Silicasulfuric acid/NaNO3 as a new reagent for the deprotection of S,S-acetals under mild conditions

Article abstract of DOI:10.1055/s-2006-926431

An efficient, mild and chemoselective method for the deprotection of S,S-acetal compounds to their corresponding carbonyl compounds using silicasulfuric acid/NaNO₃ is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926431

1480
PAPER
Silicasulfuric Acid/NaNO3 as a New Reagent for the Deprotection of
S,S-Acetals under Mild Conditions
S
ilicasulfuric Acid
b
/NaN
O
for
Deprotection
o
of
S
,
S
-Aceta
l
ls R. Hajipour,*a,b Amin Zarei,a Leila Khazdooz,a Arnold E. Ruohob
a
Pharmaceutical Research Laboratory, College of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran
Department of Pharmacology, University of Wisconsin Medical School, 1300 University Avenue, Madison, WI 53706-1533, USA
E-mail: haji@cc.iut.ac.ir
b
Received 9 January 2005; revised 2 December 2005
R1
R1
R2
S
S
NaNO3/Silicasulfuric acid
Abstract: An efficient, mild and chemoselective method for the
deprotection of S,S-acetal compounds to their corresponding car-
bonyl compounds using silicasulfuric acid/NaNO3 is reported.
(CH2)n
O
wet SiO2 (60% w/w)
CH2Cl2, r.t.
R2
n = 0, 1
R1, R2 = Alk, Ar, H
Key word: silicasulfuric acid, sodium nitrate, deprotection,
S,S-acetal
Scheme 1
The development of mild and selective methods for the
protection and deprotection of functional groups is an es-
sential step in the synthesis of natural products with mul-
Table 1 Dethioacetalization of 4-Methoxyphenyl-1,3-dithiolane in
the Presence of Supported Silicasulfuric Acid/NaNO3 on Wet SiO2
tifunctional groups. Thioacetalization is a well-known (60% w/w)
reaction that protects the carbonyl groups of aldehydes
Solvent
Time
Overall
4-Methoxy- 4-Methoxy-
and ketones,1 and is frequently used as a synthetic step for
yield (%)c benzalde- benzoic acid
the preparation of natural products.2 Their stability under
acidic and basic conditions makes thioacetals versatile
hyde (%)
(%)
5
MeCNa
18 h
25
30
85
90
98
55
20
25
75
75
93
45
carbonyl protecting groups.3,4
Acetonea
Et2Oa
18 h
5
Therefore, the protection and deprotection of carbonyl
functional groups remain crucial challenges to organic
chemists. Experience shows that the critical parameters
are generally the stability and cleavage of the protecting
group rather than its introduction. Therefore, regeneration
of the parent carbonyl group from its masked form seems
to be a useful synthetic process. While there are several
methods for the deprotection of thioacetals,5,6 most of
these methods are toxic to environment, expensive, and
their preparations are difficult.5
18 h
10
15
5
Cyclohexanea
15 min
10 min
25 min
a
CH2Cl2
Solvent-freeb
10
a Stirred at r.t.
b Ground at r.t.
c Monitored by TLC and GC.
During the course of our studies on the application of solid
acids, we have found that silicasulfuric acid has many ad-
vantages over sulfuric acid. This reagent is safe, easy to
handle, environmentally benign, and presents fewer dis-
posal problems. Therefore, silicasulfuric acid is an excel-
lent candidate for sulfuric acid replacement in organic
reactions.7 Herein, we wish to report the use of silicasul-
furic acid/NaNO3 as a convenient, mild and efficient re-
agent for conversion of S,S-acetals to the corresponding
parent carbonyl compounds (Scheme 1).
As shown in Table 1, the reaction yield in dichlo-
romethane is higher and the reaction time shorter than in
other reaction conditions. To evaluate the efficiency of
this system, we examined the reaction of 4-methoxy-
phenyl-1,3-dithiolane with silicasulfuric acid without us-
ing NaNO3 (Scheme 2).
Silicasulfuric acid
(2 mmol)
S
S
MeO
CHO
MeO
Initially, conversion of 4-methoxyphenyl-1,3-dithiolane
to 4-methoxybenzaldehyde was carried out with support-
ed silicasulfuric acid/NaNO3 on wet SiO2 (60% w/w) in
various solvents and solvent-free conditions, the results of
which are summarized in Table 1.
wet SiO2 (60%)
CH2Cl2, r.t., 18 h
(1 mmol)
negligible
Scheme 2
We also tried this reaction using only sulfuric acid. As
shown in Scheme 3, sulfuric acid was not suitable for this
conversion.
SYNTHESIS 2006, No. 9, pp 1480–1484
Advanced online publication: 11.04.2006
x
x
.
x
x
.2
0
0
6
DOI: 10.1055/s-2006-926431; Art ID: M00105SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Scheme 3
Silicasulfuric Acid/NaNO3 for Deprotection of S,S-Acetals
1481
Sulfuric acid
(25%)
S
S
MeO
MeO
CHO
+
MeO
COOH
reflux, 3 h
35%
(1 mmol)
10%
SiO2OSO3Na
+
HNO3
SiO2OSO3H
SiO2OSO3H
+
+
NaNO3
HNO3
Different kinds of S,S-acetals were treated with silicasul-
furic acid/NaNO3 and wet SiO2 (60% w/w) in dichlo-
romethane. The corresponding carbonyl compounds were
obtained in good yields (Table 2). The possible mecha-
nism for this reaction is outlined in Scheme 4. A bright-
red heterogeneous solution was obtained immediately,
what might be due to the formation of complex (I). Then
this complex undergoes hydrolysis to the corresponding
carbonyl compound as shown in Scheme 4.8
–
+
SiO2OSO3
+
NO2
+
H2O
R1
R2
S
R1
R2
S
S
(CH2)n
+
(CH2)n
+ NO2
S+
NO2 (I)
R1
R2
R1
R2
R1
R2
–H
S
(CH2)n
S
O
In order to evaluate the selectivity of this reagent, we stud-
ied the conversion of S,S-acetals to the corresponding car-
bonyl compounds in the presence of other protecting
groups (Table 3, entries 1–7). In all reactions except en-
tries 1 and 2, cleavage of S,S-acetals was carried out in
good selectivity. We also investigated dethioacetalization
reactions in the presence of oxidizable functional groups
such as alcohols (Table 3, entries 8–10). Using this re-
agent, the highly selective conversion of S,S-acetals to the
corresponding carbonyl compounds was observed.
S
(CH2)n
S
O
NO2
NO2
H
H2O
Scheme 4
Table 2 Deprotection of Various S,S-Acetals in the Presence of Silicasulfuric Acid/NaNO3 and Wet SiO2 (60% w/w) in Dichloromethane at
Room Temperaturea,b
Entry
1
Substrate
Product
Time (min)
10
Yield (%)
80c
O
S
S
CH
2
3
15
15
86
85
O
S
S
Br
Cl
Br
Cl
CH
O
CH
S
S
4
5
15
15
88
90
S
O
Cl
Cl
Cl
CH
S
S
S
O2N
O
CH
6
7
10
15
85c
84c
S
S
O
MeO
MeO
MeO
MeO
CH
O
S
S
CH
8
9
10
15
80c
86c
MeO
MeO
O
S
CH
S
O
CH
S
S
Me
Me
Synthesis 2006, No. 9, 1480–1484 © Thieme Stuttgart · New York

1482
A. R. Hajipour et al.
PAPER
Table 2 Deprotection of Various S,S-Acetals in the Presence of Silicasulfuric Acid/NaNO3 and Wet SiO2 (60% w/w) in Dichloromethane at
Room Temperaturea,b (continued)
Entry
10
Substrate
Product
Time (min)
10
Yield (%)
82c
MeO
MeO
MeO
MeO
O
S
S
CH
11
12
13
10
15
20
85c
91
90
S
S
O
CH
CH
CH
CH CH
O
S
S
O2N
CH
O2N
O
NO2
S
S
CH
NO2
14
15
16
15
15
15
88
S
O
Cl
Cl
CH
S
S
85c
82c
O
MeO
MeO
MeO
MeO
CH
S
O
S
CH
S
17
18
O
25
25
91
85
S
S
Me
Me
Me
MeO
O
O
O
S
S
S
S
Me
MeO
MeO
MeO
MeO
19
20
25
30
85
88
Me
Me
Me
S
S
Me
O2N
O2N
21
22
23
24
25
25
25
25
25
40
86
87
86
85
88
O
O
S
S
H
H
S
S
S
O
S
S
S
O
O
S
S
Me
Ph
Me
Cl
Cl
Cl
Cl
26
45
85
O
S
S
Ph
Synthesis 2006, No. 9, 1480–1484 © Thieme Stuttgart · New York

PAPER
Silicasulfuric Acid/NaNO3 for Deprotection of S,S-Acetals
1483
Table 2 Deprotection of Various S,S-Acetals in the Presence of Silicasulfuric Acid/NaNO3 and Wet SiO2 (60% w/w) in Dichloromethane at
Room Temperaturea,b (continued)
Entry
27
Substrate
Product
Time (min)
45
Yield (%)
86
O
S
S
S
Ph
Ph
28
29
40
45
90
85
O
S
O
S
S
Me
Me
Ph
Ph
a The yields refer to the isolated products after purification.
b All of the products were characterized by physical data and their spectra (IR, 1H NMR, TLC and GC).
c Corresponding acid (5%) was obtained.
Table 3 Comparison of the Cleavage of S,S-Acetals in the Presence of Other Protecting Groups and Free Alcoholsa,b
Example
1
Cleavage reaction
8 min
r.t.
S
+ PhCH2CH2OSi(Me)3
(1 mmol)
Me
CHO + PhCH2CH2OH
95%
Me
S
5%
(1 mmol)
2
3
4
10 min
r.t.
S
+
CH2OH
85%
Me
CHO
OTHP
(1 mmol)
+
Me
S
(1 mmol)
10%
15 min
S
O
O
+
O2N
CHO
Me
CHO
+
Me
Me
O2N
r.t.
S
(1 mmol)
(1 mmol)
(1 mmol)
18%
80%
NO2
NO2
O
O
S
S
O
+
Me
Me
CHO
CHO
+
O
15 min
r.t.
92%
93%
(1 mmol)
100%
5
OAc
OAc
OAc
15 min
r.t.
S
S
+
O2N
+
Me
O2N
OAc
(1 mmol)
(1 mmol)
COOEt
100%
6
7
30 min
S
+
CHO
COOEt
100%
O2N
+
O2N
r.t.
S
(1 mmol)
(1 mmol)
95%
O
O
30 min
r.t.
S
+
NHCMe
Me
CHO
+
Me
NHCMe
S
(1 mmol)
(1 mmol)
100%
90%
8c
9
S
S
30 min
+
+
MeO
O2N
CH2OH
CH2OH
Me
Me
CHO
CHO
+
+
Me
Me
MeO
O2N
CH2OH
(1 mmol)
r.t.
(1 mmol)
(1 mmol)
98%
92%
88%
30 min
r.t.
S
S
CH2OH
(1 mmol)
0%
Synthesis 2006, No. 9, 1480–1484 © Thieme Stuttgart · New York

1484
A. R. Hajipour et al.
PAPER
Table 3 Comparison of the Cleavage of S,S-Acetals in the Presence of Other Protecting Groups and Free Alcoholsa,b (continued)
Example
10
Cleavage reaction
30 min
r.t.
S
+ PhCH2OH
0%
Me
CHO
PhCH2CH2OH
(1 mmol)
+
Me
S
90%
(1 mmol)
a All reactions were carried out with NaNO3/silicasulfuric acid (1.2:2 molar ratio) and wet SiO2 (60% w/w) (0.5 g) in CH2Cl2 (8 mL).
b The progress of the reactions was determined by TLC/GC analysis.
c Only a trace of p-methoxybenzaldehyde was observed.
ed a mixture of p-methylphenyl-1,3-dithiolane (0.196 g, 1 mmol)
and 1,1-diacetoxy-1-(4-nitrophenyl)methane (0.253 g, 1 mmol) and
then the reaction mixture was stirred for 15 min. The progress of the
reaction was followed by TLC/GC. 4-Methylbenzaldehyde was ob-
tained in 93% yield and 1,1-diacetoxy-1-(4-nitrophenyl)methane
remained unaffected (Table 3, entry 5).
In conclusion, we have developed a simple, mild, inex-
pensive, and environmentally safe method for the depro-
tection of S,S-acetals. High yields and short reaction times
are noteworthy features of the reported method.
Products were characterized by comparison of authentic samples
(IR, 1H NMR spectrum, mp, mixed mp and co-TLC analysis) with
those obtained by literature methods5 or alternative methods of syn-
thesis. All mps were taken on a Gallenkamp melting apparatus and
Acknowledgment
We gratefully acknowledge the funding support received for this
project from the Isfahan University of Technology (IUT), IR Iran.
Further financial support from the Center of Excellence in Chemi-
stry Research (IUT) is gratefully acknowledged.
1
are uncorrected. H NMR spectra were recorded on a Varian 250
NMR Spectrometer operating at 250 MHz. The spectra were mea-
sured in CCl4 and CDCl3 relative to TMS (d = 0.00 ppm). GC anal-
ysis was run with a Shimadzu GC-14A instrument. IR spectra were
recorded on a Shimadzu 435 IR spectrophotometer. Spectra of sol-
ids were measured using KBr pellets. Silicasulfuric acid was pre-
pared according to a previously reported method.7
References
(1) Greene, T. W. Protective Groups in Organic Synthesis;
Wiley: New York, 1981.
(2) Kunz, H.; Waldmann, H. In Comprehensive Organic
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631.
(5) Hajipour, A. R.; Khoee, S.; Ruoho, A. E. Org. Prep. Proced.
Int. 2003, 35, 527.
Dethioacetalization of p-Chlorophenyl-1,3-dithiolane Using
Silicasulfuric Acid/NaNO3 and Wet SiO2(60% w/w);
Typical Procedure
A mixture of p-chlorophenyl-1,3-dithiolane (0.21 g, 1 mmol), sili-
casulfuric acid (0.55 g, 2 mmol), NaNO3 (0.10 g, 1.2 mmol), wet
SiO2 (0.5 g; 60% w/w) and CH2Cl2 (5 mL) was stirred for 15 min in
a round-bottom flask. The progress of the reaction was followed by
TLC/GC. After the reaction was completed, CH2Cl2 (2 × 10 mL)
was added to the reaction mixture and after vigorous stirring the sol-
id was removed by filtration through a sintered glass funnel and
then the filtrate was transferred into a separatory funnel and washed
with NaHCO3 (5%). The organic layer was dried over anhyd
Na2SO4 and the solvent was removed under reduced pressure. The
residue was purified through a short column of silica gel (cyclohex-
ane–EtOAc, 3:1) to obtain pure p-chlorobenzaldehyde [yield: 0.12
g (88%); mp 45–47 °C].
(6) Kamal, A.; Reddy, P. S. M. M.; Reddy, R. Tetrahedron Lett.
2003, 44, 2857.
(7) (a) Hajipour, A. R.; Mirjalili, B. F.; Zarei, A.; Khazdooz, L.;
Ruoho, A. E. Tetrahedron Lett. 2004, 45, 6607.
(b) Zolfigol, M. A. Tetrahedron 2001, 57, 9509.
(8) (a) Fuji, K.; Ichikawa, K.; Fujita, E. Tetrahedron Lett. 1978,
19, 3561. (b) Zolfigol, M. A.; Mirjalili, F.; Bamoniri, A.;
Karimi Zarchi, M. A.; Zarei, A.; Khazdooz, L.; Noei, J. Bull.
Korean Chem. Soc. 2004, 25, 1414.
Dethioacetalization of p-Methylphenyl-1,3-dithiolane in the
Presence of 1,1-Diacetoxy-1-(4-nitrophenyl)methane;
Typical Procedure
To a mixture of silicasulfuric acid (0.55 g, 2 mmol), NaNO3 (0.10 g,
1.2 mmol), wet SiO2 (0.5 g; 60% w/w) and CH2Cl2 (8 mL) was add-
Synthesis 2006, No. 9, 1480–1484 © Thieme Stuttgart · New York