A base-promoted deprotection of 1,3-dioxolanes to ketones

Article abstract of DOI:10.1016/j.tetlet.2012.10.037

An effective deprotection methodology of dioxolanes was developed, affording moderate to excellent yield via a LTMP-promoted reaction in THF, which displays admirable chemoselectivity in the presence of dimethylketal, 1,3-dioxane, 1,3-dithiane, or other acid-sensitive protective groups.

Full text of DOI:10.1016/j.tetlet.2012.10.037

Tetrahedron Letters 53 (2012) 6972–6976
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Tetrahedron Letters
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A base-promoted deprotection of 1,3-dioxolanes to ketones
Changchun Yuan a, , Li Yang a, , Guizhou Yue a, Tianzi Yu a, Weiming Zhong a, Bo Liu a,b,
⇑
a Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An effective deprotection methodology of dioxolanes was developed, affording moderate to excellent
yield via a LTMP-promoted reaction in THF, which displays admirable chemoselectivity in the presence
of dimethylketal, 1,3-dioxane, 1,3-dithiane, or other acid-sensitive protective groups.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 21 August 2012
Revised 26 September 2012
Accepted 9 October 2012
Available online 17 October 2012
Keywords:
Base-promoted
Deprotection
1,3-Dioxolanes
Ketones
Acetals and ketals are commonly used protective groups for car-
bonyl compounds in organic synthesis. Accordingly, there are
many solutions for the conversion of acetals and ketals into car-
bonyl compounds, mostly by acidic hydrolysis or acid-catalyzed
exchange with acetone;1 however, such conditions are incompati-
ble with acid-labile functional groups (–OTBS, –OMOM etc.) within
the same molecule. To solve this problem, milder reagents2 were
utilized for the deprotection of acetals and ketals, including the
application of a catalytic amount of transition metal or Lewis acid
reagents,3 silicon reagents,4 iodine reagents,5 and others.6 A solu-
tion under basic condition with TESOTf-2,6-lutidine or TESOTf-
2,4,6-collidine for deprotection of acetals in dichloromethane fol-
lowed by aqueous workup has been reported as well.7 However,
the development of a novel and potentially chemoselective depro-
tection method with base is still strongly desirable.
Interestingly, in the course of our total synthesis of ( )-chlo-
ranthalactone A,8 treatment of compound I with lithium 2,2,6,6-
tetramethylpiperidide9 (LTMP) not only generated the 3/5/6 tricy-
clic compound II in 90% yield smoothly, but also provided ketone
III in 3% yield (Scheme 1). Considering the successful cleavage of
1,3-dioxolane in this particular condition albeit in relatively low
yield, we anticipate that it may afford a novel method to deprotect
1,3-dioxolane of ketones.
Accordingly, we envisaged that 1,3-dioxolanes might go
through the similar mechanism with base, and generate the eno-
late of acetaldehyde and ketones (Scheme 2). Herein we would like
to report our results on this LTMP-promoted reaction.
Initial studies were focused on the deprotection of 1,3-dioxo-
lane of a-tetralone (1a) with various bases which play a very cru-
cial role in this reaction (Table 1, entries 1–8). No reactions took
place for the application of LiHMDS, KHMDS, and t-BuOK at 0 °C
or even room temperature. As for n-BuLi, ketone 2a was generated
in 28% yield, along with compound 3 in 60% yield, which was gen-
erated by n-BuLi attacking on the generated ketone 2a. Other com-
O
O
O
O
LTMP
O
+
t-BuOMe
H
H
H
O
HO
MOMO
HO
MOMO
MOMO
90%
3%
I
II
III
Scheme 1.
It is well known that when n-BuLi is stored in tetrahydrofuran,
THF may undergo metallation at the a-position; the formed anion
n-BuLi
+
O-Li+
Li
O
O
can then break down through a fragmentation process to generate
ethylene and enolate of acetaldehyde (Scheme 2).10
H
B
O
Base
O
O
O
O
R1
R2
R1
R2
O-
⇑
R1
R2
Corresponding author. Tel./fax: +86 28 8541 3712.
E-mail address: chembliu@scu.edu.cn (B. Liu).
These authors contributed equally to this work.
Scheme 2.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.037

C. Yuan et al. / Tetrahedron Letters 53 (2012) 6972–6976
6973
Table 1
mon bases such as LDA, s-BuLi, and t-BuLi were effective and affor-
ded better yields (Table 1, entries 5, 6, 7). To our delight, LTMP in
THF can provide the deprotected product in the most satisfactory
yield (76%, Table 1, entry 8). So LTMP was selected as the optimum
base for this particular reaction. We next examined the effect of
solvent and noticed that no reaction occurred in dioxane or dig-
lyme at 0 °C or even at room temperature, and inferior yields were
obtained in tert-butyl methyl ether (42%) or diethyl ether (17%).
Trace product was obtained in toluene even after the reaction
was warmed from 0 °C to room temperature for a long time. A
complex mixture of products was gained in DMF, without ketone
2a being detected. The temperature plays a very important role
for the cleavage of dioxolanes with LTMP since the best yield
Optimization of the reaction conditionsa
O
HO nBu
O
O
Base (4.0 equiv.)
Solvent
2a
3
1a
Entry
Solvent
Base
Temperature
Yield of 2ab
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
THF
THF
LiHMDS
KHMDS
t-BuOK
n-BuLi
LDA
s-BuLi
t-BuLi
LTMP
0 °C to rt
0 °C to rt
0 °C to rt
0 °C
0 °C to rt
0 °C
NRc
NR
NR
28%
61%
60%
68%
76%
NR
(91%) of
a
-tetralone (2a) can be achieved at À20 °C. It is worth not-
0 °C
0 °C
ing that the reaction activity is too low at À40 °C with 2a obtained
in only 28% yield based on the recovered starting material. Thus
the following reaction conditions were chosen as the optimal:
0.5 mmol of 1,3-dioxolanes and 2.0 mmol of LTMP in 5 mL THF at
À20 °C or a higher temperature under argon atmosphere.
9
1,4-Dioxane
DME
t-BuOMe
Et2O
Toluene
DMF
THF
LTMP
LTMP
LTMP
LTMP
LTMP
LTMP
LTMP
LTMP
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C
10
11
12
13
14
15
16
NR
42%
17%
Trace
0%
Next the scope of this reaction was further investigated and the
temperature was screened again for different substrates to ensure
the best transformation. As shown in Table 2, both the aromatic
and the aliphatic dioxolanes are applicable in this methodology.
Linear substrates 1a–1d and cyclic substrates 1j–1k pleasingly pro-
vided the desired products 2a–2d and 2j–2k in satisfying yields
(Table 2, entries 1–4 and entries 10–11). Furthermore, the reaction
was also successful for compounds 1e–1i. Substituted aromatic
dioxolanes with both electron-donating and electron-withdrawing
groups at the para positions, produced the corresponding products
À20 °C
91%
THF
À40 °C
28% brsmd
a
Unless otherwise specified, the reaction was carried out with 1a (0.5 mmol) and
the corresponding base (2.0 mmol) in solvent (5 mL) under argon atmosphere and
was monitored by TLC to ensure complete conversion.
b
Isolated yields.
NR = no reaction.
c
d
The starting material was recovered in 39% yield. brsm = based on the recovered
starting material.
Table 2
Deprotection of 1,3-dioxolane of ketonesa
O
O
R1
1a-k
O
R2
LTMP (4.0 equiv.)
THF
R1
R2
2a-k
Entry
1
Starting materialsb
O
Temperature
Product 2
Yield of 2c
O
O
1a
1b
À20 °C
2a
2b
91%
O
O
O
O
O
2
3
À20 °C
86%
80%
MeO
MeO
MeO
MeO
O
1c
0 °C - rt
2c
O
O
O
4
1d
0 °C - rt
2d
70%
63%
O
O
O
5
6
1e
1f
0 °C - rt
2e
2f
O
O
O
À20 °C - 0 °C
65%
(continued on next page)

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C. Yuan et al. / Tetrahedron Letters 53 (2012) 6972–6976
Table 2 (continued)
Entry
Starting materialsb
Temperature
Product 2
MeO
Yield of 2c
O
O
O
7
1g
0 °C - rt
2g
66%
MeO
Br
O
O
O
8
9
1h
1i
À20 °C
0 °C
2h
2i
63%
65%
Br
O
O
O
O
O
O
10
1j
À20 °C - rt
À20 °C - rt
2j
74%
85%
C5H11
O
C5H11
O
O
11
1k
2k
a
Unless otherwise specified, the reaction was carried out with 1 (0.5 mmol) and LTMP (2.0 mmol) in THF (5 mL) under argon atmosphere and was monitored by TLC to
ensure complete conversion. The reaction time is not more than 16 h (see Supplementary data).
b
All starting materials were prepared in the presence of trialkyl orthoformate and a catalytic amount of tetrabutylammonium tribromide (TBATB) in ethylene glycol.
Isolated yields.
c
Table 3
Chemoselective deprotection of dioxolanes in the presence of acid-sensitive protective groups or 1,3-dithiane of ketala
Entry
1
Starting materials
Temperature
Product 5
Yield of 5b
O
O
4a
0 °C - rt
5a
5b
77%
O
TBSO
TBSO
O
O
O
2
3
4bc
0 °C - rt
85%
78%
H
HO
MOMO
H
HO
MOMO
O
O
O
4c
0 °C - rt
5c
MeO
MeO
MeO
MeO
O
O
O
O
4
5
4d
4e
0 °C - rt
0 °C - rt
5d
5e
67%
75%
O
O
O
OMOM
S
OMOM
S
O
O
O
S
S
a
Unless otherwise specified, the reaction was carried out with 4 (0.5 mmol) and LTMP (2.0 mmol) in THF (5 mL) under argon atmosphere and was monitored by TLC to
ensure complete conversion. The reaction time is not more than 16 h (see Supplementary data).
b
Isolated yields.
c
The reaction was carried out with 4b (0.5 mmol) and LTMP (3.0 mmol) in THF (5 mL) under argon atmosphere.

C. Yuan et al. / Tetrahedron Letters 53 (2012) 6972–6976
6975
OMOM
O
OMOM
OTBS
O
O
O
LTMP (8.0 equiv.)
THF, -20 oC, 4h
1a
6a
81%
99%
OTBS
O
O
LTMP (8.0 equiv.)
THF, -20 oC, 4h
1a
6b
76%
100%
MeO OMe
O
O
LTMP (4.0 equiv.), THF
0 oC, 2h then rt,10h
LTMP (4.0 equiv.), THF
0 oC, 2h thenrt,10h
NR
NR
7
8
C5H11
Scheme 3.
O-Li+
O
Li
Li
O
O
O-Li+
O
O
O-Li+
excess LTMP
Workup
O
LTMP
C5H11
C5H11
O
O
LTMP (4.0 equiv.)
THF, 0 oC, 2h
LTMP
O
TBDPSCl
11
2e, 71%
O
OSiPh2tBu
Scheme 5.
O
(1)LTMP (4.0 equiv.)
THF, 0 oC-rt
OSiPh2tBu
(2)then TBDPSCl
(5.0 equiv.)
The observation of compound 2j could be ascribed to the inefficient
silylation of lithium enolate of 2j by TBDPSCl.11
C5H11
C5H11
C5H11
1j
2j, 47%
9, 24%
10, 92%
Interestingly, when compound 11 was treated with LTMP in
THF, 2e was obtained in 71% yield. The formation of compound
2e could be rationalized with the mechanism in Scheme 5. Other
than the unfunctionalized 1,3-dioxolanes, the stabilizing effect of
aromatic ring on carbanion makes the benzyl position deproto-
nated more facilely. The mechanistic pathway herein compensates
that illustrated in Scheme 3, altogether elucidating the reason why
dimethylketal and dioxane are inert under the same basic
condition.
In summary, we have developed an effective deprotection
methodology of dioxolanes derived from ketones, showing signifi-
cant chemoselectivity in the presence of acid-sensitive protected
hydroxyls and other ketals. We believe it could get wide applica-
tion in organic synthesis.
Scheme 4.
in similar results (Table 2, entries 5–8), illustrating that electronic
factor is not pivotal for this reaction. Accordingly compound 1i
without typical electronic contribution also provided a similar re-
sult as compounds 1e–1h (Table 2, entry 9). However, the method-
ology failed to give the desired products when it was applied to
dioxolanes from aldehydes or conjugated ketones.
More importantly, this methodology displays excellent che-
moselectivity in the presence of acid-sensitive protective groups
as illustrated in Table 3. Compounds 4a–4b with protected hydro-
xyl groups in the molecule were examined and transformed to the
deprotected ketals 5a–5b smoothly (Table 3, entries 1–2). Other
examples were shown for the smoothly chemoselective deprotec-
tion of 1,3-dioxolane in the presence of 1,3-dioxane or dimethylk-
etal or 1,3-dithiane (Table 3, entries 3–5).
Acknowledgments
We appreciate the financial support from NSFC (20872098,
21021001, 21172154, J1103315) and National Basic Research Pro-
gram of China (973 Program, 2010CB833200). We also thank the
To illustrate the generality of this chemoselectivity, control
experiments were conducted. When an equimolar mixture of
dioxolane of
a-tetralone 1a and 4-phenyl-2-butanol protected by
Analytical
recording.
& Testing Center of Sichuan University for NMR
the tert-butyldimethylsilyl (TBS) or methoxymethyl (MOM) (6a–
6b) was treated with LTMP, compound 1a was chemoselectively
deprotected over compounds 6 (Scheme 3). The preferential depro-
tection of 1,3-dioxolanes over 1,3-dioxanes and dimethylketal was
also elucidated. When 1,3-dioxane (7) or dimethylketal (8) was
treated with LTMP in THF at 0 °C for 2 h and then at room temper-
ature for 10 h, no reaction occurred in the end (Scheme 3).
To have insightful information on the reaction mechanism, a
trapping experiment was executed. Thus exposure of 1j to LTMP
in THF furnished the enolate of ketone and acetaldehyde through
a fragmentation process, which were trapped with TBDPSCl to af-
ford compounds 9 and 10 along with compound 2j (Scheme 4).
Supplementary data
Supplementary data (characterization data for new compounds)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2012.10.037.
References and notes
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6976
C. Yuan et al. / Tetrahedron Letters 53 (2012) 6972–6976
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O
OSiPh2tBu
1) base (1.6 equiv.), -78°C, 30 min
2) TBDPSCl (1.2 equiv.), -78°C-rt, 2 h
3) sat. NaHCO3 (aq)
entry
base
yield
a
b
c
LTMP 24% (40% cyclohexone recovered)
LHMDS 23% (43% cyclohexone recovered)
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KHMDS
94%
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