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Chemistry Letters Vol.37, No.1 (2008)
Lewis Base Catalyzed 1,3-Dithiane Addition to Carbonyl Compounds
Using 2-Trimethylsilyl-1,3-dithiane
Makoto Michida1 and Teruaki MukaiyamaÃ1;2
1Center for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
2Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received October 16, 2007; CL-071148; E-mail: mukaiyam@abeam.ocn.ne.jp)
Table 1. Screening of Lewis base catalysts
1,3-Dithiane addition to various aldehydes and ketones
using 2-trimethylsilyl-1,3-dithiane in the presence of a catalytic
amount of a Lewis base such as tetrabutylammonium phenoxide
(PhONn-Bu4) proceeds smoothly to afford the corresponding
ꢀ-hydroxy dithiane compounds in good to high yields under
mild conditions.
OH
S
O
H+
S
Cat. (30 mol %)
+
TMS
Ph
Solv., 0 °C−rt, 1 h
Ph
H
S
S
(1.5 equiv.)
Cat.
Entry
Solv.
DMF
Yielda/%
1
2
3
4
5
6
7
8
AcOLi
N.R.
N.R.
16
25
77
AcONn-Bu4
PhOLi
PhONa
DMF
DMF
DMF
DMF
DMF
DMSO
THF
Addition reaction of 1,3-dithiane is one of the most impor-
tant umpolung reactions in synthetic organic chemistry.1 The di-
thiane anions are widely known as masked acyl carbanions
which react with various electrophiles such as carbonyl com-
pounds to afford the corresponding protected aldehydes. The
dithiane group of the above adducts can be deprotected under
mild oxidation conditions.2
PhOK
PhONn-Bu4
PhONn-Bu4
PhONn-Bu4
96
77b
14c
In general, the dithiane addition reaction is carried out by
using 1,3-dithiane and an equimolar amount of strong bases
such as n-butyllithium, and thus-formed lithiated dithiane would
behave as a useful nucleophile. 2-Trimethylsilyl-1,3-dithiane
(TMS-dithiane) is also used as 1,3-dithiane equivalent and is ac-
tivated by a stoichiometric amount of fluoride ion such as tetra-
butylammonium fluoride (TBAF) or cesium fluoride for the gen-
eration of the corresponding carbanion.3 While most of the reac-
tions are carried out by using an equimolar amount of fluoride
reagent, only a few examples on catalytic activation of TMS-di-
thiane have been reported to date.4
aIsolated yield. bThe reaction was carried out at room tem-
perature. The reaction was carried out for 2 h.
c
Table 2. PhONn-Bu4-catalyzed dithiane addition to various
aldehydes
OH
PhONn-Bu4
(30 mol %)
S
S
O
H+
S
+
TMS
R
R
H
DMF, 0 °C−rt,1 h
S
(1.5 equiv.)
Entry
R
Yielda/% Entry
R
Yielda/%
These dithiane addition reactions are rather hard to apply to
the ketones having ꢀ-protons such as acetophenone because of
their deprotonation by dithiane anions.5 Therefore, it is required
to find conditions that are milder for the dithiane addition
reaction.
1
2
3
4
5
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
95
6
7
8
9
2-Furyl
3-Pyridyl
t-Bu
94
80
60
83
95
94
83
97
92
c-Hex
10 (E)-PhCH=CH
In our previous papers, it was shown that the nitrogen- or
oxygen-containing anions generated from amides, imides, car-
boxylic acids, or alcohols behaved as effective Lewis base cata-
lysts in the activation of trimethylsilyl (TMS) derivatives.6 Also,
addition reactions to carbonyl compounds such as aldol reaction,
trifluoromethylation, cyanomethylation, and alkynylation had
been carried out successfully in the presence of Lewis base cat-
alysts.7 In this communication, we would like to report an effec-
tive method for 1,3-dithiane addition to aldehydes and ketones
with TMS-dithiane under mild conditions by using a Lewis base
catalyst such as PhONn-Bu4.
In the first place, reactions of benzaldehyde with TMS-
dithiane were studied in the presence of catalytic amounts of var-
ious Lewis bases (Table 1). When AcOLi or AcONn-Bu4 was
used, the reaction did not proceed (Entries 1 and 2). When a
phenoxide anion was employed as a counter anion, on the other
hand, it did proceed though the yield of the desired product was
low. Effects of counter cations of the phenoxide were further ex-
amined, and the yields of the adduct turned to be higher as the
aIsolated yield.
nucleophilicities of the anion increased (Entries 3–6). Therefore,
the suitable choice of counter cation of phenoxide was crucial to
obtain the adducts in high yields, and it was confirmed that am-
monium ion gave the best results.8 Next, the effects of solvents
were further examined in the presence of a catalytic amount
of PhONn-Bu4. Dimethylsulfoxide is also a polar solvent
and the corresponding product was afforded in moderate yield
(Entry 7). On the other hand, when the reaction was carried
out in THF, the yield was very low (Entry 8). It was then found
that the TMS-dithiane activation was promoted by polar sol-
vents, and that the best result was obtained when DMF was used.
Then, reactions of various aldehydes and TMS-dithiane by
using a catalytic amount of PhONn-Bu4 were tried (Table 2). Ar-
omatic aldehydes having electron-donating or -withdrawing
groups and heteroaromatic aldehydes reacted smoothly with
TMS-dithiane to afford the adducts in good to high yields (En-
Copyright ꢀ 2008 The Chemical Society of Japan