A useful and catalytic method for protection of carbonyl compounds into the corresponding 1,3-oxathiolanes and deprotection to the parent carbonyl compounds

Article abstract of DOI:10.1055/s-2002-20466

A wide variety of carbonyl compounds 1 can be easily protected to the corresponding 1,3-oxathiolanes 2 in good yields in the presence of catalytic amount of perchloric acid in dry CH₂Cl₂ at 0-5 °C. On the other hand, various 1,3-oxathiolanes 2 can be selectively deprotected to the parent carbonyl compounds 1 in very good yields by H₂MoO₄·H₂O-H₂O₂ catalyzed oxidation of ammonium bromide in the presence of perchloric acid in CH₂Cl₂-H₂O solvent system. Mild reaction condition, high selectivity, efficient and relatively good yields are some of the major advantages of the procedure.

Full text of DOI:10.1055/s-2002-20466

LETTER
463
A Useful and Catalytic Method for Protection of Carbonyl Compounds into
the Corresponding 1,3-Oxathiolanes and Deprotection to the Parent Carbonyl
Compounds1
A
U
seful and Ca
j
talytic
a
M
ethod fo
b
r
Protection
u
l
C
ompounds Mondal, Priti Rani Sahu, Abu T. Khan*
Department of Chemistry, Indian Institute of Technology, North Guwahati, Guwahati-781039, Assam, India
Fax +91(361)690762; E-mail: atk@postmark.net
Received 2 December 2001
Dedicated to my mentor Professor Goverdhan Mehta for his constant encouragement.
iii) treating the carbonyl compounds with 2-mercaptoeth-
Abstract: A wide variety of carbonyl compounds 1 can be easily
protected to the corresponding 1,3-oxathiolanes 2 in good yields in
the presence of catalytic amount of perchloric acid in dry CH2Cl2 at
0–5 °C. On the other hand, various 1,3-oxathiolanes 2 can be selec-
anol in the presence of catalytic amount of TMSOTf.7d All
these present methods have some drawbacks, harsh reac-
tion conditions,7a,b long reaction times,7c and also require
tively deprotected to the parent carbonyl compounds 1 in very good more expensive reagent TMSOTf7d as well as it is difficult
yields by H2MoO4 H2O-H2O2 catalyzed oxidation of ammonium
to handle. Similarly, a few methods are known for depro-
bromide in the presence of perchloric acid in CH2Cl2–H2O solvent
tection of 1,3-oxathiolanes into the parent carbonyl com-
system. Mild reaction condition, high selectivity, efficient and rela-
pounds such as i) by using isoamylnitrite,8a or
tively good yields are some of the major advantages of the proce-
chloroamines-T,8b ii) by employing TMSOTf alone,7d or
dure.
in the presence of p-nitrobenzaldehyde,8c iii) by using
Key words: protection, 1,3-oxathiolanes, O,S-acetals, deprotec-
polymer supported reagents p-nitrobenzaldehyde.8d Sur-
tion, molybdic acid, hydrogen peroxide, ammonium bromide, per-
prisingly, some of these methods have serious drawbacks
chloric acid
such as difficult to remove the by-product of 1,3-oxathi-
olanes derived from p-nitrobenzaldehyde,8c,d requires ex-
pensive polymer supported reagents,8d and sometimes it
The protection and deprotection of functional groups are
very common tactics in multistep organic synthesis.
Among the various functional groups, the protection of
carbonyl group as 1,3-oxathiolane is an important one due
fails to deprotect the non-benzylic oxathioacetals and also
require long reaction times.7d Some other methods are
also well known based on halonium ion sources such as
9c,d
NCS–AgNO3,9a,b I2–AgNO2 and NBS in acetone9e for
to the following applications. They are used as acyl car-
deprotection of a wide variety of oxathioacetals. Unfortu-
banion equivalents2 for carbon-carbon bond forming reac-
nately, these methods also suffer because of requirement
tions. They also serve as valuable starting materials for the
of a large molar excess of expensive reagents such as sil-
enantioselective synthesis of tertiary -hydroxy alde-
ver salts9a–9d and are incompatible with the substrates con-
hydes, -hydroxy acids and glycols, first demonstrated by
taining allylic double bonds.9e Very recently one more
Eliel and his co-workers.3 Later on, Utimoto and his group
method has also appeared for deprotection of oxathioace-
had also shown4 the application of chiral 1,3-oxathiolanes
tals by using glyoxylic acid and Amberlyst 15 in micro-
in organic synthesis. In addition, the use of O,S-acetals is
wave oven, which is also expensive.10 Therefore, there is
more convenient than the corresponding O,O-acetals or
still a scope to develop an alternative method for the pro-
S,S-acetals because they are comparatively more stable
tection as well as deprotection of carbonyl compounds as
than the corresponding O,O-acetals in acidic conditions
oxathioacetals, which might work under mild and eco-
and also easier to remove than S,S-acetals. Though a large
nomically cheaper reaction conditions.
number of methods are developed for protection and
deprotection of carbonyl compounds as dithioacetals,5
whereas only a few methods are known in the literature6
for oxathioacetals. The existing methods for protection
available so far are i) refluxing of carbonyl compounds
and 2-mercaptoethanol in benzene in the presence of cat-
alytic amount of p-toluene sulphonic acid7a or refluxing in
the presence of equimolar amount of boron trifluoride
etherate;7b ii) reaction of carbonyl compounds with 2-
mercaptoethanol in the presence of Lewis acid ZnCl2;7c
Taking cues from the knowledge of the reactivity of diper-
oxomolybdate(VI) for oxidation of bromide11 as well as
our ongoing research project12 to develop a new method-
ology we have conceived that a H2MoO4 H2O-H2O2 cata-
lyzed oxidation of ammonium bromide can be utilized for
the cleavage of 1,3-oxathiolanes. In this communication,
we wish to report a simple and catalytic method for pro-
tection of carbonyl compounds as oxathioacetals using a
catalytic amount of perchloric acid and deprotection of the
protected compounds to the parent carbonyl compounds
by involving molybdic acid, ammonium bromide, hydro-
gen peroxide and perchloric acid (Scheme). The catalyst
molybdic acid is used for the oxidation of ammonium bro-
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0463,0467,ftx,en;G33701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

464
E. Mondal et al.
LETTER
Next, We have tried to find out the suitable reaction con-
ditions for deprotection to get the parent carbonyl com-
pound. Various reaction conditions have been
investigated, with the result that a 1:1.14:0.1:0.3:9 sub-
strate–ammonium bromide–molybdic acid–perchloric
acid–hydrogen peroxide in dichloromethane-water sol-
vent (5:1, 6 mL per mmol of substrate) provides best re-
sult. By using the above typical reaction protocol,15 the
compound 2-[p-methoxyphenyl]-1,3-oxathiolane (2a) re-
acts smoothly to give the deprotected compound (1a) in
92% yield. The deprotected product 1a is also obtained
from the compound 2a in much shorter reaction time if the
amount of molybdic acid is increased from 0.1 equiva-
lents to 0.25 equivalents and ammonium bromide from
1.14 equivalents to 3 equivalents. Likewise, various 1,3-
oxathiolanes 2b–2n are deprotected easily to the desired
parent carbonyl compounds 1b–1n in good yields under
identical reaction conditions. The results are summarized
in the Table 2 and the products are fully characterized by
1H NMR, 13C NMR, and elemental analyses16 as well as
HOCH2CH2SH/HClO4 (0.1 equiv.), dry CH2Cl2, 0-5 °C
R1
R2
R1
R2
O
S
O
2
1
.
H2MoO4 H2O/H2O2/HClO4/NH4Br, CH2Cl2-H2O, 0-5 °C
R1 = alkyl or aryl, R2 = H or alkyl or aryl
Scheme
mide by H2O2 in the presence of perchloric acid and all
these chemicals are environmentally acceptable.
First, we have tried to optimize the reaction conditions for
protection of carbonyl compounds to obtain the desired
protected 1,3-oxathiolanes. The compound p-methoxy-
benzaldehyde (1a) reacts smoothly with 2-mercaptoeth-
anol in the presence of 0.1 equivalent amount of 70%
perchloric acid at 0–5 °C in dry CH2Cl2 to give the desired
protected compound 2a within 20 min in 68% yield. Like-
wise, we have converted various carbonyl compounds
1b–1n into the corresponding 1,3-oxathiolanes 2b–2n in
relatively good yield under identical reaction conditions.13
The results are summarized in Table 1, and all the protect-
ed compounds are fully characterized by 1H NMR and by
elemental analyses.14 It is important to mention that in
case of p-nitrobenzaldehyde (1d) we have got relatively
lower yields under identical reaction conditions.
1
comparing H NMR spectra with the authentic com-
pounds. In this procedure, direct oxidation of sulfur by hy-
drogen peroxide is not possible which has already been
investigated by others.17 It is noteworthy to highlight that
we did not notice any bromination at the double bond or
at the allylic position, for instance 2f, 2g and 2i. It is also
important to mention that the substrate 2e took longer re-
action time9e for deprotection than our catalytic method.
Table 1 Protection of Various Carbonyl Compounds to the Corresponding 1,3-Oxathiolanes in the Presence of Catalytic Amount of Per-
chloric Acid
Entry
Substrate 1
Time in [min]/ h
[20]
Product 2a
Yieldb (%)
68
a
S
MeO
MeO
CHO
O
b
c
[7]
[2]
68
71
OMe
OMe
O
S
MeO
CHO
CHO
CHO
MeO
MeO
MeO
MeO
MeO
O
S
MeO
MeO
d
e
1
35
62
S
O2N
RO
O2N
RO
O
[5]
S
CHO
O
R = TBDMS
R = TBDMS
f
1.0
61
O
S
O
CHO
O
Synlett 2002, No. 3, 463–467 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Useful and Catalytic Method for Protection of Carbonyl Compounds
465
Table 1 Protection of Various Carbonyl Compounds to the Corresponding 1,3-Oxathiolanes in the Presence of Catalytic Amount of Per-
chloric Acid (continued)
Entry
Substrate 1
Time in [min]/ h
8.0
Product 2a
Yieldb (%)
58
g
O
S
O
CHO
O
h
i
[12]
[10]
75
60
CHO
CHO
O
O
S
S
j
3.0
2.0
1.5
59
57
60
CHO
O
S
k
l
CHO
O
S
O
O
S
m
n
[30]
3.5
76
70
O
O
S
O
O
S
a Products have been characterized by 1H- NMR, 13C-NMR, mass spectra, and elemental analyses.
b Isolated yield.
Table 2 Cleavage of Various 1,3-Oxathiolanes by Employing H2MoO4 H2O–H2O2 Catalyzed Oxidation of Ammonium Bromide in the
Presence of Perchloric Acid
Entry
Substrate 1
Time in h
Product 2a
Yieldb/ %
a
2.5
92
80
S
20 minc
MeO
MeO
CHO
O
b
c
2.5
3.0
80
OMe
OMe
S
MeO
MeO
CHO
O
75
MeO
MeO
MeO
MeO
S
CHO
O
MeO
MeO
Synlett 2002, No. 3, 463–467 ISSN 0936-5214 © Thieme Stuttgart · New York

466
E. Mondal et al.
LETTER
Table 2 Cleavage of Various 1,3-Oxathiolanes by Employing H2MoO4 H2O–H2O2 Catalyzed Oxidation of Ammonium Bromide in the
Presence of Perchloric Acid (continued)
Entry
Substrate 1
Time in h
3.5
Product 2a
Yieldb/ %
85
d
S
TBDMSO
TBDMSO
CHO
O
e
f
3.5
92
89
S
O2N
O
O2N
O
CHO
CHO
O
2.25
S
O
g
6.0
4.0
75
91
S
O
O
CHO
O
h
CHO
CHO
S
S
O
i
3.25
68
O
j
1.5
76
90
72
CHO
O
S
k
l
1.5
CHO
O
S
2.25
O
S
S
O
O
m
n
2.5
4.0
80
96
O
O
S
O
a Products have been characterized by 1H-NMR, 13C-NMR, mass spectra, and elemental analyses.
b Isolated yield.
c Reaction is performed by using 0.25 equivalent of molybdic acid and 3 equivalents of ammonium bromide.
The formation of the parent carbonyl compounds from sulfur to form bromosulfonium complex, which is finally
their corresponding 1,3-oxathiolanes can be rationalized11 hydrolyzed by water to the carbonyl compound.
as follows. Molybdic acid reacts with H2O2 in the pres-
In conclusion, we have devised a simple and useful cata-
ence of HClO4 to generate diperoxomolybdate(VI), which
lytic method for protection of carbonyl compounds as 1,3-
oxidizes the bromide (Br–) to Br+ (which might also exist
oxathiolanes by using a catalytic amount of perchloric
–
as Br2 or Br3 ). Then the reactive species Br+ reacts with
acid and deprotection to the parent carbonyl compounds
chemoselectively by employing ammonium bromide, mo-
Synlett 2002, No. 3, 463–467 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A Useful and Catalytic Method for Protection of Carbonyl Compounds
467
(10) Chavan, S. P.; Soni, P.; Kamat, S. K. Synlett 2001, 1251.
(11) Meister, G. E.; Butler, A. Inorg. Chem. 1994, 33, 3269.
(12) (a) Mondal, E.; Bujar Barua, P. M.; Bose, G.; Khan, A. T.
Chem. Lett. 2002, in press. (b) Bujar Barua, P. M.; Sahu, P.
R.; Bose, G.; Khan, A. T. Synlett 2002, 81. (c) Mondal, E.;
Bose, G.; Sahu, P. R.; Khan, A. T. Chem. Lett. 2001, 1158.
(d) Mondal, E.; Bose, G.; Khan, A. T. Synlett 2001, 785.
(e) Bora, U.; Bose, G.; Chaudhuri, M. K.; Dhar, S. S.;
Gopinath, R.; Khan, A. T.; Patel, B. K. Org. Lett. 2000, 2,
247.
(13) A typical protection procedure: To a solution of
compound 1a (0.680 g, 5 mmol) in dry CH2Cl2 (10 mL) were
added 2-mercaptoethanol (0.4 mL, 5.5 mmol) and 70%
perchloric acid (30 L, 0.5 mmol) and the resulting solution
was stirred at 0–5 °C. The reaction was over within 20 min
as monitored by TLC. On completion, a saturated solution of
sodium bicarbonate (2 drops) was added to neutralize the
reaction mixture and the reaction mixture was extracted with
CH2Cl2 (2 15 mL). The organic layer was separated,
washed with water, and dried over anhydrous Na2SO4. The
solvent is removed in vacuo to give crude residue, which is
purified through a column of silica gel. The product (0.688
g, 70%) was obtained as a colorless gummy liquid.
lybdic acid, H2O2 and perchloric acid under very mild
conditions. It is significant to note that neither the olefinic,
allylic position nor the aromatic ring is brominated under
the experimental conditions. Due to its simplicity, gener-
ality, efficacy and cost effectiveness, this method is ex-
pected to have much wide applicability for protection and
deprotection of carbonyl compounds as 1,3-oxathioace-
tals. A similar deprotection reaction might also be possi-
ble by employing other alkali metal bromides, and this is
currently under investigation.
Acknowledgement
The authors are pleased to acknowledge the Department of Science
of Technology (DST), New Delhi [Grant No.: SP/S1/G-15/98 to
A.T.K] for research grant. E. M. and P. R. S. are thankful to CSIR
and DST for their research fellowships. The authors are also grate-
ful to the Director, I. I. T. Guwahati for providing general facilities
for this work. We are also thankful to the referees valuable com-
ments and suggestions.
(14) Spectroscopic data for compound 2g: 1H NMR (300 MHz,
CDCl3): 1.85–2.09 (m, 6 H, cyclohexyl CH2-), 3.16–3.32
(m, 2 H, -SCH2-), 3.87–3.95 (m, 1 H, -OCH2-), 4.48–4.54
(m, 1 H, -OCH2-), 4.79–4.91 (m, 1 H, OCH-), 5.83–5.99 (m,
3 H, olefinic H, -O-CH-S), 6.89 (d, 2 H, J = 8.5 Hz, ArH),
7.39 (d, 2 H, J = 8.5 Hz, ArH). Anal. Calcd. For C15H18O2S:
C 68.67, H 6.91. Found C 68.52, H 6.88.
(15) A typical deprotection procedure: To a stirred solution of
molybdic acid (0.018 g, 0.1 mmol) in water (1.0 mL), were
added 30% hydrogen peroxide solution (1 mL, 9 mmol) and
70% perchloric acid (0.3 mmol, 18 L) at ice-bath
References
(1) Future address for author correspondence: Department of
Chemistry, Visva–Bharati, Santiniketan, West Bengal, 731
235, India.
(2) Eliel, E. L.; Morris-Natschke, S. J. Am. Chem. Soc. 1984,
106, 2937.
(3) Lynch, J. E.; Eliel, E. L. J. Am. Chem. Soc. 1984, 106, 2943.
(4) Utimoto, K.; Nakamura, A.; Matsubara, S. J. Am. Chem.
Soc. 1990, 112, 8189.
(5) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons, Inc.: New York,
1999, 329–344.
(6) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons, Inc.: New York,
1999, 346–347.
(7) (a) Djerassi, C.; Gorman, M. J. Am. Chem. Soc. 1953, 75,
3704. (b) Wilson, G. E. Jr.; Huang, M. G.; Schloman, W. W.
Jr. J. Org. Chem. 1968, 33, 2133. (c) Fallis, A. G.; Yadav,
V. K. Tetrahedron Lett. 1988, 29, 897. (d) Ravindranathan,
T.; Chavan, S. P.; Dantale, S. W. Tetrahedron Lett. 1995, 36,
2285.
(8) (a) Fuji, K.; Ichikawa, K.; Fujita, E. Tetrahedron Lett. 1978,
3561. (b) Emerson, D. W.; Wynberg, H. Tetrahedron Lett.
1971, 3445. (c) Ravindranathan, T.; Chavan, S. P.; Vargese,
P. J.; Dantale, S. W.; Tejwani, R. B. J. Chem. Soc., Chem.
Commun. 1994, 1937. (d) Ravindranathan, T.; Chavan, S.
P.; Awachat, M. M. Tetrahedron Lett. 1994, 35, 8835.
(9) (a) Fyre, S. V.; Eliel, E. L. Tetrahedron Lett. 1985, 26,
3907. (b) Eliel, E. L.; Soai, K. Tetrahedron Lett. 1981, 21,
2859. (c) Nishide, K.; Yokota, K.; Nakamura, D.; Sumiya,
T.; Node, M.; Ueda, M.; Fuji, K. Tetrahedron Lett. 1993, 34,
3425. (d) Nishide, K.; Yokota, K.; Nakamura, D.; Sumiya,
T.; Node, M.; Ueda, M.; Fuji, K. Heterocycles 1997, 44,
393. (e) Karimi, B.; Seradj, H.; Tabaei, M. H. Synlett 2000,
1798.
temperature and stirring was continued. After 20 min,
ammonium bromide (0.112 g, 1.14 mmol) was added in
portion and color changed immediately to deep yellow from
light pale yellow. Then, the substrate 2-[p-methoxyphenyl]-
1,3-oxathiolane(1a) (0.196 g, 1.0 mmol) dissolved in
CH2Cl2 (5 mL) was added to the above solution. The
reaction was completed within a 2.5 h as monitored by TLC.
The reaction mixture was finally extracted with CH2Cl2 (2
10 mL) and the organic layers were dried over anhydrous
Na2SO4. The organic phase was concentrated in vacuo to
give the crude product, which was finally purified by column
chromatography on silica gel (eluent: hexane–EtOAc, 1:1).
The pure product p-meth-oxybenzaldehyde(2a) was
obtained 0.125 g (92%).
(16) Spectroscopic data for compound 1g: 1H NMR (300 MHz,
CDCl3): 1.87–2.17 (m, 6 H, -cyclohexyl CH2-), 4.92 (bs, 1
H, -OCH-), 5.84–5.87 (m, 1 H, -CH=CH), 6.01–6.04 (m, 1
H, CH=CH), 7.01 (d, 2 H, J = 8.5 Hz, ArH), 7.82 (d, 2 H, J
= 8.6 Hz, ArH), 9.87 (s, 1 H, -CHO) Anal. Calcd. For
C13H14O2: C 77.20, H 6.98. Found C 77.01, H 6.94.
(17) Olah, G. A.; Narang, S. C.; Salen, G. F. Synthesis 1980, 657.
Synlett 2002, No. 3, 463–467 ISSN 0936-5214 © Thieme Stuttgart · New York