A catalytic amount of nickel(II) chloride hexahydrate and 1,2-ethanedithiol is a good combination for the cleavage of tetrahydropyranyl (THP) and tert-butyldimethylsilyl (TBS) ethers

Article abstract of DOI:10.1016/j.tetlet.2004.11.011

Various THP and TBS ethers can be unmasked easily to the corresponding hydroxyl compounds in good yields by using a combination of a catalytic amount of nickel(II) chloride hexahydrate and 1,2-ethanedithiol at room temperature. In addition, alkyl TBS ethers can be hydrolyzed chemoselectively in the presence of aryl TBS ethers. Moreover, alkyl TBS ethers can be cleaved easily in the presence of alkyl or aryl THP ethers using the same conditions.

Full text of DOI:10.1016/j.tetlet.2004.11.011

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9617–9621
A catalytic amount of nickel(II) chloride hexahydrate and
1,2-ethanedithiol is a good combination for the cleavage of
tetrahydropyranyl (THP) and tert-butyldimethylsilyl (TBS) ethers
a,
b
a
Abu T. Khan, Samimul Islam, Lokman H. Choudhury and Subrata Ghosh
a
*
a
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
b
Department of Chemistry, Visva-Bharati, Santiniketan, West Bengal 731 235, India
Received 27 August 2004; revised 26 October 2004; accepted 2 November 2004
This paper is dedicated to Professor H. Ila on the occasion of her 60th birthday
Abstract—Various THP and TBS ethers can be unmasked easily to the corresponding hydroxyl compounds in good yields by using a
combination of a catalytic amount of nickel(II) chloride hexahydrate and 1,2-ethanedithiol at room temperature. In addition, alkyl
TBS ethers can be hydrolyzed chemoselectively in the presence of aryl TBS ethers. Moreover, alkyl TBS ethers can be cleaved easily
in the presence of alkyl or aryl THP ethers using the same conditions.
Ó 2004 Published by Elsevier Ltd.
1
a
Tetrahydropyranyl (THP) and tert-butyldimethylsilyl
1
catalytically efficient method, which needs only mild
11
reaction conditions. Recently, we have shown that
b
(
TBS) groups are frequently employed as protecting
groups for hydroxyl functionalities in multi-step synthe-
sis due to their ease of preparation and stability under a
wide variety of reaction conditions as well as their
subsequent ease of removal. Recently new synthetic
methods have been developed for both tetra-
hydropyranylation and depyranylation employing the
anhydrous nickel(II) chloride is an efficient catalyst for
thioacetalization of aldehydes. During this investigation,
we noticed that THP ethers did not survive. At the
same time, we learnt from the literature that nickel(II)
chloride hexahydrate reacts with 1,2-ethanedithiol to
provide a polymeric nickel complex. From these re-
sults, we wondered whether a combination of a catalytic
amount of nickel(II) chloride hexahydrate and 1,2-
ethanedithiol, which might generate hydrochloric acid
on complexation with the nickel, can be used for cleav-
age of THP and TBS ethers. In this paper, we disclose
our results on the deprotection of tetrahydropyranyl
and tert-butyldimethylsilyl ethers using a catalytic
amount of nickel(II) chloride hexahydrate and 1,2-
ethanedithiol (see Scheme 1).
1
2
2
following reagents: tetrabutylammonium tribromide,
3
4
aluminium chloride hexahydrate, In(OTf)3, dialkyl-
5
imidazolium tetrachloroaluminates, InCl immobilized
3
6
in ionic liquids and bromodimethylsulfonium bro-
7
mide. Similarly, a large number of methods have been
developed for the cleavage of TBS ethers using various
chloride, bromide and fluoride based reagents as well
8
as other reagents, which have been reviewed recently.
However, some of the reported methods have draw-
backs such as the requirement for long reaction times
and harsh reaction conditions, and some of the reagents
have to be prepared prior to use and involve expensive
reagents. Although numerous synthetic methods have
R2
R2
NiCl2 6H O
/ HSCH CH SH
2 2
2
9
been developed for deprotection of THP ethers and
1
TBS ethers in recent years, there is still a need for a
R1
OP
R1
0
MeOH-CH Cl (2:5), rt
2
2
OH
1
2
1
R = alkyl /aryl / sugar residue / nucleoside residue;
Keywords: Deprotection of TBS and THP ethers.
*
2
R = H, alkyl; P = THP /TBS
Corresponding author. Tel.: +91 3612582305; fax: +91
612690762; e-mail: atk@postmark.net
3
Scheme 1.
0
040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.11.011

9618
A. T. Khan et al. / Tetrahedron Letters 45 (2004) 9617–9621
We prepared a wide variety of structurally different
7
of the aldehyde group. It is worth mentioning that no
chlorination of the double or triple bond took place.
These results are summarized in Table 1. The products
tetrahydropyranyl (THP) and tert-butyldimethylsilyl
1
3
(
TBS) ethers by following standard literature proce-
1
dures. We attempted to optimize the conditions for
cleavage of the THP and TBS ethers to obtain the par-
ent hydroxyl compounds. It was observed that a mixture
of substrate/nickel(II) chloride hexahydrate/1,2-ethane-
dithiol (1:0.2:0.2) in methanol–dichloromethane (2:5,
were characterized by recording IR, H NMR spectra
and elemental analyses. We observed that the THP ether
of 4-tetrahydropyranyloxybenzyl alcohol (run 13, Table
1) was converted chemoselectively into the 4-tetra-
hydropyranyloxybenzyl alcohol (65%) along with 20%
of the aryl deprotected THP ether.
1
4
5
mL/mmol of the substrate) provided the best results,
for example, the THP ether of cetyl alcohol (run 1) was
cleaved to give cetyl alcohol in a 90% yield within
We considered whether the same reagent would be use-
ful for deprotection of TBS ethers. When the TBS ether
of 1-octadecanol (run 1, Table 2) was treated with
0.2equiv of nickel(II) chloride hexahydrate and
0.2equiv of 1,2-ethanedithiol in dichloromethane–meth-
anol (5:2), it was converted into 1-octadecanol in a 90%
yield within 10min. Similarly, primary and secondary
TBS ethers (runs 2and 3) were hydrolyzed to the corre-
sponding hydroxyl compounds as shown in Table 2. We
noticed that phenolic TBS ethers (runs 5 and 6) could
4
0min. The product cetyl alcohol was characterized by
1
comparison of its IR and H NMR spectra with those
of an authentic sample. Similarly, several THP ethers
of primary and secondary alcohols (runs 2–8) were con-
verted into the parent hydroxyl compounds in good
yields. THP ethers containing a double or triple bond
(
runs 9 and 10) were also hydrolyzed to the parent hydr-
oxyl compounds. Moreover, aryl THP ethers (runs 11
and 12) could also be cleaved without thioacetalization
Table 1. Deprotection of various tetrahydropyranyl ethers giving the corresponding hydroxyl compounds using a catalytic amount of nickel(II)
chloride hexahydrate (0.2equiv) and 1,2-ethanedithiol (0.2equiv) in dry dichloromethane–methanol
a
Product 2
b
Yield (%)
Run
Substrate 1
Time (min/[h])
n
OTHP
n
OH
OH
1
45
90
80
84
n = 13
n = 13
OTHP
2
3
40
50
OTHP
OH
Cl
Cl
OTHP
OH
4
5
40
50
80
91
MeO
O
MeO
O
OTHP
OH
6
7
75
90
83
95
OTHP
OH
THPO
HO
OTHP
OH
8
9
40
[2]
84
85
OTHP
OH
OH
1
1
0
1
40
72
76
90
THPO
THPO
OTHP
HO
HO
Cl
Cl
1
1
2
3
THPO
CHO
90
20
HO
HO
CHO
OTHP
86
65
OTHP
THPO
a
1
All products were characterized by IR, H NMR and elemental analysis.
Isolated yield.
b

A. T. Khan et al. / Tetrahedron Letters 45 (2004) 9617–9621
9619
Table 2. Deprotection of various TBS ethers (1) to the parent hydroxyl compounds (2) using a catalytic amount of nickel(II) chloride hexahydrate
and 1,2-ethanedithiol
a
Product 2
b
Yield (%)
Run
Substrate 1
Time (min/[h])
10
n
OTBS
n
OH
1
90
95
n = 15
n = 15
OTBS
OH
2
3
5
MeO
MeO
30
99
89
TBSO
HO
4
25
OTBS
OH
S
S
S
S
5
6
OTBS
OTBS
[4.5]
[12]
OH
70
86
OH
O
O
O
OTBS
O
O
OH
O
7
45
O
93
O
O
O
OBn
O
OBn
O
TBSO
HO
BnO
8
9
[2]
45
81
86
BnO
BnO
BnO
OMe
OMe
OTBS
O
OH
O
BnO
BnO
BnO
BnO
BnO
SEt
Me
SEt
Me
BnO
O
O
HN
HN
1
0
TBSO
O
O
N
40
HO
HO
O
O
N
75
OAc
OAc
1
1
1
2
TBSO
TBSO
OTBDPS
15
20
83
80
OTBDPS
OTBS
OH
TBSO
OTBS
OTBS
OH
OTBS
13
20
75
a
1
13
All starting materials and final products were characterized by IR, H NMR, C NMR and elemental analysis.
Isolated yield.
b
also be unmasked in a similar manner. Various sub-
strates containing other functional groups such as an
isopropylidene protected sugar (run 7), a benzyl pro-
tected sugar (run 8), a benzyl protected sugar having
an SEt group in the anomeric position (run 9) and an
acetyl protected nucleoside (run 10) were cleaved to
the corresponding sugars and nucleoside in good yields.
By using our protocol, a TBS ether was chemoselectively
deprotected in the presence of TBDPS ether (run 11).
Furthermore, alkyl TBS ethers can be cleaved chemose-
lectively in the presence of aryl TBS ethers (runs 12and
TBS ethers, although THP ethers do not survive during
these experimental conditions. We prepared several
TBS ethers containing THP ethers and found that by fol-
lowing the present protocol, the TBS ethers could be
cleaved to the corresponding hydroxyl compounds in
fairly good yields without affecting the THP groups (runs
1
6
15
1–5, Table 3). By repeating our acetyl chloride method,
we confirmed that both the THP and TBS groups were
hydrolyzed simultaneously. However, it is difficult to
cleave selectively aryl TBS ethers in the presence of alkyl
THP ethers (run 6) because aryl TBS ethers take longer
to react as compared to alkyl TBS ethers. The reaction
times and yields of the products are shown in Table 3.
13). The reaction times and yields of the hydrolyzed
products are shown in Table 2.
1
5
We have shown that acetyl chloride and methanol pro-
vide dry HCl, which can be used for the deprotection of
The formation of the product can be explained as out-
lined in Scheme 2. It may be that nickel(II) chloride

9620
A. T. Khan et al. / Tetrahedron Letters 45 (2004) 9617–9621
Table 3. Chemoselective cleavage of TBS ethers in presence of a THP ether
a
b
Yield (%)
Run
1
Substrate
Time (min)
12
Product
THPO
n
OTBS
OTBS
THPO
n
OH
OH
64
65
n = 3
n = 3
THPO
n
THPO
n
2
3
12
20
n = 6
n = 6
OTBS
OH
OTHP
OTHP
OTHP
OTHP
62
65
OTBS
OH
4
20
10
n
n = 5
n
n = 5
OTBS
OH
5
6
63
70
THPO
TBSO
THPO
TBSO
OTHP
OH
30
a
1
All starting materials and final products were characterized by IR, H NMR and elemental analysis.
Isolated yield.
b
ation of the polymeric [Ni(es)] complex. However, the
n
.
NiCl 6H O
+
esH2
[ Ni (es) ] n
+
HCl
2
2
same reaction was unsuccessful when it was carried
out with 2-aminothiophenol and nickel(II) chloride
hexahydrate using the same solvent. From the chemo-
selectivity study mentioned in Table 3, it appears that
the catalytic cycle for the cleavage of a TBS ether is
faster compared to that of cleavage of THP ethers.
es = SCH CH S
2
2
HCl
ROH
ROH
We have demonstrated a simple and useful method for
deprotection of THP and TBS ethers to the correspond-
ing hydroxyl compounds using a combination of
nickel(II) chloride hexahydrate and 1,2-ethanedithiol.
It is noteworthy that no chlorination takes place at
double or triple bonds. In addition, alkyl TBS ethers
can be cleaved chemoselectively in the presence of
aryl TBS ethers. Moreover, alkyl TBS ethers can be
hydrolyzed in the presence of alkyl THP ethers.
ROTHP ROTBS
Si Cl
O
+
HCl
MeOH
MeOH
Si OMe
MeO
O
Scheme 2. Proposed mechanism for the deprotection of THP and TBS
ethers.
Acknowledgements
A.T.K. acknowledges the Department of Science and
Technology (DST), New Delhi for financial grant
hexahydrate can form hydrochloric acid and a poly-
meric nickel complex, on reaction with 1,2-ethanedithiol
(Grant No. SP/S1/G-35/98). L.H.C. and S.G. are grate-
(
esH ). We believe that the in situ generated hydrochlo-
2
ful to the IITG for their research fellowships. We are
grateful to Professor M. K. Chaudhuri for some helpful
discussion on the mechanistic aspects. We are thankful
for the refereeÕs valuable comments and suggestions.
ric acid catalyzes the deprotection of both the THP and
TBS ethers. Following the nickel chloride method, the
pH of the solution was 2.7, whereas during the acetyl
chloride method it was 1.5.
We also established that both transformations can be
achieved by employing nickel(II) chloride hexahydrate
References and notes
(
0.2equiv) and either ethanethiol or 1,3-propanedithiol.
1
. (a) Kocienski, P. J. Protecting Groups; Georg Thieme:
Stuttgart, 1994; pp 83–85; (b) Kocienski, P. J. Protecting
Groups; Georg Thieme: Stuttgart, 1994; pp 33–38.
When the TBS ether of 1-octadecanol was treated with
either ethanethiol or 1,3-propanedithiol in the presence
of nickel(II) chloride hexahydrate, it was converted to
2
3
. Naik, S.; Gopinath, R.; Patel, B. K. Tetrahedron Lett.
2
. Namboodiri, V. V.; Varma, R. S. Tetrahedron Lett. 2002,
43, 1143.
4. Mineno, T. Tetrahedron Lett. 2002, 43, 7975.
1
-octadecanol in 90% yield. The reaction took 50min
in the case of ethanethiol and 75min in the case of
,3-propanedithiol. It is quite clear that the reaction is
faster with 1,2-ethanedithiol because of the ease of form-
001, 42, 7679.
1

A. T. Khan et al. / Tetrahedron Letters 45 (2004) 9617–9621
9621
5
6
7
. Namboodiri, V. V.; Verma, R. S. Chem. Commun. 2002,
3
1,2-ethanedithiol (0.2mmol, 17lL) and the mixture stirred
at room temperature. When the reaction was over, the
mixture was passed through a silica gel column to obtain
the product. In the cases of substrates containing both
TBS and THP ethers (Table 3), the reactions were
quenched by adding saturated aqueous sodium bicarbo-
nate as soon as the starting material had disappeared.
15. Khan, A. T.; Mondal, E. Synlett 2003, 694.
42.
. Yadav, J. S.; Reddy, B. V. S.; Gnaneshwar, D. New J.
Chem. 2003, 202.
. Khan, A. T.; Mondal, E.; Borah, B. M.; Ghosh, S. Eur. J.
Org. Chem. 2003, 4113.
8
. Crouch, R. D. Tetrahedron 2004, 60, 5833.
. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons: New York,
9
16. Spectroscopic data for the THP ether of 4-tert-but-
yldimethylsilyloxybenzyl alcohol: H NMR (400MHz,
1
1
999; pp 346–347.
1
0. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons: New York,
1999; pp 127–144.
1. Khan, A. T.; Mondal, E.; Sahu, P. R.; Islam, S.
Tetrahedron Lett. 2003, 44, 919.
2. Rauchfuss, T. B.; Roundhill, D. M. J. Am. Chem. Soc.
CDCl
–SiC(CH
–OCH –), 3.93 (m, 1H, –OCH
J = 11.2Hz, –OCH –), 4.69 (m, 2H, –OCHO–, –OCH –),
3
):
d
0.19 (s, 6H, –Si(CH
), 1.51–1.87 (m, 6H, –CH
–), 4.44 (d, 1H,
3
)
2
), 0.98 (s, 9H,
–), 3.54 ( m, 1H,
3
)
3
2
2
2
1
1
1
1
2
2
6.81 (d, 2H, J = 8.4Hz, ArH), 7.23 (d, 2H, J = 8.4Hz,
ArH). Anal. Calcd for C18 Si: C, 67.03; H, 9.38%.
30 3
H O
1
975, 97, 3386.
3. Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972,
4, 6190.
Found: C, 67.30; H, 9.40%1 . For 4-tert-but-
yldimethylsilyloxybenzyl alcohol: H NMR (400MHz,
9
CDCl
–SiC(CH
3
):
d
0.19 (s, 6H, –Si(CH
), 1.64 (br s, 1H, –OH), 4.6 (s, 2H, –OCH
3
)
2
), 0.98 (s, 9H,
–),
4. General procedure for deprotection of TBS/THP ethers:
To a stirred solution of the TBS or THP ether (1mmol) in
3
)
3
2
6.83 (d, 2H, J = 8.4Hz, ArH), 7.23 (d, 2H, J = 8.4Hz,
ArH). Anal. Calcd for C H O Si: C, 65.50; H, 9.30%.
Found: C, 65.68; H, 9.25%.
5mL of dichloromethane–methanol (5:2) were added
nickel(II) chloride hexahydrate (0.2mmol, 0.047g) and
1
3
22
2