Synthesis of a multifunctional pheromone of the honeybee Apis mellifera via condensation of 7-oxooctanal with malonic acid

Article abstract of DOI:10.1023/A:1024172327822

Condensation of 7-oxooctanal with malonic acid in a Doebner reaction produces 9-oxo-2E-decenoic acid (42% yield) and a comparable amount of products from Tishchenko disproportionation of the starting aldehyde (7-oxooctyl-7- oxooctanoate) and re-esterification by acetic acid (7-oxooct-1-ylacetate and 7-oxooctanoic acid).

Full text of DOI:10.1023/A:1024172327822

Chemistry of Natural Compounds, Vol. 39, No. 1, 2003
SYNTHESIS OF A MULTIFUNCTIONAL PHEROMONE
OF THE HONEYBEE
VIA CONDENSATION
Apis mellifera
OF 7-OXOOCTANAL WITH MALONIC ACID
G. Yu. Ishmuratov, M. P. Yakovleva, L. P. Botsman,
N. M. Ishmuratova, R. R. Muslukhov,
UDC 547.36.07
G. V. Khambalova, and G. A. Tolstikov
Condensation of 7-oxooctanal with malonic acid in a Doebner reaction produces 9-oxo-2E-decenoic acid
(42% yield) and a comparable amount of products from Tishchenko disproportionation of the starting
aldehyde (7-oxooctyl-7-oxooctanoate) and re-esterification by acetic acid (7-oxooct-1-ylacetate and
7-oxooctanoic acid).
Key words: pheromone, 9-oxo-2 -decenoic acid, 7-oxooctanal, 7-oxooctyl-7-oxooctanoate, 7-oxooct-1-ylacetate,
E
7-oxooctanoic acid, Doebner and Tishchenko reactions.
The most common method of introducing the α,β-unsaturated carboxylic acid in syntheses of 9-oxo-2E-decenoic acid,
a multifunctional pheromone of the honeybee Apis mellifera L., is the Doebner condensation of 7-oxooctanal (1) with malonic
acid that is accompanied by decarboxylation [1]. It has been noted [1, 2] that 1 is difficulty available and that the yields of the
target pheromone 2 are low (32-47%). This is due to the instabilityofthe ω-acetylalkanal 1 owing to the presence of the ketone.
Attempts to protect this group by converting it to the ketal slightly increased the stability. However, the additional protection
and deprotection steps increased the use of reagents and synthesis time without substantially affecting the yield of 2.
O
O
CH (CO H)
2
2
2
1
Py + Pyp
O
O
O
O
'
3
'
1
'
5
3
5
CO H
2
'
8
O
8
4
2, 46%
°
115
O
AcOH
O
CH (CO H)
2
2
2
CO H
+
2
OAc
5
3
During an investigation of the acidic products from the reaction of 1 and malonic acid under Doebner-condensation
conditions (Py + Pyp), we detected 7-oxooctanoic acid (3) in addition to the target acid 2 (42% yield after recrystallization).
The content of 3 in the mixture varied (GC monitoring) and its formation via oxidation of 1 could not be explained because the
reaction was carried out under an inert atmosphere (Ar). Therefore, we analyzed the neutral reaction products.
Institute of Organic Chemistry, Ufa Scientific Center, Russian Academy of Sciences, 450054, Ufa, pr. Oktyabrya 71,
fax (3472) 35 60 66, e-mail: kharis@anrb.ru. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 24-26, January-
February, 2003. Original article submitted December 12, 2002.
0009-3130/03/3901-0028$25.00 ©2003 Plenum Publishing Corporation
28

We found for the first time that a mixture of the 7-oxooctyl ester of 7-oxooctanoic acid (4) and 7-oxooct-1-ylacetate
(5) that was approximately equal to the mass of the acid products was formed under the condensation conditions (Py + Pyp).
These are products of Tishchenko disproportionation of 1 and subsequent re-esterfication, respectively. The acetic acid needed
for 1 is formed via decarboxylation of the excess of malonic acid.
It should be noted that the ratio of esters 4 and 5 varies with time (from 2 to 4 h) under decarboxylation conditions
(~115°C) in favor of the latter (from about 10 to 20%). As the re-esterification of 4 proceeds, the content of saturated ketoacid
3 in the acidic products (in the same ratio) increases. This leads to contamination of the target ketoacid 2. Therefore, strict
control of the decarboxylation and its conclusion after CO evolution ceases (monitoring with a gas-bubble counter) are
2
recommended.
Base hydrolysis of esters 4 and 5 gives 3 and ketoalcohol 6 in good yields. Hydride reduction produces diol 7, which
can be readily converted to starting 1 by known methods [3-5], which enables its conversion and the yield of pheromone to be
increased (by 15-18%).
O
5% NaOH
OH
+
3 (82%)
, 81%
6
[3]
[4]
1
60%
91%
4
+
5
[5]
68%
OH
i
Bu AlH
2
OH
, 89%
7
EXPERIMENTAL
IR spectra were recorded on a UR-20 instrument in thin layers. NMR spectra were taken on a Bruker AM-300
spectrometer (working frequency 300.13 MHz for 1H and 75.47 MHz for 13C) in CDCl using the CDCl signals as standards
3
3
(in PMR, δ 7.27 ppm; in 13C NMR, δ 77.00 ppm). Chromatographic analysis used a Chrom-5 instrument [column length 1.2
m, stationary phase silicone SE-30 (5%) on Chromaton N-AW-DMCS (0.16-0.20 mm), working temperature 50-300°C] with
He carrier gas. Analytical data for the compounds agreed with those calculated.
9-Oxo-2E-decenoic Acid (2), 7-Oxooctanoic Acid (3), 7-Oxooctyl-7-oxooctanoate (4), and 7-Oxooctylacetate (5).
a. Malonic acid (10.44 g, 100 mmole) and 1 (11.00 g, 77.5 mmole, prepared as before [4]) were successively dissolved
in dry pyridine (51 mL) and treated with piperidine (2.5 mL). The reaction mixture was stored (Ar; 20°C, 48 h; 60°C, 2 h;
115°C, 2 h), cooled, diluted with Et O (300 mL), successively washed with HCl (10%, until the pH was 2) and saturated NaCl
2
solution (until the pH was 7), and treated with saturated NaHCO solution (until the pH was 8). The organic layer was
3
separated, dried over Na SO , and evaporated. A part (1 g) of the solid (5.2 g, 4/5 mixture, ~9:1 according to GC) obtained
2
4
was chromatographed (SiO , hexane:Et O, 7:3).
2
2
The aqueous layer was acidified with HCl (until the pH was 2) and extracted with Et O (3×100 mL). The combined
2
organic extracts were dried over MgSO and evaporated. The solid (7.2 g, 2/3 mixture, ~9:1 according toGC) wasrecrystallized
4
from petroleum ether:Et O (1:1) to give 2 (5.53 g, 42%), the IR and PMR spectra of which are identical to those in the literature
2
[6, 7].
b. Malonic acid (10.44 g, 100 mmole) and 1 (11.00 g, 77.5 mmole) were dissolved in drypyridine (51 mL) and treated
with piperidine (2.5 mL). The reaction mixture was stored (Ar; 20°C, 48 h; 60°C, 2 h; 115°C, 4 h) and worked up as described
in a to give the neutral reaction products (4.7 g, 4/5 mixture, ~4:1 according to GC).
The aqueous layer was acidified with HCl (until the pH was 2) and extracted with Et O (3×100 mL). The combined
2
organic extracts were dried over MgSO and evaporated. The solid (7.7 g, 2/3mixture, ~4:1 according toGC) was recrystallized
4
from petroleum ether:Et O (1:1) to give 2 (4.35 g, 33%), the IR and PMR spectra of which are identical to those in the literature
2
[6, 7].
29

7-Oxooctyl-7-oxooctanoate (4), R 0.18 (SiO , petroleum ether:Et O, 7:3). PMR spectrum (δ, ppm, J/Hz): 1.30 (10H,
f
2
2
m, H-2′—H-5′, H-3), 1.54 (4H, H-4, H-5), 2.09 (6H, s, H-8, H-8′), 2.24 (2H, t, J = 7.4, H-2), 2.39 (4H, t, J = 6.6, H-6, H-6′),
4.00 (2H, t, J = 6.6, H-1′). 13C NMR spectrum: 23.25 (t, C-5′), 23.51 (t, C-5), 24.58 (t, C-3), 25.62 (t, C-3′), 28.33 (t, C-2′),
28.47 (t, C-4), 28.82 (t, C-4′), 29.77 (q, C-8, C-8′), 33.96 (t, C-2), 43.30 (t, C-6), 43.46 (t, C-6′), 64.15 (t, C-1′), 173.31 (s, C-1),
208.86 (s, C-7′), 208.99 (s, C-7).
7-Oxooctylacetate (5), R 0.33 (SiO , petroleum ether:Et O, 7:3). PMR spectrum (δ, ppm, J/Hz): 1.22 (4H, m, H-3,
f
2
2
H-4), 1.51 (4H, m, H-2, H-5), 1.93 (3H, s, CH CO ), 2.02 (3H, s, H-8), 2.33 (2H, t, J = 7.6, H-6), 3.93 (2H, t, J = 6.6, H-1).
3
2
13C NMR spectrum: 19.55 (q, CH CO ), 22.46 (t, C-5), 24.66 (t, C-3), 27.40 (t, C-2), 27.66 (t, C-4), 28.47 (q, C-8), 42.22 (t,
3
2
C-6), 63.05 (t, C-1), 169.40 (s, CO ), 206.83 (s, C-7).
2
7-Oxooctanoic Acid (3) and 8-Hydroxyoctan-2-one (6). The mixture of 4/5 (3.00 g, ~9:1 according to GC) and
NaOH (0.55 g, 13.8 mmole) was dissolved in H O (11 mL), stored (20°C, 24 h; 60°C, 6 h), cooled, and extracted with Et O
2
2
(3×50 mL). The combined extracts were dried over Na SO and evaporated to give 6 (1.29 g, 81%), the IR and PMR spectra
2
4
of which were identical to those in the literature [6].
The aqueous layer was acidified with conc. HCl, extracted with Et O (3×50 mL), dried over MgSO , and evaporated
2
4
to give 5 (1.23 g, 82%), the IR and PMR spectra of which were identical to those in the literature [7].
1,7-Octandiol (7). The mixture of 4/5 (3.50 g, ~9:1 according to GC) in absolute Et O (129 mL) was treated dropwise
2
under Ar at 0°C with DIBAH (22 mL, 73%) in toluene, stored for 2 h at the same temperature, and treated with H O (20 mL).
2
The solid was filtered off and washed on the filter with Et O (100 mL). The filtrate was evaporated to give 7 (3.14 g, 90%),
2
the IR and PMR spectra of which were identical to those in the literature [5].
REFERENCES
1.
G. Yu. Ishmuratov, R. Ya. Kharisov, O. V. Botsman, N. M. Ishmuratova, and G. A. Tolstikov, Khim. Prir.
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2.
3.
4.
5.
6.
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V. N. Odinokov, G. Yu. Ishmuratov, I. M. Ladenkova, and G. A. Tolstikov, Khim. Prir. Soedin., 632 (1986).
A. Chattopadhyay, V. R. Mamdapur, and M. S. Chadha, Indian J. Chem., 158 (1983).
M. Nomura and Y. Fujihara, J. Jpn. Oil. Chem. Soc., 453 (1988).
Z. G. Isaeva, A. N. Karaseva, V. V. Karlin, and L. A. Savukhina, Izv. Akad. Nauk SSSR, Ser. Khim., 2134 (1986).
30