Yufeng Ren,
Bo Yang and
Xiali Liao*
Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China. E-mail: xlliao@yahoo.com
First published on 17th February 2016
Well-designed amino-appended β-cyclodextrins (ACDs) with an amino side chain of different lengths at the primary face of β-CD were synthesized and employed in the catalytic synthesis of a series of tetraketones as supramolecular catalysts in water for the first time. Yields of 58–97% were obtained with up to 30 examples of substrate. The catalyst could be recycled easily, while a 92% yield and 84% rate of catalyst recovery could be achieved after 8 cycles of catalyst recycling. Moreover, a catalytic mechanism merging supramolecular catalysis and aminocatalysis could be proposed through detailed 1D and 2D NMR, ESI-MS and Job plot analyses. This protocol retained the promising characteristics of ambient temperature, green medium, simple operation, broad substrate scope, excellent yields, superb catalyst recycling performance and unique catalytic mechanism.
Due to the biological and chemical importances of tetraketones, synthesis of such molecules has provoked more and more interests of chemists. Varies of synthetic methods were reported involving pyridine,2 TEAB,3 In(OTf),3,5 metal hydroxides,11,12 L-proline,13 molecular iodine,14 HClO4–SiO2,15 nickel nanoparticles,16 choline chloride17 and nano SiO2Cl (ref. 18) as catalysts or without any catalyst.19 Nevertheless, more efficient and environmentally benign approaches to tetraketones are still in demand.
Cyclodextrins (CDs) are a family of oligosaccharides which are usually composed of 6, 7 or 8 D-glucose monomers linked by α-1,4-glycosidic bonds, referred to as α-, β- and γ-CD respectively.20,21 In terms of their virtues of aqueous solubilities, low toxicities and biodegradability, CDs are widely utilized in chemical, food, cosmetics and pharmaceutical fields.22–25 CDs have hydrophilic outer shell and hydrophobic inner cavity, which could encapsulate guest molecules to form host–guest inclusion complexes. Water insoluble drug molecules could improve their physicochemical properties such as water solubility, stability, bioavailability and even targeted drug delivery performance by formation of inclusion complexes with CDs.26–33 In the field of organic synthesis, CDs also play a remarkable role as supramolecular catalysts in various catalytic transformations such as oxidation, reduction, hydrolysis and condensation, etc.34–41 Among CD catalysts, β-CD is the most popular one due to its readiest availability. However, catalytic reactions using native β-CD have been severely limited by its relatively low water solubility and functional homogeneity. Chemical modification of β-CD has emerged as an effective approach to addressing this issue. Inspired by the powerful organocatalysis with amines in recent decades,42–46 we designed to combine the power of supramolecular catalysis and aminocatalysis by construction of amino-appended β-CD (ACD) catalysts.
Recently, β-CD catalysts modified with amino groups were employed in catalytic reactions such as oxidation,47 addition,48–51 selective protection of amines,52 cross-couplings53,54 and synthesis of heterocyclic compounds.55–57 However, the types of amino-containing groups appended to β-CD remain very limited to date, which has severely hampered their applications. Thus newly designed ACDs are in urgent need and are of great challenge. Considering the potential unique reaction mode inside the CD cavity accompanied by possible self-inclusion between CD and amino side chains of appropriate lengths58 and its impact on catalytic performance, ACDs (Fig. 1) with amino side chains of different lengths were designed and synthesized and their performances on catalytic synthesis of tetraketones were evaluated.
The obtained ACDs were subsequently thrown in the catalytic synthesis of tetraketones. The optimization of reaction conditions was performed with benzaldehyde and dimedone in water at room temperature (Table 1). β-CD could give the highest yield (73%) among α-, β- and γ-CD with a 5 mol% catalyst loading (entries 2–4), equaling to that without no catalysts (entry 1). Moderate yields were obtained when alkali metal salts (entries 5–7) or ammonium phase-transfer catalysts (entries 8 & 9) were used, while natural amino acids gave only low to moderate yields (entries 10–12). When ACDs were employed in this reaction, yields were promoted significantly, up to 81%, 80%, 90% and 92% with catalysts a0–a3, respectively (entries 13–16). Neither increasing nor decreasing the catalyst loading of a3 (to 2% or 10%) did bring benefit to the yield (entries 17 & 18). However, it rose to 96% when reducing the reaction time from 5 h to 1 h (entry 19), and fell down to 79% when further decreasing to 0.5 h (entry 20). Noticeably, the reaction temperature was found to play a crucial role on this reaction for the yield declined sharply as cooled to 0 °C (entry 21), which could be attributed to the decreased water solubility of a3 at such a low temperature. On the contrary, moderate to good yields could be obtained at higher temperatures (entries 22 & 23). Significant solvent effects were also observed while it gave 40% and 92% yields in ethanol and DMF respectively (entries 24 & 25), as DMF was normally a superior solvent like water for ACDs.
Entry | Catalyst (mol%) | Time (h) | Temp (°C) | Yieldb (%) |
---|---|---|---|---|
a General reaction conditions: benzaldehyde (1 mmol), dimedone (2.10 mmol), and water (5 mL) at r.t.b Isolated yield.c TBAC = tetrabutylammonium chloride.d TEAI = tetraethylammonium iodide.e Ethanol as the solvent.f N,N-Dimethylformide (DMF) as the solvent. | ||||
1 | None | 5 | r.t. | 73 |
2 | α-CD (5) | 5 | r.t. | 43 |
3 | β-CD (5) | 5 | r.t. | 73 |
4 | γ-CD (5) | 5 | r.t. | 41 |
5 | NaCl (5) | 5 | r.t. | 53 |
6 | NaBr (5) | 5 | r.t. | 60 |
7 | KBr (5) | 5 | r.t. | 63 |
8 | TBACc (5) | 5 | r.t. | 72 |
9 | TEAId (5) | 5 | r.t. | 76 |
10 | L-Proline (5) | 5 | r.t. | 75 |
11 | L-Cysteine (5) | 5 | r.t. | 22 |
12 | L-Aspartic acid (5) | 5 | r.t. | 58 |
13 | a0 (5) | 5 | r.t. | 81 |
14 | a1 (5) | 5 | r.t. | 80 |
15 | a2 (5) | 5 | r.t. | 90 |
16 | a3 (5) | 5 | r.t. | 92 |
17 | a3 (2) | 5 | r.t. | 89 |
18 | a3 (10) | 5 | r.t. | 90 |
19 | a3 (5) | 1 | r.t. | 96 |
20 | a3 (5) | 0.5 | r.t. | 79 |
21 | a3 (5) | 1 | 0 | 18 |
22 | a3 (5) | 1 | 55 | 94 |
23 | a3 (5) | 1 | 80 | 81 |
24e | a3 (5) | 1 | r.t. | 40 |
25f | a3 (5) | 1 | r.t. | 92 |
The best catalytic potency of catalyst a3 in water could be supported by the evidence that it had superior water solubility of up to 656.9 mg mL−1, which was also the best among ACDs (see ESI†).
With the optimized conditions in hand, the substrate scope was explored (Table 2). Reaction of dimedone with substituted benzaldehydes with either electro-donating or withdrawing groups all gave excellent yields of expected products (85–95%, entries 2–15), as well as naphthaldehyde and heterocyclic aromatic aldehydes (92–96%, entries 16–18). Two benzenedicarboxaldehydes were also screened and both gave high yields (entries 19 & 20). Aliphatic aldehydes including acyclic and cyclic ones were also found to be expedient substrates for this reaction (92–97%, entries 21–27). Besides, 7-fluoroisatin as an aldehyde analogue gave moderate yield (entry 28). Moreover, reactions of benzaldehyde with 1,3-cyclohexanedione or 4-hydroxy-6-methyl-2H-pyran-2-one gave very good yields (entries 29 & 30) as well.
Entry | Aldehyde | 1,3-Diketone | Time (h) | Product | Yieldb (%) | Mp (°C) | |
---|---|---|---|---|---|---|---|
Obs. | Lit. | ||||||
a General reaction conditions: aldehyde (1 mmol), diketone (2.10 mmol), a3 (0.05 mmol) in water (5 mL) at room temperature.b Isolated yields.c Dimedone: 4.20 mmol. | |||||||
1 | C6H5CHO (1a) | 2a | 1 | 3a | 96 | 205–207 | 204 (ref. 16) |
2 | 4-Me-C6H4CHO (1b) | 2a | 1 | 3b | 90 | 135–136 | 132–133 (ref. 62) |
3 | 3-OH-C6H4CHO (1c) | 2a | 5 | 3c | 95 | 243 | 248–250 (ref. 3) |
4 | 4-OH-C6H4CHO (1d) | 2a | 5 | 3d | 91 | 196–197 | 187–189 (ref. 59) |
5 | 4-OMe-C6H4CHO (1e) | 2a | 2 | 3e | 93 | 143 | 138 (ref. 62) |
6 | 3,4-(OMe)2-C6H3CHO (1f) | 2a | 2 | 3f | 91 | 183 | 186–189 (ref. 18) |
7 | 2,5-(OMe)2-C6H3CHO (1g) | 2a | 2 | 3g | 93 | 154–156 | 146–148 (ref. 5) |
8 | 3,4,5-(OMe)3-C6H2CHO (1h) | 2a | 2 | 3h | 96 | 195–196 | 189–191 (ref. 15) |
9 | 3-OMe-4-OH-C6H3CHO (1i) | 2a | 2 | 3i | 94 | 206–209 | 196–197 (ref. 60) |
10 | 4-Cl-C6H5CHO (1j) | 2a | 2 | 3j | 87 | 147–148 | 146–148 (ref. 18) |
11 | 4-F-C6H4CHO (1k) | 2a | 1 | 3k | 94 | 193–195 | 190–192 (ref. 18) |
12 | 3,4-Cl2-C6H3CHO (1l) | 2a | 2 | 3l | 85 | 194 | — |
13 | 2-NO2-C6H4CHO (1m) | 2a | 1 | 3m | 96 | 191–193 | 188–190 (ref. 3) |
14 | 3-NO2-C6H4CHO (1n) | 2a | 1 | 3n | 93 | 202–205 | 197–198 (ref. 59) |
15 | 4-NO2-C6H4CHO (1o) | 2a | 1 | 3o | 95 | 195 | 190 (ref. 16) |
16 | 2-Naphthaldehyde (1p) | 2a | 1 | 3p | 96 | 218 | — |
17 | 3-Pyridinecarboxaldehyde (1q) | 2a | 1 | 3q | 93 | 98 | — |
18 | 2-Thenaldehyde (1r) | 2a | 1 | 3r | 92 | 160–162 | 156–157 (ref. 61) |
19c | Terephthalaldehyde (1s) | 2a | 5 | 3s | 97 | 322–323 | — |
20c | Isophthalaldehyde (1t) | 2a | 5 | 3t | 90 | 303–305 | — |
21 | HCHO (1u) | 2a | 1 | 3u | 95 | 188–190 | 192–193 (ref. 60) |
22 | CH3CHO (1v) | 2a | 1 | 3v | 92 | 185–186 | 182–184 (ref. 60) |
23 | HCOCO2Et (1w) | 2a | 5 | 3w | 94 | 100–101 | — |
24 | Butyraldehyde (1x) | 2a | 1 | 3x | 97 | 120–122 | 130 (ref. 16) |
25 | Isobutyraldehyde (1y) | 2a | 1 | 3y | 96 | 153 | 153–154 (ref. 3) |
26 | 3-Methyl butanal (1z) | 2a | 1 | 3z | 94 | 170–171 | — |
27 | Cyclohexanaldehyde (1aa) | 2a | 1 | 3aa | 95 | 185–186 | — |
28 | 7-Fluoroisatin (1bb) | 2a | 5 | 3bb | 58 | 308 | — |
29 | C6H5CHO (1a) | 2b | 2 | 3cc | 96 | 213–215 | 207–208 (ref. 19) |
30 | C6H5CHO (1a) | 2c | 2 | 3dd | 90 | 174–175 | 167–169 (ref. 19) |
The reaction mechanism was then extensively studied by spectroscopic analyses. The formation of inclusion complexes of ACDs with substrates was demonstrated by 1H NMR spectra of a3, a3/4-nitrobenzaldehyde complex and freeze-dried reaction mixture of a3/4-nitrobenzaldehyde/dimedone in D2O (Table 3). It was observed that downfield shifts of H-3 (0.011 ppm) and H-5 (0.004 ppm) protons of a3/4-nitrobenzaldehyde complex (B) occurred compared to that of a3 (A), which indicated the formation of inclusion complex of 4-nitrobenzaldehyde with a3. Further study on the 1H NMR spectra of the freeze-dried reaction mixture of a3/4-nitrobenzaldehyde/dimedone (C) revealed that there were significant upfield shifts of H-3 (0.057 ppm), H-5 (0.088) and H-6 (0.034 ppm) compared to that of a3 (A). This indicated that dimedone was likely to react with 4-nitrobenzaldehyde by condensation inside the cavity of a3.
In order to further explore the possible interacting mode of catalyst a3 with substrates, the ROESY of the reaction mixture of a3/4-nitrobenzaldehyde/dimedone was recorded in D2O (Fig. 2). It showed appreciable correlation of aromatic protons (Ho, Hm) of 4-nitrobenzaldehyde with inner protons (H-3, H-5) of a3, namely, Hm correlated with both H-3 and H-5, while Ho only correlated with H-3 (Fig. 2(A)). Considering that H-3 is located at the side of the secondary face of a3, this suggested the probably spatial layout of 4-nitrobenzaldehyde in the cavity of a3 with the carbonyl group near to the secondary face of a3. Besides, there were significant correlations between the ethylene protons (H-en) of the amino side chain of a3 with H-3 and H-5 (Fig. 2(B)), which were consistent with that of native a3 (see ESI†). This indicated that the amino side chain inserted inside the cavity of a3 during the reaction.
Furthermore, electrospray ionization mass spectrometry (ESI-MS) analysis of a3/4-nitrobenzaldehyde complex was used to elucidate the host–guest interactions between a3 and 4-nitrobenzaldehyde. A quasi-molecular ion of 1396.5350 (m/z) was detected, which referred to the dehydration condensation product between a3 and 4-nitrobenzaldehyde (calcd: m/z = 1396.5360 for [M + H]+) (Fig. 3).
In addition, the inclusion mode of inclusion complexation of a3/4-nitrobenzaldehyde was studied by Job's method.63,64 Within the concentration scope, the Job plot showed a maximum at a molar fraction of 0.5 (Fig. 4), which indicated a 1:
1 inclusion stoichiometry between a3 and 4-nitrobenzaldehyde.
![]() | ||
Fig. 4 Job plot for the a3/4-nitrobenzaldehyde inclusion system at λ = 267.5 nm ([a3] + [4-nitrobenzaldehyde] = 8.0 × 10−5 M) in aqueous Na2CO3–NaHCO3 buffer (pH = 10.5). |
Thus the inclusion mode of a3/4-nitrobenzaldehyde could be demonstrated as patterns of 1:
1 or 2
:
2 (Fig. 5(A) and (B)). Though more evidences were still needed to verify them, they were surely ascribed to both non-covalent and covalent interactions between the host and guest, which merged supramolecular catalysis and aminocatalysis in this reaction.
Possible reaction mechanism for the a3-catalyzed synthesis of tetraketones was proposed based on the above information (Scheme 3). It could be initiated by the formation of iminium intermediate (1) from the dehydration condensation of 4-nitrobenzaldehyde with a3 inside the cavity of a3, followed by the nucleophilic addition of a dimedone. The resultant adduct subsequently underwent a deamination reaction to form the α, β-unsaturated diketone (2) by a H-transfer, towards which a Michael addition was carried out by another dimedone to furnish the tetraketone.
The recycling performance of catalyst a3 was evaluated with benzaldehyde, dimedone and a3 in water as a model reaction (Scheme 4). Almost pure product tetraketone could be obtained by filtration after the completion of the reaction, followed by washing the filter cake with water. The filtrate containing catalyst a3 could be reused directly after removal of tetraketone without any extraction of a3 from it, without significant loss of yield even after 8 cycles (Fig. 6). Moreover, the catalyst could be easily recovered with a rate up to 84% after 8 cycles from the filtrate by washing with some ethyl acetate followed by evaporation of the aqueous phase in vacuo.
Moreover, the synthetic application of this protocol was demonstrated by the gram-scale preparation of xanthendione and acridinedione from tetraketone (Scheme 5). Xanthenedione 4a could be obtained by refluxing in acetic acid with 89% yield while acridinedione 4b was synthesized in aqueous ammonium acetate solution with 85% yield.
Footnote |
† Electronic supplementary information (ESI) available: Spectral data of catalysts and products. See DOI: 10.1039/c6ra01002d |
This journal is © The Royal Society of Chemistry 2016 |