The use of organophotoacids for deprotection reactions in organic synthesis

Article abstract of DOI:10.1016/j.tetlet.2006.09.028

o-Hydroxymethylphenol was found to be an effective and environmentally benign organophotoacid. An increased acidity in the excited state, induced by photoirradiation, was sufficient for the deprotection of several protecting groups which are widely used in organic synthesis.

Full text of DOI:10.1016/j.tetlet.2006.09.028

Tetrahedron Letters 47 (2006) 8125–8128
The use of organophotoacids for deprotection reactions
in organic synthesis
Yuichi Nishikubo, Shinya Kanzaki, Shuichi Matsumura and Kazunobu Toshima*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
Received 25 August 2006; revised 5 September 2006; accepted 7 September 2006
Available online 28 September 2006
Abstract—o-Hydroxymethylphenol was found to be an effective and environmentally benign organophotoacid. An increased acidity
in the excited state, induced by photoirradiation, was sufficient for the deprotection of several protecting groups which are widely
used in organic synthesis.
Ó 2006 Elsevier Ltd. All rights reserved.
Certain molecules show interesting properties in their
excited states with respect to acidity. Many hydroxy-
arenes (ArOH) exhibit proton transfer in competition
with excited-state decay. Hydroxyarenes have fluores-
cent conjugate bases with nonbonding oxygen-centered
molecular orbitals and excited states with charge distri-
bution at sites distal from oxygen. This reduces the
hν
OH
R-O-X
R-O-H
X=protecting group
(silyl, trityl, THP and IP)
HO
/
EtOH-H O
2
Figure 1. Deprotection reaction using organophotoacid under photo-
basicity of the excited-state anion, thus increasing the
1
irradiation.
acidity of the conjugate acid. For example, the pK
a
value of 2-naphthol in the ground state is 9.5, while that
2
in the excited state is 3.1. Molecules with these proper-
(
Bn) protecting group, using several organophotoacids,
such as 2-naphthol (2), o-, m-, p-hydroxymethylphenols
3–5), and m-methoxyphenol (6), in MeCN, under irra-
ties are called ‘super photoacids’. Although a number of
synthetic organic reactions using protic (Brønsted) acids
have been reported, the use of such organophotoacids in
organic synthesis has been investigated only to a minor
extent. In this context, we have pursued the aim of
utilizing organophotoacids in the development of envi-
ronmentally benign synthetic organic reactions. In this
letter, we report for the first time the effective and envi-
ronmentally benign use of organophotoacids for the
deprotection reactions of several protecting groups
which are widely used in organic synthesis (Fig. 1).3
(
diation from a UV lamp. TES ether is widely used as
a protecting group in organic synthesis and is known
to be labile under acidic conditions, while Bn ethers
are stable under similar conditions. We chose a Blak-
ray, 100 W lamp irradiating at 365 nm, because radia-
tion at this long wavelength is not harmful to humans.
The strength of the light, which was easily controlled
by varying the power level of the lamp and the distance
between the lamp and the reaction mixture, was mea-
3
4
5
sured using an actinometer. The results of the deprotec-
In our initial attempts to screen for a suitable organo-
photoacid for deprotection reactions, we carried out
the deprotection reactions of the triethylsilyl (TES)
group from substrate 1, which also possesses a benzyl
tion reactions carried out under various conditions are
summarized in Table 1. It was found that deprotection
of the TES group in 1 using organophotoacids 2 and 3
proceeded smoothly to produce alcohol 7 in a good yield
(
Table 1, entries 1 and 2). Other organophotoacids 4–6
did not work well due to their low solubility in the sol-
vent. However, 2 was found to undergo a significant
decomposition during the reaction; it was therefore con-
cluded that 3 was superior to 2 as an organophotoacid
Keywords: Organophotocatalyst; Organophotoacid; Deprotection;
Protecting group; Green chemistry.
*
Corresponding author. Tel./fax: +81 45 566 1576; e-mail:
toshima@applc.keio.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.028

8126
Y. Nishikubo et al. / Tetrahedron Letters 47 (2006) 8125–8128
Table 1. Deprotection of TES group in 1 using organophotoacids
Organophotoacid
hν
(365 nm, 16 mW/cm2)
OTES
OH
BnO
BnO
Solvent (0.1 M)
1
7
10 h
Entry
1
Organophotoacid
OH
Organophotoacid (equiv)
Solvent
7: Yield (%)
10
MeCN
MeCN
MeCN
71
2
OH OH
2
3
10
10
70
0
3
OH
OH
4
HO
4
5
10
10
MeCN
MeCN
0
0
OH
5
OH
OMe
6
6
7
8
9
3
3
3
3
3
10
5
3
1
0
EtOH–H
EtOH–H
EtOH–H
EtOH–H
EtOH–H
2
O (10:1)
2
O (10:1)
2
O (10:1)
2
O (10:1)
2
O (10:1)
94
93
95
61
0
1
0
catalyst. Furthermore, a mixture of EtOH and H O
did not occur without photoirradiation, but took place
smoothly under photoirradiation (Table 2, entry 5 vs
entry 6). Although partial deprotection of the TES and
DEIPS groups was observed without photoirradiation
(Table 2, entries 2 and 4), it was clear that the efficiency
of these reactions was much higher under photoirradia-
tion (Table 2, entry 1 vs entry 2, and entry 3 vs entry 4).
These results clearly demonstrate the usefulness of
organophotoacid 3 together with photoirradiation in
these deprotection reactions. Also, these phenomena
indicated that organophotoacid 3 was in the excited
state and the acidity significantly increased under photo-
irradiation as shown in Figure 2. It was confirmed that a
stronger light was required for the deprotection of more
stable silyl groups, and, in addition, that the most stable
silyl groups under acidic conditions, TIPS and TPS,
were even less active under the reaction conditions used
(data not shown). Therefore, we investigated chemose-
lective deprotection reactions using several combina-
tions of different silyl groups. As summarized in
Scheme 1, it was found that, for the combinations
TBS/TES, TIPS/TES, and TPS/TBS, chemoselective
deprotection proceeded effectively in the presence of 3
under the appropriate photoirradiation conditions to
give the mono-alcohols in good to excellent yields.
2
(
10:1) was found to be a more effective solvent than
MeCN for the reaction of 1 in the presence of 3, result-
ing in a significantly increased yield of 7 (Table 1, entry
6
). In this case, it was also confirmed that the silylated
derivatives of 3 produced during the reaction were effec-
tively converted into 3 by hydrolysis, with the result that
the unchanged 3 was recovered in a >90% yield after the
reaction was completed. In addition, it was found that
3
equiv of 3 was a sufficient amount for performing
the deprotection reaction satisfactorily with respect to
both the chemical yield and the reaction time (Table 1,
entry 8).
With these preliminary results in hand, we examined the
deprotection reactions of several other silyl groups, such
as diethylisopropylsilyl (DEIPS), t-butyldimethylsilyl
(
(
TBS), triisopropylsilyl (TIPS) and t-butyldiphenylsilyl
TPS), as well as the TES group, using organophoto-
3
acid 3 under UV irradiation. The results are shown in
Table 2. At this stage, we considered the temperature
effect due to photoirradiation, and compared the results
obtained using the UV lamp with those obtained with-
out UV at the same temperature. It was found that
the TES group as well as the DEIPS and TBS groups
underwent effective deprotection in the presence of 3
under photoirradiation (Table 2, entries 3 and 5). We
confirmed that, in the case of TBS group, deprotection
Our attention next turned to the reusability of organo-
photoacid 3. After the recovery of unchanged 3 in a

Y. Nishikubo et al. / Tetrahedron Letters 47 (2006) 8125–8128
8127
Table 2. Deprotection of various silyl groups using 3 under photoirradiation
(3 equiv.)
(365 nm)
3
h
ν
OR
OH
BnO
BnO
EtOH-H O (10:1, 0.1 M)
2
1, 8 and 9
7
10 h
Entry
R
UV strength
Temperature (°C)
7: Yield (%)
3: Recovery yield (%)
2
(
mW/cm )
1
2
3
4
5
6
TES: 1
TES: 1
DEIPS: 8
DEIPS: 8
TBS: 9
16
0
27
0
32
0
48
48
56
56
64
64
95
46
96
11
95
0
93
95
93
94
92
97
TBS: 9
-
-
OH OH
O
OH
+
OH OH
O
OH
*
+
h
ν
*
H+
+ H+
-hν
3
3*
Figure 2. Deprotection reaction profile using 3 under photoirradiation.
1
0
3
(3 equiv.),
h
ν
(365 nm, 16 mW/cm2)
OH
TBSO
EtOH-H O (10:1, 0.1 M), 10 h
2
13 (85%)
OR2
11
(3 equiv.), hν
(365 nm, 27 mW/cm2)
1
R O
3
1
2
OH
OH
1
1
1
0: R =TBS, R =TES
1: R =TIPS, R =TES
2: R =TPS, R =TBS
TIPSO
TPSO
1
2
EtOH-H O (10:1, 0.1 M), 6 h
2
1
4 (91%)
1
2
1
2
2
3
(3 equiv.),
hν
(365 nm, 32 mW/cm )
15 (95%)
EtOH-H O (10:1, 0.1 M), 10 h
2
Scheme 1. Chemoselective deprotection of silyl groups using 3 under photoirradiation.
>
90% yield (Table 2) via column chromatography con-
yl (THP), and isopropylidene (IP) groups, all of which
may be removed under acidic conditions. The results
3
comitant with purification of the product, it was found
that the recovered 3 could be reused many times without
any loss of efficiency. Furthermore, neither neutraliza-
tion of the reaction mixture nor extraction of the prod-
uct was needed after the reaction was completed,
because the removal of UV light rendered the reaction
mixture almost neutral (the pKa values of 3 in the
ground state and the excited state are 9.9 and 2.9,
respectively). The work-up for the reaction involved
only evaporation of the solvent, a mixture of EtOH
and H O, which was also found to be reusable. Overall,
the deprotection reaction exhibits several environmen-
tally benign features: (1) non-harmful UV light
are depicted in Table 3. All the deprotection reactions
proceeded effectively, to give the corresponding alcohols
in good to excellent yields. For the THP and IP groups,
a longer reaction time was needed to obtain high yields
of the corresponding alcohols (Table 3, entries 5 and 7).
Furthermore, the efficiency of the reaction under photo-
irradiation was again confirmed by comparing the
results with those obtained only under heating condi-
tions, without photoirradiation. Moreover, in all cases,
organophotoacid 3 was recovered in a >90% yield after
completion of the reaction.
2
2
(
365 nm) is used; (2) the solvent (EtOH–H O) is non-
The typical experimental protocol for the deprotection
2
toxic; (3) catalyst 3 is recoverable and may be reused
many times; (4) the work-up involves only evaporation
of the solvent, with the result that no waste is produced.
of the silyl ether in 1: To a stirred solution of 1
(0.1 mmol) in EtOH–H O (10:1, 0.1 M) was added o-
2
hydroxymethylphenol (3) (0.3 mmol). After stirring for
1
0 h under the photoirradiation using a UV lamp
2
We then applied this novel deprotection method to
deprotection reactions of other protecting groups, such
as dimethoxytrityl (DMTr), trityl (Tr), tetrahydropyran-
(365 nm, 16 mW/cm ), the mixture was concentrated
in vacuo. The purification of the residue by flash column
chromatography (silica gel, 8:1 to 1:1 hexane–ethyl

8128
Y. Nishikubo et al. / Tetrahedron Letters 47 (2006) 8125–8128
Table 3. Deprotection of various protecting groups using 3 under photoirradiation
3
h
(3 equiv.)
ν (365 nm)
OR
OH
BnO
BnO
EtOH-H O (10:1, 0.1 M)
2
1
6-18
7
2
Entry
R
UV strength (mW/cm )
Temperature (°C)
Time (h)
7: Yield (%)
3: Recovery yield (%)
1
2
3
4
5
6
DMTr: 16
DMTr: 16
Tr: 17
Tr: 17
THP: 18
THP: 18
16
0
32
0
32
0
48
48
64
64
64
64
10
10
10
10
24
24
94
0
82
29
80
22
94
97
96
92
93
94
OH
O
7
8
32
0
64
64
24
24
95
94
OH
O
BnO
BnO
1
9
20: 91
20: 19
19
acetate) gave alcohol 7 in a 95% yield, and 3 was recov-
ered in a 93% yield.
gate Chemistry’ and for Scientific Research on Priority
Areas 18032068 from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan.
4
,5
In summary, we have developed a novel deprotection
method, effective for several protecting groups, using
an organophotoacid under photoirradiation. The reac-
tion is highly efficient and environmentally benign. As
protection–deprotection reactions are an unavoidable
and indispensable step in organic synthesis, this useful
method should find wide applications in both academia
and industry. The development of several different types
of organophotocatalyst, including organophotoacids,
and their application in environmentally benign organic
synthesis is now under investigation in our laboratories.
References and notes
1. For a review of organophotoacids, see: Tolbert, L. M.;
Solntsev, K. M. Acc. Chem. Res. 2002, 35, 19.
. Bartok, W.; Hartman, R.; Lucchesi, P. Photochem. Photo-
biol. 1965, 4, 499.
. For reviews of protecting groups, see: (a) Greene, T. W.;
Wuts, P. G. Protective Groups in Organic Synthesis; John
Wiley & Sons: New York, 1999; (b) Kocienski, P. J.
Protecting Groups; Thieme: Stuttgart, 1994.
2
3
4
5
. A Blak-ray (B-100A) purchased from UVP, Inc. was used.
. A radiometer sensor (UVX-36) purchased from UVP, Inc.
was used. UV light at 16 mW/cm was obtained using one
Acknowledgement
2
lamp placed at 1 cm from the reaction mixture. UV light at
27 and 32 mW/cm was obtained using two lamps placed at
4 cm and 1 cm, respectively, from the reaction mixture.
2
This research was supported in part by a Grant-in-Aid
for the 21st Century COE Program ‘KEIO Life Conju-