Chemoselective Oxidation of p-Methoxybenzyl Ethers by an Electronically Tuned Nitroxyl Radical Catalyst

Article abstract of DOI:10.1021/acs.orglett.0c01839

The oxidation of p-methoxy benzyl (PMB) ethers was achieved using nitroxyl radical catalyst 1, which contains electron-withdrawing ester groups adjacent to the nitroxyl group. The oxidative deprotection of the PMB moieties on the hydroxy groups was observed upon treatment of 1 with 1 equiv of the co-oxidant phenyl iodonium bis(trifluoroacetate) (PIFA). The corresponding carbonyl compounds were obtained by treating the PMB-protected alcohols with 1 and an excess of PIFA.

Full text of DOI:10.1021/acs.orglett.0c01839

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Letter
Chemoselective Oxidation of p‑Methoxybenzyl Ethers by an
Electronically Tuned Nitroxyl Radical Catalyst
Shohei Hamada,* Koichi Sugimoto, Elghareeb E. Elboray, Takeo Kawabata, and Takumi Furuta
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ABSTRACT: The oxidation of p-methoxy benzyl (PMB) ethers was achieved using nitroxyl radical catalyst 1, which contains
electron-withdrawing ester groups adjacent to the nitroxyl group. The oxidative deprotection of the PMB moieties on the hydroxy
groups was observed upon treatment of 1 with 1 equiv of the co-oxidant phenyl iodonium bis(trifluoroacetate) (PIFA). The
corresponding carbonyl compounds were obtained by treating the PMB-protected alcohols with 1 and an excess of PIFA.
itroxyl radicals such as 2,2,6,6-tetramethylpiperidine N-
oxyl (TEMPO),1 2-azaadamantane N-oxyl (AZADO),2
benzylic ethers such as p-methoxybenzyl (PMB) ethers
(Scheme 1).6
N
and their derivatives3 have frequently been employed as
organocatalysts for the oxidation of alcohols under safe and
environmentally benign conditions. Generally, these catalysts
selectively oxidize primary alcohols in the presence of
secondary hydroxy groups by recognizing the steric environ-
ment of the substrates.1,3e
Scheme 1. Oxidation of PMB Ethers by Catalyst 1
Most nitroxyl-radical-catalyzed alcohol oxidation reactions
proceed via a nucleophilic addition of an oxygen atom of the
hydroxy group to the oxoammonium cations (A), followed by
proton abstraction (Figure 1).1−3 We have previously
The PMB group has been widely used as a protecting group
for alcohols,7 as it can be easily introduced via various
methods8 and removed using common oxidizing agents. For
the oxidative deprotection of PMB ethers, stoichiometric
amount of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ)9 or more than 2 equiv of ceric ammonium nitrate
(CAN)10 are usually employed, although various other
methods have been reported.11 These common methods are
not environmentally benign, as DDQ has the potential to
liberate HCN and the deprotection by CAN requires more
than 2 equiv of cerium, which is a rare-earth metal. Hence, the
development of an environmentally benign and reliable
method for the oxidative deprotection of PMB groups would
be desirable.
Figure 1. Nucleophilic addition of the oxygen atom (A) and hydride
shift (B) as the key steps in the oxidation of benzylic alcohols with
oxoammonium cations derived from the nitroxyl-type radical
oxidation catalysts.
developed “electronically tuned” nitroxyl radical catalyst 1,
which contains electron-withdrawing ester groups adjacent to
the nitroxyl group.4 This catalyst oxidizes electron-rich
benzylic alcohols much faster than electron-deficient ones, as
the oxidation of benzylic alcohols by 1 proceeds via a rate-
determining hydride transfer.5 Owing to its unique oxidation
mechanism as a nitroxyl radical catalyst, we envisaged that 1
might also be an effective oxidation catalyst for electron-rich
Received: June 1, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01839
© XXXX American Chemical Society
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A

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The direct oxidation of PMB-protected alcohols to carbonyl
compounds is also a highly useful transformation, as it enables
the one-step transformation of the protected alcohols into the
corresponding aldehydes and ketones. So far, only a few
reports regarding the direct transformation of PMB ethers into
carbonyl compounds have been reported.12 In addition, to the
best of our knowledge, reports of the direct transformation of
PMB-protected alcohols to carbonyl compounds at room
temperature with good substrate generality remain elusive.
Herein, we describe nitroxyl radical 1 catalyzed oxidative
deprotection of PMB ethers, as well as the direct oxidation of
PMB ethers into carbonyl compounds via alcohols (Scheme
1).
(entry 4). On the other hand, racemic 4, which contains an
ester group next to the nitroxyl group, drastically increased the
chemical yield (75%; entry 5). Racemic 1, which contains two
ester groups, was found to be the most suitable nitroxyl radical
catalyst for this transformation (97%; entry 6). These results
suggest that the electron-withdrawing ester groups adjacent to
the catalytically active center play a pivotal role in improving
the reactivity and selectivity of the oxidation of PMB ethers.
Additionally, a nonsubstituted benzyl group (5) could also be
deprotected by the 1/PIFA system (entry 7). In contrast, the
oxidation of electron-deficient CF3-substituted 6 resulted in
only moderate yield (entry 8).
To explore the scope of the oxidative deprotection of PMB
groups, various PMB ethers were tested (Scheme 2). PMB-
protected aliphatic primary (2a and 2b), secondary (2c), and
tertiary alcohols (2d) were efficiently deprotected to give the
desired products (3a−3d) in high yield. PMB ethers derived
from cyclic alcohols, including estradiol derivative 2g,
furnished the corresponding products (3e−3g) in high yield.
PMB-protected diverse benzylic (2h−2j), allylic (2k), and
We first examined the properties of several nitroxyl radical
catalysts for the oxidative deprotection of PMB-protected
alcohols (Table 1). Treating O-(4-methoxyphenylmethyl)-3-
Table 1. Oxidative Deprotection of Benzylic Groups by
a
Nitroxyl Radicals
Scheme 2. Oxidative Deprotection of PMB Groups by 1/
a
PIFA
a
Conversions and yields were determined by 1H NMR analysis of the
crude reaction residue using 1,3,5-trimethoxybenzene as the internal
standard.
phenylpropanol (2a) with 1.05 equiv of phenyl iodonium
bis(trifluoroacetate) (PIFA) and 4 equiv of NaHCO3 in the
presence of 10 mol% of TEMPO, PROXYL, or Nor-
AZADO3b,c in CH2Cl2 at room temperature for 3 h, followed
by quenching with aqueous sodium thiosulfate, furnished 3-
phenyl-1-propanol (3a) in low yield (15−27%; entries 1−3).
Using 4-oxo-TEMPO, which contains an electron-withdrawing
oxo group at the 4-position, also furnished 3a in low yield
a
Isolated yields unless otherwise noted. bH2O (2.0 equiv) was added.
c1.3 equiv of PIFA was used. The reaction was run for 3 h. Yield
obtained from a stoichiometric oxidation using DDQ; reaction
conditions: DDQ (1.3 equiv), CH2Cl2/H2O (50/1), rt, 3 h. Yield
was determined by H NMR analysis of the crude reaction residue
d
e
f
1
g
using 1,3,5-trimethoxybenzene as the internal standard. PMB ether
2s was recovered in 26% 1H NMR yield. h1.1 equiv of PIFA was used.
B
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propargylic alcohols (2l) also provided the targeted products
(3h−3l) in moderate to high yield. It is worth noting that
using 2 equiv of H2O in the case of 2d, 2h−2l, and 2q is
crucial to avoid the formation of 2,2,2-trifluoroacetic acid ester
derived from alcohol 3 as a side product.13 The 1/PIFA system
was also applicable to substrates that bear heteroatoms in, e.g.,
methyl ether (2m) and pyrimidine (2n) groups. Interestingly,
the 1/PIFA system deprotected the PMB groups, in a
chemoselective fashion, without affecting the related oxida-
tion-sensitive functional groups. For example, substrates
bearing a primary aliphatic hydroxy group (2o), a cyclic
benzylic ether group (2p), an iodoarene (2q), and an isolated
alkene moiety (2r) were intact under the reaction conditions.
However, a substrate with a phenol ether group (2s) did afford
only very low amounts of the desired product, given that the
produced phenol 3s is oxidizable by PIFA.14 Nevertheless, the
1/PIFA system was used to remove PMB group from the
substrates 2t and 2u, which contain additional oxidation
sensitive benzyl and 2-naphthylmethoxymethyl (NAPOM)15-
protected hydroxy groups, in chemoselective manners with
89% and 94% yield, respectively. Other selected protecting
groups for alcohols (2v−2x) and amines (2y) also showed
great resistance to 1/PIFA system.
Scheme 3. Direct Synthesis of Ketones and Aldehydes from
PMB-Protected Alcohols by 1/PIFA
a
In addition to PMB-protected alcohols, the 1/PIFA system
was also applicable to several benzyl-protected alcohols
(Scheme S1).
Subsequently, we investigated the direct oxidation of PMB-
protected alcohols to carbonyl compounds via alcohols by
treating PMB ethers 2 with 10 mol% of 1, 4 equiv of NaHCO3,
2 equiv of H2O, and 2.2 equiv of PIFA in CH2Cl2 (Scheme 3).
The direct oxidation of PMB-protected primary alcohol 2a
proceeded in only moderate yield due to the relatively low
reactivity of the intermediate alcohols. On the other hand,
PMB ethers derived from noncyclic aliphatic secondary (2c)
and benzylic alcohols (2h−2j, 2z, 2aa) afforded the
corresponding products in good to high yield. PMB-protected
cyclic aliphatic and benzylic alcohols (2ab and 2ac) also
afforded the corresponding cyclic ketones (4ab and 4ac) in
good yield. Moreover, the androsterone derivative 2ad with a
steroid skeleton was converted into ketone 4ad in 85% yield.
A plausible mechanism for the oxidation of PMB ethers by 1
is shown in Scheme 4. First, oxoammonium A is generated via
the oxidation of nitroxyl radical 1 by PIFA. Since
oxoammonium A is expected to be highly electron-deficient
due to the adjacent ester groups, it should readily undergo a
reductive transformation via hydride transfer from the PMB
group to the oxygen of the oxoammonium to afford
hydroxyamine B and oxocarbenium cation C. Then, the
addition of water to C would give deprotected alcohol 3.
Oxidation of 3 could proceed via a hydride transfer in the case
of benzylic alcohols, albeit it is unclear at present whether a
similar process occurs in the case of aliphatic alcohols.4a
In conclusion, we have disclosed the utility of nitroxyl radical
catalyst 1, which contains electron-withdrawing ester groups
adjacent to the nitroxyl group, for the oxidation of p-methoxy
benzyl (PMB) ethers in the presence of an equivalent of
phenyl iodonium bis(trifluoroacetate) (PIFA) to afford the
corresponding alcohols. This system showed an excellent
chemoselectivity profile for the deprotection of PMB ethers
from a broad range of functional groups including diverse
oxidation sensitive moieties. In addition, carbonyl compounds
were obtained by treating PMB ethers with 1 in the presence of
an excess of PIFA and water.
a
Isolated yields unless otherwise noted. bThe reaction was performed
by using an excess of DDQ instead of 1 and PIFA; reaction
conditions: DDQ (2.2 equiv), H2O (2 equiv), CH2Cl2, rt, 3 h. cYields
1
were determined by H NMR analysis of the crude reaction residue
using 1,3,5-trimethoxybenzene as the internal standard.
Scheme 4. Plausible Mechanism for the Oxidative
Deprotection of PMB Ethers Promoted by Nitroxyl Radical
1
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01839.
Example reactions for the deprotection of benzyl groups,
mechanistic studies, experimental procedures, analytical
data (1H NMR, 13C NMR, IR, HRMS) (PDF)
C
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AUTHOR INFORMATION
Corresponding Author
■
Shohei Hamada − Department of Pharmaceutical Chemistry,
Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-
8414, Japan; orcid.org/0000-0003-4352-0017;
Email: hamada@mb.kyoto-phu-ac.jp
Authors
(4) (a) Hamada, S.; Furuta, T.; Wada, Y.; Kawabata, T.
Chemoselective Oxidation by Electronically Tuned Nitroxyl Radical
Catalysts. Angew. Chem., Int. Ed. 2013, 52, 8093−8097. (b) Hamada,
S.; Wada, Y.; Sasamori, T.; Tokitoh, N.; Furuta, T.; Kawabata, T.
Oxidative Kinetic Resolution of Racemic Alkyl Aryl Carbinols by an
Electronically Tuned Chiral Nitroxyl Radical. Tetrahedron Lett. 2014,
55, 1943−1945.
Koichi Sugimoto − Department of Pharmaceutical Chemistry,
Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-
8414, Japan
Elghareeb E. Elboray − Department of Pharmaceutical
Chemistry, Kyoto Pharmaceutical University, Yamashina-ku,
Kyoto 607-8414, Japan; Department of Chemistry, Faculty of
Science, South Valley University, Qena, Egypt
Takeo Kawabata − Institute for Chemical Research, Kyoto
University, Uji, Kyoto 611-0011, Japan; orcid.org/0000-
0002-9959-0420
Takumi Furuta − Department of Pharmaceutical Chemistry,
Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-
8414, Japan; orcid.org/0000-0003-1037-9715
(5) A hydride transfer mechanism has also been proposed for the
TEMPO-derived oxoammonium cation-mediated oxidation of alco-
hols under acidic conditions; for details, see: (a) Bailey, W. F.;
Bobbitt, J. M.; Wiberg, K. B. Mechanism of the Oxidation of Alcohols
by Oxoammonium Cations. J. Org. Chem. 2007, 72, 4504−4509.
(b) Qiu, J. C.; Pradhan, P. P.; Blanck, N. B.; Bobbitt, J. M.; Bailey, W.
F. Selective Oxoammonium Salt Oxidations of Alcohols to Aldehydes
and Aldehydes to Carboxylic Acids. Org. Lett. 2012, 14, 350−353.
(6) Vankar and coworkers reported TEMPO-catalyzed oxidation of
O-benzylated glycals to afford the corresponding enones; for details,
see: Chennaiah, A.; Verma, A. K.; Vankar, Y. D. TEMPO-Catalyzed
Oxidation of 3-O-Benzylated/Silylated Glycals to the Corresponding
Enones Using a PIFA−Water Reagent System. J. Org. Chem. 2018, 83,
10535−10540.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01839
Author Contributions
All authors contributed to writing this manuscript.
Notes
(7) (a) Kocienski, P. J. Protecting Groups, 3rd ed.; Thieme: Stuttgart,
2003. (b) Wuts, P. G. M. Protective Groups in Organic Synthesis, 5th
ed.; Wiley-Interscience: New York, 2014.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This study was supported by MEXT KAKENHI grant
19K16327 (to S.H.).
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E
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