DBU-promoted facile, chemoselective cleavage of acetylenic TMS group

Article abstract of DOI:10.1055/s-2008-1032078

Acetylenic trimethylsilyl (TMS) groups were efficiently removed using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). With either 1.0 or even 0.1 equivalents of DBU, smooth desilylation of various terminal acetylenic TMS groups was accomplished selectively in the presence of alkyl silyl ethers and other base-labile groups. Furthermore, more sterically hindered terminal acetylenic silyl groups such as TBDMS and TIPS remained intact under these conditions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032078

LETTER
565
DBU-Promoted Facile, Chemoselective Cleavage of Acetylenic TMS Group
D
BU-PromotedS
h
elective Cle
a
avage of
A
n
g
S
G
roup -Eun Yeom, Mi Jeong Kim, Whail Choi, B. Moon Kim*
School of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151747, Korea
Fax +82(2)8727505; E-mail: kimbm@snu.ac.kr
Received 29 November 2007
deprotection to completion, leaving other silyl groups and
hydroxide-sensitive groups untouched.
Abstract: Acetylenic trimethylsilyl (TMS) groups were efficiently
removed using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). With
either 1.0 or even 0.1 equivalents of DBU, smooth desilylation of
various terminal acetylenic TMS groups was accomplished selec-
tively in the presence of alkyl silyl ethers and other base-labile
groups. Furthermore, more sterically hindered terminal acetylenic
silyl groups such as TBDMS and TIPS remained intact under these
conditions.
During initial optimization, we noticed that the presence
of a protic additive is essential for successful transforma-
tion. In solely aprotic medium such as anhydrous acetoni-
trile, the reaction proceeded negligibly. When a small
amount of a protic additive such as water was introduced,
the reaction accelerated dramatically, going to completion
within 40 minutes (Equation 1).8
Key words: DBU, silylacetylene, chemoselective, deprotection
To evaluate the reactivity of DBU on the cleavage of acet-
ylenic TMS in comparison with other tertiary amine
bases, a range of tertiary amine bases were screened
(Table 1). Desilylation was carried out using 1 as a repre-
sentative trimethylsilylated acetylene derivative in aque-
ous acetonitrile at 60 °C for 40 minutes, and the reaction
was monitored through GC analysis. When 1 equivalent
of an amine base such as 4-(N,N-dimethylamino)pyridine
(DMAP), diazabicyclo[3,2,0]octane (DABCO), and pro-
ton sponge (PS) was applied to desilylation (entries 3–5),
trace of or no conversion was detected. Only N,N,N¢,N¢-
tetramethylguanidine (TMG) provided a considerably
good conversion (85%, entry 6). However, desilylation
using DBU proceeded exceptionally well, exhibiting
complete conversion of the starting material (entry 1).
Moreover, even a catalytic amount (0.1 equiv) of DBU
was effective in cleaving the TMS group, though pro-
longed reaction time was required (entry 2). Consequent-
ly, it became clear that DBU has a surpassing ability to
mediate desilylation of silylated acetylene derivatives un-
like other tertiary amine bases.
Trialkylsilyl functionality has a prominent role in the or-
ganic synthesis as a protecting group of alcohols, amines
and alkynes.1 Therefore selective methods for the depro-
tection of the silyl groups have been investigated exten-
sively for a long time, however, most of them have
focused primarily upon alkyl silyl ethers.2,3 Acetylenic tri-
alkylsilyl groups have been underestimated in spite of the
importance of alkynes as building blocks of natural prod-
ucts and polymers,4 thus there are only a few reports on
the selective manipulation of alkynylsilanes.2b,5 Fluoride
ion, a standard deprotecting reagent, hardly provides a
reasonable chemoselectivity among different silyl
groups.2b Selective cleavage of acetylenic silyl groups
mainly depends upon hydroxide-based cleavage condi-
tions, and other labile functional groups such as esters sel-
dom survive during the deprotection. Recently, Pale and
co-workers reported on the chemoselective removal of
acetylenic TMS using silver salts, but this method still
suffers from the low selectivity between different silyl
groups after long exposure to deprotecting conditions.6
During our ongoing research program on development of
useful synthetic methodologies based upon the unique
property of DBU,3a,7 we encountered remarkably selective
removal of acetylenic TMS in the presence of aliphatic
TBDMS ethers (Equation 1). Furthermore, even 0.1
equivalents of DBU proved to be sufficient to drive the
With the optimized conditions using DBU established, we
studied the scope of the chemoselective removal of vari-
ous acetylenic TMS groups (Table 2). Throughout this ex-
amination, it is clear that this protocol is perfectly
compatible with bulkier alkyl silyl ethers (entries 1, 3, 8,
and 9) and base-sensitive groups such as acetate (entry 4),
benzoate (entries 5 and 7), and methyl ester (entry 11). In
OTBDMS
OTBDMS
DBU (1 equiv)
MeCN–H2O (19:1)
40 min, 60 °C
TMS
1
2, 97%
Equation 1
SYNLETT 2008, No. 4, pp 0565–0568
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1032078; Art ID: U11307ST
© Georg Thieme Verlag Stuttgart · New York

566
C.-E. Yeom et al.
LETTER
Table 1 Comparative Desilylation of 1 Using Various Tertiary Amine Basesa
OTBDMS
OTBDMS
Lewis base (1 equiv)
MeCN–H2O (19:1)
40 min, 60 °C
TMS
1
2
Entry
Base
Conversion (%)a
1
DBU
DBU
DMAP
DABCO
PSc
100
100
trace
0
2b
3
4
5
0
6
TMG
85
a Determined by GC analysis.9
b Reaction was carried out with 0.1 equiv of DBU at 60 °C for 6.5 h.
c Proton sponge [1,8-bis(dimethylamino)naphthalene].
addition, bulkier silyl acetylene derivatives such as those amount of monodeprotected compound 4 were observed
containing TBDMS (entry 12) and TIPS (entry 13) were along with compound 3. However, almost no trace of the
unaffected under these conditions. However, compounds monodesilylated compound 5 was obtained from this re-
containing a straight aliphatic chain and bulky silyl ether action.
did not proceed well in 1 hour (entries 7–9). In these cases,
As yet another comparison, a substrate possessing an acet-
more DBU and longer reaction time were needed to com-
ylenic TMS group and an acetate was exposed to desilyla-
plete the TMS removal. Catalytic reactions were attempt-
tion conditions using a frequently employed desilylating
ed to several substrates employing 0.1 equivalents of
reagent, K2CO3 in methanol (Equation 3). In this case,
DBU, and desilylation also underwent successfully when
both the TMS and the acetyl groups were removed yield-
the reactions were run for prolonged periods of time (en-
ing propargylic alcohol derivative exclusively. Further-
tries 1, 2, 5, and 11).
more, 1 equivalent of tetra(n-butyl)ammonium hydroxide
In contrast to the DBU-promoted selective removal of the (TBAOH) also afforded the same product. These two cas-
TMS group from the acetylene unit of compound 1 in the es clearly demonstrate the advantage of the DBU-mediat-
presence of alkyl tert-butyldimethylsily ether, nonselec- ed desilylation compared to the classical methods
tive removal of both silyl groups was noted as a major employing alkoxide or hydroxide reagent, which provided
course of the reaction when just 1 equivalent of TBAF no selectivity.
was employed in a comparison experiment (Equation 2).
A small amount (3%) of the starting material and a minute
promoter for the chemoselective cleavage of acetylenic
In conclusion, we disclosed that DBU is a highly efficient
TMS in the presence of bulkier alkyl silyl ethers. The re-
action is compatible with base-sensitive groups such as
OTBDMS
TBAF (1 equiv)
acetate, methyl ester, and benzyl ester. This novel method
Ph
is operationally very straightforward and convenient; sol-
vent evaporation and simple filtration of the reaction mix-
TMS
1
ture through a silica gel pad are sufficient to obtain the
desired product in pure form. Research on the further uti-
lization of the unique properties of DBU is in progress in
our laboratory, and the results will be reported in due
OTBDMS
OH
+
Ph
Ph
TMS
3, 96%
course.
1, 3%
OH
OTBDMS
K2CO3 (1 equiv)
MeOH, 60 °C
OH
OAc
+
+
Ph
Ph
Ph
Ph
TMS
or TBAOH (1 equiv)
MeCN, 60 °C
TMS
4, <1%
5, trace
>99%
Equation 2
Equation 3
Synlett 2008, No. 4, 565–568 © Thieme Stuttgart · New York

LETTER
DBU-Promoted Selective Cleavage of Acetylenic TMS Group
567
Table 2 Deprotection of Acetylenic TMS Using 1 Equivalent of DBU in 5% (v/v) Aqueous Acetonitrile at 60 °C
Entry
1
TMS alkyne
Alkyne
Timeb
Yield (%)a,b
99 (99)
OTBDMS
OTBDMS
40 min (6.5 h)
TMS
TMS
TMS
TMS
TMS
OH
OH
2
3
4
5
6
40 min (6.5 h)
99 (97)
95
OTBDPS
OAc
OTBDPS
OAc
1 h
1 h
97
OBz
OBz
1 h (6.5 h)
97 (95)
96
OTHP
OTHP
1 h
TMS
TMS
7c
8c
9c
5 h
6 h
6 h
98
93
94
OBz
OBz
TMS
TMS
OTBDMS
OTBDPS
OTBDMS
OTBDPS
CO2Me
CO2Me
11
1 h (6.5 h)
93 (94)
TMS
OTBDMS
OTBDMS
OTBDMS
12
13
40 min
40 min
0
0
TBDMS
OTBDMS
TIPS
a Yield of isolated alkyne.
b Values in parentheses are the time and yield of desilylation performed with 0.1 equiv of DBU at 60 °C.
c These substrates required 1.5 equiv of DBU for a complete conversion.
Acknowledgment
References and Notes
Generous financial support from the Korea Research Fund (KRF-
2005-041-C00247) is gratefully acknowledged.
(1) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
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(2) For review, see: (a) Lalonde, M.; Chan, T. H. Synthesis
1985, 817. (b) Crouch, R. D. Tetrahedron 2004, 60, 5833.
Synlett 2008, No. 4, 565–568 © Thieme Stuttgart · New York

568
C.-E. Yeom et al.
LETTER
(3) (a) Yeom, C.-E.; Kim, H. W.; Lee, S. Y.; Kim, B. M. Synlett
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904.
(8) A Representative Procedure the Desilylation of
Acetylenic TMS
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To a magnetically stirred solution of 1 (195 mg, 0.563
mmol) in MeCN (1.1 mL) and H2O (56 mL) were added
DBU (84 mL, 0.563 mmol) at r.t. The mixture was heated to
60 °C, and the stirring was continued for 40 min. After
completion of the reaction, the resulting residue was
concentrated under reduced pressure and purified by passing
through a short silica gel column (ca. 5 cm) to afford pure
alkyne (155 mg, 99% yield).
(9) Determined from GC analysis using HP-5 column
(crosslinked 5% PH ME polysiloxane).
Synlett 2008, No. 4, 565–568 © Thieme Stuttgart · New York

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