2
706
H. Hagiwara et al. / Tetrahedron Letters 42 (2001) 2705–2707
Table 1. Optimization of reaction condition in the conju-
gate addition of citronellal 6 to MVK 4
Table 2. Conjugate addition of various aldehyde 1 to
MVK 4
Entrya
Solvent
Amount of
amine
Product 7
Entrya
Aldehyde 1
Product 5 Yield (%)
Toluene
(
equiv.)
THF
Time (h)
Yield (%)
1
2
3
4
5
6
R=CH
R=i-Pr
R=PhCH
R=AcOC
R=THPOC
R=TBSOC
3
(CH
2
)
7
73
28
62
47
30
60
80 (83)
76
1
2
CH CN
–
0.1
1.0
0.2
0.1
0.1
0.1
0.1
0.2
0.2
0.2
0.2
50
23
5
66
28 (37)
2
3
b
c
61 (63)b
55 (73)b
–
b
H
8
16
d
e
3
4
5
CH CN
7
H
3 6
3
n-Hexane
THF
16
19
15.5
16.5
41
16
24
25
10f
8
H
16
75
c
43 (66)
45 (65)
50 (55)
73
29 (59)
87
a
6
7
CH Cl2
Reaction was carried out with 1.5 equiv. of MVK in the presence of
0.2 equiv. of Et NH at 80°C for 16 h in a sealed tube.
Yield in parentheses based on starting material consumed.
2
c
CH CN
2
3
b
8
9
CH CN
3
g
c
c
Toluene
Toluene
Toluene
1
1
0
1
h
The pathway of the present reaction is discussed as
45 (80)
follows. When the reaction of citronellal 6 with MVK 4
a
in toluene was carried out in the presence of 4 A
,
Reaction was carried out with 1.5 equiv. of MVK 4 at 80°C in a
sealed tube.
Reaction was carried out in an open vessel.
Yield in parentheses was based on starting material consumed.
Pyrrolidine was used.
molecular sieves powder, the yield of the 5-keto alde-
hyde 7 decreased to 45% along with 44% of recovered 6
(Table 1, entry 11). When diethylamino–enamine 9 was
b
c
d
e
f
1a
prepared according to the literature procedure it was
Citronellal 6 decomposed.
quite unstable and partially hydrolyzed to a mixture of
the enamine 9, decanal 8 and DEA (1:0.85:0.70) during
NMR measurement. Freshly distilled enamine 9 (0.1
equiv.) was added to the mixture of decanal 8 and
MVK 4 in MeCN. The resulting solution was heated at
reflux for 8 h to afford 1,4-conjugate addition product
Citronellal 6 could not be separable from by product.
Reaction was carried out at 130°C.
,
Reaction was carried out in the presence of 4 A sieves.
g
h
heating the toluene solution of the substrates with 0.2
equiv. of DEA at 80°C overnight in a sealed tube. After
the reaction, evaporation of the solvent in vacuo fol-
lowed by purification by medium-pressure liquid chro-
matography provided 5-keto aldehyde 7 as a 1:1
diastereomeric mixture (NMR). No aqueous work-up
was required.
1
0 in 74% yield, as shown in Scheme 3. These results
suggest that the present reaction proceeds via in situ
generated diethylamino–enamine 9 which drives the
catalytic cycle to turn around in the presence of water
4
as a mediator. Pyrrolidino–enamine of decanal 8 (0.1
equiv.) also gave the 5-keto aldehyde 10 in 90% yield.
Similarly, pyrrolidino–enamine of citronellal 6 (0.1
equiv.) provided the 5-keto aldehyde 7 in 91% yield.
Some representative examples of the present conjugate
addition of various naked aldehydes are shown in Table
2
. Taking the economy of the reaction into consider-
Substituted 5-keto aldehydes 5, thus obtained, have
been important synthons especially for substituted 2-
cyclohexenone derivatives which have been widely uti-
lized as starting materials for a variety of natural and
ation, toluene or THF was employed as a solvent. In
entry 2, the yield was low because of the volatile nature
of the product. It is noteworthy that the reaction
conditions were so mild that the acid-sensitive THP or
TBS, and the base-sensitive acetyl protecting group
survived. Not only MVK, but also 1-penten-3-one,
6
unnatural compounds. Cyclohexenone 13 was isolated
from Stevia purpurea, and its antipode has already been
7
synthesized by Jefferies et al. thereby correcting its
3
-methyl-3-buten-2-one and methyl acrylate with cit-
ronellal 6 provided the conjugate addition product in
4, 10 and 7% yield, respectively. On the other hand, in
absolute stereochemistry (Scheme 4). The 5-keto alde-
hyde 7 was transformed into the cyclohexenone 13 as a
1:1 diastereomeric mixture by a modified synthetic
sequence in 64% overall yield. After medium-pressure
LC separation, the less polar cyclohexenone 13 exhib-
ited the same NMR spectral data as well as the optical
7
the reaction of decanal 8 with cyclopentenone or vinyl-
sulfoxide the aldehyde 8 was recovered. The present
1
,4-conjugate addition was selective to contaminate no
5
self aldol condensation product of aldehyde except in
rotation of the natural 13 {[h]D −46° (c 3.1, CHCl3),
6
the reaction of methyl acrylate with decanal 8.
lit. [h]D −37° (c 3.7, CHCl )}.
3
O
O
CH CN
3
NEt2
CH (CH ) CH CHO
+
+
3
2 7
2
C H
8 17
reflux
4%
CHO
CH (CH )
7
3
2 7
9
(0.1 eq)
8
4
10
Scheme 3.