic acids in excellent
yield by controlling the amount of Oxones added in the
presence of precatalyst 22aNa (1–2 mol%) using method A
(solvent: acetonitrile; no additive), method B (solvent: ethyl
acetate; additive: anhydrous sodium sulfate) or method C
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Scheme 13 In situ-generated 7a-catalyzed selective oxidation of primary and secondary alcohols to the corresponding aldehydes or carboxylic
acids and ketones.

(solvent: nitromethane, additive: anhydrous sodium sulfate): simple filtration of most wastes derived from Oxones and
0.6–0.8 and 1.2 equiv. of Oxones were used for selective washing with water to remove catalyst derivatives.
oxidation to aldehyde and carboxylic acid, respectively. In
particular, methods B and C were effective for the selective
oxidation of acid-sensitive alcohols and the selective and rapid
oxidation of alcohols, respectively. The present protocol could
be applied to the chemoselective oxidation of alcohols bearing
several functional or protective groups such as silyloxy, benzyl- ð24Þ
oxy, ketal, alkenyl, alkynyl, halo, pyridinyl and thiophene
groups (Scheme 13). 4.3 IBS 7a-catalyzed cascade oxidative dehydrogenation of
Notably, the oxidation of N-Boc-L-prolinol 37 gave N-Boc- cycloalkanols
L-prolinal 38 without racemization in ethyl acetate (eqn (24)).
During the course of our research on the oxidation of
Benzylic sec,sec-1,2-diol 39 and aliphatic sec,sec-1,2-diol 41
cycloalkanols, we found that 7a efficiently catalyzed the
were oxidized to diketones 40 and 42 in moderate to high
cascade oxidative dehydrogenation of cycloalkanols to cyclo-
yields (Scheme 14). On the other hand, oxidation of aliphatic
alkenones. The selective oxidation of 4-tert-butylcyclohexanol
pri,sec-1,2-diol 43 gave oxidative cleavage product 44 as a
(45) to 4-tert-butylcyclohexanone (46) and successive oxida-
major product. In the non-aqueous solvent system, the desired
tion of 46 to 4-tert-butylcyclohex-2-enone (47) and 5-tert-
carbonyl products were obtained in nearly pure form by the
butyloxepan-2-one (48) proceeded in excellent yields when
we controlled the amounts of 22aNa and Oxones

Scheme 14 IBS 7a-catalyzed oxidation of 1,2-diols with Oxones. Scheme 15 IBS 7a-catalyzed cascade oxidation of 44 to 46 or 47.

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(Scheme 15). In contrast, the oxidation of 45 with Oxones in

the presence of 10 mol% of 17a gave 47 in 10% yield. To the
best of our knowledge, this is the first example of the catalytic
cascade oxidative dehydrogenation of saturated alcohols to
a,b-unsaturated carbonyl compounds.66,67 Five- and six-
membered cycloalkanols were transformed to the corresponding
enones in good yield.

4.4 Reaction mechanism of catalytic alcohol oxidation

Santagostino proposed a mechanism for the oxidation of
alcohols with IBX 2a via two steps: a fast pre-equilibrium step
(2a - 50) and a rate-determining disproportionation step
(50 - 18a).13 The catalytic cycle of 2a, which is prepared
Published on 06 March 2009 on http://pubs.rsc.org | doi:10.1039/B823399C

in situ from 17a, can be accomplished by regenerating 2a

through the oxidation of 18a with Oxones (Scheme 16). The
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catalytic cycle of IBS 7a should be essentially identical to that

of 2a. Control experiments indicated that the 5-methyl
substituent of 17h had no influence on the oxidation of
alcohols and the 5-methyl substituent of 5-Me-IBS 7b
accelerated the oxidation from I(III) to I(V).8
Based on Goddard’s theoretical study on the oxidation of
alcohols with IBX 2a,22 we also determined that the twisting
steps for the alkoxyperiodinanes 50-A and 51-A to the inter- Fig. 4 Free energy profiles relevant to 50-A - 18a.
mediates 50-B and 51-B were the rate-limiting steps
(Fig. 4 and 5).22 Interestingly, 51 has a much lower twisting
barrier than 50 (50-A - 50-C: 10.3 kcal mol1 vs. 51-A -
51-C: 6.5 kcal mol1). The hypervalent iodine–OCO and
iodine–OSO2 atom distances in 50-A and 51-A are correlated
with the twisting barriers: 2.252 Å for 51-A 4 2.193 Å for
50-A. Based on theoretical calculations, it was supposed
that the relatively ionic character of the intramolecular hyper-
valent iodine–OSO2 bond of IBS might lower the twisting
barrier of the alkoxyperiodinane intermediate 51-A. It was
confirmed that Goddard’s hypervalent twisting would be the
rate-determining step for the stoichiometric oxidation of
alcohols with not only IBX 2a but also IBS 7a. In contrast,
it was reasonable that the rate-determining step of I(V)-
catalyzed oxidations might be the regeneration of I(V) species
because the catalytic oxidation of alcohols was accelerated
with powdered Oxones.

Fig. 5 Free energy profiles relevant to 51-A - 49a.

4.5 Comparison of several transition metal-free

Scheme 16 In situ generation of IBX 2a and IBS 7a and the catalytic
cycle of alcohol oxidation.
organocatalysts for the oxidation of alcohols
Representative organocatalysts for the oxidation of alcohols
are summarized in Table 1. As described in section 3, five
methods have been reported for hypervalent iodine(III or V)-
catalyzed alcohol oxidations. However, these methods are

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Table 1 Comparison of organocatalyzed alcohol oxidation methods
a
Catalyst (mol%) Oxidant (equiv.) Additives
51
1 (1) O2 (air balloon) NaNO2/Br2
2a50 (20–40) Oxones (0.8–2.8) None
2a53 (10) Oxones (1) Bu4NHSO4
2a53 (10) TPPP (1) None
2663 (30) mCPBA (2.1) KBr
7a8 (0.05–5) Oxones (0.6–1.2) None
TEMPO68 (0.1–1) 28 or O2 or NaOCl None or NaNO2/Br2 or
KBr/Bu4NBr/NaHCO3
5269 (0.01–1) 28 or NaOCl None or KBr/Bu4NBr/
Published on 06 March 2009 on http://pubs.rsc.org | doi:10.1039/B823399C
NaHCO3
a
Isolated or in situ generated catalysis.
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associated with some disadvantages: (1) high catalyst loading,
(2) toxic and/or explosive additives such as Br2, NaNO2, (3)
low chemoselectivity, or (4) low control of the oxidation steps.
Liu’s 1/Br2/NaNO2 oxidation system49 is very attractive,
since molecular oxygen can be used as a stoichiometric
oxidant. However, primary alcohols cannot oxidize directly
to the corresponding carboxylic acids. Additionally, it may be
difficult to achieve the chemoselective oxidation of alcohols
bearing several acid-sensitive functional or protective groups,
since the strong acids HBr and HNO3 are generated in water
under these conditions.
TEMPO (a nitroxy radical)-catalyzed oxidation has
attracted great attention because molecular oxygen can also
be used as a stoichiometric oxidant.68 However, toxic and/or
explosive additives such as Br2 and NaNO2 must be used in a
halogenated solvent system. TEMPO is much less active for
the oxidation of sterically hindered alcohols. Recently,
Iwabuchi’s group developed a relatively small TEMPO analo-
gous catalyst, 1-Me-AZADO (52), which was highly effective
for the oxidation of sterically hindered alcohols.69
It is technically difficult to control the additional amounts of
gaseous oxygen as an oxidant. Moreover, gaseous oxygen is
often concentrated under high pressure to increase its reactiv-
ity despite its susceptibility to explode due to static electricity,
heating, shock, etc. In contrast, Oxones has several great
advantages of safety, stability, ease of transport, simple hand-
ling, controllable addition, nontoxic nature, etc., although
gaseous O2 is more atom-economically benign than Oxones.
In our system with catalyst 7a, environmentally benign
Oxones can be used without any toxic additives and ethyl
acetate can be used as a solvent. Various structurally diverse
primary and secondary alcohols can be oxidized smoothly
with our system. Moreover, the selective and cascade oxida-
tions of alcohols to aldehydes, ketones, carboxylic acids,
enones and lactones are possible with the additional control
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Conditions Products
H2O, 55 1C Ketones, aldehydes (low chemoselectivity)
CH3CN–H2O, 70 1C Ketones, carboxylic acids (low
chemoselectivity)
EtOAc–H2O, 70 1C Ketones, aldehydes (low chemoselectivity)
DCE or CH3CN, 80 1C Ketones, aldehydes (low chemoselectivity)
CH3CN, rt Ketones (low chemoselectivity)
EtOAc, CH3CN, or Ketones, aldehydes, carboxylic acids,
CH3NO2, 70 1C lactones, enones (cascade from alcohols)
(high chemoselectivity)
CH2Cl2, CH3CN–H2O, Ketones, aldehydes, carboxylic acids
etc., 0–80 1C (high chemoselectivity, low reactive for
sterically hindered alcohols)
CH2Cl2, 0 1C to rt Ketones, aldehydes, carboxylic acids
(high chemoselectivity, suitable for sterically
hindered alcohols)
of Oxones (i.e. primary alcohols - aldehydes - carboxylic
acids; secondary alcohols - ketones - esters; cycloalkanols -
cycloalkanones - lactones or cyclic a,b-enones, etc.).
8. Conclusions
Several arene-modified IBXs have been developed as stoichio-
metric oxidants (Fig. 1). However, there have been no reports
on the catalytic use of modified IBX analogues. We studied the
substituent effect of the aromatic ring of IBX in the catalytic
oxidation reaction of alcohols, and present here the effective-
ness of modified IBXs for the oxidation of alcohols. Electron-
donating group-substituted IBX derivatives such as 5-Me-IBX
2h, 5-MeO-IBX 2i, and 4,5-Me2-IBX 2j were superior to IBX
2a as catalysts for the oxidation of alcohols with Oxones
under our original non-aqueous conditions, which gave much
better results than known biphasic water/organic solvent
systems.48,51 Furthermore, IBS 7a was much more active than
modified IBX 2a. Thus, we developed a highly efficient and
selective oxidation of primary and secondary alcohols to
aldehydes, carboxylic acids, ketones and a,b-cycloalkenones
with powdered Oxones promoted by the catalytic use of
2-iodobenzenesulfonic acid (22a) or its sodium salt
(22aNa) in nitromethane, acetonitrile or ethyl acetate. Our
IBS–Oxone oxidation system has several advantages,
including safety, simplicity and high chemoselectivity. Our
findings regarding IBX/IBS-catalyzed oxidation chemistry
could lead to new possibilities in hypervalent iodine-catalyzed
oxidative transformations.
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