β-Ketothioester as a reactive Knoevenagel donor

Article abstract of DOI:10.1016/S0040-4039(02)00675-5

The Knoevenagel condensation of β-ketothioesters with various aldehydes proceeds efficiently, affording the condensation products in moderate to good yield even in cases where the reactions of the corresponding β-ketoesters give the adducts in only low to

Full text of DOI:10.1016/S0040-4039(02)00675-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4079–4082
b-Ketothioester as a reactive Knoevenagel donor
Yujiro Hayashi,* Yuji Miyamoto and Mitsuru Shoji
Department of Industrial Chemistry, Faculty of Engineering, Science University of Tokyo, Kagurazaka, Shinjuku-ku,
Tokyo 162-8601, Japan
Received 8 February 2002; revised 22 March 2002; accepted 5 April 2002
Abstract—The Knoevenagel condensation of b-ketothioesters with various aldehydes proceeds efficiently, affording the condensa-
tion products in moderate to good yield even in cases where the reactions of the corresponding b-ketoesters give the adducts in
only low to moderate yield. © 2002 Published by Elsevier Science Ltd.
In the course of our synthetic studies on (+)-epolac-
taene, a neuritogenic compound, we encountered a
problem with low reactivity of a b-keto amide,1 and a
b-ketoester,2 towards an aldehyde in the Knoevenagel
reaction (Table 1, entries 1 and 2). The Knoevenagel
reaction is an important, classical carbonꢀcarbon dou-
ble bond forming reaction,3 and many variations have
been published, which however, cannot be applied to
the synthesis of epolacatene owing to the labile triene
moiety.4 Searching for a suitable synthetic equivalent of
the amide moiety, we found that a b-ketothioester
reacts with this aldehyde efficiently under mild reaction
conditions, affording the Knoevenagel condensation
product in good yield, but with undesired E-stereo-
chemistry (Table 1, entry 3). Although for this reason
the Knoevenagel reaction of the b-ketothioester cannot
be used in the total synthesis of epolactaene, the high
reactivity of b-ketothioesters compared to b-ketoesters
and b-ketoamides should prove important in terms of a
useful synthetic modification of the Knoevenagel reac-
Table 1. Knoevenagel reaction in epolactaene synthesis
O
OCH2OTBS
cat.H+
O
Me
O
O
Me
O
H
Me
X
X
MeO2C Me
Me
OCH2OTBS
Me
Me
MeO2C
benzene, 12 h
Me
Me
O
O
O NH
MeO2C Me
(+)-epolacatene
Yield (%)a
Me
OH
Me
Entry
X
Z
E
1
2
3
NH2
OCH2CH2SiMe3
SEt
28b
0
0
9b
0
78
a Isolated yield.
b Starting material was recovered in 58% yield.
Keywords: Knoevenagel reaction; b-ketothioester; b-ketoester.
* Corresponding author. Tel.: +81-3-5228-8318; fax: +81-3-5261-4631; e-mail: hayashi@ci.kagu.tus.ac.jp
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00675-5

4080
Y. Hayashi et al. / Tetrahedron Letters 43 (2002) 4079–4082
tion. We have compared the reactivities of these classes
of compounds as Knoevenagel donors.5
difference in reactivity was observed between thioester
and ester. Namely, when this substituent is i-propyl or
cyclohexyl, the reaction of b-ketoesters with aldehydes
affords the condensation products in only low to mod-
erate yields (<5–67%), while moderate to good yields
(56–89%) are obtained in the reaction of the corre-
sponding b-ketothioesters. The same phenomenon was
also observed in the reactions of g,d-unsaturated and
b-aryl derivatives: good yields are obtained in the reac-
tions of S-ethyl 4-methyl-3-oxo-4-hexenethioate and S-
ethyl 3-oxo-3-phenylbutanethioate with aldehydes.
Although a b-ketothioester does not react with a bulky
aldehyde such as 2,2-dimethyl-2-propanal, a b-keto-
thioester reacts both aromatic and the other aliphatic
aldehydes including a linear aldehyde like propanal
(entries 8, 9, 18), an a-branched aldehyde like isobutyl-
aldehyde (entries 6, 11, 20, 24), and an a-alkoxyalde-
hyde like 2-(p-methoxybenzyloxy)propanal (entry 16),
affording the condensation products in good yield. As
the reaction conditions are mild, no self-condensation
products of aldehydes were observed even in the reac-
tion of an enolizable a-alkoxyaldehyde (entry 16). The
amount of an aldehyde can be reduced to 1.5 equiv. to
a b-ketothioester without affecting the yield, although
longer reaction time was necessary (entries 8 and 9).
The reason to use excess amount (4–6 equiv.) of alde-
hydes in some cases is to obtain the condensation
products in good yield in a reduced reaction time when
the reaction is slow.
We chose S-ethyl 3-oxo-3-phenylbutanethioate and
isobutyraldehyde as model substrates and screened
reaction conditions in detail. First of all, the catalyst
was examined, and the traditional ammonium ion-
based reagents such as ethylenediammonium diacetate6
were found to be more effective than Lewis acid cata-
lysts.7 Next, the dehydrating reagent and solvent were
investigated. The results are summarized in Table 2.
For molecular sieves the pave size affected the yield
considerably, and MS 5A was found to be the most
effective. Dichloromethane was the solvent of choice.
Thus, when the reaction was performed in the presence
of MS 5A and 10 mol% of ethylenediammonium diac-
etate in CH2Cl2 at rt for 6 h, the Knoevenagel adduct
was obtained in good yield (92%) with high E-selectiv-
ity (E:Z=91:9, entry 9).8 Under the same reaction
conditions, however, the reaction of the corresponding
b-ketoester, ethyl 3-oxo-3-phenylbutanoate, was slow,
affording the condensation product in moderate yield
(68%) with the same E/Z selectivity (E:Z=90:10, entry
10). Since the superiority of the b-ketothioester as a
Knoevanagel donor over the b-ketoester was confirmed
in this model reaction, the generality of this finding was
examined using several b-ketothioesters and b-
ketoesters with various aldehydes, and these results are
summarized in Table 3.9
When the b-substituent of the thioester or ester is small
(methyl), there is little difference in reactivity between
the two derivatives and both afford the adducts in good
yields, in short reaction time (3 h), as shown by the
reactions of S-ethyl 3-oxobutanethioate and methyl
3-oxobutanoate (entries 1 and 2). When the substituent
at the b-position is large, on the other hand, a marked
E/Z-selectivity is mostly dependent on the substituent
at the b-position, and differed little between b-keto-
thioester and b-ketoester. Low selectivity is observed in
the reactions of both derivatives when the b-substituent
is an alkyl group such as methyl, i-propyl and cyclo-
hexyl, while high E-selectivity is obtained with g,d-
unsaturated and b-aryl b-keto derivatives. The
bulkiness of the substituent on sulfur has a little effect
on selectivity; better Z-selectivity was observed in the
reaction of the S-tert-butyl thioester compared with
that of the S-ethyl thioester (entries 3 and 4).
Table 2. Knoevenagel reaction of b-ketothioester and
isobutyraldehydea
The Knoevenagel reaction consists of two reactions:
The first is the addition of an enolate of an active
methylene compound to an aldehyde, and an elimina-
tion of water is the next reaction.3 The high reactivity
of b-ketothioesters in comparison to b-ketoesters could
be explained as follows: (1) Because of the longer
atomic radius of sulfur than oxygen, there is less steric
repulsion in the reactions of a b-ketothioester, making
it more reactive as a Knoevenagel donor. (2) As the
HOMO level of a vinylsulfide is higher than that of a
vinylether,10 an enolate of a b-ketothioester is expected
to be more reactive than that of a b-ketoester. This is
why the first step becomes more feasible in the reaction
of a b-ketothioester. (3) As the a-proton of a thioester
is more acidic than that of an ester, the second reaction
of an elimination of water becomes fast in the reaction
of a b-ketothioester. At present we were not sure which
effect is predominant in causing the higher reactivity of
b-ketothioesters.
Entry
R
Solvent
Additiveb
Yield (%)c
E:Zd
1
2
3
4
5
6
7
8
9
SEt
SEt
SEt
SEt
SEt
SEt
SEt
SEt
SEt
OEt
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
MeOH
THF
–
54
55
64
78
23
58
35
47
92
68
92:8
92:8
92:8
91:9
89:11
92:8
90:10
91:9
91:9
90:10
MS 3A
MS 4A
MS 5A
MS 13X
CaSO4
MS 5A
MS 5A
MS 5A
MS 5A
CH2Cl2
CH2Cl2
10
a Ethylenediammonium diacetate (10 mol %) was used as an acid
catalyst and 2 equiv. of the aldehyde was used.
b 0.2 g of additive was used per 1 mmol of the ester.
c Isolated yield.
d The E:Z ratio was determined by 1H NMR.

Y. Hayashi et al. / Tetrahedron Letters 43 (2002) 4079–4082
4081
Table 3. Knoevenagel reaction of b-ketothioester and b-ketoester with various aldehydesa
O
O
10 mol% H+, MS 5A
CH2Cl2, rt
O
O
R3CHO
X eq
+
R1
R3
R2
R1
R2
1.0 eq
Entry
R1
R2
R3
X (equiv.)
Time (h)
Yieldb (%)
E:Zc
1
2
3
4
5
6
7
8
Me
Me
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
SEt
OMe
S-t-Bu
SEt
OEt
SEt
OEt
SEt
SEt
OMe
SEt
OMe
SEt
i-Pr
i-Pr
Ph
Ph
Ph
i-Pr
i-Pr
Et
Et
Et
2.0
2.0
4.0
4.0
4.0
4.0
4.0
4.0
1.5
4.0
4.0
4.0
4.0
4.0
3
3
77
72
82
89
67
56
20
78
79
30
89
36
86
57
66:34
65:35
33:67
51:49
63:37
54:46
62:38
54:46
54:46
56:44
66:34
48:52
58:42
62:38
24
10
10
16
16
10
22
10
10
10
10
10
9
10
11
12
14
15
i-Pr
i-Pr
Ph
OMe
Ph
PMBO
Me
PMBO
16
17
Cyclohexyl
Cyclohexyl
SEt
1.5
1.5
5
5
76
58:42
OMe
B5
–
Me
18
19
20
21
22
23
24
25
1-Methyl-1-propenyl
1-Methyl-1-propenyl
1-Methyl-1-propenyl
1-Methyl-1-propenyl
1-Methyl-1-propenyl
1-Methyl-1-propenyl
Ph
SEt
OMe
SEt
OMe
SEt
OMe
SEt
Et
Et
i-Pr
i-Pr
Ph
Ph
i-Pr
i-Pr
6.0
6.0
6.0
6.0
4.0
4.0
2.0
2.0
110
110
110
110
18
18
6
6
72
12
84
40
94
30
92
68
96:4
95:5
96:4
94:6
\95:5
81:19
91:9
90:10
Ph
OEt
a Ethylenediammnonium diacetate was used as a catalyst.
b Isolated yield.
c The E:Z ratio was determined by 1H NMR.
In summary, we have shown that b-ketothioesters are
reactive Knoevenagel donors which react with various
aldehydes efficiently, affording the condensation prod-
ucts in good yield under mild reaction conditions. Since
the b-ketothioester are easily prepared,11 and the
thioester moiety of the Knoevenagel adduct can be
converted to several functional groups under mild reac-
tion conditions,12 the Knoevenagel reaction of b-
ketothioesters should prove to be a synthetically useful
carbonꢀcarbon double bond forming reaction.
References
1. Hayashi, Y.; Narasaka, K. Chem. Lett. 1998, 313.
2. Hayashi, Y.; Kanayama, J. manuscript in preparation.
3. Review, see: (a) Tietze, L. F.; Beifuss, U. In Comprehen-
sive Organic Synthesis; Trost, B. M., Ed.; Pergamon
Press: Oxford, 1991; Vol. 2, 341; (b) Jones, G. Org.
React. 1967, 15, 204.
4. Though the combination of TiCl4 and a tert-amine is a
powerful Knoevenagel reaction promoter, this method
cannot be used in the synthesis of epolacataene because
of the labile triene moiety: Lehnert, W. Synthesis 1974,
667.
Acknowledgements
5. There is a report using b-ketothioester and b-ketoester as
a Knoevenagel donor, but there is no description con-
cerning the reactivity between these two esters. Moorhoff,
C. M. Synthesis 1997, 685.
This research was supported by the Sumitomo Founda-
tion and a Grant-in-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science and
Technology, Japan.

4082
Y. Hayashi et al. / Tetrahedron Letters 43 (2002) 4079–4082
6. Tietze, L. F.; Kiedrowski, G. V. Tetrahedron Lett. 1981,
succession ethylenediammonium diacetate (4.4 mg, 0.024
mmol) and molecular sieves 5 A (48.0 mg). After the
reaction mixture had been stirred for 18 h at room
temperature, the reaction was quenched by the addition
of aq. NaHCO3 (5 mL). After removal of molecular
sieves by filtration, the organic materials were extracted
with ethyl acetate and dried over anhydrous Na2SO4,
and concentrated in vacuo after filtration. Purification
by TLC (Et2O:hexane=1:3) gave 59.5 mg (94%) of S-
ethyl 2-benzylidene-4-methyl-3-oxo-4-hexenethiolate.
10. Narasaka, K.; Hayashi, Y.; Shimadzu, H.; Niihata, S. J.
Am. Chem. Soc. 1992, 114, 8869.
219.
7. The reaction scarcely proceeded in the presence of 10
mol% of the following Lewis acid; BF3·OEt2, AlCl3,
ZnI2, SnCl2, MgCl2, ZrCl4, Sn(OTf)2, Lu(OTf)3,
Dy(OTf)3, and Yb(OTf)3. The Knoevenagel product was
obtained in 30% yield in the presence of Sc(OTf)3 at
50°C for 16 h.
8. The stereochemistry was determined by observation of
the following NOEs in the NOESY spectrum of the
alcohol prepared by reduction of the condensation
product with NaBH4–CeCl3.
11. b-Ketothioesters were prepared by the aldol reaction
between aldehydes and S-ethyl acetothioate followed by
oxidation with the Dess–Martin periodinane.
O
O
O
OH
Ph
NaBH4-CeCl3
MeOH
Ph
SEt
SEt
H
H
NOE
Me
12. (a) Booth, P. M.; Broughton, H. B.; Ford, M. J.; Fox,
C. M. J.; Ley, S. V.; Slawin, A. M. Z.; Williams, D. J.;
Woodward, P. R. Tetrahedron 1989, 45, 7565; (b)
Booth, P. M.; Fox, C. M. J.; Ley, S. V. J. Chem. Soc.,
Perkin Trans. 1 1987, 121; (c) Ley, S. V.; Woodward, P.
R. Tetrahedron Lett. 1987, 28, 3019.
Me
Me
Me
9. A typical experimental procedure is as follows (Table 3,
entry 22): To a CH2Cl2 solution (0.60 mL) of S-ethyl
4-methyl-3-oxo-4-hexenethiolate (45.0 mg, 0.242 mmol)
and benzaldehyde (98 mL, 0.97 mmol) were added in