Indium tribromide-catalyzed chemoselective dithioacetalization of aldehydes in non-aqueous and aqueous media

Article abstract of DOI:10.1016/S0040-4039(00)01741-X

Indium tribromide efficiently catalyzes the chemoselective dithioacetalization of aldehydes in the presence of ketones in dichloromethane. The catalyst is also active in water, which can be reused, in the same pot, for several times without any decrease in the yield of reaction. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01741-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9695–9699
Indium tribromide-catalyzed chemoselective
dithioacetalization of aldehydes in non-aqueous and aqueous
media
Marco Antonio Ceschi, Luciana de Araujo Felix and Clovis Peppe*
Departamento de Qu´ımica, Universidade Federal da Para´ıba-UFPB, Joa˜o Pessoa PB-58059-900, Brazil
Received 24 July 2000; revised 3 October 2000; accepted 4 October 2000
Abstract
Indium tribromide efficiently catalyzes the chemoselective dithioacetalization of aldehydes in the
presence of ketones in dichloromethane. The catalyst is also active in water, which can be reused, in the
same pot, for several times without any decrease in the yield of reaction. © 2000 Published by Elsevier
Science Ltd.
The preparation of dithioacetals involves the condensation of carbonyl compounds with thiols
in the presence of a protic or a Lewis acid. Several Lewis acids catalysts, such as ZnCl2,1 LiBr,2
BF3-etherate,3 TiCl4,4 SiCl4,5 AlCl3,6 TeCl4,7 LaCl3,8 etc., have been used for this purpose.
Limitations associated with some of these methods include: presence of protic acids;1,3 excess of
thiols;3,8 anhydrous conditions;1–8 stoichiometric amount of catalyst;1,4 formation of secondary
products, such as hemithioacetals,3 and vinyl sulfides from enolizable carbonyl compounds;6
poor selectivity facing mixtures of aldehydes and ketones;6 and failure to react with aromatic
and aliphatic ketones.2
We now report that InBr3 effectively promotes the dithioacetalization of aliphatic and
aromatic carbonyl compounds. Many of the limitations pointed above were overcome. Cyclic
(1,3-dithiolanes) and acyclic (aromatic and aliphatic) dithioacetals (Table 1) have been prepared
from ethanedithiol, benzenethiol and propanethiol and the corresponding carbonyl compound.
R1R2CO 2R3SH+0.1 mol InBr3 R1R2C(SR3)2
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢁ
1
CH2Cl2 or H2O
2
* Corresponding author. E-mail: peppe@quimica.ufpb.br
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01741-X

9696
Table 1
InBr3-promoted dithioacetalization of carbonyl compounds
Entry
R1
R2
R3
Product
Yield (%)
Time (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
C6H5
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
ꢀ(CH2)2ꢀ
C6H5
C3H7
ꢀ(CH2)2ꢀ
ꢀ(CH2)2ꢀ
C6H5
C3H7
C3H7
ꢀ(CH2)2ꢀ
C3H7
C3H7
C6H5
ꢀ(CH2)2ꢀ
C3H7
C3H7
ꢀ(CH2)2ꢀ
C6H5
2a
2b
2c
2d
2e
2f
2g
2h
2i
80a
1.0
70a, 47f, 38g
98a
2.0a, 1.0f, 3.0g
0.5
C6H5
C4H3Oh
85a
3.0
2,4,5-(CH3O)3ꢀC6H2
2,4,5-(CH3O)3ꢀC6H2
2,4,5-(CH3O)3ꢀC6H2
2-CH3OꢀC6H4
4-ClꢀC6H4
C6H5CHꢂCH
C2H5
70a, 63c
95b, 98c
96b, 70c
40c
0.25a, 3.0c
1.0b, 3.0c
1.0b, 3.0c
19.0
98b, 37c, 20d, 30e
99b, 68c
99b, 12c
98b
0.5b, 20.0c, 2.0d, 2.0e
1.0b, 20.0c
0.25b, 18.0c
0.3
2j
2k
2l
C2H5
CH(CH3)2
CH(CH3)2
C(CH3)3
ꢀ(CH2)5ꢀ
ꢀ(CH2)5ꢀ
ꢀ(CH2)5ꢀ
C6H5
3,4,5-(CH3O)3ꢀC6H2
C6H5
C6H5
2m
2n
2o
2p
2q
2r
2s
2t
2u
2v
2w
2x
2y
2z
95b
1.0
97b, 14c
99b, 10c
93a, 50c
57.3a
0.25b, 16.0c
0.5b, 18.0c
1.0a, 16.0c
16.0
C3H7
74a, 14c
88a, N.R.c
73a
16.0a, 18.0c
2.0b, 20.0c
0.25
CH3 ꢀ(CH2)2ꢀ
CH3 ꢀ(CH2)2ꢀ
CH3 C6H5
CH3 C3H7
CH3 ꢀ(CH2)2ꢀ
CH3 C6H5
N.R.a
20.0
16.0
Tracesa
90b, N.R.c
N.R.a
C3H7
C2H5
C2H5
CH3
1.2b, 18c
16.0
CH3 C3H7
CH3 C3H7
Tracesa
33b
3.0
2.0
a In anhydrous CH2Cl2, 1:1 molar ratio carbonyl compd:InBr3.
b In anhydrous CH2Cl2, 1:0.1 molar ratio.
c In water, 1:0.1 molar ratio.
d In water:tetrahydrofuran 1:1, v/v, 1:0.1 molar ratio.
e In water:methanol 1:1, v/v, 1:0.1 molar ratio.
f In water (100°C), 1:0.1 molar ratio.
g In water (100°C), 1:1 molar ratio.
h 2-Furaldehyde; N.R.=no reaction.
The reactions can be carried out in anhydrous (CH2Cl2) or aqueous media, with stoichiomet-
ric or catalytic amounts of InBr3. When the chosen solvent is CH2Cl2, we have observed that no
major change in the yields occurred when the reactions were carried out adding 2–3% of H2O
to the solvent.
The experiments in anhydrous CH2Cl2 lead quickly to the corresponding dithioacetals.
Maximum reactivity was observed for 1,2-ethanedithiol, which reacts in stoichiometric amounts
with every carbonyl functionality, including the less reactive aromatic (entries 19 and 20) and
aliphatic (entries 16 and 23) ketones, to produce the corresponding 1,3-dithiolanes in good
yields.
Chemoselectivity towards aldehydes, in non-aqueous media, was observed during the prepara-
tion of acyclic dithioacetals. Benzene and propanethiol, either failed to react or produced low

Table 2
InBr3-promoted competitive dithioacetalization of carbonyl compounds
Entry
Substrates
Molar ratio (substr. 1/
substr. 2/thiol/InBr3)
Time
(min)
Product(s)
Products molar
ratio
Total yield
(%)
1
2
3
4
5
6
7
8
9
C6H5CHO+(CH2)5CO
(CH3)3CCHO+(CH2)5CO
1:1:2:0.1a
1:1:2:0.1a
1:1:2:0.1a
1:1:2:0.1a
1:1:2:0.1a
1:1:2:0.1a
1:1:2:0.1a
1:1:2:0.1b
1:1:2:0.1b
1:1:2:0.1b
120
20
20
20
20
15
20
16
18
18
2b
2o
–
–
77
85
96
86
88
85
95
37
39
63
C6H5CHꢂCHCHO+C6H5CHO
C6H5CHO+CH3CH2CHO
CH3CH2CHO+(CH3)3CCHO
(CH3)2CHCHO+CH3CH2CHO
C6H5CHꢂCHCHO+(CH3)2CHCHO
C6H5CHO+(CH3)2CHCHO
C6H5CHO+(CH2)5CO
2j+2c
2c+2k
2k+2o
2n+2k
2j+2n
2c+2n
2c+2r
2j+2c
3:2
50:3
25:3
7:4
40:33
27:2
3:1
10
C6H5CHꢂCHCHO+C6H5CHO
10:4
a In anhydrous CH2Cl2.
b In water.

9698
yields with aromatic (R3=C6H5: entry 21; R3=C3H7: entry 22) and acyclic aliphatic ketones
(R3=C6H5: entry 24; R3=C3H7: entries 25 and 26). A complete insight on the selectivity of the
present method is demonstrated by competition experiments using structurally differing car-
bonyl compounds. An equimolar mixture of two carbonyl compounds was allowed to react with
2 molar equivalents of benzenethiol (or propanethiol). The results in Table 2 show that
benzaldehyde (entry 1) and trimethylacetaldehyde (entry 2) were cleanly dithioacetalized in the
presence of cyclohexanone. Competition between aliphatic aldehydes (entries 5 and 6) estab-
lished the order of reactivity (CH3)2CHCHO>CH3CH2CHO>(CH3)3CCHO when propanethiol
is the reagent. Finally, it was demonstrated that cinnamaldehyde is preferentially dithioacetal-
ized over benzaldehyde by benzenethiol (entry 3). The sum of these results demonstrates that the
present procedure can be used in the selective conversion of aldehydes to the corresponding
dithioacetals in the presence of ketones.
The action of a Lewis acid catalyst in dithioacetalization reactions in non-aqueous media has
been ascribed to coordination of the carbonyl oxygen to the electron-acceptor site of the
catalyst,8 thereby enhancing the electrophilicity of the carbonyl carbon. Also, the action of the
Lewis acid as a water scavenger has been suggested as a factor; removal of water from the
hemithioacetal leads to the dithioacetal final product and this, indeed, requires anhydrous
conditions. Surprisingly, our results show that dithioacetalizations, intermediated by InBr3,
completely suppress the need for careful dehydration of solvents and starting materials, when
carried out in CH2Cl2 solutions, and in fact proceed even in aqueous media, with catalytic
amount of InBr3. The scope of the method in water is not so wide as it is in CH2Cl2. In fact,
it proved to be efficient only for aromatic and a,b-unsaturated aldehydes where reasonable to
good yields were obtained. There is no significant difference between reactivity of mono- and
dithiols, since similar yields were obtained in both cases. Further, competition experiments
revealed the impossibility of any carbonyl functionality be cleanly dithioacetalized in the
presence of a second (Table 2, entries 8–10). We have attempted to improve the efficiency of this
process by modifying some of the reaction conditions; nevertheless the use of excess of thiol,
stoichiometric quantity of the catalyst, addition of a co-solvent to ensure solubility of reagents,
and raise of reaction temperature did not show any significant improvement. Beside these
restrictions, reasonable (Table 1, entries 5, 7 and 10) to good (entry 6) yields were obtained,
suggesting some relevance for the methodology, particularly when consecutive experiments are
needed. Table 3 describes the yields of ten consecutive dithioacetalization reaction, carried out
in water, of 2,4,5-trimethoxy-benzaldehyde with benzenethiol to produce the dithioacetal 2f.
After the required time, the dithioacetal formed was extracted with dichloromethane, and fresh
quantities of reagent and substrate were added to the aqueous phase. After ten runs, no
appreciable decrease in the yield of reaction was observed ($3%), demonstrating that InBr3 can,
indeed, be reused as catalyst in dithioacetalization reactions in aqueous media.
Table 3
Consecutive dithioacetalization of 2,4,5-trimethoxy-benzaldehyde with benzenethiol
Run
Yield (%)
1
98
2
98
3
–
4
95
5
–
6
–
7
95
8
–
9
–
10
97

9699
We conclude by pointing to the following advantages of the present methodology: high
chemoselectivity towards aldehydes in non-aqueous media for acyclic dithioacetals; stoichiomet-
ric use of reagents; low concentration of catalyst; satisfactory yields and possibility to work
under aqueous conditions with reutilization of the catalyst, especially with aromatic and
a,b-unsaturated aldehydes.
Dithioacetalization of carbonyl compounds: general experimental procedure. (a) In CH2Cl2:
1,2-Ethanedithiol (192 mg, 2.04 mmol) and anhydrous InBr3 (71 mg, 0.20 mmol) were succes-
sively added to a stirred solution of the carbonyl compound (2.04 mmol, or 1.02 mmol for
benzene and propane thiols) in CH2Cl2 (5 mL) at 0°C under a nitrogen atmosphere. The mixture
was stirred at 0°C for 5 minutes, warmed to room temperature for the required time (see Table
1), and then diluted with CH2Cl2 (20 mL). The organic phase was washed with a saturated
solution of NaHCO3 (20 mL), H2O and dried (MgSO4). After removal of volatiles, the product
was purified by column chromatography. The purity of the product dithioacetals was checked
by GC, and characterization involved NMR (1H and 13C) spectroscopy and mass spectrometry;
in many cases spectral data were compared with reported values in the literature.9–15 The yields
in Table 1 refer to isolated, analytically pure compounds.
(b) In water: Reagents and catalyst were added as above in oxygen-free water (5mL) at room
temperature and the mixture stirred for the required time (Table 1). 10 mL of NaOH (10%) was
added and the dithioacetal extracted with CH2Cl2 (2×10 mL), dried (Na2SO4) and purified by
column chromatography.
Acknowledgements
We thank the CAPES/FAPESQ-PB and CNPq for the financial support of this work. Two of
us M.A.C. and L.A.F. thank CAPES for the award of scholarships.
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