Simple, mild and efficient thioacetalization and transthioacetalization of carbonyl compounds and deprotection of thioacetals: Unique role of thiols in the selectivity of thioacetalization

Article abstract of DOI:10.1055/s-2004-834934

Silica supported sodium hydrogen sulfate (NaHSO₄·SiO ₂) has been employed for efficient thioacetalization and transthioacetalization of carbonyl compounds in CH₂Cl₂ at room temperature. Selectivity of thioacetalization was dependent on the thiols used for the conversion. The same catalyst was also found to be effective for deprotection of thioacetals in CH₂Cl₂-H₂O at room temperature.

Full text of DOI:10.1055/s-2004-834934

250
PAPER
Simple, Mild and Efficient Thioacetalization and Transthioacetalization of
Carbonyl Compounds and Deprotection of Thioacetals: Unique Role of Thiols
in the Selectivity of Thioacetalization1
Unique Role of
T
i
hiols in
s
the
S
ele
c
w
tivity of
T
hioaceta
a
lization nath Das,* Ravirala Ramu, Majjigapu Ravinder Reddy, Gurram Mahender
Organic Chemistry Division – I, Indian Institute of Chemical Technology, Hyderabad – 500 007, India
Fax +91(40)7160512; E-mail: biswanathdas@yahoo.com
Received 6 September 2004
Abstract: Silica
supported
sodium
hydrogen
sulfate
(NaHSO4·SiO2) has been employed for efficient thioacetalization
and transthioacetalization of carbonyl compounds in CH2Cl2 at
room temperature. Selectivity of thioacetalization was dependent
on the thiols used for the conversion. The same catalyst was also
found to be effective for deprotection of thioacetals in CH2Cl2–H2O
at room temperature.
Keywords: carbonyl compounds, thioacetalization, transthioace-
talization, deprotection of thioacetals, NaHSO4·SiO2, selectivity
Scheme 1
and aliphatic) when EtSH was used for thioacetalization.
Thioacetalization is an important process for protection of The reaction was completed within 5–10 minutes to afford
carbonyl group and is frequently used in the synthesis of the products in excellent yields. Several functional groups
multifunctional organic molecules.2 Thioacetals are quite such as hydroxyl, ether, halogen, nitro, amino and allyl
stable towards different reagents under various reaction groups remained intact. Electron-donating or electron-
conditions.2 They are also useful as acyl carbanion equiv- withdrawing groups did not affect the reaction. Thioace-
alents in organic synthesis.3 The deprotection of thioace- talization was also carried out with long chain (C-10, C-
tals at the desired stage of synthesis to generate the parent 12 and C-16) thiols. The important matter is that the selec-
carbonyl compounds is also highly required. In general, tivity of the reaction was highly dependent on the thiols
thioacetalization4 and dethioacetalization5 are carried out used for the conversion. With long chain thiols, the con-
with various protic and Lewis acids. Despite their poten- version was equally efficient for the aromatic aldehydes
tial utilities many of the reported methods are associated as with EtSH to produce the corresponding thioacetals in
with certain disadvantages such as treatment with strong very high yields within 10 minutes (Table 1). However,
acids, long reaction times, drastic reaction conditions, tox- aliphatic aldehydes or ketones (aliphatic and aromatic) af-
ic reagents, expensive catalysts, multistep operations, dis- forded no product with these long chain thiols under sim-
turbance to other functional groups and unwanted side ilar experimental conditions. When the reaction times
reactions. Thus, still there is a need to develop novel and were increased to 2 hours an aliphatic aldehyde formed
efficient methods for thioacetalization and dethioacetal- the thioacetals with long chain thiols with the yields of
ization, though these conversions have been studied well. 58–64%, while a ketone formed the thioacetals with long
chain thiols in yields of 15–18% only. Thus with the prop-
In continuation of our work6 on the application of silica-
er choice of reacting thiols general thioacetalization as
supported sodium hydrogen sulfate (NaHSO4·SiO2) as a
well as selective thioacetalization of carbonyl function of
heterogeneous catalyst in organic synthesis we have re-
aromatic and aliphatic aldehydes and ketones can be
cently observed that the catalyst can be employed effi-
achieved (Schemes 2 and 3). Previously the role of thiols
ciently for thioacetalization of carbonyl compounds as
on the selectivity of thioacetalization of carbonyl com-
well as for deprotection of thioacetals (Scheme 1).
pounds has not been well studied.
Several aromatic, heterocyclic, aliphatic and conjugated
When thioacetalization was carried out with ethane dithi-
aldehydes were converted into thioacetals by treatment
ol, aldehydes were protected within 3–3.5 hours to form
with thiols in CH2Cl2 in the presence of NaHSO4·SiO2 at
the thioacetals in high yields (72–81%) while ketones like
room temperature (Table 1). Various Ketones also under-
acetophenone and benzophenone did not afford the dithi-
went thioacetalization under such treatment. The reaction
olanes during this period under the similar experimental
was carried out with thiols of different chain lengths. The
conditions (Scheme 4). Thus the differences in behavior
method was general for aldehydes and ketones (aromatic
of ethane thiol and ethane dithiol towards the thioacetal-
ization of aldehydes and ketones (regarding times and se-
SYNTHESIS 2005, No. 2, pp 0250–0254
x
x
.
x
x
.2
0
0
4
lectivity) are noteworthy.
Advanced online publication: 24.11.2004
DOI: 10.1055/s-2004-834934; Art ID: P10504SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Unique Role of Thiols in the Selectivity of Thioacetalization
251
a
Table 1 Thioacetalization and Transthioacetalization of Carbonyl Compounds Using NaHSO4·SiO2
Entry
Substrate
Product 2
Time (min)
5
Isolated
yield (%)
Ref.
5i
a
98
b
c
d
e
f
5
5
5
5
5
96
95
97
94
93
5i
5i
5i
5j
5j
g
5
96
h
i
8
5
5
92
91
94
5i
5i
5i
j
k
l
5
5
97
90
5j
m
n
10
10
93
91
5i
5j
o
8
93
5j
5i
p
q
10
10
95
80
r
s
10
10
78
75
Synthesis 2005, No. 2, 250–254 © Thieme Stuttgart · New York

252
B. Das et al.
PAPER
Table 1 Thioacetalization and Transthioacetalization of Carbonyl Compounds Using NaHSO4·SiO2a (continued)
Entry
Substrate
Product 2
Time (min)
10
Isolated
yield (%)
Ref.
t
75
u
v
10
10
90
82
5i
5f
w
10
78
5f
x
y
z
10
5
92
95
93
5i
5i
5i
10
a Products were characterized from their spectral (IR, 1H NMR and MS) data.
Scheme 4
The present method is also suitable for transthioacetaliza-
tion of carbonyl compounds. Different S,S-acetals have
been prepared from the corresponding O,O-acetals in very
high yields within a short period of time (5–10 min)
(Table 1). However, S,S-acetals on treatment with ethane-
1,2-diol or propane-1,3-diol in the presence of
NaHSO4·SiO2 in CH2Cl2 afforded O,O-acetals at room
temperature (Scheme 5).
Scheme 2
Scheme 3
Scheme 5
Synthesis 2005, No. 2, 250–254 © Thieme Stuttgart · New York

PAPER
Unique Role of Thiols in the Selectivity of Thioacetalization
253
Deprotection of thioacetals was also carried out using and deprotection of thioacetals using the same catalyst
NaHSO4·SiO2 at room temperature. Various thioacetals (NaHSO4·SiO2) in different solvent systems. The method
were converted into their parent carbonyl compounds is associated with mild experimental conditions, utiliza-
(Table 2) by employing the catalyst in CH2Cl2–H2O (4:1) tion of an inexpensive and non-toxic catalyst, short reac-
within 10–20 minutes. The yields of the carbonyl com- tion times and excellent yields. The unique feature of the
pounds were excellent. Deprotection could also be carried present thioacetalization is its selectivity depending on the
out in MeOH but time required was longer (2–3 h).
nature of the reacting thiols. Transthioacetalization can
also be achieved following the similar process. We feel
that the developed method will find important applica-
tions in organic synthesis.
The catalyst, NaHSO4·SiO2 works under heterogeneous
conditions. The catalytic activity of the reagent has not yet
been explored widely. In recent years heterocyclic cata-
lysts are of increasing attention because of economic and
environmental considerations. The present catalyst can be
easily prepared7 from the readily available ingredients,
NaHSO4 and silica gel (finer than 200 mesh). It can be
easily handled and removed from the reaction mixture by
filtration. The catalyst should be properly activated before
use. The experimental procedures for both thioacetaliza-
tion and deacetalization using this catalyst are very sim-
Melting points were measured on a Buchi 510 instrument and are
1
uncorrected. The H NMR spectra were recorded in CDCl3 on a
Varian Gemini 200 MHz spectrometer using TMS as an internal
standard and EI–MS on a VG Micromass 7070H (70eV) instru-
ment. Column Chromatography was carried out with silica gel 100–
200 mesh and TLC with silica gel GF254
.
Thioacetalization and Transthioacetalization; General Proce-
ple. In absence of the catalyst or only with NaHSO4 or dure
To a stirred mixture of a carbonyl compound (1 mmol) or an acetal
silica gel the protection of carbonyl compounds with thi-
ols as well as deprotection of thioacetals under the present
experimental conditions could not be achieved.
(1 mmol) and alkyl thiol (2.2 mmol) or ethane dithiol (1.2 mmol) in
CH2Cl2 (10 mL), activated NaHSO4·SiO2 (200 mg) was added at r.t.
The progress of the reaction was monitored by TLC. After comple-
tion of the reaction, the mixture was filtered and the filtrate was con-
centrated. The residue was subjected to column chromatography
over silica gel and the column was eluted with EtOAc–hexane (1:4)
In conclusion, we have developed a very simple and effi-
cient method for thioacetalization of carbonyl compounds
a
Table 2 Deprotection of Thioacetals Using NaHSO4·SiO2
Entry
Substrate
Product
Time (min)
10
Isolated yield (%)
96
a
b
c
15
10
93
90
d
15
85
e
f
20
20
83
80
g
15
20
78
76
h
a Products were characterized by comparison of their spectral (IR, 1H NMR and MS) data with those of authentic samples.
Synthesis 2005, No. 2, 250–254 © Thieme Stuttgart · New York

254
B. Das et al.
PAPER
to afford pure thioacetal. The spectral and analytical data of the un-
known compound are given below.
1H NMR: d = 6.98 (m, J = 1.5 Hz, 1 H), 6.82–6.75 (m, 2 H), 5.48 (s,
1 H), 4.72 (s, 1 H), 3.91 (s, 3 H), 2.54–2.40 (m, 4 H), 1.57–1.46 (m,
4 H), 1.38–1.19 (m, 52 H), 0.86 (t, J = 7.0 Hz, 6 H).
4-N,N-Dimethylbenzaldehyde Diethylthioacetal (2e)
Light yellow oil.
1H NMR: d = 7.30 (d, J = 8.0 Hz, 2 H), 6.68 (d, J = 8.0 Hz, 2 H),
4.86 (s, 1 H), 2.98 (s, 6 H), 2.62–2.43 (m, 4 H), 1.16 (t, J = 7.0 Hz,
6 H).
EIMS: m/z = 650 [M+], 635, 378, 257, 224, 123.
Anal. Calcd for C40H74O2S2: C, 73.85; H, 11.39. Found: C, 73.72;
H, 11.46.
Deprotection of Thioacetals; General Procedure
EIMS: m/z = 255 [M+], 240, 194, 179, 120.
Thioacetal (1 mmol) and NaHSO4·SiO2 (200 mg) were taken in
CH2Cl2–H2O (4:1, 10 mL). The mixture was stirred at r.t. After
completion of the reaction the mixture was filtered. The concentrat-
ed filtrate was purified by column chromatography over silica gel
using EtOAc–hexane (1:4) as eluent to produce the corresponding
parent carbonyl compound.
Anal. Calcd for C13H21NS2: C, 61.18; H, 8.24; N, 5.49. Found: C,
61.32; H, 8.17; N, 5.33.
3-Nitrobenzaldehyde Diethylthioacetal (2k)
Light yellow oil.
1H NMR : d = 8.28 (br d, J = 1.5 Hz, 1 H), 8.12 (br dd, J = 8.0, 1.5
Hz, 1 H), 7.80 (br dd, J = 8.0, 1.5 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 1 H),
4.92 (s, 1 H), 2.58–2.46 (m, 4 H), 1.22 (t, J = 7.0 Hz, 6 H).
Acknowledgment
The authors thank UGC, New Delhi for financial assistance.
EIMS: m/z = 257 [M+], 196, 168, 121.
Anal. Calcd for C11H15NO2S2: C, 51.36; H, 7.55; N, 5.45. Found: C,
51.55; H, 7.72; N, 5.38.
References
(1) Part 39 in the series ‘Studies on novel synthetic
methodologies’; IICT Communication No. 041106.
(2) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed.; Wiley: New York, 1991, 178–
207. (b) Kocienski, P. J. Protecting Groups; Thieme:
Stuttgart, 1994, 156–170.
4-Hydroxybenzaldehyde Didodecylthioacetal (2q)
Mp 141–143 °C.
1H NMR: d = 7.22 (d, J = 8.0 Hz, 2 H), 6.70 (d, J = 8.0 Hz, 2 H),
5.28 (br s, 1 H), 4.76 (s, 1 H), 2.60–2.38 (m, 4 H), 1.58–1.42 (m, 4
H), 1.38–1.04 (m, 36 H), 0.82 (t, J = 7.0 Hz, 6 H).
(3) (a) Corey, E. J.; Seebach, D. Angew Chem. Int. Ed. Engl.
1965, 4, 1075. (b) Corey, E. J.; Seebach, D. J. Org. Chem.
1966, 31, 4097.
EIMS: m/z = 508 [M+], 307, 201, 139.
Anal. Calcd for C31H56OS2: C, 73.23; H, 11.02. Found: C, 73.43; H,
11.18.
(4) (a) Colvin, E. W.; Raphael, R. A.; Roberts, J. S. J. Chem.
Soc., Chem. Commun. 1971, 858. (b) Corey, E. J.; Erickson,
B. W. J. Org. Chem. 1971, 36, 3553. (c) Ho, T. L.; Ho, H.
C.; Wong, C. M. J. Chem. Soc., Chem. Commun. 1972, 791.
(d) Dishi, T.; Kamemoto, K.; Ban, Y. Tetrahedron Lett.
1972, 13, 1085. (e) Ellision, R. A.; Lukenbach, E. R.; Chiu,
C. W. Tetrahedron Lett. 1975, 499. (f)Schmittel,M.;Levis,
M. Synlett 1996, 315. (g) Hirano, A.; Ukawar, K.; Yakabe,
S.; Clark, J. H.; Morimoto, T. Synthesis 1997, 858.
(5) (a) Dijerassi, C.; Gorman, M. J. Am. Chem. Soc. 1953, 75,
3704. (b) Fieser, L. F. J. Am. Chem. Soc. 1954, 76, 1945.
(c) Olah, G. A.; Narang, S. C.; Meider, D.; Salem, G. F.
Synthesis 1981, 282. (d) Corey, E. J.; Shimoji, K.
3-Nitrobenzaldehyde Didecylthioacetal (2r)
Mp 105–107 °C.
1H NMR: d = 8.22 (br d, J = 1.5 Hz, 1 H), 8.01 (br dd, J = 8.0, 1.5
Hz, 1 H), 7.78 (br dd, J = 8.0, 1.5 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H),
4.82 (s, 1 H), 2.62–2.38 (m, 4 H), 1.60–1.42 (m, 4 H), 1.38–1.14 (m,
28 H), 0.84 (t, J = 7.0 Hz, 6 H).
EIMS: m/z = 481 [M+], 308, 168, 140.
Anal. Calcd for C27H47NO2S2: C, 67.36; H, 9.77; N, 2.91. Found :
C, 67.52; H, 9.61; N, 2.83.
Tetrahedron Lett. 1983, 24, 169. (e) Page, P. C. B.; Prodger,
J. C.; Westwood, D. Tetrahedron 1993, 49, 10355.
(f) Tateiwa, J.; Horiuchi, H.; Uemura, S. J. Org. Chem.
1995, 60, 4039. (g) Firouzabadi, H.; Iranpoor, N.; Karimi,
B. Synthesis 1999, 58. (h) Yadav, J. S.; Reddy, B. V. S.;
Pandey, S. K. Synlett 2001, 238. (i) Kamal, A.; Choudhan,
G. Tetrahedron Lett. 2003, 44, 3337. (j) Yadav, J. S.;
Reddy, B. V. S.; Kondaji, G. Chem. Lett. 2003, 32, 672.
(6) (a) Mahender, G.; Ramu, R.; Ramesh, C.; Das, B. Chem.
Lett. 2003, 32, 734. (b) Ramesh, C.; Banerjee, J.; Pal, R.;
Das, B. Adv. Synth. Catal. 2003, 557. (c) Ramesh, C.;
Ravindranath, N.; Das, B. J. Org. Chem. 2003, 68, 7101.
(7) Breton, G. W. J. Org. Chem. 1997, 62, 8952.
4-N,N-Dimethylbenzaldehyde Didodecylthioacetal (2s)
Mp 113–115 °C.
1H NMR: d = 7.28 (d, J = 8.0 Hz, 2 H); 6.64 (d, J = 8.0 Hz, 2 H),
4.78 (s, 1 H), 2.96 (s, 6 H), 2.62–2.36 (m, 4 H), 1.55–1.40 (m, 4 H),
1.35–1.02 (m, 36 H), 0.81 (t, J = 7.0 Hz, 6 H).
EIMS: m/z = 520 [M+], 319, 201, 168.
Anal. Calcd for C33H61NS2: C, 74.02; H, 11.40; N, 2.62. Found: C,
75.24; H, 11.29; N, 2.56.
4-Hydroxy-3-methoxybenzaldehyde Dihexadecylthioacetal (2t)
Mp 186–188 °C.
Synthesis 2005, No. 2, 250–254 © Thieme Stuttgart · New York