Synthesis of Organic Compounds Using Polymer-Supported Reagents

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Synthesis of Organic Compounds Using Polymer-Supported Reagents, Catalysts, and/or Scavengers in Benchtop Flow Systems† Philip Hodge‡ Department of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, U.K.

The synthesis of organic compounds using polymer-supported catalysts, reagents, and/or scavengers, so that the required product is always in solution, has been of great interest in recent years, especially in connection with pharmaceutical research. To date, the reactions have almost always been carried out in batch mode. It is now timely to consider developing them further and carrying them out using flow systems. Advantages of flow systems typically include the following: there is little or no reaction workup, the support suffers no physical damage in use, automation is relatively easy, and extension to continuous production, even on a large scale, is a possibility. This paper gives a brief background on previous work using polymer-supported catalysts, reagents, and/or scavengers and then reviews in detail the work that has been done to date using these reactants in flow systems. It identifies some of the problems encountered and indicates how they might be solved. Rapid progress requires collaborations between organic chemists, polymer chemists, and chemical engineers. 1. Brief Overview of Past Work on Polymer-Supported Organic Reactions Polymer-supported (PS) organic reactions, i.e., reactions where at least one of the reactants is bound to a polymer, have many attractive features, the most important of which stem from the easy separation of the supported and nonsupported species at the end of the reaction. The separation is especially easy if the polymer is in the form of cross-linked, and therefore totally insoluble, polymer beads. Then, at the end of the reaction period, separation can be achieved simply by filtering off the beads and washing them with solvent. Clearly such a separation procedure can easily be automated. This concept has led to PS organic reactions being of interest for more than 60 years.1-3 They began to be studied seriously in the 1940s and early 1950s following the commercial introduction of various organic ion-exchange resins.1 The latter were usually sulfonated cross-linked polystyrene beads (strong acid cationexchange resins), cross-linked beads prepared using acrylic or methacrylic acids (weak acid cation-exchange resins), or cross-linked polymer beads containing quaternary ammonium salt residues (anion-exchange resins). Typical early studies involved using resin beads bearing sulfonic acid groups as catalysts for reactions such as sucrose inversion, alcohol dehydration, ester hydrolysis, acetalization, and acetal hydrolysis.1 Ionexchange resins were also used in an appropriate form to achieve organic separations; for example, the bicarbonate form of an anion-exchange resin could be used to separate acids from aldehydes and ketones.4 Often the use of ion-exchange materials to assist in the purification of reaction products was hidden in the details of the paper. The study of PS reactions received an enormous boost in 1963 when Merrifield,5 but also Letsinger and Kor† Dedicated to Dave Sherrington on the occasion of his 60th birthday in recognition of his many contributions to polymer science and a long and continuing friendship. ‡ Tel.: 0161 275 4707. Fax: 01524 793 252. E-mail: [email protected].

net,6 reported the first examples of “solid phase” peptide synthesis. About the same time Letsinger and Mahadevan reported the first studies of “solid phase” oligonucleotide synthesis,7 the forerunner of the technique used extensively today in connection with genetic engineering. In these methods the first residue of an oligopeptide or oligonucleotide is attached to insoluble polymer beads and more appropriate residues are added one by one until the required oligomer has been assembled. The oligomer is then cleaved from the beads. These methods were the first important examples of reactions involving PS substrates: see Scheme 1. The major advantage of these methods is that at each stage the PS oligomer is always recovered simply by filtering off and washing the beads. When carrying out such syntheses it is, however, crucial that there are no side reactions and the required reactions proceed in 100% yield because the various products bound to the beads cannot be separated unless they are first cleaved from the support. As a consequence, for every reaction the conditions need to be very carefully tuned: a challenging and time-consuming task. It is not helped by the fact that monitoring the transformations of PS species is not as easy as monitoring transformations in solution. This makes such syntheses, so-called “solid phase syntheses”, quite demanding. Even so, solid phase peptide synthesis and solid phase oligonucleotide synthesis are very important techniques. More recently, the solid phase approach has been successfully extended to oligosaccharide synthesis.8 In the early 1970s several research groups sought to extend Merrifield’s and Letsinger’s methods to other areas of organic synthesis.2,3 Sherrington has recalled many of the developments at this time.9 The supported reactant could be a substrate, a reagent, a catalyst, or a scavenger. Many examples of organic reactions using PS substrates, PS reagents, PS catalysts, or PS scavengers were investigated at this time and by 1980 approximately a thousand relevant references were to be found in the primary literature. A wide variety of supports were investigated.10 The importance of the

10.1021/ie040285e CCC: $30.25 © 2005 American Chemical Society Published on Web 05/19/2005

Ind. Eng. Chem. Res., Vol. 44, No. 23, 2005 8543 Scheme 1. General Scheme for a Reaction in “Solid Phase Synthesis”

correct choice of reaction solvent, the ideas of site isolation, and examples of microenvironmental effects were identified, studied, and substantially understood.2,11 The pros and cons of using PS substrates, PS reagents, and PS catalysts were clearly recognized and various types of separation processes were developed. It was evident that reactions using PS substrates were generally the least attractive of these three types for the reasons noted in the preceding paragraph. It was clear a much better way forward was to use PS reagents and, preferably, PS catalysts: see Scheme 2. Interest in the field of PS organic chemistry slowly waned, essentially because at the time it was an excellent technique in search of an application. The latter arrived in the late 1980s when combinatorial chemistry was introduced by Furka et al.,12 by Lam et al.,13 and by Houghten.14 Combinatorial synthesis then involved carrying out reactions with PS substrates and manipulating the beads to make large numbers of organic compounds.15 Closely related is high-throughput synthesis achieved by carrying out many reactions in parallel. Surprisingly, despite the previous difficulties noted above, reactions using PS substrates were the ones studied most extensively in the 1990s. “Linkers”, i.e., the functionalities that attach the substrate to the support, that are stable to the various reagents used in the synthesis, but are cleaved easily and efficiently at the end of the synthesis, so releasing the desired product from the support, received much attention.16 Eventually after 10-15 years it is now again being recognized that, for many purposes, such as highthroughput synthesis, the use of PS reagents or PS catalysts plus, if necessary, PS scavengers (the PS-RCS approach), is often the best way forward. With PS reagents and catalysts the PS species is generally used in only one reaction step, not all the reactive sites on the polymer beads need to react, and because the desired organic reaction product is in solution, the reactions are monitored easily using the classical methods of organic synthesis. Several examples of natural product syntheses using the PS-RCS approach have been reported in recent years.17,18 The most complex is Ley’s synthesis of epothilone C (1).18 A different type of application is illustrated by the parallel synthesis of nine small libraries of bicyclo[2.2.2]octanes with the final array of compounds possessing up to five sites of diversity. In all, ca. 130 bicyclo[2.2.2]octane derivatives were prepared rapidly and without the need for chromatographic purification steps.19

It is now timely to consider how PS reactions might be further improved and advanced. Thus far, most PS organic reactions have been carried out in the batch mode and in such systems at the end of the reaction period the polymer beads are filtered off and washed. A difficulty sometimes encountered is that during the reaction the polymer beads physically degrade to smaller particles that block the filters. This is especially so if magnetic stirrer bars have been used as these tend to grind the beads against the bottom of the reaction vessel. Flow systems are an alternative to batch systems. They have long been used very successfully in industrial synthesis, especially those in which gases are passed over solid inorganic or organic catalysts. Examples are the synthesis of tert-butyl methyl ether and the Beckmann rearrangement of cyclohexanone oxime to give -caprolactam.20 It is now timely to explore what flow systems have to offer in the research laboratory. Even though it has been noted many times in the past 30 years that reactions using PS reagents, catalysts, and/or scavengers have the potential to be used in flow systems, in only a few cases has this aspect actually been pursued. Progress in this area will be most rapid with the combined skills of organic chemists, polymer chemists, and chemical engineers. This paper briefly reviews work already carried out in flow systems using the PS-RCS approach to organic synthesis. It shows how they might be developed in future. The field has only occasionally been reviewed before.21,22 Examples not involving “solution phase synthesis” include the solid phase synthesis of peptides in flow systems.23 Flow systems involving gases have also been used occasionally in the laboratory. For example, Tundo et al. showed that organic compounds in the gas phase react readily with salts coated with a phase transfer catalyst such as poly(ethylene glycol), an example being the C-alkylation of malonate over solid potassium carbonate.24 Olah’s research group has studied many reactions by passing organic compounds, such as 2-methylpropene, over solid Nafion-type perfluorinated sulfonic acids.25 Immobilized enzymes have also been used in flow systems.26

Scheme 2. General Schemes for Reactions Using PS Catalysts and PS Reagents in “Solution Phase Synthesis”

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Ind. Eng. Chem. Res., Vol. 44, No. 23, 2005

2. Some General Comments about the Use of PS Reactants in Benchtop Flow Systems The use of PS reactants in flow systems has several advantages over conventional batch reactions. 1. The solid reactants suffer less physical damage than they do in stirred batch reactions, especially those using magnetic stirrers, and so they are expected to have a longer useful life. 2. Often they allow reactions to be carried out with little or no workup. 3. They allow reaction conditions to be reproduced relatively easily. 4. Flow systems have the potential for easy automation, including feedback on the progress of the reaction. 5. They have the potential to be adapted for the continuous production of product, and thence an easier scale-up from laboratory to plant. Several general points merit comment. First, the kind of flow system used will depend on the nature of the polymer support. In most systems one of three basic types has been used. (i) The simple fixed-bed reactor. In early work with ion-exchange resins it was soon recognized that to obtain good flow characteristics in a fixed-bed reactor and to have a column bed of constant size, it was necessary to use macroporous or macroreticular beads. Such beads are suitable because they are relatively hard and incompressible and they swell very little when placed in solvent. For the same reasons inorganic supports may also be used. In contrast microporous beads need to be swollen by solvent to gain access to the reactive moieties and their swelling properties will change as the reactive moieties on the beads react to give different moieties.11 Moreover, the small swollen beads are compressible. Accordingly, if attempts are made to use such beads alone in a simple fixed-bed column, the column will tend to change volume as the reaction proceeds and it will probably compress and clog. One solution is to mix the microporous beads with several volumes of an inert nonswellable material such as sand, Celite, or chopped glass fibers so that the swelling of the bed as a whole is attenuated. (ii) The simple fluid-bed reactor. Most PS reactions to date have been developed by organic chemists using microporous beads, so it is often helpful to be able to use these same beads directly in flow systems. One solution to the problem was noted above. Another is to use the microporous beads in a fluid-bed reactor. This may take the form of a simple glass tube sealed at the top with a septum cap.27 Solutions of the soluble reactants can be pumped to the bottom of the bed via long syringe needles. The reactants then pass up through the bed of beads and are collected at the top of the column, possibly with the aid of further syringe needles. The effective length of the tube can be altered simply by adjusting the position of the takeoff needle. The tube can be heated or cooled easily in a thermostated bath. Further advantages are that when the reaction is finished, it is easy to remove the needles and to store the tube. (iii) Monolithic reactors. A type of support that is fast gaining in popularity is the porous monolith. The monolith needs to have good flow properties. It may, for example, be one prepared by the polymerization of a high internal phase emulsion (such as a polyHIPE)28 or a rigid porous glass whose pores contain polymer particles.29 In some cases the column may be only a thin

slice from a conventional cylindrical monolith; i.e., it is a disk, perhaps only 1-5 mm thick.30 Other flow systems studied recently are those based on size-selective membranes. Here, soluble polymers or dendrimers bearing catalytic groups are retained in a reactor equipped with a membrane while the organic compounds in solution flow through.31 Also of current interest are microreactors.32 Work in these areas is, however, not the focus of the present review. They have been reviewed recently by van Koten et al.31 and by Fletcher et al.,32 respectively. Second, most organic reactions are relatively slow and even at temperatures up to 100 °C may typically take several hours to proceed to completion. This either means flow rates must be low with a residence time in the column of several hours, or they can be high but the eluate needs to be recycled through the column, ideally with online monitoring, until the reaction is complete. A possible solution that is currently becoming available is to speed up the reactions by means of microwave irradiation.33 Finally, pumping, when required, is usually by means of syringe pumps or peristaltic pumps. Depending on the reaction being carried out, all the solutions in reservoirs, on the columns and/or in product receivers, might need to be kept under a dry inert atmosphere. Since this article focuses on the PS-RCS approach, it is convenient to discuss flow systems using PS catalysts, PS reagents, and PS scavengers separately. 3. Use of PS Catalysts in Flow Systems PS catalysts are the most attractive type of PS reactant to use in a flow system because in principle they should operate successfully over a long period. However, if a side reaction occurs that destroys, say, even only 1% of the activity per hour, then after a few days the loss of activity is very serious. In general with most catalysts used in the research laboratory their long term stability is simply unclear. Their use in flow systems promises to teach us much about such issues and will help us to develop catalysts that have all the usual desirable attributes but which are also more stable and long lasting. The first use of a PS catalyst in a solution phase system was almost certainly the use of columns of acidic or basic ion-exchange resins as catalysts.1 A recent example involves the use of the scandium(III) form of a Nafion-type perfluorinated sulfonic acid, mixed with sea sand in a column, to catalyze the reaction of benzaldehyde in acetonitrile at ambient temperatures with tetraallyltin to give 3-hydroxy-3-phenylbut-1-ene in yields of 75-93%.34 Another fluorinated catalyst studied is the super Bronsted acid (2), see Scheme 3, prepared from microporous 2% cross-linked polystyrene beads.35 Celite and the beads were mixed (53:1 w/w) and packed into a 2 mL syringe equipped with a syringe filter. The Celite presumably does not swell in the reaction solvent, so this will attenuate any swelling of the polymer beads and maintain acceptable flow characteristics in the column. When a mixture of L-menthol and acetic anhydride in acetonitrile was passed once through the column over 1 h at ambient temperature, the ester was formed in 99% yield: see Reaction 1 in Scheme 3. Other esters were synthesized similarly. Other acid-catalyzed reactions carried out were the synthesis of cyclic acetals (Reaction 2), the Mukaiyama aldol reaction (Reaction 3), the Sakurai-Hosomi reaction (Reaction 4), the Mu-

Ind. Eng. Chem. Res., Vol. 44, No. 23, 2005 8545 Scheme 3. Examples of Organic Reactions Achieved Using PS Catalyst 2 in Flow Systems34

Scheme 4. Example of a Reaction Using PS Trityl Perchlorate as a Catalyst in a Flow System36

Scheme 5. Reduction of Valerophenone in a Flow System Using a Fluid Bed of PS Catalyst 537

Scheme 6. Reduction of Acetophenone Using Isopropanol and a Supported Transfer Hydrogenation Catalyst in a Flow System38 a

kaiyama-Michael addition reaction (Reaction 5), and the Mukaiyama aldol-type reaction (Reaction 6). Several of these yields are superior to those obtained using a Nafion in place of acid 2.35 A different type of PS acid catalyst has been developed by Mukaiyama and Kobayashi.36 Microporous crosslinked polystyrene beads bearing trityl alcohol groups were prepared and mixed with chopped glass fibers (1 part:5 parts by weight). The mixture was placed in a glass column and treated with perchloric acid and acetic anhydride. This converted about 7% of the alcohol residues into trityl perchlorate residues. These catalyzed several types of nucleophilic substitution on 1-O-acetyl2,3,5-tri-O-benzyl-β-D-ribose (3): see Scheme 4. For example, when a solution of compound 3 and the TMS enol ether of tert-butyl methyl ketone in dichloromethane was passed down the column, compounds 4 were formed in 80% yield with the anomeric ratio of R: β ) 24:1. The catalyst could be reused. Itsuno et al. reduced valerophenone to the corresponding alcohol using a PS chiral amino-alcohol in a fluid-bed reactor: see Scheme 5. Solutions of the ketone and of borane in tetrahydrofuran (THF) (mole ratio 0.8: 1.0) were separately and continuously pumped to the bottom of a column of microporous beads (14 cm long × 1 cm diameter) of the pre-prepared complex from borane and PS amino-alcohol 5 (2.5 g, 2.4 mmol of catalyst

a

* ) Chiral center: predominant enantiomer not determined.

residues).37 The eluate passed over from the top of the column into a receiver and was quenched with hydrochloric acid. With flow rates of 0.4 and 0.8 mL/min respectively, corresponding to residence times of 3060 min, the (R)-alcohol was obtained with an enantiomeric excess (ee) of 83-93%. With analogous batch reactions, ee values were 81-92%. Thus, with this reaction, both the flow and batch procedures gave similar results. A chiral transfer hydrogenation catalyst has been studied by van Leeuwen et al.38 A silica gel functionalized with residues 6, derived from norephedrine, was prepared. A mixture of the silica gel and [{RuCl2(η6-pcymene)}2] was slurried in propan-2-ol and after heating at 60 °C for 30 min the mixture was cooled to 0 °C and transferred to a glass flow reactor (7 mm diameter) to form a fixed bed 1.5 cm deep. The catalyst brought about the transfer hydrogenation (propan-2-ol, present as the solvent, was the reductant) of acetophenone to 1-phenylethanol: see Scheme 6. At a flow rate of 1.4 mL/h a 95% conversion was achieved and the ee was 90%. The performance was virtually unaltered for 1 week, with no significant ruthenium leaching, and the column was

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Scheme 7. Reaction of an Aromatic Aldehyde with Diethylzinc Catalyzed by PS Catalyst 7 in a Flow System39

Scheme 8. Reactions of Benzaldehyde with Diethylzinc Catalyzed by PS Catalysts 8-10 in Flow Systems27,41

still active after 3 weeks. The high stability is in contrast to that of the corresponding soluble catalyst. The reactions of aldehydes with diethylzinc to give chiral alcohols have been investigated in flow systems three times. The first system was described by Itsuno et al.39 They used what was basically a glass chromatography column with a fixed bed of catalyst prepared from 20% cross-linked polystyrene beads. The catalyst was the chiral Schiff base 7 prepared from 4-chlorobenzaldehyde and PS amino-alcohol 5 (7.1 g, 5.0 mmol of catalyst residues): see Scheme 7. 4-Chlorobenzaldehyde in toluene (0.5 M) and diethylzinc in toluene (0.7 M) (molar ratio 1.0:1.4) were passed down a column of the beads (70 cm long × 1.5 cm diameter) at 0 °C. With just one pass, the chiral alcohol was obtained in 90% yield with a 94% ee of the (S)-enantiomer. In the corresponding batch reaction, the ee was 88% (i.e., 6% less than in the flow system). The second system used a fluid bed of PS-ephedrine 8 (10.9 g; 1.8 mmol/g), see Scheme 8, prepared from microporous cross-linked beads, in a tube (90 cm long × 1.4 cm diameter). Solutions of benzaldehyde and diethylzinc in toluene at 20 °C were pumped (peristaltic pump) to the bottom of the bed via syringe needles and they reacted together as they passed up through the bed over 12 h.27 Because preliminary studies showed that better ee values were obtained with lower levels of crosslinking,40 the polymer beads were specially prepared for these experiments and were only 0.2% cross-linked. While such lightly cross-linked beads would normally be too fragile to be practically useful, they were nevertheless satisfactory in the flow tube. The percentage ee of the alcohol produced depended significantly on the concentrations and flow rates of the soluble reactants. With optimum conditions (benzaldehyde ) 0:2 M, diethylzinc ) 0:5 M and both flow rates ) 10 mL/h) (R)1-phenylpropanol was obtained in 98% yield (plus 2% of benzyl alcohol) and an ee of 98%. Under the same conditions, 4-chlorobenzaldehyde gave the corresponding alcohol with a 97% ee. These ee values are substantially better than those (ca. 78%) obtained from similar batch reactions.40 Evidence was presented that this was due mainly to the relatively high ratio of diethylzinc to aldehyde extant in the column.27 In further similar experiments but using a tube containing 1% cross-linked

polystyrene beads with camphor-derived residues 9 (0.64 mmol/g, 10.3 g of beads), benzaldehyde was reacted with diethylzinc in toluene at 20 °C.27 The aldehyde and diethylzinc solutions were 0.2 and 0.5 M, respectively. Both solutions were pumped into the reactor at a rate of 6 mL/h. A “run” lasted for 16-18 h. This gave (S)-1phenylpropanol in 95% chemical yield and 97% ee. A further 15 “runs” were carried out, some of them with different aldehydes. In total, the system was run for ca. 275 h. In the reactions using benzaldehyde (runs 1-7 and 14-16) the percentage ee of the (S)-1-phenylpropanol gradually fell from 97% to 81% and evidence was presented that the secondary alcohol groups in the catalytic sites were being racemized slowly via Meerwein-Pondorff-Verley-Oppenauer-type redox equilibria (see later). This would be avoided if the catalyst contained a tertiary, rather than a secondary, alcohol group. The final study using diethylzinc was carried out by the research groups of Luis and Martens.41 This team used a polymeric monolith prepared using 10 mol % of a monomer containing the catalyst residues and 90 mol % of divinylbenzenes. The pre-catalyst residues 10 were derived from a byproduct of an industrial pharmaceutical synthesis: see Scheme 8. Unlike in all the studies discussed so far, which used just one pass through the columns, here the column output was recirculated around the system for 24 h before workup. This afforded (R)-1-phenylpropanol in 85% yield (plus 15% of benzyl alcohol) and 99% ee. The monolith was reused three times with very similar results. As with the earlier study,27 this ee is substantially higher than that obtained from analogous batch reactions using a LMW catalyst or polymer beads. Several explanations were offered, but it seems likely that, as before,27 it may

Ind. Eng. Chem. Res., Vol. 44, No. 23, 2005 8547 Scheme 9. Example of an Asymmetric Diels-Alder Reaction Carried Out Using a PS Chiral Catalyst in a Flow System42

simply be due to a relatively high mole ratio of diethylzinc to benzaldehyde. Itsuno’s group carried out Diels-Alder reactions in a simple fixed bed of catalyst in a vertical glass column with gravity feed.42 The PS catalyst was prepared beforehand in the same apparatus from the boranedimethyl sulfide complex and a polymer containing residues 11: see Scheme 9. The polymer was specially prepared by a suspension copolymerization using 10 mol % of the novel long cross-linking agent 12. A mixture of methacrolein (0.44 M) and cyclopentadiene (0.66 M) in dichloromethane was passed down the column at -30 °C and at a rate of 10 mL/h. The column (50 cm long × 0.7 cm diameter) contained 5.7 mmol of catalyst (in 8.8 g). In total, 18.8 g of mixed adducts was obtained in 95% yield. The exo:endo ratio was 93:7. The exo-adduct 13 was isolated using column chromatography and found to have a 71% ee of the (R)-enantiomer. These values are the same as those obtained from a batch experiment. Catalysis of the Diels-Alder reaction between cyclopentadiene and 3-crotonyl-1,3-oxazolidin-2-one by TADDOL derivatives has been studied in a flow system by Luis et al.: see Scheme 10.43 The catalyst was formed by treating a monolith containing residues 14 (Ar ) 3,5dimethylphenyl), prepared using a TADDOL-containing monomer, with a solution of TiCl2(OiPr)2 in toluene. A solution of the diene and dienophile in toluene was introduced into the column and retained for 24 h. The column was then eluted with toluene and the products were isolated. The major products (>70%) were the enantiomeric endo-adducts 15 and 16. The ee of the 2S,3R-adduct 16 was only 18% but, interestingly, with an analogous batch reaction using a cross-linked poly-

Scheme 10. Asymmetric Diels-Alder Reaction Carried Out Using a PS TADDOL-Based Catalyst in a Flow System43

Scheme 11. Hydrolytic Kinetic Resolution of an Epoxide Using the Supported Catalyst 17 in a Flow System44

styrene matrix onto which residues 14 had been grafted, the 2R,3S-adduct 15 was the major isomer (17% ee). The most likely explanation for the stereochemical course of the reaction being reversed is that in the preparation of the monolith from the chiral monomer some net chirality was generated in the polymer backbone. The column could be reused many times. Over 210 days, the percentage ee values obtained essentially halved. It is not clear why the performance deteriorated. With a monolith containing residues 14 (Ar ) 2-naphthyl) the

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Scheme 12. Synthesis of β-Lactams in a Flow System45,46

2S,3R-adduct 16 was the major adduct (40% ee) in both column and batch reactions. Annis and Jacobsen have prepared a silica-supported chiral catalyst and used it in an HPLC column to achieve the hydrolytic kinetic resolution of epoxides: see Scheme 11.44 The use of silica has the advantage that it is rigid and incompressible and so ideal for use in a fixed-bed reactor. The column contained the chiral catalyst 17. On passing a 5.9:1 THF-water solution of racemic epoxide 18 through the column, one enantiomer of the epoxide reacted with water much faster (×63) than the other. The net result was that the (S)-triol 19 was obtained in 39% chemical yield and 94% ee, whereas the recovered epoxide, presumably mainly the enantiomer 20, had a 61% ee. Similar results were obtained in batch reactions. The column could be reused successfully. Leckta et al. have used PS chiral catalysts in flow systems to control the cycloaddition of ketenes to imines to give β-lactams: see Scheme 12.45,46 The reactor used PS quinine derivative 21 in a fixed bed at -43 °C. Best results were obtained when the quinine moiety was linked to the beads by the rigid “spacer” shown.46 When imine 22 was reacted with ketenes, the chemical yields were high and the products contained the cis- and trans-

Scheme 13. Examples of Oxidations in Flow Systems47,48

isomers 23 and 24 in a ratio of ca. 13:1. The cis-isomers were formed in 90-94% ee and this was usually raised to >99% ee by crystallization. When quinidine was used to prepare the PS catalyst, the reaction between phenylketene and imine 22 at -43 °C gave the cis-β-lactam 25 in 95% ee as the major product.46 4. Use of PS Reagents in Flow Systems A basic problem in using PS reagents in flow systems is that the reagents have a finite capacity and so are gradually consumed. In many potential applications a freshly charged column may last for, say, 20 reactions but eventually it will need to be replaced or regenerated. Clearly the useful life is longer if the capacity of the column is high. Simple replacement with fresh reagent would be acceptable only if the polymer was relatively cheap and regeneration would only be convenient if it could be achieved easily. This makes PS reagents prepared from the readily available macroporous commercial anion-exchange resins the most attractive. Probably the first example of a PS reagent used in a flow system not involving ion-exchange resins or solidphase peptide synthesis is the use of PS peroxy acid 26 in a simple fixed-bed column heated at 40 °C: see Scheme 13.47 The peroxy acid was prepared from macroporous polystyrene beads with a peroxy acid content of 1.9 mmol/g. When a solution of penicillin G (27) in acetone was allowed to pass down the column

Ind. Eng. Chem. Res., Vol. 44, No. 23, 2005 8549 Scheme 14. Examples of Reactions Carried Out Using the PASSflow Columns49-51

Scheme 15. Generation of Phenylketene and an Imine in Flow Systems45

Scheme 16. PS Acylating Agents Used in Flow Systems54

once with a residence time of ca. 30 min, the corresponding sulfoxide 28 was obtained in 91% yield. The column was regenerated in situ by treatment for 12 h with hydrogen peroxide and methanesulfonic acid at 20 °C. Oxidations of 2,5-di-tert-butylquinol (29) were achieved by passing acetone solutions down a simple column of the periodate form of a macroporous anion-exchange resin (6.0 g, 1.7 mmol of periodate/g) at 20 °C: see Scheme 13.48 With a residence time of 1 h, the corresponding quinone 30 was obtained in 97% yield. Kirschning and Kunz prepared novel monoliths by a precipitation copolymerization of divinylbenzenes and chloromethylstyrene within the pore volume of highly porous glass rods.49,50 The 1-5 µm polymer particles in the composite swell and shrink within the pores of the glass. The columns were 10 cm long, had ca. 0.5 cm diameter, and had capacities of ca. 1 mmol. Reaction of the chloromethyl groups in the monolith with trimethylamine gave quaternary ammonium chloride residues. The chloride counterions were then exchanged for other anions and the new forms used to carry out various reactions. For example, passing a solution of acetophenone in methanol down the borohydride-containing column at 60 °C gave 1-phenylethanol in >95% yield,49,50 passing alcohols in dichloromethane containing a catalytic amount of TEMPO down a column containing bisacetoxybromate(I) anions afforded the corresponding aldehydes or ketones in excellent yield,49,50 and passing a solution of the TMS ether of a steroidal alcohol in methanol down the fluoride-containing column at room temperature gave the steroidal alcohol in 90% yield.49 Similarly the hydroxide form of the columns could be

used to achieve Horner-Emmons olefin syntheses50,51 and Suzuki reactions.50 Examples are shown in Scheme 14. Lectka’s research group have developed a simple flow system for generating ketenes by the dehydrochlorination of acid chlorides.45 This was carried out successfully by using a fixed bed of the commercially available strong organic base PS Schwesinger base 31 at -78 °C. When, for example, a solution of phenylacetyl chloride in THF was allowed to percolate down a column of PS 31 (1.1 molar equivalents) at -78 °C, phenylketene was formed rapidly in high yield. They have also developed flow systems for generating imines.46 The imines, such as 22, were generated from N-tosyl-R-chloro-R-amino acid esters. The column was packed with a mixture of sodium hydride and Celite and solutions of the chloro compounds in THF were allowed to percolate down the columns at 23 °C. These reactions are shown in Scheme 15. Frećhet’s group developed the synthesis of polymer tubular monoliths with excellent flow properties and obtained useful loadings of functionality by grafting.52-54 For example, acylating agents 32 were grafted on. Slices of monolith, i.e., disks, functionalized with acylating groups 32 (0.34 mmol/disk) and 33 (0.40 mmol/disk) have been prepared and used to acetylate amines: see Scheme 16.54 With use of a 3-fold excess of acylating agent, p-amines in solution passing through the disk at 3 mL/h were acylated in 99% yield in 8 min. 5. Use of PS Scavengers in Flow Systems When reactions are carried out using PS catalysts or PS reagents, the desired products will, often unavoid-

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Scheme 17. Method by Which Commercial Weak Acid Cation-Exchange Resins May Be Derivatized57

Scheme 18. Examples of PS Scavengers Used in Flow Systems45,46,53

ably, be contaminated by other compounds. For example, the products from the reaction of diethylzinc with benzaldehyde under the influence of a PS β-aminoalcohol catalyst is, after quenching with aqueous acid to destroy excess diethylzinc and convert the zinc alkoxide to the desired alcohol, still likely to contain unreacted benzaldehyde together with benzyl alcohol formed from a side reaction (see discussion above).40 Similarly the product from the reaction of cyclo-octene with a PS peroxy acid reagent is likely to contain unreacted cyclo-octene.55 PS scavengers are designed to remove such impurities by selectively binding the unwanted compounds to the insoluble polymer which can then be filtered off.56 The idea is not new and appropriate traditional ion-exchange resins in suitable forms have long been used, often in the flow format, to remove acidic or basic impurities.1 However, relatively few other PS scavengers have been used in flow systems. Since a PS scavenger has a limited capacity then, as with PS reagents, it really needs to be cheap or easily regenerated. A cheap source of PS scavengers based on macroporous beads would be chemically modified ionexchange resins. A reaction useful for this purpose is shown in Scheme 17.57 Frećhet’s group have prepared disks containing azlactone residues 34 and used them to scavenge amines in a flow system: see Scheme 18.53 Cameron’s group have prepared polyHIPETM monoliths with various amine-containing residues, for example, 35 with 5.6 mmol of amine/g, and used them in flow systems to scavenge 4-chlorobenzoyl chloride: see Scheme 18.58 When a solution of the acid chloride was passed through the monolith for 10 min, >99% of the acid derivative was scavenged. The final reaction in the sequence is the scavenging of excess ketene and imine by a column of commercially available PS amine 36 at room temperature: see Scheme 18.45,46 6. Use of PS Catalysts, PS Reagents, and/or PS Scavengers in Combination in Flow Systems Thus far, all the syntheses in flow systems described here, except for a few examples shown in Scheme 3, have involved just one reaction step. Clearly more complex syntheses can be achieved by linking together several PS catalysts, reagents, and/or scavengers in sequence. This does, however, require careful planning. Thus, it would be impractical to keep on changing the

Scheme 19. Synthesis and Purification of β-Lactams 37 and 38 by Linking Together in Sequence Three Flow Systems59

reaction solvent. Accordingly, all the components of the system should use the same reaction solvent. Furthermore, the flow rates will need to be matched to that of the slowest reaction. Ideally they should also proceed at the same reaction temperature. These limitations are, however, not too inhibiting and multicomponent systems are currently being developed. Lectka et al. have synthesized β-lactams by linking together several of the reactions discussed above, viz. dehydrochlorination of acid chloride to give ketene, addition of the ketene to an imine, and purification of

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the β-lactam by removal of unreacted ketene and imine.59 THF proved to be a suitable solvent for all three stages. In one assembly phenylketene was generated in one flow system and was immediately passed, together with a solution of the imine 22, into the second column containing PS catalyst 21. The output from this column was then passed directly into the scavenger column 36. This afforded β-lactams 37 and 38 in high yield. In a second assembly, see Scheme 19, the imine 22 was also generated using a flow system and then passed with the phenylketene into a column of PS catalyst 21. As before PS scavenger 36 was used. In a third assembly the columns of PS Schwesinger base 31 and PS quinine derivative 21 were replaced by one column packed with a mixture of potassium carbonate and PS quinine derivative 19. This column operating at -43 °C achieved both the dehydrochlorination and catalysis of the cycloaddition and gave β-lactam 37 in a chemical yield of ca. 60% with an 80% ee. To ready the assemblies for further cycles, the columns were separated and regenerated or replaced. Thus, the PS Schwesinger base 31 was regenerated by rinsing with a solution of a phosphazene base, the column of catalyst was thoroughly rinsed, and the scavenger column was replaced. Frećhet’s group used in sequence the acylating disks 32 discussed above to convert amines into amides and then PS scavenger 34 to remove any excess of amine from the product.52,54 7. Conclusions: The Future It is evident from the foregoing discussion that a considerable range of organic reactions have already been carried out very successfully using PS reactants in flow systems. When asymmetric syntheses are carried out, the stereochemical results are usually comparable with those obtained with LMW systems, but sometimes they were better27,43 and in one case the stereochemistry was actually reversed.43 It has been demonstrated that syntheses can be carried out using appropriate columns in sequence provided the reaction solvent remains the same and the flow rate is compatible with that of the slowest component of the sequence. Polymeric monoliths are clearly the most appropriate type of support to use as the columns are easily handled and stored. There is now a need to develop a much greater range of reactants on monoliths. Since polymers used in flow systems suffer little or no physical damage in use, the limits on the useful life of PS reactants shifts to other factors, for example, the chemical stability of catalyst sites. A side reaction proceeding at 2% per cycle taken over, say, 20 cycles can result in a serious loss of catalyst performance. Whether such side reactions are occurring or not simply is not known from most studies using LMW reactions, but there is one example where it has been reported27 and steps taken to solve the problem.60 Future studies of PS reactants in flow systems are likely to reveal such side reactions and guide us to develop catalysts that are more stable on repeated use. Clearly in future flow systems using a greater range of PS catalysts and PS reagents are needed. So far, only a limited range of scavengers have been used in the flow mode and it is necessary to develop new ones. As noted above, ideally the reagents and scavengers will either need to be either cheap or easily regenerated. Flow systems where the reactions are accelerated by microwave irradiation are likely to become important

as this will permit greater flow rates and shorter residence times. One can imagine that in future, for example, a research team could store in a refrigerator a series of cartridges and/or septum-sealed glass tubes containing a range of PS reactants. The cartridges and/or tubes could be removed as required, coupled together in the appropriate sequence and, computer-driven, used to carry out a required synthesis or a set of parallel syntheses. When the experiments were complete, the cartridges could be disassembled and returned to the refrigerator until they were next required. Clearly work in this field is interdisciplinary and needs the combined skills of organic chemists, polymer chemists, and chemical engineers. Acknowledgment We would like to thank the EPSRC for financial support. Abbreviations Ac ) acetyl DCM ) dichloromethane DEZ ) diethylzinc Et ) ethyl ee ) enantiomeric excess h ) hour(s) LMW ) low molecular weight Me ) methyl Ph ) phenyl PS ) polymer-supported PS-RCS ) polymer-supported reagents, catalysts, and /or scavengers R ) various simple alkyl or aryl groups rt ) room temperature TADDOL ) R,R,R′,R′-tetraaryl-2,2-dimethyl-1,3-dioxolane4,5-dimethanols tBu ) tert-butyl TEMPO ) 2,2,6,6-tetramethyl-1-piperidinyloxy THF ) tetrahydrofuran TMS ) trimethylsilyl gray-shaded circle ) polystyrene beads or a monolith (gray-shaded circle)+ ) anion-exchange resin beads “silica” within a circle ) silica beads

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Received for review November 29, 2004 Revised manuscript received March 2, 2005 Accepted March 10, 2005 IE040285E

Synthesis of Organic Compounds Using Polymer-Supported Reagents

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