A simple deprotection of triflate esters of phenol derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.06.104

Efficient conversion of aryl triflates into the corresponding phenols has been accomplished with Et₄NOH. In contrast to other cleavage reactions, such functional groups as nitro, ketone, halogen, amide and sulfonamide groups were intact under the reaction conditions. This mild removal of the trifluoromethanesulfonyl group would serve a new protecting group of phenols.

Full text of DOI:10.1016/j.tetlet.2004.06.104

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6317–6320
A simple deprotection of triflate esters of phenol derivatives
Tadaaki Ohgiya and Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku,
Yokohama 223-8522, Japan
Received 15 April 2004; revised 14 June 2004; accepted 18 June 2004
Abstract—Efficient conversion of aryl triflates into the corresponding phenols has been accomplished with Et4NOH. In contrast to
other cleavage reactions, such functional groups as nitro, ketone, halogen, amide and sulfonamide groups were intact under the
reaction conditions. This mild removal of the trifluoromethanesulfonyl group would serve a new protecting group of phenols.
Ó 2004 Elsevier Ltd. All rights reserved.
The trifluoromethanesulfonyl group, a functional group
possessing powerful electron-withdrawing effect, is
widely used as an excellent leaving group rather than
protecting group.1 Aryl sulfonates such as aryl mesy-
lates are highly stable under a wide range of reaction
conditions, as compared with the corresponding alkyl
sulfonates such as alkyl mesylates. Therefore, sulfo-
nate esters have been adopted as protecting groups for
the phenol system.2,3 In addition, it is expected that
the nucleophilic reactivity of the phenol system might
effectively be decreased by adopting trifluoro-
methanesulfonyl group as a protecting group. As part
of our ongoing synthetic studies using phenols as sub-
strates,4–7 we required cleavage of aryl triflates. Several
examples of the cleavage reactions were found: solvoly-
sis of aryl triflate in trifluoroethanol, followed by zinc
reduction gave the corresponding phenol.8 Schio investi-
gated the reactivity of 4-cyanophenyl triflates towards
various amines; the aryl–sulfonate bond was cleaved
prior to the substitution reaction in the presence of oc-
tylamine.9 However, the generality of these cleavage
reactions has not been confirmed. On the other hand,
Katzenellenbogen succeeded in cleavage of aryl triflates
under strong reductive conditions with LiAlH4 in good
yield.10,11 Interestingly, cleavage of aryl triflate with n-
Bu4NF was reported to give the corresponding phenol
in moderate yield.12 Cleavage of the aryl sulfonate ester
has generally required the following conditions: reduc-
tion with Na in liquid NH3,13,14 Na-naphthanilide,15,16
Mg in methanol,17,18 hydrogenolysis with Raney-
Nickel19 and hydrolysis with alkaline metal hydroxide.3
In addition to aryl triflates, tosylates and mesylates,
other various functional groups might be susceptible
under these conditions. Relatively mild conditions using
KF on Al2O3 with a microwave were reported by Yadav
and co-workers,20 although the siloxy ether was sponta-
neously removed. We describe herein the selective cleav-
age condition of aryl triflates by Et4NOH, which would
be unprecedentedly simple and efficient methods.
As summarized in Table 1, the cleavage reaction of aryl
triflates was performed using Et4NOH in aqueous media
(conditions A and B).
General procedure: To a solution of 1h (entry 8; 271mg,
1mmol) in dioxane (3mL) was added 10% aqueous
Et4NOH solution (3.0g, 2mmol) at ambient tempera-
ture; the mixture was stirred for 1h. The reaction mix-
ture was diluted with CHCl3, washed with 1M aq
HCl, water and brine. The organic layer was dried
(Na2SO4), and concentrated in vacuo. The residue was
purified by preparative TLC to yield 2h (138mg, 99%).
The data indicated that the cleavage reactions proceeded
in excellent yields. Interestingly, no cleavage of methyl
esters was observed under our reaction conditions (en-
tries 1 and 2), although 1c underwent selective hydroly-
sis of the ester moiety.21 The well-known cleavage
conditions of aryl sulfonates using a fluoride anion12,20
resulted in undesired cleavage of siloxy ethers and sul-
fonamides. We also examined the cleavage reactions
using n-Bu4NF (conditions C and D), as contrastive
Keywords: Protecting group; Aryl sulfonates; Trifluoromethanesulfo-
nyl group; Et4NOH.
*
Corresponding author. Tel./fax: +81-45-566-1717; e-mail: nisiyama@
chem.keio.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.104

6318
T. Ohgiya, S. Nishiyama / Tetrahedron Letters 45 (2004) 6317–6320
Table 1. Cleavage reaction of aryl trifluoromethanesulfonates
Entry
1
Substrates
Products
Methoda
Temp
Time
Yield (%)
COOMe
COOMe
1a:
2a:
A
C
rt
rt
1h
1h
98
99
TfO
HO
COOMe
COOMe
2
1b:
2b:
A
rt
1h
95
TfO
COOMe
COOMe
HO
COOMe
COOMe
A
C
rt
rt
1h
3days
Traceb
98
3
4
1c:
2c:
TfO
HO
NHAc
NHAc
1d:
2d:
A
rt
1h
87
Tfo
HO
OTf
OH
5
6
7
1e:
2e:
B
50°C
1h
1h
3h
99
99
97
Me
NTf2
I
Me
NHTf
I
1f:
2f:
A
A
rt
TfO
HO
OTPS
OTPS
1g:
2g:
rt
TfO
HO
NO2
NO2
A
C
rt
rt
1h
1h
99
97
8
9
1h:
2h:
HO
TfO
1i:
2i:
A
A
A
rt
rt
rt
1h
1h
1h
99
97
99
TfO
NO2
O
HO
NO2
O
10
11
1j:
2j:
TfO
HO
OTf
OH
1k:
2k:
2l:
N
N
OMe
OMe
A
D
rt
rt
1h
5days
99
70c
12
13
1l:
TfO
HO
MeO
MeO
HO
A
A
D
rt
5h
3h
84
95
45d
1m:
2m:
60°C
rt
TfO
5days
OMe
OMe
a Method A: 2equiv of Et4NOH was used in aq dioxane. Method B: 10equiv of Et4NOH was used in aq dioxane. Method C: 1equiv of n-Bu4NF was
used in THF. Method D: 2equiv of n-Bu4NF was used in THF.
b Hydrolysis of methyl ester group was mainly observed.
c The starting material was recovered in 29% yield.
d The starting material was recovered in 53% yield.

T. Ohgiya, S. Nishiyama / Tetrahedron Letters 45 (2004) 6317–6320
Table 2. Cleavage of sulfonates using tetraethylammonium hydroxide
6319
Entrya
Substrates
Products
Temp
Time
24h
Yield (%)
NO2
NO2
NO2
NO2
1
rt
92
97
TsO
HO
2
3
rt
rt
3h
MsO
MeO
HO
MeO
6days
37b
MsO
HO
OMe
OMe
a 2equiv of Et4NOH was used in aqueous dioxane.
bThe starting material was recovered in 39% yield.
studies. Aryl compounds, 1a and 1h, having electron-
withdrawing moieties, such as a methoxycarbonyl and
nitro groups (entries 1 and 8), were susceptible to the
n-Bu4NF conditions to give the corresponding phenols,
2a and 2h. Despite a long reaction time, 1c (entry 3) pro-
vide 2c in quantitative yield, whereas 1l and 1m (entries
12 and 13) possessing electron-donating moieties exhib-
ited low reactivity, and the starting materials were
recovered in 29% and 53% yields, respectively. In con-
trast, our Et4NOH-method did not affect the functional
groups, such as nitro, ketone, halogen, amide, siloxy
ether and sulfonamide (entries 4–10). Cleavage of the
quinoline compound 1k was also smoothly accom-
plished (entry 11). The substrate 1l, possessing a meth-
oxy group as an electron-donating moiety (entry 12),
underwent smooth deprotection of an aryl tri-
fluoromethanesulfonyl group even at ambient tempera-
ture, although the n-Bu4NF method required a long
reaction time. In the case of the 2,6-disubstituted phenol
derivative 1m (entry 13) possessing not only an electron-
donating substituent in the aromatic ring, but also steric
hindrance against the trifluoromethanesulfony group,
the reaction quantitatively proceeded by using the ele-
vated temperature (60°C) to give 2m. To compare with
our method, we examined hydrolysis using NaOH,
which has been reported to provide a similar cleav-
age.3c,3d Upon using NaOH (2equivmol) in MeOH-di-
oxane at ambient temperature, 1b, 1h, 1j afforded 2b
(72%), 2h (87%) and 2j (81%), along with their phenol
methyl ether derivatives in 9%, 9% and 13% yields,
which might be produced by the attack of MeOTf in situ
generated. In the case of 1j, a base-catalyzed coupling at
the methyl ketone moieties was observed to give the cor-
responding dimmer in ca. 2% yield. These unexpected
reactions were not observed under the Et4NOH condi-
tions (entries 2, 8 and 10). When NaOH (2equivmol)
in aq dioxane at ambient temperature, was used to avoid
production of the phenol methyl ethers, yields of the
corresponding phenols were slightly lowered (2h, 87%;
2j, 87%) with the exception of 1b, which provide 2b in
32% yield, owing to hydrolysis of the methyl esters. In
contrast, treatment under the Et4NOH in aqueous diox-
ane conditions produced 2b in 95% yield.
Other aryl sulfonates, such as aryl tosylates and aryl
mesylates, were hydrolyzed in a similar manner to those
of triflates, although they required longer-reaction time
(Table 2). Especially, in entry 3, the corresponding phe-
nol was produced in low yield, owing to high electron
density around the sulfonate moiety. Based on these
observations, facility of the deprotection reaction would
be in the following order: aryl triflates>aryl mesy-
lates>aryl tosylates.
In conclusion, a new procedure to cleave aryl sulfo-
nates under mild conditions was demonstrated. In con-
trast to such usual methods as reduction, hydrolysis
and use of fluoride anion, our method was applicable
to selective cleavage of aryl triflates. Other functional
groups such as nitro, ketone, halogen, amide, siloxy
ether and sulfonamide groups were intact under the
reaction conditions.
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