A Novel Catechol Compound, an Unusual Side Reaction Product of a β-Ketoester with Pyruvic Aldehyde and Its Inhibition by Sodium Dithionite

Article abstract of DOI:10.1081/SCC-120026323

The structure of an usual catechol byproduct in the aldol condensation of the salt of 3-oxo-6-heptenoate and pyruvic aldehyde, and the discovery of an additive to inhibit its formation are described.

Full text of DOI:10.1081/SCC-120026323

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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 22, pp. 3977–3982, 2003
A Novel Catechol Compound, an Unusual Side
Reaction Product of a b-Ketoester with Pyruvic
Aldehyde and Its Inhibition by Sodium Dithionite
Takeaki Kato,1 Masao Mochizuki,2 Shigeru Okano,2
and Noritada Matsuo2,
*
1Matsugaki Chemical Industries Co. Ltd.,
Kita-ku, Osaka, Japan
2Agricultural Chemicals Research Laboratory,
Sumitomo Chemical Co., Ltd., Takarazuka, Hyogo
Japan
ABSTRACT
The structure of an usual catechol byproduct in the aldol
condensation of the salt of 3-oxo-6-heptenoate and pyruvic aldehyde,
and the discovery of an additive to inhibit its formation are
described.
*Correspondence: Noritada Matsuo, Agricultural Chemicals Research Labora-
tory, Sumitomo Chemical Co., Ltd., 4-2-1 Takatsukasa, Takarazuka, Hyogo 665-
8555, Japan.
3977
DOI: 10.1081/SCC-120026323
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3978
Kato et al.
Commercial use of synthetic pyrethroids having structures based on
natural pyrethrin as lead compounds is one of the most remarkable
success stories in insecticide development. Allethrin (1) or 2-methyl-4-
oxo-3-allylcyclopent-2-enyl 2,2-dimethyl-3-(2-methylpropenyl)cyclopro-
panecarboxylate, was first synthesized by Schechter et al. in 1949[1] and
found to be equipotent to pyrethrin I (2) , the most active component of
natural pyrethrins. This pioneering invention led to the development of
various synthetic pyrethroids[2] for agricultural use and for the control
of major household insect pests.
The synthesis of allethrolone (3), the alcohol moiety of allethrin, has
attracted considerable attention not only in its own right[3] but because of
its structural relationship to certain prostaglandin and jasmonoids.[4]
Despite extensive studies, only two industrial processes to allethrolone
are known.[5] One such process was based on the original Schechter
method starting from ethyl 3-oxo-6-heptenoate (4). The key step was
the aldol reaction between the b-ketoacid salt (5) and pyruvic aldeyde
(6) to give 3-hydroxy-8-nonene-2,5-dione (7), as in Sch. 1. However,
the yield of this aldol was consistently unsatisfactory because of the
formation of a significant amount of a higher-boiling byproduct.
In order to make this process viable, it was essential to establish the
nature of this byproduct and to find a method to inhibit its formation.
Scheme 1.

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Novel Catechol Compound
3979
We now report the structure of the major byproduct of this aldol
reaction, and the discovery of an additive which inhibits its formation.
The formation of an unidentified higher-boiling byproduct in the
aldol condensation of the salt (5) with pyruvic aldehyde (6) had been
reported in Schechter’s original studies. We found that when the
Schechter procedure was used, fractional distillation of the crude aldol
product gave 3-hydroxy-8-nonen-2,5-dione (7) in 59% yield and, from
the after-run,
a
byproduct which crystallized on cooling.
Recrystallization of this byproduct gave pale yellow needles, m.p.
114–115ꢀC, of a C12H14O3 compound which found a diacetate with
acetic anhydride and a semicarbazone on treatment with semicarbazide
hydrochloride. The 1H NMR of this compound showed, inter alia,
an apparent methyl singlet at ꢀ 2.29, and two aromatic protons
meta-coupled to each other at ꢀ 6.96 and ꢀ 7.10.
Consideration of the above data pointed to a mechanism whereby
the sodium salt (5) underwent two successive aldol condensations with
pyruvic aldehyde, followed by an aldol cyclization and dehydration, as in
the two alternative reaction sequences depicted in Sch. 2. There are two
possibilities for the final dehydration step, namely loss of OH(a) or
OH(b). Dehydration by loss of OH(a) would lead to the hydroquinone
(9a), whereas loss of OH(b) would produce the catechol 9b, both
consistent with the data provided.
Scheme 2.

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3980
Kato et al.
Differentiation between alternatives 9a and 9b was achieved by
observing NOE enhancements of both aromatic protons upon irradiation
of the methyl singlet at ꢀ 2.29, indicating that this methyl group has two
adjacent aromatic protons. Thus the byproduct formed under Schechter
conditions must be the catechol 9b. A possible origin of the regioselective
elimination of OH(b) may be that this elimination can occur from the
enediol tautomer of the a -ketol system in intemediate 8b, leading directly
by the driving force of aromatization to the observed 9b. Since the
catechol byproduct 9b was very stable, lipophilic, and sufficiently volatile,
attempts in our hands to efficiently remove 9b from 7 on an industrial
scale were unsuccessful. To obtain pure allethrolone in high yield,
inhibition of the formation of 9b was needed. Diverse additives were
empirically screened as potential inhibitors. Such agents as zinc,
sodium sulfite, sodium bisulfite, and sodium sulfide were ineffective.
Ultimately it was found that addition of sodium dithionite (Na2S2O4)
to the reaction led to an 84% yield of the desired allethrolone (7), and no
higher-boiling byproduct was observed. The role of Na2S2O4 in inhibiting
the formation of 9b is unclear, but this finding permits the Schechter pro-
cess to be suitable for production of allethrolone on a commercial scale.
EXPERIMENTAL
General
Unless otherwise noted, reagents and solvents were used as received
from commercial suppliers. All bps and mps were uncorrected. 1H NMR
was performed at 300 MHz in CDC13. Chemical shifts are in ppm down-
fieid from internal tetramethylsilane.
1-(2,3-Dihydroxy-5-methylphenyl)-4-penten-l-one (9b). According to
the reported procedure,[1] 3-hydroxy-8-nonen-2,5-dione(7) was synthe-
sized. The crude product was subjected to fractional distillation to give
7 in 59% yield and from the after-run, on cooling, crystals was collected.
Recrystallization from 50% ethanol–water gave pale yellow needles in
20% yield. M.p. 114–115ꢀC. H NMR ꢀ: 2.29 (3H ,s), 2.50 (2H, m), 3.08
1
(2H, t, J ¼ 7.1 Hz), 5.0–5.1 (2H, m), 5.66 (OH, s), 5.90 (1H, m), 6.96 (1H,
br.d, J ¼ 1 Hz), 7.10 (1H, br.d, J ¼ 1 Hz), 12.31 (OH, s). Anal. Found: C,
69.92; H, 6.91%. Calcd. for C12H14O3; 69.88; H, 6.84% FeCl3 was deep
green. Its semicarbazone, m.p.193ꢀC. Its diacetate from acetic anhydride
and sodium acetate; m.p. 70.5ꢀC.
Synthesis of 3-hydroxy-8-nonene-2,5-dione(7)[8] in the presence of
sodium dithionite. A mixture of ethyl 3-oxo-6-heptenoate (140 g,

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Novel Catechol Compound
3981
0.8 mol) and 10% aqueous sodium hydroxide (395 g) was allowed to
stand for 18 h, at 15ꢀC. After neutralization of excess alkali with 10%
hydrochloric acid on cooling, sodium dithionite (42 g, 30 w/w% of
starting ester), sodium bicarbonate (21 g), and 42% aqueous pyruvic
aldehyde (184 g, 1.07 mol) was added over 2 h under N2. Then, the
clear mixture was allowed to stand overnight at room temperature at
pH 8.0–8.5. The reaction was slightly exothermic. The reaction mixture
was saturated with sodium chloride and extracted with toluene twice.
The organic layers were combined and evaporated, and the residual oil
was distilled in vacuo. The yield of (7) was 114 g(84%). B.p. 76–78ꢀC/
0.03 mmHg any higher boiling fraction was not observed.
ACKNOWLEDGMENTS
We are grateful to Professor A. S. Kende of the University of
Rochester, Rochester, NY (USA) for his invaluable suggestions on the
reaction mechanism of the catechol formation in addition to checking
a draft.
REFERENCES
1. Schechter, M.S.; Green, N.; LaForge, F.B. Constituents of
pyrethrum flowers. XXIII. Cinerolone and the synthesis of related
cyclopentenolones. J. Am. Chem. Soc. 1949, 71, 3165–3173.
2. Naumann, K. Chemistry of Plant Protection 5, Synthetic Pyrethroid
Isectcides; Springer-Verlag, 1990.
3. Buchi, G.; Minster, D.; Young, J.C.E. A new synthesis of rethrlones.
J. Am. Chem. Soc. 1971, 93, 4319–4320; Romanet, R.F.;
Schlessinger, R.H. A new and highly efficient synthesis of rethro-
lones. J. Am. Chem. Soc. 1974, 96, 3701–3702; Ono, N.; Tanabe, Y.;
Tanikaga, R.; Kaji, A.; Matsuo, N. A new synthesis of allethrolone.
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4. Ellison, R.A. Methods for the synthesis of 3-oxocyclopentenes.
Synthesis 1973, 397–412.
5. Scettri, A.; Piancatelli, G.; D’Auria, M.; David, G. General route and
mechanism of the rearrangement of the 4-substituted 5-hydoroxy-3-
oxocyclopentenes into the 2-substituted analogs. Tetrahedron 1979,
35, 135–138.
6. Gault, H.; Burkhard, J. Ketolic condensations of acetylacetic ester
with formaldehyde. Compt. Rend. 1934, 199, 795–797; Chem. Abstr.

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3982
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1935, 29, 1390; Gault, H.; Wenling, T. Several keto condensation
products of ethyl acetoacetate and acetaldehyde. Bull. Soc. Chim.
1936, 5 (3), 53–70; Chem. Abstr. 1936, 30, 3412.
7. Kato, T.; Mochizuki, M.; Okano, S.; Yamamoto, T.
Hydroxydiketones. Japanese Patent, 30-3361 1955; Chem. Abstr.
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8. Andersen, S.H.; Das, N.B.; Jorgensen, R.D.; Kjeldsen, G.; Knudsen,
J.S.; Sharma, S.C.; Torssell, K.B.G. Silyl nitronates in organic
synthesis. Routes to heterocycles and cyclopentanoids. Synthesis of
allethrolone and calythrone. Acylation and cyanohydroxylation of
double bonds. An exploratory study. Acta Chemica Scandinavica
1982, B (36), 1.
Received in Japan May 7, 2003

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