A highly efficient procedure for regeneration of carbonyl groups from their corresponding oxathioacetals and dithioacetals using sodium nitrite and acetyl chloride in dichloromethane

Article abstract of DOI:10.1055/s-2003-37115

A wide variety of oxathioacetals 1 as well as dithioacetals 2 can be chemoselectively deprotected to the corresponding carbonyl compounds 3 in good yields by employing NaNO₂-AcCl and H₂O in CH₂Cl₂ at 0°C to room temperature. Some of the major advantages of this procedure are: mild conditions, easy to handle, highly chemoselective and efficient, high yields and inexpensive reagents. In addition, no acetylation occurs at the hydroxyl group nor chlorination takes place at the double bond.

Full text of DOI:10.1055/s-2003-37115

LETTER
377
A Highly Efficient Procedure for Regeneration of Carbonyl Groups from their
Corresponding Oxathioacetals and Dithioacetals Using Sodium Nitrite and
Acetyl Chloride in Dichloromethane
E
A
fficient
P
rocedur
b
e
for Regene
u
ration of
C
arbonyl
T
G
roups . Khan,* Ejabul Mondal, Priti R. Sahu
Department of Chemistry, Indian Institute of Technology, North Guwahati, Guwahati-781039, Assam, India
Fax +91(361)2690762; E-mail: atk@postmark.net
Received 20 November 2002
7
reagents such as silver salts and require long reaction
times. Recently, another method was reported by Kiri-
hara et al. using a catalytic amount of trichloroxyvanadi-
Abstract: A wide variety of oxathioacetals 1 as well as dithioace-
tals 2 can be chemoselectively deprotected to the corresponding car-
8
9
bonyl compounds 3 in good yields by employing NaNO –AcCl and
2
H O in CH Cl at 0 °C to room temperature. Some of the major um, which also requires drastic reaction conditions. We
2
2
2
advantages of this procedure are: mild conditions, easy to handle, have also demonstrated some new methodologies based
highly chemoselective and efficient, high yields and inexpensive on bromonium ion sources for deprotection of various
reagents. In addition, no acetylation occurs at the hydroxyl group
nor chlorination takes place at the double bond.
10a–c
10d–f
oxathioacetals
and dithioacetals,
which involve
10b,e
expensive organic ammonium tribromides
relatively long reaction times. Very recently one more
method was reported using CeCl ⋅7H O–NaI, which re-
and require
Key words: deprotection, oxathioacetals, dithioacetals, sodium
nitrite, acetyl chloride
11
3
2
quire long reaction times as well as expensive reagents.
Though a large number of methods have already been re-
12
The protection-deprotection strategy is a common prac-
tice in multistep organic synthesis. Among the various
functional groups, protection of carbonyl groups as ox-
athioacetals and dithioacetals has attracted much attention
due to their robustness under mild acidic or basic reaction
ported in the literature for deprotection of dithioacetals
to the corresponding carbonyl compounds, still there is a
need to develop a mild methodology. The usual standard
procedure for cleavage of dithioacetals involves mainly a
suitable electrophile, which is captured by a soft nucleo-
conditions. They also serve as acyl carbanion equivalents philic sulfur atom followed by hydrolysis with water. We
1
+
for carbon-carbon bond forming reactions. The most re- decided to test NO as electrophilic species for regenera-
markable application is the use of chiral oxathioacetals for tion of carbonyl compounds from the corresponding pro-
the synthesis of optically active tertiary alcohols possess- tected derivative. Sodium nitrite in combination with
1
3
5a
ing a carbonyl functionality at the α-position, first demon- trifluoroacetic acid, isoamyl nitrite and a mixture of
2
14
strated by Eliel and Lynch. Later on, the utility of oxides of nitrogen have already been used for deprotec-
oxathioacetals was further shown by Utimoto and his
tion of dithioacetals to the carbonyl compounds. Howev-
er, these procedures have some drawbacks such as
incompatibility with other protecting group like TBS
ethers due to the use of a large excess of trifluoroacetic ac-
3
group in organic synthesis. In contrast to many methods
available for deprotection of dithioacetals, a few methods
4
are known for oxathioacetals. Consequently, there is a
5
a
need to find out a better alternative for deprotection of ox-
athioacetals, which might work under mild conditions.
The existing procedures for the deprotection of oxathioac-
id, drastic reaction conditions and long reaction times,
and provide a low yield for enolizable ketones.14 In this
communication, we wish to report that sodium nitrite in
5a
etals are as follows: i) use of isoamyl nitrite and combination with acetyl chloride is a useful reagent for
5
b
6a
chloramine T, ii) treatment with TMSOTf alone, iii) or the cleavage of both oxthioacetals and dithioacetals
6
b,c
with TMSOTf in the presence of p-nitrobenzaldehyde,
(Scheme 1) under mild reaction conditions.
6
d
or polymer supported p-nitro-benzaldehyde, iv) use of
Next, we have prepared a wide variety of structurally dif-
ferent oxathioacetals 1a–n by following our reported pro-
halonium ion sources in the presence of expensive silver
7
8
salts or reaction with NBS in acetone. Unfortunately,
some of the procedures have serious drawbacks such as
the removal of the by-product oxathioacetal derived from
R1
R2
XR3
YR3
R1
R2
6
b,c
NaNO , AcCl /H O
2 2
p-nitrobenzaldehyde or the use of an expensive poly-
mer supported reagent and sometimes failure to depro-
tect non-benzylic oxathioacetals. They also require long
reaction times. Other drawbacks related to halonium ion
sources include the need for a large excess in expensive
C
C
O
6
d
0
°C, r.t., CH Cl2
2
6
a
6
d
1
or 2
3
1
2
3
1
: X = O, Y = S; R = alkyl/aryl; R = H, alkyl, aryl; R = -(CH2)2
1
2
Synlett 2003, No. 3, Print: 19 02 2003.
Art Id.1437-2096,E;2003,0,02,0377,0381,ftx,en;G31702ST.pdf.
2: X = Y = S; R = alkyl/aryl/sugar residue; R = H, alkyl, aryl;
3
R = Et, -(CH2)2, (CH2)3
©
Georg Thieme Verlag Stuttgart · New York
Scheme 1
ISSN 0936-5214

3
78
A. T. Khan et al.
LETTER
cedure.10a The substrate 2-(p-acetoxyphenyl)-1,3- ed at the same temperature by additional 15 minutes of
oxathiolane (1a) was smoothly converted to p-acetoxy- stirring. By following the typical procedure described
benzaldehyde (3a) by adding 1a to a stirring solution of above,15 various oxathioacetals 1b–n were easily trans-
NaNO –AcCl (1:1) at 0–5 °C, followed by addition of wa- formed to the parent carbonyl compounds 3b–n in very
2
ter after 10 minutes of stirring. The reaction was complet- good yields (Table 1). It is important to mention that other
Table 1 Cleavage of Various Oxathioacetals Using NaNO –AcCl–H O in CH Cl
2
2
2
2
Entry
Substrate 1
Time (min)
25
Product 3a
Yield (%)b
82
a
O
AcO
AcO
CHO
CHO
CHO
S
b
c
d
e
f
O
40
35
25
30
35
30
85
90
84
90
90
95
O2N
BnO
TBSO
O
O2N
BnO
TBSO
O
S
O
S
O
CHO
S
O
S
CHO
O
MeO
MeO
CHO
CHO
MeO
MeO
S
g
O
S
OMe
O
OMe
CHO
h
i
25
35
84
70
S
O
CHO
S
j
25
25
30
84
97
82
O
CH (CH ) CHO
3
2 10
S
k
l
O
BzO
BzO
CHO
S
CH3
CH3
O
S
O
O
m
n
25
25
80
95
O
S
O
O
S
a
Products have been characterized by co-IR with authentic compounds, H NMR, 13C NMR and elemental analyses of the samples.
Isolated yields.
1
b
Synlett 2003, No. 3, 377–381 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Efficient Procedure for Regeneration of Carbonyl Groups
379
protecting groups such as OBn, OBz, TBS and allyl (for CH COCl (1:1) at 0–5 °C, it was smoothly converted to
3
entries 1c, 1k, 1d and 1e) were unaffected under the ex- 3a in good yield. Similarly, 2b gave compound 3b in good
perimental conditions. Deprotection of compound 1f re- yield without acetylation of the hydroxyl group. Likewise,
5
a
quires longer time compared to our method. All various acyclic and cyclic dithioacetals 2c–u were also
1
6
deprotected compounds were fully characterized by IR, cleaved chemoselectively to the parent carbonyl com-
1
13
H NMR, C NMR spectroscopy by comparison with au- pounds without affecting other protecting groups. More-
thentic samples.
over, by using our protocol the open chain aldehydic
sugars 3v and 3w were prepared from the corresponding
compounds 2v and 2w (Table 2).18
Next, we have turned our attention to the deprotection of
various dithioacetals, which were prepared following our
procedure using catalytic amount of 70% HClO . When
1
7
4
compound 2a was treated with 2 equivalents of NaNO2–
Table 2 Cleavage of Various Dithioacetals Using NaNO –AcCl/H O in CH Cl
2
2
2
2
Entry
Substrate 2
Time (min)
225
Product 3a
Yield (%)b
85
a
S
S
AcO
HO
CHO
CHO
CHO
AcO
b
c
d
e
f
S
15
45
70
40
30
45
90c
97
85
97
95
97
HO
S
S
BnO
TBSO
BnO
TBSO
O
S
S
S
CHO
S
S
O
CHO
S
MeO
CHO
CHO
MeO
MeO
S
g
S
MeO
S
OMe
CHO
OMe
S
h
i
45
30
96
95
S
CH(SEt)2
CHO
j
70
45
82
94
CH3(CH2)10CH(SEt)2
CH3(CH2)10CHO
k
OTBDMS
OTBDMS
S
CHO
S
l
70
45
90
90
CH3
CH3
O
EtS
S
SEt
m
S
O
Synlett 2003, No. 3, 377–381 ISSN 0936-5214 © Thieme Stuttgart · New York

3
80
A. T. Khan et al.
LETTER
Table 2 Cleavage of Various Dithioacetals Using NaNO –AcCl/H O in CH Cl (continued)
2
2
2
2
Entry
Substrate 2
Time (min)
45
Product 3a
Yield (%)b
n
SEt
O
78
SEt
o
p
q
SEt
90
45
45
3f
3f
98
90
96
MeO
MeO
SEt
S
S
MeO
MeO
MeO
MeO
CH(SEt)2
CHO
MeO
MeO
MeO
r
s
90
60
3q
96
95
S
S
MeO
MeO
SEt
3h
SEt
t
S
S
45
45
45
60
80
87
75
72
MeO
MeO
CHO
Br
Br
u
v
w
3m
EtS
SEt
OAc
OAc
CH(SEt)2
CHO
AcO
AcO
AcO
OAc OAc
OAc
OAc OAc
OAc
CH(SEt)2
CHO
AcO
OAc OAc
OAc OAc
a
1
Products have been characterized by co-IR with authentic compounds, H NMR and elemental analyses of the samples.
Isolated yields.
b
c
After addition of the substrate, water is added after 2 min instead of 5 min.
The formation of the parent carbonyl compounds from odology is compatible with the presence of a large number
their corresponding oxathioacetals or dithioacetals can be of other protecting groups such as acetyl, benzyl, benzoyl,
rationalized as follows. Sodium nitrite reacts with acetyl TBS ether, allyl and also provide good yield for enolizable
chloride to form acetyl nitrite, which ultimately generates ketones.
+
+
a highly reactive species NO ion. The NO ion reacts
with the sulfur atom of the thioacetal to form a complex,5
which is finally hydrolyzed by water to provide the carb-
onyl compound.
a
Acknowledgement
A.T.K. acknowledges to the Department of Science and Technolo-
gy (DST), New Delhi for financial support (Grant No.: SP/S1/G-35/
In conclusion, we have presented a mild and easy proce-
dure for deprotection of oxathioacetals and dithioacetals
9
8). E. M. is thankful to the CSIR for Senior Research Fellowship.
P.R.S is thankful to DST for her fellowship. The authors are also
to the parent carbonyl compounds by using a mixture of thankful to the Director, I.I.T. Guwahati for providing general
sodium nitrite and acetyl chloride. In addition, this meth- facilities for this work. We are grateful to the referees for their
valuable comments and suggestions.
Synlett 2003, No. 3, 377–381 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Efficient Procedure for Regeneration of Carbonyl Groups
neutralized with NaHCO and extracted with CH
381
References
3
2
Cl
2
(2 × 15
mL). The organic layer was washed with water (2 × 20 mL)
(
1) (a) Eliel, E. L.; Morris-Natschke, S. J. Am. Chem. Soc. 1984,
and dried (Na SO ). Evaporation of the solvent gave the
2
4
106, 2937. (b) Corey, E. J.; Seebach, D. Angew. Chem.
crude residue, which was purified by column chromato-
graphy on silica gel (eluent: hexane–EtOAc, 19:1). Product
1965, 77, 1134. (c) Metzner, P.; Thuillier, A. Sulfur
Reagents in Organic Synthesis; Academic Press: New York,
994, 12–19.
3f was obtained as a colourless liquid 0.122 g (90%).
1
A Typical Procedure for Deprotection of Dithioacetals:
The reaction was carried out with compound 2f as stated
(
(
2) Lynch, J. E.; Eliel, E. L. J. Am. Chem. Soc. 1984, 106, 2943.
3) Utimoto, K.; Nakamura, A.; Matsubara, S. J. Am. Chem.
Soc. 1990, 112, 8189.
above except 2 equiv of NaNO and AcCl (1:1) mixture was
2
used. Product 3f was obtained as a colourless liquid 0.129 g
(
(
(
4) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
(
95%).
Synthesis, 3rd ed.; John Wiley and Sons, Inc.: New York,
(
16) Spectroscopic Data for Compound 1d, 1e, 3d and 3e:
1999, 344–346.
1
For 1d: H NMR (400 MHz, CDCl ): d = 0.20 (s, 6 H,
3
5) (a) Fuji, K.; Ichikawa, K.; Fujita, E. Tetrahedron Lett. 1978,
SiCH ), 0.97 [s, 9 H, SiC(CH ) ], 3.19 (m, 1 H, -CHS-), 3.27
3
3 3
3561. (b) Emerson, D. W.; Wynberg, H. Tetrahedron Lett.
(
-
m, 1 H, -CHS-), 3.94 (m, 1 H, -OCH-), 4.52 (m, 1 H,
1971, 3445.
OCH-), 5.99 (s, 1 H, OCHS-), 6.81 (d, 2 H, J = 8.5 Hz,
6) (a) Ravindranathan, T.; Chavan, S. P.; Dantale, S. W.
Tetrahedron Lett. 1995, 36, 2285. (b) Ravindranathan, T.;
Chavan, S. P.; Tejwani, R. B.; Vargese, J. P. J. Chem. Soc.,
Chem. Commun. 1991, 1750. (c) Ravindranathan, T.;
Chavan, S. P.; Vargese, J. P.; Dantale, S. W.; Tejwani, R. B.
J. Chem. Soc., Chem. Commun. 1994, 1937.
13
ArH), 7.35 (d, 2 H, J = 8.5 Hz, ArH). C NMR (100 MHz,
CDCl ): d = –4.45(2 C), 18.17, 25.64 (3 C), 34.03, 61.20,
3
87.01, 119.98 (2 C), 128.18 (2 C), 131.46, 156.07. Anal.
Calcd for C H O SSi: C, 60.76; H, 8.16; S, 10.81. Found:
1
5
24
2
1
C, 60.57; H, 8.10; S, 10.68. For 1e: H NMR (400 MHz,
CDCl ): d = 3.18 (m, 1 H, -CHS-), 3.28 (m, 1 H, -CHS-),
3
(d) Ravindranathan, T.; Chavan, S. P.; Awachat, M. M.
3
.91 (m, 1 H, -OCH-), 4.51 (m, 3 H, -OCH -, OCH-), 5.28
2
Tetrahedron Lett. 1994, 35, 8835.
(
dd, 1 H, J = 1.5 Hz, J = 10.5 Hz, OCH CH=CH ), 5.40 (dd,
2 2
(
7) (a) Fyre, S. V.; Eliel, E. L. Tetrahedron Lett. 1985, 26,
1
H, J = 1.5 Hz, J = 17.3 Hz, OCH CH=CH ), 5.99 (s, 1 H,
2 2
3
907. (b) Nishide, K.; Yokota, K.; Nakamura, D.; Sumiya,
T.; Node, M.; Ueda, M.; Fuji, K. Tetrahedron Lett. 1993, 34,
425.
OCHS-), 6.05 (m, 1 H, OCH CH=CH ) 6.95 (d, 2 H, J = 8.7
2
2
Hz, ArH), 7.40 (d, 2 H, J = 8.7 Hz, ArH). Anal. Calcd for
3
C H O S: C, 64.83; H, 6.35; S, 16.22. Found: C, 64.61; H,
1
2
14
2
(
(
8) Karimi, B.; Seradj, H.; Tabaei, M. H. Synlett 2000, 1798.
9) Kirihara, M.; Ochiai, Y.; Arai, N.; Takizawa, S.; Momose,
T.; Nemoto, H. Tetrahedron Lett. 1999, 40, 9055.
1
6
0
.30; S, 16.10. For 3d: H NMR (400 MHz, CDCl ): d =
.05 (s, 6 H, SiCH ), 0.79 [s, 9 H, SiC(CH ) ], 6.70 (d, 2 H,
3
3
3 3
J = 8.6 Hz, ArH) 7.54 (d, 2 H, J = 8.6 Hz, ArH), 9.94 (s, 1 H,
(
10) (a) Mondal, E.; Sahu, P. R.; Khan, A. T. Synlett 2002, 463.
b) Mondal, E.; Sahu, P. R.; Bose, G.; Khan, A. T.
CHO). Anal. Calcd for C H O : C, 74.96; H, 9.68. Found:
1
3
1
20
2
(
C, 74.69; H, 9.57. For 3e: H NMR (400 MHz, CDCl ): d =
3
Tetrahedron Lett. 2002, 43, 2843. (c) Mondal, E.; Sahu, P.
R.; Bose, G.; Khan, A. T. J.Chem. Soc., Perkin Trans. 1
4
.63 (m, 2 H, -OCH -CH=CH ), 5.34 (dd, 1 H, J = 1.5 Hz,
2 2
J = 10.5 Hz, OCH CH=CH ), 5.44 (dd, 1 H, J = 1.5 Hz,
2
2
2002, 1026. (d) Mondal, E.; Bose, G.; Sahu, P. R.; Khan, A.
J = 17.3 Hz, OCH CH=CH ), 6.06 (m, 1 H, OCH CH=CH )
2
2
2
2
T. Chem. Lett. 2001, 1158. (e) Mondal, E.; Bose, G.; Khan,
A. T. Synlett 2001, 785. (f) Khan, A. T.; Boruwa, J.;
Mondal, E.; Bose, G. Indian J. Chem., Sect. B 2001, 40,
7
.02 (d, 2 H, J = 8.8 Hz, ArH), 7.84 (d, 2 H, J = 8.7 Hz,
13
ArH), 9.88 (s, 1 H, CHO). C NMR (100 MHz, CDCl ): δ =
3
68.95, 114.94 (2 C), 118.34, 129.94, 131.94 (2 C), 132.21,
1039.
1
63.55, 190.81. Anal. Calcd for C H O : C, 74.06; H, 6.21.
1
0
10
2
(
11) Yadav, J. S.; Reddy, B. V. S.; Raghavendra, S.;
Satyanarayana, M. Tetrahedron Lett. 2002, 43, 4679.
12) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley and Sons, Inc.: New York,
Found: C, 73.95; H, 6.15.
(
(
17) Khan, A. T.; Mondal, E.; Ghosh, S., unpublished results.
(
1
18) Spectroscopic Data for Compound 3v and 3w: For 3v: H
NMR (300 MHz, CDCl ): d = 2.07 (s, 9 H, COCH ), 2.20 (s,
3
3
1999, 329–344.
3
4
H, COCH ), 4.19 (dd, 1 H, J = 4.6 Hz, J = 12.6 Hz, H-5′),
.33 (dd, 1 H, J = 2.6 Hz, J = 12.6 Hz, H-5), 5.27 (m, 1 H,
3
(13) Olah, G. A.; Narang, S. C.; Salem, G. F.; Balaram Gupta, B.
G. Synthesis 1979, 273.
H-4), 5.39 (d, 1 H, J = 2.2 Hz, H-2), 5.69 (dd, 1 H, J = 2.1
Hz, J = 8.8 Hz, H-3), 9.48 (s, 1 H, CHO). Anal. Calcd for
C H O : C, 49.06; H, 5.70. Found: C, 48.88; H, 5.63. For
(
(
14) Mehta, G.; Uma, R. Tetrahedron Lett. 1996, 37, 1897.
15) A Typical Procedure for Deprotection of Oxathioacetals:
1
3
18
9
The mixture of NaNO (0.069 g, 1 mmol) and AcCl (71 µL,
1
2
3w: H NMR (300 MHz, CDCl ): d = 1.97 (s, 3 H, COCH ),
3
3
1
mmol) in CH Cl (3 mL) was stirred for 10 min at 0–5 °C.
2 2
2.06 (s, 3 H, COCH ), 2.09 (s, 3 H, COCH ), 2.19 (s, 3 H,
3 3
Then the substrate 2-(p-methoxyphenyl)-1,3-oxathiolane 1f
0.196 g, 1 mmol) in CH Cl (2 mL) was added into the
COCH ), 4.17 (dd, 1 H, J = 4.3 Hz, J = 12.6 Hz, H-5′), 4.37
3
(
2
2
(dd, 1 H, J = 2.6 Hz, J = 12.6 Hz, H-5), 5.31 (m, 1 H, H-4),
above reaction mixture at the same temperature. After
stirring for 5 min, water (1 mL) was added and the mixture
brought to r.t. The reaction was completed with additional
stirring 20 min (TLC). Finally, the reaction mixture was
5.45 (d, 1 H, J = 2.5 Hz, H-2), 5.61 (dd, 1 H, J = 2.5 Hz,
J = 8.8 Hz, H-3), 9.50 (s, 1 H, CHO). Anal. Calcd for
C H O : C,49.06; H, 5.70. Found: C, 48.82; H, 5.74.
1
3
18
9
Synlett 2003, No. 3, 377–381 ISSN 0936-5214 © Thieme Stuttgart · New York