June 1998
SYNLETT
599
Synthesis of 5-Substituted 4,4-Disubstituted 2-Cyclohexen-1-ones by Electro-Generated Base
Promoted Michael Addition of 4,4-Disubstituted 2,5-Cyclohexadien-1-ones
Sigeru TORII*, Naoya HAYASHI, and Manabu KUROBOSHI
Dept. of Applied Chem., Faculty of Engin., Okayama Universitiy, Tsushima-naka 3-1-1, Okayama 700, JAPAN
Fax 81-86-255-3424 e-Mail: toriiken@cc.okayama-u.ac.jp
Received 31 March 1998
Abstract: 5-Substituted 4,4-dialkoxy-2-cyclohexen-1-ones were electro-
synthesized from 4,4-disubstituted 2,5-cyclohexadien-1-ones, which
were obtained from 1,4-dialkoxybenzene derivatives by electrolysis, by
electro-generated base (EG-base)-promoted Michael addition with
CH E (E = CO R, COMe) in moderate to almost quantitative yield.
2
2
2
The cyclohexenone derivatives were found to be a good precursor of
benzofuranone derivatives through acid-promoted intramolecular
lactonization.
A strategy for the synthesis of poly-oxy-functionalized benzene
derivatives involves an aromatic/non-aromatic/aromatic conversion
sequence. 4,4-Dialkoxy-2,5-cyclohexadienone 1 is one of the most
1
valuable non-aromatic intermediate for this purpose. Although Parker
reported Michael addition of 1 with several activated methylene
compounds with chemical bases such as NaOMe/MeOH, this procedure
is not reproducible mainly due to retro-Michael addition (vide infra).
We found that EG-base promotes this conjugate addition very smoothly
to afford 5-substituted 4,4-dialkoxy-2-cyclohexenone 2 in high yield
with good reproducibility. In this paper are described the experimental
2
details of EG-base promoted Michael addition with 1.
The Michael addition of 1 under electrolysis was carried out as follows
methoxy-2,5-cyclohexadien-1-one 1b also reacted with dimethyl
malonate under electrolysis conditions using azobenzene as a pro-base
to give the corresponding Michael adducts 2b in 76% yields as a
mixture of diastereomers. This Michael addition is concluded to be
strongly affected by the structure of both Michael acceptor 1 and active
methylene compounds.
(Table 1, Entry 2): In a divided cell were fitted platinum electrodes (1 x
2
1.5 cm ) and stirring bars. In the cathodic room were added substrate (1
mmol), dimethyl malonate (1 mmol), azobenzene (0.04 mmol) as a pro-
base of EG-Base, Et NOTs (0.46 mmol), and CH CN (4 mL) as a
4
3
solvent, and in the anodic room were added a CH CN (4 mL) solution of
3
Et NOTs (0.46 mmol). These mixtures were electrolyzed for 9 h at the
4
2
constant current of 0.33 mA/cm (0.17 F/mol) under vigorous stirring
before the mixture was stirred for 13 h at room temperature without
passing electricity. The results were summarized in Table 1. As a pro-
base, azobenzene was found to be a best choice to give the Michael
adduct 2a quantitatively (Entry 2): 2-pyrrolidone (Entry 5), o-
nitrotoluene (Entry 6), 4-methylimidazole (Entry 7), and benzaldehyde
oxime (Entry 8) gave 2a in only moderate yields. Without pro-base, 2a
was also obtained in 79% yield after rather longer reaction time (24 h).
And also chemical base such as NaOMe/MeOH resulted in affording 2a
in moderate yield (Entry 1).
Solvents also affected the product yield (Entries 2, 3): A combination of
acetonitrile and Et NOTs gave the best results. In all cases, only the
4
desired product and starting material were obtained, no by-products
being detected.
When methyl acetoacetate and acetylacetone were used as active
methylene compounds, the second intramolecular Michael addition
occurred to give bicyclic compounds 3a and 3b in quantitative and 57%
4
yields, respectively, while no simple Michael adducts were detected.
Allylation of 2a with AllylBr/NaH in DMF at 0 °C gave 4a in 75%
Ethyl cyanoacetate and malononitrile also reacted with 1a to give the
corresponding Michael adducts in 13 and 20% yield. 4-Allyloxy-4-
yield. Acid-catalyzed deprotection of acetal moiety followed by
Torii, Sigeru
