Low temperature syntheses of thioketals from enol ethers and carbonyl compounds

Article abstract of DOI:10.1016/S0040-4039(02)02855-1

A dithioacetalisation procedure at low temperature using TMSOTf as the promoter is described. This method proved highly efficient for unprecedented transprotection of ketone enol ethers and was successfully applied to polyfunctional sensitive substrates.

Full text of DOI:10.1016/S0040-4039(02)02855-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1491–1494
Low temperature syntheses of thioketals from enol ethers and
carbonyl compounds
Arnaud Martel, Sopa Chewchanwuttiwong, Gilles Dujardin* and Eric Brown
Laboratoire de Synthe`se Organique, UMR 6011 CNRS, Faculte´ des Sciences, Avenue Olivier Messiaen,
F-72085 Le Mans Cedex 9, France
Received 29 October 2002; accepted 11 December 2002
Abstract—A dithioacetalisation procedure at low temperature using TMSOTf as the promoter is described. This method proved
highly efficient for unprecedented transprotection of ketone enol ethers and was successfully applied to polyfunctional sensitive
substrates. © 2003 Elsevier Science Ltd. All rights reserved.
Thioacetalisation of aldehydes and ketones is often
employed in the course of the synthesis of multifunc-
tional target molecules.1 In this very active area of
protection chemistry applied to free carbonyl com-
pounds, numerous recent reports concern the develop-
ment of simple procedures using smooth catalysts
(LiBF4,2 LiBr,3 LiOTf,4 Cu(OTf)2-SiO2,5 I2,6 trichloro-
TMSOTf as the promoter. This method proved to be
particularly efficient for the transprotection of enol
ethers.
In the course of an ongoing program,14 we had to
perform the selective transformation of enol ether 1
into dithioketal 215 (Scheme 1). Due to the presence of
O,O-ketal or tert-butoxy group, which are labile under
acidic conditions, conventional methods (gaseous HCl
in chloroform)13 led only to degradation products
when applied to enol ether 1. Nearly the same
result was observed when using strong Lewis acids
(TiCl4, BF3·Et2O), and Zn(OTf)2 was ineffective at
room temperature. Use of 20 mol% SnCl4 gave the
desired transprotected compound 2, but only in moder-
ate yield.
cyanuric acid,7 InCl3 ), even under solvent-free condi-
8
tions.3–5 On the other hand transprotection methods
mainly refer to transdithioacetalisation of O,O- and
O,S-acetals.3,4,9–12 Sudalai and co-workers10 also
described the transdithioacetalisation of oximes, enam-
ines, and tosylhydrazones using a kaolinitic clay as the
catalyst, but, to our knowledge, transprotection of
ketone enol ethers have only been reported for simple
substrates using harsh acidic conditions (gaseous HCl
in chloroform).13
At −10°C, a significant degradation of 1 occurred. This
problem was solved at −60°C, but yield of 2 was still
restricted by competitive formation of the bridged,
We report here a general dithioacetalisation procedure
with 1,2-ethanedithiol at low temperature (−78°C) using
Scheme 1. Reagents and conditions: 1.0 equiv. HSCH2CH2SH, 1.25 equiv. TMSOTf, CH2Cl2, −78°C, 4 h (80%).
Keywords: thioacetals; transprotection; enol ethers; TMSOTf.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02855-1

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A. Martel et al. / Tetrahedron Letters 44 (2003) 1491–1494
di-O,S-acetalic, regioisomer. These last experiments
proved that the Lewis acid-mediated methods classi-
cally used for the transformation of ketones into
thioketals either (1) cannot be applied to the transfor-
mation of enol ethers into thioketals or (2) could
allow this transprotection, but only in the case of
rather simple substrates, which are deprived of any
other acid labile functional group. Indeed, the Lewis
acid used must respect some conditions. First, it must
lead to a protic acid in situ, in order to perform the
protonation of the double bond, and, above all, it
must have a great affinity for oxygen in order to
promote the ejection of the alkoxy group. In the spe-
cial case of 1, conditions used must be also non-
rapidly led to the degradation of enol ether 1, thus
showing the significant role of temperature.
The scope of this unusual18 thioacetalisation proce-
dure was next explored (Table 1). First, a compara-
tive study between cyclohexanone,19 its corresponding
acetal and its corresponding methyl and TBDMS enol
ethers confirmed that both enol ethers are very conve-
nient substrates under these conditions. Thus,
TBDMS enol ethers of cyclohexanone and cyclodode-
canone afforded thioketals 4a and 4b in nearly quan-
titative yields. Di-protected compound 4c was
conveniently obtained from the corresponding sensi-
tive alkyl enol ether. Another interesting feature of
this reaction was the selective transprotection of enol
ethers 6 and 7 (entries 9 and 10) without alteration of
the a-ketoester moiety. Others experiments evidenced
the convenient conversion of acyclic ketones and alde-
hydes under these conditions.
degradative
and
selective.
Trimethylsilyl
trifluoromethanesulfonate (TMSOTf) appeared to be
the ideal reagent. Indeed, the use of a slight excess of
this reagent in CH2Cl2 at −78°C led after 4 h to the
clean and regioselective protection of the enol ether
moiety. The desired crystalline thioketal 2 was iso-
lated after chromatography in 80% yield on a 1–10
mmol scale.16
Finally, this method also enabled the transformation
of bicyclic ketone 8 into dithioketal 2 (Scheme 3).
The same reaction was also performed following the
very mild conditions described by Evans and co-
workers.22 In the latter case, we obtained a lower
yield, due to the incomplete conversion of ketone 8 (a
silylhemithioketal was competitively formed). This
example23 illustrates that the use of TMSOTf at low
temperature can be complementary to the method
described by Evans and besides offers the benefit of
the low cost of the reagents used. A similar comple-
mentarity was previously reported for the conversion
of carbonyl compounds into 1,3-dioxolanes (use
of 1,2-bis-(trimethylsilyloxy)ethane/cat. TMSOTf at
−78°C24 versus use of ethyleneglycol/TMSCl at 20–
40°C25 or ethyleneglycol/alkoxysilane/cat. TMSOTf at
−20°C26).
We suppose that TMSOTf and dithiol would preform
a silylsulfonium intermediate, that would be acidic
enough to protonate the double bond and perform
the activation of enol ether 1. Then, the co-produced
thiosilane would add to the resulting oxonium. Subse-
quent activation of the methoxy group into
a
trimethylsilyloxonium would favor the final substitu-
tion by the thiol, thus leading to the thioketal 2 and
methyl trimethylsilyl ether (Scheme 2). This pathway
is supported by the fact that using catalytic amounts
ot TMSOTf (10 mol%) under the same conditions led
to a poor yield of dithiane 2 (<10%), the main reac-
tion product being the corresponding O,S-ketal 3.
The high reactivity of TMSOTf is crucial in our reac-
tion and allowed us to lower significantly the temper-
ature, thus selectively leading to the requisite
thioketal without appreciable side-reactions. TMSOTf
has already been used for the conversion of a ketal
into a dithioketal at 0°C,17 but these conditions
In conclusion, enol ethers, carbonyl compounds and
acetals can be converted into thioketals at low tem-
perature using TMSOTf as a stoichiometric reagent.
Although less economical for simple substrates than
above-mentioned catalytic procedures,1–12 this method
Scheme 2.

A. Martel et al. / Tetrahedron Letters 44 (2003) 1491–1494
1493
Table 1. Thioacetalisationa of various carbonyl compounds, enol ethers and ketal derivatives
a
Each reaction was carried out using ethanedithiol (1.0 equiv.) and TMSOTf (1.25 equiv.) in CH2Cl2 at −78°C for 4 h.
b Unoptimised yield of isolated product (after filtration over silica gel).
c Purified by flash column chromatography on silica gel.
d Prepared by PCC-oxidation of the corresponding lactol, see Ref. 20.
e
Prepared according the procedure analogous to that used for 6.
Acknowledgements
can be very useful for protection under highly-con-
trolled conditions of more elaborate and/or sensitive
substrates. This property was exemplified by the
efficient transprotection of the polyfunctional enol
ethers 1, 6 and 7.
We thank the French Embassy in Thailand and the
Thailand Research Fund for financial support (RGJ
fundings for S.C.).

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A. Martel et al. / Tetrahedron Letters 44 (2003) 1491–1494
Scheme 3. Reagents and conditions: (i) 1.1 equiv. Me3SiSCH2CH2SSiMe3, 0.03 equiv. ZnI2, Et2O, rt, 48 h (48%); (ii) 1.0 equiv.
HSCH2CH2SH, 1.25 equiv. TMSOTf, CH2Cl2, −78°C, 4 h (71%).
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