IBX-I2 redox couple for facile generation of IOH and I +: Expedient protocol for iodohydroxylation of olefins and iodination of aromatics

Article abstract of DOI:10.1021/jo9007892

(Chemical Equation Presented) IBX is readily reduced to IBAin the presence of molecular iodine in DMSO to generate hypoiodous acid (IOH), which reacts with a variety of olefins as well as R, β-unsaturated ketones leading to their respective iodohydrins with anti stereochemistry. The same redox chemistry in acetonitrile containing TFA produces iodonium ions for facile iodination of a variety of aromatic compounds in respectable isolated yields.

Full text of DOI:10.1021/jo9007892

pubs.acs.org/joc
are unknown for other oxidation reagents, the interest in
IBX chemistry continues unabated.3
IBX-I2 Redox Couple for Facile Generation of IOH
and Iþ: Expedient Protocol for Iodohydroxylation of
Olefins and Iodination of Aromatics
We have been interested in understanding the reactivity of
IBX and exploiting the same to unravel new synthetic
transformations.4 In continuation of our studies, we have
inquired into the redox chemistry of IBX with molecular
iodine. The latter and metal iodides have been oxidized by a
number of reagents to produce hypoiodous (IOH) acid and
Jarugu Narasimha Moorthy,* Kalyan Senapati, and
Sarvesh Kumar
Department of Chemistry, Indian Institute of Technology,
Kanpur 208 016, India
iodonium (Iþ) ions. Although periodic acid (HIO4 2H2O),5
3
periodate (NaIO4),6 m-iodosylbenzoic acid,7 etc. have all
been employed to oxidize molecular iodine or metal iodides,
IBX has surprisingly not been employed as an oxidant.
Herein, we report that the redox chemistry between IBX
and I2 in DMSO leads supposedly to IOH, which can be
conveniently exploited to convert a variety of e-rich olefins as
well as e-deficient R,β-unsaturated carbonyl compounds to
their corresponding iodohydrins with anti stereochemistry in
good-to-excellent isolated yields; indeed, the treatment of
iodohydrin in the same pot with NaOH leads to R,β-epoxy-
ketones in respectable isolated yields. Further, it is shown
that the redox chemistry between the IBX-I2 couple in the
presence of TFA permits facile iodination of a number of e-
rich as well as e-poor aromatic compounds via generation of
reactive iodonium ions.
moorthy@iitk.ac.in
Received April 16, 2009
To begin with, the reduction of IBX with added molecular
iodine in DMSO-d6 was examined by 1H NMR (500 MHz)
spectroscopy. As shown in Figure 1, the signals correspond-
ing to IBX completely disappeared within 0.5 h of the
addition of 2.2 equiv of iodine leading to concomitant appea-
rance of the signals that could be assigned to o-iodosoben-
zoic acid (IBA), the 2-e reduction product. Further standing
of the reaction mixture for 1-2 h at rt led to the formation of
o-iodobenzoic acid (BA) in small amounts, as monitored by
1H NMR spectroscopy, cf. Figure 1.8 A similar spectral mo-
nitoring in CD3CN containing TFA (9:1) proved difficult, as
IBX was found to be virtually insoluble. Nonetheless, the
addition of I2 to the suspension of IBX in CD3CN-TFA led
IBX is readily reduced to IBA in the presence of molecular
iodine in DMSO to generate hypoiodous acid (IOH),
which reacts with a variety of olefins as well as R,
β-unsaturated ketones leading to their respective iodohy-
drins with anti stereochemistry. The same redox chemis-
try in acetonitrile containing TFA produces iodonium
ions for facile iodination of a variety of aromatic com-
pounds in respectable isolated yields.
1
to noticeable dissolution. The H NMR monitoring of the
(3) (a) Uyanik, M.; Akakura, M.; Ishihara, K. J. Am. Chem. Soc. 2009,
131, 251. (b) Fontaine, P.; Masson, G.; Zhu, J. Org. Lett. 2009, 11, 1556. (c)
Richardson, R. D.; Zayed, J. M.; Altermann, S.; Smith, D.; Wirth, T. Angew.
Chem., Int. Ed. 2007, 46, 6529. (d) Studer, A.; Janza, B. J. Org. Chem. 2005,
70, 6991. (e) Bhalerao, D. S.; Mahajan, U. S.; Chaudhari, K. H.; Akamanchi,
K. G. J. Org. Chem. 2007, 72, 662. (f) Nicolaou, K. C.; Baran, P. S. Angew.
Chem., Int. Ed. 2002, 41, 2678. (g) Nicolaou, K. C.; Mathison, C. J. N.;
Montagnon, T. Angew. Chem., Int. Ed. 2003, 42, 4077. (h) Nicolaou, K. C.;
Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc. 2004, 126, 5192.
(4) (a) Moorthy, J. N.; Singhal, N.; Mal, P. Tetrahedron Lett. 2004, 45,
309. (b) Moorthy, J. N.; Singhal, N.; Venkatakrishnan, P. Tetrahedron Lett.
2004, 45, 5419. (c) Moorthy, J. N.; Singhal, N.; Senapati, K. Tetrahedron
Lett. 2006, 47, 1757. (d) Moorthy, J. N.; Singhal, N.; Senapati, K. Org.
Biomol. Chem. 2007, 5, 767. (e) Moorthy, J. N.; Singhal, N.; Senapati, K.
Tetrahedron Lett. 2008, 49, 80. (f) Moorthy, J. N.; Senapati, K.; Singhal, N.
Tetrahedron Lett. 2009, 50, 2493.
There is a surge of interest in hypervalent organic com-
pounds at present due to their nontoxic nature, ready avail-
ability, and environmentally benign attributes. In particular,
the pentavalent iodine compound,1 namely o-iodoxybenzoic
acid (1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide), re-
ferred to popularly as IBX, has assumed significant promi-
nence as a fantastic oxidation reagent since the demons-
tration in 1994 by Frigerio and co-workers.2 In addition to
the ease with which it is readily prepared starting from cheap
o-iodobenzoic acid, the stability and advantages associated
with obviating the use of copious amounts of metal-based
reagents render IBX an indispensable and sought-after
reagent in oxidation chemistry. Because of its mild nature
and ability to accomplish a variety of transformations that
(5) Masuda, H.; Takase, K.; Nishio, M.; Hasegawa, A.; Nishiyama, Y.;
Ishii, Y. J. Org. Chem. 1994, 59, 5550.
(6) (a) Kraszkiewicz, L.; Sosnowski, M.; Skulski, L. Synthesis 2006, 1195.
(b) Emmanuvel, L.; Shukla, R. K.; Sudalai, A.; Gurunath, S.; Sivaram, S.
Tetrahedron Lett. 2006, 47, 4793.
(7) Yusubov, M. S.; Yusubova, R. Y.; Kirschning, A.; Park, J. Y.; Chi,
K.-W. Tetrahedron Lett. 2008, 49, 1506.
(8) The doublet that appears at ca. δ 8.3 when I2 is added to IBX (and not
to IBA) is presumably due to the formation of 1-benziodoxole hypoiodide.
(1) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (b)
Ladziata, U.; Zhdankin, V. V. ARKIVOC 2006, 108, 26.
(2) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019.
DOI: 10.1021/jo9007892
r
Published on Web 07/10/2009
J. Org. Chem. 2009, 74, 6287–6290 6287
2009 American Chemical Society

Moorthy et al.
JOCNote
TABLE 1. Results of Iodohydroxylation of Olefins with IBX-I2 in
DMSOa
FIGURE 1. 1H NMR spectra in DMSO-d6 of (a) IBX, (b) IBA,
(c) o-iodobenzoic acid (BA), and (d-f) IBX þ I2, after 0.5, 1.0, and
2.0 h following the addition of I2. Notice that IBX is reduced to IBA
within 0.5 h (d), while further reduction to BA occurs only in small
amounts as reflected by the signals in the region of δ 7.0-7.5 in the
spectrum (c).
FIGURE 2. 1H NMR spectra of (a) IBA in CD3CN-TFA (9:1), (b)
IBA þ I2 in CD3CN-TFA after 1 h following the addition of I2, and
(c) IBX þ I2 after 0.5 h following the addition of I2.
SCHEME 1. The Redox Chemistry between IBX and I2 and the
Species Generated
aAll reactions were conducted on 0.5-1.5 mmol of the
olefin. bA mixture of syn and anti diastereomers. cConver-
d
sion ca. 90%. Formation of epoxide was observed in ca. 20%
yield.
DMSO leading to I(III) species, while further 2-e reduction
to I(I) occurs in acetonitrile containing TFA (Scheme 1).
As the species generated in DMSO was presumed to be
IOH, the redox reaction between IBX and I2 was conducted
in the presence of added olefins to explore the extent to which
the latter undergo iodohydroxylations.9 While e-rich olefins
were found to react readily to afford the corresponding
sample after 0.5 h revealed the signals corresponding to IBA.
After 1 h, IBA was found to be further reduced to
o-iodobenzoic acid, cf. Figure 2. Thus, it was concluded that
IBX undergoes facile 2-e reduction in the presence of I2 in
(9) The IBX-I2 reagent system in water has been reported to convert
olefins to R-iodoketones, see: Yadav, J. S.; Reddy, B. V. S.; Singh, A. P.;
Basak, A. K. Tetrahedron Lett. 2008, 49, 5880.
6288 J. Org. Chem. Vol. 74, No. 16, 2009

Moorthy et al.
JOCNote
SCHEME 2. Highly Stereoselective Anti Addition of IOH
TABLE 2. Results of Iodination of Aromatics with IBX-I2
SCHEME 3. One-Pot Conversion of R,β-Unsaturated Ketones
to R,β-Epoxyketones
iodohydrins in near-quantitative yields, e-deficient R,β-un-
saturated ketones were found to react rather slowly. The
employment of excess reagent (IBX and I2 in 1:2.2 equiv) was
found to offset the slow reaction times (entries 1 and 2,
Table 1). Thus, a variety of olefins shown in Table1 were
conveniently converted to their respective iodohydrins in
moderate durations. While the olefins such as styrene reacted
within 0.1-0.8 h (entries 16-18), the R,β-unsaturated car-
bonyl compounds reacted in 0.3-4.0 h with the notable
exceptions being nitro-substituted chalcones (entires 7 and
8) and cinnamonitrile (entry 13), which reacted rather slowly
over a period of 10-35 h. For all olefins with the exception of
p-tolyl allyl ether (entry 18), no regioisomeric iodohydrins
1
were observed as revealed by H NMR analyses of crude
reaction mixtures. Further, the fact that the addition occurs
with a very high anti stereoselectivity was established by
subjecting the pure cis and trans isomers of cinnamonitrile to
iodohydroxylations, Scheme 2; the stereochemistry of the
products was deduced based on a comparison with the
literature-reported spectral data and X-ray structure deter-
mination of one of the products, cf. the SI. 1H NMR
spectroscopic monitoring of the reactions of both pure
isomers with IBX-I2 independently revealed the formation
of corresponding iodohydrins derived via anti addition al-
most exclusively at conversions as high as 80%, cf. the SI.
The formation of the diastereomeric iodohydrin derived via
1
syn addition was barely evident (<2-3%) from H NMR
analysis in each case.
We also examined the viability of one-pot conversion of
R-iodo-β-hydroxyketones to the corresponding R,β-epoxy-
ketones by treatment with a base. Indeed, addition of 10%
NaOH solution to the reaction mixture after the disappear-
ance of R,β-unsaturated ketone, as judged by the TLC
analyses, led to the desired epoxides in respectable yields as
shown in Scheme 3.
b
c
aTFA (10%). 8% diiodo compound was isolated. 98%
H2SO4 (5 equiv).
As shown in Scheme 1, the hypoiodous acid generated in
acidic medium should liberate iodonium ions, which can be
J. Org. Chem. Vol. 74, No. 16, 2009 6289

Moorthy et al.
JOCNote
trapped for aromatic electrophilic substitutions. As revealed
by 1H NMR analysis in Figure 1, 4 mol equiv of IOH should
in principle be generated for each mole of IBX. In line
with this expectation, the 4-e reduction product, namely
o-iodobenzoic acid, was isolated in near-quantitative yields,
when the reactions were run with mesitylene as a representa-
tive case in CH3CN containing TFA. Thus, iodination of a
variety of aromatic compounds was explored with IBX-I2
in DMSO as well as in CH3CN-TFA. While the iodination
was found to occur with IBX-I2 in DMSO, the reaction
was found to be more efficient when carried out in
CH3CN-TFA (entries 1-6, Table 2). However, for less
activated aromatics, excess reagent was found to expedite
the reactions leading to excellent yields of iodinated aro-
matic products in reasonable reaction durations as shown
in Table 2. A perusal of the results in Table 2 shows that a
variety of aromatic compounds can be iodinated in either of
the two conditions involving the use of DMSO or CH3CN-
TFA. Most remarkable is the fact that e-deficient aro-
matics could also be subjected to iodination, albeit at a
relatively higher temperature with/without added H2SO4
(entries 23-25).
A variety of reagents are known for direct iodination of
aromatics based on oxidation of molecular iodine.10 It is
evident from the results described herein that IBX can be
reduced from its higher oxidation state to o-iodobenzoic
acid (BA) with concomitant formation of 4 equiv of iodo-
nium ions. This in conjunction with the use of CH3CN
or DMSO in which most aromatics that can be reacted
should make the reagent system based on IBX-I2 conve-
nient for iodination of aromatic compounds in general. It is
needless to emphasize the utility of aryl iodides in medi-
cinal and biochemistry, as radioactive markers11 and as
valuable intermediates in metal-catalyzed cross-coupling
reactions.12
for addition to e-deficeint olefins. Further, it is shown that
tandem halohydroxylation-dehydroiodocyclization of
olefins to epoxides can be conveniently carried out in one
pot. That the redox chemistry in acidic medium leads to
abundant iodonium ions for aromatic iodination is demon-
strated with diverse aromatic compounds. A variety of e-
rich as well as poor aromatics are shown to be iodinated
with the IBX-I2 reagent system in very good isolated
yields.
Experimental Section
General Procedure for Iodohydroxylation of Olefins. In a
typical procedure, 1.0-1.5 mmol of chalcone, 1.0 equiv of I2,
and 2.2 equiv of IBX in 2-3 mL of DMSO were stirred at room
temperature. For e-rich olefins, IBX (0.5 equiv) and I2 (1.1
equiv) were stirred in DMSO for 0.5 h first and then the olefin
was introduced. The progress of the reaction was monitored by
TLC analysis. After completion of the reaction, the reaction
mixture was quenched with water and extracted with ethyl
acetate. The combined organic extracts were washed with
10% aq sodium thiosulfate solution followed by water and
dried over anhydrous Na2SO4. The solvent was removed in
vacuo and the crude product was purified by column chroma-
tography over silica gel (100-200 μm). While the duration of
reaction was typically 10-45 min for e-rich olefins, it varied
from 0.3 to 14 h for e-deficient olefins such as R,β-unsaturated
carbonyl compounds.
General Procedure for One-Pot Epoxidation of Olefins. After
the disappearance of the olefin in the iodohydroxylation
reaction described above, 1.5 equiv of 10% aq NaOH solution
was added to the reaction mixture in the same pot at room
temperature. The progress of the reaction was monitored by
TLC analysis. Subsequent to the disappearance of iodohy-
drin, the reaction mixture was quenched with water. Regular
workup followed by silica gel chromatography led to the
epoxides, which were characterized by spectroscopic data,
cf. the SI.
In conclusion, we have shown that the redox chemistry
between IBX and molecular iodine leads to facile genera-
tion of hypoiodous acid, which in the presence of olefins
reacts to afford the corresponding halohydrins with a very
high anti stereoselectivity conveniently. It should be
pointed out that iodohydroxylations are largely reported
for e-rich olefins,13 and one observes only scattered and
scant examples involving e-deficient olefins.14 In the pre-
sent investigation, we have found that a variety of R,β-
unsaturated carbonyl compounds undergo conversion to
the corresponding iodohydrins. Presumably, the solvation
effects involving DMSO render IOH remarkably reactive
General Procedure for Iodination of Aromatics. In a represen-
tative reaction, IBX, I2, and the substrate, according to the
composition shown in Table 2, were taken in 2.0-3.0 mL of
DMSO or CH3CN-TFA (9:1) and stirred at the indicated
temperature. The progress of the reaction was monitored by
TLC analysis. For iodination of phenol and aniline derivatives,
the reagent was prepared first by stirring I2 and IBX in DMSO
at room temperature for 30 min and the substrate was added
later. After completion of the reaction as judged by TLC
analysis, the reaction mixture was quenched with 10% aq
sodium thiosulfate solution and extracted with ethyl acetate.
The combined organic extracts were washed with water and
brine, then dried over anhydrous Na2SO4. The solvent was
removed in vacuo and the crude product was purified by
column chromatography, using silica gel (100-200 μm). For
phenols, the aqueous reaction mixture was neutralized with
NH4Cl before extraction.
(10) For a recent review on iodinations with iodine or iodides, see:
Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2008, 1487.
(11) Handbook of Radiopharmaceuticals: Radiochemistry and Applica-
tions; Welch, M. J., Redvanly, C. S., Eds.; Wiley: Chichester, UK, 2003.
(12) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
ꢀ
(13) (a) Barluenga, J.; Marco-Arias, M.; Gonzalez-Bobes, F.; Ballesteros,
A.; Gozalez, J. M. Chem.;Eur. J. 2004, 10, 1677. (b) Corso, A. R. D.;
Acknowledgment. J.N.M. and S.K. are thankful to DST
(the Department of Science and Technology), India for
financial support. K.S. is grateful to UGC (the University
Grants Commision) for a senior research fellowship.
ꢀ
Panunzi, B.; Tingoli, M. Tetrahedron Lett. 2001, 42, 7245. (c) Iranpoor, N.;
Shekarriz, M. Tetrahedron 2000, 56, 5209. (d) Asensio, G.; Andreu, C.; Boix-
Bernardini, C.; Mello, R.; Gonzlez-Nuez, M. E. Org. Lett. 1999, 1, 2125. (e)
Stavber, G.; Iskra, J.; Zupan, M.; Stavber, S. Adv. Synth. Catal. 2008, 350,
2921. (f) Ribeiro, R. S.; Esteves, P. M.; Mattos, M. C. S. Tetrahedron Lett.
2007, 48, 8747. (g) Das, B.; Venkateswarlu, K.; Damodar, K.; Suneel, K. J.
Mol. Catal. A: Chem. 2007, 269, 17. (h) Barluenga, J. Pure Appl. Chem. 1999,
71, 431.
Supporting Information Available: Characterization data,
1H and 13C spectral reproductions for halohydrins and aryl
iodides, and crystal data for 3-hydroxy-2-iodo-1-(4-methoxy-
phenyl)-3-phenylpropan-1-one. This material is available free of
charge via the Internet at http://pubs.acs.org.
(14) (a) Urankar, D.; Rutar, I.; Modec, B.; Dolenc, D. Eur. J. Org. Chem.
2005, 2349. (b) Hajra, S.; Bhowmick, M.; Karamakar, A. Tetrahedron Lett.
2005, 46, 3073.
6290 J. Org. Chem. Vol. 74, No. 16, 2009