Oxalic acid-promoted preparation of dithioacetals from carbonyl compounds or acetals

Article abstract of DOI:10.1246/cl.2007.104

This letter describes oxalic acid-promoted syntheses of dithioacetals from carbonyl compounds and thiols. Acetals are also converted into dithioacetals by the reaction with thiols under similar conditions. Copyright

Full text of DOI:10.1246/cl.2007.104

104
Chemistry Letters Vol.36, No.1 (2007)
Oxalic Acid-promoted Preparation of Dithioacetals
from Carbonyl Compounds or Acetals
Hideyoshi Miyake,Ã1 Yuichi Nakao,2 and Mitsuru Sasaki2
1Faculty of Agriculture, Kobe University, Rokkodai, Nada-ku, Kobe 657-8501
2Graduate School of Science and Technology, Kobe University, Rokkodai, Nada-ku, Kobe 657-850
(Received September 13, 2006; CL-061052; E-mail: miyakeh@kobe-u.ac.jp)
Table 1. Synthesis of dithioacetals from carbonyl compounds
This letter describes oxalic acid-promoted syntheses of
O
dithioacetals from carbonyl compounds and thiols. Acetals are
also converted into dithioacetals by the reaction with thiols
under similar conditions.
RS SR
(COOH)2
CH3NO2
+ RSH
R1
R2
R1 R2
2
1
3
2a: 1-dodecanethiol (DodSH)
2b: thiophenol (PhSH)
2c: 1,3-propanedithiol
Recently, we have reported that oxalic acid can promote
the reaction between acetals and dithioacetals, and this reaction
is useful as a method of converting dithioacetals to carbonyl
compounds.1 In the course of the study, we have found that
the activation of some C–O bonds by oxalic acid can also be
applied to the synthesis of dithioacetals.
Dithioacetal is an important functional group not only as an
acyl anion equivalent but also as a protected carbonyl com-
pound.2 The conversion of carbonyl compounds into dithioace-
Entry Substrate (1) Thiol (2)
Dithioacetal (3) Conditions Yield/%a
O
1
rt, 48 h
60 °C, 7 h
rt, 72 h
85
86
DodS SDod
Ph
2a
Ph
H
H
2
3
4
90
69
SDod
SDod
2a
Ph
CHO
O
Ph
60 °C, 2 h
DodS SDod
H
tals can be accomplished by the reaction with thiols in the pres-
ence of some catalysts, such as BF3 OEt2, InCl3,4 TiCl4,5
2a
2a
2a
2a
5
rt, 2 h
98
Ph
Ph
H
Ph
Ph
3
.
O
O
DodS SDod
Sc(OTf)3,6 SOCl2–silica gel,7 Nafion-H,8 ZrCl4,9 heteropoly
acids,10 and SnCl2 2H2O under microwave irradiation. Some
11
6
7
8
rt, 16 h
rt, 18 h
rt, 18 h
84
78
75
.
DodS SDod
H
of these methods, however, need strong acidic conditions, and
some of the catalysts used in these methods are expensive or
troublesome to prepare. We find that the corresponding transfor-
mation can be accomplished by using oxalic acid as a catalyst.
As oxalic acid is not only an inexpensive and readily available
compound but also a relatively weak acid, the reaction is
expected to proceed with good chemoselectively. Experimental
results are summarized in Table 1.12
Ph
Ph
H
Ph
Ph
O
DodS SDod
SDod
SDod
9
10
11
2a
2b
2c
2c
rt, 16 h
rt, 48 h
rt, 2 h
91
76
95
PhCOO
PhCOO
CHO
Although a nucleophilic or radical conjugate addition of
thiol to ꢀ,ꢁ-unsaturated carbonyl compound, such as cinnamal-
dehyde, occurs easily, the formation of dithioacetal proceeded
without affecting the carbon–carbon double bond to give unsat-
urated dithioacetal (Entries 5, 6, and 11). The ester group was not
affected under these conditions (Entry 9). The reaction with 1,3-
propanedithiol (2c) proceeded more smoothly than other thiol
such as 1-dodecanethiol (2a), which is useful as odorless thiol,13
or thiophenol (2b) to give cyclic dithioacetal in excellent yield
(Entries 11 and 12).
SPh
SPh
O
O
O
S
S
S
Ph
Ph
H
Ph
Ph
H
S
12
rt, 3 h
98
aIsolated yield. Dod: dodecyl.
Acetals also reacted with thiols under similar conditions to
produce dithioacetals. Some acid catalysts are effective to the
conversion of acetals to dithioacetals. For example, BF3–OEt2,14
tetrabutylammonium tribromide (TBATB),15 and Nafion-H16 are
effective. The results of the oxalic acid-promoted conversion
are summarized in Scheme 1. Interestingly, even when a large
excess of acetal, such as 4 or 6, was added, dithioacetal was ob-
tained chemoselectively and monothioacetal was not obtained.
This outcome suggests that the monothioacetal 12 is more reac-
tive than acetal 6 under these conditions, and the equilibrium
shown in Scheme 2 gives dithioacetal 7 exclusively.
didodecylthio-2-butanone (9) was obtained at a yield of 69%.
Methoxymethyl ether 10 gave 11 and 5 under the similar condi-
tions. Such a result indicates that the present method is a useful
one for a deprotecting acetal-type protecting group. Similarly, p-
methoxybenzyl ether 13 can be converted into alcohol 11 and
sulfide 14 under similar conditions (Scheme 3), and this was
found to be useful as a method to remove the p-methoxybenzyl
ether-type protecting group. Further study on this methodology
is in progress.
Other carboxylic acids such as trichloroacetic acid, which
has similar acidity to oxalic acid, is as effective as oxalic acid
for the conversion of carbonyl compounds to dithioacetals.
Catalytic amount of (1R)-10-camphorsulfonic acid is also effec-
When 4,4-dimethoxy-2-butanone (8) was treated with
2.4 equiv. of thiol in the presence of anhydrous (COOH)2, 4,4-
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
105
carbonyl carbon gives 15. And the following acid-catalyzed
replacement of hydroxy group by alkylthio group gives dithio-
acetal.
OMe
SDod
(COOH)2
+
2a
OMe
4
CH3NO2, rt, 18 h
SDod
5
90%
4:2a:(COOH)2 = 5:1:1
In conclusion, oxalic acid and some carboxylic acids, such
as trichloroacetic acid, effectively promote the conversion of
carbonyl compounds and acetals to dithioacetals. The merits of
using oxalic acid are as follows. Oxalic acid is readily available,
and after the reaction, it can be removed easily by aqueous
workup.12
SDod
OMe
(COOH)2
+
2a
SDod
7
85%
CH3NO2, rt, 18 h
OMe
6
6:2a:(COOH)2 = 5:1:1
O
SDod
SDod
69%
O
OMe
OMe
(COOH)2
+
2a
CH3NO2, rt, 24 h
8
8:2a:(COOH)2 = 1:2.4:1
9
References and Notes
1
2
3
H. Miyake, Y. Nakao, M. Sasaki, Tetrahedron Lett. 2006, 47,
6247.
SDod
(COOH)2
Me
Ph
OH
+
Ph
O
O
+ 2a
SDod
70%
CH3NO2, rt, 20 h
10
T. W. Greene, P. G. M. Wuts, Protective Group in Organic
Synthesis, 3rd ed., Wiley, New York, 1999, pp. 329–344.
a) R. P. Hatch, J. Shringerpure, S. M. Weinreb, J. Org. Chem.
1978, 43, 4172. b) E. Fujita, Y. Nagao, K. Kaneko, Chem.
Pharm. Bull. 1978, 26, 3743. c) R. P. Hatch, J. Shringarpure,
S. M. Weinreb, J. Org. Chem. 1978, 43, 4172. d) J. A.
Marshall, J. L. Belletire, Ttrahedron Lett. 1971, 21, 871.
e) T. Nakata, S. Nagao, N. Mori, T. Oishi, Tetrahedron Lett.
1985, 26, 6461.
11 71%
5
10:2a:(COOH)2= 1:2.4:1.2
Scheme 1.
slow
fast
OMe
OMe
SDod
SDod
SDod
OMe
6
12
7
Scheme 2.
4
5
S. Muthusamy, S. A. Babu, C. Gunanathan, Tetrahedron
Lett. 2001, 42, 359.
a) V. Kumar, S. Dev, Tetrahedron Lett. 1983, 24, 1289. b)
P. Kumar, R. S. Reddy, A. P. Singh, B. Pandey, Synthesis
1993, 67. c) C. V. Asokan, A. Mathews, Tetrahedron Lett.
1994, 35, 2585.
(COOH)2 (1.2 equiv.)
+
+
2b
Ph
O
Ar
Ph
OH
PhS
Ar
CH3NO2, rt, 18 h
(1.2 equiv.)
13
11 91%
14 90%
Ar=p-methoxyphenyl
Scheme 3.
6
7
A. Kamal, G. Chouhan, Tetrahedron Lett. 2002, 43, 1347.
Y. Kamitori, M. Hojo, R. Masuda, T. Kimura, T. Yoshida,
J. Org. Chem. 1986, 51, 1427.
G. A. Olah, S. Narang, D. Meider, G. F. Salem, Synthesis
1981, 282.
H. K. Patney, S. Margan, Tetrahedron Lett. 1996, 37, 4621.
O
DodS SDod
H
+
2a
Ph
Ph
H
CH3NO2
8
CCl3COOH (2.0 equv.), rt, 1 h
(1R)-10-camphorsulfonic acid (0.3 equiv.), rt, 2 h
97%
89%
9
O
DodS SDod
10 H. Firouzabadi, N. Iranpoor, K. Amani, Synthesis 2002, 59.
11 G. Bez, D. Gogoi, Tetrahedron Lett. 2006, 47, 5155.
12 Typical procedures are as follows. The general procedures
for the dithioacetalization of carbonyl compound 1 are as
follows. A nitromethane (5 mL) solution of 1 (5.0 mmol),
(COOH)2 (12 mmol), and thiol (12 mmol for 2a or 2b,
whereas 6.0 mmol for 2c) was stirred under the conditions
shown in Table 1. The mixture was poured into water and
extracted using ethyl acetate. After the usual workup, the
crude mixture was purified by column chromatography on
silica gel. The reactions of acetals (4, 6, 8, and 10) and p-
methoxybenzyl ether (13) were also accomplished using
procedures similar to those described above.
+
2a
H
Ph
Ph
H
CH3NO2
CCl3COOH(2.0 equv.), rt, 96 h
CH3COOH(2.0 equv.), rt, 96 h
95%
0%
Scheme 4.
H
H
+O
HO S+R
HO SR
R1 R2
O
H+
H+
R1
R2
R1
R2
R1
R2
15
R
S
H
H
H
O+ SR
R
S+ SR
RS SR
SR
+
H
R1
R2
13 a) M. Node, K. Kumar, K. Nishide, S. Ohsugi, T. Miyamoto,
Tetrahedron Lett. 2001, 42, 9207. b) K. Nishide, S. Ohsugi,
T. Miyamoto, K. Kumar, M. Node, Monatsh. Chem. 2004,
135, 189. c) K. Nishide, M. Node, J. Synth. Org. Chem.
Jpn. 2004, 62, 895.
R1
R2
R1
R2
R1
R2
3
R
S
H
Scheme 5.
tive. However, acetic acid is not effective. Results are summariz-
ed in Scheme 4.
14 A. Alsarabi, J. Canet, Y. Troin, Tetrahedron Lett. 2004, 45,
9003.
These results suggest that not only oxalic acid, but also
some Brønsted acids are effective. The plausible mechanism
of this reaction is shown in Scheme 5. Brønsted acid protonates
the carbonyl oxygen, and nucleophilic attack of thiol to the
15 S. Naik, R. Gopinath, M. Goswami, B. K. Patel, Bhisma,
Org. Biomol. Chem. 2004, 2, 1670.
16 G. A. Olah, S. C. Narang, D. Meidar, G. F. Salem, Synthesis
1981, 282.
Published on the web (Advance View) November 29, 2006; doi:10.1246/cl.2007.104