Synthesis of α , α-Bis ( substituted-arylidene ) Cycloalkanones : An improved Protocol

Commercially available potassium hydroxide (KOH), a simple base, was found to be a catalyst for tandem cross-aldol condensation between cyclic ketones and aromatic aldehydes leading to a fast and easy synthesis of α,α-bis (substituted-arylidene) cycloalkanones in the shortest times of all previous methods. The reaction of aryl aldehydes with five and six-membered cyclic ketones afforded excellent yields after few seconds in most cases. The reaction conditions were compatible with various electron withdrawing and electron donating substituents, e.g. Cl, F, NO2, OMe, Me and NMe2.

Usually, the aldol reaction is catalyzed by strong acid or base, however, the yield is low in common due to reverse and side-reactions 6 .Therefore, much effort on improvement of the reaction yield were performed, the main progress was the following: (1) Using Lewis 7 acid such as RuCl 3 , SmI 3 8 , BF 3 /Et 2 O 9,10 , FeCl 3 /6H 2 O 11 , Mg(HSO4) 2   12   , Yb(OTf) 3 13 , InCl 3 /4H 2 O 14 , LiClO 4   15   , SSA 16 , NKC-9 (polymer-supported sulfonic acid) 17 , SiO 2 -Pr-SO 3 H 18 , CH 3 CO 2 Na/CH 3 CO 2 H 19 as catalyst promoted the aldol reaction.(2) The aldol reaction was catalyzed by organometallic complexes but the yields were not satisfactory 20 or required long reaction time 21 .And (3) other catalyst such as I 2   22   , TMSCl/NaI 23 , LiOH 24 , KF/Al 2 O 3 25 , BMPTO 26 , NaOH in micellar medium 27 , KOH 28 and Na-HAP 29 were also found to accelerate this type reaction.However, the use of toxic reagents, long reaction time, low yields, formation of a mixture of products and tedious separation procedures are among the drawbacks of the reported methods.In continuation 30 of synthesis of these compounds in our research group, here we want to report an easy efficient and selective method for condensation of cyclic ketones with aromatic aldehydes under soft conditions in the presence of KOH as a cheap and commercially available catalyst (Scheme 1).

Experimental
To a 10 mL solution of KOH (0.11 g) in ethanol at 40 ºC in a round bottom flask, cyclic ketone (5 mmol) and aromatic aldehyde (10 mmol) was added and the mixture was stirred for 5-120 s.The resulting product was then isolated by simple filtration from the reaction mixture and given washings with water to remove any trace of KOH remaining on the product.

Results and Discussion
Synthesis of α,ά-bis(substituted benzylidene)cycloalkanones using KOH as catalyst already reported in chemistry literature 24,28 but in all of them time is long (Table 1), yield in some cases is moderate or low (Table 1) and in all of reported paper for synthesis of α,ά-bis(substituted benzylidene)cycloalkanones number of synthesized products are limited.
It is therefore important to find a more convenient method for improve this protocol for the synthesis of cyclic chalcones.The model reaction studied was the condensation of cyclopentanone with 4-methoxybenzaldehyde to yield a bisubstituted cyclohexanone (Scheme 1).When the mixture of cyclopentanone and 4-methoxybenzaldehyde was stirred at room temperature in presence of KOH in water (5, 10, 15 mL), only a trace amount of the product was observed.However, when solvent changed to ethanol, the yield of the product increased to 20, 45 and 30 % for 5, 10, 15 mL ethanol sequentially.The same reaction was also carried out in presence of 10 mL ethanol which gave 98% yield at 40 ºC in 5 s (Table 2, Entry 2).Thus, it can be said that amount of solvent can be improved yield of product and 10 mL of ethanol is the best.
Next, we also examined scope of the reaction by using various aryl aldehydes (electrondonating and electron-withdrawing groups) and cyclic ketones (cyclopentanone, cyclohexanone, 4-methyl cyclohexanone).The results are summarized in Table 2.In general, high yields of cross-aldol products were obtained in ethanol at 40 ºC for 5-120 s.

Conclusion
In conclusion, we have developed a easy, effective, quick and cost-effective procedure for the synthesis of α,α-bis(substituted-arylidene) cycloalkanones using commercially available KOH under mild conditions.Moreover, the high yield of products, no work-up need, ready availability of the catalyst, compatibility with various functional groups and the clean procedure, will make the present method a useful and important addition to the present methodologies for this synthesis.

Table 1 .
Comparison of our results with results obtained by other groups