A mild and chemoselective catalyst for thioacetalization under solvent free conditions

Article abstract of DOI:10.1080/104265091000877

Protection of a variety of carbonyl compounds as dithioacetals using P ₂O₅/SiO₂ (75%), as a mild and chemoselective catalyst, was achieved under solvent free conditions in very good yields. Copyright Taylor & Francis Group

Full text of DOI:10.1080/104265091000877

Phosphorus, Sulfur, and Silicon, 181:387–395, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265091000877
A Mild and Chemoselective Catalyst for Thioacetalization
Under Solvent Free Conditions
Abdol R. Hajipour
Department of Pharmacology, University of Wisconsin, Medical School,
Madison, Wisconsin, USA and Pharmaceutical Research Laboratory,
Isfahan University of Technology, Isfahan, Iran
Amin Zarei
Leila Khazdooz
Saeed Zahmatkesh
Pharmaceutical Research Laboratory, Isfahan University of Technology,
Isfahan, Iran
Arnold E. Ruoho
Department of Pharmacology, University of Wisconsin, Medical School,
Madison, Wisconsin, USA
Protection of a variety of carbonyl compounds as dithioacetals using P O /SiO
2
2
5
(75%), as a mild and chemoselective catalyst, was achieved under solvent free con-
ditions in very good yields.
Keywords 1,3-dithiolane; dithioacetalization; diphosphorus pentoxide
Protection and deprotection of reactive functional groups are essen-
tial steps in the synthesis of natural products and polyfunctional com-
pounds. Dithioacetalization is well-known as a reaction that protects
carbonyl groups.1 Dithioacetals are frequently used in the synthesis of
natural products and organic compounds.2 Their stability under acidic
and basic conditions make them versatile carbonyl protecting groups.3,4
Received November 20, 2004; accepted February 22, 2005.
We gratefully acknowledge the funding support received for this project from the
Isfahan University of Technology (IUT), IR Iran (Abdol R. Hajipour), and Grant GM 33138
(Arnold E. Ruoho) from the National Institutes of Health. Further financial support from
Center of Excellency in Chemistry Research (IUT) is gratefully acknowledged.
Address correspondence to Abdol R. Hajipour, Isfahan University of Technology, Phar-
maceutical Research Laboratory, College of Chemistry, Isfahan, 84156, Iran. E-mail:
haji@ cc.iut ac.ir
387

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A. R. Hajipour et al.
For this reason, the protection and deprotection of the carbonyl func-
tional groups remain crucial challenges to the organic chemists. Experi-
ence shows that the critical parameters are generally the stability and
the cleavage of the protecting group rather than its introduction. There-
fore regeneration of the parent carbonyl groups from their masked form
seems to be a useful synthetic process. There are several methods for
the protection and the deprotection of dithioacetals.5
Literature survey shows that phosphorus pentoxide can be used as a
dehydrating agent for the formation of anhydride from two molecules of
an ordinary carboxylic acid, ketenimines from amides, vinyl ethers from
acetals, nitriles from amides,6 amides from oximes,7 phenolic esters
from carboxylic acids,8 and sulfones from sulfonic acids.9
In continuation of our ongoing program to develop environmentally
benign methods under solvent free conditions,10 we wish to report an
extremely convenient, mild, and highly chemoselective procedure for
the conversion of aldehydes and ketones into 1,3-dithiolanes using a
catalytic amount of P2O5/SiO2 (75%) under solvent free conditions.
RESULTS AND DISCUSSION
The protection of a variety of aldehydes and ketones containing
electron-withdrawing and electron-donating substituents, heteroaro-
matic and α, β-unsaturated aldehydes, and various ketones with 1,2-
ethanedithiol in the presence of catalytic amount of P2O5/SiO2(75%)
was examined under solid-state conditions at room temperature
(Scheme 1, Table I). In each case the corresponding dithioacetals were
SCHEME 1
obtained in good to excellent yields in a short reaction time. The prod-
ucts were purified by column chromatography using silica gel and the
purity of the products was determined by GC and TLC analysis.
To evaluate the selectivity of the reagent we tried the chemoselec-
tivity of this reagent. In representative examples, when an equimolar
amount of p-methoxybenzaldehyde and p-methoxyacetophenone were
treated with 1,2-ethanedithiol (an equimolar amount) and 25 mol% of
this reagent, the p-methoxybenzaldehyde was converted to the corre-
sponding 1,3-dithiolane in a 100% yield and p-methoxyacetophenon

Mild and Chemoselective Catalyst
389
was intact (Scheme 2). In competition of benzaldehyde (in an
equimolar amount) and acetophenone (in an equimolar amount) with
1,2-ethanedithiol (in an equimolar amount) in the presence of catalytic
amount of reagent (25 mol%), benzaldehyde was converted to the cor-
responding 1,3-dithiolane in a 100% yield and acetophenon was intact
(Scheme 3). In another experiment we treated an equimolar amount of
benzaldehyde, cycloheptanone, and 1,2-ethanedithiol in the presence
of 25 mol% of reagent under solvent free conditions, we observed that
benzaldehyde reacted with 1,2-ethanedithiol in an 85% yield and cyclo-
heptanone in an 15% yield (Scheme 4).
SCHEME 2
SCHEME 3
SCHEME 4
In order to show the merit of the present work in comparison
with recently reported articles, we compared our results with other

390
A. R. Hajipour et al.
TABLE I Dithioacetalization of Aldehydes and Ketones in the
Presence of P2O5/SiO2 (75%) Under Solvent Free Conditions at R.T.a,b
Time Yield
(Min) (%)
m.p.
(◦C)
Entry
1
Substrate
Product
3
3
3
87
88
90
Oil5a,5c
2
3
76
Oil
4
5
3
3
88
61-63
86c 66–67
6
7
3
3
90
88
63–64
(60–62)5a
Oil
Oil
8
3
85
9
3
3
91
83
60–61
(56–58)5a
10
66–68
(62–65)5c
(Continued on next page)

Mild and Chemoselective Catalyst
391
TABLE I Dithioacetalization of Aldehydes and Ketones in the
Presence of P2O5/SiO2 (75%) Under Solvent-Free Conditions at R.T.a,b
(Continued)
Time Yield m.p.
Entry
11
Substrate
Product
(Min) (%)
(◦C)
3
82 49–51
12
13
3
3
85 60–62
(58–59)5c
90 Oil5a
14
15
16
1
1
6
80 Oil
82 Oil15
48 Oil15,5c
17
6
40 Oil
18
19
6
6
45 Oil
42c 56–57
(Continued on next page)

392
A. R. Hajipour et al.
TABLE I Dithioacetalization of Aldehydes and Ketones in the
Presence of P2O5/SiO2 (75%) Under Solvent-Free Conditions at R.T.a,b
(Continued)
Time Yield m.p.
Entry
20
Substrate
Product
(Min)
(%)
(◦C)
4
86
Oil
21
22
4
4
85
88
Oil
53–54
a
The yields refer to the isolated products after purification.
b
All of the products were characterized from their spectral (IR, 1H-NMR,TLC, and
GC).
c
We did not observe any reduction of the nitro groups.
reagents such as NBS,11 NiCl2,12 In(OTf)35a, InCl3,13 CoCl2,14 SOCl2-
SiO2,15 LiClO4,5c and P2O5/SiO2 (Table II). The results show that the
reaction yields are compatible with the reported ones and this reagent
(P2O5/SiO2) is superior to other reagents in view of the lowest reaction
time and green chemistry view.
In conclusion, we have described a mild, efficient, and chemoselective
method for the preparation of dithioacetals from carbonyl compounds
and 1,2-ethane dithiol in the presence of P2O5/SiO2(75%) at r.t. in high
yields and short reaction times. The use of an inexpensive, relatively
nontoxic, and green catalyst are advantages of this method. Further
investigation on the new application of silica sulfuric acid is ongoing in
our laboratories.
EXPERIMENTAL SECTION
Products were characterized by comparison with authentic samples (IR,
1H NMR spectrum, CHN analysis, melting point),5,15 All m.p.s were
taken on a Gallenkamp melting apparatus and are uncorrected. 1H
NMR spectra were recorded on a Varian 250 NMR spectrometer oper-
ating at 250 MHz. The spectra were measured in CCl4 and CDCl3 rela-
tive to TMS (0.00 ppm). IR spectra were recorded on a Shimadzu 435 IR
spectrophotometer. Spectra of solids were performed using KBr pellets.

393

394
A. R. Hajipour et al.
Preparation of P2O5/SiO2(75%)
Silica gel 60 (2.5 g) and dried P2O5 (7.5 g) were mixed for 10 min in a
sealed round-bottomed flask. This reagent was stored in a sealed flask
for later using.
General Procedure
In a mortar a mixture of carbonyl compounds (1 mmol), 1,2-ethane
dithiol (0.11 mL, 1.3 mmol), and P2O5/SiO2(75%) (0.05 g, 25 mol %) was
ground with a pestle for the time specified in Table I. The progress of the
reaction was followed by TLC/GC. The product was isolated by adding
ether (2 × 15 mL), and the solid was removed by filtration through a
sintered glass funnel and the solvent was evaporated by rotary evapo-
rator. The crude product was purified through a short column of silica
gel (hexane: EtOAc, 80:20) to obtain a pure product.
4-bromophenyl-1,3-dithiolane. 1H NMR (CDCl3), δ ppm 7.50 (2 H, d,
J = 5.00 Hz), 7.20 (2 H, d, J = 5.00 Hz), 5.55 (1 H, s), 3.47–3.39 (2 H,
m), 3.34–3.28 (2 H, m).
3-chlorophenyl-1,3-dithiolane. 1H NMR (CDCl3), δ ppm 7.58 (1 H,
s), 7.43–7.37 (1 H, m), 7.28–7.21 (2 H, d, J = 7.58 Hz), 5.62 (1 H, s),
3.56–3.48 (2 H, m), 3.42–3.36 (2 H, m).
4-chlorophenyl-1,3-dithiolane. 1H NMR (CDCl3), δ ppm 7.70 (2 H,
d, J = 6.55 Hz), 7.25 (2 H, d, J = 6.55 Hz), 5.60 (1 H, s), 3.51–3.41 (2 H,
m), 3.36–3.29 (2 H, m).
3-nitrophenyl-1,3-dithiolane. 1H NMR (CDCl3), δ ppm 8.44 (1 H, s),
8.16 (1 H, d, J = 7.0 Hz), 7.87 (1 H, d, J = 7.73 Hz), 7.52 (1 H, t, J =
7.46 Hz), 5.71 (1 H, s), 3.59–3.54 (2 H, m), 3.48–3.43 (2 H, m).
3-methoxyphenyl-1,3-dithiolane. 1H NMR (CDCl3), δ ppm 7.28 (1
H, t, J = 7.56 Hz), 7.16 (2 H, s), 6.85 (1 H, d, J = 7.57 Hz), 5.67 (1 H, s),
3.85 (3 H, s), 3.52–3.51 (2 H, m), 3.37–3.36 (2 H, m).
2-methoxyphenyl-1,3-dithiolane. 1H NMR (CDCl3), δ ppm 7.78 (1 H,
d, J = 7.66 Hz), 7.29–7.26 (1 H, m), 6.99 (1 H,t, J = 7.50 Hz), 6.89 (1 H,
d, J = 8.19 Hz), 6.10 (1 H, s), 3.90 (3 H, s), 3.49–3.45 (2 H, m), 3.38–3.35
(2 H, m).
2-hydroxyphenyl-1,3-dithiolane. 1H NMR (CDCl3), δ ppm 7.34 (1 H,
d, J = 7.00 Hz), 7.26 (1 H, t, J = 8.02 Hz), 6.93–6.88 (2 H, m), 6.77(OH,
s), 5.85 (1 H, s), 3.62–3.56 (2 H, m), 3.45–3.38 (2 H, m).
2-methyl-2-(4-methoxyphenyl)-1,3-dithiolane. 1H NMR (CDCl3), δ
ppm 7.72 (2 H, d, J = 8.81 Hz), 6.88 (2 H, d, J = 8.81 Hz), 3.80 (3 H, s),
3.51–3.48 (2 H, m), 3.42–3.39 (2 H, m), 2.20 (3 H, s).

Mild and Chemoselective Catalyst
395
2-methyl-2-(3-methoxypheny)-1,3-dithiolane. 1H NMR (CDCl3), δ
ppm 7.40–7.37 (2 H, m), 7.28 (1 H, t, J = 7.93 Hz), 6.82 (1 H, d, J =
8.09 Hz), 3.86 (3 H, s), 3.52–3.48 (2 H, m), 3.44–3.38 (2 H, m), 2.20 (3
H, s).
2-methyl-2-(4-nitropheny)-1,3-dithiolane. 1H NMR (CDCl3), δ ppm
8.19 (2 H, d, J = 8.88 Hz), 7.96 (2 H, d, J = 8.86 Hz), 3.58–3.51 (2 H, m),
3.43–3.37 (2 H, m), 2.25 (3 H, s).
2-methyl-2pentyl-1,3-dithiolane. 1H NMR (CDCl3), δ ppm 3.40–3.30
(4 H, m), 1.96–1.93 (2 H, m), 1.77 (3 H, s), 1.56–1.51 (2 H, m), 1.39–1.28
(4 H, m), 0.92 (3 H, t, J = 6.82 Hz).
1,4-dithia-spiro[4.6]undecane. 1H NMR (CDCl3), δ ppm 3.30 (4 H,
m), 2.24–2.19 (4 H, m), 1.64–1.62 (8 H, m).
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