Nickel(II) chloride as an efficient and useful catalyst for chemoselective thioacetalization of aldehydes

Article abstract of DOI:10.1016/S0040-4039(02)02771-5

A wide variety of acyclic and cyclic dithioacetals can be prepared chemoselectively from the corresponding aldehydes by employing a catalytic amount of nickel(II) chloride in dry CH₂Cl₂-MeOH (5:1) at room temperature in good yields.

Full text of DOI:10.1016/S0040-4039(02)02771-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 919–922
Nickel(II) chloride as an efficient and useful catalyst for
chemoselective thioacetalization of aldehydes
Abu T. Khan,a,* Ejabul Mondal,a Priti R. Sahua and Samimul Islamb
aDepartment of Chemistry, Indian Institute of Technology, North Guwahati, Guwahati 781 039, India
bDepartment of Chemistry, Visva-Bharati, Santiniketan, West Bengal 731 235, India
Received 14 May 2002; revised 26 November 2002; accepted 6 December 2002
This paper is dedicated to my teacher Professor Kamalendu Dey, Department of Chemistry, Kalyani University
for his valuable guidance and constant encouragement
Abstract—A wide variety of acyclic and cyclic dithioacetals can be prepared chemoselectively from the corresponding aldehydes
by employing a catalytic amount of nickel(II) chloride in dry CH2Cl2–MeOH (5:1) at room temperature in good yields. Some of
the major advantages of this procedure are high chemoselectivity, ease of operation, high yields and also compatibility with other
protecting groups. © 2003 Elsevier Science Ltd. All rights reserved.
The protection of the carbonyl functionality as a
dithioacetal1 is a common practice in multistep synthe-
sis of natural2 and non-natural3 products due to the
group’s inherent stability under both acidic and basic
conditions. In addition, thioacetals are also utilized as
masked acyl anions4 or masked methylene functions5 in
carbonꢀcarbon bond forming reactions. They are usu-
ally prepared by the condensation of carbonyl com-
pounds with thiols or dithiols using a strong protic acid
relatively expensive reagents.10–15 Recently some solid
supported reagents have been used for thioacetalization
of various carbonyl compounds, e.g. SOCl2–SiO2,16
Cu(OTf)2–SiO2,17 ZrCl4–SiO2,18 TaCl5–SiO2,19 and
CoBr2–SiO2.20 Very recently new methods for protec-
tion of carbonyl compounds as their dithioacetals
employed LiBr,21a LiBF4,22a InCl3,23 molecular I2,24a
NBS,25 and Sc(OTf)3.26 Interestingly, only a few meth-
ods are known in the literature for the chemoselective
protection of aldehydes15,16,21–26 in the presence of
ketones. Some of the methods mentioned above involve
relatively harsh conditions,16 access acyclic dithioacetals
only with difficulty,16 require an inert atmosphere
such as HCl6 or Lewis acids such as BF3·OEt2 or
7
8
ZnCl2 as catalysts. Unfortunately, these procedures
have certain disadvantages such as a requirement for
stoichiometric amounts of catalyst and also provide low
yields. Other Lewis acids viz. AlCl3,9 TiCl4,10 LaCl3,11
for the
reaction15,23–25
and
involve
expensive
SiCl4,12 WCl6,13 (CH3)3SiCl,14 and 5 M LiClO4 have
reagents,17–20,23,26 are incompatible with other protect-
ing groups such as TBS ethers7b,21b,22b,24b and fail to
protect deactivated aromatic substrates.26 Conse-
quently, what is needed is a methodology, which works
15
also been employed. All these methods have some
drawbacks such as difficulties in work-up9,10 the
requirement for an inert atmosphere,15 and the use of
Scheme 1.
Keywords: protection; dithioacetals; ethanethiol; thiophenol; 1,2-ethanedithiol; 1,3-propanedithiol; nickel(II) chloride.
* Corresponding author. Fax: +91-361-2690762; e-mail: atk@postmark.net
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02771-5

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A. T. Khan et al. / Tetrahedron Letters 44 (2003) 919–922
Table 1. Protection of various aldehydes as the corresponding dithioacetals using nickel(II) chloride (NiCl2) as catalyst

A. T. Khan et al. / Tetrahedron Letters 44 (2003) 919–922
921
under mild conditions, using inexpensive reagents.
Within our ongoing research programme to develop
new synthetic methodologies,27,28 we proposed that
nickel(II) chloride, which acts as a mild Lewis acid
might be a useful catalyst for thioacetalization of car-
bonyl compounds. In this communication, we wish to
report a simple and easy method for chemoselective
thioacetalization of various aromatic and aliphatic
aldehydic compounds using nickel(II) chloride as a
new catalyst, depicted in Scheme 1.
According to expectations, the reaction of benzalde-
hyde (1 mmol) with 1,2-ethanedithiol (1.1 mmol) in
the presence of nickel(II) chloride (0.1 mmol) at room
temperature in CH2Cl2–MeOH (5:1, 3 mL) afforded
the desired 1,3-dithiolane derivative in 96% yield (run
1). Similarly, the 1,3-dithiane derivative of benzalde-
hyde was obtained from benzaldehyde (run 2), on
treatment with 1,3-propanedithiol following an identi-
cal procedure. By following this reaction procedure,29
both aromatic as well as aliphatic aldehydes (runs
3–26) were converted smoothly to the corresponding
acyclic dithioacetals or cyclic dithioacetals in good
yields, on reaction with either thiols or dithiols in the
presence of a catalytic amount of nickel(II) chloride
at room temperature. The results are summarized in
Table 1 with products fully characterized by IR, 1H
NMR, 13C NMR and elemental analysis.30 The
results shown in Table 1 clearly indicate the scope
and generality of the reaction with respect to different
aromatic, aliphatic and unsaturated aldehydes. It is
noteworthy that the conversion can be achieved in
the presence of other protecting groups such as ace-
tyl, benzyl, benzoyl, allyl, esters and TBS ethers. We
have also noticed that highly deactivated aromatic
aldehydes can be protected as dithioacetals in good
yields (runs 9 and 21) with longer reaction times. It is
important to mention that the diethyldithioacetal of
naphthaldehyde was obtained from naphthaldehyde
(run 16) by using nickel(II) chloride catalyst in 85%
yield in 3 h, which provides a much better yield than
the procedure reported recently.26 We have also
observed that nickel(II) chloride hexahydrate can be
used but requires longer reaction times than anhy-
drous nickel(II) chloride.
Scheme 2.
dithiolane derivative of the p-hydroxybenzaldehyde
was obtained, see Scheme 2.
Furthermore, the aldehyde functionality of a keto-
aldehyde, was protected chemoselectively in good
yield under identical reaction conditions, see Scheme
3.
In conclusion, we have demonstrated a very simple
and convenient protocol for the protection of various
aldehydes as dithioacetals in the presence of a wide
range of other protecting groups using a catalytic
amount of NiCl2. An aldehyde group can be pro-
tected chemoselectively in the presence of a keto
group under these conditions. Moreover, highly deac-
tivated aromatic aldehydes can be converted to the
corresponding dithioacetals without any difficulty.
Other nickel salts can be used for similar transforma-
tions and will be reported in due course.
Acknowledgements
This research work was supported in part by a grant
received from the Department of Science and Tech-
nology (DST), New Delhi (Grant No. SP/S1/G-35/
98). E.M. and P.R.S. are thankful to the CSIR and
DST, respectively, for their fellowships. We also
express our sincere thanks to Professor M. K. Chaud-
huri for his constant encouragement and to Professor
D. N. Buragohain, Director, I.I.T. Guwahati for
providing general facilities to carry out this research
work. We are thankful for referee’s valuable sugges-
tions and comments.
Interestingly, this procedure can also be extended for
chemoselective protection of an aldehyde in the pres-
ence of a ketone. For instance, when an equimolar
mixture of p-hydroxybenzaldehyde and acetophenone
was allowed to react with 1,2-ethanedithiol in pres-
ence of a catalytic amount of NiCl2 only the 1,3-
Scheme 3.

922
A. T. Khan et al. / Tetrahedron Letters 44 (2003) 919–922
23. Mathuswamy, S.; Arulananda Babu, S.; Gunanathan, C.
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1
IR (KBr): 1608, 1520, 1256, 1180, 1028 cm−1; H NMR
(400 MHz, CDCl3): l 3.30–3.35 (m, 2H, 2×-SCH-), 3.47–
3.51 (m, 2H, 2×-SCH-), 3.78 (s, 3H, OCH3), 5.63 (s, 1H,
ArCH), 6.83 (d, 2H, J=8.7 Hz, ArH), 7.44 (d, 2H,
J=8.7 Hz, ArH). Anal. calcd for C10H12OS2: C, 56.57;
H, 5.70; S, 30.20. Found: C, 56.38, H, 5.63; S, 30.01%.
For 2-(4-tert-butyldimethylsilyloxyphenyl)-1,3-dithiane: IR
1
(Neat) 1608, 1511, 1270, 1173 cm−1; H NMR (300 MHz,
CDCl3): l 0.19 (s, 6H, 2×SiCH3), 0.97 (s, 9H, Si(CH3)3),
1.83–1.98 (m, 1H, SCH2CHCH2S), 2.10–2.19 (m, 1H,
SCH2CHCH2S), 2.85–2.92 (m, 2H, 2×-SCH), 2.99–3.10
(m, 2H, 2×-SCH), 5.12 (s, 1H, ArCH), 6.78 (d, 2H,
J=8.4 Hz, ArH), 7.30 (d, 2H, J=8.4 Hz, ArH); 13C
NMR (75 MHz, CDCl3): l −4.5 (2C), 18.1, 25.0, 25.6
(3C), 32.1 (2C), 50.8, 120.1 (2C), 128.8 (2C), 131.8, 155.7.
Anal. calcd for C16H26OS2Si: C, 58.84; H, 8.02; S, 19.63.
Found: C, 58.60; H, 7.95; S, 19.70%.