focusing our group on thioesters,6 which are not only more
reactive than O-esters but also more stable and more easily
handled than regular active acylating reagents such as acid
halides and anhydrides. Indeed, thioesters act as a critical,
acylating functionality in biological systems. Based on
these facts, we considered S,O-esters 2 with one S-ester
and one O-ester as very valuable synthons.7 Herein, we
report the highly efficient dissymmetrization of symmetric
malonic acid dithioesters affording S,O-malonic acid es-
ters via catalytic and/or noncatalytic selective monoalco-
holysis through acylketenes as the key intermediate.
Table 1. Monoalcoholysis of Dithiomalonates under Neutral
Conditions
temp/ time/ conver-
yield/%
entry
R
solventa °Cb
h
sion/%
(2:6)
1
2
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Et (1b)
Et (1b)
toluene
CH2Cl2
ether
60
40
34
60
60
60
60
60
80
105
3.5
3.5
3.5
3.5
2
0
0
0
0
0
0
0
3
4
THF
trace
Scheme 1
5
CH3CN
DMF
99 96 (2a) (>20:1)
>99 83 (2a) (>20:1)
>99 83 (2a) (11:1)
6
1.2
0.3
1
7
DMSO
CH3CN
DMF
8
0
0
9
2
95 84 (2b) (12:1)
95 74 (2c) (3.5:1)
10
C
12H25 (1c) DMF
0.5
a 0.1 M. b Internal temperature.
longer reaction time, reacted with 1a to afford the S,O-
dissymmetric malonates 2 with high selectively in good to
excellent yields (entries 1À6). Unsaturated alcohols, such
as allyl alcohol and propargyl alcohol, however, did not
react at all under the standard conditions (entries 7À8).
We first attempted the alcoholysis of malonic acid
diphenyl dithioester (1a) by mixing butanol in toluene,
CH2Cl2, and ether, but no reaction occurred (Table 1,
entries 1À3). However, when the mixture was placed in
THF at 60 °C, a trace amount of the dissymmetric S,O-
malonate 2a could be detected (entry 4). Encouraged by
this result, we examined more polar solvents in the alco-
holysis of the dithiomalonate 1a with butanol. Accord-
ingly, the monoalcoholysis proceeded very smoothly in
acetonitrile to afford 2a almost quantitatively within 2 h,
and only a trace amount of dibutyl malonate was detected,
Table 2. Monoalcoholysis of Dithiomalonates with Alcohols
ROH
time/
h
conver-
sion/%
entry
(equiv)
yield/%a
1
2
3
4
5
6
7
8
t-BuCH2OH (3)
dodecanediol (3)
s-BuOH (3)
7
6
98
98
93
97
>99
75
0
93 (2d)
89 (2e)
92 (2f)
93 (2g)
92 (2h)
70 (2i)
0
24
24
5
i-PrOH (3)
1
based on H NMR analysis (entry 5). In the more polar
menthol (3)
solvents of DMF and DMSO, the reactions were further
accelerated, but the yield was slightly diminished (entries
6À7) and a small amount of dibutyl malonate was gener-
ated. The dialkyl dithiomalonate (1b) did not react with
butanol in acetonitrile (entry 8), but in DMF the desired
product 2b was obtained at higher temperature along with
a small amount of 6 (entries 9À10). Consequently, we
decided to examine the dissymmetrization of 1a with
various alcohols in acetonitrile at 60 °C.
Based on these results, we examined the monoalcoho-
lysis of diphenyl dithiomalonates with various alcohols as
shown in Table 2. Primary, secondary, and even sterically
hindered tertiary alcohols, which however required a
t-BuOH (3)
24
24
24
propargyl alcohol (3)
allyl alcohol (3)
0
0
a O,O-Malonates were generated in less than 5% yield.
In order to increase the reactivity, the copper catalyst 7,
developed for activation of thioesters in the one-pot trans-
esterificationÀWittig lactonization,6 was employed in the
˚
presence of 4 A molecular sieves (17 mg per 1 mmol of the
substrates), and it resulted in a considerable acceleration as
shown in Table 3. Monoalcoholysis with BuOH and t-
BuOH was complete within 1 h, and the less reactive allyl
and propargyl alcohols afforded the dissymmetric S,O-
esters in excellent yield with acceptable selectivity (Table 3,
entries 1À4). Although the alcoholysis was retarded by the
introduction of the R-alkyl-substitution on the dithioma-
lonates, the catalyst could accelerate the reaction suffi-
ciently to afford the desired products in good yield (entries
(6) Matsuo, K.; Shindo, M. Org. Lett. 2010, 12, 5346–5349.
(7) (a) Takayama, H.; Fujiwara, R.; Kasai, Y.; Kitajima, M.; Aimi,
N. Org. Lett. 2003, 5, 2967–2970. (b) Vedejs, E.; Nader, B. J. Org. Chem.
1982, 47, 3193–3195. (c) Imamoto, T.; Kodera, M.; Yokoyama, M. Bull.
Chem. Soc. Jpn. 1982, 55, 2303–2304.
Org. Lett., Vol. 13, No. 16, 2011
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