Green, catalyst-free thioacetalization of carbonyl compounds using glycerol as recyclable solvent

Article abstract of DOI:10.1016/j.tetlet.2010.06.049

We describe herein the use of glycerol as an efficient and a recyclable solvent in the thioacetalization of aldehydes and ketones. The catalyst-free reactions proceed easily using glycerol at 90 °C and the corresponding thioacetals were obtained in good to excellent yields. Glycerol was recovered and utilized for further thioacetalization reactions.

Full text of DOI:10.1016/j.tetlet.2010.06.049

Tetrahedron Letters 51 (2010) 4354–4356
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Green, catalyst-free thioacetalization of carbonyl compounds using glycerol
as recyclable solvent
Gelson Perin a, , Luzia G. Mello , Cátia S. Radatz , Lucielli Savegnago , Diego Alves , Raquel G. Jacob ,
a
a
b
a
a
*
a
Eder J. Lenardão
a
Instituto de Química e Geociências, LASOL, Universidade Federal de Pelotas, UFPel, 96010-900 Pelotas, RS, Brazil
Universidade Federal do Pampa, UNIPAMPA, Campus de Uruguaiana, BR 472, Km 7, Uruguaiana, RS, Brazil
b
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe herein the use of glycerol as an efficient and a recyclable solvent in the thioacetalization of
aldehydes and ketones. The catalyst-free reactions proceed easily using glycerol at 90 °C and the corre-
sponding thioacetals were obtained in good to excellent yields. Glycerol was recovered and utilized for
further thioacetalization reactions.
Received 13 May 2010
Revised 2 June 2010
Accepted 11 June 2010
Available online 19 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Glycerol
Thioacetals
Green chemistry
7
8
The protection of carbonyl groups as thioacetals is a general and
a popular protocol in organic chemistry and is frequently used as
reactions was recently demonstrated by us and others. These in-
1
8a–c
8a
8b
clude Pd-catalyzed Heck
and Suzuki cross-couplings, base-
and acid- promoted condensations, catalytic hydrogenation,
7
a
8c,d
a synthetic step for the preparation of many important natural/
unnatural organic compounds.2 Thioacetals are useful carbonyl-
protecting groups, thanks to their inherent stability under both
8c
and asymmetrical reduction.
The peculiar physical and chemical properties of glycerol, such
as polarity, low toxicity, biodegradability, high boiling point, and
ready availability from renewable feed stocks, prompted us to ex-
tend its use as a green solvent in organic synthesis. In this sense,
we describe here the catalyst-free synthesis of thioacetals using
glycerol as a solvent (Scheme 1).
Firstly, we reacted benzaldehyde 1a and benzenethiol 2a using
glycerol as solvent at different temperatures to optimize the reac-
tion conditions to access the thioacetal 3a. When the reactions
were performed both at room temperature and at 60 °C, 3a was
formed in poor yields. To our satisfaction, by increasing the tem-
perature to 90 °C the reaction proceeds smoothly, furnishing thi-
oacetal 3a in excellent yield (Table 1; entry 1). In an optimized
reaction, benzaldehyde 1a (1.0 mmol) was dissolved in glycerol
(3 mL) and reacted with benzenethiol 2a (2.0 equiv) at 90 °C during
1
acidic and basic conditions. Commonly, these compounds are pre-
9
pared by the reaction of carbonyl compounds with thiols or dithi-
3
3a
3b
3i
ols catalyzed by protic and Lewis acids, such as HCl and PTSA,
3
c
3d
3e
3f
3g
3h
BF
3
ÁOEt
2
,
AlCl
3
,
TiCl
4
,
,
TeCl
molecular I
4
,
LaCl
3
,
SiCl
4
,
3 3
(CH ) SiCl,
,3 LiBr, InCl
j
3k
3l
3m
NBS, and selenonium
3n
2
SOCl –SiO
2
3
2
,
3
o
ionic liquid. Unfortunately, the majority of these protocols have
certain disadvantages, such as the requirement for stoichiometric
amounts of catalysts, the use of expensive reagents and/or toxic
chlorinated organic solvents and, in most of the cases, the harsh
reaction condition.3
In this context, the choice of the solvent is a crucial step in a
chemical reaction. The development of green solvents from renew-
able resources has gained much interest recently because of the
extensive uses of solvents in almost all of the chemical industries,
4
10
and of the predicted disappearance of fossil oil. The wanted char-
3.5 h, yielding 3a in 96% yield (Table 1).
acteristics for a green solvent include no flammability, high avail-
ability, obtaining from renewable sources, and biodegradability.
To explore the scope and limitations of this new protocol, a
range of aromatic and aliphatic aldehydes and ketones with
5
With the increase in biodiesel production world-wide, the market
saturation of glycerol, a side product of biodiesel production, is
6
inevitable. The use of glycerol as a promising medium for organic
SR2
S
O
2
HS
SH
R SH
SR2
S
R
R1
R
glycerol, 90 o
C
R
glycerol, 90 o
C
R1
R1
*
Corresponding author. Tel./fax: +55 5332757354.
E-mail addresses: gelson_perin@ufpel.edu.br, perin@pq.cnpq.br (G. Perin).
Scheme 1.
0
040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.049

G. Perin et al. / Tetrahedron Letters 51 (2010) 4354–4356
4355
Table 1
Reaction of benzenethiol 2a with carbonyl compounds 1a–n in glycerol
Table 1 (continued)
a
Entry
Carbonyl compound
Time (h)
8.0
Product yieldb (%)
O
6 5
SC H
O
C H S
SC H
6 5
glycerol
90 o
6
5
SC6H5
R1
+
C6H5SH
R
R
1
C
R1
a-n
2a
13
3
a-n
3
m (98)
1m
Entry
1
Carbonyl compound
Time (h)
3.5
Product yieldb (%)
SC
O
4-ClC
4-ClC H S
6 4
6 4
H S
O
H
6 5
H
14c
4.5
H
SC
6
H
5
1
a
3n (90)
1
a
1
3
a (96)
a
O
SC
6
H
5
Reactions performed in the presence of carbonyl compound (1 mmol), ben-
zenethiol (2.0 mmol) in glycerol (3 mL) at 90 °C.
b
H
O
SC
6
H
5
Yields are given for isolated products. The compounds were identified by mass
2
3
8.0
spectrometry, H, and C NMR and compared with the literature data.3
1
13
c
4
-Chlorobenzenethiol (2.0 mmol) was used.
3
b (94)
b
1
SC H
6
5
various substitution patterns were reacted with benzenethiol 2a
under the optimized conditions. As can be seen from Table 1, most
of the substrates gave good yields of the corresponding thioacetals.
Except for p-(N,N-dimethyl)-benzaldehyde 1c (Table 1; entry 3),
all the aromatic aldehydes containing electron-donating or elec-
tron-withdrawing groups gave good yields of the corresponding
products (Table 1; entries 2, 4, and 5).
H
SC H
6 5
18.0
N
N
3
c (50)
c
O
SC H
6 5
H
SC
6
H
5
4
5
6.0
7.0
Heteroarylaldehyde 1f yielded thioacetal 3f in 76% yield after
h (Table 1; entry 6). Thioacetals 3g–i were obtained in satisfac-
Cl
Cl
2
1
d
3
d (96)
tory yields starting from the parent alkyl aldehydes 1g–i after stir-
ring for 3–4 h (Table 1; entries 7–9). When 4-chlorobenzenethiol
was used instead of 2a in the reaction with benzaldehyde, the cor-
responding thioacetal 3n was obtained in excellent yield after 4.5 h
(Table 1; entry 14). Not only aldehydes 1a–i but also ketones 1j–m
reacted very smoothly using glycerol as the solvent. Thus, bis-aryl,
alkyl-aryl, and cyclic ketones reacted with benzenethiol 2a and the
respective products 3j–m were obtained in satisfactory yields but
longer reaction times (Table 1; entries 10–13). Similar to the con-
ventional, acid-catalyzed thioacetalizations, aldehydes were more
reactive than ketones, except for substituted aromatic aldehydes
1b–e (Table 1, entries 2–5).
To expand the synthetic scope of this protocol, we carried out
the reaction using 1,2-ethanedithiol 2b. The results revealed that
the reaction worked well using benzaldehyde, acetophenone,
benzophenone, and cyclohexanone, furnishing the corresponding
1,3-dithiolanes 3o–r in good yields (Table 2; entries 1–4).
In order to explore the ability of glycerol act as a selective sol-
vent, we carried out a competitive thioacetalization reaction using
an equimolar mixture of benzaldehyde 1a (1.0 mmol) and aceto-
phenone 1j (1.0 mmol) with benzenethiol 2a (2.0 mmol)
(Scheme 2). After 12 h of reaction, a mixture of thioacetal 3a, de-
rived from benzaldehyde and 3j, derived from acetophenone, was
isolated in 96% yield and in a 3a/3j ratio = 97:3.
O
SC H
6
5
H
SC
6
H
5
O N
O N
2
2
1
e
3e
(89)
O
SC H
6 5
SC H
6 5
H
6
7
2.0
4.0
O
O
1
3
f (76)
f
O
SC H
6 5
H
SC H
6 5
1
g
3g (75)
O
SC H
6 5
8
9
3.5
3.0
H
SC H
6 5
1
h
3
h (65)
O
SC H
6 5
H
SC H
6
5
1
i
3
i (80)
O
C H S
SC H
6 5
6
5
A reuse study of the glycerol was carried out for the reaction
10
11
12
12.0
11
1
1
showed in Table 3. After completion of thioacetalization, the reac-
tion mixture was diluted with hexanes and the product was iso-
lated. After complete removal of residual hexanes, the glycerol
was directly reused for further reactions. Glycerol maintained its
good level of efficiency even after being reused four times (Table 3).
The product 3a was obtained in 96%, 96%, 96%, 94%, and 90% yields
after successive cycles. The effect of the presence of water in the
yield of 3a was verified using a mixture glycerol/water (97:3) as
the solvent. In this case, the product 3a was obtained only in 25%
yield after 5 h.
1
j
3j (80)
O
C
6
H
5
S
SC H
6 5
1
k
3
k (78)
O
C H S
SC H
6 5
6
5
9.5
In summary, glycerol has proved to be an efficient and recycla-
ble solvent for the catalyst-free thioacetalization of aldehydes
and ketones. The reactions proceed easily using low-cost and
3
l (97)
1
l

4
356
G. Perin et al. / Tetrahedron Letters 51 (2010) 4354–4356
Table 2
appropriate to the green chemistry concept. Applications of glyc-
erol in other organic reactions are ongoing in our laboratory.
Reaction of 1,2-ethanedithiol 2b with carbonyl compoundsa
O
glycerol
90 C
S
S
Acknowledgments
+
o
R
R1
a,j-l
HS
SH
R
R1
1
2b
3
o-r
We are grateful to FAPERGS, FINEP, CAPES, and CNPq for the
financial support.
Entry
1
Carbonyl compound
Time (h)
4.0
Product yield (%)b
O
References and notes
S
S
H
H
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1
k
3
q (83)
O
S
S
4
11.5
1
l
3
r (85)
a
Reactions performed in the presence of carbonyl compound (1 mmol), 1,2-eth-
anedithiol (1.0 mmol) in glycerol (3 mL) at 90 °C.
1
919–1921.
(a) Handy, S. T. Chem. Eur. J. 2003, 9, 2938–2944; (b) Leitner, W. Green Chem.
007, 9, 923; (c) Horváth, I. T. Green Chem. 2008, 10, 1024–1028; (d) Giovanni,
b
Yields are given for isolated products. The compounds were identified by mass
4.
spectrometry, 1H, and C NMR and compared with the literature data.
13
3
2
I.; Silke, H.; Dieter, L.; Burkhard, K. Green Chem. 2006, 8, 1051–1055; (e) Clark, J.
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5
.
.
O
O
C
6
H
5
S
SC
H
6
H
5
C
6
H
5
S
6 5
SC H
6
Johnson, D. T.; Taconi, K. A. Environ. Prog. 2007, 26, 338–348.
C H SH, 2a
6
5
H
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ARKIVOC 2009, xi, 221–227.
+
glycerol
+
1
2 h, 90 oC
3
j
1
a
1j
3a
Scheme 2.
8
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Table 3
Reuse of glycerol in thioacetalization of benzaldehyde 1a
O
C H S
SC H
6
5
6
5
glycerol
+
C H SH
o
H
H
6
5
90 C
9.
2
a
1
a
3a
1
0. General procedure for the thioacetalization reactions: To a round-bottomed flask
containing the appropriate carbonyl compound (1.0 mmol) and glycerol (3 mL)
was added benzenethiol 2a (2.0 mmol) or 1,2-ethanethiol 2b (1.0 mmol). The
reaction mixture was allowed to stir at 90 °C for the time indicated in Tables 1
and 2. After that, the reaction mixture was washed with hexanes (3 Â 5 mL)
Run
Reaction time (h)
Yield 3ac (%)
1a
3.5
3.5
3.5
3.5
5.0
96
96
96
94
90
b
2
b
3
4
and the upper organic phase was separated from glycerol, dried with MgSO ,
b
4
and evaporated under reduced pressure. The product was isolated by column
chromatography using hexane or hexane/ethyl acetate as eluent. Selected
b
5
12
a
spectral data for 1-(phenyl(phenylthio)methylthio)benzene 3a: Yield: 96%.
13
Reactions performed in the presence of benzaldehyde 1a (1 mmol), benzene-
thiol 2a (2.0 mmol) in glycerol (3 mL) at 90 °C.
1
H NMR (200 MHz, CDCl
50 MHz, CDCl ) d 139.6, 134.5, 132.5, 128.8, 128.4, 128.0, 127.8, 127.7, 60.4.
1. Reuse of glycerol: To a round-bottomed flask containing benzaldehyde 1a
1.0 mmol) and glycerol (3 mL) was added benzenethiol 2a (2.0 mmol). The
3
) d 7.37–7.22 (m, 15H), 5.43 (s, 1H); C NMR
(
3
b
Recovered glycerol was used.
Yields are given for isolated products.
1
1
c
(
reaction mixture was allowed to stir at 90 °C for 3.5 h. After that, the reaction
mixture was washed with hexanes (3 Â 5 mL) and the upper organic phase was
separated from glycerol. The product was isolated according to the procedure
described above. The glycerol was dried under vacuum and reused for further
reactions.
renewable feedstock glycerol and the thioacetals were obtained in
good to excellent yields. Glycerol can be easily recovered and uti-
lized for further thioacetalization reactions and is particularly
2. Wu, Y. C.; Zhu, J. J. Org. Chem. 2008, 73, 9522–9524.