Mild, selective deprotection of PMB ethers with triflic acid/1,3-dimethoxybenzene

Article abstract of DOI:10.1016/j.tetlet.2011.08.102

An efficient method for the cleavage of the p-methoxybenzyl protecting group of several alcohols in the presence of 0.5 equiv of trifluoromethanesulfonic acid and 1,3-dimethoxybenzene in dichloromethane at room temperature is described.

Full text of DOI:10.1016/j.tetlet.2011.08.102

Tetrahedron Letters 52 (2011) 6051–6054
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Tetrahedron Letters
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Mild, selective deprotection of PMB ethers with triflic
acid/1,3-dimethoxybenzene
⇑
Michael E. Jung , Pierre Koch
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the cleavage of the p-methoxybenzyl protecting group of several alcohols in the
presence of 0.5 equiv of trifluoromethanesulfonic acid and 1,3-dimethoxybenzene in dichloromethane at
room temperature is described.
Received 29 June 2011
Revised 16 August 2011
Accepted 18 August 2011
Available online 25 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ether deprotection
Triflic acid
PMB ether deprotection
Selective deprotection
O-allyl
AcO
AcO
O
The p-methoxybenzyl (PMB) group is a very useful protecting
group for alcohols since it is generally stable toward a variety of
reaction conditions and can be selectively cleaved in the presence
of unsubstituted benzyl ethers.1 Numerous methods exist for the
selective removal of the PMB group including oxidative removal
with ceric ammonium nitrate (CAN)2 or 2,3-dichloro-5,6-dic-
yanobenzoquinone (DDQ).3 Cleavage in the presence of a combina-
tion of a Lewis acid and a soft nucleophile, such as AlCl3–EtSH,
MgBr2–Me2S, CeCl3Á7H2O–NaI, SnCl4–PhSH, NaCNBH3–BF3ÁEt2O,
ZrCl4–CH3CN, or TMSCl–SnCl2–anisole, has also been reported.4
Although PMB ethers are stable under many acidic conditions, they
may be cleaved in the presence of strong acids, for example, AcOH
at 90 °C,5 10% trifluoroacetic acid (TFA) in dichloromethane,6 TFA
or methanesulfonic acid (MsOH) with 1,3-dimethoxybenzene in
toluene,7 or TFA-anisole in dichloromethane.8 It has also been
reported that the PMB group can be transferred from alcohols to
Me
PMBO
O
O
NH
CCl3
AcO
NPhth
HO
OAc
1
2
O-allyl
Me
O
O
HO
AcO
AcO
TMSOTf (0.2eq)
CH2Cl2, 0 °C, 1 h
O
OAc
AcO
NPhth
78%
3
Scheme 1. TMSOTf-promoted glycosidation of 1 and 2.
glycosidic bond took place, but the PMB group at the 4-OH position
of the rhamnose unit was also cleaved.
Since Wolbers and Hoffmann had previously reported that the
PMB group was unstable under the influence of the Lewis acid
TMSOTf,11 we wanted to explore the possibility of using TMSOTf
as a general method to deprotect PMB ethers.
sulfonamides in the presence of
a
catalytic amount of
trifluoromethanesulfonic acid (triflic acid, TfOH).9 However, when
the sulfonamide was omitted from this reaction, no PMB cleavage
occurred.9
During the course of our studies toward the synthesis of the
carbohydrate moiety of Brasilicardin A,10 we carried out the tri-
methylsilyl trifluoromethanesulfonate (TMSOTf)-catalyzed glycos-
idation reaction of the 3-OH-rhamnose donor 1 and imidate 2
(Scheme 1). To our surprise, the coupled alcohol 3 was isolated
as the sole product of this reaction, in which the formation of the
To check the generality of this novel process, we treated a solu-
tion of the PMB ether of the L-rhamnose derivative 1 in dichloro-
methane with a catalytic amount of TMSOTf (Table 1; all yields
in Tables are isolated yields). Fair yields (50–54%) of the diol 4
were obtained with 0.05–0.2 equiv of TMSOTf, although the yield
decreased when a larger amount (0.4 equiv) was used (entries
a–d). The highest yield of the diol 4 (63%) was obtained by adding
an additional 0.05 equiv of TMSOTf 5 min after the first addition
(entry e). When undried dichloromethane was used, the yield of
⇑
Corresponding author.
E-mail address: jung@chem.ucla.edu (M.E. Jung).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.102

6052
M. E. Jung, P. Koch / Tetrahedron Letters 52 (2011) 6051–6054
Table 1
a slight decrease in yield (entry g). Replacement of dichloro-
Cleavage of the PMB ether of 1
methane with toluene was tolerated, but when we performed
the reaction in THF, a dramatic decrease in yield was observed
(entries h and i). When we used TFA as the acid instead of TfOH,
we could detect no cholesterol (6) after 15 min. After 48 h using
this weaker acid, we were able to isolate only 16% of compound
6 (entry j).
O-allyl
O-allyl
Me
PMBO
Me
HO
15 min
21 °C
O
O
HO
HO
OAc
OAc
1
4
The results of the removal of the PMB group of various sub-
strates using 0.5 equiv of TfOH in dichloromethane as optimal
reaction conditions are listed in Table 3.12 All of the PMB ethers
were prepared from the corresponding alcohol using the adapted
protocol of Rai and Basu.13 TfOH in dichloromethane cleaved the
PMB ethers of primary and hindered secondary alcohols in excel-
lent yields (88–94%, entries a–d). The PMB group could be che-
moselectively removed in the presence of a simple benzyl ether
(86%, entry e). These conditions are mild enough so that even sub-
strates 17 and 19, that have a phenolic TBS, an ester group, an allyl
ether, an acetonide, and an anomeric acetal, were readily con-
verted into the corresponding alcohols 18 and 20 in 79% and 83%
yield, respectively (entries f and g). However, compounds that
can easily generate carbocations could not be cleaved by this
method (entries h and i). In neither case, could a clean product
be isolated and only decomposition was observed.
Entry
Reagent
Amount (equiv)
Solvent
Yield (%)
a
b
c
d
e
f
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TfOH
0.05
0.1
0.2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
50
54
51
27
63
36
50
59
0.4
2 Â 0.05
a
0.1
CH2Cl2
g
h
0.1
2 Â 0.05
CH2Cl2
CH2Cl2
TfOH
a
Not dried.
the diol 4 decreased significantly (entry f). In order to confirm
whether the strong Brønsted acid triflic acid was generated during
the reaction conditions and caused the PMB cleavage, we treated
the PMB ether 1 with TfOH. Comparable yields of the diol 4 were
obtained (compare entries b vs g, and e vs h). In these cases, the al-
lyl ether, the anomeric acetal, and the acetate protecting groups of
the rhamnose derivative remained intact.
Since we wanted to eliminate any neighboring group effects
caused by the adjacent hydroxyl function in 1, we chose the
PMB ether of cholesterol 5 to investigate the cleavage of the
PMB group (Table 2). The use of TMSOTf in this case resulted
in the formation of side products, and the corresponding alcohol
6 was obtained only in poor yield (31%). An incomplete reaction
was observed after 15 min when 0.1 equiv of TfOH was used
(entry b), but no side products were detected. Increasing the
amount of TfOH to 0.5 equiv increased the yield of cholesterol
(6) to 85%. By using this amount of TfOH, we shortened the
reaction time to 5 min and obtained an 82% yield of compound
6 (entry f). Lengthening the reaction time to 30 min resulted in
Since yields of >50% can be achieved with only 10% of triflic acid
in an aprotic solvent, there must be a way for additional protons to
be generated during the reaction. We hypothesized that this pro-
Table 3
Selective cleavage of the PMB group by triflic acid in dichloromethanea
Entry Substrate
Product
Yield
(%)
a
Me(CH2)8CH2OPMB
Me(CH2)8CH2OH
93
7
8
OPMB
OPMB
OH
b
c
88
91
10
9
OH
12
11
Me
Me
d
94
OPMB
Me
OH
Me
Me
Me
14
BnO
13
BnO
Table 2
Cleavage of the PMB ether of 5a
OPMB
OH
e
f
86
79
16
15
Me
Me
OTBS
OTBS
Me
Me
H
Me
O
O
OPMB
OH
H
H
O
O
RO
17
18
O-allyl
O-allyl
R = PMB
R = H
6
5
Me
PMBO
Me
HO
O
O
O
O
g
83
O
O
Entry
Reagent (amount)
Solvent
Time
Yield (%)
Me
Me
Me
Me
a
b
c
d
e
f
g
h
i
TMSOTf (0.1 equiv)
TfOH (0.1 equiv)
TfOH (0.2 equiv)
TfOH (0.5 equiv)
TfOH (1.0 equiv)
TfOH (0.5 equiv)
TfOH (0.5 equiv)
TfOH (0.5 equiv)
TfOH (0.5 equiv)
TFA (0.5 equiv)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
15 min
15 min
15 min
15 min
15 min
5 min
30 min
15 min
15 min
48 h
31
42
77
85
44
82
75
79
12
16
20
19
Ph
Ph
Ph
Ph
OPMB
OH
h
i
0
0
21
Me
OPMB
23
22
Me
OH
24
j
CH2Cl2
a
Conditions: PMB ether (0.2 mmol), TfOH (0.1 mmol), CH2Cl2(1 mL), 21 °C,
15 min.
a
Conditions: PMB ether 5 (0.2 mmol), solvent (1 mL), 21 °C.

M. E. Jung, P. Koch / Tetrahedron Letters 52 (2011) 6051–6054
6053
matic ring to react with the triflate D and generate additional triflic
acid more rapidly. This turned out to be the case. Addition of
3 equiv of 1,3-dimethoxybenzene to the reaction mixture short-
ened the reaction time to 10 min and gave very good yields of
the alcohols, up to 98%, as shown in Table 4.14 For almost all of
the substrates, the yield increased upon addition of the 1,3-dime-
thoxybenzene when compared to the yields given in Tables 2
and 3. In all the cases, 1,3-dimethoxy-4-(4-methoxybenzyl)ben-
zene could be isolated, as expected.
We tried to adapt our method to the cleavage of PMB ethers
containing a conjugated diene system. Onoda, et al., reported
this cleavage using MgBr2ÁOEt2–Me2S, but other reagents like
DDQ, CAN, TFA, TFA-ethanethiol, and BBr3 were unsuccessful.4b
We worried that the conjugated diene would suffer an electro-
philic attack by the PMB triflate under our conditions. Indeed,
the PMB group of the two dienyl ethers 25 and 27 could not
be cleaved by TfOH in dichloromethane (Scheme 3). Instead,
the alkenyl tetrahydrofurans 26 and 28 were obtained in 42%
and 39% yield, respectively. We believe that under these acidic
conditions, the alcohol 29 and the PMB triflate (or carbocation)
D are generated. The triflate D is then attacked by the diene sys-
tem to form the relatively stable allylic carbocation G. Cycliza-
tion with the loss of triflic acid would produce the observed
tetrahydrofurans 26 and 28. When the reaction of 25 was carried
out in the presence of 1,3-dimethoxybenzene, the adduct 30 was
obtained in 36% yield, presumably via simple protonation of the
diene and trapping.
OMe
OMe
H
O
TfOH
+
ROH
C
O
R
R
_
A
TfO
B
OMe
OMe
OMe
A
+
TfO
O
R
D
_
H
OTf
OMe
Ar
E
etc.
+
TfOH
O
R
F
Scheme 2. Mechanism of deprotection.
duction of protons occurred via an intermolecular Friedel–Crafts
alkylation process (Scheme 2). Thus protonation of the PMB ether
A with triflic acid would give the salt B, which could then be
cleaved to the observed alcohol product C and the PMB triflate D.
Under the reaction conditions, we propose that this very reactive
species D (which could be in equilibrium with the PMB cation tri-
flate salt) would react with the activated aromatic ring of another
PMB ether A to generate the Friedel–Crafts intermediate E. Loss of
a proton would generate an arylmethyl PMB ether F and regener-
ate an equivalent of triflic acid to continue the process. Thus the
reaction is theoretically catalytic in triflic acid and therefore less
than 1 equiv of the acid could generate >90% yield of the alcohols.
If this mechanism (or a similar one) were active, we argue that
we could improve the process by adding a more electron-rich aro-
In conclusion, we have reported a fast and efficient method for
the selective removal of PMB ethers to generate alcohols, in which
the deprotection proceeds smoothly by treatment of the PMB ether
Table 4
Selective cleavage of the PMB group with triflic acid/1,3-dimethoxybenzene in dichloromethanea
Entry
Substrate
Product
Yield (%)
Me
Me
Me
Me
C6H13
C6H13
Me
H
Me
H
a
91
97
H
H
H
H
HO
PMBO
6
5
b
Me(CH2)8CH2OPMB
Me(CH2)8CH2OH
7
8
OPMB
OH
c
93
89
10
9
OPMB
OH
d
12
11
Me
Me
e
98
OPMB
OH
Me
13
BnO
Me
Me
Me
14
BnO
OPMB
OH
f
94
85
16
15
OTBS
OTBS
gb
O
O
OPMB
OH
O
O
17
18
a
Conditions: PMB ether (0.2 mmol), TfOH (0.1 mmol), 1,3-dimethoxybenzene (0.6 mmol), CH2Cl2 (1 mL), 21 °C, 10 min.
Reaction time: 1 min.
b

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M. E. Jung, P. Koch / Tetrahedron Letters 52 (2011) 6051–6054
R
MeO
References and notes
0.5 eq
TfOH
R
R
R
OPMB
1. (a) Kocienski, P. J. Protecting Groups, third ed.; Georg Thieme: Stuttgart, 2005;
(b) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis,
fourth ed.; John Wiley & sons: Hoboken, NJ, 2007.
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3. (a) Okiawa, Y.; Yoshioko, T.; Yonemitsu, O. Tetrahedron Lett. 1982, 23, 885–888;
(b) Horita, K.; Yoshioka, T.; Tanaka, T.; Okiawa, Y.; Yonemitsu, O. Tetrahedron
1986, 42, 3021–3028.
4. (a) Bouzide, A.; Sauvé, G. Synlett 1997, 1153–1154; (b) Onoda, T.; Shirai, R.;
Iwasaki, S. Tetrahedron Lett. 1997, 38, 1443–1446; (c) Cappa, A.; Marcantoni, E.;
Torregiani, E.; Bartoli, G.; Belucci, M. C.; Bosco, M.; Sambri, L. J. Org. Chem. 1999,
64, 5696–5699; (d) Yu, W.; Su, M.; Gao, X.; Yang, Z.; Jin, Z. Tetrahedron Lett.
2000, 41, 4015–4017; (e) Fuji, K.; Ichikawa, K.; Node, M.; Fujita, E. J. Org. Chem.
1979, 44, 1661–1664; (f) Srikrishna, A.; Viswajanani, R.; Sattigeri, J. A.;
Vijaykumar, D. J. Org. Chem. 1995, 60, 5961–5962; (g) Akiyama, T.; Shima, H.;
Ozaki, S. Synlett 1992, 415–416; (h) Sharma, G. V. M.; Reddy, C. G.; Krishna, P. R.
J. Org. Chem. 2003, 68, 4574–4575; (i) Bartoli, G.; Dalpozzo, R.; De Nino, A.;
Maiuolo, L.; Nardi, M.; Procopio, A.; Tagarelli, A. Eur. J. Org. Chem. 2004, 2176–
2180.
H
O
25 R = Me E/Z 1.5:1
26 R = Me 42%
28 R = H 39%
27 R = H
E/Z 1.5:1
TfOH
- TfOH
MeO
R
R
R
PMB-OTf
+
R
OH
D
_
O
H
TfO
H
29
G
OMe
TfOH (0.5 eq), CH2Cl2
1,3-(MeO)2C6H4 (3 eq)
25
Me
OMe
21 °C, 10 min
36%
Me
OPMB
5. Yan, L.; Kahne, D. Synlett 1995, 523–524.
30
6. Hodgetts, K. J.; Wallace, T. W. Synth. Commun. 1994, 24, 1151–1155.
7. Davidson, J. P.; Sarma, K.; Fishlock, D.; Welch, M. H.; Sukhtankar, S.; Lee, G. M.;
Martin, M.; Cooper, G. F. Org. Process Res. Dev. 2010, 14, 477–480.
8. De Medeiros, E. F.; Herbert, J. M.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1
1991, 2725–2730.
Scheme 3. Attempted deprotection of dienyl PMB ethers.
9. Hinklin, R. J.; Kiessling, L. L. Org. Lett. 2002, 4, 1131–1133.
10. Jung, M. E.; Koch, P. Org. Lett. 2011, 13, 3710–3713.
11. Wolbers, P.; Hoffmann, H. M. R. Tetrahedron 1999, 55, 1905–1914.
12. General procedure for the deprotection of a PMB ether by TfOH in dichloromethane.
To a solution of the PMB ether (0.2 mmol) in dichloromethane abs (1 mL) was
added TfOH (0.1 mmol) (the reaction turns pink or purple). The reaction
mixture was stirred for 15 min at 21 °C and then purified by flash column
chromatography (SiO2, hexanes/ethyl acetate) to yield the alcohol. All products
were identified by proton NMR spectroscopy by comparison to the authentic
material.
with 0.5 equiv of TfOH and 3 equiv of 1,3-dimethoxybenzene in
dichloromethane at room temperature.
Acknowledgments
P.K. gratefully acknowledges support by the Deutsche Fors-
chungsgemeinschaft (KO 4111/1-1). We also thank Abraxis-CNSI
at UCLA for support and Jonah Chang for helpful discussions.
13. Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267–2269.
14. General procedure for the deprotection of
dimethoxybenzene in dichloromethane. To
a
PMB ether by TfOH/1,3-
a
solution of the PMB ether
(0.2 mmol) and 1,3-dimethoxybenzene (0.6 mmol) in dichloromethane abs
(1 mL) was added TfOH (0.1 mmol) (reaction turns yellow or red). The reaction
mixture was stirred for 10 min at 21 °C and then purified by flash column
chromatography (SiO2, hexanes/ethyl acetate) to yield the alcohol. All products
were identified by proton NMR spectroscopy by comparison to the authentic
material.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.102.