A mild and chemoselective dithioacetalization of aldehydes in the presence of anhydrous copper (II) sulfate

Article abstract of DOI:10.1080/10426500500330810

Various aldehydes have been protected with different thiols as dithioacetals with excellent yields using anhydrous copper sulfate as a mild and chemoselective catalyst. The reaction is carried out in a solvent and/or under solvent-free conditions. The transthioacetalization of oxyacetals into dithioacetals was also achieved in an excellent yield. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500500330810

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Phosphorus, Sulfur, and Silicon
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A Mild and Chemoselective
Dithioacetalization of
Aldehydes in the Presence of
Anhydrous Copper (II) Sulfate
Firouz Matloubi Moghaddam a , Ghasem Rezanejade
Bardajee a & Afsane Arefi Oskui a
a Sharif University of Technology, Department of
Chemistry , Tehran, Iran
Published online: 01 Feb 2007.
To cite this article: Firouz Matloubi Moghaddam , Ghasem Rezanejade Bardajee &
Afsane Arefi Oskui (2006) A Mild and Chemoselective Dithioacetalization of Aldehydes
in the Presence of Anhydrous Copper (II) Sulfate, Phosphorus, Sulfur, and Silicon and
the Related Elements, 181:6, 1445-1450, DOI: 10.1080/10426500500330810
To link to this article: http://dx.doi.org/10.1080/10426500500330810
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Phosphorus, Sulfur, and Silicon, 181:1445–1450, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500500330810
A Mild and Chemoselective Dithioacetalization
of Aldehydes in the Presence of Anhydrous
Copper (II) Sulfate
Firouz Matloubi Moghaddam
Ghasem Rezanejade Bardajee
Afsane Arefi Oskui
Sharif University of Technology, Department of Chemistry, Tehran, Iran
Various aldehydes have been protected with different thiols as dithioacetals with
excellent yields using anhydrous copper sulfate as a mild and chemoselective cata-
lyst. The reaction is carried out in a solvent and/or under solvent-free conditions.
The transthioacetalization of oxyacetals into dithioacetals was also achieved in an
excellent yield.
Keywords Aldehydes; anhydrous copper (II) sulfate; dithioacetalization; protection;
transthioacetalization
INTRODUCTION
The conversion of aldehydes and ketones to dithioacetals and dithioke-
tals is a common practice in a multistep synthesis due to their sta-
bility under both acidic and basic conditions.1 In addition, thioacetals
are also used as masked acyl anions2 and methylene functions3 in
carbon-carbon bond forming reactions. Commonly, these compounds
are prepared by protic or lewis acid-catalyzed condensation of carbonyl
compounds with thiols.4 Lewis acid catalysts such as ZnCl2,5 LnCl3,6
FeCl3/SiO2,7 AlCl3,8 ZrCl4/SiO2,9 TeCl4,10 SnCl2,11 SiCl4,12 TiCl4,13
BF3 · OEt2,14 LaCl3,15 WCl6,16 (CH3)3SiCl,17 5 M LiClO4,18 Mg(OTf)319,
CoCl3,20 Molybdenyl acetylacetonate,21 In(OTf)3,22 NiCl2,23 Yttrium
triflate,24 Bismuth nitrate,25 etc. have been used for this purpose. Al-
though many methods have been reported for the dithioacetalization of
aldehydes and ketones, there still is a great demand for the introduction
of mild, efficient, and chemoselective practical methods. Interestingly,
Received June 20, 2005; accepted July 28, 2005.
Address correspondence to Firouz Matloubi Moghaddam, Sharif University of
Technology, Department of Chemistry, PO Box 11365-9516, Tehran, Iran. E-mail:
matloubi@sharif.edu
1445

1446
F. M. Moghaddam et al.
only a few methods are known in the literature for the chemoselective
protection of aldehydes in the presence of ketons.20,22−23 In general, the
reported procedures are associated with certain limitations, such as
low yields, harsh reaction conditions, longer reaction times, and costly
reagents, as well as an inconvenience in handling reagents. Previously,
copper (II) salts were used for the dithioketalization of ketones in boil-
ing dry THF for several hours.26 The method is not chemoselective,
and drastic reaction conditions have been used (along reaction time,
high temperature). Herein we report an efficient, clean, fast, and mild
method for the chemoselective dithioacetalization of aldehydes in a sol-
vent and/or under solvent-free conditions in the presence of anhydrous
copper sulfate.
RESULTS AND DISCUSSION
In order to find the best reaction conditions, different variations were
examined. At first, the reaction was carried out in different solvents.
The reaction could be performed efficiently in CHCl3, CH2Cl2, benzene,
acetonitrile, and n-hexane. Due to the higher solubility of the substrates
and higher rates of the reactions, CH2Cl2 was chosen as the suitable
solvent. It should be pointed out that in the absence of anhydrous
copper sulfate, the reaction did not proceeded in CH2Cl2 even after pro-
longed reaction times. In a typical procedure, benzaldehyde (2.5 mmol)
with benzyl mercaptane (3 mmol) in the presence of anhydrous copper
sulfate (3.5 mmol) at r.t. in CH2Cl2 afforded the desired dithioacetal in
a 95% yield. Various thiols and dithiols (such as 1,2 and 1,3-dithiols)
were used with different types of aldehydes (Scheme 1). Except for
SCHEME 1
thiophenol, the other thiols and dithiols reacted efficiently with aldehy-
des in dichloromethane at r.t. in a short reaction time, and pure products
were obtained in excellent yields by crystallization or PTLC. Results
are summarized in Table I. All products were characterized by spectro-
scopic analysis and also by comparison of the data obtained with those

Dithioacetalization of Aldehydes
1447
TABLE I Anhydrous Copper (II) Sulfate Catalyzed Protection of
Aldehydes and Transthioacetalization of Oxyacetals at RT
Time (min)/ Time (min)/
Yield (%)a,b Yield (%)a,c
Entry
Aldehyde
Benzaldehyde
4-Fluorobenzaldehyde
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
4-Methoxybenzaldehyde
Benzaldehyde
Thiol
PhCH2SH
PhCH2SH
PhCH2SH
PhCH2SH
EtSH
EtSH
EtSH
EtSH
EtSH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
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
27
28
29
5/95
5/97
5/97
5/97
5/94
5/94
5/95
5/95
5/94
5/97
5/97
5/97
5/98
5/98
5/96
7/95
5/98
5/97
5/94
5/94
5/97
5/96
5/97
5/96
5/98
5/97
40/55
55/50
50/94
5/95
5/96
5/96
4-Fluorobenzaldehyde
4-Chlorobenzaldehyde
Pentaldehyde
Benzaldehyde
5/97
5/95
4-Methoxybenzaldehyde
4-Chlorobenzaldehyde
4-Bromobenzaldehyde
4-Nitrobenzaldehyde
4-Methylbenzaldehyde
3,4-Dimethoxybenzaldehyde HSCH2CH2SH
Furfural
Cinnamaldehyde
Hexaldehyde
Hexaldehyde
5/98
5/95
10/80
5/95
5/96
5/94
5/94
5/96
5/94
5/95
5/95
5/97
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2CH2SH
HSCH2CH2CH2SH
HSCH2CH2CH2SH
HSCH2CH2CH2SH
HSCH2CH2CH2SH
HSCH2CH2CH2SH
HSCH2CH2CH2SH
PhSH
Benzaldehyde
4-Methoxybenzaldehyde
4-Chlorobenzaldehyde
2-Nitrobenzaldehyde
4-Nitrobenzaldehyde
4-Methylbenzaldehyde
Benzaldehyde
20/60
20/55
30/90
4-Methoxybenzaldehyde
PhSH
HSCH2CH2CH2SH
30
31
32
HSCH2CH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
50/95
50/97
60/94
aAll yields refer to isolated products, and all products were characterized by m.p., IR,
and 1H-NMR. Their physical data were similar to those reported in the literature.
bDichloromethane as a solvent.
cSolvent-free conditions.

1448
F. M. Moghaddam et al.
of authentic samples. We found that the reaction is almost independent
of a substituent on aromatic aldehydes (entries 1, 2, 3, 5, 10, 11, 12,
21, 22, 23 in Table I). It also has been observed that the position of the
substituent on the ortho or para positions of the aromatic ring does not
alter the rate and yield of the reaction (entries 24 and 25 in Table I).
Also the presence of two electron-donating substituents on the benzene
ring of aldehyde has a slight decreasing effect on the relative rate of
the reaction compared to benzaldehyde (entry 16, Table I). Aliphatic
and α, β-unsaturated aldehydes were also dithioacetalized in excellent
yields (entries 9, 18, 19, and 20 in Table I).
Transthioacetalization of oxyacetals in CH2Cl2 was also achieved
efficiently in the presence of anhydrous copper sulfate to afford the
corresponding dithioacetals in high yields (entries 29–32 in Table I). In
this case, the time was longer (Scheme 2).
SCHEME 2
Interestingly, this procedure can also be extended for the chemoselec-
tive protection of an aldehyde in the presence of a ketone. For instance,
when an equimolar mixture of benzaldehyde and acetophenone or
p-methylacetophenone was allowed to react with 1,3-ethanedithiol in
the presence of anhydrous copper sulfate, only the 1,3-dithiane deriva-
tive of the benzaldehyde was obtained in an excellent yield (Scheme 3).
SCHEME 3

Dithioacetalization of Aldehydes
1449
We have also investigated the reaction under solvent-free conditions.
The reaction proceeded at 40–50◦C in very short reaction time (less than
five minutes). The behavior of solvent-free conditions is similar to using
dichloromethane as a solvent (Table I).
The anhydrous copper-sulfate support is prepared conveniently com-
pared to other reported reagents. Also, this support is nonvolatile, non-
flammable, eco-friendly, safe, clean, cheap, and recyclable.
In conclusion, aldehydes were protected chemoselectively as their
thioacetals under mild reaction conditions in the presence of anhydrous
copper sulfate. Transthioacetalization reactions of oxyacetals were also
easily achieved by using this reagent. In addition, high chemoselec-
tivity observed for functional group interconversions presents useful
synthetic potentials of the method.
EXPERIMENTAL
Compounds gave satisfactorily all spectroscopic data. IR spectra were
taken as thin films for liquid compounds and as KBr pellets for solids
on a Nicolet spectrometer (Magna 550). A bruker (DRX-500 Avance)
1
NMR was used to record the HNMR spectra. All NMR spectra were
determined in CDCl3 at an ambient temperature. Melting points were
determined on a Buchi B540 apparatus.
The Thioacetalization of Aldehydes and
Transthioacetalization of Acetals in a Solvent
General Procedure
The dithiol (3 mmol) or thiol (5–6 mmol) was added to a stirring solu-
tion of aldehydes or acetals (2.5 mmol) in CH2Cl2 (15 mL). Then, anhy-
drous copper sulfate (3.5 mmol) was added, and the resulting mixture
was stirred at r.t. for an appropriate time as required for completion
of the reaction, which was monitored by TLC (petroleum ether:ethyl
acetate, 4:1). After separation of the catalyst by filtration, the solvent
was removed under reduced pressure. In all these cases, crude products
were sufficiently pure (TLC and 1H-NMR), and the further pure prod-
ucts were obtained by crystallization from petroleum ether (b.p. 100–
140◦C) or PTLC.
The Thioacetalization of Aldehydes in a Solvent-Free
Condition
General Procedure
The dithiol (3 mmol) or thiol (5–6 mmol) and anhydrous copper
sulfate (3.5 mmol) were added to a solution of aldehydes or acetals

1450
F. M. Moghaddam et al.
(2.5 mmol) in diethyl ether (5 mL). After evaporation of the solvent un-
der vacuum, the solid residue was heated at 40–50◦C for an appropriate
time as required for completion of the reaction, which was monitored
by TLC. Then, CH2Cl2 (20 mL) was added, and a catalyst was sepa-
rated. The remainder of the procedure is similar to that described in
the previous section.
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