Odorless thioacetalization reagent 2-[1,3] dithian-2-ylidene-3-oxo- butanamide and its chemoselectivity

Article abstract of DOI:10.1081/SCC-200043220

2-[1,3]Dithian/dithiolan-2-ylidene-3-oxo-butanamide 2a/2b were synthesized and investigated in the thioacetalization reaction of aldehydes/ketones 3. The experiments revealed that 2a could be used as a nonthiolic, odorless 1,3-propanedithiol equivalent in the conversion of aldehydes/ketones into the corresponding dithianes 4, however, 2b was less effective. Moreover, the chemoselectivity of the thioacetalization of 3 in the presence of 2a is discussed.

Full text of DOI:10.1081/SCC-200043220

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Odorless
Thioacetalization Reagent
2‐[1,3]Dithian‐2‐Ylidene‐3‐Oxo‐Bu
and Its Chemoselectivity
Jun Liu a , Qun Liu a , Haifeng Yu a , Yan Ouyang a
& Dewen Dong a
a Department of Chemistry, Northeast Normal
University, 5268 Renmin Street, Changchun,
130024, P. R. China
Published online: 10 Jan 2011.
To cite this article: Jun Liu , Qun Liu , Haifeng Yu , Yan Ouyang
& Dewen Dong (2004): Odorless Thioacetalization Reagent
2‐[1,3]Dithian‐2‐Ylidene‐3‐Oxo‐Butanamide and Its Chemoselectivity, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:24, 4545-4556
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 24, pp. 4545–4556, 2004
Odorless Thioacetalization Reagent 2-[1,3]
Dithian-2-Ylidene-3-Oxo-Butanamide and
Its Chemoselectivity
Jun Liu, Qun Liu, Haifeng Yu, Yan Ouyang,
*
and Dewen Dong
Department of Chemistry, Northeast Normal University,
Changchun, P. R. China
ABSTRACT
2-[1,3]Dithian/dithiolan-2-ylidene-3-oxo-butanamide
2a/2b
were
synthesized and investigated in the thioacetalization reaction of
aldehydes/ketones 3. The experiments revealed that 2a could be used as
a nonthiolic, odorless 1,3-propanedithiol equivalent in the conversion of
aldehydes/ketones into the corresponding dithianes 4, however, 2b was
less effective. Moreover, the chemoselectivity of the thioacetalization
of 3 in the presence of 2a is discussed.
Key Words: Carbonyl compounds; Chemoselectivity; a-oxo ketene
dithioacetals; 1,3-propanedithiol equivalent.
*
Correspondence: Dewen Dong, Department of Chemistry, Northeast Normal Univer-
sity, 5268 Renmin Street, Changchun 130024, P. R. China; Fax: þ86(431)5098966;
E-mail: dongdw663@nenu.edu.cn.
4545
DOI: 10.1081/SCC-200043220
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Liu et al.
INTRODUCTION
Thioacetals have been extensively investigated as carbonyl protection
groups and versatile intermediates in the synthesis of multifunctional
complex molecules and natural products.[1,2] To date, there are many
methods reported for the preparation of thioacetals from carbonyl compounds
or O,O-acetals with thiols employing various acid catalysts such as protonic
acids, Lewis acids, and solid acids.[3,4] However, the traditional methods
suffer from the use of volatile, foul-smelling, low molecular weight thiols
that lead to serious safety and environment problems. To resolve these pro-
blems, some attempts have been made to develop odorless substitutes for
these noxious thiols.[5–7] Generally, an alkyl chain of over 12 carbon atoms
in a thiol is crucial in reducing the offending smell. Therefore, a range of odor-
less or faintly smelling thiols has been developed by increasing alkyl chain
length of thiol or introducing the trialkylsilyl group into the benzene ring of
benzyl mercaptan and benzenethiol.[5] Incorporation of 1,3-propanedithiol
functions within linear and cross-linked copolymeric reagents[6] or conversion
of the thiol to its odorless dithioester have been reported and applied in organic
synthetic chemistry.[7] However, there is no mention about the chemoselectiv-
ity of the thioacetalization in the above work. Moreover, the multistep process
of preparation, the high cost of catalysts, and the toxicity of some precursors
limit the further utilization of the thiol reagents or their equivalents.
Our laboratory has been engaging in the synthesis and application of
ketene dithioacetals for over a decade.[8] Recently, we developed novel non-
thiolic, odorless 1,3-propanedithiol equivalents based on cyclic ketene
dithioacetals, e.g., 1a and its precursor 1b (Sch. 1).[9] In the presence of 1a
or 1b, the thioacetalization of a range of aldehydes and ketones has been
achieved under mild conditions along with high chemoselectivity. These
results encourage us to believe that a wide range of known and/or unknown
cyclic ketene dithioacetals might be used as dithiol equivalents in thioacetali-
zation if appropriate conditions are employed. With the expectation of obtain-
ing efficient and practical thioacetalization reagents, we investigated a-oxo
cyclic ketene dithioacetals, 2-[1,3]dithian-2-ylidene-3-oxo-butanamide 2a,
Scheme 1.

Thioacetalization Reagent 2-[1,3] Dithian-2-Ylidene-3-Oxo-Butanamide
4547
and its analogue 2b (Sch. 1) as dithiol equivalents in the thioacetalization with
the selected aldehydes and ketones 3.
RESULTS AND DISCUSSION
Thioacetalization of Carbonyl Compounds 3 with 2
Extensive work on the synthesis and application of a-oxo ketene dithio-
acetals has been reported elsewhere.[8,10] According to the procedure described
in literature,[11] a-oxo ketene dithioacetals 2a and 2b can be readily prepared
from 3-oxo-butanamide, carbon disulfide, and 1,3-dibromopropane/1,2-
dibromoethane in the presence of K2CO3 in good yields (80%). It is note-
worthy that both 2a and 2b are odorless solids and stable under ambient
atmosphere, and they are associated with some synthetic advantages, such
as simple procedure, mild conditions, high yields, and commercial starting
materials without foul smell.
In our previous work,[9b] the production of HCl by addition of acetyl
chloride to reagents 1b in dry methanol has proved to be a convenient way
to achieve the thioacetalization of a range of aldehydes and ketones. There-
fore, in the present work we also selected acetyl chloride as catalyst and
methanol as reaction medium to investigate the thioacetalization of selected
aldehydes and ketones 3 with 2.
The reactions between the selected carbonyl compounds 3 and 2
proceeded via a very simple procedure (Sch. 2); preparation of 4a from the
reaction between 2a and 3a was described as an example (Table 1, entry 1):
3a (1.0 mmol), 2a (1.0 mmol), methanol (10 mL), and acetyl chloride
(0.18 mL, 2.5 mmol) were added into a flask equipped with a condenser.
The mixture was heated to reflux and stirred for about 120 min as indicated
by TLC for a complete reaction. The resulting mixture was then allowed to
cool down to room temperature and neutralized with aqueous NaHCO3
(10%). After extractive work-up, separation was carried out over silica gel
Scheme 2. Thioacetalization of carbonyl compounds 3 with 2.

4548
Liu et al.
Table 1. Thioacetalization of carbonyl compounds 3 with 2a/2b.
Time
(min)
Yield
(%)b
Entry
Substrate 3
R1
R2
Product 4a
1
2
3a
3b
3c
3d
3e
3f
Ph
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
120
165
150
110
130
60
76
80
4-CH3Ph
4-Cl Ph
4-NO2 Ph
3-NO2 Ph
2-Furyl
2-Thiophene
(CH2)4
(CH2)5
Et
3
90
95
4
5
92
70
6
7
3g
3h
3i
4g
4h
4i
70
76
90
77
8
9
110
200
250
280
180
360
720
960
960
360
82
78
10
11
12
13
14
15
16
17
18
3j
Me
Me
Me
Me
Ph
H
4j
3k
3l
Ph
4k
4l
90
94
4-Cl Ph
4-NO2 Ph
Ph
3m
3n
3a
3d
3m
3n
4m
4n
5a
5d
5m
5n
93
92
Ph
40 (56)
35 (59)
11 (85)
0 (98)
4-NO2 Ph
4-NO2 Ph
Ph
H
Me
Ph
aAll products were characterized by 1H NMR and IR spectra.
bIsolated yields by column chromatography over silica gel, the data in bracket are the
recoveries of compounds 3.
chromatography (eluent: petroleum ether : ethyl acetate ¼ 60 : 1, v/v) to give
a pure product in 76% yield, which was identified as dithioacetal 4a. It is
worth mentioning that nearly no free 1,3-propanedithiol is released within
the reaction system because only a very faint smell of thiol can be perceived
during both the reaction process and the work-up process. Following the above
procedure, a range of selected carbonyl compounds with different chemical
structures were converted into the corresponding dithioacetals 4 in good-to-
high yields (up to 95%); some of the results are summarized in Table 1
(entries 1–14). The presented results exhibit the scope and generality of the
thioacetalization with respect to the different carbonyl compounds, i.e., aro-
matic, aliphatic, and heterocyclic aldehydes or ketones. It is worth noting
that the reaction rates for the thioacetalization with aromatic aldehydes are
slightly faster in comparison to that with the corresponding aromatic
ketones, as can be seen in Table 1 by comparing entries 3 and 12 or entries
4 and 13. This difference should be attributed to the steric effect from the
chemical structures of the aromatic aldehydes and ketones. That is the

Thioacetalization Reagent 2-[1,3] Dithian-2-Ylidene-3-Oxo-Butanamide
4549
reason why the protection of the sterically hindered aromatic ketone 3n (entry
14) needs even more long reaction time.
We next investigated 2b, the analogue of 2a, in the thioacetalization of
the selected carbonyl compounds 3 under the same procedure described
above (Sch. 2); some of the results are also summarized in Table 1 (entries
15–18). It is worth noting that the selected carbonyl compounds, except the
sterically hindered aromatic ketone 3n (entry 18), could be converted into
the corresponding dithiacetals 5 in the presence of 2b. However, the conver-
sions are too low, even though the reactions proceeded for more than 12h
under reflux temperature. The results indicate that 2b is much less effective
as a practical thioacetalization reagent under the studied conditions. The
different results achieved from the thioacetalization with 2a and that with
2b might stem from the differences of the rigidity and the steric effect of
their bis(alkylthio) groups, which deserves further investigation.
Chemoselectivity of the Thioacetalization
The difference of the reactivities between aldehyde and ketone suggest that
the thioacetalization might be used for the selective protection of these groups,
namely, provide a convenient route for the protection of an aldehyde in the pre-
sence of a ketone. Then several reactions of 2a with the different mixtures of aro-
matic aldehyde (or aliphatic ketone) and aromatic ketone were carried out under
the above reaction conditions. In all the cases, the feed molar ratio of reactant
aromatic aldehyde (or aliphatic ketone), aromatic ketone, and thioacetaliztion
reagent 2a was kept constant at 1 : 1 : 1. Some of the results are summarized in
Table 2. As shown in Table 2, the chemoselectivity of the thioacetalization of
carbonyl compounds depended on the reactivity differences among the reactant
carbonyl compounds. In some cases (entries 1–4), chemoselective protection
Table 2. Chemoselectivity of thioacetalization of 3 in the presence of 2a.
Entry
Substrate 3
Product 4a
Time (min)
Yield (%)b
1
2
3
4
5
3a/3k
3d/3m
3i/3k
3j/3k
3h/3i
4a
4d
180
150
140
300
300
75 (96)
81 (97)
82 (96)
77 (95)
43/46
4i
4j
4h/4i
1
aAll products were characterized by H NMR and IR spectra.
bIsolated yields by column chromatography over silica gel, the data in bracket are the
recovery of the unreacted compounds 3.

4550
Liu et al.
was achieved in which the reactant carbonyl compounds showed obviously
different reactivities. For example, the reaction of 3i/3k/2a was performed
under the same procedure described above (Sch. 3, entry 2). Subsequently, thioa-
cetal 4i was obtained in 82% yield, while starting material 3k was almost
completely recovered back (96%), and thioacetal 4k was even not detectable.
However, in the case of 3h/3i/2a (Sch. 3, entry 5), mixed dithioacetals 4h
and 4i were obtained, meanwhile both unreacted 3h and 3i were detected.
1
According to their H NMR spectra, the ratio of 4h and 4i is 1 : 1.1. The
yields for 4h and 4i were obtained as 43% and 46%, respectively. The results
reveal that the reactivity difference between cyclohexanone and cyclopentanone
is not big enough for the selective protection under the studied conditions. Never-
theless, the present work has well demonstrated that the thioacetalization of car-
bonyl compounds 3 in the presence of 2a exhibits significantly high
chemoselectivity, providing selective protection of aromatic aldehyde or ali-
phatic ketone from an aromatic ketone.
Mechanism of the Thioacetalization
To investigate the mechanism of the thioacetalization reaction, one more
reaction was carried out. The mixture of 3e (1.0 mmol), 2a (1.0 mmol), and
acetyl chloride (0.18 mL, 2.5 mmol) in methanol (10 mL) was stirred at
reflux temperature for 40 min. Then the reaction mixture was allowed to
cool down to room temperature and neutralized with 10% aqueous K2CO3.
Scheme 3. Chemoselectivity of thioacetalization of 3 in the presence of 2a.

Thioacetalization Reagent 2-[1,3] Dithian-2-Ylidene-3-Oxo-Butanamide
4551
Scheme 4. A proposed mechanism for the thioacetalization of carbonyl compounds
3 with 2a.
From this system, thioacetal 4e and intermediate 10 (Sch. 4) were obtained in
41% and 24% yields, respectively, while starting materials 2a and 3e were
recovered in 30% and 52% yields, respectively. In our recent studies on the
carbon-carbon cleavage of a-acyl ketene dithioacetals, the deacylation was
found to occur very easily and usually under acidic conditions.[12,13] On the
basis of the obtained results combined with our previous studies,[9,12,13]
a
mechanism for the thioacetalization is proposed as shown in Sch. 4. The reac-
tion commences from the generation of HCl based on the esterification
between acetyl chloride and methanol. Catalyzed by the released HCl,
a-oxo ketene dithioacetal 2a undergoes deacylation to give ketene dithiolace-
tal 6. Followed by the addition of proton to its carbon-carbon double bond,
ketene dithiolacetal 6 is converted into a carbon cation 7, which is stablized
by the electron donating bis(alkylthio) groups. With the attacks by H2O or
methanol, the carbon cation 7 leads to the formation of the intermediate 10
through the intermediates 8 or 9. Finally, a transthioacetalization reaction
takes place between the intermediate 10 and carbonyl compound 3 to give
the corresponding dithioacetals 4. It is obvious that 3-amino-3-oxopropanoic
acid and its methyl ester are generated as by-products in our present studies.
These compounds are more easily removed during the extractive work-up

4552
Liu et al.
process than acetylacetic acid and its methyl ester, as described in our previous
work.[9b] The results provide a convenient way to isolate the by-products from
the resulting reaction mixture. Additionally, these by-products are very useful
because they can be used as precursors for the synthesis of ketene dithioace-
tals. Meanwhile, 3-amino-3-oxopropanoic acid, its methyl ester and com-
pound 2a as well might buffer the reaction medium and hence increase the
reaction yields, especially in the cases of the acid-sensitive substrates. Actu-
ally, in the case of 3f, the yield was increased to around 10% compared
with the corresponding result in our earlier work.[9b] Further applications of
the novel thiol equivalent reagent in other organic reactions and the recycling
of the by-products are currently under investigation in our laboratory.
CONCLUSIONS
In summary, a promising, efficient, and practical thioacetalization
reagent, 2-[1,3]dithian-2-ylidene-3-oxo-butanamide 2a, has been developed.
In the presence of the nonthiolic, odorless 1,3-propanedithiol equivalent 2a,
a wide range of selected carbonyl compounds were converted into the corre-
sponding dithioacetals 4, and the relatively slow reaction rate of aromatic
ketones allows chemoselective protection of an aromatic aldehyde or aliphatic
ketone from an aromatic ketone. This thioacetalization associated with its
mild reaction conditions, simple procedure, high yields, and perfect chemo-
selectivity provides a very efficient and convenient protocol for the syntheses
of thioacetals and chemoselective protection of carbonyl compounds as
dithianes in academia and industry.
EXPERIMENTAL
General
All reagents were purchased from commercial sources and used without
treatment, unless otherwise indicated. The products were purified by column
chromatography over silica gel. 1H-NMR spectra were recorded at 258C on a
Varian INOVA500 (500 MHz) spectrometer in CDCl3 and TMS as internal
standard. Mass spectra were obtained on a Hewlett-Packard GC 6890/MS
5973 spectrometer. IR spectra (KBr) were recorded on a Magna-560 FTIR
spectrophotometer in the range of 400–4000 cm21. Elemental analyses
were measured on a PE-2400 analyzer (Perkin-Elmer).

Thioacetalization Reagent 2-[1,3] Dithian-2-Ylidene-3-Oxo-Butanamide
Typical Procedure for Dithioacetals 4 and 5
4553
3a (1.0 mmol), 2a (1.0 mmol), methanol (10 mL), and acetyl chloride
(0.18 mL, 2.5 mmol) were added into a flask equipped with a condenser.
The mixture was heated to reflux and stirred for about 120 min as indicated
by TLC for a complete reaction. The reaction mixture was allowed to cool
down to room temperature and neutralized with aqueous NaHCO3 (10%).
After extractive work-up, separation was carried out over silica gel chrom-
atography (eluent: petroleum ether : ethyl acetate ¼ 60 : 1, v/v) to give
dithioacetal 4a as a white solid in 76% yield.
This procedure was followed by all the reactions listed in Tables 1 and 2.
All the dithioacetals 4 and 5 listed in Tables 1 and 2 are known compounds,
and their spectroscopic data (1H NMR and IR) and elemental analyses are
in good agreement with that in the literature.
Intermediate 10: 1H NMR (500 MHz, CDCl3): 1.40 (1H, t, J ¼ 8 Hz, SH),
1.91 (2H, m, CH2 CH2SH), 2.60 (2H, m, CH2SH), 3.03 (2H, t, J ¼ 7 Hz,
CH2SC), 3.55 (2H, s, CH2CO), 5.91 (1H, broad, NH2), 6.7 (1H, broad,
NH2); IR (cm21): 3429, 3331, 3188, 2927, 2556, 1673,1384, 1262, 1189,
1016; MS m/z [Mþ]: 193.
ACKNOWLEDGMENTS
This research was supported by NNSFC (20272008) and the Key Project
of Chinese Ministry of Education (03059).
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Received in Japan June 16, 2004