A Facile Solvent Free Claisen-Schmidt Reaction: Synthesis of α,α′-bis-(Substituted-benzylidene)cycloalkanones and α,α′-bis-(Substituted-alkylidene)cycloalkanones

Solvent-free Claisen-Schmidt reactions of cycloalkanones with various substituted benzaldehydes (aryl aldehydes) using solid NaOH (20 mol%) and applying a grinding technique were studied. Quantitative yields (96–98%) of α,α'-bis-(substituted-benzylidene)cycloalkanones were obtained. Aliphatic aldehydes also provided α,α'-bis-(substituted-alkylidene)cycloalkanones in very good yields with minor amounts of α-(substituted-alkylidene)cycloalkanones. The catalytic performance of solid NaOH was examined. The molar ratio of NaOH was optimized. The catalytic effect of solid NaOH was also evaluated by comparing it with KOH, NaOAc, and NH4OAc and it turns out that 20 mol% of solid NaOH was good enough to catalyze the Claisen-Schmidt reactions of cycloalkanones with various substituted benzaldehydes. Additionally, the regioselectivity of the Claisen-Schmidt reaction of acetone with benzaldehyde was examined. Using the same method, we could synthesize the corresponding bis-benzylidene- and mono-benzylideneacetone separately in 98% and 96% yields, respectively.

In our recent studies, we have synthesized ,-bis-(substituted-benzylidene)-cycloalkanones and substituted-benzylidene heteroaromatics using NaOAc [74] and NH 4 OAc [75] as catalysts. Due to the importance of the Claisen-Schmidt reaction in synthetic organic chemistry and of ,-bis-(substituted-benzylidene)-cycloalkanones as precursor for various natural products, we wish to report herein a facile solvent-free Claisen-Schmidt reaction using a grinding technique for the synthesis of ,-bis-(substituted-benzylidene)cycloalkanones, di-and/or mono-benzylidene acetone and benzylidene camphor using solid NaOH as catalyst.

,-bis-(Substitutedbenzylidene)cycloalkanones
The Claisen-Schmidt reaction of cyclopentanone (1a, 10 mmol) or cyclohexanone (1b, 10 mmol) with benzaldehyde (2a, 20 mmol) in the presence of an equimolar amount of solid NaOH without any solvent after grinding with a mortar and pestle for 5 min. afforded the corresponding ,-bisbenzylidenecyclopentanone (3a) or ,-bis-benzylidenecyclohexanone (3e), both in 99% yield (Scheme 1).  We next examined the catalytic ability of NaOH by grinding cyclohexanone (1b, 10 mmol) with benzaldehyde (2a, 20 mmol) in presence of various molar ratios of NaOH (1-100) using the same procedure to afford the corresponding ,-bis-benzylidenecyclohexanone (3e). The results indicate that 20 mol% of NaOH gave satisfactory yield (98%) compared with a stoichiometric amount of NaOH. The results are summarized in Table 1. It should be noted that 10 mol% of NaOH gave 95% of the corresponding target compound 3e, while 80 mol% and an equimolar amount of NaOH gave 99% yields. Furthermore, we evaluated the effect of NaOH on the Claisen-Schmidt reaction of cyclohexanone (1b) with benzaldehyde (2a) over KOH and our previously reported catalysts NaOAc [74], and NH 4 OAc [75], ( Table 2). The highest yield (98%) was achieved using 20 mol% of solid NaOH after grinding with a mortar and pestle for 5 minutes (entry 1, Table 2), while a slightly lower yield (85%) was obtained with 20 mol% of solid KOH (entry 2, Table 2). In addition, different experimental conditions were also applied to optimize the catalytic performance of solid NaOH by introducing solvent (EtOH) at room temperature as well as under refluxing conditions. When we stirred the reaction mixture with 20 mol% of NaOH in ethanol at room temperature for 24 hours (entry 3, Table 2), the product was obtained, but with low yield (40%), and much longer time (5 days) was required to obtain a 66% yield (entry 5, Table 2). After having no promising results with stirring at room temperature for 5 days, we then heated the reaction mixture of cyclohexanone (1b) and benzaldehyde (2a) to reflux for 8 hours with 20 mol% of NaOH in ethanol and this afforded the corresponding ,bis-benzylidenecyclohexanone (3e) in 93% yield (entry 3, Table 2). Comparing all the results (entries 1 to 6, Table 2) with our previously reported methods (entries 7 and 8, Table 2) [74,75], we found that 20 mol% of solid NaOH and grinding with a mortar and pestle for 5 minutes is better than any other catalyst (such as KOH, NaOAc and NH 4 OAc tested) for the Claisen-Schmidt reaction of cyclohexanone (1b) with benzaldehyde (2a). Subsequently, we examined the scope and limitation of NaOH (20 mol%) as catalyst for the Claisen-Schmidt reaction of selected cycloalkanones (1a and 1b) and a number of electronically modified aryl aldehydes 2a-h employing grinding with a mortar and pestle for 5 minutes without any solvent to afford the corresponding ,-bis(substituted-benzylidene)cycloalkanones 3a-h; the results are summarized in Table 3. The electronic nature of the substituent on the benzene ring of compounds 2a-h and the ring size of cycloalkanones (compounds 1a and 1b) did not affect the reaction and high yields (96-98%) were obtained for all the entries. We then attempted to prepare substituted-alkylidenecycloalkanones 3i and 3j from the reactions of cyclohexanone (1b) with acetaldehyde (2g) and iso-propanal (2h) using the optimized molar ratio of solid NaOH (20 mol%) to obtain the corresponding 2,6-bis-ethylidenecyclohexanone (3i) and 2,6-bis-isobutylidenecyclohexanone (3j). It should be noted that we obtained a small amount of mono-substituted alkylidenecycloalkanone (4a and 4b) along with the desired major products 3i and 3j (Scheme 2) and the conversion of 1b was 100%.

Reaction of Acetone (5) with Benzaldehyde (2a)
The Claisen-Schmidt reaction for acetone (5, 10 mmol) and benzaldehyde (2a, 20 mmol) was conducted for the preparation of bis-benzylidene acetone (6) using similar reaction conditions as shown in scheme 2, but the reaction time was only for 2 min. instead of 5 (Scheme 3). The reaction of 5 with 2a gave a mixture of 6 and 7 in 53% and 42% yields, respectively.  Then we examined the regioselectivity of the reaction and the results are summarized in Table 4. Use of excess amount of 5 (5 equiv.) resulted in mainly 7 (96%) with a trace amount of 6, while on the other hand, when we used an excess of 2a (3 equiv.) bis-benzylideneacetone was obtained in 98% yield as a single product.

General
Melting points were recorded on a Fisher-Jones melting point apparatus and are uncorrected. Nuclear magnetic resonance (NMR) spectra were recorded using a Bruker 250 spectrometer (250 MHz for 1 H-NMR and 62.5 MHz for 13 C-NMR) and are reported in parts per million (ppm) from the internal standard tetramethylsilane. Electrospray ionization (ESI) mass spectrometry (MS) experiments were performed on LCQ advantage-trap mass spectrometer (Thermo Finnigan, San Jose, CA, USA).

Conclusions
A facile solvent-free Claisen-Schmidt reaction between cyclopentanone (1a)/cyclohexanonoe (1b) and different substituted benzaldehydes 2a-h catalyzed by solid NaOH (20 mol%) by applying a grinding technique using a mortar and pestle for 5 minutes was performed, resulting in excellent yields (96-98%) of the corresponding ,-bis(substituted-benzylidene)cyclo-alkanones 3a-h. The Claisen-Schmidt reaction using NaOH was optimized and it turned out that 20 mol% of NaOH is sufficient to perform the reactions. The catalytic effect was also examined and we found 20 mol% of solid NaOH is better than any other catalyst tested such as KOH, NaOAc and NH 4 OAc, for the Claisen-Schmidt reaction under solvent free condition. Beside aryl aldehydes, alkyl aldehydes were also converted to their corresponding bis-alkylidenecycloalkanones along with a little mono alkylidene cycloalkanone by the method in question. Additionally, we examined the regioselectivity of the Claisen-Schmidt reaction by reacting acetone (5) with benzaldehyde (2a) leading to give the corresponding bis-benzylideneacetone in 98% yield using the same method.