Synthesis of exocyclic α , β -unsaturated ketones

This review describes synthetic procedures for the preparation of selected groups of the most important exocyclic α , β -unsaturated ketones. Some of these α , β -enones, víz. aurones and 3-benzylidene-4-chromanones belong to the natural products. The others are synthetic substances which are convenient and especially important intermediates for the stereoselective synthesis of polycyclic ring systems. To illustrate the utility of any special procedures, relevant examples have been included. However, it is not the aim of the present review article to list and evaluate all the papers published in this field. Owing to the huge number of papers, such a goal would be an almost unrealizable task.


Preparation of arylidenecyclanones
Arylidenecyclanones are frequently used α,β-unsaturated ketones.Their most important synthesis is based on the reaction of the appropriate cyclic ketone with aldehydes, the well known aldol reaction, which was discussed in deatail by Nielsen and Houliham. 60For this reason, in this review article examples will be shown only for the synthesis of selected groups, víz.arylidenecyclopentanones, arylidenecyclohexanones and some hetero-analogues.

Synthesis of 2-arylidene-1-indanones
2-Arylidene-1-indanones ( 14) are important intermediates for the synthesis of a wide variety of heterocyclic ring systems.For this reason, it is useful to have simple and convenient procedures for their preparation.Most of the hitherto utilized syntheses are based on the condensation of 1indanones (13) with aldehydes in the presence of catalyst to afford E-2-arylidene-1-indanones
The above discussed procedures made possible the preparation of both diastereomers of the 2-arylidene-1-indanones ( 14) which can be used as intermediates for the stereospecific synthesis of a wide variety of heterocyclic ring systems.
by photoisomerization (Scheme 7). 94,100,125In this way both diastereomers became available as starting materials for the preparation of polycyclic organic compounds.

Synthesis of aurones
Aurones belong to the naturally occurring flavonoids and, therefore, their syntheses are usually described in comprehensive books of flavonoids. 1,3,4Since aurones can be considered oxa analogues of the 2-arylidene-1-indanones (14), it seemed expedient to include the most important procedures used for their preparation.
2'acetoxychalcones are first bromomethylated and the ring closure of the bromodihydro-chalcones provides aurones.However, none of these procedures can be considered as rational methods for the synthesis of aurones.
The most common synthetic procedures are based on the condensation of coumaran-3-ones (20) with benzaldehydes in the presence of catalyst to afford Z-aurones (21).Sodium hydroxide, 136,137 hydrochloric acid 138 or H 3 PO 4 139 were used as catalysts for this condensation (Scheme 9).

Scheme 10
Recently, a convenient one-step synthesis has been published. 149Equimolar amounts of (2methylthio)benzoic acid (24) and aromatic aldehydes were allowed to react with two equivalents of LDA in THF at 0 o C to yield Z-1-thioaurones (Z-23) (Scheme 11).

Scheme 12
For this reason, this condensation has also been performed under various reaction conditions.Farkas et al. [171][172][173] accomplished the reaction of the appropriate ketone and aldehyde in hot acetic anhydride, which is a very simple and convenient method, but sometimes it requires a prolonged (e.g.80 h) refluxing.This disadvantage may be a reason that this method has not become a widely used one.
On all these bases, it can be concluded that the 3-arylidene-4-chromanones (26) are not only useful intermediates for the synthesis of various heterocyclic ring systems but also for the preparation of naturally occurring homoisoflavones and their synthetic analogues.

Scheme 17
Prior to our own study, 210 neither inorganic nor organic bases had been used as catalysts for the preparation of 3-arylideneflavanones (34) by the condensation of flavanones (33) with aromatic aldehydes.We have introduced a very simple base-catalyzed condensation for the synthesis of E-3-arylideneflavanones (E-34).A mixture of equimolar amounts of flavanone (33)  and aromatic aldehyde and a few drops of piperidine was allowed to react at 150 o C and E-3arylideneflavanone (E-34) was obtained in good yield without any purification. 180,210Later, this simple and convenient method was used by other groups 11,12,211 to prepare E-3arylideneflavanones (E-34).It should be mentioned also that if benzaldehydes with strongly electron-withdrawing substituent(s) are used, 3-benzylflavones (35) can be prepared instead of E-3-benzylideneflavanones (E-34) by using a higher amount of piperidine for longer reaction times (Scheme 18).E-3-Arylideneflavanones (E-34) prepared by the above-discussed procedures have been converted into Z-3-arylideneflavanones (Z-34) (Scheme 17) by photoisomer-ization. 205,[213][214][215] The two diastereomers can be differentiated easily by NMR spectroscopic measurements.

Scheme 19
However, this procedure can be used only for the synthesis of Z-3-benzylidene-1thioflavanones substituted with electron donating or slightly electron-withdrawing substituent(s) in the benzylidene moiety.Where benzaldehydes substituted with strongly electron-withdrawing substituent(s) were used, 3-benzyl-1-thioflavones (38) were obtained as the sole isolable products (Scheme 20). 196,218It is worth mentioning that this is the first synthesis of the latter.Z-3-Arylidene-1-thioflavanones (Z-37) have been converted into their E-isomers (E-37) by photoisomerization. 197,215The two diastereomers can be differentiated by NMR spectroscopy.

Closing remarks
In this short review article the most important procedures used for the synthesis of both diastereomers of selected groups of α,β-unsaturated ketones have been compiled and discussed.These α,β-enones are useful intermediates for the stereoselective syntheses of a wide variety of heterocyclic compunds with a polycyclic skeleton.A major aim of the present review article has been to concentrate on exocyclic α,β-unsaturated ketones derived from heterocyclic ketones, víz.coumaran-3-ones, 4-chromanones and their thio analogues.
Literature data published until the end of June 2003 have been included to help the reader to find information appropriate for the synthesis of a particular exocyclic α,β-unsaturated ketone.