Continuous Microflow Synthesis of Butyl Cinnamate by a Mizoroki-Heck Reaction Using a Low-Viscosity Ionic Liquid as the Recycling Reaction Medium

A continuous microflow system was developed with efficient catalyst recycling for a Mizoroki-Heck reaction of iodobenzene with butyl acrylate, using a low-viscosity ionic liquid ([bmim]NTf2) as the reaction medium. Using a CPC CYTOS Lab System as the microreaction apparatus, in combination with an originally developed microextraction/catalyst recycling system, the reaction medium, which contained Pd catalyst could be continuously recycled to provide a total of 115.3 g (80%, 10 g/h) of the desired product. Introduction Microreaction (miniaturized chemical reaction) technology has opened up new perspectives for chemistry and the chemical industry.1 Microreactors are expected to have a significant impact on chemical synthesis and production because of their many advantageous characteristics, such as highly efficient micromixing, a high volume-to-area ratio, efficient heat transfer ability, the avoidance of “hot spots” by effective temperature control, and a high operational safety.2 Transition-metal-catalyzed reactions have previously been performed using a microflow system.3 For example, hydrogenation,3a,b oxidation,3c,d Suzuki-Miyaura coupling,3e and the Kumada-Corriu reaction3f have been reported. Most of them dealt with heterogeneous catalysts, and this is probably because heterogeneous catalysis can take advantage of the high volume-to-surface ratio ensured by the microchannels. However, we focus on the potential of this new technology for use in reactions using homogeneous catalysts. Ionic liquids are considered to be environmentally benign alternatives for traditional volatile organic solvents in terms of their low vapor pressure and tunable miscibility with other organic or inorganic chemicals.4 The immobilization of the catalyst in the ionic liquid is another attractive advantage of this new reaction system, since this would facilitate the separation of both the catalyst and reaction media from the products. Our interest has focused on the use of a microflow system in homogeneous catalysis using ionic liquids as the reaction media. We previously reported on the application of a microflow system to the Sonogashira coupling reaction using an ionic liquid, which was particularly useful, when an IMM micromixer with a channel width of 40 μm was employed.5 If a flow reactor, irrespective of whether it is “micro” or “conventional”, was to be applied to a continuous recycling process, the need to discontinue the reaction because of the subsequent separation processes after the reaction (extraction of product from the resulting reaction mixture and separation), has to be eliminated. The Mizoroki-Heck reaction,6 one of the most useful of the palladium-catalyzed reactions, has already been carried out successfully in ionic liquids,7 such as 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF6) and ammonium salts. [Bmim]PF6 functions well, not only for the reaction itself but also for efficient recovery of the catalyst.7a Both product and ammonium salts can be readily separated from the ionic liquid containing Pd catalyst by successive biphasic workup procedures, and the Pd catalyst, retained in the ionic liquid, can be recycled (Scheme 1). [Bmim]PF6, however, is a highly viscous liquid, and as an alternative, we focused on the use of a low* Author for correspondence. E-mail: [email protected]. Telephone and fax: +81-72-254-9695. (1) (a) Ehrfeld, W.; Hessel, V.; Löwe, H. Microreactor: New Technology for Modern Chemistry; Wiley-VCH: Weinheim, 2000. (b) Jas, G.; Kirschning, A. Chem. Eur. J. 2003, 9, 5708. (c) Jähnisch, K.; Hessel, V.; Löwe, H.; Baerns, M. Angew. Chem., Int. Ed. 2004, 43, 406. (2) (a) Skelton, V.; Greenway, G. M.; Haswell, S. J.; Styring, P.; Morgan, D. O.; Warrington, B.; Wong, S. Y. F. Analyst 2001, 126, 7. (b) Doku, G. N.; Haswell, S. J.; McCreedy T.; Greenway, G. M. Analyst 2001, 126, 14. (c) Watts, P.; Wiles, C.; Haswell, S. J.; Pombo-Villar, E.; Styring, P. Chem. Commun. 2001, 990. (d) Suga, S.; Okajima, M.; Fujiwara, K.; Yoshida, J. J. Am. Chem. Soc. 2001, 123, 7941. (e) Hisamoto, H.; Saito, T.; Tokeshi, M.; Hibara, A.; Kitamori, T. Chem. Commun. 2001, 2662. (f) TaghaviMoghadam, S.; Kleemann, A.; Golbig, K. G. Org. Process Res. DeV. 2001, 652. (g) Watts, P.; Wiles, C.; Haswell, S. J.; Pombo-Villar, E. Tetrahedron 2002, 5427. (h) Schwalbe, T.; Autze, V.; Wille, G. Chimia 2002, 56, 636. (i) Suga, S.; Nagaki, A.; Yoshida, J. Chem. Commun. 2003, 354. (j) Ueno, M.; Hisamoto, H.; Kitamori, T.; Kobayashi, S. Chem. Commun. 2003, 936. (k) Panke, G.; Schwalbe, T.; Stirner, W.; Taghavi-Moghadam, S.; Wille, G. Synthesis 2003, 2827. (3) (a) Wiessmeier, G.; Hönicke, D. Ind. Eng. Chem. Res. 1996, 35, 4412. (b) de Bellefon, C.; Tanchoux, N.; Caravieilhes, S.; Grenouillet, P.; Hessel, V. Angew. Chem., Int. Ed. 2000, 39, 3442. (c) Kestenbaum, H.; de Oliveira, A. L.; Schmidt, W.; Schüth, F.; Ehrfeld, W.; Gebauer, K.; Löwe, H.; Richter, T.; Lebiedz, D.; Untiedt, I.; Züchner, H. Ind. Eng. Chem. Res. 2002, 41, 710. (d) Niwa, S.; Eswaramoorthy, M.; Nair, J.; Raj, A.; Itoh, N.; Shoji, H.; Namba, T.; Mizukami, F. Science 2002, 295, 105. (e) Greenway, G. M.; Haswell, S. J.; Morgan, D. O.; Skelton, V.; Styring, P. Sens. Acuators B 2000, 63, 153. (f) Haswell, S. J.; O’Sullivan, B.; Styring, P. Lab Chip 2001, 1, 164. (4) For reviews, see: (a) Welton, T. Chem. ReV. 1999, 99, 2071. (b) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3772. (c) Sheldon, R. Chem. Commun. 2001, 2399. (d) Gordon, C. M. Appl. Catal. A: Chem. 2001, 222, 101. (e) Olivier-Bourbigou, H.; Magna, L. J. Mol. Catal. A: Chem. 2002, 182-183, 419. (f) Baudequin, C.; Baudoux, J.; Levillain, J.; Cahard, D.; Gaumont, A. C.; Plaquevent, J. C. Tetrahedron: Asymmetry 2003, 14, 3081. (5) Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I. Org. Lett. 2002, 4, 1691. (6) For a review, see: Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009. (7) (a) Carmichael, A. J.; Earle, M. J.; Holbrey, J. D.; McCormac, P. B.; Seddon, K. R. Org. Lett. 1999, 1, 997. (b) Kaufmann, D. E.; Nouroozian, M.; Henze, H. Synlett 1996, 1091. (c) Böhm, V. P. W.; Herrmann, W. A. Chem. Eur. J. 2000, 6, 1017. (d) Xu, L.; Chen, W.; Xiao, J. Organometallics 2000, 19, 1123. (e) Calò, V.; Nacci, A.; Lopez, L.; Mannarini, N. Tetrahedron Lett. 2000, 41, 8973. Organic Process Research & Development 2004, 8, 477−481 10.1021/op034200h CCC: $27.50 © 2004 American Chemical Society Vol. 8, No. 3, 2004 / Organic Process Research & Development • 477 Published on Web 04/01/2004 viscosity ionic liquid, 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([bmim]NTf2), for this study,10 since it diffuses in microchannels more rapidly and less pressure drop and higher extraction efficiency would be expected for low-viscous reaction media. We report herein that the Mizoroki-Heck reaction using ionic liquids can be successfully conducted in a microflow system. We also report on a model study, which achieved the multi-ten gram-scale production of butyl cinnamate using a continuous microflow reactor, a CPC CYTOS Lab System,11 combined with our originally developed workup system, based on a dual micromixer assisting extraction system. Results and Discussion Mizoroki-Heck Reaction in a Microflow System. The reaction of iodobenzene (1) with butyl acrylate (2) in an ionic liquid was examined in a microflow system as a model reaction, to produce butyl cinnamate (3) as the product (Scheme 2). Both highand low-viscosity ionic liquids, [bmim]PF6 (312 mPa‚s, 303 K)12 and [bmim]NTf2 (52 mPa‚ s, 293 K),8 were tested for comparison. In many Pd-catalyzed reactions using ionic liquids, Pd-carbene complexes, which are generated in situ by the reaction of Pd complexes with ionic liquids, are thought to be the key catalyst species.13 However, such an in situ procedure would make the microflow system vulnerable to clogging, because the initial Pd complexes, such as Pd(PPh3)4 and PdCl2(PPh3)2, are insoluble in ionic liquids. Because of this, we used a Pdcarbene complex 4,14 which is soluble in these ionic liquids. Initially, we employed an IMM micromixer having 2 × 15 interdigitated channels (channel width ) 40 μm) (Scheme 3) and found that it worked reasonably well. The results obtained using the microflow system are summarized in Table 1. The mixture of reactants (iodobenzene (1), butyl acrylate (2), tripropylamine, and tetradecane as an internal standard) were loaded in syringe A. A solution of 5 mol % of Pd catalyst 4 dissolved in an ionic liquid, was loaded in syringe B (Scheme 3). These two syringes were operated by syringe pumps. When the reaction was performed using an IMM micromixer alone (method I) at a flow rate of 0.1 mL/h in [bmim]PF6 at 130 °C, the reaction was sluggish, resulting in only a 12% yield of the desired coupling product with the recovery of a large amount of starting substrates (entry (8) Bonhôte, P.; Dias, A. P.; Papageorgiou, N.; Kalyanasundaram, K.; Grätzel, M. Inorg. Chem. 1996, 35, 1168. (9) For the use of low-viscosity ionic liquids [bmim]NTf2 in continuous flow processes with supercritical CO2, see: (a) Bösmann, A.; Franciò, G.; Janssen, E.; Solinas, M.; Leitner, W.; Wassersheid, P. Angew. Chem., Int. Ed. 2001, 40, 2697. (b) Lozano, P.; de Diego, T.; Carrié, D.; Vaultier, M.; Iborra, J. L. Chem. Commun. 2002, 692. (c) Reetz, M. T.; Wiesenhöfer, W.; Franciò, W.; Leitner, W. Chem. Commun. 2002, 992. (e) Dzyuba, S. V.; Bartsch R. A. Angew. Chem., Int. Ed. 2003, 42, 148. (f) Webb, P. B.; Sellin, M. F.; Kunene, T. E.; Williamson, S.; Slawin, A. M. Z.; Cole-Hamilton, D. J. J. Am. Chem. Soc. 2003, 125, 15577. (10) For the use of [bmim]NTf2 in Pd-catalyzed reactions, see: Liu, S.; Fukuyama, T.; Sato, M.; Ryu, I. Submitted for publication. (11) The CYTOS Lab System was developed by CPC-Cellular Process Chemistry Systems GmbH, Germany. Schwalbe, T.; Golbig, K.; Hohmann, M.; Georg, P.; Oberbeck, A.; Dittmann, B.; Stasna, J.; Oberbeck, S. (Cellular Process Chemistry Inc., U.S.A.) Eur. Pat. Appl. EP 1 123 734, 2001; Chem. Abstr. 2001, 135, 154468b. The effective reaction volume of the CYTOS microreactor is 1.2 mL; however, along with the feed lines inside the cell, the total volume results in 2.0 mL. In the standard configuration additional reaction volume is provided by equipping the residence time unit of 15 mL. Further information is available on the Internet: www.cpc-net.com. CYTOS is registered by CPC-Systems GmbH. See also ref 2k. (12) (a) Suarez, P. A. Z.; Einloft, S.; Dullius, J. E. L.; de Souza, R. F.; Dupont, J. J. Chim. Phys.-Chim. Biol. 1998, 95, 1626. (b) Suarez, P. A. Z.; Dullius, J. E. L.; Einloft, S.; de Souza, R. F.; Dupont, J. Polyhedron 1996, 15, 1217. (13) (a) Mathews, C. J.; Smith, P. J.; Welton, T.; White, A. J. P.; Williams, D. J. Organometallics 2001, 20, 3848. (b) McLachlan, F.; Mathews, C. J.; Smith, P. J.; Welton, T. Organometallics 2003, 22, 5350. See also ref 7d. (14) The Pd-carbene complex 4 was prepared from PdCl2(CH3CN)2 with 1-butyl3-methylimidazolium chloride and triphenylphosphine in THF. The details will be published in a separate paper. Scheme 1. Typical workup process for Mizoroki-Heck reaction in ionic liquids Scheme 2. Pd-carbene complex 4 and ionic liquids used in a microflow system Scheme 3. Two methods for a microflow reaction using an IMM micromixer 478 • Vol. 8, No. 3, 2004 / Organic Process Research & Development 1). Increasing the reaction temperature to 150 °C gave a 67% yield of the desired product 3 (entry 2). Since the low yields are due simply to low conversions, we attached an additional stainless steel tube reactor (diameter ) 1000 μm, length ) 1 m) to extend the residence time in order to ensure the completion of the reaction (method II). With an increased flow rate, 0.5 mL/h, the extended system, comprising a micromixer plus a tube reactor, resulted in a smooth reaction to give an 87% yield of product within 50 min at 100 °C in [bmim]PF6 (entry 3). With a decreased amount of Pd catalyst (2 mol %), heating to 150 °C was necessary, but yields as high as 98% were obtained (entry 4). Comparable yields were obtained when the reaction was conducted in a low-viscosity ionic liquid, [bmim]NTf2 (entry 5). After the reaction, the product and ammonium salts were separated by successive extraction with hexane and water, and the remaining ionic liquid containing Pd catalyst was employed in the next reaction. Although the second run, using a mixture of [bmim]NTf2 and catalyst recovered from prior reactions and conducted at 150 °C resulted in a low efficiency (entry 6), we were pleased to find that 130 °C is a suitable temperature for both the reaction and the reuse of the catalyst (entries 7 and 8). A Continuous Flow System Using an Automated Microflow Apparatus. With these favorable results in hand, we embarked on work to construct an automated continuous microflow system for use in the Mizoroki-Heck reaction. To achieve such a continuous microflow system, which involves the reaction, separation of the product and catalyst, and reuse of the catalyst, the problem of designing a continuous workup system arose. For the continuous reaction system, we used an automated microflow apparatus, CPC CYTOS Lab System,11 which is equipped with pumps, a micromixer (channel width ) 100 μm, inner volume ) 2 mL), and a residence time unit (inner volume ) 15 mL), with an intelligent control unit (left-hand side of Scheme 4). To realize a flow of 0.5 mL/min in the microchannels, the use of the low-viscosity ionic liquid [bmim]NTf2, was essential, since a high-viscosity ionic liquid [bmim]PF6 did not flow smoothly and overburdened the pumps. Using this automated microflow apparatus, a neat liquid containing iodobenzene (1), butyl acrylate (2), and tripropylamine was introduced from one inlet of the micromixer (0.5 mL/min), and the low-viscosity ionic liquid containing the Pd catalyst 4 was introduced from the other inlet (0.5 mL/min). The catalytic reaction took place after the two solutions were mixed at the CPC microreactor and was brought to completion in the residence time unit (residence time, 17 min at a total flow rate of 1.0 mL/min). The temperature of both the microreactor and the residence time unit was controlled at 130 °C. From the resulting mixture, the product, butyl cinnamate, was obtained by conventional extraction with hexane. The yields were consistently higher than 90%. The byproduct, an ammonium salt, was removed from the resulting ionic liquid layer by washing with copious amount of water. The ionic liquid recovered in this procedure could be used again in the next run without any drop in product yield (90-99%), suggesting that the Pd catalyst remained active in the ionic liquid even after completion of the recycling procedure. The repeated use of the Pd catalyst in the ionic liquid led us to explore a totally automated flow system with continuous catalyst recycling. To achieve such a flow workup system, we used T-shaped micromixers (channel diameter ) 300 μm) to facilitate the extraction of the product and ammonium salt. The setup is schematically outlined in the right-hand side of Scheme 4. In Scheme 5, we present a totally automated catalytic flow system with microextraction units attached to the microflow reaction system. The ionic liquid solution exiting from the microflow reaction apparatus was introduced into a T-shaped static micromixer, where the ammonium salt was washed by mixing with 0.5 M NaOH aqueous solution. The mixture solution was then mixed by another T-shaped static micromixer, where hexane was mixed to extract the product. On standing in the Y-shaped glass flask, the resulting mixture separated into three phases, a hexane layer containing the product and tripropylamine, an aqueous layer containing the inorganic salt, and the ionic liquid layer containing the Pd catalyst. The ionic liquid in the bottom layer was pumped back to container B for recycling the Pd catalyst. After running the complete system for 11.5 h, where 144.8 g (0.71 Table 1. Mizoroki-Heck reaction using ionic liquids in a microflow system in conjunction with an IMM micromixera entry ionic liquid methodb temp (°C) Pd cat. (mol %) residence time (min)c yield of 3 (%)d 1 [bmim]PF6 I 130 5 10 12 2 [bmim]PF6 I 150 5 10 67 3 [bmim]PF6 II 150 5 50 87 4 [bmim]PF6 II 150 2 50 98 5 [bmim]NTf2 II 150 2 50 88 6 [bmim]NTf2 II 150 recoverede 50 65 7 [bmim]NTf2 II 130 5 50 97 8 [bmim]NTf2 II 130 recoveredf 50 99 a Reaction conditions; iodobenzene (1):butyl acrylate (2):tripropylamine ) 1:1.2:1.5. b Method I: IMM micromixer (40 μm), flow rate, 0.1 mL/h. Method II: IMM micromixer (40 μm) + stainless tube reactor (1000 μm × 1 m), flow rate, 0.5 mL/h. c The residence time was determined by the total volume of the microreactor and the flow rates of both A and B. d Yields were determined by GC using tetradecane as an internal standard. e Recycled Pd catalyst in the ionic liquid from entry 5 was used. f Recycled Pd catalyst in ionic liquid from entry 7 was used. Scheme 4. Schematic drawing of the automated microflow apparatus, CPC CYTOS lab system and flow workup processes Vol. 8, No. 3, 2004 / Organic Process Research & Development • 479 mol) of iodobenzene together with the corresponding amount of acrylate and amine were consumed (total volume 408 mL), 115.3 g of trans-butyl cinnamate was obtained in an 80% (10 g/h) yield after purification by silica gel chromatography. This corresponds to a performance in which the ionic liquid with the Pd catalyst (90 mL) was recycled about five times during this overall catalytic reaction.