Chemoselective and solvent-free thioacetalization of aldehydes by a catalytic amount of NBS

Article abstract of DOI:10.1080/00397910600767538

A chemoselective, straightforward, and rapid method for thioacetalization of aldehydes by use of 1,2-ethandithiol and a catalytic amount of N-bromosuccinimide under solvent-free conditions is reported. The reaction takes place in excellent yields and shor

Full text of DOI:10.1080/00397910600767538

Synthetic Communicationsw, 36: 2807–2811, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600767538
Chemoselective and Solvent-Free
Thioacetalization of Aldehydes by a
Catalytic Amount of NBS
Abdol Reza Hajipour and Seied Ali Pourmousavi
Pharmaceutical Research Laboratory, College of Chemistry,
Isfahan University of Technology, Isfahan, Iran
Arnold E. Ruoho
Department of Pharmacology, University of Wisconsin, Madison,
Wisconsin, USA
Abstract: A chemoselective, straightforward, and rapid method for thioacetalization of
aldehydes by use of 1,2-ethandithiol and a catalytic amount of N-bromosuccinimide
under solvent-free conditions is reported. The reaction takes place in excellent yields
and short reaction times.
Keywords: Thioacetalization, NBS, solvent-free, chemoselective, aldehydes
INTRODUCTION
One of the major challenging problems during multistep syntheses is protection
of carbonyl functional groups from nucleophilic attack until their electrophilic
nature is exploited. For this reason, the protection of carbonyl groups is essential
for organic chemists. Among carbonyl protecting groups, dithioacetals consti-
tute an important class of compounds as acyl anion equivalents[1] or masked
methylene functions in carbon–carbon bond-forming reactions. On the other
hand, these substrates are versatile[2] because of their straightforward prep-
aration and also their stability under basic or mildly acidic conditions.[3,4]
Received in the U.K. August 16, 2005
Address correspondence to Abdol Reza Hajipour, Pharmaceutical Research Labora-
tory, College of Chemistry, Isfahan University of Technology, Isfahan 84156, Iran.
E-mail: haji@cc.iut.ac.ir
2807

2808
A. R. Hajipour, S. A. Pourmousavi, and A. E. Ruoho
Generally, thioacetals are prepared by condensation of carbonyl compounds
with thiols or dithiols employing strong acid catalysts such as HCl,[5]
PTSA,[6] AlCl3,[7] TiCl4,[8] and LaCl3.[9] A large number of these methods
require long reaction times, reflux temperature, and stoichiometric amounts of
catalyst and provide low yields. Most recently, some methods employing
LiBr,[10] LiBF4,[11] InCl3,[12] Sc(OTf)3,[13] and I2[14] have been reported. Inter-
estingly, only a few of these methods have demonstrated chemoselective protec-
tion of aldehydes in the presence of ketones. Some methods failed to protect
deactivated aromatic substrates.[13] Therefore, there is still a need to develop
a simple and efficient method for chemoselective protection of aldehydes.
RESULTS AND DISCUSSION
In continuation of our research on ammonium and phosphonium salts,[15]
in this communication we introduce a mild and highly chemoselective
procedure for thioacetalization of aldehydes in the presence of ketones
using 1,2-ethandithiol in the presence of a catalytic amount of N-bromosucci-
nimide under solvent-free conditions (Scheme 1).
In comparison to the reported[16] method for thioacetalization of aldehydes
using NBS as catalyst, which suffered from using an organic solvent such as
dichloromethane and longer reaction times (30–180 min), in our method the
reaction was carried out under solvent-free conditions with higher yields and
the reaction time is much more shorter (2–7 min) (Table 1).
Moreover, this procedure is highly chemoselective, providing selective
protection of an aldehyde in the presence of a ketone. Treatment of an
equimolar mixture of benzaldehyde and acetophenone in the presence of
1,2-ethanedithiol and a catalytic amount of NBS under solvent-free
conditions produced only 1,3-ditholane derivative of the benzaldehyde,
whereas the acetophenone was completely was recovered. This competitive
reaction illustrating the chemoselectivity of the present method (Scheme 2).
In conclusion, we have developed a simple and efficient method for
chemoselective dithioacetalization of various aldehydes under solvent-free
conditions with high yields and short reaction times. This method is a
chemoselective procedure for protection of aldehydes in the presence of ketones.
Scheme 1.

Chemoselective and Solvent-Free Thioacetalization
2809
Table 1. Thioacetalization of aldehyde with NBS under solvent-free
conditions at room temperaturea
Time
(min) [sol]c
Yield
(%)b [sol]c
Entry
R1
1a
1b
1c
1d
1e
1f
Ph
2-(Cl)C6H4
5 [40]
7
97 [80]
95
98
3-(Cl)C6H4
4-(Cl)C6H4
3
2 [30]
95 [80]
95
90
3-(O2N)C6H4
4-(O2N)C6H4
2-(MeO)C6H4
3-(MeO)C6H4
4-(MeO)C6H4
4-(Me)C6H4
5
5
1g
1h
1i
7
95
98
3
5 [30]
96 [75]
98
95
1j
2
1k
1l
2-(HO)C6H4
5-(Br)-2-(HO)C6H3
4-(Br)C6H4
7
5
98
95
1m
1n
1o
1p
1q
1r
1s
3
3,4-(Dimethoxy)C6H3
2,4-(Dimethoxy)C6H3
4-(Me2N)C6H4
2-Furyl
3
98
95
5
3
3 [30]
98
92 [90]
98
95
2-(5-(Me)Furyl)
PhCH55CH
3
5
aConfirmed by comparison with authentic samples (TLC, IR, and
NMR).
bYield of isolated pure product after purification.
cReaction in dichloromethane solution.[15]
Scheme 2.

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A. R. Hajipour, S. A. Pourmousavi, and A. E. Ruoho
EXPERIMENTAL
General
Yields refer to isolated pure products. The products were characterized
by comparison of their spectral (1H NMR, IR), melting point, and boiling
point with authentic samples (authentic samples prepared by reported
methods).[17] All 1H NMR spectra were recorded at 500 MHz in CDCl3,
relative to TMS (0.00 ppm). All reactions were carried out under solvent-
free conditions at room temperature in a hood with strong ventilation.
Dithioacetalization of 4-Methylbenzaldehyde 1j: A Typical
Procedure
A mixture of 4-methylbenzaldehyde 1j (10 mmol, 1.20 g), 1,2-ethanedithiol
(12 mmol, 1.13 g), and NBS (1 mmol, 0.18 g) in a mortar was ground with
a pestle for the time specified in Table 1. Monitoring the reaction by TLC
(silica-gel ethyl acetate–cyclohexane, 15:85). After disappearance of the
starting material, the mixture was washed with Et2O (4 Â 10 mL) and
filtered. The filtrated was evaporated under reduced pressure. Evaporation
of the solvent gave 2-(4-methylphenyl)-1,3-dithiolane 2j. The yield was
1.92 g (98%) of colorless solid 2j, mp 55–578C. IR (neat): 3004, 1510,
1
1437, 1411, 1277, 1177, 1165, 830, 777 cm21. H NMR: d 2.32 (s, 3 H),
3.29–3.52 (m, 4 H), 5.62 (s, 1 H), 7.10 (d, J ¼ 6.5 Hz, 2 H), 7.40
(d, J ¼ 6.5 Hz, 2 H). 13C NMR: d 21.11, 40.20 (2 CH2), 56.12, 127.80,
129.15, 137.10, 137.84.
ACKNOWLEDGMENTS
We gratefully acknowledge the funding support received for this project from
the Isfahan University of Technology (IUT), I.R. Iran (A. R. H.) and Grants
GM 033138, MH 065503, NS 033650 (A. E. R.) from the National Institutes
of Health, USA. Further financial support from Center of Excellence in
Chemistry Research (IUT) is gratefully acknowledged.
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