Gold-catalyzed transesterification of ortho-alkynylbenzoic acid esters: a novel protecting group for alcohols and phenols

Article abstract of DOI:10.1016/j.tetlet.2008.09.146

Treatment of ortho-alkynylbenzoic acid esters with excess amounts of EtOH in the presence of a gold catalyst results in the liberation of alcohols or phenols in high yields under mild conditions. The protection of alcohols and phenols proceeds smoothly by use of ortho-alkynylbenzoic acid or ortho-iodobenzoyl chloride. Highly chemoselective deprotections are described.

Full text of DOI:10.1016/j.tetlet.2008.09.146

Tetrahedron Letters 49 (2008) 7046–7049
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Tetrahedron Letters
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Gold-catalyzed transesterification of ortho-alkynylbenzoic acid
esters: a novel protecting group for alcohols and phenols
Kazuteru Umetsu a, Naoki Asao a,b,
*
a Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
b Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2008
Revised 21 September 2008
Accepted 25 September 2008
Available online 30 September 2008
Treatment of ortho-alkynylbenzoic acid esters with excess amounts of EtOH in the presence of a gold
catalyst results in the liberation of alcohols or phenols in high yields under mild conditions. The protec-
tion of alcohols and phenols proceeds smoothly by use of ortho-alkynylbenzoic acid or ortho-iodobenzoyl
chloride. Highly chemoselective deprotections are described.
Ó 2008 Elsevier Ltd. All rights reserved.
Transesterification under acidic conditions is one of the most
fundamental transformations in organic synthesis not only for
preparation of new ester compounds but also for release of alco-
hols and phenols as a deprotection method.1,2 A number of cata-
lysts have been developed for promoting the deprotection so far.
However, such conditions sometimes have encountered limita-
tions on its applications for multifunctional substrates having
acid-labile groups. While some catalysts have been developed for
promoting the transesterification under neutral conditions, high
temperatures were generally needed.3 In this Letter, we describe
a gold-catalyzed transesterification of ortho-alkynylbenzoic acid
esters with EtOH under mild conditions, which can be used as a no-
vel deprotection process of ester-protected alcohols and phenols
(Scheme 1). Moreover, it provides an effective discriminative
deprotection approach over other protected alcohols.4
Recently, we have reported that ortho-alkynylbenzoic acid alkyl
ester 1 is a masked electrophile, and it behaves as an effective
alkylating agent for etherification and Friedel–Crafts alkylation in
combination with a gold catalyst.5 The process would proceed
through the indirect activation of the ester moiety of 1 through
the formation of zwitterionic intermediate 5 (vide infra) by the
alkynophilic gold catalyst.6 To expand the synthetic utility of this
activation method of ester functionalities, we examined the transe-
sterification of 1 as a new deprotection method of ester-protected
alcohols, and the results are shown in Table 1. When the ester 1a
(R = PhCH2CH2, R0 = Bu) was treated with a mixture of Ph3PAuCl
(1 mol %) and AgOTf (1 mol %) at rt in a 1:1 mixture of benzene
and EtOH as solvent, the desired phenethylalcohol 2a was obtained
in 91% yield in 20 min (entry 1). On the other hand, the reaction of
phenethyl benzoate, having no alkynyl group, did not take place at
all under the same reaction conditions, and the starting material
was recovered nearly quantitatively even after 1 d. These results
clearly indicated that the alkynyl group of the ester 1 plays a cru-
cial role in this reaction. Other silver additives, such as AgBF4 and
AgSbF6, were less effective. Without silver catalysts, no reaction
took place. The chemical yield of 2a was increased up to 100% by
using 1c, having ortho-methoxyphenyl (o-anisyl) group at the ter-
minus of the alkynyl moiety (entry 3). Besides benzene, other sol-
vents such as toluene, hexane, CH2Cl2, and THF are suitable
although longer reaction times were needed for completion (en-
tries 4–7). The reaction also proceeded smoothly, in ethanol with-
out any co-solvents (entry 8). To know the generality of the current
protocol, we conducted the reaction with other substrates. Depro-
tection of dodecanol from 1d proceeded quantitatively (entry 9).
Benzyl alcohol was obtained from 1e in 83% yield together with
benzyl ethyl ether in 13% yield (entry 10). The reactions with cis-
and trans-4-phenyl-cyclohexyl esters 1f–g proceeded smoothly
and the corresponding cyclohexanol derivatives were obtained
nearly quantitatively in both cases (entries 11–12). Deprotections
are conducted not only with alkyl esters but also with aryl esters
1h–j, and the corresponding phenol analogs 2f–h were obtained
in high yields (entries 13–15). On the other hand, the present pro-
tocol is not suitable for deprotection of esters derived from cin-
namyl alcohol and 1-phenylcyclohexanol due to the formation of
the corresponding ethyl ethers in high yields.5 In the current cata-
lyst system, TfOH might be produced during the reaction. How-
ever, deprotection of 1c did not proceed at all with 10 mol % of
O
R
Au cat.
EtOH
O
ROH
2
R`
1
Scheme 1.
* Corresponding author. Tel.: +81 22 795 3898; fax: +81 22 795 3899.
E-mail address: asao@m.tains.tohoku.ac.jp (N. Asao).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.146

K. Umetsu, N. Asao / Tetrahedron Letters 49 (2008) 7046–7049
7047
Table 1
Gold-catalyzed deprotection of alcohols and phenolsa
O
R
1 mol % Ph3PAuCl
O
ROH
1 mol % AgOTf
EtOH-solvent, rt
2
R'
1
Entry
1
R
R0
Solvent
Time (h)
2
Yieldb (%)
1
2
3
4
5
1a
1b
1c
1c
1c
1c
1c
1c
1d
1e
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
CH3(CH2)11
PhCH2
Bu
Ph
C6H6–EtOH
C6H6–EtOH
C6H6–EtOH
Toluene–EtOH
Hexane–EtOH
CH2Cl2–EtOH
THF–EtOH
EtOH
0.3
0.3
0.3
0.8
0.8
1.2
1.5
0.5
1.0
1.0
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
91
92
100
96
100
100
100
100
100
83e
o-Anisylc
o-Anisyl
o-Anisyl
o-Anisyl
o-Anisyl
o-Anisyl
o-Anisyl
o-Anisyl
6
7
8d
9
C6H6–EtOH
C6H6–EtOH
10
11
12
1f
o-Anisyl
o-Anisyl
C6H6–EtOH
C6H6–EtOH
1.0
0.5
2d
2e
99
99
Ph
Ph
1g
13
14
15
1h
1i
1j
2-Naphthyl
p-NO2C6H4
p-MeOC6H4
o-Anisyl
o-Anisyl
o-Anisyl
C6H6–EtOH
C6H6–EtOH
C6H6–EtOH
0.5
0.5
0.5
2f
2g
2h
99
98
99
a
The reaction was carried out in the presence of 1 mol % of catalyst at rt in a 1:1 mixture of the indicated solvent and EtOH unless otherwise noted.
Isolated yield.
o-Anisyl = ortho-methoxyphenyl.
The reaction was conducted in EtOH only.
Benzyl ethyl ether was obtained in 13% yield.
b
c
d
e
TfOH even after 1 d. Besides alcohols 2, ortho-alkynylbenzoic acid
ethyl esters 10 were formed together with a small amount of iso-
coumarins 3 in each reaction in Table 1.7
Et
R
O
O
On the basis of these results, a plausible mechanism is illus-
trated in Scheme 2.8 The coordination of the triple bond of 1 to
the gold catalyst enhances the electrophilicity of alkyne, and the
subsequent nucleophilic attack of the carbonyl oxygen to the elec-
tron-deficient alkyne forms the intermediate 5 through 4.9,10 Then,
the nucleophilic attack of EtOH to 5 gives ortho-ester type interme-
diate 6. Elimination of ROH 2 occurs through 7 to afford 50. The gold
catalyst is reproduced by the formation of transesterification prod-
uct 10 via retro-cyclization of 50. Obviously, all processes in this
scheme are reversible, but the deprotection reaction proceeds
due to the existence of a large amount of EtOH. Previously, we re-
ported the gold-catalyzed etherification with 1 as a masked elec-
trophile.5 In that case, even if intermediate 50 would be formed
from 5, it would be changed back to 5 reversibly because the
amount of alcohol was small and finally, etherification products
would be obtained. On the other hand, even with excess amounts
of EtOH, etherification products were obtained from several esters
derived from benzyl, cinnamyl, and 1-phenylcyclohexyl alcohols as
mentioned before. In these cases, EtOH would attack R group of 5
preferably because R–O bond would be significantly weakened
due to the high stability of the resulting carbocation intermediates.
The formation of 3 might be accounted for by the hydrolysis of the
intermediate 5 with small amounts of water, which might exist in
the reaction medium.
O
O
R
'
1'
R'
1
R
M
Et
O
O
O
O
'
R
R'
M
5'
4
M
ROH
2
H
O
R
O
M
R
O
Et
O
O
R'
R'
5
H
7
M
R
O
O
Et
R'
O
H2O
EtOH
O
M
6
We next investigated the selective deprotection using 1c and
other protected alcohols 8, and the results are summarized in Table
2. Treatment of 1:1 mixture of 1c and benzyl acetate 8a with the
gold catalyst resulted in the chemoselective deprotection of 1c
over 8a, and phenethyl alcohol 2a was produced quantitatively
O
R'
3
Scheme 2.

7048
K. Umetsu, N. Asao / Tetrahedron Letters 49 (2008) 7046–7049
Table 2
Table 3
Selective deprotection between 1c and 8a
Protection of alcohols and phenols with 9
O
CO2H
CO2R
1. (COCl)2
Ph
O
R
+
2. ROH (2), Py
O
Ph
R'
R'
9
1
8
o-Anisyl
1c
Ph
Yielda (%)
+
R0
ROH (2)
1
HO
Ph
Entry
9
HO
1
2
3
9a
9b
9c
Bu
Ph
o-Anisyl
PhCH2CH2OH (2a)
PhCH2CH2OH (2a)
PhCH2CH2OH (2a)
1a
1b
1c
77
80
81
2a
2c
Yieldb (%)
Entry
8
R
Conditions
OH
2a
2c
4
5
9c
9c
o-Anisyl
o-Anisyl
1f
85
93
1
2
3
4
5
6
8a
8b
8c
8c
8d
8d
Ac
Bz
TBS
TBS
THP
THP
Ph3PAuCl–AgOTfc
Ph3PAuCl–AgOTfc
Ph3PAuCl–AgOTfc
TBAFe
100
100
100
0d
0d
0d
99
0d
99
(2d)
Ph
Ph
OH
(2e)
0f
1g
Ph3PAuCl–AgOTfc
TsOHg
100
0f
6
7
8
9c
9c
9c
o-Anisyl
o-Anisyl
o-Anisyl
2-Naphthol (2f)
p-NO2C6H4OH (2g)
p-MeOC6H4OH (2h)
1h
1i
1j
86
83
85
a
The reaction was carried out with 1:1 mixture of 1c and 8.
Isolated yield.
The reaction was carried out with a mixture of Ph3PAuCl (1 mol %) and AgOTf
b
c
a
(1 mol %) in a 1:1 mixture of benzene and EtOH at rt within 1 h.
Isolated yield.
d
8 was recovered, quantitatively.
The reaction was carried out with TBAF (1.1 equiv) in THF at rt for 1 h.
1c was recovered quantitatively.
e
f
g
The reaction was carried out with TsOH (10 mol %) in a mixture of MeOH and
COCl
I
O
I
THF at rt for 1 h.
Ph
O
OH
Ph
97%
2a
10a
together with the recovered 8a (entry 1). The selective deprotec-
tion of 1c was also observed against benzyl benzoate 8b (entry
2). In the case of a mixture of 1c and TBDMS ether 8c, each of them
was deprotected selectively by use of the gold catalyst and
1.1 equiv of TBAF, respectively (entries 3 and 4). Analogously,
selective deprotections of 1c and THP ether 8d were achieved with
the gold catalyst and a 10 mol % of TsOH, respectively (entries 5
and 6).
1. o-MeOC6H4CCH, Pd cat.
2. Ph3PAuCl-AgOTf cat., EtOH
96%
Scheme 3.
The protection of alcohols and phenols can be achieved easily
by the esterification with ortho-alkynylbenzoic acid 9, using oxalyl
chloride under the standard conditions. Irrespective of alcohols
and phenols, the protection proceeded smoothly, and the corre-
sponding esters 1 were obtained in good to high yields (Table 3).
It is worth mentioning that ortho-halo-benzoyl chloride is an
alternative protecting agent for the present protocol. Indeed, the
protection of 2a with commercially available ortho-iodobenzoyl
chloride gave 10a in 97% yield. Deprotection of 10a can be con-
ducted by the conversion of iodo group to the alkynyl group by
the Sonogashira coupling, followed by the gold-catalyzed transe-
sterification; 2a is obtained in 96% overall yield from 10a as shown
in Scheme 3. We also examined the same protocol with chiral (S)-
2-octanol 2i. Successive protection and deprotection reaction
afforded (S)-2i via the formation of 10b without loss of enantio-
meric purity, which was determined from its benzoate deriva-
tive 2j by HPLC analysis with a Daicel Chiralpak AD-H column
(Scheme 4).
In conclusion, ortho-alkynyl benzoyl moiety was found to be
useful protecting group for alcohols and phenols due to its easy
protection and deprotection procedure. The alkynophilicity of the
gold catalyst enables the chemoselective deprotections over other
protected alcohols, such as acetate, benzoate, TBS ether, and THP
ether. The protection can be conducted easily by esterification with
ortho-alkynylbenzoic acid 9. Alternatively, ortho-iodobenzoyl chlo-
ride can be used as a protecting agent. The resulting esters can be
cleaved by successive alkynylation and gold-catalyzed transesteri-
fication. Further, studies to extend the scope of synthetic utility are
in progress in our laboratory.
O
I
CH3
C6H13
CH3
CH3
C6H13
O
RO
C6H13
RO
92%
87%
10b
2i: R = H
2i
2j: R = Bz 97% ee
2j 97% ee
Scheme 4.
References and notes
1. For reviews, see: (a) Otera, J. Chem. Rev. 1993, 93, 1449–1470; (b) Grasa, G. A.;
Singh, R.; Nolan, S. P. Synthesis 2004, 971–985; (c) Hoydonckx, H. E.; De Vos, D.
E.; Chavan, S. A.; Jacobs, P. A. Top. Catal. 2004, 27, 83–96.
2. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.;
John Wiley and Sons: New York, 1999; (b) Kocienski, P. J. Protective Groups, 3rd
ed.; Thieme: Stuttgart, 2003.
3. For examples, see: (a) Xiang, J.; Toyoshima, S.; Orita, A.; Otera, J. Angew. Chem.,
Int. Ed. 2001, 40, 3670–3672; (b) Baumhof, P.; Mazitschek, R.; Giannis, A.
Angew. Chem., Int. Ed. 2001, 40, 3672–3674; (c) Ramalinga, K.; Vijayalakshmi,
P.; Kaimal, T. N. B. Tetrahedron Lett. 2002, 43, 879–882.
4. For recent reviews on the Au-catalyzed reactions, see: (a) Hoffmann-Röder, A.;
Krause, N. Org. Biomol. Chem. 2005, 3, 387–391; (b) Zhang, L.; Sun, J.; Kozmin, S.
A. Adv. Synth. Catal. 2006, 348, 2271–2296; (c) Hashmi, A. S. K.; Hutchings, G. J.
Angew. Chem., Int. Ed. 2006, 45, 7896–7936; (d) Jiménez-Núñez, E.; Echavarren,
A. M. Chem. Commun. 2007, 333–346; (e) Gorin, D. J.; Toste, F. D. Nature 2007,
446, 395–403; (f) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180–3211; (g)
Fürstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410–3449; (h) Shen,
H. C. Tetrahedron 2008, 64, 3885–3903; (i) Skouta, R.; Li, C.-J. Tetrahedron 2008,
64, 4917–4938.
5. Asao, N.; Aikawa, H.; Tago, S.; Umetsu, K. Org. Lett. 2007, 9, 4299–4302.
6. Electrocyclization of ortho-alkynylbenzoic acid alkyl ester has been reported
for synthesis of isocoumarin. For examples, see: (a) Oliver, M. A.; Gandour, R. D.
J. Org. Chem. 1984, 49, 558–559; (b) Rossi, R.; Carpita, A.; Bellina, F.; Stabile, P.;

K. Umetsu, N. Asao / Tetrahedron Letters 49 (2008) 7046–7049
7049
Mannina, L., Tetrahedron 2003, 59, 2067–2081; (c) Yao, T.; Larock, R. C. J. Org.
Chem. 2003, 68, 5936–5942; (d) Marchal, E.; Uriac, P.; Legouin, B.; Toupet, L.;
Van de Weghe, P. Tetrahedron 2007, 63, 9979–9990.
Chem. Soc. 2003, 125, 10921–10925; (c) Asao, N.; Aikawa, H.; Yamamoto, Y. J.
Am. Chem. Soc. 2004, 126, 7458–7459; (d) Asao, N. Synlett 2006, 1645–1656.
9. Zhu, J.; Germain, A. R.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2004, 43, 1239–
1243.
7. The deprotected alcohols 2 were easily separated from byproducts 10 and 3 by
standard purification procedure with silica gel column chromatography.
8. (a) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc.
2002, 124, 12650–12651; (b) Asao, N.; Nogami, T.; Lee, S.; Yamamoto, Y. J. Am.
10. Kusama, H.; Iwasawa, N. Chem. Lett. 2006, 35, 1082–1087.