Clean and efficient benzylic C-H oxidation in water using a hypervalent iodine reagent: Activation of polymeric iodosobenzene with KBr in the presence of montmorillonite-K10

Article abstract of DOI:10.1021/jo8012435

(Chemical Equation Presented) We have found that unreactive and insoluble polymeric iodosobenzene [PhIO]_n induced aqueous benzylic C-H oxidation to effectively give arylketones, in the presence of KBr and montmorillonite-K10 (M-K10) clay. Water-soluble and reactive species 1 having the unique I(III)-Br bond, in situ generated from [PhIO]_n and KBr, was considered to be the key radical initiator during the reactions.

Full text of DOI:10.1021/jo8012435

competitive side reactions, c.f., ring bromination, for which their
applications are strictly limited. Therefore, a survey of a facile
and selective new method in water using an alternative suitable
oxidant is of great importance.
Clean and Efficient Benzylic C-H Oxidation in
Water Using a Hypervalent Iodine Reagent:
Activation of Polymeric Iodosobenzene with KBr
in the Presence of Montmorillonite-K10
Recently, hypervalent iodine reagents have received much
attention by virtue of their low toxicity, ready availability, and
reactivity similar to those of heavy metal oxidants.6 In organic
solvents, it is known that few active cyclic iodine(III) com-
pounds show radical reactivities to induce benzylic oxidation.7
A pentavalent iodine reagent, o-iodoxybenzoic acid (IBX), also
oxidizes alkylarenes to arylketones in DMSO.8 These reported
methods, albeit useful and versatile, are restricted in their use
in organic solvents because of low solubilities and reactivities
of the organoiodine compounds in water. Herein, we now report
a promising new method for clean benzylic C-H oxidation in
water by utilizing water-soluble and highly reactive oxidant 1,9
in situ generated from iodosobenzene [PhIO]n and KBr (eq 1).
Toshifumi Dohi,† Naoko Takenaga, Akihiro Goto,
Hiromichi Fujioka, and Yasuyuki Kita*,†
Graduate School of Pharmaceutical Sciences, Osaka
UniVersity, 1-6 Yamada-oka, Suita, Osaka, 565-0871 Japan
kita@phs.osaka-u.ac.jp
ReceiVed June 9, 2008
We have found that unreactive and insoluble polymeric
iodosobenzene [PhIO]n induced aqueous benzylic C-H
oxidation to effectively give arylketones, in the presence of
KBr and montmorillonite-K10 (M-K10) clay. Water-soluble
and reactive species 1 having the unique I(III)-Br bond, in
situ generated from [PhIO]n and KBr, was considered to be
the key radical initiator during the reactions.
In our study for developing new environmentally benign
oxidation reactions, we have been engaged in the practical
utilization of hypervalent iodine reagents in water, especially
with trivalent organoiodine compounds.9,10 In particular, we
have previously found that the activation of the iodosobenzene
polymer ([PhIO]n) by inorganic bromide salts in water is a
powerful method for the effective and unprecedented hyperva-
lent iodine(III)-induced oxidation of alcohols.9 Detailed studies
on the mechanism revealed that the reaction involves the
generation of a water-soluble species 1 having the unique
I(III)-Br bond as a reactive intermediate. On the basis of a
previous report and unique reactivity of hypervalent iodine(III)-
halogen bonds for initiating radical reactions,11 we assumed that
the reaction of 1 in water is the development of a new aqueous
benzylic oxidation via the radical pathway (Scheme 1).12
Development of aqueous-phase reactions is one of the active
fields in organic synthesis due to a recent demand for realization
of green chemical processes.1 Benzylic oxidation is a funda-
mental transformation that is useful for the conversion of
alkylarenes into the corresponding carbonyl compounds. Con-
cerning this important transformation, numerous methods have
been developed using a variety of oxidants and conditions in
organic solvents,2 whereas only a few examples performed in
water have been described thus far. The photocatalytic TiO2/
O2 system3 and the methods using a stoichiometric chromate
(6) Recent reviews, see: (a) Stang, P. J.; Zhdankin, V. V. Chem. ReV. 1996,
96, 1123. (b) Kita, Y.; Takada, T.; Tohma, H. Pure Appl. Chem. 1996, 68, 627.
(c) Kirschning, A. Eur. J. Org. Chem. 1998, 2267. (d) Koser, G. F. Aldrichim.
Acta 2001, 34, 89. (e) Zhdankin, V. V.; Stang, P. J. Chem. ReV. 2002, 102,
2523. (f) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893. (g) Wirth, T. Angew.
Chem., Int. Ed. 2005, 44, 3656.
5
salt4 or NaIO4 were examined, but there still exist serious
drawbacks such as low yields, complicated procedures, and
(7) (a) Ochiai, M.; Ito, T.; Masaki, Y.; Shiro, M. J. Am. Chem. Soc. 1992,
114, 6269. (b) Ochiai, M.; Ito, T.; Takahashi, H.; Nakanishi, A.; Toyonari, M.;
Sueda, T.; Goto, S.; Shiro, M. J. Am. Chem. Soc. 1996, 118, 7716.
(8) (a) Nicolaou, K. C.; Zhong, Y.-L.; Baran, P. S. J. Am. Chem. Soc. 2001,
123, 3183. (b) Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.-L. J. Am.
Chem. Soc. 2002, 124, 2245.
(9) (a) Tohma, H.; Takizawa, S.; Maegawa, T.; Kita, Y. Angew. Chem., Int.
Ed. 2000, 39, 1306. (b) Tohma, H.; Maegawa, T.; Kita, Y. AdV. Synth. Catal.
2002, 344, 328.
(10) (a) Tohma, H.; Takizawa, S.; Watanabe, H.; Kita, Y. Tetrahedron Lett.
1998, 39, 4547. (b) Tohma, H.; Morioka, H.; Harayama, Y.; Hashizume, M.;
Kita, Y. Tetrahedron Lett. 2001, 42, 6899. For iodosylbenzene (PhIO2), see: (c)
Tohma, H.; Takizawa, S.; Watanabe, H.; Fukuoka, Y.; Maegawa, T.; Kita, Y. J.
Org. Chem. 1999, 64, 3519.
(11) (a) Banks, D. F.; Huyser, E. S.; Kleinburg, J. J. Org. Chem. 1964, 29,
3692. (b) Tanner, D. D.; Van Bosteien, P. B. J. Org. Chem. 1967, 32, 1517. (c)
Amey, R. L.; Martin, J. C. J. Am. Chem. Soc. 1979, 101, 3060.
† Present address: College of Pharmaceutical Sciences, Ritsumeikan Univer-
sity, 1-1-1 Nojihigashi, Kusatsu, Shiga, 525-8577.
(1) (a) Lindstrom, U. M. Chem. ReV. 2002, 102, 2751. (b) Klijn, J. E.;
Engberts, J. B. F. N. Nature 2005, 435, 746. (c) Li, C. -J.; Chen, L. Chem. Soc.
ReV. 2006, 35, 68.
(2) Recent reports, see: (a) Bonvin, Y.; Callens, E.; Larrosa, I.; Henderson,
D. A.; Oldham, J.; Burton, A. J.; Barrett, A. G. M. Org. Lett. 2005, 7, 4549. (b)
Catino, A. J.; Nichols, J. M.; Choi, H.; Gottipamula, S.; Doyle, M. P. Org. Lett.
2005, 7, 5167. (c) Gupta, M.; Paul, S.; Gupta, R.; Loupy, A. Tetrahedron Lett.
2005, 46, 4957. (d) Khan, A. T.; Parvin, T.; Choudhury, L. H.; Ghosh, S.
Tetrahedron Lett. 2007, 48, 2271. (e) Nakanishi, M.; Bolm, C. AdV. Synth. Catal.
2007, 349, 861, and references cited therein.
(3) Gonzalez, M. A.; Howell, S. G.; Sikdar, S. K. J. Catal. 1999, 183, 159.
(4) Friedman, L.; Fishela, D. L.; Shechter, H. J. Org. Chem. 1965, 30, 1453.
(5) Shaikh, T. M. A.; Emmanuvel, L.; Sudalai, A. J. Org. Chem. 2006, 71,
5043.
10.1021/jo8012435 CCC: $40.75
Published on Web 08/26/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7365–7368 7365

TABLE 1. Optimization of the Reaction Conditionsa
SCHEME 1. Radical Formation from 1 via Homolytic
Cleavage of the Labile I(III)-Br Bond in Water
entry
bromide
KBr
additive
conversion (%)b
5a (%)b
1c
2
3
4
5
6
7
8
9
none
17
73
99
100
99
99
99
20
24
6
39d
70d
72d
61
34
38
trace
trace
SCHEME 2. Aqueous Benzylic Oxidation of Aromatic
Compounds Having Activated Benzyl Groups
-
-
-
H3[PW12O40]e
M-K10e
-
-
M-KSFe
-
Nafion NR50e
Amberlyst 15-He
M-K10e
-
Bu4N+Br-
Bu4P+Br-
-
a Reactions were performed using 3 equiv of [PhIO]n and 1 equiv of
the bromides and additives unless otherwise noted. b Determined by 1H
NMR. c Reaction was performed at r.t. d Isolated yield. e 100 mg/mL of
H2O.
Accordingly, by the simple mixing of aromatic compounds
2a-c having activated benzyl groups, [PhIO]n (3 equiv) and
KBr (0.2 equiv for 2a, 1 equiv for 2b and 2c) in water (0.2 M)
at room temperature, the starting suspensions of the reaction
mixtures became clear and the desired 3a-c were successfully
produced in good yields as a result of the selective oxidation at
the benzyl positions adjacent to the heteroatoms (Scheme 2).
Under these mild reaction conditions, aryl ring oxidation or
further oxidation of the aryl ketone was not observed. As
mentioned in the Introduction, organoiodine(III) compounds are
generally not very reactive by nature in water, and hence neither
the reactions with [PhIO]n nor PhI(OAc)2 in the absence of KBr
resulted in the formation of the oxidation products 3a-c. In
the present aqueous system, the benzamide 3c rather than the
corresponding imine of 2c was formed.13 The observed yields
and reaction rates in water were compatible to those of the
methods using organoiodine oxidants in organic solvent systems.7,8
However, when we tried to apply the reaction using other
compounds without any activated benzyl groups, that is,
ethylbenzene derivatives, the arylketones were obtained in low
yields (less than 20% conversion of ethylbenzenes). We then
attempted to use several common Lewis acids in the hypervalent
iodine(III)-induced reactions,6 such as BF3 ·Et2O, TMSOTf, and
TMSBr, for the purpose of activation of [PhIO]n. In fact, the
addition of these acids allowed the conversion of the substrates
to be enchanced, but undesired ring bromination usually ac-
companied the benzylic oxidation. Under such situations, we
further explored more suitable reaction conditions using 4-bro-
moethylbenzene 4a as the model case (Table 1).
friendly heterogeneous catalysts possessing soft counteranions,
in which negative charges of the oxygen atoms are highly
dispersed over the entire sheets of the molecules.15 During our
investigations, H3[PW12O40] and montmorillonite-K10 (M-K10)
were found to be the most suitable as mild catalysts, and the
benzylic oxidation proceeded with complete conversion of 4a
to give the corresponding ketone 5a in better yields (entries 3
and 4). A slightly more acidic phyllosilicate mineral clay,
M-KSF, gave an inferior result compared to M-K10 (entry 5).
The nature of the counteranion in the additives seems to be
important, as the addition of sulfonated acidic resins, ex. Nafion
NR-50 and Amberlyst 15-H, led to a decrease in the yield of
the benzylic oxidation product 5a (entries 6 and 7). With regard
to the bromide source, an interesting fact is revealed that the
replacement of KBr with other organic bromides, Bu4N+Br-
(entry 8) and Bu4P+Br- (entry 9), gave disappointing results;16
in these unsuccessful cases, the generation of molecular bromine
(Br2) was assumed by the rapid color change of the solutions
from orange to dark brown. Under the optimized reaction
conditions in entry 4,17 [PhIO]n was the best oxidant versus the
other iodine(III) and iodine(V) compounds (PhI(OAc)2, PhI(O-
COCF3)2, PhI(OH)OTs, Dess-Martin Periodinane and PhIO2).
In this context, the optimized reaction conditions expanded
the scope of the substrates (Table 2). Another liner alkylbenzene
4b gave the product 5b in a good yield (entry 2). Cyclic
compounds, such as indan 4c and tetralin 4d, afforded the
corresponding arylketones 5c and 5d in high yields (entries 3
and 4). This reaction system was mild enough to be suitable
for the conversion of 4e bearing an acetoxy group (entry 5).
Although a good yield of the ketone 5a was obtained at the
elevated temperature of 80 °C with drastic improvement in the
conversion of 4a, a large amount of 4a was still recovered from
the [PhIO]n/KBr combination (entries 1 and 2). Therefore,
alternative mild activators not causing any undesired side
reactions were further investigated. Taking into account the
nature of the anion parts of the acid additives, we specifically
focused on utilizing solid Bro¨nsted acid catalysts, such as
heteropoly acids (HPA) and montmorillonitic clays, for the
reactions.14 These solid acids are known to be environmentally
(14) Related studies using heteropoly acids in our laboratory: (a) Hamamoto,
H.; Anilkumar, G.; Tohma, H.; Kita, Y. Chem. Commun. 2002, 450. (b)
Hamamoto, H.; Shiozaki, Y.; Nambu, H.; Hata, K.; Tohma, H.; Kita, Y. Chem.-
Eur. J. 2004, 10, 4977. (c) Hata, K.; Hamamoto, H.; Shiozaki, Y.; Kita, Y. Chem.
Commun. 2005, 2465.
(15) For montmollironites, see: (a) Varma, R. S. Tetrahedron 2002, 58, 1235.
For heteropoly acids, see: (b) Kozhevnikov, I. V. Chem. ReV. 1998, 98, 171. (c)
Mizuno, N.; Misono, M. Chem. ReV. 1998, 98, 199.
(16) Formation of bisacetoxy bromate(I) was proposed by the reaction of
PhI(OAc)2 and Bu4N+Br-: (a) Kirschning, A.; Hashem, M. A.; Monenschein,
H.; Rose, L.; Schoning, K.-U. J. Org. Chem. 1999, 64, 6522. (b) Kirschning,
A.; Jesberger, M.; Monenschein, H. Tetrahedron Lett. 1999, 40, 8999. (c)
Monenschein, H.; Sourkouni-Argirusi, G.; Schubothe, K. M.; O’Hare, T.;
Kirschning, A. Org. Lett. 1999, 1, 2101.
(17) Due to the easy removal of the added M-K10 from the reaction mixtures
by simple filtration through celite, we have selected M-K10 rather than the water-
soluble heteropoly acid.
(12) Recently, we have reported a new lactone forming method using
ArI(OAc)2 and powdered KBr in organic solevnt via benzylic C-H activaion: Dohi,
T.; Takenaga, N.; Goto, A.; Maruyama, A.; Kita, Y. Org. Lett. 2007, 9, 3129.
(13) (a) Larsen, J.; Jorgensen, K. A. J. Chem. Soc., Perkin Trans. 2 1992,
1213. (b) Ochiai, M.; Inenaga, M.; Yoshimitsu, N. Tetrahedron Lett. 1988, 29,
6917.
7366 J. Org. Chem. Vol. 73, No. 18, 2008

TABLE 2. [PhIO]n/KBr/MK-10 System for Benzylic Oxidation of Alkylbenzene Derivatives 4a
a Reactions were performed using 3 equiv of [PhIO]n, 1 equiv of KBr, and M-K10 (100 mg/mL) in H2O (0.1M) at 80 °C unless otherwise noted.
b Isolated yield after purification. c Reaction was performed at r.t. d In the absence of M-K10.
SCHEME 3. Proposed Reaction Mechanism
No hydrolysis of 4e and the product 5e was observed. The
selective benzylic oxidation occurred in the substrate 4f having
other reactive C-H bonds of the cyclopropane (entry 6).18 In
4-ethyltoluene 4g, the secondary benzyl group was chemose-
lectively oxidized (entry 7). The presence of an electron-
withdrawing group at the aryl ring somewhat lowered the rate
of the reaction and yield (entry 8). On the other hand, the
diphenylmethane motif was less subject to the ring substitution
effect (entries 9 and 10). Surprisingly, the benzylic oxidation
was preferred to the sulfide oxidation as shown in the substrate
4k (entry 11). Fluorene 4l, diarylmethanes 4m and 4n including
a heteroaromatic ring also provided the oxidation products in
good yields (entries 12-14). These results clearly show the
versatility of the present aqueous system over the previous ones
performed in water using a metal catalyst or inorganic oxidants.3-5
A plausible explanation for the reaction mechanism is
seems to assist in the efficient formation and activation of 1.
exemplified by the transformation of 4-bromoethylbenzene 4a
The reactive 1 could produce the iodanyl radical A19 by facile
(Scheme 3). First, as we previously confirmed,9 polymeric
homolytic cleavage of the labile I(III)-Br bond, initiating the
radical reaction with 4a. Thus, selective abstraction of the
benzylic hydrogen atom in 4a by the iodine-centered radical A
iodosobenzene [PhIO]n was depolymerized in water by the aid
of KBr that generated the reactive species 1. The added M-K10
would produce the corresponding benzyl radical. Indeed, when
the reaction was performed in organic solvents, radical coupling
(18) It is known that the cyclopropylbenzyl radicals are more stable than
the corresponding ring-opend forms: (a) Bowry, V. W.; Lusztyk, J.; Ingold, K. U.
J. Chem. Soc., Chem. Commun. 1990, 923. (b) Halgren, T. A.; Roberts, J. D.;
Horner, J. H.; Martinez, F. N.; Tronche, C.; Newcomb, M. J. Am. Chem. Soc.
2000, 122, 2988.
(19) Rusell, G. A. J. Am. Chem. Soc. 1958, 80, 4987. Also, see refs 7 and
11.
J. Org. Chem. Vol. 73, No. 18, 2008 7367

SCHEME 4. Detection of Benzyl Bromide 6
and reactivities. Further studies on the application of this
aqueous system are now in progress in our laboratory.
Experimental Section
Typical Procedure for Experiment in Scheme 2. To a suspen-
sion of 2a (24.0 mg, 0.2 mmol) in H2O (1 mL) was added [PhIO]n
(132.0 mg, 0.6 mmol) and KBr (23.8 mg, 0.2 mmol) at room
temperature. The mixture was then stirred for 2 h. The resulting
reaction mixture was quenched by aqueous saturated NaHCO3, and
extracted with CH2Cl2. The organic phase was dried over anhydrous
Na2SO4, and concentrated in Vacuo. Purification of the residue by
column chromatography on silica gel gave 3H-isobenzofuran-1-
one 3a (25.8 mg, 0.19 mmol) in 96% yield: white crystals; mp
75-76 °C; 1H NMR (300 MHz, CDCl3) δ5.34 (s, 2H), 7.50-7.57
(m, 2H), 7.70 (t, J ) 7.5 Hz, 1H), 7.94 (d, J ) 7.5 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ69.6, 122.0, 125.5, 125.6, 128.9, 133.9,
146.4, 171.1; IR (KBr) cm-1: 1765, 1468, 1288, 1219, 1053, 1005,
912, 743.
homodimers were sometimes obtained, that is, the dimer 9 from
the compound 8. The resulting benzyl radical was probably
trapped by the persistent bromo radical in situ giving rise to
the stable benzyl bromide intermediate 6. The conversion of
the bromide intermediate 6 to the alcohol 7 and subsequent
oxidation of 7 by the second molecule of the oxidant 19 would
conclude the series of benzylic oxidation processes to afford
the observed arylketone 5a.
Gram Scale Preparation of 5m. To a suspension of the substrate
4m (2.52 g, 15.0 mmol) in water (75 mL) was added iodosobenzene
[PhIO]n (9.90 g, 45.0 mmol), and the resulting suspension was
vigorously stirred for 5 min. The reaction flask was then placed in
an ultrasonic bath for a minute with stirring. M-K10 (3.75 g) was
added to the mixture, and warmed to 80 °C. KBr (1.80 g, 15.0
mmol) was added, and the mixture was vigorously stirred for 24 h.
After cooling to room temperature, the reaction mixture was filtered
through celite and the solvent was removed under vacuum.
Purification of the residue by column chromatography on silica gel
gave diphenylmethanone 5m (2.38 g, 13.1 mmol) in 87% yield:
At ambient temperature, the reaction of 4a could proceed
quite slowly. We thus stopped the reaction at the 17%
conversion of the substrate 4a and checked the products by GC
1
colorless oil; H NMR (300 MHz, CDCl3) δ7.47 (t, J ) 7.5 Hz,
1
4H), 7.58 (t, J ) 7.2 Hz, 2H), 7.78-7.81 (m, 4H); 13C NMR (75
and H NMR (Scheme 4). These measurements revealed that
the formation of benzyl bromide 6 along with a small amount
of the final arylketone product 5a. Upon heating, both the
reaction mixture and isolated 6 afforded the arylketone 5a in
good yields under the standard reaction conditions of [PhIO]n/
KBr/M-K10. Alcohol 7 was also detected as the sole product
from the reaction mixture of the isolated 6 and M-K10 in water
MHz, CDCl3) δ128.2, 130.0, 132.3, 137.4, 196.7; IR (KBr) cm-1
:
3059, 1659, 1599, 1578, 1447, 1275, 1177, 920, 810, 638.
Acknowledgment. This work was supported by a Grant-in-
Aid for Scientific Research (A) and for Encouragement of
Young Scientists, and by a Grant-in-Aid for Scientific Research
on Priority Areas “Advanced Molecular Transformations of
Carbon Resources” from the Ministry of Education Culture,
Sports, Science, and Technology, Japan. T. D. also thanks the
Industrial Technology Research Grant Program from the New
Energy and Industrial Technology Development Organization
(NEDO) of Japan.
1
at 80 °C (confirmed by GC and H NMR) in the absence of
[PhIO]n and KBr. From these observations, we now propose
the above-mentioned reaction mechanism, although further study
is required to make the conclusion.
In summary, we have achieved an aqueous benzylic C-H
oxidation using [PhIO]n/KBr in the presence of M-K10, as
efficient, clean and environmentally benign reactions. A water-
soluble and reactive iodine(III) species 1 containing the labile
I(III)-Br bond acts as an effective radical initiator, so that this
[PhIO]n/KBr system improves several drawbacks of the hyper-
valent iodine(III) reagents using in water, that is, low solubilities
Supporting Information Available: Experimental details and
spectroscopic data of the reaction products. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO8012435
7368 J. Org. Chem. Vol. 73, No. 18, 2008