FeCl3-catalyzed self-cleaving deprotection of methoxyphenylmethyl-protected alcohols

Article abstract of DOI:10.1021/acs.orglett.5b00106

4-Methoxyphenylmethyl ethers are widely utilized as alcohol protecting groups. FeCl₃ effectively catalyzes the deprotection of methoxyphenylmethyl-type ethers in a self-cleaving manner to produce oligomeric derivatives and alcohols. Remarkably, the highly pure mother alcohols can be obtained without silica gel column chromatography by using the 2,4-dimethoxyphenylmethyl group as a protective group.

Full text of DOI:10.1021/acs.orglett.5b00106

Letter
pubs.acs.org/OrgLett
FeCl3‑Catalyzed Self-Cleaving Deprotection of
Methoxyphenylmethyl-Protected Alcohols
Yoshinari Sawama,* Masahiro Masuda, Shota Asai, Ryota Goto, Saori Nagata, Shumma Nishimura,
Yasunari Monguchi, and Hironao Sajiki*
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
S
* Supporting Information
ABSTRACT: 4-Methoxyphenylmethyl ethers are widely utilized as
alcohol protecting groups. FeCl3 effectively catalyzes the deprotection
of methoxyphenylmethyl-type ethers in a self-cleaving manner to
produce oligomeric derivatives and alcohols. Remarkably, the highly
pure mother alcohols can be obtained without silica gel column
chromatography by using the 2,4-dimethoxyphenylmethyl group as a
protective group.
ince the protection of functional groups is frequently
CH2Cl2. Therefore, we initially investigated the catalyst
Srequired to synthesize important target molecules, the efficiency of various Lewis acids using 4-MPM ether (1a)
derived from 1-decanol as a substrate (Table 1). Although an
development of efficient deprotection methods with tolerance
toward other functional groups is eagerly desired.1 4-
Methoxyphenylmethyl (4-MPM) ethers are widely utilized as
alcohol protecting groups, and their deprotection is generally
carried out by the use of stoichiometric oxidants [2,3-dichloro-
5,6-dicyano-p-benzoquinone (DDQ)2 and ceric ammonium
nitrate (CAN)3] or nucleophiles in the presence of catalytic or
Table 1. Lewis Acid and Solvent Efficiency in Deprotection
of 4-MPM Ether
5
stoichiometric Lewis acids.4 Ph3C·BF4 and the chlorosulfonyl
a
entry
1
Lewis acid
solvent
yield of 1a/2/3 (%) (time, h)
isocyanate (CSI)−NaOH combination6 as stoichiometric
reagents are also applicable for the deprotection of the 4-
MPM ether. Although only a catalytic method that uses ZrCl4
(20 mol %) in CH3CN has been reported for deprotection, the
details including the reaction mechanism were not inves-
tigated.7 A purification process is necessary to remove the
residue derived from the deprotected MPM moiety and
reagents in all reported cases. Although the Pd/C-catalyzed
hydrogenation under atmospheric hydrogen is also a useful
deprotection method, simple benzyl (Bn) ethers are preferen-
tially hydrogenated in the presence of the 4-MPM ether.1 We
now demonstrate the efficient iron-catalyzed deprotection of
various MPM type ethers in the presence of the Bn ether, and
the reaction mechanism has been investigated in detail.
Furthermore, an unprecedented green deprotection method
has been developed using the 2,4-dimethoxyphenylmethyl (2,4-
DMPM) protective group; it does not require SiO2 flash
chromatography purification of the alcohol products.
We have recently revealed that FeCl3 can efficiently activate
benzylic C−O bonds toward the subsequent nucleophilic
substitution with various nucleophiles accompanied by cleavage
of the benzylic C−O bonds.8 Although FeCl3 (excess amount)
is traditionally utilized for the deprotection of Bn ethers,9 we
hypothesized that catalytic FeCl3 in the presence of
nucleophiles could also facilitate the deprotection of Bn and
MPM ethers. Our pre-examination indicated that only 5 mol %
of FeCl3 could achieve the deprotection of the 4-MPM ether in
FeCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
0/67/32 (1)
0/65/33 (1)
0/55/43 (1)
0/59/40 (6)
2/58/33 (6)
no reaction (6)
no reaction (6)
22/59/16 (6)
no reaction
b
2
FeCl3
3
AuCl3
4
TMSOTf
BF3·Et2O
FeCl2·4H2O
Fe(acac)3
FeCl3
5
6
7
8
9
FeCl3
THF
10
11
12
FeCl3
1,4-dioxane
toluene
n-hexane
no reaction
FeCl3
0/48/48 (6)
FeCl3
74/8/12 (6)
a
b
The yields were calculated on the basis of 1H NMR. 2 equiv of H2O
was added. 4-MPM: 4-methoxyphenylmethyl.
undesirable byproduct (3)10 was obtained during the
deprotection of 1a, FeCl3 was found to be the most effective
catalyst for producing 1-decanol (2a) when compared other
Lewis acids (AuCl3,11 TMSOTf, BF3·Et2O) (entries 1 vs 3−5).
The formation of the byproduct (3) was confirmed in only the
deprotection of 1a for some unknown reason. Such byproducts
were never observed during the deprotection of other MPM
ether derivatives shown in Figure 1, Scheme 1, eqs 2 and 3, and
Received: November 19, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00106
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Letter
Table 2. Scope and Limitation
Figure 1. Scope of various benzyl-type ethers. (a) Yield of recovered
starting material. (b) 5 mol % of TMSCl was added as an additive. (c)
1.1 equiv of FeCl3 and 1.1 equiv of TMSCl were used. PG: protecting
group. MPM: methoxyphenylmethyl. DMPM: dimethoxyphenylmeth-
yl.
Scheme 1. Proposed Reaction Mechanism Based on ESI/MS
Analysis of Side Products in FeCl3-Catalyzed Deprotection
of 3,4-DMPM Ether (1e)
a
b
5 mol % of TMSCl was added as an additive. 1.1 equiv of FeCl3 and
c
1.1 equiv of TMSCl were used. Yield of recovered starting material.
d
e
The TBS ether moiety was partially deprotected. Highly pure
product was obtained without silica gel column chromatography.
f
Spectral data are shown in the Supporting Information. The yield was
1
calculated on the bass of H NMR using 1,1,2,2-tetrachloroethane as
g
an internal standard. The product was purified by silica gel column
chromatography due to the contamination of unidentified byproducts.
MPM: methoxyphenylmethyl. DMPM: dimethoxyphenylmethyl
in toluene and n-hexane gave low yields of the deprotected
alcohol (2), while THF and 1,4-dioxane were ineffective and
led to no reactions (entries 9−12). The addition of water (2
equiv) did not affect the efficiency of the FeCl3−catalyzed
deprotection in CH2Cl2 (entries 1 vs 2), which obviously
indicated that water never promoted the present deprotection.
The deprotection efficiency using various MPM- (1a−g) and
Bn-type (1h,i) ethers was next compared to elucidate the
reaction efficiency (Figure 1). The deprotection reactivity of
Table 2. Other iron catalysts such as FeCl2·4H2O and Fe(acac)3
were ineffective (entries 6 and 7). Solvents also strongly
influenced the reaction efficiency, the deprotection in CHCl3
requiring a longer reaction time (entries 1 vs 8). The reaction
B
DOI: 10.1021/acs.orglett.5b00106
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Letter
the 2-MPM ether (1b) was lower than that of the 4-MPM ether
(1a) due to the steric hindrance of 1b around the benzylic
position, and the deprotection of 1b was not complete even
after 6 h. Among the dimethoxyphenylmethyl (DMPM)-type
ethers, the deprotection of the 2,4-DMPM (1c) and 2,6-
DMPM (1d) ethers bearing two electron-donating methoxy
groups at the meta-position on each aromatic ring were
completed in very short reaction times in comparison to those
of the other 3,4-DMPM (1e) and 2,5-DMPM (1f) ethers. 1-
(4′-Methoxyphenyl)ethyl ether (1g) possessing a methyl
substituent on the benzylic position was less reactive in
comparison to 1a, which also clearly showed that the steric
hindrance around the benzylic position strongly influenced the
deprotection efficiency. Meanwhile, the Bn (1h), diphenyl-
methyl (1i), and 2-naphthyl (1j) ethers underwent no
deprotection at all in the presence of a catalytic amount of
FeCl3 (5 mol %). A catalytic amount of TMSCl (5 mol %)12
enhanced the Lewis acidity of FeCl3, and the deprotection of
1b was completed in a shorter time. Furthermore, deprotection
of the Bn ether (1h) could be accomplished using a
stoichiometric amount of FeCl3 and TMSCl (1.1 equiv).13
On the basis of the results shown in Figure 1, the present
deprotection is effectively facilitated by the use of electron-
sufficient (highly nucleophilic) MPM-type ethers (preferably,
m-dimethoxybenzene derivatives) without steric hindrance. An
ESI/MS analysis of the byproducts obtained during the
deprotection process of 1e indicated that the mixture of the
cyclic trimer, tetramer, pentamer, and hexamer (m/z 478.1934,
623.2623, 773.3293, 923.3951 [M + Na]+) of the 3,4-DMPM
moiety were produced together with the deprotected 1-decanol
(2) (Scheme 1, eq 1).14,15 Therefore, the present deprotection
is presumed to proceed via the iron-catalyzed self-assembling
mechanism shown in Scheme 1. First, the benzylic position,
activated by coordination of FeCl3 with the benzylic oxygen
atom of the substrate (1), undergoes intermolecular
nucleophilic attack by the electron-rich aromatic ring of the
MPM moiety in the other substrate to give the deprotected
alcohol (2) and the corresponding dimer (4) derived from the
MPM moieties. Repeated similar reactions then give the
oligomers 5 and 6, in which the benzylic position and the
benzene moiety allow the intramolecular annulation to provide
the calixarene derivatives (7). Therefore, the deprotection of
DMPM ethers bearing two methoxy groups at ortho- and para-
positions (1c and 1d) is very smoothly completed as shown in
Figure 1 due to dual activation of the nucleophilic (electron
rich) position on the aromatic ring by the ortho−para
orientation of two electron-donating methoxy groups.
The present iron-catalyzed deprotection method was applied
to various 4-MPM, 2-MPM, and 2,4-DMPM ethers as
substrates (Table 2). The 4-MPM ether derived 2-decanol as
a secondary alcohol was also efficiently deprotected by the
independent use of only 5 mol % of FeCl3 (entry 1), while the
2-MPM ether underwent the quantitative deprotection using
the FeCl3−TMSCl (each 5 mol %) combination (entry 2).
Phenyl 4-MPM ether was inapplicable, since the phenol and
phenol derivatives were also good nucleophiles and gave a
complex mixture (entry 3). As expected from the results in
Figure 1, the presence of 5 mol % of FeCl3 as catalyst allowed
the chemoselective deprotection of MPM ethers in the
presence of Bn ethers within the same molecule (entries 4
and 5), while the deproteciton of both the 4-MPM and Bn
ethers could be achieved using a stoichiometric amount of the
FeCl3 and TMSCl combined system (entry 6). Additionally, an
alkyne and silyl ether tolerated the FeCl3-catalyzed depro-
tection conditions to give the corresponding alcohols (entries 7
and 8). Furthermore, the silica gel column chromatography-free
method could be adapted for the deprotection of various 2,4-
DMPM ethers derived from secondary, benzyl, and primary
alcohols (entries 9−11). Additionally, the deprotection of 2,4-
DMPM ethers bearing a TBS ether, acetoxy group, and
hydroxyl group in same molecule could be applied (entries 12−
14). Meanwhile, the ketal moiety was partially deprotected to
the ketone product probably by the contamination of water
resulting from the hygroscopic FeCl3 (entry 15). The present
deprotection efficiency was not influenced even by an amide
compound in the reaction system (entry 16). Fortunately, the
2,4-DMPM phenyl ether derived from the phenol also
underwent the chemoselective deprotection to phenol in high
yield due to the highly nucleophilic nature of the 2,4-
dimethoxyphenyl group in comparison with that of the
phenoxy moiety in the substrate and phenol as the product
(entry 17).
In conclusion, we report an efficient, green, and chemo-
selective deprotection method for MPM-type ethers that uses
FeCl3 without any additional nucleophiles. The present
deprotection proceeds via a self-cleaving mechanism of the
electron-rich MPM protective group itself to give the mother
alcohol at room temperature in a short time. Additionally, the
deprotection of the 2,4-DMPM ethers produces a less soluble
precipitate derived from the 2,4-DMPM protective group which
gives highly pure alcohols after simple filtration and extraction
without silica gel column chromatography. Therefore, the
present unprecedented deprotection method is an environ-
mentally friendly, simple, and industrially applicable process.
It is noteworthy that the FeCl3-catalyzed deprotection of the
2,4-DMPM ether (1c) produced the resorcinarene derivative
(7c)16 as a less-soluble precipitate, and only 1-decanol (2) was
obtained without any byproducts derived from the 2,4-DMPM
protective group after simple filtration and extraction (eq 2).14
Similarly, 2,4-dibutoxyphenylmethyl ether (1k) also effectively
underwent the FeCl3-catalyzed deprotection to 1-decanol (2)
in 97% yield accompanying the formation of the highly
lipophilic resorcin[4]arene octabutyl ether (7k: m/z 959.6376
[M + Na]+) (eq 3),14 which clearly indicated that the present
deprotection could proceed via a self-cleaving mechanism of
the DMPM moiety. Additionally, the use of other Lewis acids
(e.g., AuCl3, TMSOTf, and BF3·Et2O) also could realize the
efficient deprotection of 1c into 2 in excellent yields within 5
min without purification by silica gel column chromatog-
raphy.17,18
ASSOCIATED CONTENT
■
S
* Supporting Information
Typical procedures and spectroscopic data of products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: sawama@gifu-pu.ac.jp.
*E-mail: sajiki@gifu-pu.ac.jp.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b00106
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