Chapter 1.
Introduction.
1.1 Asymmetric catalysis and organocatalysis
Chirality is “the geometric property of a rigid object (or spatial arrangement of points or atoms) of being nonsuperposable on its mirror image. Such an object has no symmetry elements of the second kind (a mirror plane, σ = S1, a centre of inversion, i = S2, a rotation-reflection axis, S2n). If the object is superposable on its mirror image the object is described as being achiral”.1
Chirality plays an important role in life sciences, as most of the biological macromolecules of living systems occur in nature in one enantiomeric form only. A biologically active chiral compound interacts with its receptor site in a chiral manner, and enantiomers may be discriminated by the receptor in very different ways. Thus it is not surprising that the two enantiomers of a drug may interact differently with the receptor, leading to different effects.2 Examples of this behaviour are the gypsy moth sex pheromone, the Japanese beetle sex pheromone and the drug thalidomide (Figure 1). The gypsy moth sex pheromone disparlure is active in very dilute concentrations, while the (R)- enantiomer is not active even in very high concentration.3 In the case of the Japanese beetle sex pheromone, when the (S)- enantiomer in contaminated with only 2% of (R)- enantiomer, the mixture is three times less active than the pure enantiomer.4 The drug thalidomide was sold in Europe during 1950s as sedative and antinausea agent, considered appropriate for use during early pregnancy. Unfortunately the drug was sold as racemate and it was discovered that the (S)- enantiomer was teratogen, while the (R)- was not.5 It is, thus, clear that obtaining enantiomerically pure compounds is of great interest, both for academics and industries.
1.1-ASYMMETRIC CATALYSIS AND ORGANOCATALYSIS
All methods of preparing chiral compounds in enantiomerically pure form are collectively called EPC-syntheses. The term was proposed by Seebach in 19806 and the definition was lately refined as "any type of synthesis leading to enantiomerically pure compounds".7 EPC-syntheses can be carried out via three approaches:8
• Resolution of a racemic mixture
• Synthetic transformation of an enantiomerically pure compound into the target compound without a step causing racemization.
• Stereoselective reactions that involve at least one enantiomerically pure reactant (stoichiometric or catalytic) that is not incorporated into the final product.
The last approach is interesting because, in principle, it doesn’t require the consumption of any chiral starting compounds and allows to increase the value of rough starting materials by enantiocontrolled introduction of new stereogenic centers. The strategy is more or less equivalent to the concept of asymmetric synthesis, as defined by Marckwald in 1904:9 "Asymmetric syntheses are those reactions which produce optically active substances from symmetrically constituted compounds with the intermediate use of optically active materials but with the exclusion of all analytical processes". Hence, in modern terms, the locution ‘asymmetric syntheses’ has the meaning of any reaction, or sequences of reactions, which produce chiral nonracemic substances from achiral compounds with the intermediate use of chiral nonracemic materials, but excluding a separation operation.8
In this respect, catalysis may fit perfectly the requirements of EPC-syntheses through stereoselective reactions in that an achiral substrate can be converted into a definite enantiomer of a given chiral product, provided that the proper chiral non racemic catalyst is used. This approach combines the advantages of asymmetric syntheses with the specific features of catalysis, often leading to processes that are more efficient and atom-economical than the corresponding synthetic schemes based on optical resolution or stereocontrolled transformation of enantiopure starting compounds. With respect to the former, the asymmetric catalytic approach has the advantage of avoiding the formation of the large amount of waste material, represented by the unwanted enantiomer (which has to be disposed or recycled in some way after the resolution step). With respect to the latter, it often leads to shorter
substrates as starting materials with the only exception of a limited amount of the chiral catalyst.
Asymmetric catalysis is built on three main approaches: biocatalysis, metal catalysis, and organocatalysis. Biocatalysis is the use of natural catalysts, such as isolated enzymes or whole living cells.10 Metal catalysis usually employs complexes of transition metals with (elaborate) chiral organic ligands while organocatalysis refers to the use of small organic molecules, where an inorganic element is not part of the active principle.11
The first catalytic asymmetric transformation was an enzymatic reaction reported by Pasteur in 185812 while the first non-enzimatic process was reported only in 1912, in a pioneering investigation by Bredig.13
Until late 1960s most of the known asymmetric catalyst were enzymes and only few examples of man-made systems were known.14 In that period many chemists doubted that synthetic chiral catalysts would ever play an important role in asymmetric synthesis. Only after the publication of the Monsanto process for L-DOPA15 asymmetric catalysis has undergone explosive growth.16
Since then many catalytic systems involving transition metal complexes have been developed for a variety of asymmetric reactions, including polymerization,17 cyclopropanation,18 hydrogenation,15, 19 hydrosilylation,20 Ni and Pd-catalysed C-C coupling,21 Wacker-type oxidation,22 Diels-Alder reaction,23 dihydroxylation,24 epoxidation,25 aminohydroxylation,26 aziridination,27 alkene methathesis,28 alkene chlorohydroxylation29 and others.30
On the other hand, even if the studies in organocatalysis predated those on transition metal-based systems, organocatalysis developed slower.31 Until the late 1970’s only the Hajos-Parrish-Wiechert annulation32 proved to be an asymmetric organocatalytic reactions of practical usefulness in synthetic organic chemistry.33 Nonetheless, this field started to emerge again in 1980s, with some papers describing the use of Cinchona alkaloids as phase transfer catalysts34 and of oligopeptides or aminoalcohols as metal-free systems for the asymmetric epoxidation of chalchones,35 and the enantioselective diborane reduction of ketones.36
1.1-ASYMMETRIC CATALYSIS AND ORGANOCATALYSIS
Moreover, triggered by seminal papers by List and co-workers on asymmetric aldol and Michael reactions,37 asymmetric organocatalysis has seen an amazing rise in popularity since 2000.11
Such a growing interest witnesses the recognition of the potential advantages of organocatalysis over conventional chiral metal catalysis. For example, it is worth noting that the purity issues associated with transition metal leaching are avoided with organocatalysis. Although little is known about the toxicity of many organic catalysts,38 this may help to circumvent a sometimes tedious problem when dealing with pharmaceutical ingredients. In addition, many organocatalytic reactions are tolerant to water and air, are easy to perform and proceed with high chemical and stereochemical efficiency, even on densely functionalized substrates. Because these factors often affect negatively metal catalysed reactions, a significant advantage of organicatalysis in terms of operational simplicity may result.38 Indeed, at present the main disadvantage of asymmetric organocatalysis with respect to with metal- and enzyme-catalysis is probably represented by the need of generally high catalytic loadings (typically 5-30 mol%)39 Nonetheless, it seems that this gap also is being progressively filled in by the progresses in the field.40
The range of different reactions that can be catalyzed by chiral organocatalysts make them a complementary tool to conventional metal catalysts.38 Books41 and reviews38,
42
discussing the scope of organocatalysts report an incredibly high number of applications: aldol condensation, Mannich-type reactions, conjugate additions, Baylis-Hillman reaction, α- and γ-amination and aminoxylation of carbonyls, oxidations, Diels–Alder reaction, cyclopropanation, alkylations and arylations of carbonyls, reductive alkylation, reductive amination, halogenation, addition to imines, cycoadditions, epoxydation, conjugate reduction of enals, cyanosilylation, Stetter reactions, Strecker reactions, asymmetric hydrophosphorylation, asymmetric polymerizations. A general schematic overview is given by McMillan.43 Furthermore, many catalysts are now commercially available, which will be expected to stimulate further the application of organocatalysis for stereoselective synthesis.39
In his introduction in the 2007 Chemical Reviews special issue on organocatalysis,11 List indentifies four types of organocatalysts according to their chemical properties: a) Lewis bases,44 b) Lewis acids,45 c) Brønsted bases,46 d) and Brønsted acids.47 In his review, Gaunt38 classifies the organocatalysts according to the reaction mechanisms:
a) secondary amine catalysis via enamines, b) secondary amine catalysis via iminium ions, c) phase-transfer catalysis, d) nucleophilic and Brønsted base catalysis, e) H-bonding catalysis. The two classifications are not conflicting because they are taking into account two different aspects of organocatalysts. Moreover, the boundaries between each group are vague since many organocatalysts are bifunctional11 or because the same catalyst shows different behaviours depending on the substrate.38 Recently, the complementary character of organocatalysis and transition-metal catalysis has been investigated more in depth and the two strategies combined to perform reactions otherwise impossible using only one of them.48
1.2 Recoverable enantioselective catalysts.
Simple separation of a catalyst from the reaction mixture and easy isolation of the reaction product are important factors in establishing the convenience of any catalytic transformation.49 Moreover, recovery and recycling of catalyst components (e.g. metal or ligand) can become a mandatory task if their value is higher than that of the products.50 In these circumstances, the modification of soluble catalysts with the aim of improving their separation efficiency can be a viable option en route to more economic and environmentally friendly processes. In this regard the range of possibilities include the binding of the original catalyst to soluble polymers51 and dendrimers,52 self-supported catalysts,53 and the choice of alternative reaction media such as fluorous solvents,54 supercritical CO2,55 water56 and ionic liquids.57
Soluble polymer and dendritic systems are molecularly enlarged catalysts that work in the homogeneous phase during the catalysis step and can be separated from the product, after the reaction, by solvent precipitation or ultra-filtration.58 Self-supported catalysts are metal-organic coordination polymers generated by self-assembling of multitopic ligands with metal ions. As long as they are scarcely soluble in the reaction medium, they can be used as heterogeneous catalysts without the need of any exogenous support.59 Reactions performed in alternative reaction media usually involve liquid biphasic systems, where the homogeneous catalyst and the product are recovered in different phases at the end of the reaction. For example, the fluorous solvents used for this purpose show different solubility in common organic solvents at different temperatures; so, catalysts tagged with fluorous groups are dissolved in a homogeneous phase at higher temperature and then are recovered
1.2-RECOVERABLE ENANTIOSELECTIVE CATALYSTS.
Ionic liquids (ILs) are an emerging support for catalysts. They are composed of large organic cations and organic or inorganic anions, and display novel physicochemical properties: e.g. low melting point, negligible vapour pressure, low flammability, and tunable polarity and miscibility with other organic or inorganic compounds.60 While most of these methods have the advantage that catalysis takes place in the homogeneous phase, they may present the drawbacks of limited scope, use of additional organic solvents or expensive components, need of very specific reaction and separation conditions and, in some cases, incomplete recovery of the catalyst.61 From this point of view, the immobilization of the homogeneous catalytic system onto an insoluble support could be a better choice. Ideally, with this approach the high performance and versatility of homogeneous catalysts can be combined with the easy separation, by mechanical means, of heterogeneous catalysts. However, the activity and selectivity of a homogeneous catalyst can be significantly reduced when heterogenized.62 In general, the performance of heterogeneous catalysts is strongly dependent upon the choice of support material and the method by which the active site is immobilized on it.50
Common strategies employed in catalyst immobilization are:
- surface functionalization of nanoporous inorganic materials, such as silica and zeolite;
- anchoring onto or within an insoluble resin.
1.2.1 Silica and zeolite surfaces functionalised with enantioselective catalysts
Inorganic solid supports, such as silica gel and zeolites, possess good thermal and mechanical resistance, relatively high surface area and tunable pore sizes.50
Zeolites are crystalline aluminosilicates with specific internal microporous (pore size <2 nm) structures. Although there are many examples of heterogenizing catalysts on zeolites, the pore size limits the use of zeolite with small molecules. After the development of the MCM family of mesoporous materials by Mobil Corporation, several ordered porous structures with tunable pore size and pore morphology have been developed.63 The typical synthesis of these structurally well defined mesoporous silicas is based on a surfactant micelle templating approach. These
tetraethoxysilane (TEOS). By either calcination or acid extraction, the organic surfactants are removed, leaving an inorganic mesoporous silica framework.
a) Noncovalent Binding of Homogeneous Catalysts
Homogeneous catalysts can be adsorbed on the silica surface through noncovalent interactions, such as van der Waals or electrostatic interactions. It a straightforward method to immobilize catalysts, but due to the weak interactions the catalyst can readily leach into the solution. For this reason just a few examples of this approach will be discussed herein for illustrative purposes.
Bianchini et al.64 reported a chiral rhodium complex featuring a sulfonic functional group anchored on the silica surface through this approach (Figure 2). Catalytic asymmetric hydrogenation of dimethyl itaconate, ethyl trans-β-(methyl) cinnamate, and α-(acetamido)acrylate were performed. Recycling of the material and no loss of catalytic activity was possible when washing with nonpolar solvent, whereas catalysts leaked considerably upon washing with protic, polar solvents like methanol and ethanol.
Figure 2 – Immobilization of a rhodium complex by adsorption through hydrogen bonding between surface silanols and sulfonic acid.
Gruttadauria et al.65 reported a heterogeneous proline catalyst anchored through surface adsorption by the assembly of an amphiphilic ionic liquid film (Figure 3). Notably, in an aldol reaction this surface-modified silica catalyst maintains high recyclability as well as enantioselectivity, much higher than that obtained by a simple adsorption method. Moreover, this catalytic system avoids the viscosity problem seen when using ionic liquids as solvents on an industrial scale.
1.2-RECOVERABLE ENANTIOSELECTIVE CATALYSTS.
Figure 3 – Supportation of proline by adsorption in an amphiphilic ionic liquid film.
b) Immobilization of Catalysts on the Surface Through Covalent Bonds This type of immobilization enhances long-term stability of anchored molecules. It can be performed following two strategies: (i) post-synthetic grafting silylation, where a homogeneous catalysts is immobilized on the surface of a pre-synthesized silica support through a silylation reaction under moisture-free condition; (ii) co-condensation, where a functional organoalkoxysilane is included into an aqueous solution of surfactants and tetraethoxysilicate (TEOS) subjected to the sol-gel process.
In the former approach the siliceous support is treated with a silylating agent bearing the catalyst or catalyst precursor, such as a trichlorisilane, trialkoxysilane or disilazane. Alternatively, reactive functional groups (e.g. –SH) are covalently bound to the support by this technique and then exploited for grafting the an organic ligand, organocatalyst or metal complex by a thiol-ene addition. These procedure allow the functionalization of the surface with a variety of organic units, but may result in a inhomogeneous surface coverage of catalytic sites.66
In the latter approach some prerequisite must be fulfilled. The functional organoalkoxysilane has to interact with both the surfactant micelles and the silicate
for the synthesis of mesoporous silicas and the subsequent removal of surfactants. In addition bulky organosilanes interfere with the development of the silica structure and the amount of functional groups introduced cannot exceed 25% surface coverage.50 Despite these limitations, as recently reviewed by Stein et al.67 it has been demonstrated that the spatial distribution of pore surface-immobilized organic groups in mesoporous silica materials functionalized by the co-condensation method is more homogeneous than that for the post-synthesis grafting approach. This technique can be used for obtaining siliceous supports homogeneously functionalised with reactive thiol groups,68 which can be exploited then for the grafting of catalysts or ligands as discussed above.
An example of the grafting approach was reported by Burguete et al (Scheme 1a).69 The Spanish authors introduced two allyl chains on the central methylene bridge of chiral bis(oxazoline) (BOX) ligand and then performed the thiol-ene radical addition with mercaptopropyl-functionalised silica to effect the anchoring. After loading with a Cu(II) salt, the resulting insoluble catalyst was employed in cyclopropanation, Friedel–Crafts hydroxyalkylation, and Diels–Alder reactions. Compared to the homogeneous catalyst, the regioselectivity was similar, while the enantioselectivity was significantly lower. Corma et al.70 used the same strategy, but with one longer tether only (Scheme 1b). In addition, in this case residual silica surface –OH groups were end-capped to prevent any interference in the catalyzed reaction.71 The corresponding Cu(II) catalyst was employed in the alkylation of 1,3-dimethoxybenzene with 3,3,3-trifluoropyruvate with ee values slightly lower than in the homogeneous case. The catalyst was recyclable and no metal leaching was detected.
1.2-RECOVERABLE ENANTIOSELECTIVE CATALYSTS. O N N O 1) MeLi 2) Allylbromide O N N O Si SH O O O 1) AIBN 2) Cu(OTf)2 Si O O O Si O O O O N N O S S Cu OTf OTf R R R R R R R = Ph, Bn,tBu 1) 2) hexamethyl disilazane OH OH OH OH O Si SH O O O TMS O N N O (MeO)3Si SH Cu OTf OTf AIBN O Si O O O TMS O N N O Cu OTf OTf S 7 9 Ph Ph Ph Ph a) b) Scheme 1
Thomas et al.72 grafted two asymmetric diamine ligands [(S)-(-)-2-aminomethyl-1-ethylpyrrolidine and (1R,2R)-(+)-1,2-diphenylethylenediamine] on siliceous supports with the intent of preparing supported Rh(I) and Pd(II) complexes (Scheme 2). The heterogenization was performed on MCM-41 and on commercial nonporous Cab-O-Sil®, both of which are siliceous materials but possess surfaces of opposite morphology (concave for the former and convex for the latter, Figure 4).
Cat Cat
Mesoporous silica concave surface
Cab-O-Sil convex surface Figure 4 – Schematic representation of concave and convex silica surface
Interestingly, the authors found that the catalyst supported on MCM-41 slightly enhanced enantioselectivity compared with Cab-O-Sil® and with the homogeneous catalyst in the asymmetric hydrogenation of (E)-phenylcinnamic acid and methyl benzoylformate (20 bar H2, 80-99% conversions, up to 96% ee). Heterogenized
catalyst on MCM-41 proved to be recyclable up to three cycles with minimal ee erosion.
Scheme 2
In 2011 Shi et Al.73 prepared a hollow-structured phenylene-bridged periodic mesoporous organosilica (PMO) spheres with a uniform particle size of 100–200 nm using α-Fe2O3 as a hard template. This material was easily functionalized with
MacMillan catalyst by a co-condensation process and post-modification by CuAAC. The synthesized catalyst 1 has been found to exhibit high catalytic activity (98% yield, 81% ee for the endo product and 81% ee for the exo) in asymmetric Diels– Alder reactions with water as solvent (Scheme 3). The catalyst could be reused for at least seven runs without a significant loss of catalytic activity. It was observed that hollow structured PMO spheres exhibit higher catalytic efficiency than solid (nonhollow) PMO spheres, and that catalysts prepared by the co-condensation process and “click chemistry” postmodification exhibit higher catalytic efficiency than those prepared by a grafting method.
1.2-RECOVERABLE ENANTIOSELECTIVE CATALYSTS.
Scheme 3
1.2.2 Insoluble resin-supported catalyst
Most insoluble resins used as catalyst supports are polystyrene-based cross-linked polymers. Their advantages towards other polymers are the cheapness, large availability and good chemical inertness that does not preclude, however, the possibility of being functionalized. According to the degree of cross-linking and morphology, these resins can be divided into two categories: macroporous and microporous materials.74
Macroporous resins generally refers to materials with a high cross-linking degree (up to >50%, typically 20–25%) and a permanent porosity in the dry state (macroporosity).75 As a consequence, the structure of these materials is rather rigid, they swell to a limited extent, are more resistant to mechanical wearing, and have accessible sites even in non-compatible solvents. In this systems, solvents and reagents may fill the pores throughout the resin bead without having to take into account issues about swelling. Hence a broad range of solvents, including protic alcohol and water, are often tolerated. However, these macroporous resins have some drawbacks such as low loading capacity (typically 0.8–1.0 mmol/g),62, 76 lower reactivities than microporous resins and brittleness.74, 77
Microporous resins (also known as gel type resins) are weakly reticulated polymers (0.5-2% of cross-linking).62, 76 This class includes chloromethylated
poly(styrene–co-1
divinylbenzene) (Merrifield resin) and its derivatives, which are the most commonly employed gel type materials for solid-phase synthesis and catalyst immobilization, due to their easy handling and relatively low cost. With these supports, solvent swelling is required in order to allow reagents in solution to access the internal sites. Otherwise retarded reaction kinetics or even the suppression of any catalytic activity may result, due to the difficult diffusion inside the bulk of the polymer. In cases where sufficient swelling cannot be attained (e.g. when using protic solvents such as alcohols or water) the use of these resins may lead to poor results.75 In order to solve these problems amphiphilic PS–PEG [polystyrene–graft-poly(ethylene glycol)] hybrid resins (TentaGel®) have been introduced.
Amongst the many examples of reported so far of covalent immobilization of chiral catalysts onto organic supports, just a few cases will be discussed herein.
Uozumi et al.78 reported the use of a PS–PEG resin to perform a combinatorial screening of a series of supported chiral phosphine–palladium complexes (Scheme 4) The chiral phosphine ligands were anchored to the resins using (S)-amino acids tethers, which also exerted a significant influence on the enantioselectivity. Optimum results were obtained with catalyst 2, obtaining 77% yield and 90% ee in the benchmark asymmetric allylic substitution of 1,diphenyl-2-propenyl acetate with 3-methyl-2,4-pentanedione, with 2 mol% of the catalyst in a basic aqueous solution.
Scheme 4
Wang’s group79 developed a diphenylprolinol-derived catalyst for the asymmetric addition of Et2Zn to aldehydes (Scheme 6). The author found that the insoluble resin
supported catalyst precursor (3) was superior to the soluble MeOPEG (MW = 2000) supported analogue for a wide range of aromatic aldehydes. However, both the
2
1.2-RECOVERABLE ENANTIOSELECTIVE CATALYSTS.
Scheme 5
Mao et al.80 reported several novel chiral oxazolidine ligands for the alkynylation of aromatic aldehydes with high yields and ee. The ligand 4 was identified to be a better ligand providing the desired products in 71–96% yields and 77–95% ee.
O H N O R O H R' H /Ti(OiPr)4 Et2Zn, THF, RT R H R' R = aromatic, heteroaromatic R' = phenyl, p-tolyl Scheme 6
Fenniri et al.81 reported the application of an alkaloid phthlazine ether grafted to TentaGel® (5b) for the asymmetric dihydroxylation (AD) of styrene derivatives (Scheme 7). Using the experimental conditions employed for AD-mix at 20 °C, the supported ligand 5b showed only a slightly inferior catalytic performance to that of the homogeneous ligand 5a in the reactions of styrene, 2-chlorostyrene, 2,6-dichlorostyrene and 4-trifluoromethylstyrene (74-98% ee). However, in the case of 3-fluorostyrene, a significant decrease in enantioselectivity was observed (63% vs. 82% ee). In addition, 5b was recovered and reused three times without any
3
4
3
results can be compared with those obtained in the group where this Thesis was carried out.82 In such study several cross-linked materials were prepared by copolymerization of polar cross-linkers with styryl monomers containing alkaloid phthalazine ether units. The supported ligands 5c-d afforded excellent enantioselectivities (87–99% ee) in the AD of various substrates and could be used more than 20 times without any degradation of catalyst performance. In the same work the importance of performing proper heterogeneity test was also stressed, in view of the high sensitivity of the homogeneous AD reaction to even minute amounts of leached ligand. N N N MeO O N H N OMe O N H R R = Et R = S H N O TentaGel R2 R3 H OH R3 H R2 OH 1 mol% OsO4(0.2 mmol%) K3Fe(CN)6/K2CO3(3 equiv) tBuOH/H2O (1/1), 20 °C R1 R1 N N N MeO O N H N OMe O N H O2 S RO 6 O R = H R = R2 R3 H R1 = Cl Cl Cl F3C F R2 R3 H R1 = Ph COOiPr Ph O 3 O O HO S 5a 5b 5a-d 5c 5d
1.3-ASYMMETRIC TRANSFORMATIONS IN FLOW.
Scheme 7
Zhao et al.83 reported the immobilization of a Corey–Bakshi–Shibata catalyst on polystyrene resin. Supported sulfonamide 6 was successful in both the reduction of prochiral ketones and α-keto esters to provide secondary alcohols and 1,2-diols with slightly better yields and enantioselectivities than the original homogeneous ligand. In this case, the enantioselectivity was highly dependent on the reaction temperature: the highest ee was obtained in THF at reflux while with much lower ee at room temperature. It is noteworthy that the cheap reductant system NaBH4/Me3SiCl could
be used instead of the toxic and expensive borane with comparably successful results. In addition, catalytic system could be reused in these two reductant systems up to five times without decreases in yields and ee.
Scheme 8
1.3 Asymmetric transformations in flow.
Thanks to their potential84 for performing organic transformations in a more selective, safe, and cheap manner compared to traditional batch-wise approaches,85 continuous (micro)flow systems are emerging as valid alternatives to the traditional reactions performed in round-bottom flasks.86
In some cases the use of fluidic devices is suggested by safety issues, thanks to the smaller amount of reagents that at any given time are present in the reaction zone of the flow reactor in comparison with a corresponding stirring-tank one. Such a feature
6
conditions. To this it can be added that the absence of stirring and the better thermal management, together with improved heat transfer and mixing, contribute to the lowering of the energetic costs and increase of productivity and selectivity. As a result, flow reactors can provide much shorter time-to-market, better use of feedstock, reduced waste, simplified product purification, and easier operation of the continuous process with respect to the batch one. Finally, flow systems can easily integrate multistep transformation and can be coupled in a straightforward manner with special energy-delivery techniques like photochemistry,87 electrochemistry,88 sonochemistry,89 and microwave (MW),90 resistive91 or inductive heating.92
These possibilities often result in the continuous production of significant quantities of compound at higher efficiency, lower costs86 and higher reproducibility since the reaction conditions can be finely tuned and controlled.
A particularly interesting advantage of flow systems in the industrial perspective is the possibility of increasing the production by numbering-up, i.e. by arranging a sufficient number of identical devices in a parallel fashion. In principle, this strategy allows to use the very same reaction conditions optimized for a single device, thus avoiding the time-consuming stages required to scale-up a batch process from the laboratory bench to the actual plant.93
Flow chemistry is included in the list of the so-called enabling technologies in organic synthesis compiled by Kirschning et al,92a that is the set of experimental tools developed in order to speed up synthetic transformations and to simplify isolation and work up of products. From this point of view, continuous flow devices have also the potential for being combined with the use of supported catalysts, another enabling technology contained in the Kirschning list.
Given the opportunity of performing two unit operations (catalysis and catalyst separation and recovery) into a single piece of equipment, the successful achievement of this task would provide an answer to the increasing pressure from economics and a clear example of compliance with the principles of green chemistry.85e, 94 In this regard it is not surprising, then, that the same Author identified the development of flow systems containing immobilized catalyst (herein: catalytic flow reactor, CFR) as one of the ten key issues in modern flow chemistry.92a, 95
1.3-ASYMMETRIC TRANSFORMATIONS IN FLOW.
>m or 10-1000 >m, depending on the author),85c, 85d, 86e, 95c, 96 while those characterized by larger sections are called mini- and mesoreactors. With sub-millimetre channels, microreactors can exploit to the maximum extent the advantages of laminar flow and high surface-to-volume ratio, but suffer from the limitation of small product throughput and are often plagued by the tendency to clog. By contrast, mini- and mesoreactors suffer from the less effective mixing of the streams and the reduced heat-transfer capability, but fit better the needs of small and medium-scale production of chemicals.93a, 97
A different kind of classification is based on the structure of the device, either tubular or flat-shaped (chip-type), and the material the device is made of. This can be metal, fused silica, glass, quartz, silicon, poly(dimethylsiloxane) (PDMS), and fluoro- or chloropolymers.
There are only a few examples of homogeneous enantioselective reactions carried out in continuous flow, and these have been performed in microfluidic flow systems consisting usually of micro-channels.98 The use of microreactors for homogeneous reactions has been found to be especially useful for catalyst/ligand screening, as only low amounts of catalysts and reagents is required.
Even though dedicated instrumentation can be purchased from a number of manufacturer, it has been noted that “the exciting world of the small [scale flow chemistry] may be explored using tools that are ubiquitous in organic laboratories”.86e This statement looks particularly true in the case of CFR’s, because many of the reported devices have been developed by adapting standard chromatography components like HPLC pumps, columns, mixers, etc. In this regard it should be mentioned that parameters which have to be taken into account during the design of a CFR are the channel’ size and the material to be used for fabricating the reactor (that has to be compatible with the chemistry supposed to take place inside the device). Moreover, the development of a CFR requires to devise a way for retaining the supported catalyst inside the reaction zone. Apart from leaching problems, in the case of monoliths and wall-coated system discussed below the solution to this challenge is largely implicit in the techniques employed in their preparation. On the contrary, powder or beads materials are kept inside the device by some restriction at the reactor outlet, e.g. by using porous frits in the case of mini- and meso-sized tubular devices, or weirs made of micro-sized pillars for chip microreactors.99 For the
latter, step-profiled rectangular wells and chips with a top plate provided with a large central port for catalyst introduction have been proposed also.100
In fact, the realisation of CFRs has been pursued following three main techniques: the use of packed-bed reactors, monolithic systems, and open architecture (or wall-coated) devices.101 Any of these approaches leads to reactors differing from the others in one or more key features: simplicity and robustness of the manufacturing procedure, amount of catalyst immobilized inside a given volume, and morphological and fluid dynamic properties of the resulting system (void volume, exposed surface area, velocity profile, flow resistance, etc.).
1.3.1 Packed-bed CFRs.
The common strategy to set-up a packed-bed CFR is to prepare the supported catalyst ex-situ, by either grafting of the catalyst on the support or by copolymerization (see 1.2), and then to use the resulting powder or beads for filling a piece of tubing, column, or chip-type device. This approach allows an easier characterization of the supported system by standard techniques (such as IR and solid state NMR) and, in some cases, the preparation of materials loaded with a large weight fraction of the active species.102 Many organocatalysts require high catalyst loadings in batch (e.g. 10-30 mol%), so the packing-bed option may be an especially appealing solution for this issue.
However, the use of beads or powder material in flow reaction may raise concerns about the effect of irregular packing.103 This can result in the formation of hot spots or stagnating pools inside the device and wide distribution of residence times for the flowing-through substrate. Especially for organic materials, another serious drawback of this approach can be the insufficient rigidity of the beads and their tendency to swell or stick together, which may cause clogging of the device.
Inorganic supports, like silica-gel, mesoporous silicates, and zeolites posses high rigidity and reduced tendency of the beads to adhere each other.104 These qualities help to circumvent some of the problems noted above, but clogging due to tight particle packing can still remain an issue. As anticipated, inorganic supports may also suffer from a limited degree of functionalization,105 as well as from problems connected with the highly polar nature of the surface (like, e.g. occurrence of
1.3-ASYMMETRIC TRANSFORMATIONS IN FLOW.
unwanted71, 106 or unexpected surface effects,107 and risk of substantial leaching of the anchored organic fragments).82, 108
Amongst the two main classes of organic polymeric supports (see paragraph 1.2.2), macroporous resins possess higher mechanical properties than gel-type materials. From the fluid-dynamic point of view, in principle macroporous materials are therefore better apt for flow applications than gel-type resins.74 However, when the aspect of specific catalytic activity is considered the opposite conclusion if often drawn. This is a consequence of the anticipated limitations of macropouros resins in terms of catalyst loading (typically for materials obtained by grafting)102a and accessibility of active sites (especially for supported catalysts obtained by copolymerization, where part of the catalyst units are deeply buried inside highly cross-linked regions, and therefore virtually inactive).109 On this ground it is not surprising that most of the examples reported to date of packed-bed chiral CFRs deal with the use of gel-type supported catalysts. Under these conditions, the main problem arises from the fact that even if the swollen state is essential for catalytic activity, the large volume increase of the polymer gel (in many cases up to more than two times the volume in the dry state) and the tendency of the beads to stick together can seriously hamper the passage of the liquid stream. In order to circumvent this drawback, some kind of a trick had to be adopted like, e.g. mixing the supported catalyst beads with an inert rigid material (sand or glass beads),110 or filling just a fraction of the reactor chamber’ volume with the dry resin. In some cases the amount of catalyst placed inside the reactor was calculated for filling precisely the available volume once the resin had swollen in the reaction medium111; in others, the system could be thought as a fluidized bed reactor, with the gel polymer particles free to tumble into the solution to some extent.112
Early studies with packed systems revealed several features of CFRs, including the selectivity improvement permitted by the large catalyst/substrate ratio in the reaction zone and by the continuous removal of the reaction product.112
While investigating the use of a Ni(II)-salen complex 7 supported onto a Merrifield resin for the Kumada coupling (Scheme 9), Styring et Al. observed that the reaction rate in flow was more than three orders of magnitude larger than in batch.113 This phenomenon, later reported for other reactions too,114 was explained by assuming that the forced flow in the CFR device causes a more effective mass-transfer to and
from the catalytic sites than the slower diffusion process operating in the stirred reactor.
Scheme 9
Pericàs et Al. used a highly fluorescent coumarin dye to visualise the flow profile inside a meso-sized reactor filled with a swollen functional resin (Merrifield-type).115 The observation of a flat and uniform liquid front led to the conclusion that the device was operating as a plug flow reactor, i.e. a system perfectly mixed in the radial direction but not in the axial one.116 Under these conditions the reaction may be thought to proceed in as a series of infinitely thin coherent plugs and a simple relationship can be found between the volume occupied by the catalyst, the flow-rate of the limiting reagent, the reaction rate, and the conversion along the catalytic bed.115, 117
Recently, the same group reported the preparation of a single continuous flow process for the addition of diethylzinc to various aldehydes (Scheme 10).117 Reagent solutions were fed by piston-pump driven flow through a fritted column packed with chiral amino-alcohol functionalized Merrifield resin 8. Under optimal conditions (10 °C, a flow rate of 0.24 mL min−1 and a slight excess of Et2Zn) a residence time of only
9.8 min was required for 98% conversion of benzaldehyde to the desired (S)-1-phenyl-propanol, with 93% enantioselectivity. In comparison, the reaction time in batch for the analogous reaction was 1.5 h.
7
1.3-ASYMMETRIC TRANSFORMATIONS IN FLOW.
Scheme 10
Salvadori and co-workers118 described the use of a flow reactor comprised of a stainless steel column packed with bisoxaline ligand functionalized polystyrene 9 for the ene reaction of ethyl glyoxylate with α-methylstyrene (Scheme 11). At a flow rate of 0.015–0.025 mL min−1, an 83% conversion to the desired product 10 was achieved. After initial loading of the Cu(OTf)2 catalyst, the column was used for up to
five runs (over 80 h), with essentially no erosion of enantioselectivity and yield observed between each run and without the need for catalyst regeneration, providing 78% total yield of 10 with 88% ee.
Scheme 11
1.3.2 Monolithic CFRs.
According to the IUPAC definition, a monolith is ‘‘a shaped, fabricated intractable article with a homogeneous microstructure that does not exhibit any structural
119
8
10 9
Monolithic CFRs are interesting devices for flow chemistry because they can be obtained as continuous yet porous insoluble structures, which tight-fill the reaction zone of the fluidic device.120 In the present context, the interest for monoliths descends from the fact that shaped materials containing a proper combination of “narrow” and “large” pores can prove very convenient support materials for the development of CFRs.
The requirement for “large” pores can be understood on the basis of the Hagen-Poiseuille law, which describes the pressure drop ∆p across a straight tube of length L and radius r:
2
8
r
L
u
p
=
⋅
⋅
⋅
η
∆
where u and η are the average linear velocity and dynamic viscosity of the flowing-through fluid, respectively. This relationship shows that the pressure drop should decrease exponentially with increasing the radius. Thus, if the radius is large enough a liquid can be forced to pass-through at a substantial flow-rate without experiencing an exceedingly high backpressure.
This hypothesis has been confirmed qualitatively for a number of real monoliths, observing also that the fluid dynamic properties of the system are dictated by the maximum (mode) of pore size distribution curve of the material, and much less by its specific chemical nature.121 Concerning the quantitative agreement, it is noteworthy that the recorded ∆p values for real monolithic columns can be up to two orders of magnitude larger than those calculated by the previous equation. These findings are a consequence of the tortuous shape of the channels inside the monolith’ structure compared to the ideal straight tube of the Hagen-Poiseuille law,121 and have the practical consequence that monoliths for liquid chromatography or catalysis applications need to contain a network of interconnected channels with an average radius r > 1 µm (convective or flow-through pores).
Although the presence of macropores (1-10 µm) is associated with the possibility of unhindered convective flow, their contribution to the surface area of the material is almost negligible. Catalytic applications require a high surface area (typically > 100 m2 g-1) that is mainly provided by micropores (diameter smaller than 2 nm) and mesopores (diameter between 2 and 50 nm).121 Taken together, these facts imply
1.3-ASYMMETRIC TRANSFORMATIONS IN FLOW.
that the monolithic supports for flow catalysis must possess a hierarchically porous structure, comprising both a network of flow-through pores (macropores) and diffusive mesopores.120b
The strategy for preparing inorganic monoliths involves the hydrolytic polycondensation of tetralkoxysilane precursors inside a mould,120a, 120b usually triggered by an acid catalyst.135a, 135b One technique for obtaining macroporous silica monoliths follows the micelle approach introduced in section 0 for siliceous and zeolite supports. It employs a highly hydrophobic compound stabilised by a surfactant agent (e.g. dodecane and a quaternary ammonium salt) as the template. The resulting oil-in-water ‘‘high internal phase emulsion’’ (HIPE) induces the formation of macropores, whose structure is stabilized after ageing (3 days to 1 week) and thermal curing (180-650°C).122 Compared to other strategies, the resulting Si(HIPE) monoliths display polydispersed flow-through pores (e.g. 0.5-10 µm), increased macropore volume (up to 3 mL g-1) and a distribution of narrow pores often (but not always) skewed towards the microporous end-side.120b
In another strategy the polycondensation of tetralkoxysilanes is carried out in the presence of a water-soluble polymer (e.g. polyethylene oxide, PEO) that acts as a template for the forming macroporous network. During this polycondensation it is important to obtain a bicontinuous liquid-in-gel network by the so-called spinodal decomposition of the solution (Figure 5). For this purpose, the Si/polymer ratio in the sol/gel mixture must fall within appropriate limits, because silicate contents lower or higher than an optimal concentration window will result in the formation of separated beads or occluded channels, respectively. After ageing, the removal of the liquid phase affords a material characterized by the presence of continuously interconnected macrochan-nels. Mesoporosity in the struts can be induced at this stage by treatment with a base (e.g. aqueous ammonia). Finally, drying and calcination decompose the Figure 5 - Formation of silicate microstructures
organic additives and stabilise the hydrophilic surface. The macroporous silica monoliths obtained by this procedure (MonoSil) may possess surface area values up to 600 m2 g-1 and porous volumes around 1 mL g-1 for both macropores and mesopores.120b
The resulting materials feature much better thermal and mechanical properties (e.g. elasticity limit up to 3 MPa and Young modulus up to 0.5 GPa) when compared to organic monoliths.123 Moreover, the uniform radial permeability and the isotropic macroporosity often result in a nearly plug-flow velocity profile and even distribution of contact times. In the ageing and drying stages, the materials undergoes shrinking that prevents their use in the original mould for flow applications. Instead, the recovered monolith is usually placed inside a heat-shrinkable polymer sheath (e.g. PTFE), which guarantees the absence of void space around the porous rod and provides also a means for hydraulic connections.120a, 120b
In general, the preparation of silicate monoliths embedding covalently-bound ligands or organocatalysts follows the same strategies outlined for non-monolithic siliceous supports (1.2.1b). The introduction of organic molecules may be carried out during the sol-gel step, by including a functional trialkoxysilane into the solution,122a, 124 but due to the harsh curing treatment involved in many of the reported procedures (e.g. heating to 50-180°C),122a, 124a the integrity of all but the most stable organic derivatives can be at question. Moreover, this approach is incompatible with the final calcination step, usually performed in order to destroy organic contaminants in the material (otherwise hard to be removed even after intensive washing of the monolith).122a, 122b From this point of view an alternative and more general route can be the post-synthesis functionalization of the bare porous support. In these cases the covalent grafting of ligands or organocatalysts can be readily achieved through in continuo silanization of the surface silanol groups.125 Alternatively, the bare monolith can be employed for loading metal nanoparticles (NPs) to give, e.g., Pd-containing MonoSil rods used as a CFR for the catalysis of the Suzuki–Miyaura reaction.126 Zeolites are a class of microporous aluminosilicate materials with remarkable intrinsic catalytic properties and a large potential as catalyst supports. Until recently the development of zeolite monolithic CFRs has been hampered by the fact that the classical procedures for preparing these aluminosilicates afford 2-10 >m-sized crystals and not the required continuous macroporous bodies.120b However, recent
1.3-ASYMMETRIC TRANSFORMATIONS IN FLOW.
advances in the field have open the route to monolithic zeolites provided with a suitable network of interconnected macropores. This task has been accomplished by using either replica-template techniques or pseudomorphic transformations. In the former, the zeolite synthesis is carried out in the presence of a macroporous carbonaceous monolith (e.g. a CL polymer or carbon), whose removal by calcination leaves behind the zeolite body as the negative replica of the original template. In the latter approach, an amorphous macroporous silica monolith (a MonoSil, prepared as described above) is converted into a corresponding crystalline zeolite by exposure to an aluminium-containing solution. Under appropriate conditions this transformation takes place without disrupting the original macroporous texture and provides porous zeolite rods that can be used as CFR after cladding inside a length of heat-shrinkable tubing. This approach allowed Galarneau et Al. to develop the first example of a catalytic flow process involving a zeolite monolith (Scheme 12).127 Interestingly, testing in a model Knoevenagel condensation reaction indicated that the monolithic CFR could attain a larger productivity than the analogous reactor packed with the crushed zeolite catalyst.
Scheme 12
The preparation of organic porous monoliths involves a precipitation-polymerization process inside a tubular or a flat mould.74, 120c, 121 To achieve this goal the feed solution has to contain a large amount of a difunctional monomer (CL agent) and a solvent (porogen) that, at some point, will induce the phase separation (precipitation) of the growing macromolecular chains. The polymerization process begins with the formation of small microgel regions, made of separated CL nuclei. As the reaction proceeds the latter link together to give an infinite CL network (macrogelation). At this point, if polymer precipitation takes place (before or after macrogelation), the segregation of the components into two interpenetrating continuous phases can
such a phenomenon and the morphology of the resulting material depend critically on a number of factors, including the nature of the monomer, CL agent, and porogen, the CL degree, the porogen content in the feed mixture, and the polymerization temperature.
In general, any factor retarding the onset of phase separation tends to provide materials featuring a higher proportion of micro- and meso-pores and a larger surface area. Typically this is observed when a large amount of a good solvent for the growing polymer chains is used as the porogen. By contrast, if phase-separation ensues earlier during the polymerization (e.g. because of the use of a porogen with poor solvating properties) materials characterized by a significant content of macropores and a lower surface area are obtained. Similarly, the change of the polymerization temperature within a relatively narrow window (e.g. 55-80°C) can result in a shift of two orders of magnitude of the mode of the pore size distribution curve.121 These effects have been interpreted at the microscopic level by reasoning that a late phase-separation provides a large number of tiny interconnected polymer globules, whereas an early phase-separation leads to a relatively smaller number of larger aggregates.74, 121
The preparation of an organic porous monolith embedding a catalyst or catalyst precursor has to take into account a number of factors, which are potentially contrasting each other. For instance, the aim of obtaining materials with a high catalyst content is typically limited by the need of relatively large amounts of CL agent (typically >30 mol%) and porogens (60-70 vol%) in the feed mixture. The former is required for the macroporous texture to develop and remain stable, the latter dictates the fraction of void space in the final monolith, i.e. the porous volume of the material.74 Therefore it is not possible to increase the amount of catalyst indefinitely, without compromising the stability of the monolith and its fluid-dynamic properties. To this it must be added that the ratio between the amount of CL and porogen must fall within appropriate limits for the precipitation-polymerization to take place correctly and that the choice of the porogen should lead to an acceptable balance between the fraction of large pores (which sustain the convective flow) and that of micro- and mesopores (favourable for catalysis).
Given the crucial importance of the solubility properties of the growing polymer chains for the macroporous texture, changing the structure of the monomers may
1.3-ASYMMETRIC TRANSFORMATIONS IN FLOW.
imply a careful optimization study in order to attain a satisfactory compromise between all of the relevant characteristics (mechanical strength, catalyst loading, flow-through pore volume, total surface area). However, thanks to the work of Frechét et Al.,121 several reliable procedures are available for the preparation of styrene and acrylic monoliths embedding simple functional monomers (e.g. chloromethylstyrene, glycidyl methacrylate). When required, these protocols (based on radical polymerization chemistry) can be taken as the starting point for attempting the synthesis of macroporous monoliths including more elaborate functional monomers. For instance, this latter approach allowed Luis et Al. to set-up an organic monolithic CFR containing a TADDOL-Ti(IV) complex 11, which was subsequently used for promoting asymmetric Diels-Alder reactions (Scheme 13).128 Although the enantioselectivity in this initial study was not particularly high (18-40% ee), further efforts by the same group along the same route led to the introduction of very effective CFRs containing a range of different chiral catalytic systems (metal/bis-oxazoline type).129
Scheme 13
Burguete et al.130 developed a monolithic chiral amino alcohol 12 and reported its use for the enantioselective addition of diethylzinc to benzaldehyde. The reaction mixture
11a 11b
of benzaldehyde and an excess of Et2Zn was then pumped and recirculated through
the column over 24 h, resulting in complete conversion of benzaldehyde to the desired (R)-alcohol 13 with 85:15 selectivity and 99% ee (Scheme 14). Lower enantioselectivities were observed in batch reactions using a homogeneous analogue (87% ee) and also for a heterogeneous analogue with the catalyst grafted onto Merrifield resin (89% ee).
Scheme 14
Two additional types of monoliths for continuous-flow transformations have been proposed separately by Buchmeiser et Al.120c, 131 and Kirschning et Al.92a, 132 In the approach of the former group, the macromolecular network is generated by the “living” ring opening metathesis polymerization (ROMP) of norbornene monomers and catalytic units are introduced by including functional monomers in the feed mixture (Scheme 15),133 or by grafting unsaturated compounds to the Ru-terminated ROMP chains. The resulting CFRs have been used for olefin ring-closing metathesis (RCM)134 and other continuous-flow transformations.135 By contrast, the latter group introduced the use of glass-polymer composite monoliths (PASSflow: Polymer Assisted Solution-Phase Synthesis flow-through technique),92a, 132 is an effort to overcome the issue raised by the limited mechanical properties of organic materials. In this approach a Frechét-type precipitation-polymerization is carried out in the presence of (or inside) a porous glass support, which acts as a rigid, yet porous, carrier (Figure 6). An impressive number of applications of the PASSflow meso-sized reactors have been reported, including cross-metathesis, RCM,136 and enyne
12
1.3-ASYMMETRIC TRANSFORMATIONS IN FLOW.
coupling,137 Suzuki-Miyaura, Sonogashira, and Heck reactions,138 racemic epoxide HKR,139 and transfer hydrogenation.140
Scheme 15
PASSflow devices were used for the dynamic kinetic resolution of epibromohydrin
14, using a monolith reactor functionalized with a chiral Co(salen) complex 15
(Scheme 16).139 Three consecutive 1 mmol scale runs (20 h each), where a solution of epibromohydrin was continuously circulated through the reactor via a pump, were performed without any loss of enantioselectivity and catalyst activity (76–87% yield, 91–93% ee). A fourth, larger scale run (10 mmol) was performed continuously over a 6 day period (until complete consumption of epibromohydrin), providing the desired (R)-diol 16 also in similar yield and enantioselectivity.
Porous glass support
Feeding solution
Precipitation polymerization Porous glass support
filled with feeding solution
Organic monolith interpenetrated with the porous
glass support
Figure 6 – Schematic representation of the preparation of PASSflow microreactor, where an organic monolith is prepared in the presence of a porous glass support.
O N N O Co H H tBu tBu tBu Ac O O O O O Br Br OH OH 1.5 eq H2O THF, RT 20 h (91-93% ee)73-87% Scheme 16 1.3.3 Wall-coated CFRs.
This strategy, aimed to overcome the strong propensity of the flow devices of the smallest section to clog, is based on the idea of anchoring the catalyst onto the channel’ inner walls so as to leave a free central bore for unhindered flow.
Given the limited specific surface area of the materials used for microreactor fabrication, the approach might look less than optimal because of the minute amount of active species which can be immobilized onto the CFR’ walls. In order to solve this problem, most of the reported studies included the lining of the reactor’ walls with a film of a polymeric material (either organic or inorganic)141 as the technique for increasing the loading capacity.
For example, Trapp et Al. took advantage of the well established technology for the preparation of capillary GC columns and set up a fused silica CFR containing a chiral V(=O)(salen) complex immobilized in a cross-linked PDMS film.142 The device afforded rather unsatisfactory results (Scheme 17) in what remains, nonetheless, the only example reported to date of an enantioselective CFR of the wall-coated type.
Scheme 17
15
14
16
1.4-PROLINE AND PYRROLIDINE SUPPORTED ORGANOCATALYSTS.
1.4 Proline and pyrrolidine supported organocatalysts.
L-Proline (17) is small organic molecule that can be regarded as the simplest ‘‘enzyme’’. Its use as an asymmetric organocatalyst began in the ‘70s with the pioneering work of Hajos and Parrish (Hoffman-La Roche) and Eder, Wiechert and Sauer (Schering) on the enantioselective cyclization of triketones to afford steroid precursors.34 Since then, much more applications have been reported which include the intermolecular aldol reaction,143 Robinson annulation,32, 144 Mannich reaction,37a,
145
Michael addition,146 direct electrophilic α-amination,147 Diels–Alder cycloaddition,148 Baylis–Hillman149 and aza-Morita-Baylis–Hillman reactions,150 α -selenenylation,151 oxidation,152 chlorination153 and others.154
Figure 7 – Structure of L-proline
Proline is an inexpensive substance and is commercially available in both enantiomeric forms. Considering also that any approach for improving its recovery is likely to involve solvents or starting compounds much more expensive of proline itself (e.g. ionic liquids, 4-hydroxyproline, etc.), efforts in this direction could be viewed as useless. However, at least two ‘‘driving forces’’ for proline immobilization have been outlined in the literature.155 The first one is that supported analogues of 17 afforded enhanced activity and stereoselectivity at much reduced loading than required in the corresponding homogeneous reaction with the soluble organocatalyst (typically used in amounts up to 30 mol%).156 The second reason is that, in some way, proline has become a benchmark for the assessment of recovery techniques for organocatalysts. Therefore, the merits and the drawbacks of any newly introduced procedure can be compared and contrasted against a wealth of previously reported alternative techniques. Once this test has been passed, the new approach can be applied to a more expensive organocatalyst, for which recovery and re-use could be of higher value.155
1.4.1 Supported proline catalysts
a) PEG-supported proline
Benaglia et Al.157 reported the immobilization of (2S,4R)-4-hydroxyproline on PEG500
monomethyl ether by means of a succinate spacer. The resulting soluble catalyst (18) was used in the enantioselective aldol condensation of acetone or hydroxyacetone with various aldehydes and in the Mannich reaction (Scheme 18). The molecularly enlarged derivative 18 gave a similar yield and enantioselectivity compared to the parent proline organocatalyst (17) and could be effectively recovered by solvent precipitation and re-used a few times.
O O O O NH COOH = MeO-(CH2CH2O)n-CH2CH2 RCHO O R1 R = 4-NO2-Ph, Ph, 4-Br-Ph R1= H R = c-C6H11 R1= OH R O R' OH Yield: 8-77%, ee: 21-98% Yield: 48%, anti:syn >20:1, ee: 96%
O O2N N PMP (30 mol%) solvent, r.t. 20-130 h PMP = 4-CH3O-Ph O NH PMP O2N Yield: 43-81%, ee: 60-96% 3 cycles yield: 64-81%, ee: 96-97% (30 mol%)
DMSO, r.t. 24-72 h
Scheme 18
Catalyst 18 was also employed for the addition of ketones to β-nitrostyrene and in the addition of 2-nitropropane to cyclohexenone.158 In these cases results were generally less satisfactory: For instance, in the former reaction (Scheme 19) the addition products were obtained in fair yield (up to 60%) and good diastereoselectivity (up to 95:5 syn:anti ratios), but with low enantioselectivity (no more than 40% ee).
18 18
1.4-PROLINE AND PYRROLIDINE SUPPORTED ORGANOCATALYSTS.
Scheme 19
By using MeOPEG monosuccinate (MW = 2000 or 5000), Gu et Al.159 prepared the PEG/Pro catalysts 19-21 (Figure 8). Best results in the addition of cyclohexanone to
β-nitrostyrene (see Scheme 19) were obtained by using 5 mol% of catalyst 19 (yield: 92%, syn:anti: 98:2, ee: 46%). Interestingly, comparison with the performance of the low molecular weight catalyst 22 (10 mol%, yield: 59%, syn :anti: >98:2, ee: 54%) and unmodified proline 17 (yield: 29%, syn:anti: 97:3, ee: 39%, under comparable conditions) revealed an adverse effect of the immobilization technique.
O H N O NH COOH S O O NH N H COOH O H N O S N H O O NH COOH
Figure 8 – Chemical structures for catalysts 19-22
In a different approach, Chandrasekhar et Al.160 used PEG400 as the reaction medium
for the aldol addition of acetone to aldehydes with unmodified proline (10 mol%) as the catalyst (Scheme 20). The reactions were faster than in DMSO, giving good isolated yields (58–94%). However, in several cases ee values were lower (58-84%) than those obtained with the same organocatalyst in DMSO. This methodology allowed the recovery of proline by means of extraction of the product with diethyl
18
= PEG MW 2000 (20) or 5000 (21) 22 = PEG MW 5000 (19)
ten cycles a slowly decreasing yield was observed (94–84%) while enantioselectivity remained the same.
Scheme 20
b) Polystirene supported proline
Font et Al.161 prepared the resin 23 by 1,3-dipolar cycloaddition of an azide-substituted Merrifield resin with trans-4-propargyloxy proline. The material was used in the aldol reaction between several ketones (cyclohexanone, cyclopentanone, acetone and hydroxyacetone) and arylaldehydes (Scheme 21). Solvent screening showed that the reaction worked nicely in neat water, where diastereo- and enantioselectivity were good. By contrast, dry DMF and DMSO gave lower stereoselectivity. However, the addition of small amounts of water allowed the attainment of higher stereoselectivity in these solvents also.
N H COOH O N N N PS RCHO O R1 R2 (10 mol%) DiMePEG (10 mol%) H2O, 18-144h r.t. R R1 O R2 OH R R1 O R2 OH Yield: 45-97% anti/ syn: 58/42 - 98/2 ee: 45-97% R = Ph, 4-NO2-Ph, 2-naphthyl, 4-Br-Ph, 4-Ch3O-Ph, 2-furyl, 4-CF3-Ph, 2-Cl-Ph O R1 R2 = O O OH O O Scheme 21
Later, five polystyrene-supported proline resins (Figure 9) were investigated in the aldol reaction between cyclohexanone and benzaldehyde in water (compare Scheme
23 23
1.4-PROLINE AND PYRROLIDINE SUPPORTED ORGANOCATALYSTS.
21).162 Using 10 mol% of catalyst, best results were obtained with resin 24 (after 24 h: yield: 74%; anti:syn 96:4; ee: 98%). The reaction time was shortened (12 h), without deterioration in stereocontrol, when the reaction was carried out at 40 °C.
N H COOH O N N N N H COOH O N N N PEG N H COOH O N H COOH O N N N N H COOH O N N N O
PS-PEG NovaBioSyn resin Argopore resin
Merrifield resin
Merrifield resin
Merrifield resin
Figure 9 – Chemical structures of polystyrene-supported proline resins
Giacalone et Al.151b immobilized proline on polystyrene by using a different strategy. The anchorage was accomplished by thiol-ene coupling between a polystyrene resin functionalised with thiol groups and a styrenic derivative of hydroxyproline, followed by deprotection (Scheme 22). Catalyst 25 was employed in the aldol reaction between cyclohexanone and several 4-substituted benzaldehydes in the presence of water (compare Scheme 21). Conversions (71–98%), d.r. [(92:8)–(96:4) anti:syn] and ee (93–98%) were high. After four cycles no decrease in stereoselectivity was observed, while a progressive reduction of the aldehyde substrate conversion was noted.
23
Scheme 22
c) Silica-supported proline
Dhar et Al.163 reported the preparation of proline immobilized on a mesoporous silica support (MCM-41) or silica gel. Both materials were tested in the aldol reaction of acetone with two aromatic aldehydes (Scheme 23). Even if the organocatalyst onto the ordered silicate MCM-41 (26) proved superior to that immobilized onto the amorphous support (silica gel), the results in this study were less than optimal.
Scheme 23
Doyagüez et Al.164 reported the preparation of a similar catalyst (27), embedding cis-4-aminoproline units. The reaction between 4-nitrobenzaldehyde and dioxanone 28 (Scheme 24) proceeded more efficiently in hydrophilic polar solvent and the addition of small amount of water (up to 5 equiv.) had a positive effect on the rate and the
25
26
