L-Proline as an efficient and reusable promoter for the synthesis of coumarins in ionic liquid

L-Proline as an efficient and reusable promoter for the synthesis of coumarins in ionic liquid first-author corresp ‡Corresponding Author ‡Corresponding Author †E-mail:shangzc@zju.edu.cn †E-mail:shangzc@zju.edu.cn shangzc@zju.edu.cn Department of Chemistry, Zhejiang University, Hangzhou 310027, China Department of Chemistry, Zhejiang University, Hangzhou 310027, China The effect of L-proline as a promoter on the condensation reaction of salicylaldehyde or its derivatives with ethyl acetoacetate in neutral ionic liquid [emim]BF 4 was studied. All reactions were carried out under mild reaction conditions and achieved high yields. Moreover, the ionic liquid containing L-proline could be recycled and reused for several times without noticeably decreasing in productivity. The results show that the L-proline-[emim]BF 4 system has a potential in contribution to the development of environmentally friendly and inexpensive processes in organic syntheses. L-Proline Ionic liquid Coumarins Knoevenagel condensation INTRODUCTION 1 The Knoevenagel condensation has often been used to prepare substituted coumarin, one of the most important chemicals in the cosmetics, agricultural, pharmaceutical and material industries for its bioactivity and photodynamic effect (Kostova et al., 1993 1993 ; Palmer and Josephs, 1995 1995 ; Mitra et al., 1998 1998 ; Wang et al., 2002 2002 ). Highly efficient reactions have been reported, involving the condensation of salicylaldehydes with malonates in the presence of piperidine under microwave conditions (Bogdal, 1998 1998 ), and the use of montmorillonite KSF (Bigi et al., 1999 1999 ) which requires high temperature and long reaction time (100 °C, 24 h). Solid-phase syntheses of 3-alkoxy-carbonylcoumarins (Watson and Christiansen, 1998 1998 ) and 3-acetylcoumarin utilizing the polymer reagent (vanden Eynde and Rutot, 1999 1999 ) were also reported; however, they are not so effective in terms of yield and purity of products or recyclability of the polymer reagent. Furthermore, although P(RNCH 2 CH 2 ) 3 N as an efficient promoter (Kisanga et al., 2002 2002 ) has been introduced recently, the reaction has to be conducted in benzene or isobutyronitrile, which are not environmentally friendly solvents. Alternatively, coumarins could also be synthesized by other methods including Pechmann (Gu et al., 2005 2005 ; Fang et al., 2008 2008 ), Perkin (Camur and Bulut, 2008 2008 ), Reformatsky (Chen et al., 2005 2005 ), Wittig (Yavari et al., 1998 1998 ) reactions, and by flash vacuum pyrolysis (Cartwright and McNab, 1997 1997 ). Room temperature ionic liquids are emerging as potential green alternatives to volatile organic solvents, and recently have been used as environmentally benign media for several important reactions due to their unique physical and chemical properties. L-Proline in combination with ionic liquids has proved to be an efficient system for Knoevenagel condensation (Wang et al., 2006 2006 ), direct asymmetric aldol reactions (Loh et al., 2002 2002 ; Kotrusz et al., 2002 2002 ; Gruttadauria et al., 2004 2004 ; Salaheldin et al., 2004 2004 ), cross-aldol reactions (Córdova, 2004 2004 ), Michael additions (Kitazume et al., 2003 2003 ; Hagiwara et al., 2004 2004 ; Kotrusz et al., 2004 2004 ; Rasalkar et al., 2005 2005 ), α-aminations of aldehydes and ketones (Kotrusz et al., 2005 2005 ), Ullmanntype reactions (Wang et al., 2005 2005 ), as well as Mannich reactions (Chowdari et al., 2003 2003 ). To the best of our knowledge, there is no attempt of the use of L-proline as a promoter in ionic liquid for the synthesis of coumarins. We, therefore, present an efficient and practical synthesis of substituted coumarins from the corresponding salicylaldehyde and ethyl acetoacetate. The method applied here resulted in easier product work-up in this milder condition compared with that reported in the literature, and in high yields (81%~95%). In addition, the ionic liquid containing L-proline could be recycled and reused for several times without noticeably decreasing in productivity in subsequent reactions. RESULTS AND DISCUSSION 1 To a dry round bottom flask charged with 2 mmol substrate and 2.1 mmol ethyl acetoacetate, was added the ionic liquid [emim]BF 4 (1 ml), followed by 40 mol% L-proline, and the reaction mixture was stirred at room temperature. At the end of the reaction, water was added with continuous stirring, and then the solid material was filtered off to give high purity products without further purification of column chromatography. The achieved results are summarized in Table 1 1 . The reaction worked well with aromatic salicylaldehydes containing electrondonating and electron-withdrawing substituents present in the aromatic rings. Compared with salicylaldehyde, the yield of the reaction of 2-hydroxy-1-naphthaldehyde (Table 1 1 , entry 9) with ethyl acetoacetate was a bit low maybe due to hindrance effect, and this was also reflected by the higher yields in entries 2 and 7 compared respectively with entries 3 and 8 in Table 1 1 . However, the reaction between 2-hydroxyaceto-phenone and ethyl acetoacetate produced no product in this system even when it was stirred at 60 °C for 24 h (Table 1 1 , entry 10), indicating that the presence of methyl prevented the reaction from continuing. http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=23541826&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=23541831&type= http://html.publish.founderss.cn/rc-pub/api/common/picture?pictureId=23541828&type= Our efforts began with salicylaldehyde and ethyl acetoacetate in ionic liquid [emim]BF 4 at room temperature without L-proline (Table 2 2 ). The catalytic activity of L-proline for these reactions was investigated, and no reaction took place in ionic liquid in 24 h in the absence of L-proline (Table 2 2 , entry 1). When 5 mol% L-proline was added, the reaction yield was 85% (Table 2 2 , entry 2), and when 40 mol% L-proline was added, the reaction yield increased to 95% (Table 2 2 , entry 5). However, using 50 mol% L-proline resulted in lower yield (Table 2 2 , entry 6). The amount of ionic liquid used in the reaction was also optimized, and the results show that the yield increased as the amount of ionic liquid increased from 0.5 ml (Table 2 2 , entry 8) to 1 ml (Table 2 2 , entry 5); however, the yield began to decrease as IL increased to 1.5 ml (Table 2 2 , entry 9). Therefore, the best result was observed when 40 mol% L-proline was used as a promoter in 1 ml ionic liquid. The reaction gave almost no products of CH 3 CN, tetrahydrofuran (THF), and CH 2 Cl 2 , and yielded a low level of dimethyl sulfoxide (DMSO) in the presence of L-proline when the reaction time was prolonged to 48 h. In summary, both L-proline and [emim]BF 4 had an important effect to the reaction: without one of the two, the reaction would not take place. The reaction was conducted with 2 mmol salicylaldehyde and 2.1 mmol ethyl acetoacetate in the presence of L-proline and/or [emim]BF 4 at room temperature; Isolated yield Entry L-proline (mol%) Ionic liquid (ml) Yield (%) b b 1 0 1 0 2 5 1 85 3 10 1 92 4 30 1 90 5 40 1 95 6 50 1 86 7 40 0 0 8 40 0.5 76 9 40 1.5 80 Since the L-proline and ionic liquid [emim]BF 4 are soluble in water, they were extracted with water and the solid material was filtered off to give high purity products. The water solution containing L-proline was distilled under a reduced pressure, and the remaining ionic liquid containing L-proline was recycled and reused at least five times without noticeably decreasing the productivity (Table 3 3 ). Compared with conventional methods, the L-proline-[emim]BF 4 system offers a clean, efficient, eco-friendly protocol for the synthesis of coumarins, with a high yield and a simple work-up procedure, and also a recyclable reaction medium. The reaction was conducted with 40 mol% L-proline, 2 mmol 2-hydroxybenzaldehyde and 2.1 mmol ethyl acetoacetate in 1 ml ionic liquid [emim]BF 4 at room temperature; Isolated yields Run Yield (%) b b 1 95 2 95 3 93 4 94 5 93 EXPERIMENTAL SECTION 1 Melting points (mp) were obtained on WRS-1A apparatus and are uncorrected, infrared radiation (IR) spectra were recorded on an NEXUS 470 FT-IR spectrophotometer using KBr optics, and 1 H NMR data were recorded at Advance DMX 500 MHz in CDCl 3 or DMSO- d 6 using tetramethylsilane (TMS) as internal standard. Materials 2 Ionic liquids were prepared by the procedures given in the literature (Joseph et al., 2005 2005 ). All other chemicals and reagents were commercial materials of analytical grade. General experimental procedures for the L-proline catalyzed Knoevenagel condensation reaction in neutral ionic liquid 2 In a typical experiment, 2 mmol of salicylaldehyde or its derivatives and 2.1 mmol of ethyl acetoacetate were added into a 25 ml round bottom flask and stirred with a magnetic stir bar. To this, 1 ml ionic liquid and 40 mol% L-proline were added. Afterwards, the reaction mixture was stirred at room temperature until TLC (thin-layer chromatography) shows the complete disappearance of salicylaldehyde or its derivatives. Then 10 ml water was added and stirred for 5 min, the resulting mixture was filtered, and the solid residue was dried under infrared lamp to give the products in high purity without being further purified by column chromatography. General experimental procedures for the recycling of L-proline and ionic liquid 2 After the reaction was completed, the solid material was filtered off. The water solution containing L-proline was distilled under a reduced pressure, and then dried in vacuum to completely remove the water, avoiding the use of toxic and volatile extractants. The L-proline-[emim]BF 4 system was recharged with a new batch of substrates. Table 3 3 illustrates that the ionic liquid [emim]BF 4 containing L-proline can be reused for at least five times without sacrificing the yields. Spectral data of some products (Table 1 1 ) 2 1. 3-Acetylcoumarin (entry 1) 3 Yield: 95%; mp: 118 °C [mp 119~220 °C in (Hirai and Togo, 2005 2005 )]; IR (KBr): 1 732, 1 677, 1 613, 1 557, 1 455, 1 233, 1 210, 979, 756 cm −1 ; 1 H NMR (CDCl 3 , 500 MHz): δ =2.73 (s, 3H, CH 3 ), 7.33~7.39 (m, 2H, Ar-H), 7.64~7.67 (m, 2H, Ar-H), 8.51 (s, 1H, CH). 2. 3-Acetyl-7-methoxycoumarin (entry 2) 3 Yield: 86%; mp: 170 °C [mp 171~172 °C in (Fry et al., 2004 2004 )]; IR (KBr): 1 736, 1 672, 1 616, 1 504, 1 366, 1 210, 989, 837, 767 cm −1 ; 1 H NMR (CDCl 3 , 500 MHz): δ =2.71 (s, 3H, CH 3 ), 3.92 (s, 3H, OCH 3 ), 6.84 (d, J =2.30 Hz, 1H, Ar-H), 6.91 (q, J =3.70 Hz, 1H, Ar-H), 7.55 (d, J =8.70 Hz, 1H, Ar-H), 8.50 (s, 1H, CH). 3. 3-Acetyl-8-methoxycoumarin (entry 3) 3 Yield: 81%; mp: 172 °C [mp 174 °C in (Mogilaiah et al., 2003 2003 )]; IR (KBr):1 735, 1 686, 1 602, 1 568, 1 282, 1 201, 950, 801, 766 cm −1 ; 1 H NMR (CDCl 3 , 500 MHz): δ =2.73 (s, 3H, CH 3 ), 3.99 (s, 3H, OCH 3 ), 7.18~7.29 (m, 3H, Ar-H), 8.48 (s, 1H, CH). 4. 3-Acetyl-6-chlorocoumarin (entry 4) 3 Yield: 90%; mp: 204 °C [mp 206 °C in (Czerney and Hartmann, 1982 1982 )]; IR (KBr): 1 739, 1 677, 1 611, 1 553, 1 359, 1 234, 1 205, 983, 973, 837 cm −1 ; 1 H NMR (CDCl 3 , 500 MHz): δ =2.73 (s, 3H, CH 3 ), 7.33 (d, J =8.80 Hz, 1H, Ar-H), 7.60 (q, J =3.77 Hz, 1H, Ar-H), 7.63 (d, J =2.35 Hz, 1H, Ar-H), 8.41 (s, 1H, CH). 5. 3-Acetyl-6-bromocoumarin (entry 5) 3 Yield: 95%; mp: 231~233 °C [mp 220~221 °C in (Hirai and Togo, 2005 2005 )]; IR (KBr): 1 736, 1 676, 1 608, 1 551, 1 357, 1 234, 1 206, 983, 970, 835 cm −1 ; 1 H NMR (CDCl 3 , 500 MHz): δ =2.73 (s, 3H, CH 3 ), 7.27 (d, J =7.57 Hz, 1H, Ar-H), 7.73 (q, J =3.61 Hz, 1H, Ar-H), 7.78 (d, J =2.01 Hz, 1H, Ar-H), 8.41 (s, 1H, CH). 6. 3-Acetyl-6-nitrocoumarin (entry 6) 3 Yield: 90%; mp: 178~179 °C [mp 192 °C in (Mogilaiah et al., 2003 2003 )]; IR (KBr): 1 752, 1 680, 1 607, 1 536, 1 346, 1 239, 1 213, 960, 851, 821, 768, 749 cm −1 ; 1 H NMR (CDCl 3 , 500 MHz): δ =2.74 (s, 3H, CH 3 ), 7.52 (d, J =9.15 Hz, 1H, Ar-H), 8.50 (q, J =2.20 Hz, 1H, Ar-H), 8.55 (s, 1H, CH), 8.59 (d, J =2.45 Hz, 1H, Ar-H). 7. 3-Acetyl-6-hydroxycoumarin (entry 7) 3 Yield: 92%; mp: 220 °C; IR (KBr): 3 178, 1 742, 1 645, 1 569, 1 281, 1 244, 930, 830, 716 cm −1 ; 1 H NMR (DMSO- d 6 , 500 MHz): δ =2.57 (s, 3H, CH 3 ), 7.16 (t, J =4.38 Hz, 1H, Ar-H), 7.23 (s, 1H, Ar-H), 7.30 (d, J =8.87 Hz, 1H, Ar-H), 8.55 (s, 1H, CH), 9.90 (s, 1H, OH). 8. 3-Acetyl-8-hydroxycoumarin (entry 8) 3 Yield: 87%; mp: 253 °C; IR (KBr): 3 227, 1 697, 1 602, 1 566, 1 297, 1 227, 1 205, 797, 772, 740 cm −1 ; 1 H NMR (DMSO- d 6 , 500 MHz): δ =2.59 (s, 3H, CH 3 ), 7.21 (t, J =2.62 Hz, 2H, Ar-H), 7.36 (q, J =3.0 Hz, 1H, Ar-H), 8.59 (s, 1H, CH), 10.38 (s, 1H, OH). 9. 3-Acetylbenzo cumarin (entry 9) 3 Yield: 88%; mp: 189~190 °C [mp 190 °C in (Czerney and Hartmann, 1982 1982 )]; IR (KBr): 1 732, 1 676, 1 557, 1 246, 1 218, 976, 825, 750 cm −1 ; 1 H NMR (CDCl 3 , 500 MHz): δ =2.79 (s, 3H, CH 3 ), 7.48 (d, J =9.0 Hz, 1H, Ar-H), 7.62 (t, J =7.57 Hz, 1H, Ar-H), 7.74~7.77 (m, 1H, Ar-H), 7.93 (d, J =8.05 Hz, 1H, Ar-H), 8.11 (d, J =9.05 Hz, 1H, Ar-H), 8.37 (d, J =8.40 Hz, 1H, Ar-H), 9.32 (s, 1H, CH). 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