HETEROCYCLES

Paper | Regular issue | Vol. 92, No. 6, 2016, pp. 1031-1039
Received, 3rd February, 2016, Accepted, 24th March, 2016, Published online, 8th April, 2016.

■ 1-Methylimidazolium Trifluoroacetate Efficiently Catalyzed Three Component Synthesis of Diazaspiro[5.5]undecane-1,5,9-trione Derivatives under Solvent-Free Conditions

Zhaohui Xu,* Houfu Zhang, Chunhua Lin, and Deyong Liu

College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330027, China

Abstract

A simple, green and efficient method for the synthesis of 2,4-dioxa- 8,10-diazaspiro[5.5]undecane-1,5,9-trione derivatives has been developed by the reaction of aromatic aldehydes with urea and 1,3-dioxane-4,6-dione catalyzed by 1-methylimidazolium trifluoroacetate under solvent-free conditions.

INTRODUCTION
Nitrogen-containing heterocyclic compounds have attracted considerable attention1 owing to their potential involvement as key component for various pharmacological activities.2,3 Among the various spiroheterobicyclic compounds, 2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-trione derivatives exhibit
antiviral, antitumor, antihypertensive, anti-HIV, narcotic and analgesic.4-7 In addition, there are also spiroheterocyclic units in several bioactive natural products.8-10 Therefore the preparation of spiroheterobicyclic derivatives is of much current importance.
Diverse synthetic methodologies available for the synthesis of 2,4-dioxa-8,10-diazaspiro[5.5]undecane-
1,5,9-trione derivatives have been developed. One type of spiroheterocycles was generally synthesized from the reaction of aromatic aldehydes, 2,2-dimethyl-1,3-dioxane-4,6-dione and urea in the presence of
either Brønsted acids (cellulosesulfuric acid,11 H7P2W18VO62,12 and p-toluenesulfonic acid13) or Lewis acids (iodine,14 TMSCl,15,16 SnCl2,17 NiCl2,18 NBS/AIBN,19 and boric acid20), or without any catalyst,21 or microwave irradiation.22 However, many of these methodologies have not been entirely satisfactory, suffering drawbacks from low yields, long reaction times, high catalyst loading, environmentally unfavorable solvents, and tedious work-up, to waste production. Thus, an efficient, and enviromentally friendly method using economical catalyst is actively desirable.
In recent years, ionic liquids (ILs) have attracted increasing interests and been successfully used in a variety of catalytic reactions due to their relatively low viscosities, low vapor pressure, and high thermal and chemical stability.23-25 Protic ionic liquids, in particular, can play dual roles, as both solvent and catalyst,26,27 in some reactions like Biginelli and Hantzsch reactions.28,29 Herein, we report 1-methylimidazolium trifluoroacetate ([Hmim][TFA]) as an effective and reusable catalyst for the synthesis of 3,3-butylidene-2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-trione derivatives. Moreover, this reaction condition can also be successfully applied to 2,2-pentamethylene-1,3-dioxane-4,6-dione system and furnish the desired products in good to excellent yields (Scheme 1).

RESULTS AND DISCUSSION
Reactions were started by examing the rection of benzaldehyde (10 mmol), urea and 2,2-butylidene-1,3-dioxane-4,6-dione as model reaction. As is shown in Table 1, without catalyst, only a trace amount of product was detected in glycerol, polyethylene glycol 400, ethylene glycol and water (Table 1, Entries 1-4). While the reaction proceeded sluggishly in DMF and DMSO, a huge improvement was obtained in toluene, EtOH and ethyl acetate, and the yield reached to 62% effectively under neat conditions (Table 1, Entries 5-10). However, under solvent-free conditions the highest yield was obtained in the persence of 15 mol% [Hmim]TFA (Table 1, Entry 12). The catalyst ([Hmim][TFA]) plays a crucial role in the success of the reaction in terms of the yields. Increasing the dosage of catalyst to 20 and 25 mol% resulted in improving reaction yields to 85% and 85% respectively at 80 oC (Table 1, Entries 12, 13). Use of just 15 mol% [Hmim][TFA] is sufficient to push the reaction forward. Higher amounts of the catalyst did not enhance yields. Thus, 15 mol% [Hmim][TFA] was chosen as a quantitative catalyst for these reactions. The optimum reaction time and reaction temperature were also found respectively. The best result was obtained when the reaction was conducted at 80 oC, for 4.0 h, in the presence of 15 mol% [Hmim][TFA] under neat conditions (Table 1, Entry 12). The possibility to recycle catalyst was also examined. The catalyst was reused four times with the yields of 85%, 85%, 83% and 80%, respectively (Table 1, Entry 12).

Using the optimized reaction conditions in hand, various aromatic aldehydes were tested to investigate the generality of the reaction. The results were summarized in Table 2. The results exhibited various para-substituted benzaldehydes with electron withdrawing groups (-Cl, -NO2,-F) and electron donating groups (Me) have given good yields. 3-Chlorobenzaldehyde at the meta position also afforded the desired products in high yield. Conversely, it proceeded only up to Knoevenagel adducts, when electron-releasing para-substituted benzaldehydes were used (R=OMe, N(Me)2).

Inspired by the successful synthesis of 5a-5f in the sustainable catalytic system consisting of [Hmim][TFA] without solvents, we then attempted to expand its application to the synthesis of 6a-6f. Therefore, the desired products were obtained in 72-86% yields.

From the above results and literatures,7,21 a reasonable mechanism for the [Hmim][TFA]-catalyzed one-pot, three-component synthesis of the corresponding spiroheterocycle 5a is depicted in Scheme 2. Firstly, benzaldehyde and urea would easily form the intermediate acylimine 7, followed by a Michael-type addition reacting with 8 to give the open chain ureide 9. Subsequently, intermediate 9 involved condensation of benzaldehyde to form intermediate 10 and ultimately cyclized to the spiroheterocyclic compound 5a.

EXPERIMENTAL
All chemicals were purchased from Aladdin, Aldrich and Fluka Chemical Companies and without further purification. Melting points were measured on XT-4 digital micro melting point apparatus and are uncorrected. IR spectra were taken on a Nicolet-360 FT-IR spectrometer by incorporating samples in KBr disks. 1H NMR spectra were recorded on a BRUKER AVANCE 400 MHz spectrometer using DMSO as the solvent and TMS as the internal standard. 13C NMR data were collected on a BRUKER AVANCE 100 MHz instrument with DMSO as the solvent and TMS as the internal standard. The analytical MS of the compounds was performed on Agilent LC-MSD Trap VL Apparatus.
General procedure for the synthesis of 1-mthylimidazolium trifluoroacetate ([Hmim][TFA])
A solution of trifluoroacetic acid (11.4 g, 0.1 mol) in CH2Cl2 (50 mL) was added to N-methylimidazole (8.21 g, 0.1 mol)) in CH2Cl2 (40 mL) solution at 0-5 oC. Then the mixture was stired at room temperature for 2 h. The solvent was evaporated at reduced pressure and the remaining product was washed with 2-methoxy-2-methylpropane (3×10 mL) to remove non-ionic residues and dried under vacuum.
1-Mthylimidazolium trifluoroacetate([Hmim][TFA]): white solid; IR (KBr, cm-1): ν 3154, 2968, 2871, 1680, 1589, 1424, 1286, 1205, 1135; 1H NMR (DMSO-d6) δ 3.82 (s, 3 H, CH3), 7.62 (t, 1 H, J = 1.5 Hz), 7.66 (t, 1 H, J = 1.5 Hz), 8.95 (s, 1 H); 13C NMR (DMSO-d6) δ 35.13, 113.60, 116.1, 118.31, 120.15, 120.70, 122.95, 135.88, 158.20, 158.07, 158.33, 158.58, 158.81.
General procedure of the preparation of products 5a, 5b, 5c, 5d, 5e, and 5f
3,3-Butylidenediphenyl-2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-trione (5a): To a 50 mL tube equiped with a stirring bar were added urea 1 (300 mg, 5 mmol), 2,2-butylidene-1,3- dioxane-4,6-dione 3 (851 mg, 5 mmol), aromatic aldehyde 2a (1060 mg, 10 mmol) and 1-mthylimidazolium trifluoroacetate ([Hmim][TFA]) 15 mol%. The vessel was then sealed with a screw cap and at 80 oC for 4.0 h. Upon completion of the reaction, as confirmed by thin-layer chromatography (petroleum ether/EtOAc 2:1), the reaction mixture was treated with cold water. The aqueous layer consisting the acidic IL, was recovered after removal of water under reduce pressure and was reused for subsequent reactions. The crude solid product was filtered and then purified by recrystallization from EtOAc to afford the pure product 5a; a white solid; mp 208-210 oC. IR (KBr, cm-1): ν 3198, 3061, 1772, 1735, 1683; 1H NMR (400 MHz, DMSO-d6) 0.65-0.81 (m, 4 H), 1.29-1.33 (m, 4 H), 5.30 (s, 2 H), 7.20-7.22 (m, 4 H), 7.32 (s, 2 H, NH), 7.36-7.39 (m, 6 H); 13C NMR (100 MHz, DMSO-d6) 22.21, 38.26, 58.98 (Cspiro), 61.98, 114.28, 128.10, 129.21, 129.75, 135.98, 155.71, 160.45, 166.30; ESI-MS m/z: 407.2 [M＋H]＋.
3,3-Butylidene-bis(4-flurophenyl)-2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-trione (5b): a white solid; mp 206-208 oC. IR (KBr, cm-1): ν 3212, 3075, 1768, 1730, 1684; 1H NMR (400 MHz, DMSO-d6) 0.77-0.92 (m, 4 H), 1.34-1.40 (m, 4 H), 5.32 (s, 2 H), 7.24-7.28 (m, 8 H), 7.37 (s, 2 H, NH); 13C NMR (100 MHz, DMSO-d6) 22.37, 38.47, 59.06(Cspiro), 61.24, 114.44, 116.02,116.24, 130.28, 132.12, 132.16, 155.58, 160.53, 164.17, 166.23; ESI-MS m/z: 443.1 [M＋H]＋.
3,3-Butylidene-bis(4-chlorophenyl)-2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-trione(5c): a white solid; mp 207-209 oC. IR (KBr, cm-1): ν 3201, 3062, 1766, 1731, 1692; 1H NMR (400 MHz, DMSO-d6) 0.77-0.93 (m, 4 H), 1.36-1.39 (m, 4 H), 5.33 (s, 2 H), 7.21 (d, J = 8.0 Hz, 4 H), 7.42 (s, 2 H, NH), 7.48-7.63 (m, 4H); 13C NMR (100 MHz, DMSO-d6) 22.49, 38.63, 58.29 (Cspiro), 61.25, 114.82, 124.40, 129.81, 142.93, 148.52, 155.33, 160.09, 165.68; ESI-MS m/z: 475.1 [M＋H]＋.
3,3-Butylidene-bis(4-methylphenyl)-2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-trione (5d): a white solid; mp 195-198 oC. IR (KBr, cm-1): ν 3226, 3081, 1773, 1735, 1686; 1H NMR (400 MHz, DMSO-d6) 0.70-0.86 (m, 4 H), 1.22-1.31 (m, 4 H), 2.29 (s, 6 H), 5.25 (s, 2 H), 7.12 (d, J = 8.0 Hz, 4 H), 7.48 (d, J = 8.0 Hz, 4 H), 7.24 (s, 2 H, NH); 13C NMR (100 MHz, DMSO-d6) 22.33, 28.26, 38.47, 58.61 (Cspiro), 61.66, 114.78, 127.95, 129.35, 133.00, 139.01, 155.67, 156.11, 166.23; ESI-MS m/z: 435.2 [M＋H]＋.
3,3-Butylidene-bis(4-nitrophenyl)-2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-trione (5e): a light yellow solid; mp 201-202 oC. IR (KBr, cm-1): ν 3231, 3081, 1767, 1729, 1692; 1H NMR (400 MHz, DMSO-d6) 0.72-0.90 (m, 4 H), 1.28-1.36 (m, 4 H), 5.56 (s, 2 H), 7.50 (d, J = 8.0 Hz, 4 H), 7.66 (s, 2 H, NH), 8.30 (d, J = 8.0 Hz, 4 H); 13C NMR (100 MHz, DMSO-d6) 22.49, 38.63, 58.29 (Cspiro), 61.25, 114.82, 124.40, 129.81, 142.93, 148.52, 155.33, 160.09, 165.68; ESI-MS m/z: 497.1 [M＋H]＋.
3,3-Butylidene-bis(3-chlorophenyl)-2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-trione (5f): a white solid; mp 192-194 oC. IR (KBr, cm-1): ν 3202, 3062, 1767, 1730, 1692; 1H NMR (400 MHz, DMSO-d6) 0.80-0.90 (m, 4 H), 1.36-1.40 (m, 4 H), 5.34 (s, 2 H), 7.16 (d, J = 4.0 Hz, 2H), 7.23 (s, 2 H, NH), 7.42-7.49 (m, 6 H); 13C NMR (100 MHz, DMSO-d6) 22.37, 38.49, 58.70 (Cspiro), 61.23, 114.59, 127.02, 127.91, 129.84, 131.22, 133.86, 138.18, 155.42, 160.37, 165.95; ESI-MS m/z: 475.1 [M＋H]＋.
General procedure of the preparation of products 6a, 6b, 6c, 6d, 6e, and 6f
3,3-Pentylidene-diphenyl-2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-trione (6a): To a 50 mL tube equiped with a stirring bar were added urea 1 (300 mg, 5 mmol), 2,2-pentylidene-1,3-dioxane-4,6-dione 4 (921 mg, 5 mmol), aromatic aldehyde 2a (1060 mg, 10 mmol) and 1-mthylimidazolium trifluoroacetate ([Hmim][TFA]) 15 mol%. The vessel was then sealed with a screw cap and at 80 oC for 4.0 h. Upon completion of the reaction, as confirmed by thin-layer chromatography (petroleum ether/EtOAc 2:1), the reaction mixture was treated with cold water. The aqueous layer consisting the acidic IL, was recovered after removal of water under reduce pressure and was reused for subsequent reactions. The crude solid product was filtered and then purified by recrystallization from EtOAc to afford the pure product 6a; a white solid; mp 218-220 oC. IR (KBr, cm-1): ν 3201, 3060, 1771, 1734, 1685; 1H NMR (400 MHz, DMSO-d6) 0.43 (s, 4 H), 1.07 (s, 6 H), 5.30 (s, 2 H), 7.21-7.23 (m, 4 H), 7.31 (s, 2 H, NH), 7.35-7.40 (m, 6 H); 13C NMR (100 MHz, DMSO-d6) 21.88, 23.28, 36.99, 59.06 (Cspiro), 62.01, 105.99, 128.16, 129.13, 129.72, 136.04, 155.72, 160.35, 166.17; ESI-MS m/z: 421.2 [M＋H]＋.
3,3-Pentylidene-bis(4-flurophenyl)-2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-trione (6b): a white solid; mp 216-217 oC；IR (KBr, cm-1): ν 3207, 3074, 1768, 1734, 1683 cm-1; 1H NMR (400 MHz, DMSO-d6) 0.54 (s, 4 H), 1.12 (s, 6 H), 5.32 (s, 2 H), 7.22-7.28 (m, 8 H), 7.36 (s, 2 H, NH); 13C NMR (100 MHz, DMSO-d6) 21.87, 23.22, 37.16, 59.17 (Cspiro), 61.27, 106.11, 115.94, 116.16 130.34, 130.42, 132.20, 132.23, 155.55, 160.45, 161.75, 164.20, 166.12; ESI-MS m/z: 457.1 [M＋H]＋.
3,3-Pentylidene-bis(4-chlorophenyl)-2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-trione (6c): a white solid; mp 210-212 oC. IR (KBr, cm-1): ν 3208, 3086, 1771, 1729, 1683; 1H NMR (400 MHz, DMSO-d6) 0.54 (s, 4 H), 1.12 (s, 6 H), 5.33 (s, 2 H), 7.22 (d, J = 6.0 Hz, 4 H), 7.41 (s, 2 H, NH), 7.49 (d, J = 4.0 Hz, 4 H); 13C NMR (100 MHz, DMSO-d6) 21.89, 23.17, 37.15, 58.91 (Cspiro), 61.34, 106.17, 129.20, 130.09, 131.63, 134.89, 155.52, 160.36, 166.00; ESI-MS m/z: 489.1 [M＋H]＋.
3,3-Pentylidene-bis(4-methylphenyl)-2,4-dioxa-8,10-diazaspiro[5.5]undecane-1,5,9-trione (6d): a white solid; mp 202-205 oC. IR (KBr, cm-1): ν 3226, 3081, 1773, 1735, 1686; 1H NMR (400 MHz, DMSO-d6) 0.46 (s, 4 H), 1.08 (s, 6 H), 2.26 (s, 6 H), 5.23 (s, 2 H), 7.08 (d, J = 8.0 Hz, 4 H), 7.18 (d, J = 8.0 Hz, 4 H), 7.22 (s, 2 H, NH); 13C NMR (100 MHz, DMSO-d6) 21.11, 21.94, 23.31, 37.03, 59.15 (Cspiro), 61.87, 106.11, 128.03, 129.55, 133.07, 139.19, 155.78, 160.55, 166.35; ESI-MS m/z: 449.2 [M＋H]＋.
3,3-Pentylidene-bis(4-nitrophenyl)-2,4-dioxa-8,10-diazaspiro[5.5]-undecane-1,5,9-trione(6e): a light yellow solid; mp 211-212 oC. IR (KBr, cm-1): ν 3229, 3078, 1769, 1727, 1691; 1H NMR (400 MHz, DMSO-d6) 0.49 (s, 4 H), 1.07 (s, 6 H), 5.57 (s, 2 H), 7.50 (d, J = 8.0 Hz, 4 H), 7.67 (s, 2 H, NH), 8.30 (d, J = 8.0 Hz, 4 H); 13C NMR (100 MHz, DMSO-d6) 21.80, 23.07, 37.24, 58.48 (Cspiro), 61.37, 106.54, 124.32, 129.91, 143.01, 148.55, 155.34, 160.14, 165.62; ESI-MS m/z: 511.1 [M＋H]＋.
3,3-Pentylidene-bis(3-chlorophenyl)-2,4-dioxa-8,10-diazaspiro[5.5]-undecane-1,5,9-trione(6f): a white solid; mp 196-198 oC. IR (KBr, cm-1): ν 3201, 3064, 1771, 1734, 1689; 1H NMR (400 MHz, DMSO-d6) 0.55 (s, 4 H), 1.13 (s, 6 H), 5.34 (s, 2 H), 7.16 (d, J = 4.0 Hz, 2 H), 7.23 (s, 2H, NH), 7.41-7.49 (m, 6 H); 13C NMR (100 MHz, DMSO-d6) 21.81, 23.16, 37.11, 58.84 (Cspiro), 61.28, 106.32, 127.11, 127.97, 129.80, 131.13, 133.90, 138.24, 155.42, 160.32, 165.86; ESI-MS m/z: 489.1 [M＋H]＋.

ACKNOWLEDGEMENTS
This work was supported by the National Natural Science Foundation of China (No. 20566004). We also thank the support from the Graduate Innovation Fundation of Jiangxi Province (No.YC2015-B023).

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