Ca(OH)2-Catalyzed Condensation of Aldehydes with Methyl ketones in Dilute Aqueous Ethanol: A Comprehensive Access to α,β-Unsaturated Ketones.

Cheap, abundant but seldom-employed Ca(OH)2 was found to be an excellent low-loading (5-10 mol%) catalyst for Claisen-Schmidt condensation of aldehydes with methyl ketones under mild conditions. It was interesting that dilute aqueous ethanol (20 v/v%) was unexpectedly discovered to be the optimal solvent. The reaction was scalable at least to 100 mmol and calcium could be precipitated by CO2 and removed by filtration. Evaporation of solvent directly afforded the product in the excellent 96% yield with high purity, as confirmed by its (1)H NMR spectrum.

α,β-Unsaturated ketones, including dimethylidene acetone derivatives, are not only important building blocks in organic synthesis, but also key chemicals in many fields including perfumery, biochemistry, agriculture, food chemistry, polymer and material science, and others1234. Therefore, the synthesis of these compounds is of great importance in both academic and industrial circles. Among reported works, Claisen-Schmidt condensation appears to be the most practical method to prepare α,β-unsaturated ketones owing to its directness, clean procedures and accessible starting materials. Despite being discovered over 100 years ago, the enthusiasm for Claisen-Schmidt condensations never reduces and in recent years, a series of novel catalysts have been developed for this reaction, such as solid bases56, nano catalysts78, ionic liquid catalysts9, fluorous based catalysts1011, metal-organic frame works (MOFs)12 and organocatalysts1314. Nevertheless, cheap and abundant NaOH would be expected to be the most common catalyst for the reaction due to its availability in laboratory, and indeed this method is still widely employed up to the present151617. But reactions performed in strong alkaline conditions are corrosive to equipment and generate unmanageable and corrosive solid waste. These drawbacks have limited the large-scale application of NaOH. Moreover, methods for the synthesis of dimethylidene acetone derivatives, especially for those dissymmetrically substituted compounds, have not been well documented yet. Thus, developing novel alternative synthetic methodologies with broad scope using mild and common base catalysts is not only desirable but timely for the field.

Calcium hydroxide is also a readily accessible base and compared with NaOH, it is much cheaper and less alkaline. Moreover, Ca(OH)2 is easily neutralized and precipitated by CO2, which is beneficial from the point of industrial use. However, despite several well-known applications in industrial production, examples of the employment of Ca(OH)2 as a base catalyst in organic synthesis are rare18. As part of our continuing cooperative research projects with industrial partners to develop green synthetic methodologies19202122232425262728, we reported an organoselenium-catalyzed green oxidation of α,β-unsaturated ketones to prepare vinyl esters, which serve as versatile copolymers in material science24. To facilitate industrial application, a green and practical synthesis of α,β-unsaturated ketones (the starting material for vinyl ester synthesis) was desired. To that end, we investigated the Ca(OH)2-catalyzed Claisen-Schmidt condensations to prepare α,β-unsaturated ketones. During this work, dilute aqueous ethanol was unexpectedly found to be the optimal solvent and calcium could be precipitated by CO2 and removed by filtration to afford high purity products after solvent evaporation. The method allows comprehensive access to versatile α,β-unsaturated ketones, including the challenging dissymmetrically substituted dimethylidene acetone derivatives. Herein, we wish to report our findings.

Results

We initially chose the Ca(OH)2-catalyzed Claisen-Schmidt condensation of benzaldehyde 1a with acetone 2a as the model reaction to find optimal conditions (Fig. 1). After heating 1a, 2a and 10 mol% of Ca(OH)2 in EtOH at 50 °C for 20 h, the product benzylideneacetone 3a could be isolated in 68% yield (Table 1, entry 1). During the reaction process, we observed Ca(OH)2 precipitation at the bottom of the tube, which implied the low efficiency of alkali utilization. Therefore, water was then added to increase the Ca(OH)2 solubility. When the reaction was performed in EtOH/H2O (80:20), it was significantly accelerated and finished in 16 h, giving 3a in 69% yield (entry 2). The reaction was further accelerated and the product yields were enhanced greatly by increasing the proportional of water in the solvent (entries 3–4). Surprisingly, EtOH/H2O (20:80) as solvent gave the highest product yield in 85% (entry 4). Increased ratios of water in the solvent only resulted in reduced product yield and extended reaction times (entry 5), possibly due to the reduced substrate dissolution that inhibited the reaction. When the reactions were taken in highly diluted aqueous EtOH (entry 6) or pure water (entry 7), no product 3a was observed. It is notable that the combination of EtOH with water played a key role in this reaction. A series of parallel reactions showed that the effect of EtOH/H2O was not only solvent for both organic substrates and inorganic base, but it also activated the Ca(OH)2. Experiments performed in acetone or acetone/EtOH resulted in very low product yields despite the reaction temperature. For details, please see the Supplementary Information.

Figure 1

Condensation of 1a with 2a.

Table 1

Optimization of the reaction conditionsa.

Entry	EtOH/H2Ob	t/h	3a/%c
1	100:0	20	68
2	80:20	16	69
3	50:50	14	84
4	20:80	10	85
5	10:90	24	79
6	5:95	36	0
7	0:100	36	0

aReaction conditions: 1 mmol 1a, 3 mmol 2a, 0.1 mmol Ca(OH)2 and 1 mL of solvent were employed.

bVolume ratio of EtOH with water.

cIsolated yields of 3a based on 1a.

With the optimized conditions in hand, a series of aldehydes 1 and ketones 2 were then employed to examine the scope of the reaction (Fig. 2). Results in Table 2 clearly show that the electron-enriched aldehydes had reduced reactivities for this reaction, which resulted in both extended reaction times and decreased product yields (Table 2, entries 2–5 vs. 1). For 4-methoxybenzaldehyde 1e, the reaction should be carried out at room temperature with excess acetone, otherwise the dialkylated product (1E,4E)-1,5-bis(4-methoxyphenyl)penta-1,4-dien-3-one 4c was obtained instead of the desired (E)-4-(4-methoxyphenyl)but-3-en-2-one 3e (Table 2, entry 5). The electron-deficient aldehydes obviously had higher reactivities and their reactions were accelerated, but resulted in reduced product yields due to the generation of a series of unidentified byproducts (Table 2, entries 6–11). The reactions of electron-deficient aldehydes could be improved using milder conditions. For example, treating 2-chlorobenzaldehyde 1h with acetone under the standard reaction conditions (50 °C) afforded the product 3h in only 40% yield, but the yield could be improved of room temperature (ca. 25 °C), affording 3h in 52% yield (Table 2, entry 8). Similarly, for 4-(trifluoromethyl)benzaldehyde 1j, reaction with acetone under standard conditions gave 3j in very low yield, but was also improved to 72% at room temperature (Table 2, entry 10). The reaction of 4-nitrobenzaldehyde 1k with acetone led to poor product yield, but this was improved at room temperature (Table 2, entry 11). Bulky aldehyde 1l was also tested, giving the desired product 3l in moderate yields (Table 2, entry 12). We were also interested in the synthesis of heterocycle containing α,β-unsaturated ketones because of their bioactivities and potential applications in medicinal chemistry. The reaction of picolinaldehyde 1m with acetone was tested, but gave 3m in very low yield. Fortunately, the reaction could be improved to give 3m in moderate yield under milder conditions using excess acetone (Table 2, entries 13). Interestingly, the reaction of thiophene-2-carbaldehyde 1n with acetone afforded 3n quickly in the excellent 90% yield under the standard conditions (Table 2, entry 14). The α,β-unsaturated aldehyde 1o was also good substrate for the reaction, giving 3o in 91% yield (Table 2, entry 15). The reaction of aliphatic aldehyde gave the product in low yield (Table 2, entry 16).

Figure 2

Substrate extension of the Ca(OH)2-catalyzed Claisen-Schmidt condensation.

Table 2

Substrate extension of the Ca(OH)2-catalyzed Claisen-Schmidt condensationa.

Entry	1: R1; 2: R2	3: t/hb, yield/%c
1	1a: Ph; 2a: Me	3a: 10 h, 85
2	1b: 4-MeC6H4; 2a: Me	3b: 36 h, 83
3	1c: 3-MeC6H4; 2a: Me	3c: 24 h, 67
4	1d: 2-MeC6H4; 2a: Me	3d: 28 h, 60
5	1e: 4-MeOC6H4; 2a: Me	3e: 48 h, 61d,e
6	1f: 4-FC6H4; 2a: Me	3f: 9h, 78
7	1g: 4-ClC6H4; 2a: Me	3g: 10 h, 72
8	1h: 2-ClC6H4; 2a: Me	3h: 8 h, 52d
9	1i: 4-BrC6H4; 2a: Me	3i: 10 h, 71
10	1j: 4-CF3C6H4; 2a: Me	3j: 24 h, 72d
11	1k:4-NO2C6H4; 2a: Me	3k: 8 h, 50d
12	1l:1-C10H7; 2a: Me	3l: 36 h, 58
13	1m: 2-C5H4N-; 2a: Me	3m: 24 h, 55d,f,g
14	1n: 2-C4H3S-; 2a: Me	3n: 10 h, 90
15	1o: E-PhCH = CH-; 2a: Me	3o: 30 h, 91
16	1p: c-C6H11; 2a: Me	3p: 48 h, 30h,i
17	1a: Ph; 2b: Ph	3q: 18 h, 71
18	1a: Ph; 2c: 4-MeC6H4	3r: 48 h, 61h
19	1a: Ph; 2d: 4-ClC6H4	3s: 40 h, 68
20	1a: Ph; 2e: n-Bu	3t: 48 h, 54h,i
21	1a: Ph; 2f: i-Pr	3u: 48 h, 60h

aReaction conditions: without special instructions, 1 mmol of 1, 3 mmol of 2 and 0.1 mmol Ca(OH)2 were heat in 1 mL of EtOH/H2O (20 v/v%) at 50 °C.

bReactions monitored by TLC (eluent: petroleum ether/EtOAc 9:1).

cIsolated yields based on 1.

dReaction performed at room temperature (ca. 25 °C).

e10 mmol of acetone was employed.

fCa(OH)2 loading was reduced to 5 mol%.

g1 mL of acetone was employed.

hReaction uncompleted.

iReaction performed at 120 °C in a pressure tube.

Besides acetone, other methyl ketones could also be employed. The reaction of acetophenone 2b with benzaldehyde 1a led to 3p in 71% in 18 h (Table 2, entry 17). But the electron-riched substrate 2c obviously had lower reactivity and the reaction did not complete even after 48 h (Table 2, entry 18). Reaction of the electron-deficient substrate 2d with 1a led to their product 3r in 68% yield in 40 h, with a series of unidentified by-products observed by TLC (Table 2, entry 19). Reactions of the alkyl methyl ketones 2e and 2f with 1a afforded the corresponding products 3s and 3t in moderate yields (Table 2, entries 20–21). A more detailed substrate expansion table was also given in the Supplementary Information.

The synthesis of the dimethylidene acetone derivatives was our next concern because of the great application potential of these bioactive compounds (Fig. 3). Fortunately, during the previous optimization study, we serendipitously found that the symmetrically substituted dibenzylidene acetone 4a could be easily synthesized in good yield from 1a and 2a at 80 °C (Table 3, entry 1). As shown in Table 3, other symmetrically substituted dimethylidene acetone derivatives could be smoothly synthesized in this way. Obviously, the electron-enriched aldehydes 1b and 1e had poor reactivity for the reaction, giving 4b and 4c in only 31–39% yields (Table 3, entries 2–3). The electron-deficient aldehydes 1f and 1j were much more activated (Table 3, entries 4–5), and the reaction of 1j with acetone even led to 4e in excellent 92% yield (Table 3, entry 5). Heterocycle-substituted aldehydes were also suitable substrates for the reaction, giving corresponding products in moderate to good yields (Table 3, entries 6–7).

Figure 3

Synthesis of symmetrically substituted dimethylidene acetone derivatives.

Table 3

Synthesis of symmetrically substituted dimethylidene acetone derivativesa.

Entry	1: R	4: yield/%b
1	1a: Ph	4a: 84
2	1b: 4-MeC6H4	4b: 39
3	1e: 4-MeOC6H4	4c: 31
4	1f: 4-FC6H4	4d: 78
5	1j: 4-CF3C6H4	4e: 92
6	1n: 2-C4H3S-	4f: 62
7	1p: 2-C4H3O-	4g: 80

aReaction conditions: 2 mmol 1, 1 mmol 2 and 0.1 mmol Ca(OH)2 were heat in 1 mL of EtOH/H2O (20 v/v%) at 80 °C.

bIsolated yields based on 2a.

We also tried to synthesize the dissymmetrically substituted dimethylidene acetone derivatives using this Ca(OH)2-catalyzed methodology (Fig. 4). Initially, the reaction of aldehyde 1a with a stoichiometric amount of 3a led to 4a in 82% yield (Table 4, entry 1). This two-step protocol was then employed to synthesize other dissymmetrically substituted dimethylidene acetone derivatives. Treating aldehydes 1b-q with 3a at 80 °C in the presence of Ca(OH)2 catalyst afforded the corresponding products 4h-4n smoothly (Table 4). The electron-deficient aldehydes led to higher product yield than the electron-riched aldehydes (Table 4, entries 4–5 vs. 2–3). Heterocycle-contained aldehydes 1n and 1p were also fit for the reaction (Table 4, entries 6–7), but the alkyl substrate 1q resulted in poor product yield (Table 4, entry 8).

Figure 4

Synthesis of dissymmetrically substituted dimethylidene acetone derivatives.

Table 4

Synthesis of dissymmetrically substituted dimethylidene acetone derivativesa.

Entry	1: R	4: yield/%b
		Multi-stepc	One-pot
1	1a: Ph	4a: 82 (70)	4a: 71
2	1b: 4-MeC6H4	4h: 62 (53)	4h: 68
3	1e: 4-MeOC6H4	4i: 52 (44)	4i: 46
4	1f: 4-FC6H4	4j: 81 (69)	4j: 75
5	1j: 4-CF3C6H4	4k: 90 (77)	4k: 92
6	1n: 2-C4H3S-	4l: 68 (58)	4l: 61
7	1p: 2-C4H3O-	4m: 72 (61)	4m: 80
8	1q: c-C6H11-	4n: 24 (20)	4n: 21

aReactions were performed in 1 mL of EtOH/H2O (20 v/v%) catalysed by 0.1 mmol of Ca(OH)2.

bIsolated yields. cTotal yields from 1a and 2a in parentheses (×85%).

The synthetic efficiency could be improved using a one-pot strategy. Although the product yields of the one-pot synthesis were reduced in some cases (Table 4, entries 1,3–4, 6–8), considering of the loss of the starting materials in 3a preparation step (Table 2, entry 1, 85% yield), their total yields were higher than that of the multi-step methods (Table 4, entries 1–8).

The role of Ca(OH)2 in the reaction was investigated through a series of control experiments. Using 20 mol% of NaOH as base afforded 3a in only 47% yield (Table 5, entry 1). But with the addition of 10 mol% of the neutral CaCl2, the yield of 3a could be largely enhanced to 78% (Table 5, entry 5). Similar phenomena were also observed in reactions using organic bases (Table 5, entries 3 vs 4). LiOH, an alkali weaker than NaOH, but with a “hard” alkali metal, led to a significantly elevated 3a yield (Table 5, entries 5 vs 1). These experimental results suggested that the “hard” Ca2+ is the key factor for the excellent catalytic performance.

Table 5

Control experimentsa.

Entry	Cat. (mol%)	3a yield/%b
1	NaOH (20)	47
2	NaOH (20) + CaCl2 (10)	78
3	Et3N (20)	35
4	Et3N (20) + CaCl2 (10)	53
5	LiOH (20)	71

a1 mmol 1a, 3 mmol 2a, and 1 mL of solvent were employed.

bMolar ration based on 1a in parentheses.

cIsolated yields based on 1a.

Finally, to examine the practicability of the method, a 100 mmol scale reaction of 1a with 2a was performed. After the reaction, calcium was precipitated by CO2 and removed through filtration. Evaporation of the solvent directly afforded 3a in 96% yield with high purity (Fig. 5), as confirmed by its 1H NMR spectrum (Fig. 6).

Figure 5

The simple separation procedure for the product.

Figure 6

1H NMR spectrum of the product 3a after the evaporation of solvent.

Conclusion

In conclusion, we have developed a practical synthesis of α,β-unsaturated ketones, including the symmetrically or dissymmetrically substituted dimethylidene acetone derivatives, which are promising compounds for medicinal chemistry. The method employed very low loading (5–10 mol%) Ca(OH)2 catalyst, which could be removed by CO2. The reactions were performed in cheap and benign dilute aqueous ethanol (20 v/v%). This work shows that Ca(OH)2, the abundant but seldom employed base, might find further application in organic synthesis.

Methods

General Considerations

Aldehydes were purchased from the reagent merchant. The liquid aldehydes were distilled under vacuum before use, while the solid aldehydes were recrystallized in EtOH-H2O under N2 before use. Ethanol was analytical pure (AR) and directly used without any special treatment. All reactions were carried out in N2 and monitored by TLC. Melting points were measured by WRS-2A digital instrument. IR spectra were measured on Bruker Tensor 27 Infrared spectrometer. 1H and 13C NMR spectra were recorded on a Bruker Avance 600/400 instrument (600 or 400 MHz for 1H and 150 MHz for 13C NMR spectroscopy) using CDCl3 as the solvent and Me4Si as the internal standard. Chemical shifts for 1H and 13C NMR were referred to internal Me4Si (0 ppm) and J-values were shown in Hz. Mass spectra were measured on a Shimadzu GCMS-QP2010 Ultra spectrometer (EI).

Typical procedure for the synthesis of 3

0.1 mmol of Ca(OH)2 (7.4 mg) was first added into a reaction tube, which was then charged with N2. A solution of 1 mmol of aldehyde 1 and 3 mmol of methyl ketone 2 in EtOH/H2O (1 mL, 20 v/v%) was then injected into the reaction tube. The mixture was heat at 50 °C under N2 protection and the reaction was monitored by TLC. When the reaction terminated, the solvent was evaporated under vacuum and the residue was purified by preparative TLC (eluent: petroleum ether/EtOAc, 2: 1 for 3m, 15: 1 for rest compounds).

Typical procedure for the synthesis of symmetrically substituted dimethylidene acetone derivatives 4

0.1 mmol of Ca(OH)2 (7.4 mg) was first added to a reaction tube, which was then charged with N2. A solution of 2 mmol of aldehyde 1 and 1 mmol of acetone 2a in EtOH/H2O (1 mL, 20 v/v%) was then injected into the reaction tube, which was then sealed under N2 and heat at 80 °C for 48 h. The reaction mixture was isolated by preparative TLC (eluent: petroleum ether/EtOAc, 15: 1).

Typical procedure for the synthesis of dissymmetrically substituted dimethylidene acetone derivatives 4 (multi-step)

0.1 mmol of Ca(OH)2 (7.4 mg) and 1 mmol of 3a were added into a reaction tube, which was then charged with N2. A solution of 1 mmol of aldehyde 1 in EtOH/H2O (1 mL, 20 v/v%) was then injected into the reaction tube. The mixture was heat at 80 °C under N2 for 48 h and then isolated by preparative TLC (eluent: petroleum ether/EtOAc, 15: 1).

Typical procedure for the synthesis of dissymmetrically substituted dimethylidene acetone derivatives 4 (one-pot)

0.1 mmol of Ca(OH)2 (7.4 mg) was first added into a 10 mL round bottom flask, which was then charged with N2. A solution of 1 mmol of aldehyde 1 and 3 mmol of methyl ketone 2 in EtOH/H2O (1 mL, 20 v/v%) was then injected into the reaction tube. The mixture was heat at 50 °C under N2 protection. After 10 h, the solvent was evaporated under vacuum and another solution of 1 mmol of aldehyde 1 in EtOH/H2O (1 mL, 20 v/v%) was then injected. The mixture was heat at 80 °C under N2 for 48 h and isolated by preparative TLC (eluent: petroleum ether/EtOAc, 15:1).

Procedure for the large-scale reaction

To a 250 mL three-neck flask, 10 mmol of Ca(OH)2 (0.74 g) was added. The flask was then charged with N2. A solution of 100 mmol of benzaldehyde 1a and 300 mmol of acetone 2a in 100 mL EtOH/H2O (20 v/v%) was then injected. The mixture was stirred at 50 °C under N2 protection for 10 h and then cooled to room temperature. CO2 was then charged into the liquid and the pH was controlled to 7.0 (monitored by a pH meter). The precipitated CaCO3 was removed by filtration and the filtrate was collected. After the evaporation of the solvent, 14.0 g of the product 3a was obtained in the excellent 96% yield. The product was directly sent to 1H NMR analysis without any further purification and the results in Fig. 2 confirmed its high purity.

Additional Information

How to cite this article: Yu, L. et al. Ca(OH)2-Catalyzed Condensation of Aldehydes with Methyl ketones in Dilute Aqueous Ethanol: A Comprehensive Access to a,β-Unsaturated Ketones. Sci. Rep. 6, 30432; doi: 10.1038/srep30432 (2016).