P-chlorobenzyl ether: A p-methoxybenzyl ether in disguise

Article abstract of DOI:10.1021/acs.orglett.6b02672

In the chemistry of polyfunctionalized organic compounds, protecting groups that can undergo mild and selective cleavage while still being stable during the entire synthetic sequence are often required. In this work, we present a straightforward conversion of the robust p-chlorobenzyl ether into the more labile and well-described p-methoxybenzyl ether using palladium catalysis. This reaction was demonstrated to be high yielding and compatible with a wide range of functionalities, thereby providing a useful supplement to the conventional ether protecting groups.

Full text of DOI:10.1021/acs.orglett.6b02672

Letter
pubs.acs.org/OrgLett
p‑Chlorobenzyl Ether: A p‑Methoxybenzyl Ether in Disguise
Agnete H. Viuff, Mads Heuckendorff, and Henrik H. Jensen*
Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark
S
* Supporting Information
ABSTRACT: In the chemistry of polyfunctionalized organic
compounds, protecting groups that can undergo mild and
selective cleavage while still being stable during the entire
synthetic sequence are often required. In this work, we present
a straightforward conversion of the robust p-chlorobenzyl
ether into the more labile and well-described p-methoxybenzyl
ether using palladium catalysis. This reaction was demonstrated to be high yielding and compatible with a wide range of
functionalities, thereby providing a useful supplement to the conventional ether protecting groups.
While the PClB group has all the advantages of a permanent
protecting group, it still suffers from the same drawbacks such
as deprotection by hydrogenolysis as the benzyl group.
However, preliminary results from our group have shown
that employing the conditions developed by Cheung and
Buchwald for the methoxylation of aryl chlorides14 it was
possible to convert PClB protecting groups into the well-
known PMB group in good yield in the presence of ethers and
an O,S-acetal in the form of a thioglycoside.1
Provided that conversion of PClB to PMB is a general
transformation, we envision the former to be a valuable stable
protecting group for introduction at an early stage of the
synthesis and possess well-documented chemistry as its PMB
congener.5 PClB still has the option of being cleaved under
hydrogenolysis conditions1,5 but otherwise be cleaved over two
steps as is the case for the allyl ether protecting group.
While our previous study has shown that the Pd-mediated
(multiple) conversion of Cl into OCH3 was possible in
thioglycosides, we did not investigate functional group
tolerance. For the utilization of the PClB group to be successful
it is paramount that the conversion from PClB to PMB is able
to take place in the presence of a wide range of functionalities.
In order to investigate this we synthesized a total of 11 PClB
protected carbohydrate derivatives as models of a densely
functionalized small organic molecule. The protection of an
alcohol functionality as a PClB ether was found to be
uneventful following normal benzylation procedures (Scheme
1).15
he use of protecting groups is essential when working with
Torganic synthesis on polyfunctionalized substrates such as
carbohydrates and other natural products. Protecting groups
are used to mask specific functionalities and render them
unreactive to achieve specific chemical transformations on
other reactive sites. In carbohydrate chemistry, the choice of
protecting groups is often used to influence the reactivity and
stereochemical outcome of the glycosylation reaction.1,2
Common types of hydroxyl protecting groups are the benzyl
(Bn) and allyl (All) ethers. The benzyl ether is a very robust
protecting group that is typically introduced as a permanent
protecting group in the beginning of a synthetic sequence and
cleaved in one of the final steps of the synthesis. The most
commonly used conditions for the deprotection of benzyl
ethers is palladium-catalyzed hydrogenolysis,3 which is not
compatible with functionalities such as alkenes or alkynes.
Furthermore, it is our impression that benzyl ether removal by
hydrogenolysis occasionally can be an unreliable reaction.
The allyl ether, on the other hand, is often used as a
temporary protecting group, which is either cleaved directly4 or
in a two-step procedure starting with isomerization of the
double bond and then cleavage.5 The allyl deprotection can
also be problematic due to low reactivity or competing side
reactions.6 An alternative for the protection of hydroxyl groups
is the p-methoxybenzyl (PMB) ether group, which can easily be
deprotected using a wealth of different methods.5,7 The most
popular of these deprotection strategies is either DDQ
oxidation8 or acidic treatment.9 The mild deprotection
conditions for PMB cleavage comes at the cost of lower
stability, making this group unsuitable for some synthetic
protocols.10
For the methoxylation we decided to use Rockphos Pd G3 (5
mol %) and Rockphos ligand (5 mol %)16 together with
NaOtBu and CH3OH in 1,4-dioxane as we found these
conditions to give high conversion17 similar to the conditions
reported by Cheung and Buchwald.14
These conditions resulted in high yields with PClB-protected
primary alcohols of glucose and galactose (Table 1, entries 1
and 4) and secondary alcohols (entry 2) as well as anomeric
A less known hydroxyl protecting group is the p-chlorobenzyl
(PClB) ether.11 The PClB group is as stable as the benzyl ether,
while also being found to have a stabilizing effect on glycosidic
linkage due to its electron withdrawing nature.12 Additionally
the PClB group has been shown to induce crystallinity into
molecules,13 providing a straightforward way to obtain crystals
from otherwise noncrystalline compounds.
Received: September 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02672
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. General Reaction Scheme
Table 2. Conversion of Aryl Chlorides into Aryl Methoxides
According to the General Reaction Scheme in the Presence
of Base-Sensitive Functionalities*
Table 1. Conversion of Aryl Chlorides into Aryl Methoxides
According to the General Reaction Scheme*
*
Reaction conditions: RockPhos Pd G3 (5 mol %), RockPhos ligand
a
(5 mol %), 1.4 equiv of NaOtBu, 5 equiv of CH3OH, 60 °C. Isolated
yields after chromatography. Conditions using 4.2 equiv of Cs2CO3
b
and 15 equiv of CH3OH.
Cheung and Buchwald14 and heating the reaction to 60 °C in
order to shorten the reaction time allowed us to obtain the
PMB ether in the presence of a pivaloyl ester in high yield in
only 1.5 h (entry 2). The benzoyl ester was unfortunately still
labile under these conditions. Using the conditions on a
TBDMS-protected compound gave a very sluggish reaction that
only showed 50% conversion after 20 h as well as deprotection
of the silyl ether (entry 3). On the other hand, switching to the
more stable TIPS ether gave good results, with a yield of 90%
after only 2.5 h (entry 4). Lastly, testing the reaction on tri-p-
chlorobenzylated glucal gave us conversion of all three benzyl
ethers in 64% isolated yield, corresponding to 86% per
substitution (entry 5).
As a final example of the effectiveness of this protocol, we
were able to synthesize per-PClB-protected β-cyclodextrin and
convert all 21 PClB groups into PMB groups in only 19 h in
79% isolated yield, corresponding to a yield of 99% per
substitution (Scheme 2).
In conclusion, we have explored the scope of the Pd-
catalyzed conversion of PClB ethers into the well-studied PMB
ethers and found that this reaction is high yielding and versatile.
The reaction conditions were found to be compatible with a
wide range of functionalities, including acetals, thioacetals, silyl
ethers, esters, and alkenes. We believe that the PClB protecting
group is a valuable tool for the general organic chemist,
providing a good supplement to the conventional protecting
groups such as benzyl, allyl, and p-methoxybenzyl protecting
groups due to its chameleon-like properties of superior stability
and ease of deprotection.
*
Reaction conditions: RockPhos Pd G3 (5 mol %), RockPhos ligand
a
(5 mol %), 1.4 equiv of NaOtBu, 5 equiv of CH3OH, 50 °C. Isolated
yields after chromatography.
PClB-protected glucose (entry 3). The method was also fully
compatible with the presence of ethers (entries 1 and 3),
thioacetals (entry 2), and acetals (entry 2, 4, and 5). It was also
possible to employ the reaction conditions directly on p-
chlorobenzylidene-protected glucose, converting it into the p-
methoxybenzylidene in 83% yield (entry 5).
With these promising results in hand, we continued to
investigate if the method was compatible with more challenging
substrates containing functionalities that are labile under basic
conditions. For this purpose, we chose to use substrates
containing functionalities such as esters, silyl ethers, and alkenes
(Table 2). We found that both the benzoyl and pivaloyl esters
were labile using the conditions described above with NaOtBu
as the base. Changing the base to Cs2CO3 as described by
B
DOI: 10.1021/acs.orglett.6b02672
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Conversion of All 21 PClB Ethers in Per-PClB-Protected β-Cyclodextrin into 21 PMB Ethers
(13) Koto, S.; Inada, S.; Morishima, N.; Zen, S. Carbohydr. Res. 1980,
87, 294.
(14) Cheung, C. W.; Buchwald, S. L. Org. Lett. 2013, 15, 3998−4001.
(15) See the Supporting Information
(16) (a) Wu, X.; Fors, B. P.; Buchwald, S. L. Angew. Chem., Int. Ed.
2011, 50, 9943. (b) Bruno, N. C.; Buchwald, S. L. Org. Lett. 2013, 15,
2876. (c) Bruneau, A.; Roche, M.; Alami, M.; Messaoudi, S. ACS Catal.
2015, 5, 1386.
(17) Conditions: 1.4 equiv of base and 5 equiv of methanol per PClB
group, while the catalyst load is kept at 5 mol % regardless of the
number of PClB groups in the molecule.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02672.
■
S
General procedures and NMR spectra of all synthetic
compounds. (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hhj@chem.au.dk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Christian Marcus Pedersen (University of
Copenhagen) and Mr. Rasmus Telving (Aarhus University) for
running MALDI experiments and the Villum Foundation for
funding.
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