Chemoselective thioacetalization in water: 3-(1,3-dithian-2-ylidene) pentane-2,4-dione as an odorless, efficient, and practical thioacetalization reagent

Article abstract of DOI:10.1021/jo050271y

A chemoselective thioacetalization utilizing 3-(1,3-dithian-2-ylidene) pentane-2,4-dione as a novel nonthiolic, odorless 1,3-propanedithiol equivalent catalyzed by p-dodecylbenze-nesulfonic acid in water has been developed.

Full text of DOI:10.1021/jo050271y

TABLE 1. Reaction between 1 and 2a in Aqueous Media
Chemoselective Thioacetalization in
Water: 3-(1,3-Dithian-2-ylidene)pentane-
2
,4-dione as an Odorless, Efficient, and
Practical Thioacetalization Reagent
Dewen Dong,* Yan Ouyang, Haifeng Yu, Qun Liu,*
Jun Liu, Mang Wang, and Jing Zhu
1,
2a,
H2O,
mL
DBSA,
mmol
time,
h
yield,a
%
entry
mmol
mmol
Department of Chemistry, Northeast Normal University,
Changchun, 130024, P. R. China
1
2
3
4
5
6
2
2
2
2
2
2
2
2
2
2
2
2
12.0
6.0
4.0
3.0
3.0
3.0
1.0
1.0
1.0
1.0
1.6
3.0
8.0
4.3
3.0
2.2
0.9
0.8
98
98
98
97
98
95
dongdw663@nenu.edu.cn
Received February 10, 2005
a
Isolated yields for 3a.
flammable, harmful, and odorous reagents, which can
lead to serious environmental and safety problems.
Recently, we have developed a novel thioacetalization
procedure using nonthiolic, odorless 2-(2-chloro-1-(1-
chloroethenyl)-2-propenylidene)-1,3-dithiane, or 3-(1,3-
dithian-2-ylidene)pentane-2,4-dione as 1,3-propanedithiol
A chemoselective thioacetalization utilizing 3-(1,3-dithian-
2
1
-ylidene)pentane-2,4-dione as a novel nonthiolic, odorless
9
,3-propanedithiol equivalent catalyzed by p-dodecylbenze-
equivalents. It should be noted that this protocol involves
nesulfonic acid in water has been developed.
the use of methanol, a highly volatile and harmful
organic solvent. In our ongoing research program to
circumvent the above drawback in thioacetalization, we
found that p-dodecyl benzenesulfonic acid (DBSA), a
surfactant-type Bronsted acid, can be used as an acid
catalyst for the cleavage of ketene dithioacetals to form
odorless thio-containing intermediates. The results
prompted us to explore the feasibility of the thioacetal-
ization in aqueous media. In the present work, we
describe our preliminary results on a novel thioacetal-
ization in water using DBSA as the catalyst and 3-(1,3-
dithian-2-ylidene)pentane-2,4-dione 1 as a 1,3-propane-
dithiol equivalent.
The initial studies were performed on the reaction
between piperonal 2a and 1 with various feed ratios of
DBSA in water with stirring at reflux. To our delight,
all the reactions of 2a proceeded in water affording
dithioacetal 3a in excellent yields and some of the results
are summarized in Table 1. It was observed that the
Over the past decade, organic reactions in water
without the use of organic solvents have attracted a great
deal of attention since water is an easily available,
economical, and safe solvent, especially in relation to
1,2
recent environmental concerns. It has been demon-
strated that a variety of organic reactions, including
dehydration, can be realized in the presence of surfac-
tant-type Lewis or Bronsted acid catalysts in water.3
Recently, Kobayashi reported that thioacetalization can
be conducted in aqueous media with surfactant-type
4
Bronsted acid catalysts. Thioacetals have been widely
used as carbonyl protecting groups and intermediates in
the conversion of a carbonyl function to a hydrocarbon
derivative to form a C-C bond.5 Generally, thioacetals
are prepared by the condensation of carbonyl compounds
and low molecular weight thiols, such as 1,2-ethanedithi-
ol and 1,3-propanedithiol, in the presence of various types
of acidic catalysts.7 Unfortunately, these thiols are
,6
,8
(
5) (a) Kocienski, P. J. Protecting Groups; Thieme: Stuttgart,
Germany, 1994. (b) Greene, T. W.; Wuts, P. G. M. Protective Groups
in Organic Synthesis, 3rd ed.; John Wiley and Sons: New York, 2004.
(6) (a) Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097. (b)
Seebach, D. Angew. Chem., Int. Ed. Engl. 1979, 18, 239. (c) Rych-
novsky, S. D. Chem. Rev. 1995, 95. (d) Smith, A. B., III; Condon, S.
M.; McCauley, J. A. Acc. Chem. Res. 1998, 31, 35. (e) Breit, B. Angew.
Chem., Int. Ed. 1998, 37, 7 (4), 453. (f) Smith, A. B., III; Pitram, S.
M.; Gaunt, M. J.; Kozmin, S. A. J. Am. Chem. Soc. 2002, 124, 14516.
(7) (a) Ku, B.; Oh, D. Y. Synth. Commun. 1989, 19, 433. (b) Page,
P. C. B.; Prodger, J. C.; Westwood, D. Tetrahedron 1993, 49, 10355.
(c) Kumar, P.; Reddy, R. S.; Singh, A. P.; Pandey, B. Synthesis 1993,
67. (d) Anand, R. V.; Saravanan, P.; Singh, V. K. Synlett 1999, 415.
(e) Tietze, L. F.; Weigand, B.; Wulff, C. Synthesis 2000, 69.
(8) (a) Garlaschelli, L.; Vidari, G. Tetrahedron Lett. 1990, 31, 5815.
(b) Patney, H. K. Tetrahedron Lett. 1991, 32, 2259. (c) Saraswathy, V.
G.; Sankararaman, S. J. Org. Chem. 1994, 59, 4665. (d) Firouzabadi,
H.; Iranpoor, N.; Hazarkhani, H. J. Org. Chem. 2001, 66, 7527. (e)
Kamal, A.; Chouhan, G. Tetrahedron Lett. 2002, 43, 1347. (f) Firouza-
badi, H.; Iranpoor, N.; Amani, K. Synthesis 2002, 59. (g) Kamal, A.;
Chouhan, G. Tetrahedron Lett. 2003, 44, 3337.
(9) (a) Liu, Q.; Che, G.; Yu, H.; Liu, Y.; Zhang, J.; Zhang, Q.; Dong,
D. J. Org. Chem. 2003, 68, 9148. (b) Yu, H.; Liu, Q.; Yin, Y.; Fang, Q.;
Zhang, J.; Dong, D. Synlett. 2004, 6, 999.
(
1) (a) Aqueous-Phase Organometallic Catalysis. Concepts and Ap-
plications; Cornils, B., Herrmann, W. A.; Eds.; Wiley-VCH: Weinheim,
Germany, 1998. (b) Organic Synthesis in Water; Grieco, P. A., Ed.:
Blackie Academic and Professional: London, UK, 1998. (c) Li, C.-J.;
Chan, T.-H. Organic Reactions in Aqueous Media; John Wiley &
Sons: New York, 1997. (d) Kobayashi, S.; Manabe, K. In Stimulating
Concepts in Chemistry; Shibasaki, M., Stoddart, J. F., Vogtle, F., Eds.;
Wiley-VCH: Weinheim, Germany, 2000.
(
2) (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159. (b) Li, C.-J. Chem.
Rev. 1993, 93, 2023. (c) Genet, J. P.; Savignac, M. J. Organomet. Chem.
1
999, 576, 305. (d) Fringuelli, F.; Piermatti, O.; Pizzo, F.; Vaccaro, L.
Eur. J. Org. Chem. 2001, 439. (e) Kobayashi, S.; Manabe, K. Acc. Chem.
Res. 2002, 35, 209.
(
3) (a) Kobayashi, S.; Wakabayashi, T. Tetrahedron Lett. 1998, 39,
5
389. (b) Manabe, K.; Mori, Y.; Kobayashi, S. Synlett 1999, 1401. (c)
Manabe, K.; Kobayashi, S. Org. Lett. 1999, 1401. (d) Otto, S.; Engberts,
J. B. S. N.; Kwak, J. C. T. J. Am. Chem. Soc. 1998, 120, 9517. (e)
Rispens, T.; Engberts, J. B. S. N. Org. Lett. 2001, 3, 941. (f) Manabe,
K.; Sun, X.-M.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123, 10101.
(
4) (a) Manabe, K.; Limura, S.; Sun, X.-M.; Kobayashi, S. J. Am.
Chem. Soc. 2002, 124, 11978. (b) Limura, S.; Manabe, K.; Kobayashi,
S. Org. Lett. 2003, 5 (2), 101.
1
0.1021/jo050271y CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/19/2005
J. Org. Chem. 2005, 70, 4535-4537
4535

amount of the surfactant DBSA has a great effect on the
rate of thioacetalization. The reactions are significantly
TABLE 2. DBSA-Catalyzed Thioacetalization of Various
Carbonyl Compounds 2 with 1 in Water
2
speeded up by increasing the feed ratio of DBSA-H O,
in particular at low ratio values. It appeares that there
might exist a critical ratio for the thioacetalization, in
other words there is nearly no change on the rate of the
reaction beyond this ratio. The highest catalytic activity
is attained when the reaction proceeds in the presence
substrate
product time, yield,a
entry
2
R1
R2
3
h
%
of a 1:100 molar ratio of DBSA-H
to the conversion of 2a into 3a in 98% yield within 1 h
entry 5). It is noteworthy that in all the cases the
2
O at reflux, leading
1
2
3
4
5
6
7
8
9
2a
3,4-O CH Ph
2
2
H
H
H
H
H
H
H
H
H
H
H
H
Me
3a
3b
3c
3d
3e
3f
0.9
1.3
1.4
1.5
2.1
2.0
1.6
2.8
2.0
2.5
2.7
2.0
2.2
1.5
2.5
8.0
8.0
8.0
8.0
1.5
2.0
98
89
93
96
97
94
95
90
93
88
72
90
89
96
81
69
39
25
66
91
90
(
2b
Ph
2c
4-MePh
4-MeOPh
4-(Me)2NPh
4-HOPh
2-HOPh
2-thiophen
PhCHdCH
4-ClPh
4-O NPh
n-C4H9
n-C4H9
-(CH2)5-
-(CH2)6-
Ph
4-ClPh
4-HOPh
4-O2NPh
reaction mixture forms white turbid emulsions at the
beginning. However, when heated to 80 °C, the mixtures
become clear. This phenomena suggests that micelles are
formed in the reaction system and the reaction should
take place on the interface or inside of the micelles.
Moreover, due to the hydrophobic nature of the micelles
the product would be expected to go inside the micelles
2d
2e
2f
2g
3g
3h
3i
3j
3k
3l
2h
2i
1
0
2j
11
2k
2
1
1
1
1
2
3
4
5
2l
2
and the byproduct H O would be expelled out of the
2m
2n
3m
3n
3o
3p
3q
3r
3s
3b
3n
micelles, which might accelerate the reaction. In fact, the
thioacetalization proceeds much faster in water than in
2o
9
b
organic solvent. In addition, the protocol is associated
with very simple separation processes. In the above cases,
the product is a solid and deposits from the reaction
system once formed. The pure product is obtained in
excellent yield after the solid is filtered and washed with
water. All the above results fully demonstrate that
compound 1 is an efficient and practical thioacetalization
reagent even in aqueous systems, and that DBSA is an
efficient catalyst for thioacetalization.
16
2p
Me
Me
Me
Me
1
1
1
2
7
8
9
0
2q
2r
2s
b
b
2b + 2p
2n + 2p
21
a
Isolated yields for 3, in the cases of entries 1-10, products
were obtained by washing with water while the others were
b
obtained by silica gel chromatography. The molar ratio of 1:al-
dehyde:ketone is 1:1:1
To test the general applicability of this protocol, we
next investigated the thioacetalization of 1 with various
types of selected aldehydes and ketones 2 using optimized
conditions. The reactions were refluxed in the presence
SCHEME 1. DBSA-Catalyzed Thioacetalization of
Carbonyl Compounds 2t with 1 in Water
2
of DBSA-H O (1:100 by molar ratio) with a 5:5:4 feed
molar ratio of 1:2:DBSA, respectively. A selection of the
results are listed in Table 2. It is clear that all the
aromatic aldehydes with electron-donating or electron-
withdrawing groups could be converted into the corre-
sponding dithianes 3 in the presence of DBSA in excellent
yields. Similarly, aliphatic aldehydes and ketones also
gave high yields of the corresponding dithianes 3. In
contrast, the product yields in the cases of aromatic
ketones 2p-2s were very low even with prolonged
reaction times. Apparently, the thioacetalization of aro-
matic ketones proceeds with greater difficulty than that
of the counterpart aldehyde, which is attributed to their
reactivity differences based on steric and electronic
effects. Nonetheless, all the results demonstrate the scope
and generality of the thioacetalization with respect to a
variety of aldehydes and aliphatic ketones using 1 as the
ried out under the above conditions. In one representative
case, the reaction of 2b/2p/1 with a 1:1:1 molar ratio was
performed under the above conditions (entry 20). Sub-
sequently, thioacetal 3b was obtained in 91% yield, while
starting material 2p was almost completely recovered
(
98%) and 3p was not detected. In another case, com-
pound 2t with two different carbonyl groups on the same
molecule was synthesized to further validate the concept.
As shown in Scheme 1, the reaction between 2t and 1
with a 1:1 molar ratio proceeded within 2 h to afford
product 3t in 94% yield. All the results reveal that the
thioacetalization in water exhibits significantly high
chemoselectivity among various carbonyl compounds in
the presence of 1.
1
,3-propanedithiol equivalent in aqueous media. It is
On the basis of the above experimental results together
worth mentioning that in all the cases nearly no free 1,3-
propanedithiol is generated during the reaction since only
a very faint odor of thiol can be detected during both the
reaction and the workup processes.
9
with our previous work, a mechanism for the thioac-
etalization reaction in aqueous media is proposed as
shown in Scheme 2. On the interface of the micelles, 1
undergoes deacylation catalyzed by DBSA to give ketene
dithiolacetal 4. This is followed by the addition of a proton
to its carbon-carbon double bond, and the ketene dithi-
olacetal 4 is converted into a carbocation 5 that is
stablized by the electron-donating bis(alkylthio) groups.
The reactivity difference between aldehydes and ke-
tones suggests that the thioacetalization might be used
for the selective protection of different carbonyl groups.
Some competitive reactions among aromatic aldehydes,
aliphatic ketones, and aromatic ketones were then car-
2
With the attack of H O, the carbocation 5 is transformed
4536 J. Org. Chem., Vol. 70, No. 11, 2005

SCHEME 2. A Proposed Mechanism for the
Thioacetalization of Carbonyl Compound 2 with 1
in Water
In conclusion, we describe a novel thioacetalization
reaction in water in the presence of DBSA. The results
demonstrate that 3-(1,3-dithian-2-ylidene)pentane-2,4-
dione 1 is an efficient and practical thioacetalization
reagent in aqueous media. Associated with mild condi-
tions, simple procedure, high yield, and environmentally
benign reagents, this novel thioacetalization provides a
convenient protocol for the synthesis of thioacetals and
the protection of carbonyl compounds with high chemose-
lectivity.
Acknowledgment. Financial support of this re-
search by the NNSFC (20272008) and the Key Grant
Project of Chinese Ministry of Education (10412) is
acknowledged.
Supporting Information Available: Experimental de-
tails for the thioacetalization of 1 with selected carbonyl
compounds 2. This material is available free of charge via the
Internet at http://pubs.acs.org.
to an oxygen cation 6, which leads to the formation of
the intermediate 7 through a deprotonation and decy-
clization process. Finally, intermediate 7 reacts with
carbonyl compound 2 to yield the corresponding dithiane
3.
JO050271Y
J. Org. Chem, Vol. 70, No. 11, 2005 4537