A new protocol for a regioselective aldol condensation as an alternative convenient synthesis of β-ketols and α,β-unsaturated ketones

Article abstract of DOI:10.1021/jo0200872

A general and convenient synthesis of β-ketols and α,β-alkenones has been achieved by a Knoevenagel condensation of a β-ketoacid with an aldehyde in aqueous medium. Saponification of a β-ketoester by an aqueous KOH 10% solution gives the potassium salt of the β-ketoacid, which is condensed in situ with an aldehyde at pH 7.8-8.0, at 60 °C for 5-6 h. The intermediate β-ketocarboxylate is smoothly decarboxylated in the reaction medium, giving the β-ketol in high yield (75-90%). Acidification of the reaction mixture at pH 1 and heating at 70 °C under vigorous stirring for 6 h, leads directly to the corresponding α,β-unsaturated ketone in good yield (65-75%).

Full text of DOI:10.1021/jo0200872

J . Org. Chem. 2002, 67, 4615-4618
4615
A New P r otocol for a Regioselective Ald ol
Sch em e 1
Con d en sa tion a s a n Alter n a tive Con ven ien t
Syn th esis of â-Ketols a n d r,â-Un sa tu r a ted
Keton es
§
§
Therapia Kourouli, Panagiotis Kefalas,
§
Nikitas Ragoussis, and Valentine Ragoussis*
Vioryl S.A. Research Department, Kato Kifissia,
4564 Athens, Greece and Department of Chemistry
1
Laboratory of Organic Chemistry, University of Athens,
Panepistimiopolis Zographou, 157 71 Athens, Greece
ragousi@chem.uoa.gr
Received February 4, 2002
Abstr a ct: A general and convenient synthesis of â-ketols
and R,â-alkenones has been achieved by a Knoevenagel
condensation of a â-ketoacid with an aldehyde in aqueous
medium. Saponification of a â-ketoester by an aqueous KOH
7
equate catalysts. The one-step synthesis of alkenones
8
by the Horner-Emmons-Wadsworth reaction is also
1
0% solution gives the potassium salt of the â-ketoacid,
well-known.
which is condensed in situ with an aldehyde at pH 7.8-8.0,
at 60 °C for 5-6 h. The intermediate â-ketocarboxylate is
smoothly decarboxylated in the reaction medium, giving the
â-ketol in high yield (75-90%). Acidification of the reaction
mixture at pH 1 and heating at 70 °C under vigorous stirring
for 6 h, leads directly to the corresponding R,â-unsaturated
ketone in good yield (65-75%).
â-Ketoesters 4a have been utilized as active methylene
compounds in Knoevenagel condensations with alde-
hydes, giving R-alkenyl-â-ketoesters 7a (Scheme 1). An
approach to the R,â-alkenone unit could be the saponi-
fication and decarboxylation of the R-alkenyl-â-ketoester
a . However, usual alkaline hydrolysis of the â-ketoesters
for the production of a ketone is often complicated by a
competing fission reaction that affords esters or acids,
particularly when the R position is substituted. For this
reason this approach has not been used for the regio-
specific synthesis of R,â-unsaturated ketones.
It has been reported that â-ketoacids 4b (Scheme 1)
give condensation reactions with aldehydes to yield
â-ketols or R,â-unsaturated ketones.
overall yields are low and the experimental conditions
do not allow for an extensive application of the method.
The main inconvenience is that the â-ketoacid 4b has to
be carefully isolated from its aqueous solution before the
9
7
1
0
In tr od u ction
There is a general interest in the synthesis of al-
kenones, because this structural unit is the main function
of various natural fragrant compounds and pheromones,
and also it is a versatile intermediate in the synthesis of
various natural products. For example (E)-5-methylhept-
11,12
However, the
2
-en-4-one 1 (filbertone) has been isolated from hazel-
1
nuts, (E)-7-methyloct-4-en-3-one 2 from the marine
sponge Plakortis zygompha, and (E)-2-octen-4-one 3 has
2
been found as a volatile constituent of raw and roasted
12
condensation with the aldehyde. The isolation of the
carob.3
thermally unstable â-ketoacids is not a simple procedure,
especially for multigram preparations. The extraction of
a â-ketoacid from an aqueous solution and the condensa-
tion of the solvent have to be done rapidly at a temper-
ature below 30 °C, and the crude acid must be kept at
-
20 °C, not longer than one week.12 Moreover, the
condensation with the aldehyde was accomplished either
in pyridine12 or DMF, solvents that are difficult to
handle in large scale preparations. The reported conden-
13
The most common access to this structural unit is by
the aldol condensation, a reaction that is amply docu-
mented and described. Significant improvement on the
4
(5) (a) d’Angelo, J . Tetrahedron 1976, 32, 2979-2990. (b) Stork, G.;
Kraus G. A.; Garcia, G. A. J . Org. Chem. 1974, 23, 3459-3460.
regioselectivity of the reaction can be obtained by a
preformed specific enol equivalent such as a kinetic
(
6) Rasmussen, J . K. Synthesis 1977, 91-110.
(7) (a) Mahrwald, R.; H. Schick, H. Synthesis 1990, 592-595. (b)
5
6
Kobayashi, S. Eur. J . Org. Chem. 1999, 15-27.
enolate, an O-silylated enolate, or by the use of ad-
(
8) Wadsworth, W. S. In Organic Reactions; J ohn Wiley & Sons:
New York, 1977; vol. 25, pp 73-250.
*
To whom correspondence should be addressed. Phone: + 30 10
(9) J ones, G. In Organic Reactions: J ohn Wiley & Sons: New York,
1967; vol. 15, pp 204-599.
7
274497 Fax: + 30 10 7274761.
§
Vioryl S. A. Research Department.
(10) House, H. O. In Modern Synthetic Methods, 2nd ed.; Benjamin,
W. A., Ed.; New York, 1972; pp 492-546.
(1) (a) J auch, J .; Schmalzing, D.; Schuring, V.; Emberger, R.; Hopp,
R.; Kospel, M.; Silberzahn, W.; Werkhoff, P. Angewante Chem., Int.,
Ed. Engl. 1989, 28, 1022-1023. (b) J auch, J .; Czesla, H.; Schuring, V.
Tetrahedron 1999, 55, 9787-9792.
(11) (a) Schopf, C.; K.Thierfelder, K. Liebigs Ann. Chem. 1935, 518,
127-155. (b) Stiles, M.; Wolf, D.; G. V. Hudson, G. V. J . Am. Chem.
Soc. 1959, 81, 628-632.
(2) Faulkner, D. J .; Ravi, B. N. Tetrahedron Lett. 1980, 21, 23-26.
(3) Cantalejo, M. J . J . Agric. Food Chem. 1997, 45, 1345-1350.
(4) Nielsen, A. T.; Houlihan, W. J . In Organic Reactions; J ohn Wiley
(12) Grayson, D. H.; Tuite, M. R. J . J . Chem. Soc., Perkin Trans. 1
1986, 2137-2142.
(13) Naf, F.; Decorzant, R.; W.Thommen, W. Helv. Chim. Acta 1982,
65, 2212-2223.
&
Sons: New York, 1968; vol. 16, pp 1-438.
1
0.1021/jo0200872 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/24/2002

4
616 J . Org. Chem., Vol. 67, No. 13, 2002
Notes
Sch em e 2
Sch em e 3
sation of benzaldehyde with acetoacetic acid 4b (Scheme
) in neutral phosphate buffer was accomplished in 14
an aldehyde even after 3 days. Also the condensation with
a ketone (entry 11, Table 1) was unsuccessful.
The dehydration of an isolated pure â-ketol was studied
under various conditions. Reflux in benzene or toluene
in the presence of p-toluenesunfonic acid, HCl (gas), or
1
1
1
days, and the â-ketol 8 was isolated in low yield. Even
though the experimental conditions in the above reports
were not attractive and the reported yields were moder-
ate, we anticipated that the condensation of a â-ketoacid
with an aldehyde could be a general synthetic approach
to R,â-alkenones.
In this paper a new very simple protocol for the
condensation of a â-ketoacid with an aldehyde to the
corresponding â-ketol and/or Râ-unsaturated ketone is
described, providing a highly regioselective aldol conden-
sation alternative. The utility of the method has been
illustrated by the synthesis of the (E)-5-methylhept-2-
en-4-one (filbertone) 1, the (E)-7-methyloct-4-en-3-one 2,
the (E)-2-octen-4-one 3 and a series of other simple R,â-
unsaturated ketones and â-ketols.
anhydrous CuSO gave the R,â-unsaturated ketone in
4
good yield. However, the final product was contaminated
with the corresponding â,γ-unsaturated ketone at a
proportion ranging from 5 to 15%. We found that excel-
lent regioselectivity and very good yield (75-92%) on the
dehydration of pure â-ketol can be obtained by heating
its aqueous emulsion at pH 1 at 70 °C for 5 h (Table 1).
It is worth mentioning that the formation of the R,â-
unsaturated ketone can be achieved as a one-step pro-
cedure, i.e., without the isolation of the intermediate
â-ketol. Therefore, when the condensation of the â-keto-
acid with an aldehyde is finished, the reaction medium
is acidified by concentrated hydrochloric acid to pH 1 and
heated at 60-70 °C with stirring until the dehydration
is accomplished. In most of the cases the dehydration is
complete after 5 h and the product can be easily recovered
by a simple extraction of the reaction medium (Scheme
Resu lts a n d Discu ssion
During the present study for a regiospecific synthesis
of R,â-unsaturated ketones, our effort was focused on the
conditions for a direct condensation of a â-ketoacid with
an aldehyde. To avoid the tedious isolation of pure
â-ketoacids, their sodium or potassium salts in an aque-
ous solution are used. For this purpose, a â-ketoester is
smoothly saponified by an aqueous alkali metal hydrox-
ide solution, at room-temperature overnight, giving a
clear homogeneous solution of its alkali metal salt. The
pH of the obtained aqueous solution is adjusted to 7.8-
3
). Thus, if the R,â-unsaturated ketone is the desired
product, the intermediate â-ketol does not need to be
isolated.
The above one-pot procedure is successfully applied for
the synthesis of the natural compounds (E)-5-methylhept-
2
-en-4-one 1 (filbertone), (E)-7-methyloct-4-en-3-one 2,
(E)-2-octen-4-one 3 and for a series of other simples R,â-
unsaturated ketones, which are illustrated in Table 1.
In conclusion, a new simple protocol for the condensa-
tion of a â-ketoacid with an aldehyde, to â-ketol and/or
R,â-alkenone, has been described. The presented method
provides a general regioselective alternative to the aldol
condensation, particularly convenient in practical terms.
The advantages lie in the mildness of experimental
conditions, the short reaction time, the availability of
reagents, and the high yield of pure products.
8
.0, by addition of a buffer of pH 8, and then the addition
of the aldehyde is followed. If the pH is higher than 8.5,
the self-condensation of the aldehyde is the main reac-
tion. If the pH is lower than 7.5, the reaction is very slow
and the procedure becomes nonpractical. In the case of
a condensation with a water insoluble aldehyde, a phase
transfer catalyst has to be added in the reaction mixture.
Finally, depending on the nature and the availability of
the reagents, an excess of one of the reactants can be
used to improve the yield.
Exp er im en ta l Section
The reaction is better accomplished at 60 °C. In most
of the cases the aldehyde has reacted in less than 6 h,
without any self-condensation taking place (Scheme 2).
When the aldehyde is volatile (e.g., acetaldehyde, propi-
onaldehyde), the reaction mixture is first stirred at room
temperature for 2 h and then heated at 40 °C, until the
reaction is complete. Then, the reaction mixture is cooled
at room temperature, and the â-ketol, which is the unique
reaction product, can be easily isolated, by extraction
with a common solvent. The main impurity is the
corresponding R,â-unsaturated ketone, which has never
been found at a concentration of more than 2%. Distil-
lation of the crude product gave the â-ketol in excellent
purity and very good yield (75-90%).
IR spectra were obtained in 5% CCl
spectra were recorded on a 200 MHz spectrometer in CDCl
TMS as internal standard). Mass spectra were taken on a GC-
MS system at 70 eV. GC analyses were performed on carbowax
4
solutions. 1H NMR
(with
3
2
0M 50m or SE30 50m fused silica capillary columns. All
aldehydes were washed with an aqueous 10% NaHCO solution,
dried over anhydrous Na SO , and then purified by distillation.
3
2
4
Acetaldehyde and propionaldehyde, however, were used without
further purification, provided that their acidity was less than
1
%. Ethyl acetoacetate, ethyl 3-oxopentanoate, and ethyl 3-oxo-
heptanoate are commercially available (Aldrich), and they were
used without further purification. Ethyl 3-oxo-4-methylhex-
14
anoate was prepared according to the reported procedure, from
2-methylbutyryl chloride.
P r ep a r a tion of â-Ketol. Into a cold (+10 °C) aqueous 2 M
solution of KOH (520 mL, 1.05 mol) was added the â-ketoester
The results of some representative condensations of
â-ketoesters and aldehydes for the synthesis of â-ketols
are summarized in Table 1. The R-branched â-ketoesters
such as ethyl 2-methylacetoacetate and ethyl 2-ethyl-
acetoacetate (entry10, Table 1) failed to condense with
(1 mol), and the solution was stirred overnight at room temper-
(14) Oikawa, Y.; Yoshioka, T.; Sugano, K.; Yonemitsu, O. Organic
Synthesis; Saucy G. G., Ed.; J ohn Wiley & Sons: New York, 1985; vol.
63, pp 198-202.

Notes
J . Org. Chem., Vol. 67, No. 13, 2002 4617
Ta ble 1. Syn th esis of â-k etols a n d r,â-Un sa tu r a ted Keton es
a
Yields refer to the dehydration of pure â-ketol. b The isolated product contains also 27% of the 1-phenyl-1-buten-3-one 21.
ature. A solution of tetrabutylammonium hydrogenosulfate
TBAHSO 1.7 g, 5 mmol) in water (10 mL) was added, followed
by a phosphate buffer pH 8 (Na HPO -NaOH) (100 mL). The
× 150 mL). The organic phase was washed with water (100 mL)
and saturated aqueous NaHCO (100 mL) and dried over
anhydrous Na SO , and the solvent was evaporated under
reduced pressure. The product was purified by distillation under
vacuum, to give pure R,â-unsaturated ketone.
On e-P ot P r ep a r a tion of r,â-Un sa tu r a ted Keton es. The
general procedure for the preparation of â-ketols was followed
until the reaction of the aldehyde and the â-ketoester was
complete. Then, concentrated HCl (150 mL) was added, until
pH 1, and the reaction mixture was heated under vigorous
stirring at 70 °C for 5 h. Following the previously described
workup, pure R,â-unsaturated ketone was obtained.
(
4
3
2
4
2
4
pH of the final solution was adjusted at 7.8 using 0.1 N NaOH
or 0.1 N HCl. Then the aldehyde (0.5 mol) was added, and the
reaction mixture was stirred for 5-7 h at 60 °C. In the case of
volatile aldehydes as acetaldehyde or propionaldehyde, the
reaction mixture was first stirred at room temperature for 2 h
and then at 40 °C. When GC analysis indicated complete
consumption of the starting aldehyde, the reaction mixture was
taken to room temperature and extracted with diethyl ether or
CH
2
Cl
2
(3 × 150 mL). The organic phase was washed with water
(100 mL) and dried over anhydrous Na
2
SO , and the solvent was
4
4-H yd r oxyoct a n -2-on e (10). Obtained from ethyl aceto-
acetate (130 g, 1 mol) and n-valeraldehyde (43.0 g, 0.5 mol) as
a colorless liquid (57.6 g, yield 80%): bp 88-92 °C/1.5 mmHg
evaporated under reduced pressure. The crude product, which
is contaminated with less than 2% of the corresponding R,â-
unsaturated ketone, is purified by distillation under vacuum
giving the â-ketol in excellent purity.
Deh yd r a tion of Isola ted â-Ketol. The pure â-ketol was
added to an equal volume of water, and the well-stirred emulsion
was acidified by concentrated HCl to pH 1 and then heated
under vigorous stirring at 70 °C, until the end of the reaction,
generally 5 h. After being cooled to room temperature, the
(lit.,15 45-47 °C/0.1 mmHg); IR (cm ) 3550, 1700; H NMR δ
0.80 (t, J ) 7.2 Hz, 3H), 1.02-1.26 (m, 6H), 2.21 (s, 3H) 2.48-
2.58 (m, 2H), 4,00 (m, 1H); MS m/z (relative intensity) 126 (5,
M - 18), 111 (5), 97 (2), 87 (51), 55 (19), 43 (100).
-1
1
4-H yd r oxyn on a n -2-on e (12). Obtained from ethyl aceto-
acetate (130 g, 1 mol) and n-hexanal (50 g, 0.5 mol) as a colorless
reaction medium was extracted with diethyl ether or CH
2
Cl
2
(3
(15) Curran, D. P. J . Am. Chem. Soc. 1983, 105, 5826-5833.

4
618 J . Org. Chem., Vol. 67, No. 13, 2002
Notes
1
6
liquid (59.1 g, yield 75%): bp 95-100 °C/2 mmHg (lit., 60 °C/
3-Non en -2-on e (13). Obtained from ethyl acetoacetate (130
g, 1 mol) and n-hexanal (50 g, 0.5 mol) as a yellowish liquid (49
1
0
,1 mmHg); IR (cm-1) 3520, 1700; H NMR δ 0.80 (t, J ) 7.2
2
1
Hz, 3H), 1.00-1.22 (m, 8H), 2.10 (s, 3H), 2.50-2.62 (m, 2H),
g, yield 70%): bp 70-75 °C/4 mmHg (lit., 106-107 °C/32
1 1
-
3
1
.80-4.00 (m, 1H); MS m/z (relative intensity) 143 (1, M - 15),
mmHg); IR (cm ) 1696, 1676,1627, 981; H NMR δ 0.85 (t, J )
7.2 Hz, 3H), 1.15-1.68 (m, 6H), 2.15-2.26 (m, 2H), 2.28 (s, 3H),
6.02 (d, J ) 16.0 Hz, 1H), 6.70 (dt, J ) 6.8 and 16.0 Hz, 1H);
40 (3), 111 (3), 97 (2), 87 (42), 58 (11), 55 (12), 43 (100).
4
-H yd r oxyd eca n -2-on e (14). Obtained from ethyl aceto-
acetate (130 g, 1 mol) and n-heptanal (57 g, 0.5 mol) as a colorless
liquid (62.0 g, yield 72%): bp 120-125 °C/3 mmHg (lit., 67
C/0.5 mmHg); IR (cm ) 3540, 1705; H NMR δ 0.80 (t, J ) 7.2
Hz, 3H), 1.10-1.25 (m, 10H), 2.14 (s, 3H), 2.45-2.52 (m, 2H)
.00-4.20 (m, 1H); MS m/z 154 (3, M - 18), 139 (2), 111 (3), 97
5), 87 (56), 69 (7), 58 (14), 43 (100).
-Hyd r oxyu n d eca n -2-on e (16). Obtained from ethyl aceto-
acetate (130 g, 1 mol) and n-octanal (64 g, 0.5 mol) as a colorless
+
MS m/z (relative intensity) 140 (12, M ), 125 (35), 111 (10), 97
1
7
(20), 82 (11), 71 (19), 55 (100), 43 (71).
-
1
1
°
3-Decen -2-on e (15). Obtained from ethyl acetoacetate (130
g, 1 mol) and n-heptanal (57 g, 0.5 mol) as a clear yellowish liquid
2
2
4
(
(45.3 g, yield 66%): bp 80-83 °C/3 mmHg (lit., 104-109 °C/
1 1
-
20 mmHg); IR (cm ) 1697, 1676, 1627, 976; H NMR δ 0.80 (t,
J ) 7.0 Hz, 3H), 1.18 (bs, 6H), 1.33-1.35 (m, 2H), 2.12 (s, 3H),
2.09-2.14 (m, 2H), 5.95 (d, J ) 16.0 Hz, 1H), 6.65 (dt, J ) 6.6
4
-
1
+
liquid (65.3 g, yield 70%): bp 98-100 °C/0.5 mmHg; IR(cm
)
and 16.0 Hz, 1H); MS m/z (relative intensity) 154 (4, M ), 139
1
3
1
550, 1705; H NMR δ 0.82 (t, J ) 7.2 Hz, 3H), 1.10-1.30 (m,
(18), 125 (6), 111 (9), 97 (21), 69 (42), 55 (82), 43 (100).
3-Un d ecen -2-on e (17). Obtained from ethyl acetoacetate (130
g, 1 mol) and n-octanal (64 g, 0.5 mol) as a clear yellowish liquid
2H), 2.15 (s, 3H), 2.50-2.64 (m, 2H), 3.90-4.20 (m, 1H); MS
m/z 171 (1, M - 15), 125 (2), 110 (3), 87 (35), 69 (10), 58 (8), 55
2
3
(9), 43 (100).
(54.6 g, yield65%): bp 80-83 °C/3 mmHg (lit., 68 °C/0,5 mmHg);
1 1
-
4
-Hyd r oxy-6-m eth ylh ep ta n -2-on e (18). Obtained from eth-
yl acetoacetate (130 g, 1 mol) and isovaleraldehyde (43 g, 0.5
IR (cm ) 1695, 1675, 1626, 980; H NMR δ 0.85 (t, J ) 7.2 Hz,
3H), 1.22 (bs, 8H), 1.33-1.36 (m, 2H), 2.20 (s, 3H), 2.12-2.26
(m, 2H), 6.00 (d, J ) 16.2 Hz, 1H), 6.70 (dt, J ) 7.0 and 16.2
mol) as a colorless liquid (61.0 g, yield 85%): bp 60-62 °C/0.7
-
1
1
+
mmHg; IR (cm ) 3540, 1700; H NMR δ 0.80 (d, J ) 6.7 Hz,
Hz, 1H); MS m/z (relative intensity) 168 (1, M ), 153 (10), 125
6
2
(
H), 1.01-1.06 (m, 1H), 1.28-1.32 (m, 1H), 1.65-1.69 (m, 1H),
.05 (s, 3H), 2.41-2.44 (m, 2H), 3.98-4.00 (m, 1H); MS m/z
(4), 97 (14), 83 (9), 69 (31), 55 (62), 43 (100).
6-Meth yl-3-h ep ten -2-on e (19). Obtained from ethyl aceto-
acetate (130 g, 1 mol) and isovaleraldehyde (43 g, 0.5 mol) as a
yellowish liquid (47.0 g, yield 75%): bp 83-85 °C/20 mmHg
relative intensity) 129 (3, M - 15), 111 (6), 108 (9), 87 (35), 69
(16), 58 (24), 55 (16), 43 (100).
(lit.,24 43 °C/3 mmHg); IR (cm ) 1699, 1674, 1628, 983; H NMR
δ 0.85 (d, J ) 6.6 Hz, 6H), 1.70 (m, 1H), 2.04 (t, J ) 7.0 Hz, 2H),
2.17 (3H, s), 6.00 (d, J ) 16.0 Hz, 1H), 6.70 (dt, J ) 7.0 and 16.0
-1
1
1
-P h en yl-1-h yd r oxybu ta n -3-on e (20). Obtained from ethyl
acetoacetate (130 g, 1 mol) and benzaldehyde (53 g, 0.5 mol), as
a yellowish liquid (54.0 g), containing also the corresponding
unsaturated ketone 1-phenyl-1-buten-3-one (21). GC-MS analy-
sis of the obtained product showed the presence of 1-phenyl-1-
hydroxybutan-3-one and of 1-phenyl-1-buten-3-one at a ratio
of 2:1. The above compounds were identified by their mass
spectra, which were consistent with the literature.
-Hyd r oxy-7-m eth ylocta n -3-on e (22). Obtained from ethyl
-oxopentanoate (26.0 g, 0.2 mol) and isovaleraldehyde (17.2 g,
+
Hz, 1H); Ms m/z (relative intensity) 126 (6, M ), 111 (25), 108
(12), 84 (32), 71 (15), 69 (85), 55 (62), 43 (100).
1
8
7
1-P h en yl-1-b u t en -3-on e (21). Obtained from ethyl aceto-
acetate (130 g, 1 mol) and benzaldehyde (53 g, 0.5 mol) as a clear
7
,18
7
colorless liquid (52.5 g, yield 72%): bp 96-98 °C/1 mmHg (lit.,
-
1
1
5
160 °C/27 mmHg); IR (cm ) 1692, 1668, 1626, 1610, 976; H
3
0
NMR δ 2.32 (s, 3H), 6.62 (d, J ) 16.0 Hz, 1H), 7.20-7.60 (m,
6H); MS m/z (relative intensity) 145 (30, M - 1), 131 (80), 103
(100).
.2 mol) as a colorless liquid (28.1 g, yield 90%): bp 65-67 °C/1
-
1
1
mmHg); IR (cm ) 3550, 1705; H NMR δ 0.81 (d, J ) 7.0 Hz,
6
1
H), 0.95 (t, J ) 7.2 Hz, 3H), 1.02 (m, 1H), 1.31-1.38 (m, 1H),
.66-1.71 (m, 1H), 2.30-2.45 (m, 4H), 3.99-4.03 (m, 1H); MS
7-Meth yl-4-octen -3-on e (2). Obtained from ethyl 3-pen-
tanoate (26 g, 0.2 mol) and isovaleraldehyde (17 g, 0.2 mol) as a
m/z (relative intensity) 143 (5, M - 15), 129 (9), 111 (31), 101
yellowish liquid (18.0 g, yield 65%): bp 53-55 °C/1 mmHg (lit.,
92-94 °C/30 mmHg); IR (cm-1) 1702, 1677, 1632, 983;
H NMR
2
(
35), 69 (42), 57 (100), 55 (38), 43 (88).
-Hyd r oxyocta n -4-on e (23). Obtained from ethyl 3-oxohep-
tanoate (86 g, 0.5 mol) and acetaldehyde (31.5 g, 0.75 mol) as a
1
2
δ 0.84 (d, J ) 6.8 Hz, 6H), 1.01 (t, J ) 7.3 Hz, 3H), 1.66-1.70
(m, 1H), 2.01 (t, J ) 7.0 Hz, 2H), 2.48 (q, J ) 7.3 Hz, 2H), 5.97
(d, J ) 16.5 Hz, 1H), 6.72 (dt, J ) 6.9 and 16.5 Hz, 1H); MS m/z
1
9
colorless liquid (56.1 g, yield 78%): bp 60-62 °C/0,8 mmHg (lit.,
-
1
1
+
6
1-62 °C/1,0 mmHg); IR (cm ) 3500, 1706; H NMR δ 0.93 (t,
J ) 7.2 Hz 3H), 1.18 (d, J ) 6.8 Hz, 3H), 1.35 (m, 2H), 1.56 (m,
H), 2.42 (t, J ) 6.4 Hz, 2H), 2.52-2.60 (m, 2H), 4.12 (m, 1H);
(relative intensity) 140 (5, M ), 111 (28), 97 (1), 83 (4), 69 (21),
55 (100), 57 (10), 43 (27).
2-Octen -4-on e (3). Obtained from ethyl 3-oxo-heptanoate (86
2
+
MS m/z (relative intensity) 144 (1, M ), 129 (2), 103 (10), 87 (16),
5 (19), 69 (27), 58 (45), 43 (100).
-Hyd r oxy-5-m eth ylh ep ta n -4-on e (24). Obtained from eth-
yl 3-oxo-4-methylhexanoate (43 g, 0.25 mol) and acetaldehyde
13.2 g, 0.3 mol) as a colorless liquid (24.8 g, yield 75%): bp 62-
g, 0.5 mol) and acetaldehyde (31.5 g, 0.75 mol) as a clear
8
yellowish liquid (45.5 g, yield 67%): bp 50-52 °C/4 mmHg (lit.,25
2
68-70 °C/17 mmHg); IR (cm-1) 1697, 1677, 1633, 971;
1
H NMR
δ 0.88 (t, J ) 6.0 Hz, 3H), 1.25-1.98 (m, 2H), 1.54-1.65 (m,
2H), 1.94 (d, J ) 7.2 Hz, 3H), 2.55 (t, J ) 7.0 Hz, 2H), 6.15 (d,
J ) 16.0 Hz, 1H), 6.82 (dq, J ) 7.0 and 16.0 Hz, 1H); MS m/z
(
-1
6
5 °C/1,0 mmHg (lit.,20 40 °C/0,025 mmHg); IR (cm ) 3500, 1705;
1
+
H NMR δ 0.72 (t, J ) 7.4 Hz, 3H), 0.91 (d, J ) 7.1 Hz, 3H),
126 (1, M ), 111 (11), 97 (2), 84 (38), 69 (100), 57 (5), 55 (5), 41
1
.03 (d, J ) 6.3 Hz, 3H), 1.20-1.28 (m, 2H), 2.26-2.33 (m, 1H),
(80).
2
.44-2.48 (m, 2H), 4.05-4.07 (m, 1H); MS m/z (relative inten-
5-Meth yl-2-h ep ten -4-on e (1). Obtained from ethyl 4-methyl-
3-oxo-hexanoate (40 g, 0.23 mol) and acetaldehyde (10.2 g, 0,23
mol) as a clear yellowish liquid (18.8 g, yield 64%): bp 65-70
+
sity) 144 (1, M ), 116 (3), 103 (7), 87 (42), 85 (9), 69 (12), 57
(
52), 43 (100).
-Octen -2-on e (11). Obtained from ethyl acetoacetate (130
g, 1 mol) and n-valeraldehyde (43 g, 0.5 mol) as a colorless liquid
3
°C/16 mmHg (lit.,
969;
1
70 °C/20 mmHg); IR (cm-1) 1692, 1671, 1631,
1
H NMR δ 0.86 (t, J ) 7.5 Hz, 3H), 1.06 (d, J ) 7.0 Hz,
-1
(
1
4
46.5 g, yield 74%): bp 60-62 °C/2 mmHg; IR (cm ) 1696, 1675,
3H), 1.32-1.45 (m, 1H), 1.61-1.75 (m, 1H), 1.88 (d, J ) 6.8 Hz
1
627, 980; H NMR δ 0.88 (t, J ) 7.2 Hz, 3H), 1.20-1.80 (m,
H), 2.20 (m, 2H), 2.30 (s, 3H), 6.00 (d, J ) 16.5 Hz, 1H), 6.68
3H), 2.58-2.70 (m, 1H), 6.18 (d, J ) 15.7 Hz, 1H), 6.88 (dq, J )
+
15.7 and 6.8 Hz, 1H); MS m/z 126 (8, M
), 111 (15), 98 (17), 69
(
(
(
dt, J ) 16.5 and 7.0 Hz, 1H); MS m/z (relative intensity) 126
(100), 57 (5), 41 (75).
+
6, M ), 111 (14), 97 (29), 71 (15), 69 (21), 57 (63), 55 (100), 43
J O0200872
64).
(
(
16) Molander G. A.; Hahn, G. J . Org. Chem. 1986, 51, 2596-2599.
17) Inokuchi, T.; Kusumoto M.; Torii, S. J . Org. Chem. 1990, 55,
(21) Klein, E.; Thomel, F.; Winkler, H. Liebigs Ann. Chem. 1973,
1004-1017.
1
548-1553.
18) Choudary, B. M.; Kantam, M. L.; Kavita, B.; Reddy, Ch. V.;
Rao, K. K.; Figueras, F. Tetrahedron Lett. 1998, 39, 3555-3558.
19) Niznik, G. E.; Morrison, W. H., III.; Walborsky, H. M. J . Org.
Chem. 1974, 39, 600-604.
20) Seebach, D.; Ehrig, V.; Teschner, M. Liebigs Ann. Chem. 1976,
357-1369.
(22) Hideg, K.; Lex, L. J . Chem. Soc., Perkin Trans. 1 1986, 1431-
(
1438.
(23) Villieras, J .; M. Rambaud, M. Synthesis 1983, 300-303.
(
(24) Bienvenue, A.; Dubois, J . E. Bull. Soc. Chim. Fr. 1969, 391-
396.
(
(25) Bestmann, H. J .; Schmidt, M.; Schobert, R. Synthesis 1988, 49-
53.
1