42 Microwave synthesis

Microwave synthesis

ELENA PETRICCI MAURIZIO TADDEI

Microwave assisted reactions with gas reagents ABSTRACT Controlled microwave heating has found many important applications in organic synthesis. Almost all kinds of reactions have been tested using microwaves. Major successes in carrying out rapid organic transformations have been achieved when high temperatures are required and substrates or reagents do not survive to prolonged heating. On the other hand, very few reports deal with the use of gas as reagent inside a microwave oven, even though many organic transformations that employs gas are carried out under heating and could take advantage of the use of microwaves. This review collects all the contributions reported until now on microwave-assisted reaction using gas reagents. Except for a few examples, all the reactions selected have been carried out using commercially available instruments for synthesis with minor modifications. INTRODUCTION The use of microwaves to heat organic reactions has attracted considerable interest in the last 15 years. This technique allows to reduce the time of chemical transformations and consequently the formation of by products is reduced, often with improved yields and purity of the products. Practically any kind of transformation has been tested under microwave irradiation, in many instances giving better results than conventional heating (1). Although microwave irradiation might seem simply an alternative for introducing energy into reactions, the use of this technology has launched a new concept in organic synthesis because the transmission and absorption of energy is different from conventional thermal heating (2-5). Moreover, several reaction types can be carried out successfully under solvent-free conditions, in which case the energy is not dispersed in the solvents, but directly absorbed by the reagents. This last possibility is also attractive in offering reduced pollution and low cost together with the simplicity of processing and handling (6-8). The temperature profiles achieved by microwave heating cannot easily be duplicated with traditional heating and allow kinetic control (9). Moreover, several reactions have been reported in which the chemo-, regio- and stereo-selectivity changed under microwave conditions in comparison to conventional heating in an oil bath (1, 10). The success of this technique is confirmed by the number of scientific publications (and patents) that increases every year. Amongst different reaction conditions tested inside a microwave cavity, the use of gas has been scarcely investigated and only in the latest years some manuscripts appeared in the literature. As most of the reactors for microwaves are designed to work under the pressure

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developed by the solvent under heating, the microwave reaction tube can be considered as a potential small autoclave that could be used for reaction with gas reagents. However, only few examples of reactions that use gases have been tried in microwave-ovens. Probably, the major concern is the safety of using gases (often flammable) in a microwave cavity that is know to produce “hot spot” with potential risks of explosion, besides it is not so trivial to preload some of the commercially available microwave vessels with gas. From the reports reviewed in this article, it seems that the techniques could be applied safely and that microwave ovens can be used also as small lab-top autoclaves with the possibility to speed up the reactions. The examples reported deal with hydrogenation (including hydrodechlorination), carbonylation, carboxylation and hydroformylation reactions carried out in previously pressurized vessels containing the reaction gas. However, it must be point out that several groups have also described the use of solid sources of hydrogen or CO to carry out this kind of reactions. CARBONYLATION REACTIONS Carbonylation is an important industrial process for the preparation of a wide range of products including amides, esters and carboxylic acids (11). It is widely used in organic synthesis and represents a useful method for the preparation of a variety of cyclic compounds (12, 13). With the aim of applying microwaves to this chemistry, several approaches have been developed to circumvent the problem of working with gaseous carbon monoxide. Even if thermal decomposition of DMF in highly basic conditions has been employed, Mo(CO)6 was the most represented source of CO applied to the synthesis of amides, esters and carboxylic acids starting from aryl iodides (14-16). Advantages of using Mo(CO)6 as a replacement for gaseous CO include the fact that it is solid and can be used on a small scale in commercial monomode microwave ovens with no modification required. However, Mo(CO)6 is toxic and its stechiometric use results in metal waste; this being a particular problem if the reaction is to be scale-up. Leadbeater and Kormos firstly reported microwavepromoted hydroxy- and alkoxycarboxylation of aryl

Scheme 1

chimica oggi • Chemistry Today • Vol 25 nr 3 • May/June 2007

iodides using heavy-walled quartz reaction vessels pre-pressurized with CO in the presence of Pd(OAc)2 as catalyst (17, 18). The reactor used is a multimode microwave (Anton Paar Synthos 3000) equipped with a gas-loading interface, allowing the vessels to be prepressurized to up to 20 bar prior to placing in the microwave cavity (19). Different conditions for the conversion of 4-iodoanisole into 4-methoxybenzoic acid and esters have been tested. A CO pressure of 14 bar, 1 mol% of Pd(OAc)2, Na2CO3 as base, H2O as the solvent and microwave irradiation at 165°C for 20 minutes have been selected as the best conditions for hydroxycarbonylation. On the other hand alkoxycarbonylation of aryl iodides gives good results with lower pressure of CO (10 bar) and with lower amounts of Pd(OAc)2 (0.1 mol%). The methodology has been applied to a wide range of substrates with interesting results (Table 1). Different aryl iodides were converted to the corresponding benzoic acids including o-substituted compounds. Generally product yields are higher using higher catalyst loading, heterocyclic iodide gave only moderate yields of carboxylic acid (Table 1, entry 9) because of competitive decomposition as well as difficulty in isolating the acidic product from the reaction mixture. Aryl bromides proved to be completely inactive under these conditions (Table 1, entry 2). It is interesting to note that the expected alkoxy products are obtained in higher yield than the corresponding carboxylic acids probably because carbon monoxide is significantly more soluble in short chain alcohols than in water. HYDROGENATION AND HYDROGENOLYSIS Hydrogenation and hydrogenolysis are processes of major industrial importance. These transformations often required long reaction times, high pressures and temperatures. Hydrogenation and hydrogenolysis reactions carried out inside microwave reactors have been usually driven using reagents that generate the hydrogen gas in situ or transfer hydrogen directly to the substrate even if H2 is the best hydrogen donor, especially


Microwave synthesis

Table 1

in terms of atom economy. Hydrogen donors used in microwave-assisted hydrogenations included ammonium formate (20-23), solid supported formats (24, 25), sodium formate (26) or isopropanol (27, 28). Microwave-assisted hydrogenation of olefins, aromatics and azide, as well as debenzylation have been optimized in a dedicated reactor constructed by MLS/Milestone (29). The reactor consists of a polyetrafluoroethylene (PTFE) tube which is covered by a polyetheretherketone (PEEK) tube to protect the system from explosions (30). The gas inlet, including a back pressure valve preventing the back flow of the reaction mixture is on the bottom side of the microwave oven and outside of the reaction room. A pressure sensor, a temperature sensor, an excess pressure valve (30 bar) and an outlet valve are located on the top of this tube. With this apparatus, pyperidine-2carboxylic acid was trasformed into (racemic) pipecolic acid using Scheme 2 PtO2 as catalyst, in EtOH at 25 bar of H2, at 125°C (Scheme 2). The expected product was obtained in quantitative yields after 1 h instead of 12-24 h required by the classical procedure (60 bar, 160 °C). In the same paper, Pd-C has been tested for microwaveassisted debenzylation, and for azide and alkene hydrogenation in high yields (Scheme 3). Another generally applicable method for the introduction of gaseous hydrogen into a sealed reaction system for microwave assisted organic synthesis has been proposed by CEM (31). The system uses a dedicated glassware that can be inserted inside the standard microwave monomode cavity and allow the contemporary registration of internal pressure and temperature. Different products are easily reduced using Pd-C in short reaction times with moderate temperature between 80°C and 100°C at a relatively low H2 pressure (3.4 bar). The chemistry reported in that paper seems to benefit from use of simultaneous cooling (Table 2, entry 7-9) in reactions that require higher power levels to achieve complete hydrogenation. All the examples reported demonstrate that hydrogenations under microwaves led to substantially shorter reaction times and often better yields than traditional heating. A possible explanation of this performance can be the possibility that microwaves may interact with the surface of the heterogeneous catalyst and create active “hot sopts” on the catalyst Scheme 3 surface.

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Microwave synthesis

The use of an H2 atmosphere has been also successfully applied to microwave assisted hydrodechlorination of chlorobenzenes using Pd/Al2O3 as catalyst (32). This reaction was carried out at atmospheric pressure in a continuous phase microwave reactor (CEM, ModelVoyager) equipped with a pressure pump (for feeding the substrate), a stirrer and a fiber optic temperature sensor as shown in scheme 4. The catalyst was packed in a 15 mL quartz U-tube (1.1 cm i.d, 12.5 cm long) placed in the microwave chamber. Chlorobenzene was fed to the reactor at an adjustable flow rate by the pressure pump along with a controlled flow of hydrogen from a cylinder. The reactor was subjected to microwave irradiation at 100 W power for a given time. The temperature of the system was monitored by a fiber optic temperature sensor attached to the U tube reactor and was maintained constant at a predetermined value by automatic variation of the MW power. The outlet of the reactor flowed through a pre-cooled collector where the products were recovered. It has been observed that hydrochlorination reaction can be significantly improved by conducting the reaction under microwave irradiation conditions rather than conventional heating. Moreover, catalyst poisoning by chlorine ions may be minimized especially at elevated temperature which facilitates their relatively easy removal

Scheme 4

from the catalyst surface. In terms of energy utilization, the authors measured a significant reduction in the power consumption during the microwave reaction compared with conventional heating reactions (32). MICROWAVE-ASSISTED REACTIONS IN ATMOSPHERE OF ETHYLENE Ethylene have been used as dienophile in microwave assisted Diels–Alder reaction of variously functionalized 2(1H)-pyrazinones giving cyclic products (Scheme 5) (33). Under conventional heating, these reactions have to be carried out in an autoclave applying 25-40 bar of ethylene pressure heating to 110°C for several hours or even days. Some studies on how a pressurised microwave protocol can speed up these transformation have been done using a prototype, bench-top multimode microwave reactor (19, 34). Different reaction conditions and substrates have been tested; best results have been obtained by microwave irradiation of a solution of the pyperazinone 30 in DCB under pressure of ethylene (10 bar) at 190°C for 20 minutes and hydrolyzing the adduct 31 by treatment with NaOH in THF under microwave irradiation at 70°C for 5 minutes. A camparison is made with conventional heating conditions, revealing that no improvement in the yields wasobserved using microwave irradiation. However, the use of microwave dramatically speed up the overall process. The nature of the substituent at C3 position of the 2(1H)-pyrazinone also influences the rate of the reaction (Table 3). Gaseous ethylene was also used in a microwave-assisted intermolecular ene-yne methatesis (EYM). The synthesis of enantiomerically enriched 2-(N-1-acetyl-1-arylmethyl)1,3-butadienes, important building blocks for synthesis of potential biologically active compounds, has been

Scheme 5

Table 2

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Table 3


Microwave synthesis

Scheme 7

Scheme 6

reported starting from chiral 1-arylpropargyl amides and ethylene using an unmodified CEM Discover Unit. The best conversion of (R)-33 with ethylene under microwave irradiation was achieved using 10 mol% of second generation Grubbs’ catalyst, in toluene at 80°C for 20 minutes at atmospheric pressure of ethylene (Scheme 6) (35, 36).

Scheme 8

SYNTHESIS OF CYCLIC CARBONATES Carbon dioxide is a renewable resource and can be used as a safe and cheap C1 building block to synthesize useful organic compounds without producing any co-products (37, 38). The solvent free synthesis of cyclic carbonates from CO2 and epoxides was carried out under microwave irradiation with controlled temperature and pressure (39). Microwave assisted reactions were carried out in a IMCR-25003 microwave reactor from IDX corporation (40). Different zinc salts, five kind of ionic liquids at different pressure of CO2 and reaction temperatures were investigated in detail finding that best results can be obtained using ZnPO, Bu4NBr, using 30 bar of CO2, irradiating at 120°C for 15 minutes. A kinetic analysis from the perspective of employing different heating source was attempted by the authors finding a first order plots for microwave and thermal activation as revealed by the values of k calculated for CO2 coupling reaction with PO obtained from microwave and oil bath at temperature ranged from 70 to 100°C. From the extrapolation of Ea and A values it seemed that both parameters were significantly influenced by microwave irradiation, and decreased remarkably compared with that of oil bath. TOF values for the tested catalytic systems were calculated showing that the catalyst consist of ZnPO and Bu4NBr under microwave irradiation provide the highest TOFs reported in the literature for this kind of reaction. HYDROFORMYLATION Since its discovery in 1938, hydroformylation of olefins has evolved into one of the industrially most important processes which rely on homogeneous catalysis (41, 42). Recently we reported a general applicable procedure for microwave-assisted hydroformylation of terminal olefins adapting a Discover microwave oven equipped with the 80 mL vial for reaction under pressure (43, 44). Several terminal alkenes were submitted to optimised

Table 5

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Table 4

reaction conditions and all gave high conversion into the linear aldehydes without notable formation of the branched isomers with the exception of styrene which gave a mixture of products respectively (Table 4). Similar results were observed under standard hydroformylation conditions using Wilkinson catalyst and XANTPHOS. These results suggest that for the hydroformylation reaction no special effects can be ascribed to the microwaves except for a tremendous increase of the reaction rate. The compatibility of the process with different functional groups is demonstrated by the high yielding transformations carried out successfully (Table 4). Tandem microwave-assisted hydroformylation reductive amination have been also optimized subjecting octene and 4-phenyl-1-buten-1ol to hydroformylation in the presence of amines (Scheme 9). Different reaction conditions have been tested finding that using EtOH as solvent is possible to obtain expected compounds 41a,b,f,g in good yields (70-90 percent) starting from secondary ammines. On the contrary in the presence of primary amines only imine intermediates were isolated in good yields (Table 5). These results show that the hydroformylation reaction runs but the hydrogenation of the intermediate imine did not occur even changing catalyst, solvent, reaction temperature and time (45). The possibility to drive tandem hydroformylation and Pictet-Spengler’s reaction have been evaluated as well. Intermulecolar Pictet-Spengler’s reaction on indole derivatives gave only intermediate imines. Expected product has been obtained preforming the aldehyde by microwave-assisted hydroformylation and successively


CONCLUSIONS This article has collected the very few examples of reaction performed inside a microwave cavity with gases as reagents. Despite potential risk, the reports do not register any accident occurred during experiments. Great care must be done especially to prevent entrance of oxygen in the vessel. However, microwave demonstrates to be able to accelerate also reactions with gases, opening new possibility to develop new reactions and procedure. We hope that this short review will inspire to more successful research in this area and that the use of gas in microwave chemistry both in batch than in continuous flow could replace conventional autoclave chemistry in the future. ACKNOWLEDGMENT The authors thank CEM Italia s.r.l. and Siena Biotech S.p.A. for financial support. REFERENCES AND NOTES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

C. O. Kappe Angew. Chem. Int. Ed. 43, 6250-6284 (2004). D. R. Baghurst, D. M. P. Mingos J. Chem. Soc. Chem. Commun. 674-676 (1992). A. Loupy, R. S. Varma, Chemistry Today 24, 36-40 (2005). C. O. Kappe, A. Stadler “Microwaves in Organic and Medicinal Chemistry”, Wiley-VCH: Weinheim, 2005. P. Lidström, J. P. Tierne, “Microwave-assisted Organic Synthesis”, Blackwell: Oxford 2005. R. S. Varma Green Chem. 1, 43-55 (1999). K. Tanaka, F. Toda Chem. Rev. 100, 1025-1074 (2000). N. Kuhnert, T. N. Danks Green. Chem. 3, 68-70 (2001). N. F. Leadbeater, S. J. Pillsbury, E. Shanahan, V. A. Williams Tetrahedron 61, 3565-3585 (2005). C. O. Kappe, D. Dallinger, Nature Rev. Drug. Discov. 5, 51-63 (2006). A. Zapf, M. Beller Chem. Comm. 431-440 (2005). B. El Ali, Alper H. Synlett 161-171 (2000). S. Ma, B. Wu, X. Jiang J. Org. Chem. 70, 2588-2593 (2005). O. Legerlund, M. Larhed J. Comb. Chem. 8, 4-6 (2006). X. Y. Wu, M. Larhed J. Org. Chem. 70, 3094-3098 (2005). J. Wannberg, M. Larhed J. Org. Chem. 68, 5750-5753 (2003). C. M. Kormos, N. E. Leadbeater Synlett 1663-1666 (2006). C. M. Kormos, N. E. Leadbeater Org. Biomol. Chem. 5, 65-68 (2007).

Scheme 9

Microwave synthesis

irradiating in the presence of the indol compound at 100°C (Scheme 10) (45). On the other hand, Intramolecular tandem hydroformylation and PictetSpengler cyclisation was successful applied to both aromatic and protected indol compounds giving tricyclic derivatives in accettable yields (Scheme 11) (45).

Scheme 10 19. A. Stadler, B. H. Yousefi, D. Dallinger, P. Walla, E. Van der Eycken, N. Kaval, C. O. Kappe Org. Process Res. Dev. 7, 707-716 (2003). 20. H. Berthold, T. Schotten, H. Hönig Synthesis 1607-1610 (2002). 21. M. C. Daga, M. Taddei, G. Varchi. Tetrahedron Lett. 42, 5191-5194 (2001). 22. B. K. Banik, K. J. Barakat, D. R. Wagle, M. S. Manhas, A. K. Bose J. Org. Chem. 64, 5746-5753 (1999). 23. N. Stiansi, C. O. Kappe ARKIVOC viii, 71-73 (2002). 24. B. Desai, T. N. Danks Tetrahedron Lett. 42, 5963-5965 (2001). 25. T. N. Dank, B. Desai Green. Chem. 4, 179-180 (2002). 26. A. Arcadi, G. Cerichelli, M. Chiarini, R. Vico, D. Zorzan Eur. J. Org. Chem. 3404-3407 (2004). 27. M. T. Reetz, X. Li J. Am. Chem. Soc. 128, 1044-1045 (2006). 28. K. Laijondahl, A.-B. L. Fransson, J.-E. Bäckvall J. Org. Chem. 71, 8622-8625 (2006). 29. E. Heller, W. Lautenschläger, U. Holzgrabe Tetrahedron Lett. 46, 1247-1249 (2005). 30. http://www.milestonesci.com/synth-tech.php. 31. G. S. Vanier Synlett 131-135 (2007). 32. U. R. Pillai, E. Sahle-Demessie, R. S. Varma Green Chem. 6, 295-298 (2004). 33. K. Loosen, M. F. Khorasani, S. M. Toppet, G. J. Hoornaert Tetrahedron 47, 9269-9278 (1991). 34. N. Kaval, W. Dehaen, C. O. Kappe, E. Van der Eycken Org. Biomol. Chem. 2, 154-156 (2004). 35. D. Castagnolo, M. L. Renzulli, E. Galletti, F. Corelli, M. Botta Tetrahedron Asymm. 16, 2893-2896 (2005). 36. No details on how to charge the reaction tube with ethylene are reported. 37. W. Leitner Coord. Chem. Rev. 155, 257-260 (1996). 38. D. J. Darensbourg, M. W. Holtcamp Coord. Chem. Rev. 153, 155-158 (1996). 39. F. Ono, K. Qiao, D. Tomida, C. Yokoyama J. Mol. Catal. A.: Chem. 263, 223-226 (2007). 40. http://www.idx-net.co.jp/index2.html. 41. O. Roelen, (Chemische Verwertungsgesellschaft, mbH Oberhausen) German Patent DE 849,548, 1938/1952; U.S. Patent 2,317,066, 1943; Chem. Abstr. 38, 550 (1944). 42. See for instance: B. Cornils, C. D. Frohning, C. W. Kohlpaintner J. Mol. Catal. A: Chem. 104, 17-85 (1995). 43. E. Petricci, A. Mann, A. Schoenfelder, A. Rota, M. Taddei Org. Lett. 8, 3725-3728 (2006). 44. www.cem.com/synthesis/index.asp 45. Unpublished results from our laboratory.

ELENA PETRICCI, MAURIZIO TADDEI

Scheme 11

Università degli Studi di Siena Dipartimento Farmaco Chimico Tecnologico Via A. Moro 2 53100 Siena, Italy


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