Acid-promoted thioacetalization in water using 2-(1,3-dithian-2-ylidene) malonic acid as an odorless and efficient thioacetalization reagent

Article abstract of DOI:10.1080/00397910601163984

Thioacetalization using 2-(1,3-dithian-2-ylidene)malonic acid 1 as a nonthiolic, odorless 1,3-propanedithiol equivalent promoted by p-dodecylbenzenesulfonic acid in water has been achieved. A range of selected carbonyl compounds 2 was converted into the corresponding dithioacetals 3 in high yields. Moreover, the thioacetalization showed high chemoselectivity between aldehydes and ketones. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910601163984

This article was downloaded by: [University Of Maryland]
On: 18 October 2014, At: 17:12
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Acid‐Promoted Thioacetalization in Water
using 2‐(1,3‐Dithian‐2‐ylidene)malonic Acid
as an Odorless and Efficient Thioacetalization
Reagent
Yan Ouyang a , Dewen Dong a , Yongjiu Liang a , Yanyan Chai, a & Qun Liu a
a Department of Chemistry , Northeast Normal University , Changchun,
China
Published online: 24 Feb 2007.
To cite this article: Yan Ouyang , Dewen Dong , Yongjiu Liang , Yanyan Chai, & Qun Liu (2007) Acid‐Promoted
Thioacetalization in Water using 2‐(1,3‐Dithian‐2‐ylidene)malonic Acid as an Odorless and Efficient
Thioacetalization Reagent, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:6, 993-1000, DOI: 10.1080/00397910601163984
To link to this article: http://dx.doi.org/10.1080/00397910601163984
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 37: 993–1000, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910601163984
Acid-Promoted Thioacetalization in Water
using 2-(1,3-Dithian-2-ylidene)malonic Acid
as an Odorless and Efficient
Thioacetalization Reagent
Yan Ouyang, Dewen Dong, Yongjiu Liang, Yanyan Chai,
and Qun Liu
Department of Chemistry, Northeast Normal University,
Changchun, China
Abstract: Thioacetalization using 2-(1,3-dithian-2-ylidene)malonic acid 1 as a non-
thiolic, odorless 1,3-propanedithiol equivalent promoted by p-dodecylbenzenesulfonic
acid in water has been achieved. A range of selected carbonyl compounds 2 was
converted into the corresponding dithioacetals 3 in high yields. Moreover, the thio-
acetalization showed high chemoselectivity between aldehydes and ketones.
Keywords: chemoselectivity, 2-(1,3-dithian-2-ylidene)malonic acid, p-dodecylbenze-
nesulfonic acid, thioacetalization, water
INTRODUCTION
The use of water as a solvent in organic chemistry was rediscovered in the
1980s in Breslow’s work, which showed that hydrophobic effect can
strongly enhance the rates of some organic reactions.[1] The organic
reactions in water without the use of any organic solvent can also benefit
from the fact that water is an easily available, cheap, safe, and environmen-
tally benign solvent.[2,3]
Recently, Iimura, and co-workers reported that thioacetalization can be
conducted in aqueous media with surfactant-type Brønsted acid catalysts.[4]
Received in Japan July 15, 2006
Address correspondence to Dewen Dong, Department of Chemistry, Northeast
Normal University, Changchun 130024, China. E-mail: dongdw663@nenu.edu.cn
993

994
Y. Ouyang et al.
Thioacetals have been extensively investigated as carbonyl protection groups
and versatile intermediates in the synthesis of multifunctional complex
molecules and natural products.[5,6] Generally, thioacetals are prepared by
the condensation of carbonyl compounds with thiols or dithiols employing
various acidic catalysts.[7,8] However, these thiols are flammable, harmful,
and odorous reagents, which can lead to serious environmental and safety
problems. Very recently, we have developed a novel thioacetalization
reaction using nonthiolic, odorless cyclic ketene dithioacetals as 1,3-propane-
dithiol equivalents[9] and found that p-dodecylbenzenesulfonic acid (DBSA),
a surfactant-type Brønsted acid, can be used as an acid catalyst for the thioa-
cetalization in water.[10] With the aim of obtaining a more efficient and
practical reagent for general application, we investigated the thioacetalization
reaction of 2-(1,3-dithian-2-ylidene)malonic acid 1 with a range of selected
carbonyl compounds 2 catalyzed by DBSA in water. In the present work,
we report our findings.
RESULTS AND DISCUSSION
According to the reported procedure,[11] diethyl 2-(1,3-dithian-2-ylidene)ma-
lonate was prepared from diethyl malonate, carbon disulfide, 1,3-dibromopro-
pane and K2CO3 in nearly quantitative yield, which was then transformed into
compound 1 via a hydrolysis process.[12]
The reaction of 1 with benzaldehyde 2a (1.0 equiv) was initially
performed in the presence of 0.17 mol/L of DBSA-H2O (Table 1, entry 1).
After the mixture was heated to reflux and stirred for about 6 h, 2a was
consumed, as indicated by thin-layer chromatography (TLC). A white solid
Table 1. Reactions between 1 and benzaldehyde 2a
Entry
1 (mmol) 2a (mmol)
DBSA/H2O (mol/L)
Time (h)
Yielda (%)
1
2
3
4
5
6
5
5
5
5
5
5
5
5
5
5
5
5
0.17
0.22
0.28
0.33
0.39
0.56
6.0
4.0
2.5
1.8
1.2
1.1
89
88
89
90
91
90
aIsolated yields.

Acid-Promoted Thioacetalization
995
was deposited from the reaction system when the resulting mixture was cooled
down to ambient temperature, which was filtered and washed with water to
afford a quite pure product characterized as 2-phenyl-1,3-dithiane 3a (89%).
To optimize the conditions of the thioacetalization, the reactions of 1 and
2a were carried out in varied concentrations of DBSA in water (Table 1,
entries 2–6). The reactions are significantly accelerated when increasing the
concentration of DBSA, in particular at low concentrations. It appears that
there might exist a critical micelle concentration for the thioacetalization.
The highest reaction activity is attained when it proceeds in the presence of
0.39 mol/L of DBSA-H2O at reflux, leading to the conversion of 2a into 3a
in 91% yield within 1.2 h (Table 1, entry 5). The reaction mixture forms
white turbid emulsions at the beginning and becomes clear when heated to
temperatures higher than 808C. The phenomena suggest that micelles would
be formed in the reaction system and the reaction should take place on the
interface or inside the micelles. Moreover, because of the hydrophobic
nature of the micelles, the product would be expected to go inside the
micelles and the by-product H2O would be expelled out of the micelles,
which might accelerate the reaction. It is worth noting that the thioacetaliza-
tion proceeds much faster in water compared with that in organic solvent.[9]All
these 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.
In the next studies, we investigated the thioacetalization of 1 with various
types of selected aldehydes and ketones 2 under conditions identical to those
described in entry 5, Table 1. Some of the results are summarized in Table 2. A
range of aromatic aldehydes (Table 2, entries 1–6), heterocyclic aldehyde
(Table 2, entry 7), aliphatic aldehyde (Table 2, entry 8), and ketones
(Table 2, entries 9 and 10) could be converted into the corresponding
dithianes 3 in the presence of DBSA under reflux conditions in water in
high yields. In contrast, the reactions of aromatic ketones proceed with
greater difficulty than that of the counterpart aldehyde based on the lower con-
version, even with prolonged reaction times (Table 2, entries 11 and 12). This
might be attributed to their reactivity differences based on steric and electronic
effects.
The difference of the reactivity between aldehydes and ketones suggests
that the thioacetalization can be used for the selective protection of different
carbonyl groups. Some competitive reactions among aromatic aldehydes,
aliphatic ketones, and aromatic ketones were then carried out. When
aromatic aldehyde 2a, aromatic ketone 2k, and 1 with a 1 : 1 : 1 molar ratio
were subjected to the identical conditions, thioacetal 3a was obtained in
90% yield, and starting material 2k was almost completely recovered
(Table 2, entry 13). Similarly, the competitive reaction of aliphatic cyclic
ketone 2j, aromatic ketone 2k, and 1 with a 1 : 1 : 1 molar ratio gave thioacetal
3j in 93% yield along with intact starting material 2k (Table 2, entry 14). The
validity of the two reactions prompted us to examine the chemoselective

996
Y. Ouyang et al.
Table 2. Thioacetalization reactions of selected aldehydes/ketones 2 with 2-(1,3-
dithian-2-ylidene) malonic acid 1 in water
Entry Substrate 2
R1
R2
Product 3 Time (h) Yielda (%)
1
2
2a
2b
Ph
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
1.2
1.0
2.0
2.0
2.1
2.0
2.6
2.0
2.2
1.5
8.0
8.0
1.2
1.5
91
98
3, 4-OCH2OPh
4-NMe2Ph
4-HOPh
4-ClPh
3
2c
2d
93
94
4
5
2e
92
91
6
2f
2g
PhCH55CH
2-thienyl
n-C4H9
7
3g
3h
3i
90
90
8
2h
2i
9
n-C4H9
(CH2)5
Me
88
95
10
11
12
13
14
2j
2k
(CH2)5
Me
Me
3j
Ph
4-ClPh
3k
3l
67
42
90(98)b
93(97)b
2l
2a þ 2k
3a
3h
2j þ 2k
aIsolated yields.
bMolar ratio of 1 : 2a(2j) : 2k is 1 : 1 : 1, the data in brackets are recovery of 2k.
thioacetalization of the compound 2m with two different carbonyl groups on
the same molecule. As shown in Scheme 1, the reaction between 2m and 1
with a 1 : 1 molar ratio proceeded within 2.5 h to afford product 3m in 92%
yield. All the results reveal that the thioacetalization in water exhibits signifi-
cantly high chemoselectivity among various carbonyl compounds in the
presence of 1.
Scheme 1. Chemoselective thioacetalization of 2m with 1 in water.

Acid-Promoted Thioacetalization
997
Scheme 2. Proposed mechanism for the thioacetalization of 2 with 1 in water.
On the basis of these experimental results together with our previous
studies,[9,10] a mechanism for the thioacetalization reaction in water is
proposed as shown in Scheme 2. Compound 1 undergoes decarboxylation
catalyzed by DBSA to give ketene dithiolacetal 4, which is followed by the
addition of a proton to its carbon–carbon double bond, and the ketene dithio-
lacetal 4 is converted into a carbocation 5, which is stabilized by the electron-
donating bis(alkylthio) groups. With the attack of H2O, the carbocation 5 is
transformed to an oxocation 6, which leads to the formation of the intermedi-
ate 7 through a deprotonation and decyclization process. Finally, intermediate
7 reacts with carbonyl compound 2 to yield the corresponding dithiane 3.
CONCLUSIONS
In summary, odorless 2-(1,3-dithian-2-ylidene)malonic acid 1 has been inves-
tigated as a 1,3-propanedithiol equivalent in thioacetalization promoted by
DBSA in water. In the presence of 1, a range of carbonyl compounds 2,
aldehydes, and aliphatic ketones has been converted into corresponding dithioa-
cetals 3 in high yields. The relatively slow reaction rate of aromatic ketones
allows chemoselective protection of an aromatic aldehyde or an aliphatic
ketone from an aromatic ketone. Associated with mild conditions and simple
procedure, the reported procedure provides a convenient and clean protocol
for the protection of various carbonyl compounds with high chemoselectivity.
EXPERIMENTAL
All reagents were purchased from commercial sources and used without
1
treatment, unless otherwise indicated. H NMR spectra were recorded at

998
Y. Ouyang et al.
258C on a 500-MHz spectrometer in CDCl3 and TMS as internal standard. IR
spectra (KBr) were recorded on a FTIR spectrophotometer in the range of
400–4000 cm21
.
General Procedure for Dithioacetals 3
To a 50-mL single-necked flask equipped with a condenser, 1 (5.0 mmol), 2a
(5.0 mmol), H2O (9.0 mL), and DBSA (3.5 mmol) were added. The mixture
formed white turbid emulsions immediately. When heated to reflux, the
mixture became clear as observed by naked eyes. After stirring at reflux temp-
erature for about 1.2 h, the reaction was complete as indicated by TLC and
was then allowed to cool down to ambient temperature. The white solid
was collected by filtration and washed with aqueous NaHCO3 (10%,
25 mL ꢀ 3) and water (25 mL ꢀ 3) to give dithioacetal 3a (yield: 91%).
In the cases of liquid products 3h and 3j, the resulting mixture was neu-
tralized with aqueous NaHCO3 (10%, 10 mL) and extracted with diethyl ether
(3 ꢀ 20 mL). The extracts was washed with H2O (3 ꢀ 30 mL) and dried over
Na2SO4. Evaporation of the solvent gave almost pure product. Further purifi-
cation was carried out over flash silica-gel chromatography (eluent: petroleum
ether–ethyl acetate ¼ 75 : 1, v/v).
Data
2m: white solid; yield: 96%; mp: 104–1068C. 1H NMR (CDCl3, 500 MHz) d
2.57 (s, 3H), 4.43 (s, 4H), 6.98–7.02 (dd, J ¼ 9.0, 8.5 Hz, 4H), 7.85-7.97 (dd,
J ¼ 9.0, 8.5 Hz, 4H), 9.90 (s, 1H). 13C NMR (CDCl3, 125 MHz) d 26.7, 66.6,
66.8, 114.5, 115.1, 130.6, 130.9, 131.0, 132.3, 162.5, 163.7, 191.1, 197.1. IR
(KBr, cm21) 1673, 1600, 1570, 1247, 1162. Anal. calcd. for C17H16O4: C,
71.82; H, 5.67; found: C, 71.90; H, 5.64.
3m: white solid; yield: 94%; mp: 160–1628C. 1H NMR (CDCl3, 500 MHz) d
1.90–1.93 (m, 1H), 2.16 (m, 1H), 2.57 (s, 3H), 2.89–2.92 (m, 2H), 3.03–3.08
(m, 2H), 4.34–4.38 (dd, J ¼ 5.0, 5.0 Hz, 4H), 5.14 (s, 1H), 6.90-6.99 (dd,
J ¼ 8.5, 8.5 Hz, 4H), 7.40–7.42 (d, J ¼ 8.5 Hz, 2H), 7.94–7.96
(d, J ¼ 8.5 Hz, 2H). 13C NMR (CDCl3, 125 MHz) d 25.3, 26.7, 32.4, 50.9,
66.5, 66.8, 114.5, 115.0, 129.3, 130.9, 132.2, 158.7, 162.7, 197.1.IR (KBr,
cm21) 3446, 2934, 1675, 1601, 1508, 1245, 1175. Anal. calcd. for
C20H22O3S2: C, 64.14; H, 5.92; found: C, 64.19; H, 5.58.
Dithioacetals 3a–l prepared in the present work are known compounds and
identified by NMR, IR spectroscopy, and elemental analyses; the data for
these compounds are in good agreement with those in literatures (Ref. 9a
and 10).

Acid-Promoted Thioacetalization
ACKNOWLEDGMENTS
999
Financial support of this research by the National Natural Science Foundation
of China (20572013), the Ministry of Education of China (105061 and 10412),
and the Department of Science and Technology of Jilin Province (20050392)
is greatly acknowledged.
REFERENCES
1. (a) Breslow, R.; Rideout, D. C. Hydrophobic acceleration of Diels–Alder
reactions. J. Am. Chem. Soc. 1980, 102, 7816–7817; (b) Breslow, R. Hydrophobic
effects on simple organic reactions in water. Acc. Chem. Res. 1991, 24, 159–164;
(c) Breslow, R. Determining the geometries of transition states by use of antihydro-
phobic additives in water. Acc. Chem. Res. 2004, 37, 471–478.
2. (a) Cornils, B.; Herrmann, W. A. Aqueous-Phase Organometallic Catalysis:
Concepts and Applications; Wiley-VCH: Weinheim, 1998; (b) Grieco, P. A.
Organic Synthesis in Water; Thomson Science: Glawsgow, Scotland, 1998;
(c) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media; John Wiley &
Sons: New York, 1997; (d) Kobayashi, S.; Manabe, K.; Shibasaki, M.;
Stoddart, J. F.; Vogtle, F. In Stimulating Concepts in Chemistry; Wiley-VCH:
Weinheim, 2000.
3. (a) Li, C.-J.; Chan, T.-H. Organic syntheses using indium-mediated and catalyzed
reactions in aqueous media. Tetrahedron 1999, 55, 11149–11176; (b) Li, C.-J.
Organic reactions in aqueous media with a focus on carbon–carbon bond
formation. Chem. Rev. 1993, 93, 2023; (c) Li, C.-J. Organic reactions in
aqueous media with a focus on carbon–carbon bond formations: A decade
update. Chem. Rev. 2005, 105, 3095–3165; (d) Kobayashi, S.; Manabe, K. Devel-
opment of novel Lewis acid catalysts for selective organic reactions in aqueous
media. Acc. Chem. Res. 2002, 35, 209–217.
4. (a) Iimura, S.; Manabe, K.; Kobayashi, S. Hydrophobic polymer-supported
catalyst for organic reactions in water: Acid-catalyzed hydrolysis of thioesters
and transprotection of thiols. Org.Lett. 2003, 5 (2), 101–103; (b) Manabe, K.;
Iimura, S.; Sun, X.-M.; Kobayashi, S. Dehydration reactions in water. Brøsnsted
acid–surfactant combined catalyst for ester, ether, thioether, and dithioacetal
formation in water. J. Am. Chem. Soc. 2002, 124, 11971–11978.
5. (a) Kocienski, P. J. Protecting Groups; Thieme: Stuttgart, 1994; (b) Greene, T. W.;
Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.; John Wiley &
Sons: New York, 1999.
6. (a) Breit, B. Dithioacetals as an entry to titanium-alkylidene chemistry: A new and
efficient carbonyl olefination. Angew. Chem. Int. Ed. 1998, 37 (4), 453–456;
(b) Smith, A. B., III; Pitram, S. M.; Gaunt, M. J.; Kozmin, S. A. Dithiane
additions to vinyl epoxides: Steric control over the SN2 and SN20 manifolds.
J. Am. Chem. Soc. 2002, 124, 14516–14517.
7. (a) Page, P. C. B.; Prodger, J. C.; Westwood, D. Diastereoselectivity in the addition
of Grignard reagents to ketones controlled by the 1,3-dithiane 1-oxide asymmetric
building block. Tetrahedron 1993, 49, 10355–10368; (b) Tani, H.; Masumoto, K.;
Inamasu, T.; Suzuki, H. Tellurium tetrachloride as a mild and efficient catalyst for
dithioacetalization. Tetrahedron Lett. 1991, 32, 2039–2042; (c) Tietze, L. F.;

1000
Y. Ouyang et al.
Weigand, B.; Wulff, C. A mild and efficient method for the preparation of 1,3-
dithianes from aldehydes and ketones. Synthesis 2000, 69–71.
8. (a) Garlaschelli, L.; Vidari, G. Anhydrous lanthanum trichloride, a mild and con-
venient reagent for thioacetalization. Tetrahedron Lett. 1990, 31, 5815–5186;
(b) Kumar, P.; Reddy, R. S.; Singh, A. P.; Pandey, B. H-Y zeolite: An efficient
catalyst for thioacetalization. Tetrahedron Lett. 1992, 33, 825–826;
(c) Saraswathy, V. G.; Sankararaman, S. Chemoselective protection of
aldehydes as dithioacetals in lithium perchlorate–diethyl ether medium:
Evidence for the formation of oxocarbenium ion intermediate from acetals.
J. Org. Chem. 1994, 59, 4665–4670; (d) Anand, R. V.; Saravanan, P.;
Singh, V. K. Solvent free thioacetalization of carbonyl compounds catalyzed by
Cu(OTf)2-SiO2. Synlett 1999, 415–416; (e) Firouzabadi, H.; Iranpoor, N.;
Hazarkhani, H. Iodine catalyzes efficient and chemoselective thioacetalization of
carbonyl functions, transthioacetalization of O,O- and S,O-acetals and acylals.
J. Org. Chem. 2001, 66, 7527–7529; (f) Muthusamy, S.; Babu, S. A.;
Gunanathan, C. Indium(III) chloride as an efficient, convenient catalyst for thioa-
cetalization and its chemoselectivity. Tetrahedron Lett. 2001, 42, 359–362;
(g) Kamal, A.; Chouhan, G. Scandium triflate as a recyclable catalyst for chemo-
selective thioacetalization. Tetrahedron Lett. 2002, 43, 1347–1350; (h) Kamal, A.;
Chouhan, G. Chemoselective thioacetalization and transthioacetalization of
carbonyl compounds catalyzed by immobilized scandium(III) triflate in ionic
liquids. Tetrahedron Lett. 2003, 44, 3337–3340.
9. (a) Liu, Q.; Che, G.; Yu, H.; Liu, Y.; Zhang, J.; Zhang, Q.; Dong, D. The first non-
thiolic, odorless 1,3-propanedithiol equivalent and its application in thioacetaliza-
tion. J. Org. Chem. 2003, 68, 9148–9150; (b) Yu, H.; Liu, Q.; Yin, Y.; Fang, Q.;
Zhang, J.; Dong, D. a,a-Diacetyl cyclic ketene dithioacetals: Odorless and
efficient dithiol equivalents in thioacetalization reactions. Synlett 2004,
999–1002; (c) Liu, J.; Liu, Q.; Yu, H.; Ouyang, Y.; Dong, D. Odorless thioaceta-
lization reagent 2-[1,3]dithian-2-ylidene-3-oxo-butanamide and its chemoselectiv-
ity. Synth. Commun. 2004, 34 (24), 4545–4556.
10. Dong, D.; Ouyang, Y.; Yu, H.; Liu, Q.; Liu, J.; Wang, M.; Zhu, J. Chemoselective
thioacetalization in water: 3-(1,3-Dithian-2-ylidene)pentane-2,4-dione as an
odorless, efficient and practical thioacetalization reagent. J. Org. Chem. 2005,
70, 4535–4537.
11. (a) Choi, E. B.; Youn, I. K.; Pak, C. S. Preparation of protected b-keto aldehydes
from b-keto ester via selective reduction of acyl(alkoxycarbonyl)ketene dithioace-
tals. Synthesis 1988, 792–794; (b) Mellor, J. M.; Schofield, S. R.; Korn, S. R.
Routes to building blocks for heterocyclic synthesis by reduction of ketene dithioa-
cetals. Tetrahedron 1997, 53 (50), 17151–17162.
12. Zhao, Y.; Liu, Q.; Sun, R.; Zhang, Q.; Xu, X. Iododecarboxylation reactions of
a-oxo ketene dithioacetals: The new route to a-iodo ketene dithioacetals. Synth.
Commun. 2004, 34 (3), 463–469.