Novel Kn?evenagel-type reaction via titanium enolate derived from Ti(O-i-Pr)4 and diketene

Article abstract of DOI:10.1016/j.tet.2004.06.018

Kn?evenagel-type reaction between diketene and aldehydes proceeded in the presence of Ti(O-i-Pr)₄. This reaction proceeded via titanium enolate derived from Ti(O-i-Pr)₄ and diketene. As for the stereoselectivity of the products, E-is

Full text of DOI:10.1016/j.tet.2004.06.018

Tetrahedron 60 (2004) 6777–6783
¨
Novel Knoevenagel-type reaction via titanium enolate derived
from Ti(O-i-Pr)4 and diketeneq
*
Masahiko Hayashi, Norihiro Nakamura and Kohei Yamashita
Department of Chemistry, Faculty of Science, Kobe University, Nada, Kobe 657-8501, Japan
Received 14 May 2004; revised 5 June 2004; accepted 7 June 2004
¨
Abstract—Knoevenagel-type reaction between diketene and aldehydes proceeded in the presence of Ti(O-i-Pr)4. This reaction proceeded
via titanium enolate derived from Ti(O-i-Pr)4 and diketene. As for the stereoselectivity of the products, E-isomers were produced
predominantly in the case of aromatic aldehydes.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Ti(O-i-Pr)4-promoted reaction of diketene with aldehydes,
we found that a change of the order of addition of the
reagents afforded different products (Eqs. (2) and (3)). That
is, 5-hydroxy-3-ketoesters 1 were obtained when diketene
was added to the mixture of aldehydes and Ti(O-i-Pr)4 in
CH2Cl2. On the other hand, when diketene and Ti(O-i-Pr)4
were mixed in advance and the mixture was stirred for 3 h,
subsequent addition of aldehydes to the reaction mixture
¨
The Knoevenagel reaction is a classical and well-known
reaction as a condensation between carbonyl compounds
and activated methylene compounds catalyzed by amines.1
As activated methylene compounds, alkyl acetoacetates and
dialkyl malonates have been often used.
¨
gave Knoevenagel reaction products 2.
In 1994, we reported that the reaction of diketene with
aldehydes was promoted by Ti(O-i-Pr)4 and demonstrated
the first example of an asymmetric version of this reaction.
That is, chiral Schiff base-titanium alkoxide complexes
promoted the enantioselective reaction of diketene to
aldehydes which leads to the asymmetric synthesis of
optically active 5-hydroxy-3-ketoesters (Eq. (1)).2 This
reaction was applied to asymmetric synthesis of potential
inhibitors of HMG coenzyme reductase.3
ð2Þ
ð3Þ
Since a mixture of 1 and 2 was obtained when aldehydes
were added instantly after diketene and Ti(O-i-Pr)4 were
mixed, the stirring time of 3 h is important for the reaction
of Eq. (3). The titanium enolate species were considered to
be generated from Ti(O-i-Pr)4 and diketene as intermediate.
The reaction of titanium enolates prepared from titanium
reagents/amine system with electrophiles such as alkyl
halides and aldehydes has been well studied,4 but to our
ð1Þ
2. Results and discussion
During the course of our study of the reaction mechanism of
q Supplementary data associated with this article can be found in the online
version, at doi: 10.1016/j.tet.2004.06.018.
¨
knowledge, few examples of this type of Knoevenagel
reaction using diketene were reported so far.5,6 In this paper,
we would like to report the details of a new type of
¨
Keywords: Knoevenagel reaction; Titanium enolate; Diketene.
*
¨
Knoevenagel reaction via titanium enolate derived from
Ti(O-i-Pr)4 and diketene.
Corresponding author. Tel.: þ81-78-803-5687; fax: þ81-78-803-5688;
e-mail address: mhayashi@kobe-u.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.018

6778
M. Hayashi et al. / Tetrahedron 60 (2004) 6777–6783
Table 1. Effect of the ratio of Ti(O-i-Pr)4 and diketene on the chemical yield of the producta
Entry
Ti(O-i-Pr)4/equiv
Diketene/equiv
Conditions
Product
Temp/8C
Time/h
% Yield (E/Z)b
1
2
3
1
2
1
1
1
2
20
25
24
48
43
44
34 (88/12)
68 (89/11)
0 (–)
a
1.0 equiv. of PhCHO was used.
E/Z ratio was determined by 1H NMR analysis.
b
At first, we examined the effect of the ratio of Ti(O-i-Pr)4
and diketene on the chemical yield of the product (Table 1).
As shown in Table 1, the ratio of Ti(O-i-Pr)4, diketene and
benzaldehyde in 2:1:1 afforded the product in highest yield
(68%). However, when 2.0 equiv of diketene was used, no
product was obtained. To understand these results and to
confirm the generation of titanium enolate, we measured the
1H NMR spectra of mixtures of Ti(O-i-Pr)4 and diketene in
a variety of ratios (Figs. 1–3).
1:1 enolate, 31% of 1:2 enolate and 47% of Ti(O-i-Pr)4. The
ratio of 1:1 enolate, 1:2 enolate and Ti(O-i-Pr)4 was
calculated by integration of five methine proton peaks in
isopropoxide moiety which appeared in the region of
4.9–4.5 ppm in Figure 1. The geometry of titanium enolate
was determined by NOE experiment (see supplementary
information).
1
Figure 2 shows the H NMR spectrum of the mixture of
Ti(O-i-Pr)4 and diketene in a ratio of 1:2 in CDCl3 after 6 h.
The peaks of Ti(O-i-Pr)4 were completely diminished. The
product distribution was found to be 26% of 1:1 enolate, 74%
of1:2enolateand26% ofdiketene. Ti(O-i-Pr)4 didnotremain.
1
Figure 1 shows the H NMR spectrum of the mixture of
Ti(O-i-Pr)4 and diketene in a ratio of 1:1 in CDCl3 after
3.5 h. The generated species were assumed as titanium
enolate 3b with a double bond at the internal site of the
isopropyl acetoacetate moiety. The peaks which appeared in
4.9 ppm of 1H NMR and in 92 ppm of the 13C NMR spectra
should indicate the presence of double bond of internal
titanium enolate. It should be noted that the peaks of Ti(O-i-
Pr)4 remained, although diketene disappeared completely in
the reaction mixture. This result thus indicates that the
diketene does not only react with Ti(O-i-Pr)4 in a ratio of
1:1, but also reacts in the 1:2 ratio. We presumed that each
peak of 1:1 and 1:2 enolates would be the same chemical
shift value. When Ti(O-i-Pr)4 was mixed with diketene in a
ratio of 1:1, the product distribution was found to be 22% of
1
Furthermore, Figure 3 shows the H NMR spectrum of the
mixture of Ti(O-i-Pr)4 and diketene in a ratio of 2:1 after
2.5 h which afforded the products in 5% of 1:1 enolate, 19%
of 1:2 enolate and 76% of Ti(O-i-Pr)4.
¨
A possible mechanism of the Knoevenagel-type reaction via
titanium enolate is illustrated in Scheme 1. The titanium
enolate 3a which has a double bond at the terminal site of the
isopropyl acetoacetate moiety should be first generated from
Ti(O-i-Pr)4 and diketene. However, it will immediately
isomerize to the internal titanium enolate 3b. Therefore, the
1
Figure 1. H NMR spectrum of the mixture of Ti(O-i-Pr)4 and diketene in the ratio of 1:1.

M. Hayashi et al. / Tetrahedron 60 (2004) 6777–6783
6779
Figure 2. 1H NMR spectrum of the mixture of Ti(O-i-Pr)4 and diketene in the ratio of 1:2.
Figure 3. 1H NMR spectrum of the mixture of Ti(O-i-Pr)4 and diketene in the ratio of 2:1.
Scheme 1.
terminal titanium enolate 3a was not observed by 1H NMR.
Subsequent reaction of internal titanium enolate 3b with
¨
aldehydes produces Knoevenagel reaction products. When
free Ti(O-i-Pr)4 did not exist in the mixture (Fig. 2), the
that the presence of free Ti(O-i-Pr)4 is necessary should
indicate that titanium enolate 3b itself has not enough
reactivity to react with aldehydes. The activation of
aldehyde by Ti(O-i-Pr)4 will be required. We consider that
the 1:1 enolate would be more reactive than 1:2 enolate.
reaction did not proceed at all (entry 3 in Table 1). The fact

6780
M. Hayashi et al. / Tetrahedron 60 (2004) 6777–6783
Table 2. Reaction of titanium enolate with a variety of aldehydesa
Entry
Aldehyde
Conditions
Product
Conventional Knoevenagel conditionb
Temp/8C
Time/h
% Yield (E/Z)c
% Yield (E/Z)c
1
2
3
4
5
C6H5CHO
28
21
21
21
21
48
46
48
48
6
2a 79 (91/9)
2b 77 (96/4)
2c 70 (94/6)
2d 62 (91/9)
2e 76 (60/40)
48 (31/69)
70 (40/60)
62 (36/64)
54 (37/63)
73 (35/65)
p-ClC6H4CHO
p-MeC6H4CHO
p-MeOC6H4CHO
6
7
C6H11CHO
22
21
17
5
2f 80 (60/40)
2g 90 (31/69)
80 (35/65)
36 (35/65)
8
22
22
2h 70 (33/67)
46 (48/52)
a
The ratio of diketene: Ti(O-i-Pr)4:aldehyde was 1:2:1.
The ratio of isopropyl acetoacetate:aldehyde:piperidine was 1:1:0.1.
E/Z ratio was determined by the integration of vinylic proton in the compounds 2a–2h by 1H NMR analysis.
b
c
¨
1:1:2 gave Knoevenagel product 2 (59%) in the E/Z ratio of
97.3 (Eq. (4)).
Aiming at improvement of chemical yield and stereo-
selectivity, we examined solvents suitable for this reaction.
As a result, it was found that toluene was a suitable solvent
for this reaction.
A variety of aldehydes were employed in the reaction with
titanium enolate (Table 2). Generally, aliphatic aldehydes
exhibited higher reactivity than aromatic aldehydes. As for
the geometry of the products, the reaction of aromatic
aldehydes (entries 1–4) afforded E-geometrical isomers
ð4Þ
predominantly, which was in sharp contrast with the
7
conventional Knoevenagel reaction. The configurations
¨
¨
In conclusion, the present Knoevenagel reaction has the
of E and Z were identified by NOE experiment (see
supplementary information). That is, when benzaldehyde
was treated with isopropyl acetoacetate in the presence
of piperidine, mixtures of E- and Z-isomers (31/69) were
obtained.
following characteristic features. (1) Alkyl acetoacetate is
not used, but diketene was used as the C-4 unit source. (2)
The reaction takes place not under basic conditions like
the conventional Knoevenagel reaction, but proceeds under
mild acidic conditions. (3) The stereoselectivity of the
double bond of the products was in contrast to the
¨
On the other hand, in the cases of aliphatic aldehydes, the
mixtures of E- and Z-isomers were obtained in different
ratio in each aldehyde. The reaction of cinnamaldehyde and
cyclohexanecarboxaldehyde furnished the E-isomer prefer-
entially (60/40), but that of n-butanal and 3-phenyl
propionaldehyde produced the Z-isomer preferentially
(31/69 and 33/67, respectively). When we traced the
¨
conventional Knoevenagel reaction. Especially, in the case
of aromatic aldehydes, E-isomers were produced
exclusively.
3. Experimental
1
reaction by H NMR, the ratio of E/Z isomers was not
changed during the reaction. Furthermore, we confirmed
that it took 6–18 h to reach equilibrium (thermodynamic)
ratio even at high temperature (90 8C) in the case of a
cyclohexane derivative.8 Although the detailed mechanism
of this reaction including stereoselectivity is unclear, we
consider that the reactivity of aldehydes affects the
selectivity.
3.1. General methods
All melting points were measured on a Yanaco MP-500D
and uncorrected. 1H and 13C NMR spectra (400 and
100.6 MHz, respectively) were recorded on a JEOL JNM-
GX 400 by use of CDCl3 containing TMS as the internal
standard. IR spectra were measured on a HITACHI I-2000.
Elemental analyses were performed on a Yanaco CHN
Corder MT-5. Mass spectra were taken on a Shimadzu
GCMS-QP 2000A. Thin-layer chromatography (TLC) was
carried out on foil plates, Silica Gel 60 F254 (E. Merck;
layer thickness 0.2 mm). Preparative column chroma-
tography was carried out on Fuji Silysia BW-820MH.
Finally, we found that when isopropyl acetoacetate was
used as substrate instead of diketene, titanium enolate
species were also generated from Ti(O-i-Pr)4 and isopropyl
acetoacetate. The reaction of isopropyl acetoacetate and
benzaldehyde in the presence of Ti(O-i-Pr)4 in the ratio of

M. Hayashi et al. / Tetrahedron 60 (2004) 6777–6783
6781
¨
3.2. Typical procedure for the Knoevenagel type
reaction via titanium enolate
(22%), 131 (47%), 103 (31%), 77 (22%), 43 (100%); Anal.
Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.43; H,
7.06.
A mixture of Ti(O-i-Pr)4 2.95 mL (10 mmol) and toluene
5 mL was placed in a Shlenk tube under argon atmosphere.
To this solution, diketene 0.39 mL (5 mmol) was added and
stirred at 0 8C for 3 h. Then, benzaldehyde 0.51 mL
(5 mmol) was added and the mixture was stirred at room
temperature for 48 h. After the reaction mixture was poured
into 1 N HCl and vigorously stirred at 0 8C for 1 h, it was
extracted by ethyl acetate and the extract was washed with
sodium bicarbonate and brine solution. The organic layer
was dried with anhydrous sodium sulfate and evaporated.
An aliquot for 1H NMR measurement to determine the E/Z
ratio was removed. After purification by silica-gel column
chromatography (50:1 hexane–ethyl acetate), isopropyl
2-acetyl-3-phenyl-2-propenoate (2) 926.9 mg (79%) was
obtained in the E/Z ratio of 91/9.
3.4.2. (Z)-Isopropyl 2-acetyl-3-phenyl-2-propenoate ((Z)-
2a). Rf¼0.32 (5:1 hexane–ethyl acetate); IR (KBr, nmax
1
(cm21)): 1728, 1666, 1620; H NMR: d 7.56 (s, 1H), 7.5–
7.4 (m, 5H), 5.3–5.2 (m, 1H), 2.42 (s, 3H), 1.27 (d, J¼
6.0 Hz, 6H); 13C NMR: d 194.5, 167.3, 140.8, 135.0, 133.1,
130.6, 129.6, 128.7, 69.5, 26.6, 21.5; MS m/z (relative
intensity): 232 (26%), 189 (36%), 173 (17%), 131 (28%),
103 (18%), 77 (12%), 43 (100%); Anal. Calcd for
C14H16O3: C, 72.39; H, 6.94. Found: C, 72.22; H, 7.02.
3.4.3. (E)-Isopropyl 2-acetyl-3-(p-chlorophenyl)-2-pro-
penoate ((E)-2b). Rf¼0.51 (5:1 hexane–ethyl acetate);
IR (KBr, nmax (cm21)): 1705, 1627, 1589; 1H NMR: d 7.57
(s, 1H), 7.34 (s, 4H), 5.2–5.1 (m, 1H), 2.35 (s, 3H), 1.31 (d,
J¼6 Hz, 6H); 13C NMR: d 202.9, 163.6, 138.6, 136.3,
135.0, 131.3, 130.8, 129.0, 69.3, 31.0, 21.6; MS m/z
(relative intensity): 266 (10%), 231 (4%), 223 (6%), 209
(25%), 165 (18%), 43 (100%); Anal. Calcd for C14H15O3Cl:
C, 63.04; H, 5.67. Found: C, 63.07; H, 5.74.
¨
3.3. Typical procedure for the conventional Knoevenagel
reaction catalyzed by piperidine
A mixture of isopropyl acetoacetate 0.77 mL (5 mmol),
benzaldehyde 0.51 mL (5 mmol), and toluene 5 mL was
placed in a Shlenk tube under argon atmosphere. To this
solution, piperidine 0.05 mL (0.5 mmol) was added and
stirred at room temperature for 48 h. After the reaction
mixture was poured into 1 N HCl and vigorously stirred at
0 8C for 1 h, it was extracted by ethyl acetate and extract
was washed with sodium bicarbonate and brine solution.
Organic layer was dried with anhydrous sodium sulfate and
evaporated. An aliquot for 1H NMR measurement to
determine the ratio of E- and Z-isomers was removed.
After purification by silica-gel column chromatography
(50:1 hexane–ethyl acetate), isopropyl 2-acetyl-3-phenyl-2-
propenoate (2) 556.8 mg (48%) was obtained in the E/Z
ratio of 35/65.
3.4.4. (Z)-Isopropyl 2-acetyl-3-(p-chlorophenyl)-2-pro-
penoate ((Z)-2b). Rf¼0.32 (5:1 hexane–ethyl acetate);
mp 49.0–51.0 8C; IR (KBr, nmax (cm21)): 1736, 1666,
1
1620, 1589, H NMR: d 7.49 (s, 1H), 7.41 (d, J¼8.4 Hz,
2H), 7.36 (d, J¼8.4 Hz, 2H), 5.3–5.2 (m, 1H), 2.41 (s, 3H),
1.28 (d, J¼6.4 Hz, 6H), 13C NMR: d 194.0, 167.5, 139.0,
136.7, 135.3, 131.5, 130.8, 129.0, 69.9, 26.0, 21.4; MS m/z
(relative intensity): 266 (5%), 231 (3%), 209 (13%), 189
(14%), 165 (12%), 43 (100%); Anal. Calcd for C14H15O3Cl:
C, 63.04; H, 5.67. Found: C, 63.04; H, 5.67.
3.4.5. (E)-Isopropyl 2-acetyl-3-(p-methylphenyl)-2-pro-
penoate ((E)-2c). Rf¼0.50 (5:1 hexane–ethyl acetate); IR
1
(KBr, nmax (cm21)): 1705, 1620, H NMR: d 7.61 (s, 1H),
3.4. Reaction of benzaldehyde with isopropyl
acetoacetate promoted by Ti(O-i-Pr)4 (Eq. (4))
7.29 (d, J¼8.4 Hz, 2H), 7.17 (d, J¼8.4 Hz, 2H), 5.2–5.1 (m,
1H), 2.36 (s, 6H), 1.31 (d, J¼6.4 Hz, 6H); 13C NMR: d
203.7, 164.1, 140.9, 140.3, 133.5, 130.2, 129.8, 129.6, 69.1,
31.2, 21.8, 21.4; MS m/z (relative intensity): 246 (7%), 189
(47%), 145 (24%), 115 (25%), 43 (100%); Anal. Calcd for
C15H18O3: C, 73.15; H, 7.37. Found: C, 72.99; H, 7.51.
A mixture of isopropyl acetoacetate 0.77 mL (5 mmol),
benzaldehyde 0.51 mL (5 mmol), and dichloromethane
5 mL was placed in a Shlenk tube under argon atmosphere.
To this solution, Ti(O-i-Pr)4 2.95 mL (10 mmol) was added
and stirred at room temperature for 47 h. After the reaction
mixture was poured into 1 N HCl and vigorously stirred at
0 8C for 1 h, it was extracted by ethyl acetate and the extract
was washed with sodium bicarbonate and brine solution.
The organic layer was dried with anhydrous sodium sulfate
3.4.6. (Z)-Isopropyl 2-acetyl-3-(p-methylphenyl)-2-pro-
penoate ((Z)-2c). Rf¼0.34 (5:1 hexane–ethyl acetate); IR
(KBr, nmax (cm21)): 1728, 1666, 1604; 1H NMR: d 7.51 (s,
1H), 7.38 (d, J¼8 Hz, 2H), 7.18 (d, J¼8 Hz, 2H), 5.3–5.2
(m, 1H), 2.39 (s, 6H), 1.29 (d, J¼6.4 Hz, 6H); 13C NMR: d
194.6, 167.6, 141.3, 140.8, 134.0, 130.1, 129.8, 129.5, 69.4,
26.5, 21.5; MS m/z (relative intensity): 189 (88%), 145
(37%), 115 (35%), 43 (100%); Anal. Calcd for C15H18O3:
C, 73.15; H, 7.37. Found: C, 73.43; H, 7.51.
1
and evaporated. An aliquot for H NMR measurement to
determine the E/Z ratio was removed. After purification by
silica-gel column chromatography (50:1 hexane–ethyl
acetate), isopropyl 2-acetyl-3-phenyl-2-propenoate (2)
685.2 mg (59%) was obtained in the E/Z ratio of 93/7.
3.4.7. (E)-Isopropyl 2-acetyl-3-(p-methoxylphenyl)-2-
propenoate ((E)-2d). Rf¼0.34 (5:1 hexane–ethyl acetate);
3.4.1. (E)-Isopropyl 2-acetyl-3-phenyl-2-propenoate
((E)-2a). Rf¼0.51 (5:1 hexane–ethyl acetate); mp 42.6–
1
IR (KBr, nmax (cm21)): 1705, 1605; H NMR: d 7.58 (s,
1
43.6 8C; IR (KBr, nmax (cm21)): 1704, 1620; H NMR: d
1H), 7.36 (d, J¼8.4 Hz, 2H), 6.88 (d, J¼8.4 Hz, 2H), 5.3–
5.2 (m, 1H), 3.83 (s, 3H), 2.37 (s, 3H), 1.31 (d, J¼6.4 Hz,
6H); 13C NMR: d 203.9, 164.3, 161.4, 140.0, 131.8, 131.7,
125.6, 114.4, 69.0, 55.4, 31.2, 21.8; MS m/z (relative
intensity): 262 (9%), 231 (15%), 189 (36%), 145 (12%), 43
7.64 (s, 1H), 7.4–7.3 (m, 5H), 5.2–5.1 (m, 1H), 2.35 (s,
3H), 1.32 (d, J¼6.0 Hz, 6H); 13C NMR: d 203.8, 163.9,
140.0, 134.2, 133.0, 130.4, 129.8, 128.9, 69.0, 31.6, 21.8;
MS m/z (relative intensity): 232 (42%), 189 (62%), 173

6782
M. Hayashi et al. / Tetrahedron 60 (2004) 6777–6783
(100%); Anal. Calcd for C15H18O4: C, 68.69; H, 6.92.
Found: C, 68.52; H, 6.97.
1.6–1.5 (m, 2H), 1.29 (d, J¼6.0 Hz, 6H), 0.90 (t, J¼7.6 Hz,
3H); 13C NMR: d 201.2, 164.1, 148.4, 135.0, 68.8, 31.3,
31.1, 21.9, 21.8, 13.8; MS m/z (relative intensity): 198 (1%),
156 (13%), 137 (26%), 96 (44%), 43 (100%); Anal. Calcd
for C11H18O3: C, 66.64; H, 9.15. Found: C, 65.26; H, 9.15.
3.4.8. (Z)-Isopropyl 2-acetyl-3-(p-methoxylphenyl)-2-
propenoate ((Z)-2d). Rf¼0.17 (5:1 hexane–ethyl acetate);
IR (KBr, nmax (cm21)): 1720, 1658, 1597; 1H NMR: d 7.49
(s, 1H), 7.45 (d, J¼8.8 Hz, 2H), 6.89 (d, J¼8.8 Hz, 2H),
5.3–5.2 (m, 1H), 3.84 (s, 3H), 2.39 (s, 3H), 1.31 (d,
J¼6.4 Hz, 6H); 13C NMR: d 194.6, 167.9, 161.7, 140.7,
132.6, 131.8, 125.3, 114.3, 69.2, 55.4, 26.5, 21.6; MS m/z
(relative intensity): 262 (5%), 231 (16%), 189 (37%), 145
(14%), 43 (100%); Anal. Calcd for C15H18O4: C, 68.69; H,
6.92. Found: C, 68.48; H, 6.99.
3.4.14. (Z)-Isopropyl 2-acetyl-2-hexenoate ((Z)-2g).
Rf¼0.44 (5:1 hexane–ethyl acetate); IR (KBr, nmax
1
(cm21)): 1728, 1674, 1635; H NMR: d 6.83 (t, J¼7.6 Hz,
1H), 5.3–5.2 (m, 1H), 2.31 (s, 3H), 2.29 (q, J¼7.6, 7.6 Hz,
2H), 1.5–1.4 (m, 2H), 1.32 (d, J¼6.0 Hz, 6H), 0.96 (t,
J¼7.6 Hz, 3H); 13C NMR: d 195.0, 166.1, 147.7, 137.5,
68.9, 31.7, 26.9, 21.7, 21.6, 13.8; MS m/z (relative
intensity): 156 (4%), 137 (2%), 96 (11%), 43 (100%);
Anal. Calcd for C11H18O3: C, 66.64; H, 9.15. Found: C,
65.81; H, 9.21.
3.4.9. (E,E)-Isopropyl 2-acetyl-5-phenyl-2, 4-pentadi-
enoate ((E)-2e). Rf¼0.53 (5:1 hexane–ethyl acetate); mp:
67.0–67.4 8C; IR (KBr, nmax (cm21)): 1689, 1604, 1574; 1H
NMR: d 7.50 (d, J¼7.6 Hz, 2H), 7.44 (d, J¼ 11.6 Hz, 1H),
7.4–7.3 (m, 3H), 7.30 (d, J¼15.2 Hz, 1H), 7.06 (d,
J¼15.2 Hz, 1H), 5.2–5.1 (m, 1H), 2.45 (s, 3H), 1.33 (d,
J¼6.4 Hz, 6H); 13C NMR: d 200.5, 164.9, 145.4, 144.8,
135.7, 132.4, 129.8, 128.9, 127.8, 123.5, 68.8, 31.2, 21.8;
MS m/z (relative intensity): 258 (8%), 215 (29%), 171
(22%), 128 (31%), 43 (100%); Anal. Calcd for C16H18O3:
C, 74.40; H, 7.02. Found: C, 74.31; H, 6.98.
3.4.15. (E)-Isopropyl 2-acetyl-5-phenyl-2-pentenoate
((E)-2h). Rf¼0.53 (5:1 hexane–ethyl acetate); IR (KBr,
1
nmax (cm21)): 1704, 1635, 1604; H NMR: d 7.3–7.2 (m,
5H), 6.92 (t, J¼7.6 Hz, 1H), 5.2–5.1 (m, 1H), 2.78 (t,
J¼7.6 Hz, 2H), 2.58 (q, J¼7.6, 7.6 Hz, 2H), 2.18 (s, 3H),
1.27 (d, J¼6.0 Hz, 6H); 13C NMR: d 208.0, 163.9, 147.2,
140.5, 136.3, 128.6, 128.4, 126.3, 68.8, 34.7, 31.1, 30.8,
21.7; MS m/z (relative intensity): 218 (8%), 200 (19%), 104
(7%), 91 (100%); Anal. Calcd for C16H20O3: C, 73.82; H,
7.74. Found: C, 73.59; H, 7.83.
3.4.10. (Z,E)-Isopropyl 2-acetyl-5-phenyl-2,4-pentadi-
enoate ((Z)-2e). Rf¼0.32 (5:1 hexane–ethyl acetate); IR
(KBr, nmax (cm21)): 1712, 1612, 1581; 1H NMR: d 7.49 (d,
J¼7.6 Hz, 2H), 7.42 (d, J¼11.6 Hz, 1H), 7.4–7.3 (m, 3H),
7.30 (d, J¼11.6 Hz, 1H), 7.09 (d, J¼14.8 Hz, 1H), 5.3–5.2
(m, 1H), 2.40 (s, 3H), 1.39 (d, J¼6.4 Hz, 6H); 13C NMR: d
195.5, 165.9, 145.5, 144.2, 135.7, 132.8, 129.9, 128.9,
127.7, 123.6, 69.0, 38.0, 21.9; MS m/z (relative intensity):
258 (6%), 215 (17%), 171 (15%), 128 (20%), 43 (100%);
Anal. Calcd for C16H18O3: C, 74.40; H, 7.02. Found: C,
74.31; H, 6.98.
3.4.16. (Z)-Isopropyl 2-acetyl-5-phenyl-2-pentenoate
((Z)-2h). Rf¼0.38 (5:1 hexane–ethyl acetate); IR (KBr,
1
nmax (cm21)): 1720, 1628; H NMR: d 7.3–7.2 (m, 5H),
6.83 (t, J¼7.6 Hz, 1H), 5.2–5.1 (m, 1H), 2.81 (t, J¼7.6 Hz,
2H), 2.65 (q, J¼7.6, 7.6 Hz, 2H), 2.29 (s, 3H), 1.31 (d,
J¼6.4 Hz, 6H); 13C NMR: d 195.0, 165.8, 146.6, 140.3,
137.6, 128.5, 128.2, 126.3, 67.0, 34.4, 31.4, 27.0, 21.7; MS
m/z (relative intensity): 260 (1%), 200 (15%), 104 (6%), 91
(81%), 43 (100%); Anal. Calcd for C16H20O3: C, 73.82; H,
7.74. Found: C, 73.59; H, 7.83.
3.4.11. (E)-Isopropyl 2-acetyl-3-cyclohexyl-2-propenoate
((E)-2f). Rf¼0.64 (5:1 hexane–ethyl acetate); IR (KBr, nmax
(cm21)): 1705, 1635; 1H NMR: d 6.69 (d, J¼10.8 Hz, 1H),
5.2–5.1 (m, 1H), 2.36 (s, 3H), 2.4–2.3 (m, 1H), 1.7–1.6 (m,
4H), 1.28 (d, J¼6.4 Hz, 6H), 1.3–1.2 (m, 6H); 13C NMR: d
201.4, 164.2, 152.5, 134.4, 68.7, 38.2, 31.9, 31.3, 25.6, 25.1,
21.7; MS m/z (relative intensity): 238 (3%), 195 (7%), 178
(26%), 135 (25%), 83 (12%), 43 (100%); Anal. Calcd for
C14H22O3: C, 70.56; H, 9.30. Found: C, 70.49; H, 9.49.
Acknowledgements
This research was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan. We are grateful to Dr.
Hideki Amii for valuable discussions.
3.4.12. (Z)-Isopropyl 2-acetyl-3-cyclohexyl-2-propenoate
((Z)-2f). Rf¼0.50 (5:1 hexane–ethyl acetate); IR (KBr, nmax
(cm21)): 1728, 1674, 1628; 1H NMR: d 6.62 (d, J¼10.0 Hz,
1H), 5.3–5.2 (m, 1H), 2.4–2.3 (m, 1H), 2.30 (s, 3H), 1.8–
1.7 (m, 4H), 1.32 (d, J¼6.4 Hz, 6H), 1.3–1.2 (m, 6H); 13C
NMR: d 195.4, 166.3, 152.0, 135.6, 68.8, 39.2, 31.8, 26.9,
25.6, 25.2, 21.8; MS m/z (relative intensity): 238 (1%), 195
(3%), 178 (26%), 135 (22%), 83 (9%), 43 (100%); Anal.
Calcd for C14H22O3: C, 70.56; H, 9.30. Found: C, 70.40; H,
9.39.
References and notes
1. Jones, G. Org. React. 1967, 15, 204–582.
2. (a) Hayashi, M.; Inoue, T.; Oguni, N. J. Chem. Soc., Chem.
Commun. 1994, 341–342. (b) Hayashi, M.; Inoue, T.;
Miyamoto, Y.; Oguni, N. Tetrahedron 1994, 50, 4385–4398.
(c) Hayashi, M.; Kaneda, H.; Oguni, N. Tetrahedron Asymmetry
1995, 6, 2511–2516. (d) Hayashi, M.; Tanaka, K.; Oguni, N.
Tetrahedron Asymmetry 1995, 6, 1833–1836.
3. Hayashi, M.; Yoshimoto, K.; Hirata, N.; Tanaka, K.; Oguni, N.;
Harada, K.; Matsushita, A.; Kawachi, Y.; Sasaki, H. Isr.
J. Chem. 2001, 41, 241–246.
3.4.13. (E)-Isopropyl 2-acetyl-2-hexenoate ((E)-2g).
Rf¼0.61 (5:1 hexane–ethyl acetate); IR (KBr, nmax
1
(cm21)): 1705, 1635; H NMR: d 6.89 (t, J¼7.6 Hz, 1H),
4. (a) Lehnert, W. Tetrahedron 1972, 28, 663–666. (b) Reetz,
M. T.; Itzsten, M. V. J. Organomet. Chem. 1987, 334, 85–90.
5.2–5.1 (m, 1H), 2.36 (s, 3H), 2.22 (q, J¼7.6, 7.6 Hz, 2H),

M. Hayashi et al. / Tetrahedron 60 (2004) 6777–6783
6783
(c) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau,
M. T. J. Am. Chem. Soc. 1990, 112, 8215–8216. (d) Bonner,
M. P.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113,
1299–1308.
reaction, see: Shibata, I.; Nishio, M.; Baba, A.; Matsuda, H.
Chem. Lett. 1993, 1219–1222.
6. Reaction of diketene with benzaldehyde in the presence of
sulfuric acid was reported, see: Kato, T.; Chiba, T.; Sato, M.
Chem. Pharm. Bull. 1987, 26, 3877–3879.
5. Shibata and his co-workers reported the reaction of diketene
with aldehydes promoted by bis(tributyltin) oxide ((n-Bu3Sn)2O)
which afforded a,b-unsaturated methyl ketones accompanied
by decarboxylation. We reinvestigated this reaction and found
the product was not affected by the order of addition of
the reagents. That is, in both cases when the diketene was added
to the mixture of benzaldehyde and (n-Bu3Sn)2O, and when
aldehyde was added to the mixture of diketene and
(n-Bu3Sn)2O, the product was the same a,b-unsaturated methyl
ketones. This was in contrast to the Ti(O-i-Pr)4-promoted
¨
7. Conventional Knoevenagel reaction of methyl acetoacetate with
aldehydes catalyzed by piperidine was studied by Tanikaga and
his co-workers, see: Tanikaga, R.; Konya, N.; Hamamura, K.;
Kaji, A. Bull. Chem. Soc. Jpn 1988, 61, 3211–3216.
8. From the E-isomer (100%) it took 6 h at 90 8C to reach
thermodynamic ratio (E/Z¼33/67) (at room temperature it took
more than 2 weeks). On the other hand, from the Z-isomer it
took 18 h to reach thermodynamic ratio (E/Z¼33/67) at the
same temperature.