Positional chemoselectivity in the Zn(II)-mediated removal of phenol protecting groups

Article abstract of DOI:10.1016/j.tetlet.2012.07.103

A protocol was developed for the chemoselective ortho-deprotection of polyphenolic substrates using readily available Zn^IIX₂ salts. This procedure provides exceptional positional selectivity for the deprotection of phenols that reside adjacent to directing carbonyl functionality in the presence of similar protecting groups at the meta and para positions. Good to excellent yields of the desired free phenols were obtained (≤96%), and a wide assortment of protecting groups was readily removed under the reaction conditions.

Full text of DOI:10.1016/j.tetlet.2012.07.103

Tetrahedron Letters 53 (2012) 5376–5379
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Positional chemoselectivity in the Zn(II)-mediated removal of phenol
protecting groups
⇑
Lauren M. Fleury, Joseph B. Gianino, Brandon L. Ashfeld
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46637, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A protocol was developed for the chemoselective ortho-deprotection of polyphenolic substrates using
readily available ZnIIX2 salts. This procedure provides exceptional positional selectivity for the deprotec-
tion of phenols that reside adjacent to directing carbonyl functionality in the presence of similar protect-
ing groups at the meta and para positions. Good to excellent yields of the desired free phenols were
obtained (696%), and a wide assortment of protecting groups was readily removed under the reaction
conditions.
Received 16 May 2012
Revised 20 July 2012
Accepted 24 July 2012
Available online 31 July 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Chemoselectivity
Phenol deprotection
Lewis acids
Protecting groups
The chemoselective removal of protecting groups in the synthe-
sis of complex molecular targets continues to be a major challenge
in organic chemistry.1 As the complexity of a synthetic target in-
creases, invariably the need for a protecting group strategy that en-
ables the selective installation and mild removal of widely used
protecting groups becomes crucial. A major challenge encountered
in total synthesis is the selective removal of protecting groups that
reside in similar stereoelectronic environments. In the context of
our current synthetic efforts toward members of the calyxin family
of natural products, a class of antitumor diarylheptanoid plant
metabolites,2 we encountered complications in the selective instal-
lation and removal of aryl ether protecting groups. The multitude
of phenolic groups in the calyxins, as illustrated by blepharocalyx-
ins A and B (Fig. 1),2c prompted us to explore a universal protec-
tion–deprotection strategy of this pervasive functional group.
Recently, Yadav et al. demonstrated the ortho-selective depro-
tection of methyl and allyl ethers using CeCl3,3 and Keith showed
that I2/MeOH would selectively remove MOM and PMB ethers.4
Additionally, ultrasound sonication has proven effective at the
selective desilylation of phenols,5 whereas benzyl ethers are read-
ily cleaved in the presence of a Brønsted acid (e.g., TFA).6 During
our work on phosphine-mediated, titanocene-catalyzed multicom-
ponent couplings with aryl aldehydes, we required a general meth-
od that would enable the selective ortho deprotection of
benzaldehyde derivatives 1 containing similar protecting groups
at various positions around the benzene ring.7 We speculated that
a mild Lewis acid, such as a ZnX2 salt, would participate in a
directed ortho-deprotection through carbonyl oxygen chelation to
provide phenols 2 (Scheme 1). Herein, we disclose the successful
Figure 1. The blepharocalyxins.
⇑
Corresponding author.
E-mail address: bashfeld@nd.edu (B.L. Ashfeld).
Scheme 1. Selective ortho-deprotection.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.103

L. M. Fleury et al. / Tetrahedron Letters 53 (2012) 5376–5379
5377
Table 2
implementation of this approach as a general orthogonal deprotec-
Temperature and additive effect on metallationa
tion strategy for a wide spectrum of phenolic protecting groups.
In an effort to establish the optimized conditions necessary for
the ortho deprotection of benzaldehyde derivatives, we began by
ascertaining the optimal Zn(II) salt in the deprotection of bis-TBS
ether 1a (Table 1). Although, ZnI2 proved ineffective, the addition
of ZnBr2 or ZnCl2 in CH2Cl2 at room temperature for 6 h provided
ortho-desilylated phenol 2a in 78% and 77% yields, respectively
(entries 1–3). Continuing our optimization studies with ZnCl2, we
found that ethereal solvents failed to yield phenol 2a in greater
than trace quantities (entries 4–6). In contrast to CH2Cl2, CHCl3
proved ineffective, whereas Cl(CH2)2Cl showed comparable reac-
tivity, providing phenol 2a in 83% yield (entries 7 and 8). Increasing
the reaction temperature to 80 °C in Cl(CH2)2Cl led to a further
improvement in the yield of 2a (entry 9). Attempts to reduce the
amount of ZnCl2 from 2 equiv to 1.5 and 1.05 equiv led to a modest
reduction in the yield of 2a (entries 10 and 11). Performing the
reaction at 80 °C with 1.05 equiv of ZnCl2 failed to improve upon
this result (entry 12). Employing ZnBr2 and ZnI2 in Cl(CH2)2Cl gave
similar results obtained with CH2Cl2 as the solvent (entries 13 and
14). Given the relative overall ease of handling ZnCl2, we settled on
the use of this readily available Zn(II) salt for the continuation of
our study.
Entry
1
Substrate
Product
Yield (%)b
61
2
3
78
67
4c
82
With optimized conditions in hand, we next examined the scope
of ortho-selectivity observed in the desilylation of poly-TBS ether
substituted benzaldehydes 1 (Table 2). In general, good yields of
2-hydroxy benzaldehydes 2 were obtained upon treatment of 1
with ZnCl2 in Cl(CH2)2Cl regardless of the aryl substitution pattern.
Benzaldehydes 1b and 1c bearing TBS-ethers in the meta position
remained intact leading to 2-hydroxy benzaldehydes 2b and 2c in
61% and 78% yields, respectively (entries 1 and 2). Additionally,
2,3,4-tris-silyl ether 1d underwent smooth ortho selective desilyla-
tion to provide benzaldehyde 2d in 67% yield (entry 3). Interest-
ingly, 2,4,6-tris-silyloxy benzaldehyde 1e underwent mono-ortho
deprotection in 82% yield even in the presence of excess ZnCl2 (en-
try 4).
a
Reactions conducted on a 0.2 mmol scale using 1.05 equiv of ZnCl2 at 0.1 M
(see Supplementary data for details).
b
Isolated yield after chromatographic purification.
Reaction was conducted at 25 °C for 9 h.
c
vide phenol 4a in 71% yield (entry 1). Deacylation of ortho-acetate
groups also proved effective (entry 2). With exception of the
methoxyethoxymethyl (MEM) group, which provided an optimal
yield of 26% under our standard conditions, the selective ortho
deprotection of methoxy ether derived protecting groups generally
performed better in ether than chlorinated solvents (entries 3–5).
Interestingly, treatment of 2-benzyloxy benzaldehyde 3f with
ZnCl2 in DCE for 24 h at 80 °C provided the expected ortho-phenol
4f in 72% yield (entry 6), whereas the 2,4-dimethoxy benzaldehyde
3g proved unreactive (entry 7). Likewise, sulfonates 3h and 3i also
failed to undergo desulfonylation, resulting in nearly quantitative
yields of the starting benzaldehyde derivatives (entries 8 and 9).
These composite results not only demonstrate the positional selec-
tivity in the ortho deprotection of silyl, acetyl, methoxy, and benzyl
groups, but also the chemoselectivity for these groups over
sulfonyl and methyl groups.
We next turned our attention toward determining the general-
ity of this method for the selective ortho deprotection of other
commonly employed phenol protecting groups (Table 3). Removal
of the ortho-TIPS group in benzaldehyde 3a occurred readily to pro-
Table 1
Optimization of bis-silyloxy ortho-deprotectiona
Given the synthetic utility of allyl ether protecting groups, we
chose to examine the 2,4-bisallyloxy benzaldehyde 3j using our
optimized conditions (Eq. 1). Interestingly, the expected ortho-
deprotection product was not observed, but instead provided the
3-allyl arylation adduct 5 in 58% yield. The reaction likely proceeds
through an aromatic Claisen rearrangement mediated by the ZnII
Lewis acid.9 Exploitation of this unexpected reactivity for the mild
ortho functionalization of allyl aryl ethers would enable the site-
selective allylation of benzoyl derivatives, and is under current
investigation.
Entry
X
Solvent
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
I
Br
Cl
Cl
Cl
Cl
Cl
Cl
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
25
25
25
25
25
25
25
25
80
25
25
80
25
25
NR
78
77
<5
<5
<5
<5
83
91
85
88
87
79
NR
1,4-Dioxane
THF
CHCl3
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl(CH2)2Cl
Cl
Cl (1.5 equiv)
Cl (1.05 equiv)
Cl (1.05 equiv)
Br
I
a
To determine the extent to which Lewis basic functionality other
than that of aldehydes is capable of directing the ortho selective
deprotection of phenolic ethers, we next examined 2,4-bissilyloxy
Reactions conducted on
a 0.5 mmol scale using 2 equiv of ZnX2 at 0.1 M
(see Supplementary data for details).
b
Isolated yield after chromatographic purification.

5378
L. M. Fleury et al. / Tetrahedron Letters 53 (2012) 5376–5379
Table 3
Protecting group versatilitya
Entry Substrate
Product
Temp
(°C)
Yieldb
(%)
25
80
12
71
1
25
80
130
NR
<5
Based on the observed influence of solvent and temperature on
ortho deprotection efficiency, it is noteworthy that selective re-
moval of orthogonal ortho protecting groups is possible through
a judicious selection of reaction conditions. For instance, ortho-
TBS groups (DCE, 25 °C: 88%; Table 1, entry 11) are readily cleaved
in the presence of ortho-TIPS groups (DCE, 25 °C: 12%; Table 3, en-
try 1). Additionally, ortho-silyl ethers in general are reliably
cleaved in the presence of ortho-acetates, which require elevated
temperatures and long reaction times (PhCl, 130 °C: 59%; Table 3,
entry 2).8 The observation that the removal of methoxy ether
derivatives occurs more readily in Et2O led us to speculate that
exploitation of this reactivity would enable orthogonal deprotec-
tion in the presence of other phenolic ethers (Scheme 2). Thus,
treatment of ketone 9 with ZnCl2 in Et2O at 25 °C led to dealkyla-
tion of the BOM group to provide phenol 10a in 86% yield. How-
ever, attempts to orthogonally deprotect the TBS group in 9 led
to a 1:1 mixture of phenols 10a and 10b resulting from the inde-
pendent removal of both the TBS and BOM groups. As observed
with aldehyde 1e, only removal of one protecting group was ob-
served under the reaction conditions.
59c
2
3
4d
5d
6
25
25
25
80
80
26
71
55
72
NR
The results described herein indicate a mechanism that likely
involves coordination of the Lewis acidic ZnX2 with the directing
carbonyl functionality. This effectively activates the ortho-pro-
tected phenol for deprotection and appears highly dependent on
7
—
8
—
—
80
80
NR
NR
9
a
Reactions conducted on a 0.15 mmol scale using 1.05 equiv of ZnCl2 at 0.1 M
(see Supplementary data for details).
b
Isolated yield after chromatographic purification.
Reaction conducted in PhCl.
Et2O used as solvent.
c
d
Scheme 2. Orthogonal ortho-deprotection.
benzyl ketone 6a and benzoate 6b under our optimized reaction
conditions (Eq. 2). Upon treatment with ZnCl2, the corresponding
2-hydroxy benzoyl derivatives 6a and 7b were obtained in 86%
and 96% yields, respectively. Although ketones and esters under-
went ortho-selective desilylations in excellent yields, amide 6c
provided phenol 7c in diminished yield, and benzyl alcohols proved
ineffective at directing the deprotection reaction, resulting in
complete recovery of the starting benzyl alcohol. The Lewis basic
benzoyl group adjacent to the site of deprotection is crucial to the
observed reactivity, as demonstrated by the observation that
2,4-silyloxy toluene 8 failed to provide any products resulting from
desilylation, giving only a quantitative recovery of the starting
material (Eq. 3).
Scheme 3. Proposed mechanism.

L. M. Fleury et al. / Tetrahedron Letters 53 (2012) 5376–5379
5379
the nature of the protecting group.3–5,9 A likely mechanism in-
Acknowledgment
volves formation of intermediates 12a and 12b resulting from
ZnX2 coordination to the carbonyl group as either a monodentate
Lewis acid, or chelation to the adjacent phenolic oxygen in a biden-
tate fashion10 respectively upon exposure to benzoyl derivative 11
(Scheme 3). The presence of bulky ortho ethers (e.g., TBSOAr) likely
prevents bidentate chelation,11 whereas less sterically demanding
groups, such as the methoxy methyl derivatives and benzyl, enable
the formation of intermediate 12b.12 Regardless of whether ZnX2
behaves as a monodentate or bidentate Lewis acid, the enhanced
electrophilicity of the ortho ether in 12a and 12b and increased sta-
bility of the resulting phenoxide lead to the observed chemoselec-
tivity. Addition of exogenous halide from the Zn(II) salt at the more
electrophilic ether leads to liberation of the 2-hydroxy group and
formation of zinc phenoxide 13. Experiments were performed
using anhydrous ZnCl2 weighed in a glove box for accuracy and
reproducibility. However, it is noteworthy that comparable results
were obtained with ZnCl2 exposed to air without the strict exclu-
sion of water or oxygen. These observations suggest that although
adventitious water may aid in cleavage of the ortho protecting
group, a more likely mechanism involves phenol displacement by
residual halogen. Subsequent protonation of zinc phenoxide 13
upon aqueous workup provides the observed phenol 14.
The authors thank the University of Notre Dame for financial
support of this research.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
07.103.
References and notes
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In conclusion, the method described herein enables the selec-
tive ortho-deprotection of phenol derivatives in the presence of
other hydroxy groups bearing the same protecting group. This
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ZnCl2 or ZnBr2, and avoids the more conventional harshly Brønsted
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