P-Methylbenzyl Group: Oxidative Removal and Orthogonal Alcohol Deprotection

Article abstract of DOI:10.1021/acs.orglett.9b02144

We describe the practical removal of p-methylbenzyl (MBn) protections of alcohols by treatment with 2,3-dichloro-5,6-dicyano-p-benzoquinone. When a molecule bears benzyl and MBn groups, the oxidant selectively removes the latter groups. Further, the MBn groups tolerate ceric ammonium nitrate, resulting in chemoselective removal of the p-methoxybenzyl group in the presence of the MBn groups. These orthogonal alcohol deprotections would provide novel synthetic strategies of organic compounds.

Full text of DOI:10.1021/acs.orglett.9b02144

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
p‑Methylbenzyl Group: Oxidative Removal and Orthogonal Alcohol
Deprotection
Kazutada Ikeuchi,*,†,‡ Kentaro Murasawa,† Kenya Ohara,† and Hidetoshi Yamada*,†
†School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda 669-1337, Japan
‡Department of Chemistry, Faculty of Science, Hokkaido University, North 10, West 8, Kita-ku, Sapporo 060-0810, Japan
S
* Supporting Information
ABSTRACT: We describe the practical removal of p-
methylbenzyl (MBn) protections of alcohols by treatment
with 2,3-dichloro-5,6-dicyano-p-benzoquinone. When a mole-
cule bears benzyl and MBn groups, the oxidant selectively
removes the latter groups. Further, the MBn groups tolerate
ceric ammonium nitrate, resulting in chemoselective removal of
the p-methoxybenzyl group in the presence of the MBn groups.
These orthogonal alcohol deprotections would provide novel
synthetic strategies of organic compounds.
ydroxy group protections are one of the most widely
used strategies in organic synthesis.1 Among multiple
The p-methylbenzyl (MBn) group is an uncommon
analogue of the benzyl protecting group family. It has been
used for the protection of phenols7 and carbohydrates,8 and its
deprotection proceeds similar to that of the Bn group under
hydrogenolysis7a−c,8,9 and with the use of a Lewis acid.7d,10
Additionally, a trifluoroacetic acid (TFA) cocktail (2% each of
H2O, ethanedithiol, and triisopropylsilane in TFA)11 enables
its removal, indicating that it is weaker than the Bn group
(Scheme 1a). Further, results suggesting potential oxidative
removal of the MBn group have been reported (Scheme
1b,c),12−14 highlighting the possibilities for deprotection of this
group using multiple approaches. As the PMB group also
cleaves under acidic15,16 and oxidative conditions,3 variations
in the reaction conditions for the removal of the Bn, MBn, and
PMB groups would expand the orthogonality of their
deprotection strategies. We report herein, practical oxidative
cleavage conditions for the removal of the MBn protection and
the chemoselective removal of the PMB group in the presence
of the MBn group.
We explored the differences in the reactivity of the PMB and
MBn groups under oxidative reaction conditions and exposed
MBn ether 117 to the typical oxidative conditions used for the
removal of the PMB group (Scheme 2). The reactions were
carried out with 2,3-dichloro-5,6-dicyano-p-benzoquinone
(DDQ) and ceric ammonium nitrate (CAN) as the oxidants.18
While the reaction employing DDQ proceeded smoothly at
ambient temperature to provide 2 in 93% yield, the reaction
using CAN did not remove the MBn group effectively. The
latter result suggests the possibility for the use of CAN for
chemoselective deprotection of the PMB group in the presence
H
hydroxy groups, protection and deprotection of a selected one
are necessary for conducting reactions at the specific site.
Protecting groups of the hydroxy groups are generally classified
into acetal, acyl, ethereal, and silyl ethereal types.1 The benzyl
(Bn) group is one of the most frequently used ethereal
protecting group (Figure 1) because it survives under various
Figure 1. Benzyl-type protecting groups.
reaction conditions and cleaves specifically by hydrogenoly-
sis.1b,2 Analogues of the Bn group are also used to vary stability
and to modulate their protection and deprotection con-
ditions.1a Among these, the p-methoxybenzyl (PMB) group is
a prominent protecting group due to its lability under oxidative
conditions.3 In the case of Bn-derived groups bearing electron-
withdrawing substituents on the benzene ring, the deprotection
protocol typically requires two steps. For example, cleavage of
the p-nitrobenzyl group proceeds via reduction of the nitro
group and subsequent oxidation of the produced p-amino-
benzyl group.4 Similarly, the removal of the p-bromobenzyl
group proceeds in a two-step process via palladium-mediated
amination followed by treatment with a protic or Lewis acid.5
Differences in the reactivity for the removal of Bn protection
analogues provides orthogonality6 and enables the conversion
of polyhydroxy-functionalized compounds.
Received: June 21, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02144
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. (a) Known Acidic Cleavage of the MBn Group;
(b) Results Suggesting Potential Oxidative Removal of the
MBn Protection; (c) Oxidative Prins Cyclization
Table 1. Scope and Limitations of MBn Protections Using
DDQ
Scheme 2. Use of DDQ and CAN for the Oxidative Removal
of the MBn Protecting Group
of MBn moieties in compounds bearing both of the protecting
groups.
Having achieved MBn group deprotection using DDQ
mediated oxidative reaction, we turned our attention to the
study of the scope of this reaction with various reactants (3a−i,
Table 1).17 In the case of MBn protection for primary or
secondary alcohols, the deprotection to corresponding alcohol
proceeded in acceptable yield (entries 1−3). Notably, the MBn
ester in 3c survived under the deprotection conditions. We
explored next the simultaneous cleavage of two vicinal MBn
ethers in glucose derivative 3d, which provided the 1,2-diol 4d
in 87% yield (entry 4). While DDQ-mediated deprotection of
the Bn groups is reported,19 the MBn group cleaved swiftly in
the presence of the Bn group, showing chemoselectivity
(entries 5−7). Deprotection of MBn ethers 3e and 3f carrying
the Bn protection proceeded with the predominant formation
of the alcohols 4e and 4f in 92 and 73% yield, respectively.20
Furthermore, the reaction of 3g with 2.1 equiv of DDQ gave a
64:19 mixture of 4ga and 4gb, indicating that the reactivity of
the MBn group at O3 of glucose is greater than that at O2.21
The result depicted in entry 8 was remarkable. Thus, the
removal of the MBn group protecting the secondary alcohol
prevailed to that protecting the primary alcohol to provide an
11:1 mixture of 4ha and 4hb in 66% yield with recovered 3h in
20% yield.22 The selectivity would be attributed to the
difference in the electron density between the two MBn
groups. The reaction of aryl MBn ether 3i did not finish in 24
h, despite being conducted at 40 °C, and furnished the phenol
4i in 28% yield with a recovery of 3i in 51% yield (entry 9).
The MBn protections of ester 3c and aryl ether 3i, both of
which hardly reacted with DDQ, were cleaved via hydro-
genolysis (Scheme 3). The treatment of 3c and 3i with
a
b
At 40 °C. The recovered yield of the reactant.
Scheme 3. Hydrogenolysis of the MBn Groups
hydrogen gas and palladium on carbon gave 4c′ and 4i in both
excellent yields, along with the removal of the MBn ether in
the case of 3c. Hydrogenolysis of MBn groups typically
requires high pressures,9,23 and it is noteworthy that the
hydrogenolysis of 3c and 3i proceeded smoothly under an
atmospheric pressure of hydrogen.
B
DOI: 10.1021/acs.orglett.9b02144
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
We next focused on chemoselective removal of the PMB
group in the presence of the MBn group. As suggested in
Scheme 2, the use of CAN as the oxidant allowed selective
removal of the PMB group in the reactants 5a−g (Scheme
4a).17 The PMB protections for primary and secondary
of 3.3 equiv of CAN resulted in the disappearance of 7 and
highly selective production of 6b, the total yield of 6b and 6b′
was reduced due to overreaction. p-Methylbenzaldehyde was
1
detected in these crude H NMR spectra (see the Supporting
Information), indicating that the chemoselective removal of
the NAP group is tricky under oxidative conditions. We also
examined acidic hydrolysis of 7; however, 59% of 7 was
recovered along with 30% yield of 6b and 6b′, the latter being
the major product.
Scheme 4. (a) Selective PMB Deprotection in the Presence
of the MBn group(s). (b) Selective NAP Deprotection
The methyl group was determined as the most adequate
para-substituent for the reaction with DDQ through evaluation
of alkyl and aryl substituents as shown in Scheme 5. To probe
Scheme 5. Effect of the Substituent Group at the 4-Position
on the Bn Group
a
Pyrazine was used as the internal standard.
a
the substituent effect, we examined DDQ mediated depro-
tection of reactants 8a−f using identical reaction conditions;
where DDQ (1.3 equiv with respect to 8), the pH of the
phosphate buffer (7.4), the reaction temperature (room
temperature), and the reaction time (1.0 h) were the same
for all reactions. While the PMB group on 8a was completely
removed, the MBn group on 8b was partly retained. On the
other hand, the introduction of other alkyl groups led to a
decrease in reactivity. A conversion yield was 68% with the use
of the p-(n-butyl)benzyl group (8c), which was 14% lower
than that obtained for 8b. In addition, the reactivity of the p-
(tert-butyl)benzyl group (8d) was inferior to that of 8c. While
the removal of the p-phenylbenzyl group (8e) proceeded
similar to that described in a previous report,26 the conversion
yield was similar to that obtained with 8d. Further, compound
8f bearing the Bn protection remained intact in the presence of
DDQ. These results suggest that hyperconjugation of alkyl or
aryl substituents 8b−e is essential for the reaction of the
reactants with DDQ. Increase in electron density on the
benzene ring through the inductive effect of the substituents
allows the formation of a charge-transfer complex between the
substituted benzyl group and DDQ. The different conversion
yields obtained for 4a from 8b−e indicated that steric
hindrance of the substituent group inhibits the deprotection
reaction. The smaller size of the methyl group in comparison
to other alkyl and aryl substituents facilitates the formation of
the charge-transfer complex between the MBn group and
DDQ, which induces the oxidation of the MBn group in the
deprotection sequence.
Isolated yield with the use of concd HCl aq as the reagent.
alcohols (5a and 5b) gave the corresponding alcohols 6a
and 6b, respectively, in excellent yields by the treatment with
CAN. The allylic MBn ether in the acyclic compound 5c
tolerated this condition to provide the primary alcohol 6c in
74% yield. For 5d, the PMB group was selectively removed to
furnish 6d in 85% yield despite a report of CAN-mediated
acetonide removal.24 Simultaneous cleavage of two PMB
groups in 5e also proceeded smoothly to give the diol 6e in
77% yield. In addition, glucose derivative 5f and acyclic alkene
5g bearing the Bn, PMB, and MBn groups underwent selective
removal of the PMB group, affording the corresponding
alcohols 6f and 6g in 85% and 81% yield, respectively. We
further confirmed that treatment of 5a and 5b with concd HCl
aq induced chemoselective hydrolysis of the PMB group to
afford alcohols 6a and 6b, respectively, in good yields,
indicating that the MBn group tolerates the acidic conditions.
Thus, when the instability of the PMB group under acidic
conditions hinders intended transformation, the MBn group
could serve as a useful alternative.
We further attempted the selective oxidative removal of 2-
naphthylmethyl (NAP) group in 7 bearing the MBn group
because the NAP group is also removable under oxidative
conditions (Scheme 4b).25 When 1.2 equiv of DDQ was used,
the reaction was not completed to give a 16:1 mixture of 6b
and 6b′ in 53% yield with recovered 7 in 14% yield. Treatment
with 2.1 equiv of CAN gave the similar result. Although the use
C
DOI: 10.1021/acs.orglett.9b02144
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) (a) Sun, F.; Xu, G.; Wu, J.; Yang, L. Tetrahedron: Asymmetry
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In summary, we revealed that the MBn groups installed on
both primary and secondary alcohols smoothly cleave by the
use of DDQ. The oxidation is believed to be promoted by the
inductive effect of the methyl group. Additionally, the selective
removal of the PMB group in the presence of the MBn group
was achieved by the treatment of CAN. These results will
accelerate the use of the MBn group in organic synthesis and
will advance site-specific transformations in polyhydroxy
systems.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02144.
Experimental procedures, analytical data, and copies of
1
the H and 13C NMR spectra for all new products
(PDF)
(15) Selected papers for the deprotection of the PMB groups by
using a protic acid: (a) Ai, Y.; Kozytska, M. V.; Zou, Y.; Khartulyari,
A. S.; Maio, W. A.; Smith, A. B., III J. Org. Chem. 2018, 83, 6110.
(b) Guillaume, J.; Seki, T.; Decruy, T.; Venken, K.; Elewaut, D.; Tsuji,
M.; Calenbergh, S. V. Org. Biomol. Chem. 2017, 15, 2217. (c) Mondal,
S.; Sureshan, K. M. J. Org. Chem. 2016, 81, 11635. (d) Swarts, B. M.;
Guo, Z. J. Am. Chem. Soc. 2010, 132, 6648.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ikeuchi@sci.hokudai.ac.jp.
*E-mail: hidetosh@kwansei.ac.jp.
ORCID
(16) Selected papers for the deprotection of the PMB groups by
Kazutada Ikeuchi: 0000-0001-5343-3502
Hidetoshi Yamada: 0000-0003-2272-319X
Notes
́
using a Lewis acid: (a) Glaus, F.; Dedic, D.; Tare, P.; Nagaraja, V.;
Rodrigues, L.; Aínsa, J. A.; Kunze, J.; Schneider, G.; Hartkoorn, R. C.;
Cole, S. T.; Altmann, K.-H. J. Org. Chem. 2018, 83, 7150. (b) Yoshida,
R.; Ouchi, H.; Yoshida, A.; Asakawa, T.; Inai, M.; Egi, M.;
Hamashima, Y.; Kan, T. Org. Biomol. Chem. 2016, 14, 10783.
(c) Sawama, Y.; Masuda, M.; Asai, S.; Goto, R.; Nagata, S.;
Nishimura, S.; Monguchi, Y.; Sajiki, H. Org. Lett. 2015, 17, 434.
(d) Carr, J. L.; Offermann, D. A.; Holdom, M. D.; Dusart, P.; White,
A. J. P.; Beavil, A. J.; Leatherbarrow, R. J.; Lindell, S. D.; Sutton, B. J.;
Spivey, A. C. Chem. Commun. 2010, 46, 1824.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
JSPS KAKENHI (Grant Nos. JP19K15549, JP18H04429, and
JP19H02727) partly supported this work.
■
(17) All of the MBn group(s) in the reactants as shown in Schemes
2 and 4, and Table 1 were incorporated via the Williamson ether
synthesis. See the Supporting Information for details.
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