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Facile Synthesis of Koser’s Reagent and Derivatives SCHEME 1. Applications of HTIBs in Organic Synthesis
from Iodine or Aryl Iodides

Eleanor A. Merritt,† V^ ania M. T. Carneiro,†,‡

Luiz F. Silva Jr.,‡ and Berit Olofsson*,†
†
Department of Organic Chemistry, Arrhenius Laboratory,
Stockholm University, SE-106 91 Stockholm, Sweden, and
‡
Instituto de Quı´mica, Universidade de S~
ao Paulo,
Av. Prof. Lineu Prestes, 748, CP 26077, CEP 05513-970
S~
ao Paulo SP, Brazil

[email protected] R-Tosyloxy ketones are important synthetic intermediates

in the synthesis of heterocycles, enediynes, and natural
Received June 23, 2010 products.9,10 Recently, the use of chiral HTIBs has been
reported, as well as catalytic applications.11-13
Substituted versions of HTIB (i.e., [hydroxy(tosyloxy)-
iodo]arenes 1) and perfluorinated analogues are useful to
vary the reactivity of the reagent14-16 and to synthesize sub-
stituted diaryliodonium17-22 and alkynyl(aryl)iodonium
salts.23,24
Synthetic routes to [hydroxy(tosyloxy)iodo]arenes usually
consist of two steps, with initial oxidation of an iodoarene to
give the corresponding (diacetoxyiodo)arene or a similar
The first one-pot synthesis of neutral and electron-rich iodine(III) species, and subsequent treatment with p-tolue-
[hydroxy(tosyloxy)iodo]arenes (HTIBs) from iodine and nesulfonic acid (TsOH) to give the target compound.1 Togo
arenes is presented, thereby avoiding the need for expen- and co-workers recently reported a one-pot synthesis, where
sive iodine(III) precursors. A large set of HTIBs, includ- iodoarenes were treated with m-chloroperbenzoic acid
ing a polyfluorinated analogue, can be obtained from the (mCPBA) at room temperature in chloroform to give HTIBs
corresponding aryl iodide under the same conditions. The in high yields.25 The same group has also reported the catalytic
reaction proceeds under mild conditions, without excess formation of HTIBs, using similar conditions, in R-tosyloxy-
lation of carbonyl compounds.12,13 Another one-pot protocol
reagents, and is fast and high-yielding. Together, the two
involves the oxidant Selectfluor.26
presented routes give access to a wide range of HTIBs,
During our ongoing investigations into efficient one-pot
which are useful reagents in a variety of synthetic trans-
routes to iodonium salts,27-33 we have found conditions that
formations. allow fast and efficient synthesis of Koser’s reagent, and

(11) Altermann, S. M.; Richardson, R. D.; Page, T. K.; Schmidt, R. K.;

Hypervalent iodine reagents have recently found extensive Holland, E.; Mohammed, U.; Paradine, S. M.; French, A. N.; Richter, C.;
use as mild oxidants in organic synthesis.1-3 Iodine(III) com- Bahar, A. M.; Witulski, B.; Wirth, T. Eur. J. Org. Chem. 2008, 5315–5328.
pounds like (diacetoxyiodo)benzene and [hydroxy(tosyloxy)- (12) Yamamoto, Y.; Togo, H. Synlett 2006, 798–800.
(13) Tanaka, A.; Togo, H. Synlett 2009, 3360–3364.
iodo]benzene (HTIB, Koser’s reagent) are employed in a wide (14) Nabana, T.; Togo, H. J. Org. Chem. 2002, 67, 4362–4365.
range of transformations, including oxidation of olefins, ring (15) Zhdankin, V. V.; Kuehl, C. J.; Simonsen, A. J. J. Org. Chem. 1996,
61, 8272–8276.
contractions and expansions, dearomatization of phenols, syn- (16) Zagulyaeva, A. A.; Yusubov, M. S.; Zhdankin, V. V. J. Org. Chem.
thesis of iodonium salts, and R-oxidation of carbonyl com- 2010, 75, 2119–2122.
pounds (Scheme 1).1,4-8 (17) Ito, M.; Ogawa, C.; Yamaoka, N.; Fujioka, H.; Dohi, T.; Kita, Y.
Molecules 2010, 15, 1918–1931.
(18) Dohi, T.; Ito, M.; Morimoto, K.; Minamitsuji, Y.; Takenaga, N.;
Kita, Y. Chem. Commun. 2007, 4152–4154.
(1) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299–5358. (19) Dohi, T.; Yamaoka, N.; Kita, Y. Tetrahedron 2010, 66, 5775–5785.
(2) Varvoglis, A. Hypervalent Iodine in Organic Synthesis; Academic Press: (20) Margida, A. J.; Koser, G. F. J. Org. Chem. 1984, 49, 3643–3646.
San Diego, CA,1997. (21) Koser, G. F.; Wettach, R. H.; Smith, C. S. J. Org. Chem. 1980, 45,
(3) Hypervalent Iodine Chemistry; Wirth, T., Ed.; Springer: Berlin, Germany, 1543–1544.
2003. (22) Carroll, M. A.; Pike, V. W.; Widdowson, D. A. Tetrahedron Lett.
(4) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed. 2009, 48, 9052– 2000, 41, 5393–5396.
9070. (23) Rebrovic, L.; Koser, G. F. J. Org. Chem. 1984, 49, 4700–4702.
(5) Koser, G. F. Aldrichim. Acta 2001, 34, 89–102. (24) Zhdankin, V. V.; Stang, P. J. Tetrahedron 1998, 54, 10927–10966.
(6) Moriarty, R. M.; Vaid, R. K.; Koser, G. F. Synlett 1990, 365–383. (25) Yamamoto, Y.; Togo, H. Synlett 2005, 2486–2488.
(7) Kita, Y.; Morimoto, K.; Ito, M.; Ogawa, C.; Goto, A.; Dohi, T. J. Am. (26) Ye, C.; Twamley, B.; Shreeve, J. M. Org. Lett. 2005, 7, 3961–3964.
Chem. Soc. 2009, 131, 1668–1669. (27) Bielawski, M.; Olofsson, B. Chem. Commun. 2007, 2521–2523.
(8) Silva, L. F., Jr. Molecules 2006, 11, 421–434. (28) Bielawski, M.; Zhu, M.; Olofsson, B. Adv. Synth. Catal. 2007, 349,
(9) Nicolaou, K. C.; Montagnon, T.; Ulven, T.; Baran, P. S.; Zhong, 2610–2618.
Y. L.; Sarabia, F. J. Am. Chem. Soc. 2002, 124, 5718–5728. (29) Zhu, M.; Jalalian, N.; Olofsson, B. Synlett 2008, 592–596.
(10) Rebrovic, L.; Koser, G. F. J. Org. Chem. 1984, 49, 2462–2472. (30) Bielawski, M.; Aili, D.; Olofsson, B. J. Org. Chem. 2008, 73, 4602–4607.

7416 J. Org. Chem. 2010, 75, 7416–7419 Published on Web 10/06/2010 DOI: 10.1021/jo101227j
r 2010 American Chemical Society
Merritt et al.
JOC Note
derivatives, from simple and inexpensive arenes. To the best TABLE 1. Synthesis of Substituted HTIBs from Iodoarenesa
of our knowledge, this is the first report on the synthesis of
HTIBs directly from iodine and arenes,34 thereby avoiding
the need for expensive aryl iodides, two-step processes, and
long reaction times.
Recent developments in the synthesis of hypervalent iodine
compounds involve the use of 2,2,2-trifluoroethanol (TFE)
and similar fluorinated solvents.35,36 Enhanced reactivity and
new reaction pathways are often observed in these solvents,
the beneficial effects of which are suggested to originate from
stabilization of cationic and radical intermediates.17,19,37
Kita and co-workers reported the use of fluoroalcohols in
the synthesis of diaryliodonium salts,17-19 and we have
subsequently used TFE as cosolvent in our one-pot synthesis
of diaryliodonium tosylates from arenes and iodine or
iodoarenes.29 We noticed an enhanced reaction rate also in
the formation of Koser’s reagent when the oxidation of
iodoarenes was with mCPBA conducted in a mixture of
dichloromethane and TFE. Under these conditions, HTIB (1a)
was formed in excellent yield in only 15 min at room temperature
(Table 1, entry 1). The reaction was easily scaled up to 10 mmol
(entry 2), and the yield could be further improved by allowing
30 min reaction time (entry 3). These results should be
compared to the 2 h reaction time needed in chloroform.25
The scope of this reaction was screened with substituted
iodoarenes. Electron-deficient derivatives of HTIBs show
enhanced reactivity in oxidation reactions and are therefore
of synthetic interest. As electron-rich HTIBs can be used in
the synthesis of iodonium salts, iodoarenes with both types
of substituents were evaluated in the reaction.
Substrates with a methyl substituent in the ortho or para
position gave high yields of 1b and 1c, respectively (entries 4
and 5). More electron rich aryl iodides, such as 4-methox-
yiodobenzene, were too reactive and gave black mixtures
with byproduct formation. Gratifyingly, product 1d could be
obtained in good yield simply by avoiding TFE as cosolvent
(entry 6). As previously reported, this compound is unstable
and decomposes under vacuum or on storage.38
The performance of electron-deficient iodoarenes was then
investigated. Halo-substituted substrates were efficiently con-
verted to products 1e,f (entries 7 and 8). As expected, strongly
electron-withdrawing substituents, such as trifluoromethyl,
resulted in decreased reactivity. Still, product 1g was obtained a
The reactions were performed on 0.10 mmol scale in CH2Cl2 (0.5 mL)
in good yield when a longer reaction time was allowed (entries and TFE (0.5 mL). bIsolated yields. c10.0 mmol scale. dThe reaction was
9-11). Alternatively, a reaction temperature of 40 °C delivered performed in CH2Cl2. ePerformed at 40 °C.
1g within 30 min (entry 12). m-Trifluoromethyl and p-nitro-
substituted aryl iodides could also be employed (entries 13-15).
Even the polyfluorinated analogue 2 could be obtained SCHEME 2. Direct Synthesis of Polyfluorinated Analogue 2
directly from trifluoroethyl iodide (Scheme 2). Although a long

(31) Merritt, E. A.; Malmgren, J.; Klinke, F. J.; Olofsson, B. Synlett 2009,
2277–2280.
(32) Jalalian, N.; Olofsson, B. Tetrahedron 2010, 66, 5793–5800.
(33) Bielawski, M.; Olofsson, B. Org. Synth. 2009, 86, 308–314.
(34) The direct synthesis of other iodine(III) compounds from iodine and reaction time was required for this transformation, it represents
arenes has been reported, see refs 27-29 and the following: (a) Hossain, the first direct synthesis of a [hydroxy(tosyloxy)iodo]poly-
M. D.; Kitamura, T. Tetrahedron Lett. 2006, 47, 7889–7891. (b) Hossain,
M. D.; Kitamura, T. Bull. Chem. Soc. Jpn. 2007, 80, 2213–2219. fluoroalkane. These interesting compounds have previously
(35) Dohi, T.; Maruyama, A.; Minamitsuji, Y.; Takenaga, N.; Kita, Y. been obtained from the corresponding (diacetoxyiodo) or bis-
Chem. Commun. 2007, 1224–1226.
(36) Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.; Fujioka, H.; Kita, Y.
(trifluoroacetoxy)iodo derivatives, the synthesis of which re-
Tetrahedron 2009, 65, 10797–10815. quire 24-48 h of reaction time.15,16
(37) Dohi, T.; Ito, M.; Yamaoka, N.; Morimoto, K.; Fujioka, H.; Kita, Y. We subsequently investigated the preparation of HTIBs 1
Angew. Chem., Int. Ed. 2010, 49, 3334–3337.
(38) Papoutsi, I.; Spyroudis, S.; Varvoglis, A.; Raptopoulou, C. P. Tetra- directly from iodine and arenes. These are the expected
hedron 1997, 53, 6097–6112. intermediates in our synthesis of diaryliodonium tosylates
J. Org. Chem. Vol. 75, No. 21, 2010 7417
JOC Note Merritt et al.

TABLE 2. Synthesis of HTIBs 1 from Iodine, Arenes, and Sulfonic SCHEME 3. Synthesis of 1a from Iodine and Benzene
Acids

SCHEME 4. Formation of Byproduct 1c

tert-Butylbenzene was an excellent substrate, delivering

product 1j as the only regioisomer in 85% yield (entry 2).
p-Xylene and mesitylene could also be employed, giving 1k and
1l, respectively (entries 3 and 4). Biphenyl was surprisingly
unreactive, and prolonged reaction time failed to improve
the yield of 1m (entry 5). Again, p-methoxy derivative 1d was
obtained in good yield in the absence of TFE (entry 6).
The acid was subsequently varied using benzene as the
arene. Methanesulfonic acid, 2-naphthalenesulfonic acid,
and benzenesulfonic acid all delivered the corresponding
HTIBs in good yields (entries 7-9), whereas camphorsulfo-
nic acid did not work.39
When benzene was reacted with tosic acid, product 1a was
surprisingly obtained as a mixture with byproduct 1c (entry 10).
Furthermore, 1c was the only observed product in reactions
of bromobenzene or chlorobenzene with tosic acid (entry 11).
An optimization of the reaction with benzene revealed that
1c was formed only in the presence of TFE. The oxidation was,
however, slow in reactions without TFE, as we have previously
experienced for unactivated arenes.29
We therefore turned to the use of TfOH, as this should
result in rapid formation of an iodine(III) intermediate,27
which could be converted to Koser’s reagent by addition of
tosic acid to the reaction mixture. This sequential one-pot
procedure proved fruitful, and compound 1a was cleanly
formed in 75% yield (Scheme 3).
This sequential one-pot protocol could be used also in the
synthesis of HTIBs from the alkyl-substituted arenes in
Table 2, but did not result in better yields compared to the
direct reaction with tosic acid.
The formation of byproduct 1c in reactions with unactivated
arenes was intriguing. Indeed, 1c was formed when iodine was
a
Isolated yields. bReaction time 60 min. cThe reaction was performed treated with mCPBA and TsOH also in the absence of an arene.
in CH2Cl2. dContains 0.1 equiv of TsOH. e4 equiv of mCPBA was used.
f With the correct stoichiometry of iodine and tosic acid, 1c was
Np = 2-naphthyl. gYield based on the amount of TsOH used.
isolated in 47% yield (Scheme 4). The addition of 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) as a radical scavenger
from iodine and arenes with mCPBA and tosic acid.29 Thus, completely inhibited the reaction, indicating that 1c is formed
we were aware of the difficulties in iodinating unactivated from TsOH via a radical mechanism.
arenes in the absence of very strong acids, such as trifluoro- To conclude, a fast and efficient synthesis of a wide range
methanesulfonic acid (TfOH). of electron-deficient and electron-rich HTIBs 1 from iodoarenes
Therefore, the reaction was initially examined with use of has been developed. The use of TFE as cosolvent increased
electron-rich arenes. The reaction conditions were adjusted the reaction rate, resulting in much shorter reaction times
to allow complete consumption of the iodine by changing the than previously reported in oxidations of iodoarenes. A poly-
stoichiometry of oxidant and acid. Indeed, treatment of fluorinated analogue of Koser’s reagent, 2, has also been
toluene with iodine, mCPBA, and TsOH resulted in formation synthesized. Furthermore, the direct synthesis of neutral to
of [hydroxy(tosyloxy)iodo]arenes 1c and 1b in a 6:1 ratio
(Table 2, entry 1). The regioisomeric mixture of products was (39) The reaction of PhI, mCPBA, and CSA according to Table 1 gave the
product in 88% yield. Direct formation from PhH and I2 gave no iodine(III)
expected as the iodination of toluene proceeds with moderate compound, with the solution remaining purple, indicating that iodination
para:ortho selectivity.27-29 did not proceed.

7418 J. Org. Chem. Vol. 75, No. 21, 2010

Merritt et al.
JOC Note
electron-rich HTIBs from iodine, arenes, and various sulfo- Synthesis of Koser’s Reagent (1a) from Iodine and Benzene. To
nic acids has been demonstrated, thereby avoiding the need a solution of benzene (36 μL, 0.40 mmol) in dichloromethane
for expensive iodoarenes. Together, the two presented routes (2 mL) were added sequentially iodine (51 mg, 0.20 mmol),
give access to a wide range of [hydroxy(tosyloxy)iodo]- mCPBA (80% active oxidant, 174 mg, 0.80 mmol), and TfOH
arenes, which are useful reagents in a variety of synthetic (18 μL, 0.20 mmol). The solution was stirred at room tempera-
ture for 10 min, then TsOH 3 H2O (77 mg, 0.40 mmol) was added.
transformations.
The mixture was stirred for a further 10 min at room tempera-
ture and concentrated in vacuo, then diethyl ether (2 mL) was
Experimental Section added to the residue. The suspension was stirred at room
General Procedure for the Synthesis of HTIBs 1 from Iodoarenes. temperature for 30 min, then filtration afforded the title com-
To a stirred solution of iodoarene (0.10 mmol) in dichloro- pound (118 mg, 75%) as a colorless solid. Analytical data were
methane/TFE (1:1 v/v, 1 mL) was added mCPBA (0.10 mmol), in agreement with the literature.25
followed by TsOH 3 H2O (0.10 mmol). The resulting solution Synthesis of 1c from Iodine. Iodine (25.0 mg, 0.10 mmol) was
was stirred at room temperature for 30 min and concentrated dissolved in dichloromethane (0.5 mL) at room temperature and
under a stream of air, then diethyl ether (2 mL) was added to the TFE (0.5 mL) was added. To the resulting stirred solution was
remaining residue. The resulting precipitate was filtered off and added mCPBA (81% active oxidant, 86 mg, 0.40 mmol), fol-
dried in vacuo to give compound 1 as a solid. lowed by TsOH 3 H2O (76 mg, 0.40 mmol). The solution was
1-[Hydroxy(tosyloxy)iodo]-4-trifluoromethylbenzene (1g). Color- stirred at room temperature for 30 min and concentrated under
less solid: mp 146-148 °C; 1H NMR (400 MHz, CD3OD) δ 8.52 (d, a stream of air, then diethyl ether (2 mL) was added to the
J = 8.4 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), remaining residue. The suspension was stirred at room tempera-
7.24 (d, J = 8.4 Hz, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, ture for 30 min, then the solid was isolated by filtration and dried
CD3OD) δ 142.9, 142.0, 137.2, 135.6, 129.9, 129.5, 129.4, 126.9, in vacuo to give 1c (38.0 mg, 47%). Analytical data were in
124.7 (q, J = 270 Hz), 21.3. agreement with the literature.26
General Procedure for the Synthesis of HTIBs 1 from Iodine
and Arenes. Iodine (0.20 mmol) was dissolved in dichloro- Acknowledgment. This work was financially supported by
methane (1 mL) and TFE (1 mL) was added. To the resulting the Swedish Research Council, Wenner-Gren Foundations,
stirred solution was added arene (0.40 mmol), followed by the Swedish Foundation for International Cooperation in
mCPBA (0.60 mmol) and TsOH 3 H2O (0.40 mmol). The mixture Research and Higher Education (STINT), K & A Wallenberg
was stirred at room temperature for 30 min. Workup and
Foundation, and the Brazilian Council of Scientific and
purification as described above.
1-[Hydroxy(tosyloxy)iodo]-4-tert-butylbenzene (1j). Colorless Technological Development (CNPq).
solid: mp 135-137 °C; 1H NMR (400 MHz, CD3OD) δ 8.27 (dd,
J = 6.8, 2.0 Hz, 2H), 7.73 (dd, J = 6.8, 2.0 Hz, 2H), 7.67 (d, J = Supporting Information Available: General experimental
6.4, 2.0 Hz, 2H), 7.22 (dd, J = 6.4, 2.0 Hz, 2H), 2.37 (s, 3H), 1.38 conditions, analytical data, and 1H and 13C NMRs of products 1
(s, 9H); 13C NMR (100 MHz, CD3OD) δ 159.6, 143.3, 141.8, and 2. This material is available free of charge via the Internet at
138.3, 137.3, 130.1, 129.8, 127.0, 36.5, 31.3, 21.3. http://pubs.acs.org.

J. Org. Chem. Vol. 75, No. 21, 2010 7419