Benzylic carbon oxidation by an in situ formed o-iodoxybenzoic acid (IBX) derivative

Article abstract of DOI:10.1055/s-0028-1087384

Benzylic C-H bonds are selectively oxidized to the corresponding carbonyl functionalities using catalytic quantities of 2-iodobenzoic acid (2IBAcid) and Oxone. The reported procedure tolerates different functional groups and operates under mild conditions. A radical mechanism is proposed for the transformation and evidence supporting the proposed mechanism is also presented. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087384

LETTER
117
Benzylic Carbon Oxidation by an in situ Formed o-Iodoxybenzoic Acid (IBX)
Derivative
B
enzylic Carbo
a
n
O
xidationwanya R. Ojha, Shashi Kudugunti, Padma P. Maddukuri, Amitha Kommareddy, Meena R. Gunna, Praveen
Dokuparthi, Hima B. Gottam, Kiran K. Botha, Divya R. Parapati, Thottumkara K. Vinod*
Department of Chemistry, Western Illinois University, Macomb, IL 61455, USA
Fax +1(309)2982180; E-mail: mftkv@wiu.edu
Received 25 September 2008
oxidation of alcohols have been reported by us6 and oth-
Abstract: Benzylic C–H bonds are selectively oxidized to the cor-
responding carbonyl functionalities using catalytic quantities of 2-
iodobenzoic acid (2IBAcid) and Oxone®. The reported procedure
tolerates different functional groups and operates under mild condi-
ers.7 We wondered whether a similar catalytic protocol
could be used for the oxidation of benzylic C–H bonds.
Such a procedure would also offer a user-friendly alterna-
tions. A radical mechanism is proposed for the transformation and tive to benzylic C–H oxidation that required superstoichi-
ometric amounts of IBX in DMSO.3a,b Herein, we report
evidence supporting the proposed mechanism is also presented.
the first use of an in situ generated hypervalent iodine re-
agent for such a purpose. We also provide a plausible
mechanistic rationale for the observed product distribu-
tion during the oxidation reaction.
Key words: oxidation, o-iodoxybenzoic acid (IBX), single-
electron transfer, rearrangement, Oxone®
Selective oxidation of activated and unactivated C–H
bonds continues to interest organic chemists.1 Growing
concerns over the environmental impact of the use of tran-
sition-metal oxidants have forced chemists to develop
sustainable oxidation methods using benign and user-
friendly reagents.2 The development of oxidation proce-
dures that completely eliminate the use of transition-
metal-based reagents is a desirable research objective.
The hypervalent iodine reagent, o-iodoxybenzoic acid
(IBX), has recently emerged as a reagent of choice for a
plethora of unique and selective oxidative transformations
including the oxidation of benzylic C–H bonds.3 Oxida-
tive transformations using IBX, a potentially shock-sensi-
tive reagent,4 are usually carried out in DMSO due to the
solubility limitation of the reagent in other user-friendly
solvents. Our group and others have addressed the limited
solubility of IBX by functionalizing the arene moiety of
IBX to impart solubility in water and to improve solubility
in other solvents.5 Catalytic protocols that involve in situ
generation of IBX from 2-iodobenzoic acid (2IBAcid) in
combination with co-oxidant Oxone® and its use for the
Diphenylmethane (1) was chosen as our initial benzylic
substrate (Scheme 1). First, we decided to ascertain the
extent of background reaction of 1 with Oxone®, since it
was previously reported that benzophenone (2), was ob-
tained in 10% yield when the oxidation was carried out in
water.8 Our repeated attempts at oxidation of 1 in 2:1 ac-
etonitrile–water mixture using 1.5 equivalents of Oxone®
gave only a maximum of 6% isolated yield of 2. Con-
vinced that the extent of background oxidation by Oxone®
is minimal, at best, we decided to attempt an oxidation of
1 using 0.2 equivalents of 2IBAcid and 1.2 equivalents of
Oxone® as the co-oxidant9 and observed a 50% conver-
sion to 2, along with trace amounts of 3. We were, how-
ever, surprised when an attempted oxidation of 1 using
IBX (preformed rather than prepared in situ) in aqueous
acetonitrile failed. The encouraging result using the in situ
generated reagent and the extent of oxidation beyond 20%
clearly indicated that Oxone® is capable of regenerating
the active catalyst by re-oxidizing the reduced form of the
reagent during the reaction.
O
Oxone® (1.2 equiv)
MeCN–H2O (2:1)
70 °C, 12 h
IBX (1.2 equiv)
No Reaction
O
2, ~6%
MeCN–H2O (2:1)
70 °C, 12 h
2IBAcid (0.2 equiv)
O
2
+
Oxone® (1.2 equiv)
MeCN–H2O (2:1)
70 °C, 12 h
50%
1
3, trace
Scheme 1
SYNLETT 2009, No. 1, pp 0117–0121
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087384; Art ID: S09108ST
© Georg Thieme Verlag Stuttgart · New York

118
L. R. Ojha et al.
LETTER
O
O
O
HO
HO
HO
O
O
O
S
I
I
I
N
O
O
O
Me
6
5
4
O
O
O
SO3K
KO3S
O
O
O
O
OH
I
O
I
O
O
OH
OH
I
I
2 KHSO5
KHSO5
– H2O
O
O
O
CO2H
O
O
2IBAcid
IBX
7
8
Scheme 2
Table 1 Efficacy of Oxone® as a Co-oxidant
Considering the fact that preformed IBX does not oxidize
1 to 2 in aqueous acetonitrile and that the active catalyst
prepared in situ remained soluble during the reaction, we
hypothesized that the active hypervalent iodine reagent
may not be IBX per se, but a soluble peroxy ligand ap-
pended (KHSO5 from Oxone®) derivative of IBX such as
7 or 8. Modulation of IBX reactivity through ligand com-
plexation is well documented by Nicolaou with the use of
IBX–DMSO (4), IBX–THF (5), and IBX-N-oxide (6) for
benzylic site oxidation and other unique oxidative trans-
formations (Scheme 2).3b
2IBAcid
(equiv)
Oxone
(equiv)
Yield (%) Theoretical yield of 2
(%)b
2
3
0.0
0.2
0.2
0.2
0.25
0.3
0.5
0.5
0.2c
1.50
0.8
6
42
–
2
6
7
9
4
5
8
–
43
74
88
89
74
54
100
–
1.38
1.65
1.75
1.50
1.25
2.50
1.75
68
77
74
At this juncture we set out to establish the efficiency of
Oxone® as a co-oxidant for the oxidation of 1 by varying
molar ratios of 2IBAcid and Oxone® and measuring the
extent of oxidation by NMR methods. The results from
our optimization experiments are shown in Table 1. In all
cases, the Baeyer–Villiger product 3 was observed as a
minor product in the product mixture. We surmised that
by comparing the maximum yield of the oxidized prod-
ucts 2 and 3 to the maximum available oxidants in the re-
action medium we would be able to shed light on the
overall reaction mechanism.
68
48
87
ca. 5
a All reactions were carried out at 1.2 mmol scale at 70–80 °C for 48
h in 2:1 MeCN–H2O.
b Theoretical yield of 2 based on the total consumption of available
oxidants.
c Reaction was carried out with 1.1 equiv of the radical scavenger
galvinoxyl.
Salient features of the proposed mechanism shown in
Scheme 3 include: (a) initiation of the reaction via a ben-
zylic H-atom abstraction by the I=O bond, similar to the
first step in C–H oxidation by reagents that possess
of 11 to 2 either uses up IBX (reactions 2 and 3) or uses
up an additional equivalent of KHSO5, as a nucleophilic
oxidant, in rxn 1. Subsequent catalytic cycles can only
start with the regeneration of 8 from IBA (reactions 2 and 3)
or 8 from IBX (reaction 1) leading to an overall consump-
tion of equal amounts of KHSO5. The theoretical yield re-
ported in Table 1 was calculated using the formula and by
noting that there is approximately a 20% loss of Oxone®
due to thermal decomposition during the 48 hours reaction
period.11
metal=O bonds (CrO3, RuO2, and MnO4 ),10 (b) a single-
–
electron transfer (SET) from the resonance stabilized ben-
zylic radical 9 to the odd electron iodine center in 10 pro-
ducing the crucial diphenyl carbocation 11 and the
peroxy-IBX anion 12, the collapse of which regenerates
IBX which can re-enter the catalytic cycle through further
activation by KHSO5, and (c) three plausible routes for the
transformation of 11 to 2, each requiring equal amounts of
Oxone® in the overall catalytic cycle. A careful evaluation
of the proposed mechanism reveals that the amount of
KHSO5 required to complete the first catalytic cycle of
substrate oxidation is 4.0 times the molar equivalent of
2IBAcid used, and every subsequent cycle requires twice
the molar equivalent of 2IBAcid employed. The overall
KHSO5 requirement for complete consumption of the sub-
strate can be calculated using the formula 4y + (1/y – 1)2y
where y is the molar equivalent of 2IBAcid employed.
The amount of KHSO5 needed is independent of the fate
of the carbocation intermediate 11, since transformation
The involvement of the initial radical intermediate in the
proposed mechanism is substantiated by the almost com-
plete inhibition of the reaction with the addition of 1.0
equivalent of galvinoxyl, an effective radical scavenger
(Table 1, footnote c).
We next investigated the oxidation of benzo-fused sub-
strates 16–20 (Scheme 4). Except in the case of fluorene
20, products were isolated in higher than 70% yield from
the oxidation of the benzo-fused substrates. Oxidation of
16 gave the expected 1-indanone 21 in 67% isolated yield
Synlett 2009, No. 1, 117–121 © Thieme Stuttgart · New York

LETTER
Benzylic Carbon Oxidation
119
O
O
SO3K
O
O
O
O
SO3K
HO
•
Ph
H
O
2IBAcid (0.3 equiv)
Oxone® (1.81 equiv)
Ph
Ph
+
+
I
••
•
••
H
O
+
O
H
Ph
22, 8%
21, 67%
23, 60%
16
17
18
O
O
O
9
10
7
1
O
O
SET
O
O
SO3K
O
SO3K
HO
HO
O
••
••
Ph
Ph
24, 12%
O
I
I
••
••
H
+
IBX
O
O
12
2
12
11
O
O
O
SO3K
25, 93%
Ph
KHSO5
O
(reaction 1)
H
Ph
Ph
13
IBX
OH
H2O
26, 78%
27, 0%
19
2
H
11
– IBA
(reaction 2)
Ph
14
Ph
Ph
H
O
O
20
O
I
IBX
O
2
Scheme 4
(reaction 3)
– IBA
15
O
along with a complex mixture of oxygenated products in-
cluding 34, 35, and importantly benzaldehyde (36) and
benzoic acid (37). The recognition of the presence of the
peroxysulfate ester intermediate 38 and the possibility of
an accompanied Criegee rearrangement succinctly ac-
counts for the cleavage of the C–C bond in the acidic re-
action medium.12 Benzaldehyde and benzyl alcohol
produced from this rearrangement are further oxidized by
KHSO513 and IBX,14 respectively, accounting for the loss
of total available oxidant. Interested in establishing a sub-
strate scope for the reaction, we oxidized a select group of
phenylalkanes using excess Oxone® to compensate for the
oxidation of the cleaved products formed during the reac-
tion (Scheme 6).
Scheme 3
along with 8% of indenone 22. Similarly oxidation of 17
yielded 23 and 24 in 60% and 12%, respectively. o-Iodox-
ybenzoic acid is known to dehydrogenate ketones and al-
dehydes to generate a,b-unsaturated derivatives and as
such, the formation of 22 and 24 is not unexpected from
these oxidations.3a,b Oxidation of 18 gave 25 in 93% yield
by the selective oxidation of the doubly benzylic carbon,
a reflection of the enhanced stability of the resulting radi-
cal. Oxidation of 19 provided phenanthrene 26 as the only
product, the formation of which is explained by the loss of
a proton from the carbocation intermediate (Scheme 3).
The most striking support for the proposed mechanism is
the complete lack of oxidation of fluorene 20, which
would necessitate the formation of the unstable anti-aro-
matic fluorenyl cation along the reaction path.
The plausible mechanistic considerations discussed so far
imply that phenylcycloalkanes that carry an abstractable
benzylic hydrogen can lead to benzoylalkanoic acids as
products (Scheme 7). As such, we hypothesized that it
would be possible to synthesize benzoylalkanoic acids
from the appropriate phenylcycloalkanes.
Interested in extending the scope of this reaction, we de-
cided to investigate the oxidation of phenyl and diphenyl-
alkanes. 4-Bromoethylbenzene (28) and 1,2-diphenyl-
ethane (33) were chosen as representative substrates
(Scheme 5). Oxidation of 28 gave a 73% isolated yield of
29. The 1H NMR spectrum of the crude product from this
attempt indicated the presence of trace amounts of 4-
bromobenzoic acid (verified with GC-MS) and more im-
portantly showed three small, overlapping quartets be-
tween d = 4.98–4.82 ppm and three corresponding
doublets between d = 1.48–1.26 ppm. We believe that
these signals indicate the presence of the intermediates
30–32, from the capture of the benzyl carbocation by the
nucleophiles in the reaction (Scheme 3). The presence of
4-bromobenzoic acid was initially not a concern until we
attempted the oxidation of 33 under identical reaction
conditions and recovered 70% of the starting material
The carbocation 44 that results from a Criegee rearrange-
ment can be trapped with water or KHSO5 leading to ei-
ther 45 or 47, respectively. Decomposition of 45 in the
acidic reaction medium and subsequent oxidation will
lead to benzoylalkanoic acid 46. The intermediate 47 can
partake in a second Criegee rearrangement,12c leading to
48, which again under the reaction conditions will hydro-
lyze to give benzoic acid. We tested this hypothesis with
the oxidation of phenylcyclopentane (42), phenylcyclo-
hexane (49), and phenylcycloheptane (50) using 0.2
equivalents of 2IBAcid and 4.6 equivalents of Oxone®.
Oxidation of 42 gave 4-benzoylbutanoic acid (46) along
with benzoic acid (37) in 42% and 22% yield, respective-
ly. Oxidation of 49 and 50 provided the corresponding
benzoylalkanoic acids 51 and 52 in 40% and 38% yield,
Synlett 2009, No. 1, 117–121 © Thieme Stuttgart · New York

120
L. R. Ojha et al.
LETTER
Br
Br
Br
Br
Br
2IBAcid (0.3 equiv)
Oxone® (1.81 equiv)
2IBAcid
Oxone®
H2O
HO
H
O
OSO3K
O
O
H
H
H
O
HO
O
O
O
I
30
28
O
O
42
43
45
44
29, 73%
KHSO5
KO3S
31
O
H2O
32
X
X
O
X
KO3SO
2IBAcid (0.3 equiv)
O
O
HO
O
+
O
O
Oxone® (1.81 equiv)
~30% conversion
37
O
CO2H
O
36, X = H
34, X, X = H
35, X, X = =O
46
47
48
37, X = OH
33
2IBAcid (0.2 equiv)
Oxone® (4.6 equiv)
+
OH
HO
O
O
41
37
O
HO
H2O
O
O
H3O
O
H
CO2H
n
n
O
– KSO4
46, n = 0, 42%
51, n = 1, 40%
52, n = 2, 38%
42, n = 0
49, n = 1
50, n = 2
SO3K
Scheme 7
39
40
36
38
Scheme 5
tively cleaved products. Attempts are currently under way
to identify other nucleophilic oxidants which would elim-
inate or reduce the extent of oxidative cleavage that ac-
companies the benzylic site oxidation.
respectively. We are currently optimizing the reaction
conditions to improve the yield of benzoylalkanoic acids
products and concurrently identifying tolerance for func-
tional groups on the cycloalkyl moiety during the oxida-
tion.
Acknowledgment
In summary we have developed a catalytic benzylic oxi- The authors gratefully acknowledge the National Science Foundati-
on (CHE-0412614) for support of this research. The authors also
dation protocol using an in situ generated hypervalent io-
thank the University Research Council of Western Illinois Univer-
sity for providing a SEED grant to initiate this study.
dine reagent. Suggested mechanistic proposals account
for the intermediates and explain the presence of oxida-
O
CO2H
2IBAcid (0.3 equiv)
6%
64%
O
Oxone® (3.0 equiv)
8 h
MeO
MeO2C
Ph
MeO
MeO2C
Ph
MeO
MeO2C
Ph
CO2H
5%
68%
O
CO2H
32%
60%
O
CO2H
38%
54%
O
CO2H
6%
CN
CO2H
CN
CO2H
82%
O
CO2H
8%
74%
Scheme 6
Synlett 2009, No. 1, 117–121 © Thieme Stuttgart · New York

LETTER
Benzylic Carbon Oxidation
121
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(9) Oxone® is a 2:1:1 mixture of KHSO5, KHSO4, and K2SO4.
For the use of Oxone® for the oxidation of 2IBAcid to IBX,
see: Frigerio, M.; Santagostino, M.; Sputore, S. J. Org.
Chem. 1999, 64, 4537.
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Oxone® remaining after heating a solution of Oxone® in the
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