Chemoselective oxidation and deprotection of para-methoxybenzylic position with (diacetoxyiodo)benzene in acetic-trifluoroacetic acid

Article abstract of DOI:10.1016/j.tetlet.2017.12.060

(Diacetoxyiodo)benzene in the presence of acetic–trifluoroacetic acid in THF has been developed for the chemoselective para-methoxybenzylic C–H bond oxidation to provide aryl carbonyl compounds at room temperature. The reaction condition is also applicable for the chemoselective deprotection of para-methoxybenzyl (PMB) ether in the presence of benzyl ether.

Full text of DOI:10.1016/j.tetlet.2017.12.060

Accepted Manuscript
Chemoselective Oxidation and Deprotection of para-Methoxybenzylic Position
with (Diacetoxyiodo)benzene in Acetic-Trifluoroacetic Acid
Chun-Yu Lin, Ping-Shin Yang, Pang-Yu Chou, Chi Wi Ong
PII:
S0040-4039(17)31579-4
https://doi.org/10.1016/j.tetlet.2017.12.060
TETL 49562
DOI:
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
26 October 2017
14 November 2017
17 November 2017
Please cite this article as: Lin, C-Y., Yang, P-S., Chou, P-Y., Ong, C.W., Chemoselective Oxidation and Deprotection
of para-Methoxybenzylic Position with (Diacetoxyiodo)benzene in Acetic-Trifluoroacetic Acid, Tetrahedron
Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.12.060
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Chemoselective Oxidation and Deprotection
of para-Methoxybenzylic Position with
(Diacetoxyiodo)benzene in Acetic-
Trifluoroacetic Acid.
Leave this area blank for abstract info.
Chun-Yu Lin, Ping-Shin Yang, Pang-Yu Chou and Chi Wi Ong∗
Department of Chemistry, National Sun Yat Sen University, Kaohsiung 804, Taiwan

1
Tetrahedron Letters
journal homepage: www.els evier.com
Chemoselective Oxidation and Deprotection of para-Methoxybenzylic Position with
(Diacetoxyiodo)benzene in Acetic-Trifluoroacetic Acid
Chun-Yu Lin, Ping-Shin Yang, Pang-Yu Chou and Chi Wi Ong∗
Department of Chemistry, National Sun Yat Sen University, Kaohsiung 804, Taiwan
ARTICLE INFO
ABSTRACT
Article history:
Received
(Diacetoxyiodo)benzene in the presence of acetic - trifluoroacetic acid in THF has been
developed for the chemoselective para-methoxybenzylic C-H bond oxidation to provide aryl
carbonyl compounds at room temperature. The reaction condition is also applicable for the
chemoselective deprotection of para-methoxybenzyl (PMB) ether in the presence of benzyl
ether.
Received in revised form
Accepted
Available online
2017 Elsevier Ltd. All rights reserved
Keywords:
Chemoselective para-methoxybenzylic C-H
oxidation
(Diacetoxyiodo)benzene
para-Methoxybenzyl ether removal
1. Introduction
trifluoroacetic acid mixture with THF as solvent at room
temperature.
The direct functionalization of the benzylic C-H bond is an
important toolbox for the synthesis of versatile new building
blocks in organic synthesis. Benzylic C-H oxidation to carbonyl
group is consider as one of the most important transformations in
which transitional metals have play a key role.1 Recently,
2. Results and discussion
For our initial studies, we explored the reaction of para-
methoxytoluene as the substrate with (diacetoxyiodo)benzene
(DAIB) under various conditions (Table 1). In the absence of
acetic or trifluoroacetic acid, the reaction does not take place.
hypervalent iodine reagents have emerged as
a
new
environmental friendly metal-free condition to facilitate
numerous organic transformations, such as oxidation, carbon-
carbon bonds formation, and carbon-heteroatom bonds
formation.2 Nicolaou et al. reported the first use of hypervalent
iodine (V) reagent (IBX in wet DMSO) for the hitherto unknown
benzylic C-H oxidation of arylmethylenes to provide the
corresponding carbonyl compounds for use as versatile building
blocks in organic synthesis.3 The hypervalent iodine (III) is more
stable and safer as compared to hypervalent iodine (V) reagents.
Consequently, Kita et al. utilized polymeric iodobenzene with
KBr with the presence of montmorillonite-K10 in water at 80 °C
for the efficient benzylic C-H bond oxidation.4 Recently,
Table 1.
Reaction conditions for DAIB mediated benzylic C-H
oxidation of para-methoxytoluene.
Entry
Reaction conditions
Yield
1
no reaction
DAIB(1 equiv), DMSO, 80℃, 2 days
DAIB(1 equiv), THF, rt (or reflux)
2
3
no reaction
traces
5%
30%
80%
Telvekar et
al. used the commercially available
DAIB(1 equiv), AcOH(1 equiv), THF, rt
DAIB(1 equiv), TFA(1 equiv), THF, rt
(diacetoxyiodo)benzene in the presence of a catalytic amount of
sodium azide at room temperature for the benzylic C-H
oxidation.5
A drawback of these reported hypervalent iodine reagents for
the benzylic C-H oxidation is the low chemo- and regio-
selectivity that often resulted in a mixture of products. Herein,
we report our new findings whereby para-methoxy substituent on
the aryl ring can have a directing effect on the chemo- and regio-
selective benzylic C-H oxidation to aryl carbonyl compounds
4
5
DAIB(1 equiv), TFA(1 equiv), AcOH(1 equiv), THF, rt
DAIB(6 equiv), TFA(4 equiv), AcOH(1 equiv), THF, rt
DAIB(6 equiv), TFA(4 equiv), AcOH(2 equiv), THF, rt
DAIB(6 equiv), TFA(4 equiv), AcOH(4 equiv), THF, rt
DAIB(1 equiv), TFA(1 equiv), AcOH(6 equiv), THF, rt
DAIB(3 equiv), TFA(2 equiv), AcOH(1 equiv), THF, rt
6
7
93%
85%
20%
50%
8
9
10
It was found that treatment of para-methoxytoluene with DAIB
in the presence of trifluoroacetic acid (TFA)/acetic acid (AcOH)
using (diacetoxyiodo)benzene (DAIB) in the presence of acetic –
———
∗ Corresponding author. Tel: + 886 7 5252000 ext. 3923; e-mail: cong@mail.nsysu.edu.tw

2
Tetrahedron
(1:1) in THF at room temperature give the benzylic C-H
Table 2.
oxidation product, para-methoxybenzaldehye, in 30% yield
(Table 1, entry 5). Next, we systematically examined the
influence on the amount of DAIB, TFA and AcOH to optimize
the reaction conditions. To our delight, the reaction condition
with 6 equiv of DAIB, 4 equiv TFA and 2 equiv AcOH in
tetrahydrofuran at room temperature (Table 1, entry 7)
dramatically improved the yield to 93% and all further reactions
were carried out using these optimized condition. It is noteworthy
that the oxidation of para-methoxytoluene selectively stopped at
the aldehyde without any over-oxidation to the acid.
Chemo- and regio-selective benzylic C-H oxidation directed
by the aromatic substitutions with DAIB (6 equiv)/TFA (4
equiv) /AcOH (2 equiv).
With these results in hand, we first investigated the electronic
influence of the aryl ring and scope of the reactions (Table 2).
Our results show that the benzylic C-H oxidation can be very
sensitive to the nature and position of the substituents. Toluene,
para-nitrotoluene, para-bromotoluene did not undergo benzylic
C-H oxidation under the optimized reaction condition (Table 2,
entries 1-3). This is in stark contrasts to the previously reported
benzylic C-H oxidation using hypervalent iodine reagents that
showed only slight dependency on the electronics nature of the
substituents on the aryl containing substrates.3,4 On the other
hand, our reagent with DAIB/TFA/AcOH at room temperature
preferred the benzylic C-H oxidation of para-methoxytoluene
over that of ortho-methoxytoluene (Table 2, entries 4, 5) The
meta-methoxytoluene did not undergo benzylic C-H oxidation.
The electronic properties of additional substituents on para-
methoxytoluene may also influence the reaction. Electron
donating group such as methoxy moiety at the ortho-positions of
para-methoxytoluene was successfully converted into the
corresponding aldehydes, while electron withdrawing group
(ortho-nitro) hampered the reaction (Table 2, entries 7 and 8).
This clearly indicates that the inductive effect of the substituents
on the aryl ring also plays an important role during benzylic C-H
oxidation. In addition, 1-ethyl-4-methoxy benzene was
successfully oxidized to the corresponding ketone under the
same reaction condition (Table 2, entry 9).
Entry
1
Substrate
Product
Yield
no reaction
2
3
no reaction
no reaction
4
5
6
7
8
93%
25%
no reaction
75%
no reaction
The selective mono-oxidation of aromatic rings with more than
one benzylic positions can be somewhat challenging. This result
prompted us to investigate further the chemoselective oxidation
of the para-methoxybenzylic position. As anticipated, our
condition gave site selective para-benzylic mono-oxidation
product of 6-methoxy-1,2,3,4-tetrahydronaphthalene and 4-
methoxy-1,2-dimethylbenzene in good yield (Table 2, entry 10,
11, 73-75%). It has been reported that TiO2-sensitized
photooxidation of 4-methoxy-1,2-dimethylbenzene gave the 1-
methyl group mono-oxidation product in very low yield (20%).6
Furthermore it is extremely interesting to note that in the case of
1-methoxy-4-(para-tolyloxy-methyl)benzene, selective oxidation
at the para-methyl position is favored over the para-benzylic
ether position (Table 2, entry 12). The oxidation of the 4-
allyloxytoulene also proceeded selectively at the benzylic
position (Table 2, entry 13). To our delight, our reaction
condition can be used for the selective cleavage of para-
methoxybenzyl (PMB) ether in the presence of benzyl ethers in
good yield (Table 2, entry 14). This new method can complement
the existing strategy of utilization DDQ (2,3-dichloro-5,6-
dicyanobenzoquinone) for the fast and selective removal of
PMB-ether to regenerate alcohol in organic synthesis.7
9
61%
73%
10
11
12
75%
70%
13
14
60%
70%
A study on hypervalent iodine(III) reactive intermediates in
solutions using electrospray ionization mass spectrometry has
been reported.8 The reactive iodine (III) species present in
solutions of DAIB are highly dependent on the solvent utilized.
The ESI-MS spectrum without matrix using DAIB (6 equiv) in
TFA (4 equiv) and AcOH (2 equiv) in THF solution for our
optimized reaction condition showed two most abundant peaks of
nearly equal intensity at m/z 440.8 and 482.8 that correspond to
the reported dioxo-bis(iodobenzene) species I, [Ph2I2O2Ac]+, and
II, [Ph2I2O2H]+ respectively (Fig. 1). The formation of I and II
from the reactions of PhIO, [PhIOAc]+ and [PhIOH]+ during

3
DAIB disproportionate were previously discussed in the
literature (Scheme 1).8 However, this is in contrast to the reported
most abundant peak corresponding to [PhIOAc]+ observed for
DAIB in AcOH as solvent.8 Our reaction condition has
attenuated the formation of I and II and can also be envisage to
simultaneously exist in the form of zwitterions.
4. Experimental Section
General Procedure for the Benzylic C-H Oxidation:
To a solvent of (bisacetoxyliodo)benzene (DAIB) (4.75 g,
14.75 mmol) in dry THF (20-30 mL) was added trifluoroacetic
acid (1.12 g, 9.83 mmol) and acetic acid (0.29 g, 4.92 mmol).
The mixture stirred for 30 minutes, after which the compound
added for benzylic C-H oxidation (2.46 mmol) and further
reacted for 24 hours. The progress of the chemical reaction was
monitored using thin-layer chromatography with pre-coated silica
gel 60 (0.25 mm thickness) plates. The reaction was quenched
with 1 mL of sat. NaHCO3 (aq), and the solvent removed in
vacuo on a rotatory evaporator. The residue was extracted with
ethyl acetate (30 mL×2) and water (20 mL). The combined
organic extracts were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated in vacuo.
In this regard, it is most likely that the dioxo-bis(iodobenzene)
derivatives I and II act as the reactive species, rather than DAIB.
Although at present a detailed understanding of the reaction
mechanism must await further study, our results indicate a
conventional electrophilic-like reactivity pattern for the benzylic
C-H oxidation reaction using DAIB/AcOH/TEA at ambient
temperature in THF. As such, the chemoselective benzylic C-H
oxidation arises from the electrophilic nature of the observed
hypervalent iodine species. The use of highly electrophilic
iodonium species for numerous C-H functionalization have also
been reported and found useful applications in organic synthesis.9
Our reaction condition thus complement the highly electrophilic
nature of the iodine atom that has been reported for hypervalent
(III) reagents.10-12 The hypervalent iodine mediated benzylic C-H
oxidation generally proceeded through a SET from the aromatic
ring. Thus, we sought evidence for the intermediacy of a radical
species under our reaction condition by carrying out the reaction
of para-methoxytoluene with the radical scavengers, 2,2,6,6-
tetramethylpiperidine-N-oxyl radical (TEMPO) and 2,4,6-tri-tert-
butylphenol, and no aldehyde product was detected.
Acknowledgments
We thank MOST-Taiwan for financial support of this research
and Professor Koichi Narasaka for helpful discussions and
suggestions.
Supplementary Data
Supplementary data for the 1H, 13C NMR and Mass spectra of
products in Table 2 associated with this article are available
online.
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