Mild, efficient and rapid O-debenzylation of ortho-substituted phenols with trifluoroacetic acid

Article abstract of DOI:10.1016/j.tetlet.2008.06.022

The mild and efficient deblocking of aryl benzyl ethers with TFA is reported. Cleavage was fastest with ortho-electron-withdrawing groups on the phenolic ring, which we have attributed to a proton chelation effect, furnishing the deprotected phenols in excellent yields. The corresponding para-methoxybenzyl, allyl and iso-propyl ethers were also cleanly removed under these conditions. In addition, the selective aryl benzyl ether debenzylation in the presence of benzyl ester, Cbz carbamate and Boc carbamate functionalities was also observed. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2008.06.022

Tetrahedron Letters 49 (2008) 4817–4819
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Mild, efficient and rapid O-debenzylation of ortho-substituted
phenols with trifluoroacetic acid
*
*
Steven Fletcher , Patrick T. Gunning
Department of Chemistry, University of Toronto, Mississauga, ON L5L 1C6, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
The mild and efficient deblocking of aryl benzyl ethers with TFA is reported. Cleavage was fastest with
ortho-electron-withdrawing groups on the phenolic ring, which we have attributed to a proton chelation
effect, furnishing the deprotected phenols in excellent yields. The corresponding para-methoxybenzyl,
allyl and iso-propyl ethers were also cleanly removed under these conditions. In addition, the selective
aryl benzyl ether debenzylation in the presence of benzyl ester, Cbz carbamate and Boc carbamate func-
tionalities was also observed.
Received 21 May 2008
Revised 2 June 2008
Accepted 4 June 2008
Available online 10 June 2008
Crown Copyright Ó 2008 Published by Elsevier Ltd. All rights reserved.
Phosphotyrosines feature in the design of inhibitors of several
protein targets, including protein tyrosine phosphatase 1B
(PTP1B).1 However, these moieties suffer from hydrolytic lability
to cellular phosphatases and poor cell penetration due to the asso-
ciated dianionic charge.1 To address these issues, salicylic acid
derivatives (and closely-related analogues) have become popular
mimetics of phosphotyrosine in small molecule inhibitors.1–5 Turk-
son et al. have recently reported on NSC74859 (1), a potent, sali-
cylic acid-based inhibitor of the oncogenic protein Stat3.6 As part
of our structure–activity relationship (SAR) studies on NSC74859
(1), we sought to debenzylate both the phenol ether and benzoate
ester in 2 without reducing the aryl-bromide bond, a common
undesired side reaction that occurs with hydrogen gas and Pd/C
catalyst.7
organic acids (e.g., trifluoromethanesulfonic acid9) or a large excess
of nucleophilic scavenger (e.g., thioanisole, which accelerates the
reaction by a ‘push–pull’ mechanism10) are typically required. Re-
cent work by Ploypradith et al. describes the mild deprotection of
aromatic ethers with sub-stoichiometric para-toluenesulfonic acid
on solid support.11 In a special case, O-benzyl-protected ortho-
nitrophenol was cleaved rapidly (<5 min) with neat TFA,12 which
we considered was due to the ability of the substrate to chelate a
proton since the structurally-similar ortho-hydroxybenzoates
(salicylates) are well-known to chelate copper ions and iron ions.
We reasoned that 2 (and indeed 3) may similarly undergo acceler-
ated debenzylation with TFA. In fact, as shown in Scheme 1, treat-
ment of 2 (or 3) with a 1:1 mixture of TFA/toluene led to rapid
debenzylation (5 min for 2; 1 h for 3) in 91% yield for 2 (or 85%
yield for 3). In this Letter, we will explore the structural require-
ments of the phenol component that increase the lability of the
O-benzyl phenol ether bond in the presence of TFA. In addition,
Br
O
O
O
HN
O
S
O
S
Br
Br
O
N
O
N
phosphotyrosine
mimetic
OH
O
O
a
O
S
O
S
HO
O
OBn
N
O
N
O
N
N
O
OBn
1 (NSC74859)
2
OBn
OH
OR
O-Benzyl-protected phenols are known to undergo debenzyla-
tion with trifluoroacetic acid (TFA)8 by an initial protonation of
the weakly basic phenol oxygen, although additives such as strong
O
OR
O
2 (R = Bn)
3 (R = H)
4 (R = Bn)
5 (R = H)
c
b
* Tel.: +1 905 828 5354; fax: +1 905 828 5425 (P.T.G.).
E-mail addresses: steven.fletcher@utoronto.ca (S. Fletcher), patrick.gunning@
utoronto.ca (P. T. Gunning).
Scheme 1. Reagents and conditions: (a) TFA/toluene, 1:1, rt, 5 min, 91% (for 4) or
1 h, 85% (for 5); (b) LiOHÁH2O, THF/H2O, 3:1, rt, 24 h, 83%; (c) NaOH, THF/H2O, 3:1,
60 °C, 4 h, 61%.
0040-4039/$ - see front matter Crown Copyright Ó 2008 Published by Elsevier Ltd. All
rights reserved.

4818
S. Fletcher, P. T. Gunning / Tetrahedron Letters 49 (2008) 4817–4819
we will explore the selectivity of this mild debenzylation tech-
nique with respect to other aromatic ethers and examine the sta-
bility of other benzyl-based protecting groups to these reaction
conditions.
wed down the debenzylation (e.g., entries 6g and 6h), relative to
the control compound 6l, which itself could only be obtained in
moderate purity by this method. The
r-withdrawing (and p-
donating) bromophenols 6i–k were insufficiently deactivated to
benzyl cation scavenging and were contaminated with several
by-products. Importantly, n-butyl benzyl ether 8 was unaffected
by TFA under the reaction conditions, indicating this procedure is
selective for aryl benzyl ethers. In addition, the results in Table 1
suggest that this procedure is suitable only for phenols substituted
A series of 12 O-benzyl-protected phenols was prepared by
standard procedures in near quantitative yields. Each of these
ethers was then deprotected with a 1:1 mixture of TFA/toluene;
our observations are summarized in Table 1. In certain cases,
O?C benzyl migration (Friedel–Crafts reaction) by-products
(610%) were occasionally inseparable from the product by silica
gel flash column chromatography. Thus, several benzyl cation cap-
tors were investigated for their abilities to improve yields and puri-
ties of the debenzylation reactions. Three to ten equivalents of p-
cresol, anisole and triethylsilane were employed, but these exerted
little effects on reducing by-product formation. Conversely, we dis-
covered that including the more nucleophilic scavenger thioanisole
as an additive to the co-solvent toluene typically, after silica gel
flash column chromatography, furnished products in P95% puri-
ties (and higher yields), as judged by 1H NMR. Nevertheless, we
envisaged any Friedel–Crafts impurities would be more readily
separable on slightly more complex aryl benzyl ethers, as we ob-
served with the substrates shown in Scheme 1 and Tables 3 and
4 (>99% purities (1H NMR) in each case). Whilst likely leading to
even higher yields and purities, large excesses of thioanisole
(50 equiv) are also known to accelerate TFA-mediated debenzyla-
tion.10 However, in our hands just 3 equiv of thioanisole had little
effect on the rate of debenzylation, allowing us to attribute the
deprotection rates solely to the structure of the phenol. Electron-
rich phenols are good scavengers of benzyl cations,13 and since
preliminary experiments with electron-rich phenols generated
complex mixtures of Friedel–Crafts by-products under these deb-
enzylation conditions, we chose to investigate only electron-poor
phenols in this study.
with p-electron-withdrawing groups.
Since the debenzylation mechanism with TFA proceeds via an
initial protonation of the phenol ether oxygen, the more available
the ether oxygen lone pairs are, the faster the reaction will be.
Hence, the slower reaction times for the phenols bearing meta-
and para-electron-withdrawing groups make sense, although this
is not true for the ortho-functionalized aryl benzyl ethers. As
hypothesized for the bis-benzyl salicylate derivative 2 earlier, we
considered these ortho-substituted phenols were capable of chelat-
ing the acidic hydrogen atom from TFA which therein facilitated
the acid-mediated debenzylation via a six-membered cyclic inter-
mediate, as proposed in Scheme 2. A similar chelation intermediate
has been put forward by Baldwin and Haraldsson to account for the
Lewis acid MgBr2-mediated debenzylation of aromatic benzyl
ethers ortho to an aldehyde group.14
Accordingly, to test this hypothesis we expanded this series of
ortho-substituted aryl benzyl ethers, and the results from their deb-
enzylation reactions with TFA are summarized in Table 2. These
substrates have been listed in order of increasing approximate
CF3
O
O
H
OH
O
TFA
O
O
OMe
toluene
O-Benzyl-protected phenols with
p-ortho-electron-withdraw-
OMe
ing groups (6a, 6b, 6d, 6f) were swiftly (several in less than 3 h
cf. 24 h for unsubstituted phenol 6l) and cleanly debenzylated,
with less than 5% of the undesired C-benzylated phenol by-prod-
ucts. In contrast, meta- and para-electron-withdrawing groups slo-
7b
6b
Scheme 2. Proposed chelation mechanism to account for accelerated TFA-mediated
debenzylation with ortho-substituted phenols.
Table 1
TFA-mediated debenzylation of O-benzyl-protected phenolsa
OBn
OH
Table 2
TFA-mediated debenzylation of O-benzyl-protected, ortho-substituted phenolsa
TFA
R
R
toluene
OBn
OH
TFA
R
R
6
7
toluene
Substrate
R
Time (h)b
Yieldc (%)
6
7
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
o-CO2Me, md-NHAc
o-CO2Me
p-CO2Me
o-CO2Bn
p-CO2Bn
o-NO2
m-NO2
p-NO2
o-Br
5 min
5 min
36e
5 min
36e
3
93
94
b
Substrate
R
pKaH
Timec (h)
Yieldd (%)
Relative rate
63 (85f)
93
6m
6n
6o
6b
6d
6p
6f
CO2NH2
CHO
CO2H
CO2Me
CO2Bn
CN
À2
À7
À8
24
3.5
1
5 min
5 min
>48
3
83
1
94e
91
6.9
24
288
288
—
8
1.5
1
58 (79f)
97
36e
36e
16
75 (98f)
À8.5
À8.5
94
93
66 (98f)
g
À10
51 (95f)
97
—
—
—
g
NO2
Br
H
À12
—
m-Br
p-Br
H
30
36
24
g
g
6i
6l
16
24
—
—
g
g
—
—
n-BuOBn (8)
—
24
No reaction
a
The reaction was carried out with 6 (0.5 mmol) in a 1:1 mixture of TFA/toluene
a
(5 ml) at rt, with 3 equiv of thioanisole.
The reaction was carried out with 6 (0.5 mmol) in a 1:1 mixture of TFA/toluene
b
Approximate pKaH of conjugate acid of R group.15
Time taken for all starting material to be consumed.
Isolated yield after silica gel flash column chromatography.
Including thioanisole in the deprotection of 6n led to further by-products, thus
(5 ml) at rt, with 3 equiv of thioanisole.
c
b
Time taken for all starting material to be consumed.
Isolated yield after silica gel flash column chromatography.
meta to phenol oxygen AND para to ester.
Reaction was slow and incomplete after 3 days.
Yield based on recovered starting material.
Complex mixture of products.
d
c
e
d
e
no scavenger was used and compound 7n could be obtained in only 90% purity.
f
f
Yield based on recovered starting material.
Complex mixture of products.
g
g

S. Fletcher, P. T. Gunning / Tetrahedron Letters 49 (2008) 4817–4819
4819
Table 4
acidity of the conjugate acid (decreasing pKaH) of the ortho-elec-
tron-withdrawing substituent.15 There appears to be an optimal
pKaH of around À8.5, that is exhibited by carboxylic esters, which
lead to the fastest rate of debenzylation with TFA. In an approxi-
mate bell-shaped distribution of reaction rate versus ortho-substi-
tuent pKaH—that was interrupted only by ortho-cyanophenol
6p—protonatable groups with pKaH’s <À8.5 or >À8.5 were less
effective at accelerating the TFA-mediated debenzylation. These
data concur with our chelation hypothesis: groups that are too ba-
sic bind more strongly to the TFA proton making it less available for
sharing with, and ultimately releasing to, the phenol ether oxygen;
groups that are weakly basic do not bind the TFA proton as well,
leading to reduced chelation and hence less rate enhancement.
The anomalous result for ortho-cyanophenol 6p was anticipated
since this compound was selected as a negative control. Phenol
6p is geometrically incapable of chelating a proton, because the lin-
ear, sp-hybridized nitrile functionality directs its basic nitrogen
atom (pKaH ꢀ À10) away from the phenol oxygen. As predicted,
there was no rate enhancement for the TFA-mediated debenzyla-
tion of 6p relative to phenol 6l. In fact, 6p was only slowly deben-
zylated, at a rate that was comparable with the m-nitro and
p-nitro derivatives 6g and 6h, respectively.
We next wanted to investigate the selectivity for the deprotec-
tion of the benzyl group over other phenol protecting groups.
Accordingly, the benzyl group in salicylate derivative 9a was varied
with para-methoxybenzyl (PMB; 9b), methyl (9c), allyl (9d) and
iso-propyl (i-Pr; 9e). These substrates were then debenzylated with
a 1:1 mixture of TFA/toluene; our findings are reported in Table 3.
Any impurities this time were minor and readily separable from
the products, eliminating the need for the additive thioanisole.
The relative rates at which these protecting groups were removed
was para-methoxybenzyl > benzyl > allyl > iso-propyl ꢁ methyl,
which reflects the stability of the carbocations. These data suggest
that in salicylates such as 9, the benzyl phenol protecting group
(R = Bn) can be removed with TFA in the presence of the corres-
ponding allyl, iso-propyl and methyl ethers.
Selectivity investigation into the TFA-mediated debenzylation of aryl benzyl ethersa
OBn
OH
TFA
CO2Bn
CO2Bn
toluene
R
R
11
12
Substrate
R
Yieldb (%)
6dc
11a
11b
11cd
H
93
92
93
54
NHAc
NHCbz
NHBoc
a
The reaction was carried out with 11 (0.5 mmol) in a 1:1 mixture of TFA/toluene
(5 ml) at rt for 5 min, then all solvents were evaporated.
b
Isolated yield after silica gel flash column chromatography.
For compound 6d, 3 equiv of thioanisole were also used.
After 5 min, the reaction mixture was diluted with CH2Cl2 and then immedi-
c
d
ately neutralized with 1 M NaOH. The organic layer was then separated and
evaporated.
In summary, we have presented the mild, efficient and rapid
deblocking of ortho-substituted aryl benzyl ethers with TFA. Deb-
enzylation was fastest when the ortho group was a carboxylic ester,
which we have attributed to a proton chelation effect. Other ortho
groups that accelerated the TFA-mediated debenzylation included
carboxylic acid, aldehyde and nitro. In addition, we have shown
that in such ortho-functionalized phenols, benzyl could be
removed in the presence of the corresponding iso-propyl, allyl
and methyl ethers. Moreover, the benzyl ether could be selectively
cleaved in the presence of benzyl ester, Cbz carbamate and Boc
carbamate functionalities.
Acknowledgements
The authors gratefully acknowledge financial support for this
work from the Canadian Foundation of Innovation and the Univer-
sity of Toronto (Connaught Foundation).
Finally, we explored the selectivity of this mild debenzylation
technique over other benzyl-based protecting groups, as shown
in Table 4. As the results demonstrate, it was possible to deblock
the O-benzyl ether in the presence of a benzyl ester (6d) and in
the presence of a benzyl carbamate (11b), thereby increasing the
orthogonality of O-benzyl phenol ethers of salicylate derivatives.
Interestingly, it was even possible to cleave the benzyl group in
11c with TFA in the presence of an N-Boc-protected aniline.
References and notes
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Table 3
TFA-mediated deprotection of O-blocked phenol ether derivatives of methyl
4-acetamidosalicylatea
NHAc
NHAc
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TFA
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see also: http://www2.lsdiv.harvard.edu/labs/evans/pdf/evans_pKa_table.pdf.
toluene
OR
OMe
OH
OMe
O
O
9
10
Substrate
R
Timeb (h)
Yieldc (%)
9a
9b
9c
9d
9e
Bn
PMB
Me
Allyl
i-Pr
5 min
2 min
48
20
36
91
90
0d
91
92
a
The reaction was carried out with 9 (0.5 mmol) in a 1:1 mixture of TFA/toluene
(5 ml) at rt.
b
c
Time taken for all starting material to be consumed.
Isolated yield after silica gel flash column chromatography.
Only starting material remained after 48 h, at which point the reaction was
d
aborted.