WO2017008832A1

WO2017008832A1 - Polymer supported fluorinated organocatalyst

Info

Publication number: WO2017008832A1
Application number: PCT/EP2015/065866
Authority: WO
Inventors: Miguel Ángel PERICÀS BRONDO; Irina SAGAMANOVA; Sonia SAYALERO SANZ; Carles Rodríguez Escrich
Original assignee: Fundació Institut Català D'investigació Química
Priority date: 2015-07-10
Filing date: 2015-07-10
Publication date: 2017-01-19

Abstract

Polymer supported fluorinated compound of formula I, wherein the meaning for each R₁is as disclosed in the description. These compounds are useful as catalysts, particularly in Michael addition reactions under continuous flow.

Description

POLYMER SUPPORTED FLUORINATED ORGANOCATALYST

The invention relates to a polymer-supported fluorinated organocatalyst of formula I and to its use in enantioselective Michael addition reactions, particularly in the enantioselective addition of aldehydes to nitroalkenes. The invention also relates to the process for preparing the organocatalyst.

BACKGROUND ART Sustainability concerns have conveyed a change of paradigm where not only cost reduction, but also waste minimization and catalyst recovery are crucial issues in process design. In this context, continuous flow chemistry is one of the tools expected to help in process intensification, reducing the footprint of the chemical plants while increasing their productivity, modularity and flexibility. Despite the potential of immobilized chiral catalysts for enantioselective flow processes, the fine chemical industry is still reluctant to apply these techniques. This may be due to the limited lifespan of some of the species reported so far. Therefore, the preparation of supported catalysts with improved stability and high activity and selectivity holds great interest for the chemical community.

Since the works on organocatalysis reported by List, Lerner, Barbas (see J. Am. Chem. Soc. 2000, 122, 2395) and MacMillan (see J. Am. Chem. Soc. 2000, 122, 4243), efforts devoted to the preparation of metal-free catalysts with an increased activity profile have blossomed. One of the most successful organocatalysts is the diarylprolinol trimethylsilyl ether, commonly known as the J0rgensen-Hayashi catalyst (see Acc. Chem. Res. 2012, 45, 248). Given the versatility of this species, which is able to exploit both the enamine and iminium ion activation mode for a substrate bearing a carbonyl group (e.g. aldehydes or ketones), several research groups have embarked in the development of immobilized analogues. With the aim of enhancing the sustainability profile of this catalyst, the preparation of a set of solid-supported derivatives whose robustness was tested through recycling and implementation of enantioselective continuous flow processes has been reported (see J. Org. Chem. 2015, 1 173).

However, the robustness of the catalyst is compromised by the lability of the trimethylsilyl ether group. Several approaches have been tackled to solve this issue. Accordingly, it has been demonstrated that resilylation is indeed possible (see Adv. Synth. Catal. 2009, 351 , 3051 ), although this is not completely convenient from an operational point of view and it precludes continuous flow application. The analogous methyl ether (see Org. Lett. 2005, 7, 4253) (rather than silyl) was described but the polymer-supported version turned out to be less active and selective (see Chem. Eur. J. 201 1 , 17, 1 1585). Finally, albeit catalysts also tend to deactivate in the long run, with bulkier silyl ethers they have shown increased stability,. Additionally, an homogeneous pyrrolidine derivative catalyst for asymmetric aminocatalysis has been described (see Angew. Chem. Int. Ed. 2009, 48, 3065; and J. Org. Chem. et al. in 2009) which has turned out to promote reactions such as epoxidations and aziridinations with great success, even outperforming the J0rgensen-Hayashi catalyst in some cases.

Therefore, it would be desirable to provide a polymer-supported organocatalyst which would display increased robustness when compared to the structurally related silyl ethers and which would be useful in Michael reactions being versatile and convenient for being used either in batch or in continuous flow.

SUMMARY OF THE INVENTION

Inventors have prepared and tested a polymer supported catalyst bearing a fluorine group that displays enhanced robustness than the catalysts of the state of the art, while being potentially used in continuous flow applications or in batch conditions. A first aspect of the present invention relates to a compound of formula I:

I

wherein:

each Ri independently represents Pi or Cyi Pi;

each Pi independently represents a polymeric support;

each Cyi independently represents a monocyclic or bicyclic 6 to 10-membered carbocyclic ring, wherein Cyi is saturated, partially unsaturated or aromatic, wherein Cyi is bonded to the rest of the molecule through any available C atom, and wherein Cyi is optionally substituted with one or more R2;

each R₂ independently represents halogen, Ci-4alkyl, C2-4alkenyl, C2-4alkynyl, CN, N0₂, -OR3 or -SR3, wherein each d-₄alkyl, C₂-₄alkenyl, C₂-₄alkynyl are optionally substituted with one or more R₄;

each R3 independently represents H or Ci-₄alkyl; and

each R₄ independently represents, halogen, CN, NO2, -OR3 or -SR3.

A second aspect of the present invention relates to a process to obtain the compound of formula I as defined above, wherein the process comprises the reaction between one or more compounds comprising a group selected from the groups of formula FGi and Cyi-FGi and a compound of formula II:

II

wherein:

R6 is selected from three groups of formula FG2 and C 1-FG2;

R₇ is selected from the groups of formula FG3 and C 1-FG3; Cyi have the meaning previously described in relation with the compound of formula I of the first aspect of the invention;

R5 is selected from H, tert-butyloxycarbonyl (Boc), tosyl (Ts), fluorenylmethyloxycarbonyl (Fmoc) and benzyl (Bn);

each FGi , FG₂ and FG₃ is independently selected from vinyl (HC=CH₂), SiX₃, -OH, -NCO, glucosyl, galactosyl, -COOH, -NH₂, and oxiranyl; and

X is halogen or -OCi-4alkyl.

A third aspect of the invention relates to the use of the compound of formula I as defined above, as a catalyst.

The compounds of the invention are efficient catalysts for Michael addition reactions, as described in the Examples. Being non soluble in most organic solvents, the compounds of the invention are suitable for applications in flow catalysis.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1. Shows the continuous flow set up for the Michael addition of aldehydes to β-nitroalkene compounds with catalyst la of the examples. A set of two pumps (one with only solvent for swelling before and rinsing at the end) is connected to the packed bed reactor with the solid-supported catalyst. After the column, a third pump is used to introduce aqueous base for the work-up in-line.

Finally, the liquid-liquid separator leaves the organic phase free of additive and allows to recover pure product provided that (a) the aldehyde is volatile and (b) the conversion is complete. The set-up comprises:

A: mixture of reagents and additive in solution;

B: solvent (for swelling and, optionally, dilution);

C: pump;

D: 3-way valve;

E: packed bed reactor filled with catalyst la;

F: aqueous solution of NaOH (0.1 M) G: back-pressure regulator;

H: T-junction;

I: coil;

J: liquid-liquid separator (for in-line work-up);

K: aqueous phase (additive removed from mixture)

L: organic phase containing the reaction product and the excess volatile starting material.

Fig. 2. Shows the results for the continuous process carried out as depicted in Figure 1 . Reaction conversion (circles) and enantiomeric excess (triangles) are plotted against time, which shows that the resin performs very well (after 13 h at 0.1 ml_ min^-1 conversion and ee are still >95%).

DETAILED DESCRIPTION OF THE INVENTION

All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set-out definition provides a broader definition.

Along the description, Ci-₄alkyl as a group or part of a group, means a straight or branched saturated hydrocarbon chain which contains from 1 to 4 carbon atoms and includes the groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and te/f-butyl.

A C2-₄alkenyl group means a straight or branched hydrocarbon chain which contains from 2 to 4 C atoms, and also contains one or two double bonds. Examples include the groups ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1 - butenyl, 2-butenyl, 3-butenyl and 1 ,3-butadienyl.

A C2-₄alkynyl group means straight or branched hydrocarbon chain which contains from 2 to 4 C atoms, and also contains one or two triple bonds. Examples include the groups ethynyl, 1 -propynyl, 2-propynyl, 1 -butynyl, 2- butynyl, 3-butynyl and 1 ,3-butadiynyl.

Halogen or its abbreviation halo means fluoro, chloro, bromo or iodo.

A -OCi--₄alkyl, as a group or part of a group, means a group of formula Ci-₄alkoxy group, wherein the Ci_-4alkyl moiety has the same meaning as previously described. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and te/f-butoxy.

The term Cyi refers to a 6 to 10-membered carbocyclic ring that may be monocyclic or bicyclic. Cyi can be saturated, partially unsaturated or aromatic. Cyi can be bonded to the rest of the molecule through any available C atom. And Cyi is optionally substituted with one or more R₂. Examples include, among others, phenyl, tolyl, cyclohexyl, decalinyl, cyclohexenyl, cyclohexadienyl and naphthyl.

The term "polymeric support" is art-recognized and refers to a polymer onto which the active unit is anchored directly or through a linker (e.g. Cyi ). Many suitable polymeric supports are known, and include among others a polyolefin, polyurethane, polyamide, polycarbonate, polyglycol, a polysaccharide, polyester, polysiloxane, mixtures thereof and co-polymers thereof. More concrete examples include, among others, polyethylene (PE), polypropylene (PP), polyurethane (PU), nylon, polystyrene (PS), polystyrene cross-linked with divinylbenzene, polystyrene cross-linked with 1 ,4-bis(4-vinylphenoxy)butane (jandajel®), polystyrene cross-linked with divinylbenzene wherein at least one phenyl ring is substituted with polyethyleneglycol (tentagel®), polyethylene glycol (PEG), dextran, agarose, polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polynorbornene (PNB), polycarbonate (PC), polymethylmethacrylate (PMMA) polysiloxane, mixtures thereof and copolymers thereof. In the context of the invention, the term "continuous flow process" refers to a process wherein the reagents of the process, either in solution (i.e. dissolved into a solvent) or neat, are constantly fed into a reactor in the right proportions, thus allowing for the continuous production of the product. When a catalyst is present, the reactor further comprises the catalyst, preferably as an insoluble solid.

The "enantiomeric excess" or "ee" is a measure of the excess of one enantiomer over a racemic mixture of a chiral compound, which is commonly expressed as a percentage. Enantiomeric excess is defined as the absolute difference between the mole fraction of each enantiomer [ee = F(+)- F(-)]. If the moles of each enantiomer are known, the percent enantiomeric excess can be determined by the following formula: ee = ((R-S)/(R+S)) x 100, where R and S are the respective molar fractions of enantiomers in the mixture such that R+S=1.

In the above definition of Cyi when the examples listed refer to a bicycle in general terms, all possible dispositions of the atoms are included. When in the definitions used throughout the present specification for cyclic groups the examples given refer to a radical of a ring in general terms all the available bonding positions are included.

The expression "optionally substituted with one or more" means that a group can be substituted with one or more, preferably with 1 , 2, 3 or 4 substituents, more preferably with 1 , 2 or 3 substituents, and still more preferably with 1 or 2 substituents, provided that said group has enough positions susceptible of being substituted. The substituents can be the same or different and can be placed on any available position.

In the above definitions of FG1 , FG2 and FG3, "FG" refers to a functional group. According to a compound of formula II and a compound comprising a group of formula FG1 or Cyi-FG1 , each FG independently represents vinyl (HC=CH₂), S1X3, -OH, -NCO, glucosyl, galactosyl, -COOH, -NH₂, and oxiranyl, wherein X represents halogen or -OCi-4alkyl. In certain embodiments of the invention, Cyi represents a phenyl group substituted at one or two of positions 3, 4 and 5 with a Ri group. This means that the phenyl group is either substituted with one Ri group at position 3, 4 or 5 of the phenyl ring, or with two Ri groups (which can be the same or different) at positions 3 and 4, positions 4 and 5 or positions 3 and 5 of the phenyl ring.

The compounds of the present invention may exist as several diastereoisomers and/or several optical isomers. Diastereoisomers can be separated by conventional techniques such as chromatography or fractional crystallization. Enantiomers can be resolved by conventional techniques of optical resolution to give optically pure isomers. This resolution can be carried out on any chiral synthetic intermediate or on products of formula I. Optically pure isomers can also be individually obtained using enantioselective synthesis or optically pure starting materials. The present invention covers all individual isomers as well as mixtures thereof (for example racemic mixtures or mixtures of diastereomers), whether obtained by synthesis or by physically mixing them. The use of an optically pure compound of formula I is advantageous as it allows for obtaining Michael addition products with high optical purity.

In an embodiment of the first aspect of the invention relates to the compound as defined above, wherein each Ri independently represents CyiPi .

In another embodiment the invention relates to the compound as defined above, wherein each Ri independently represents Pi . In another embodiment the invention relates to the compound of formula I, wherein each each Pi is independently selected from a polyolefin, a polyurethane, a polyamide, a polycarbonate, a polyglycol, a polysaccharide, a polyester, a polysiloxane, mixtures thereof and co-polymers thereof.

In another embodiment the invention relates to the compound of formula I, wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polyurethane (PU), nylon, polystyrene (PS), polystyrene cross-linked with divinylbenzene, (polystyrene cross-linked with 1 ,4-bis(4- vinylphenoxy)butane (jandajel®), polystyrene cross-linked with divinylbenzene wherein at least one phenyl ring is substituted with polyethyleneglycol (tentagel®), polyethylene glycol (PEG), dextran, agarose, polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polynorbornene (PNB), polycarbonate (PC), polymethylmethacrylate (PMMA) polysiloxane , mixtures thereof and co-polymers thereof. In another embodiment the invention relates to the compound of formula I, wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polystyrene (PS), polystyrene cross-linked with divinylbenzene, polystyrene cross-linked with 1 ,4-bis(4-vinylphenoxy)butane (jandajel®), polystyrene cross-linked with divinylbenzene wherein at least one phenyl ring is substituted with polyethyleneglycol (tentagel®), polyethylene glycol (PEG), polynorbornene (PNB), mixtures thereof and co-polymers thereof;

In another embodiment the invention relates to the compound of formula I, wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polystyrene (PS), polystyrene cross-linked with divinylbenzene, polystyrene cross-linked with 1 ,4-bis(4-vinylphenoxy)butane (jandajel®), polystyrene cross-linked with divinylbenzene wherein at least one phenyl ring is substituted with polyethyleneglycol (tentagel®), polyethylene glycol (PEG), mixtures thereof and co-polymers thereof.

In another embodiment the invention relates to the compound of formula I, wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polyurethane (PU), nylon, polystyrene (PS), polyethylene glycol (PEG), dextran, agarose, polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polynorbornene (PNB), polycarbonate (PC), polymethylmethacrylate (PMMA) polysiloxane (PS), mixtures thereof and co- polymers thereof,

In another embodiment the invention relates to the compound of formula I, wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polystyrene (PS), polyethylene glycol (PEG), polynorbornene (PNB), mixtures thereof and co-polymers thereof;

In another embodiment the invention relates to the compound of formula I, wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polystyrene (PS), polyethylene glycol (PEG), mixtures thereof and co-polymers thereof.

In another embodiment the invention relates to the compound of formula I, wherein each Pi is polystyrene (PS). In another embodiment the invention relates to the compound of formula I, wherein each Cyi independently represent a monocyclic or bicyclic 6 to 10-membered carbocyclic ring, wherein Cyi is aromatic, wherein Cyi is bonded to the rest of the molecule through any available C atom, and wherein Cyi is optionally substituted with one or more R₂.

In another embodiment the invention relates to the compound of formula I, wherein each Cyi is independently selected from phenyl and naphthyl, and wherein Cyi is optionally substituted with one or more R₂. In another embodiment the invention relates to the compound of formula I, wherein each Cyi is independently selected from phenyl and naphthyl, and preferably wherein each Cyi is phenyl, even more preferably each Cyi is unsubstituted phenyl.

In another embodiment the invention relates to the compound of formula I, wherein each R₂ independently represents halogen, Ci_-4alkyl, CN, N0₂ or -OR3, and preferably wherein each R₂ independently represents halogen, Ci_-4alkyl, CN, N0₂ or OCi_-4alkyl.

In another embodiment the invention relates to the compound of formula I, wherein each R₄ independently represents, halogen, CN, N0₂ or -OR3, preferably wherein each R₄ independently represents, halogen, CN, N0₂ or -OCi_-4alkyl, and more preferably wherein each R₄ independently represents, halogen, CN, N0₂ or -OMe. In another embodiment the invention relates to the compound of formula I, wherein:

each Ri independently represents CyiPi; and

each Pi is independently selected from a polyolefin, a polyurethane, a polyamide, a polycarbonate, a polyglycol, a polysaccharide, a polyester, a polysiloxane, mixtures thereof and co-polymers thereof, preferably wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polyurethane (PU), nylon, polystyrene (PS), polyethylene glycol (PEG), dextran, agarose, polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polynorbornene (PNB), polycarbonate (PC), polymethylmethacrylate (PMMA) polysiloxane (PS), mixtures thereof and co-polymers thereof, more preferably, wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polystyrene (PS), polyethylene glycol (PEG), polynorbornene (PNB), mixtures thereof and co-polymers thereof; even more preferably wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polystyrene (PS), polyethylene glycol (PEG), mixtures thereof and co-polymers thereof, and particularly preferably wherein each Pi is polystyrene (PS). In another embodiment the invention relates to the compound of formula I, wherein:

each Ri independently represents Cyi Pi ;

each is independently selected from a polyolefin, a polyurethane, a polyamide, a polycarbonate, a polyglycol, a polysaccharide, a polyester, a polysiloxane, mixtures thereof and co-polymers thereof, preferably wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polyurethane (PU), nylon, polystyrene (PS), polyethylene glycol (PEG), dextran, agarose, polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polynorbornene (PNB), polycarbonate (PC), polymethylmethacrylate (PMMA) polysiloxane (PS), mixtures thereof and co-polymers thereof, more preferably, wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polystyrene (PS), polyethylene glycol (PEG), polynorbornene (PNB), mixtures thereof and co-polymers thereof; even more preferably wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polystyrene (PS), polyethylene glycol (PEG), mixtures thereof and co-polymers thereof, and particularly preferably wherein each Pi is polystyrene (PS); and wherein each Cyi independently represents a monocyclic or bicyclic 6 to 10-membered carbocyclic ring, wherein Cyi is aromatic, wherein Cyi is bonded to the rest of the molecule through any available C atom, and wherein Cyi is optionally substituted with one or more R₂, preferably wherein each Cyi is independently selected from phenyl and naphthyl, and more preferably wherein each Cyi is unsubstituted phenyl.

In another embodiment the invention relates to the compound of formula I, wherein:

each R† independently represents Cyi Pi ; and

each Cyi independently represent a monocyclic or bicyclic 6 to 10-membered carbocyclic ring, wherein Cyi is aromatic, wherein Cyi is bonded to the rest of the molecule through any available C atom, and wherein Cyi is optionally substituted with one or more R₂, preferably wherein each Cyi is independently selected from phenyl and naphthyl, and more preferably wherein each Cyi is unsubstituted phenyl.

each Ri independently represents CyiPi;

each Pi is independently selected from a polyolefin, a polyurethane, a polyamide, a polycarbonate, a polyglycol, a polysaccharide, a polyester, a polysiloxane, mixtures thereof and co-polymers thereof, preferably wherein each is independently selected from polyethylene (PE), polypropylene (PP), polyurethane (PU), nylon, polystyrene (PS), polyethylene glycol (PEG), dextran, agarose, polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polynorbornene (PNB), polycarbonate (PC), polymethylmethacrylate (PMMA) polysiloxane (PS), mixtures thereof and co-polymers thereof, more preferably, wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polystyrene (PS), polyethylene glycol (PEG), polynorbornene (PNB), mixtures thereof and co-polymers thereof; even more preferably wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polystyrene (PS), polyethylene glycol (PEG), mixtures thereof and co-polymers thereof, still more preferably wherein each Pi is polystyrene (PS); and wherein each Cyi independently represent a monocyclic or bicyclic 6 to 10-membered carbocyclic ring, wherein Cyi is aromatic, wherein Cyi is bonded to the rest of the molecule through any available C atom;

Cyi is optionally substituted with one or more R2, preferably wherein each Cyi is independently selected from phenyl and naphthyl, and more preferably wherein each Cyi is unsubstituted phenyl; and

each R₂ independently represents halogen, Ci-4alkyl, CN, N0₂ or OR3, and preferably wherein each R₂ independently represents halogen, Ci_-4alkyl, CN, N0₂ or -OCi_-4alkyl.

In another embodiment the invention relates to the compound of formula I, wherein: each R† independently represents Cyi Pi ;

wherein Cyi is optionally substituted with one or more R2, preferably wherein each Cyi is independently selected from phenyl and naphthyl, and more preferably wherein each Cyi is unsubstituted phenyl;

each R₂ independently represents halogen, Ci_-4alkyl, CN, N0₂ or -OR3, and preferably wherein each R₂ independently represents halogen, Ci_-4alkyl, CN, N0₂ or -OCi_-4alkyl; and

each R₄ independently represents, halogen, CN, N0₂ or -OR3, preferably wherein each R₄ independently represents, halogen, CN, N0₂ or -OCi_-4alkyl, and more preferably wherein each R₄ independently represents, halogen, CN, N0₂ or -OMe. In another embodiment the invention relates to the compound of formula I, wherein:

each Ri independently represents Cyi Pi ; each Cyi independently represents a monocyclic or bicyclic 6 to 10-membered carbocyclic ring, wherein Cyi is aromatic, wherein Cyi is bonded to the rest of the molecule through any available C atom, and wherein Cyi is optionally substituted with one or more R2, preferably wherein each Cyi is independently selected from phenyl and naphthyl, and more preferably each Cyi is unsubstituted phenyl; and

each R₂ independently represents halogen, Ci_-4alkyl, CN, N0₂ or -OR3, and preferably wherein each R₂ independently represents halogen, Ci_-4alkyl, CN, N0₂ or -OCi_-4alkyl.

each Ri independently represents CyiPi;

each Cyi independently represents a monocyclic or bicyclic 6 to 10-membered carbocyclic ring, wherein Cyi is aromatic, wherein Cyi is bonded to the rest of the molecule through any available C atom, and wherein Cyi is optionally substituted with one or more R₂, preferably wherein each Cyi is independently selected from phenyl and naphthyl, and more preferably each Cyi is unsubstituted phenyl;

each R₂ independently represents halogen, Ci_-4alkyl, CN, N0₂ or -OR3, and preferably wherein each R₂ independently represents halogen, Ci_-4alkyl, CN, N0₂ or O Ci_-4alkyl; and

each R₄ independently represents, halogen, CN, N0₂ or -OR3, preferably wherein each R₄ independently represents, halogen, CN, N0₂ or -OCi_-4alkyl, and more preferably wherein each R₄ independently represents, halogen, CN, N0₂ or -OMe.

each Ri independently represents CyiPi;

each Cyi is phenyl;

each Pi is polystyrene (PS). In another embodiment the invention relates to the compound of formula I, which comprises from 0.5 to 2 mmol of pyrrolidinyl moiety per gram of compound of formula I, and preferably which comprises from 0.7 to 1 .5 mmol of pyrrolidinyl moiety per gram of compound of formula I.

The second aspect of the invention relates to a process for the preparation of a compound of formula I as described above wherein the process comprises the reaction between one or more compounds comprising a group selected from the groups of formula -FGi and -Cy FGi and a compound of formula II.

Preferably, the process of the second aspect of the invention comprises the reaction between one or two compounds comprising a group selected from the groups of formula FGi and Cy FGi and a compound of formula II.

In a preferred embodiment of the second aspect of the invention, the compound comprising a group selected from the groups of formula FGi and Cyi-FGi is a compound of formula H-Cyi-FGi, wherein Cyi and FGi are as defined above. As is known in the art, the skilled in the art person will carefully select the appropriate FGi , FG2 and FG3 groups so as to form the polymer support Pi:

- when, in the compound of formula I, Pi is a polyolefin, FGi, FG₂ and FG3 are preferably vinyl; or, alternatively,

- when, in the compound of formula I, Pi is a polyglycol, FGi , FG₂ and FG3 are preferably selected from oxiranyl and OH; or, alternatively,

- when, in the compound of formula I, Pi is a polyester, FGi , FG₂ and FG3 are preferably selected from COOH and OH; or, alternatively,

- when, in the compound of formula I, Pi is a polyamide, FGi, FG₂ and FG3 are preferably selected from COOH and NH₂; or, alternatively, - when, in the compound of formula I, Pi is a polysaccharide, FGi , FG₂ and FG3 are preferably selected from glucosyl and galactosyl; or, alternatively, - when, in the compound of formula I, Pi is a polyurethane, FGi, FG₂ and FG3 are preferably selected from NCO and OH; or, alternatively,

- when, in the compound of formula I, Pi is a polycarbonate, FGi , FG₂ and FG3 are preferably OH, and the reaction further comprises phosgene; or, alternatively,

- when, in the compound of formula I, Pi is a polysiloxane, FGi , FG₂ and FG3 are preferably a group of formula SiX3 wherein X is halogen or -OCi_-4alkyl. The appropriate choice of these units, as well as their relative amounts, will determine the physical properties of the material prepared, including the swelling ability in different solvents, which can have an impact in its behavior. In this sense, hybrid polymers, i.e. co-polymers or mixtures of polymers, can also be prepared.

In a preferred embodiment of the second aspect of the invention, the compound comprising a group selected from the groups of formula FGi and Cyi-FGi is selected from the group consisting of ethylene, propylene, polyurethane (PU), nylon, styrene, divinylbenzene, 1 ,4-bis(4-vinylphenoxy)butane, ethylene oxide, glucose, galactose, tetrafluoroethylene, vinylidene fluoride, norbornene, bis- phenol A, methylmethacrylate, polysiloxane , mixtures thereof, polymers thereof and co-polymers thereof. Preferably, the compound comprising a group selected from the groups of formula FGi and Cyi-FGi is selected from the group consisting of ethylene, propylene, styrene, divinylbenzene, 1 ,4-bis(4- vinylphenoxy)butane, ethylene oxide, mixtures thereof, polymers thereof and co-polymers thereof. Even more preferably, the compound comprising a group selected from the groups of formula FGi and Cyi-FGi is styrene.

In another embodiment of the second aspect of the invention, FG₂ and FG3 are the same, and preferably FG₂ and FG3 are vinyl. In another embodiment of the second aspect of the invention, the process also comprises the reaction between a compound comprising a group selected from the groups of formula FGi and Cyi-FGi as defined above and a compound of formula II wherein R6 and R₇ are each respectively Cyi-FG2 and Cyi-FG3, wherein Cyi, FG₂ and FG₃ are as defined above.

In another embodiment of the second aspect of the invention, Cyi is as defined in the embodiments of the first aspect of the invention, preferably Cyi is phenyl, more preferably Cyi is phenyl; and FG₂ and FG3 are vinyl, and even more preferably Cyi is phenyl; FGi, FG₂ and FG₃ are vinyl; and the compound comprising a group selected from the groups of formula FGi and Cyi-FGi is styrene.

The compounds of formula I and of formula II can be obtained by following the processes described below. As it will be obvious to one skilled in the art, the exact method used to prepare a given compound may vary depending on its chemical structure. Moreover, in some of the processes described below it may be necessary or advisable to protect the reactive or labile groups with conventional protecting groups. Both the nature of these protecting groups and the procedures for their introduction and removal are well known in the art (see for example Greene T.W. and Wuts P.G.M, "Protecting Groups in Organic Synthesis", John Wiley & Sons, 4^th edition, 2006). Whenever a protecting group is present, a later deprotection step will be required, which can be performed under standard conditions in organic synthesis, such as those described in the above-mentioned reference.

Unless otherwise stated, in the methods described below the meanings of the different substituents are the meanings described above with regard to a compound of formula I.

In preferred embodiments, compounds of formula I can be obtained in several synthetic steps by the method described in Scheme 1 : COO

VII VI V

HFC, or HCy_rFG-_|

III II

Scheme 1

wherein Ri, R₅, R₆, R₇, Pi , FGi , and Cyi have the meaning previously described in relation with a compound of formula I or a compound of formula II; and each X represents halogen, and preferably each X represents Br.

In step a, the reaction between a compound of formula VII and the Grignard reagents of formula V and VI may be carried out in the present of a solvent, such as THF, to obtain a compound of formula IV.

In step b, the protecting group R5 of a compound of formula IV may be removed under standard experimental conditions to obtain a compound of formula III.

In step c, a compound of formula II may be obtained substituting the hydroxyl group of a compound of formula III by a F in the presence of a fluorinating agent such as, for example, DAST; and in the presence of a solvent, such as dichloromethane.

A compound of formula I may be obtained by the reaction of the compound of formula II as described above.

As described above, another aspect of the present invention relates to the use of the compound of formula I as defined above, as a catalyst. The catalyst of the invention can be used as a heterogeneous catalyst in batch and flow conditions. Preferably, the use of a compound of formula I as catalyst is characterized in that the catalyst is used under continuous flow. In another embodiment, the use of a compound of formula I as catalyst is characterized in that the catalyst is used in a Michael addition reaction, and even more preferably wherein the Michael addition reaction is the addition of aldehydes to β-nitroalkenes. More preferably, the use of a compound of formula I as catalyst is characterized in that the catalyst is used under continuous flow in the Michael addition of aldehydes to β-nitroalkenes. This flow application has allowed isolating the product after simple evaporation of the outlet stream, given the fact that the work-up, including separation of organic and aqueous phase, is performed in-line, i.e. under flow conditions. The substitution of a silyl ether for a much more stable C-F bond completely suppresses catalyst deactivation due to cleavage of this moiety, resulting in long-term performance of the catalyst of the invention. This has allowed recycling the same sample of catalyst several times in batch conditions with very small losses of the catalytic activity and the use of the catalyst under continuous flow. Moreover, the fact that the catalyst is co-polymerized decreases the cost significantly because the precursors are cheaper and a functionalized resin is not required.

Accordingly, another embodiment refers to the use of the compound of the formula I as defined above as a catalyst characterized in that the catalyst is used under continuous flow and the work-up is performed in-line. A work-up performed in-line means that the product can be isolated from the reaction mixture under flow conditions, thereby advantageously saving the step of stopping the flow operation of the reaction in the step of isolating the product.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skilled in the art to which this invention belongs. Methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. Throughout the description and claims the word "comprise" and its variations are not intended to exclude other technical features, additives, components, or steps. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration and are not intended to be limiting of the present invention.

EXAMPLES

Example 1 : Preparation of the polymer-supported pyrrolidine (la)

(S)-bis(4-Vinylphenyl)prolinol ferf-butyl carbamate (IVa)

Magnesium turnings (1 .23 g, 50.6 mmol) and a tip of were added to a dry, 250-ml, two-necked round-bottom flask fitted with a reflux condenser and it was flame dried under nitrogen. After that, a solution of 4-bromostyrene (6.30 mL, 48.2 mmol) in 35 mL of THF was added dropwise during 10 min. Once the addition was complete, the mixture was stirred for 40 min. Then it was cooled to -5 °C and a solution of /V-Boc-L-proline methyl ester (3.76 g, 15.09 mmol) in 25 mL of THF was added. The reaction mixture was stirred at room temperature overnight and then 20 mL of saturated aqueous NH4CI were added, followed by addition of 150 mL of water and extraction with Et₂O (3 ^χ 70 mL). The combined organic layers were dried over anhydrous MgSO4. After solvent removal, the crude product was purified by silica gel column chromatography with cyclohexane/EtOAc 95:5 as the eluent to afford alcohol 5 as a white solid in 87% yield (5.35 g, 13.19 mmol). ¹H NMR (500 MHz, CDCI₃): δ 7.35 (bs, 4H), 7.34 (bs, 4H), 6.72 (dd, J = 10.9, 17.6 Hz, 1H), 6.71 (dd, J = 10.9, 17.6 Hz, 1H), 5.76 (dd, J = 1.0, 17.6 Hz, 1H), 5.74 (dd, J = 1.0, 17.6 Hz, 1H), 5.24 (dd, J = 1.0, 10.9 Hz, 1H), 5.24 (dd, J = 1.0, 10.9 Hz, 1H), 4.88 (dd, J = 3.6, 9.0 Hz, 1H), 3.35 (bs, 1H), 2.88 (bs, 1H), 2.10 (dq, J = 8.8, 13.4 Hz, 1H), 1.91 (ddt, J = 4.2, 8.1, 13.0 Hz, 1H), 1.47 (bs, 1H), 1.47 (bs, 1H), 1.44 (s, 9H), 0.85 (bs, 1H).

¹³C NMR (126 MHz, CDCI₃): δ 146.10, 143.6, 136.7, 136.6, 136.5, 136.4, 128.5 (^χ2), 128.0 (x2), 125.9 (x2), 125.4 (x2), 114.0, 113.8, 81.7, 80.8, 65.8, 48.0, 29.8, 28.5 (x3), 23.2.

(S)-bis(4-Vinylphenyl)prolinol (Ilia)

A 250-ml round-bottom flask was charged with 5 (5.30 g, 13.07 mmol), KOH (7.33 g, 0.131 mol), 87 mL MeOH and 87 mL DMSO. The solution was heated at 120 °C for 30 h. Then, crushed ice was carefully added to the solution and it was extracted with EtOAc (3 ^χ 70 mL). The combined organic extracts were dried under MgSO₄ and the residue obtained after evaporation was purified by flash column chromatography (eluent CH₂Cl₂MeOH from 99:1 to 95:5) to furnish amino alcohol as a white solid in 95% yield (3.78 g, 12.38 mmol).

¹H NMR (500 MHz, CDCI₃): δ 7.54-7.51 (m, 2H), 7.48-7.43 (m, 2H), 7.36-7.31 (m, 4H), 6.67 (dd, J = 10.9, 17.6, 1H), 6.66 (dd, J= 10.9, 17.6, 1H), 5.693 (dd, J = 0.9, 17.6 Hz, 1H), 5.688 (dd, J= 0.9, 17.6 Hz, 1H), 5.20 (dd, J= 0.9, 10.9 Hz, 1H), 5.19 (dd, J= 0.9, 10.9 Hz, 1H), 4.24 (t, J= 7.7 Hz, 1H), 3.04 (ddd, J = 4.9, 6.7, 9.3 Hz, 1 H), 3.0 (dt, J = 7.5, 9.3 Hz, 1 H), 1.80-1.52 (m, 5H). ¹³C NMR (126 MHz, CDCI₃): δ 147.9, 145.1 , 136.7, 136.5, 136.0, 135.8, 126.3 (^χ2), 126.1 (x2), 126.0 (x2), 125.8 (x2), 1 13.7, 1 13.5, 77.2, 64.5, 46.9, 26.4, 25.6. (S)-2-(Fluoro-bis(4-vinylphenyl)methyl)pyrrolidine (Ma)

A 250 mL round-bottom flask was charged with compound Mia (1 .05 g, 3.44 mmol), purged with nitrogen and dry DCM (78 mL) was added. The solution was cooled to -5 °C and DAST (0.9 mL, 6.88 mmol) was added dropwise. The reaction was gradually warmed to rt over a period of 10 h and quenched with sat. aq. NaHCO₃ (60 mL). The layers were separated and the aqueous phase was back-extracted with CH2CI2 (3 ^χ 20 mL). The combined organic phases were dried under MgSO4 and concentrated in vacuum. The residue was purified by silica gel column chromatography (S1O2 with 2.5% EtsIM; eluent from DCM to DCM/MeOH 95:5) to afford Ma as a yellow oil (867 mg, 2.82 mmol, 82 % yield). IR (ATR): v = 3276, 2943,1628, 1509, 1402, 991 , 913, 828, 729, 517 cm^"1.

[a]_D ²⁵ (CH2CI2, c 0.1 ) +106.2

1H NMR (500 MHz, CDCI3): δ 7.53-7.46 (m, 2H), 7.41 -7-7.34 (m, 6H, C₆H₅), 6.680 (dd, J = 17.6, 10.9 Hz, 1 H), 6.676 (dd, J = 10.9, 17.6 Hz, 1 H), 5.723 (dd, J = 0.9, 17.6 Hz, 1 H), 5.721 (d, J = 0.9, 17.6 Hz, 1 H), 5.230 (dd, J = 0.9, 10.9 Hz, 1 H), 5.234 (dd, J = 0.9, 10.9 Hz, 1 H), 4.21 -4.1 1 (m, 1 H), 3.10-3.05 (m, 1 H), 2.90-2.84 (m, 1 H), 1 .88 (bs, 1 H), 1 .82-1.66 (m, 4H).

1³C NMR (126 MHz, CDCI3): δ 142.5 (d, J = 23.7 Hz), 142.1 (d, J = 24.3 Hz), 137.0 (d, J = 1.5 Hz), 136.8 (d, J = 1 .4 Hz), 136.4, 136.3, 126.4 (x2), 126.2 (x2, d, J = 1 .3 Hz), 125.9 (x2, d, J = 8.9 Hz), 125.2 (x2, d, J = 9.0 Hz), 1 14.3 (x2), 100.2 (d, J = 182.5 Hz), 64.5 (d, J = 22.1 Hz), 47.6, 26.6 (d, J = 3.4 Hz), 26.1. ¹⁹F NMR (376 MHz, CDCI₃): δ = -169.8 (d, ³J_H,F = 27.6 Hz).

HRMS (ESI) Calculated mass for C₂iH₂₂FN [M+H]⁺ 308.1809, found 308.1799.

Polystyrene-supported S)-2-(fluorodiphenylmeth l)pyrrolidine (la)

P-i = polystyrene li-Q water (65 ml_) was degassed under a stream of nitrogen during 3 h and polyvinyl alcohol (63 mg, 0.6 μηποΙ PvOH, MW 104500) was added. The mixture was dissolved upon heating this suspension at 80 °C during 4 h. After cooling the solution to 20 °C, sequential addition of monomer Ma (923 mg, 3.0 mmol) in 0.8 ml_ of toluene and styrene (3.5 ml_, 30.3 mmol) with AIBN (35 mg, 0.21 mmol) in 0.5 ml_ of toluene was carried out. After that, the mixture was stirred for 30 min at 20 °C.

The temperature was then raised to 80 °C and the reaction mixture was stirred vigorously for 38 h at 600 rpm. The resulting polymer beads were filtered and washed with hot water (50 °C) several times, then with methanol, THF and CH₂CI₂, followed by drying under reduced pressure at 40 °C, which afforded the desired cross-linked chiral polymer la (1 .95 g, 67% incorporation of monomer according to elemental analysis).

Elemental analysis for the first batch: %C, 85.60; %H, 7.33; %N, 1.45; %F, 1.02.

According to the nitrogen value in the EA, the functionalization level was 1 .03 mmol g^"1

Elemental analysis for the second batch: %C, 87.42; %H, 7.55; %N, 1 .13; %F, 1.29.

According to the nitrogen value in the EA, the functionalization level was 0.807 mmol g^"1 Elemental analysis for the third batch: %C, 84.85; %H, 7.19; %N, 1 .61 ; %F, 1 .78.

According to the nitrogen value in the EA, the functionalization level was 1 .1 15 mmol g^"1

IR (ATR): v = 3083, 3059, 3024, 2919, 2850, 1629, 1601 , 1492, 1450, 1 182, 987, 905, 826, 755, 697, 541 cm^-1.

RAMAN: v = 3057, 2908, 1629, 1602, 1582, 1 149, 1322, 1 182, 1030, 1001 , 795, 621 , 229.

Example 2: Michael addition reactions using catalyst (la) in batch conditions

O O R'

>L _{+ R}, /^ NO₂ !! ^ ^LLA_v/ NO₂

I additive (10 mol%) T

R solvent, rt R

IX X VIII A) Screening of additives and solvent

(E)-p-nitrostyrene (R -Ph, 22.4 mg, 0.15 mmol), catalyst la (10 mol%), additive (10 mol%) were weighed in a vial and 300 μΙ_ of solvent were added at room temperature, followed by propanal (R=CH₃, 33 μΙ_, 0.45 mmol). The suspension was stirred at room temperature for the specified time and filtered to separate the solid catalyst. The polymer was washed with CH2CI2 and the combined organic extracts were washed with 0.1 M NaOH (10 ml_) and concentrated under reduced pressure. A ¹ H NMR spectrum was acquired to calculate the conversion and the diastereomeric ratio (dr) and enantiomeric excess was measured by chiral HPLC. For volatile aldehydes, the Michael adduct was obtained as the evaporation residue without further purification. Table 1 summarizes the obtained results.

Table 1 : Screening of reaction conditions Entry Additive Solvent Time Conv. d.r. ee(%)

(h) (isolated

yield) (%)

1 - CH2CI2 1 1 100 (99) 96:4 94

2 CF3COOH CH2CI2 5 14 (n.d.) 67:33 -

3 2-fluorobenzoic CH2CI2 3.5 100 (97) 93:7 95

acid

4 (R)-mandelic CH2CI2 5 81 (n.d.) 85: 15 94

acid

5 PhCOOH CH2CI2 3.5 100 (98) 95:5 94

6 CH3CH2COOH CH2CI2 4 98 (n.d.) 96:4 94

7 4-nitrophenol CH2CI2 1 .5 100 (99) 95:5 95

8 4-nitrophenol Toluene 5 100 (98) 95:5 96

9 4-nitrophenol EtOAc 16 99 (n.d.) 95:5 93

10 4-nitrophenol THF 16 65 (n.d.) 93:7 92

1 1 4-nitrophenol H₂0 1 .5 100 (99) 95:5 95

12 4-nitrophenol CH2CI2 1 .5 100 (99) 95:5 95

Table 1 shows that the catalyst of the invention is useful with a broad scope of solvents (from polar to apolar and protic to aprotic) and using different kinds of additives.

B) Substrate scope study

Nitroalkene (0.15 mmol), catalyst la (10 mol%) and 4-nitrophenol (2.1 mg, 0.015 mmol) were weighed in a vial and CH2CI2 (0.3 ml_) was added, followed by the aldehyde (0.45 mmol). The suspension was stirred at room temperature for the specified time and filtered to separate the solid catalyst. The polymer was washed with CH2CI2 and the combined organic extracts were washed with 0.1 M NaOH (10 ml_) and concentrated under reduced pressure. A ¹ H NMR spectrum was acquired to calculate the conversion and the diastereomeric ratio (dr). For volatile aldehydes, the Michael adduct was obtained as the evaporation residue without further purification. In other cases, purification by flash chromatography on silica gel (eluent cyclohexane/EtOAc 20:1 to 4:1 ) afforded the Michael adduct compound VIII.

Table 2 shows the results obtained for the substrate scope study of the reaction.

18 i-Pr 4-Br-Ph 13 99 95:5 99

19 i-Pr 2-Br-Ph 1 1 .5 96 98:2 99

C) Recycling of catalyst la

95% ee The recycling experiment was performed by weighing (E)-p-nitrostyrene (41 mg, 0.275 mmol), 4-nitrophenol (3.9 mg, 0.028 mmol) and catalyst la (10 mol%) in a vial. Then, CH₂CI₂ (0.55 mL, 0.5 M) and propionaldehyde (60 μΙ, 0.83 mmol) were added and the reaction progress was monitored by gas chromatography until consumption of starting material. After that, the reaction mixture was filtered, and rinsed with 20 mL of CH₂CI₂. The polymer was dried and used directly in the next run. The filtrate was extracted with 0.1 M NaOH (20 mL), concentrated at reduced pressure and purified by column chromatography on silica gel to afford the Michael adduct VIII (whenever full conversion was achieved, the adduct could be isolated without additional purification). The results are presented in the following Table 3:

Run Time (h) Conversion (%) Yield (%)

1 1.5 100 99

2 2 100 98

3 2.5 100 97

4 4 100 98

5 6 100 97

6 12 84 83

7 24 100 97

8 24 70 68 The results of Table 3 show that the compound of formula la can be recycled as catalyst for Michael addition reactions. Similar results were obtained when the reaction was carried out under exposure to oxygen and in the presence of water, clearly demonstrating the robustness of such catalyst.

Example 3: Use of compound la as catalyst for Michael addition reactions under flow conditions

A) Flow production of (2 3S)-3-(4-bromophenyl)-2-methyl-4-nitrobutanal

8.87 g

(31.0 mmol, 95% yield) dr 95:5, 96% ee

Figure 1 shows the experimental set-up for the experiments related to the use of catalyst la in Michael additions under flow conditions.

For the continuous flow, dry CH₂CI₂ was degassed; a solution of 4-nitrophenol and frans-P-nitrostyrene (0.5 M in this CH₂CI₂) was prepared inside the glovebox. Addition of propionaldehyde and degassed H₂O was then performed under nitrogen. The flow process was set up under a nitrogen atmosphere (pressurized reservoir bottles).

An Omnigit glass column (1 cm internal diameter) was loaded with catalyst la (500 mg, 0.515 mmol, f = 1 .03 mmol g^_1 ). The column was assembled to an Asia120R flow chemistry system developed by Syrris. First, CH₂CI₂ was flushed for half an hour at 100 μΙ_ min^-1 flow rate to swell the resin. After that, the solvent channel was switched to the solution containing propionaldehyde (7.1 ml_, 98 mmol), 4-nitrophenol (1 .82 g, 13.1 mmol), frans-P-nitrostyrene (7.425 g, 32.6 mmol) and water (1.2 ml_, 65.1 mmol) in 65 ml_ CH₂CI₂. This feed mixture was pumped through the reactor at a flow rate of 0.1 ml_ min^-1. The reactor outlet was connected to a second pump fed with 0.1 M NaOH at 150 μΙ_ min^-1 flow rate. Further downstream, the resulting biphasic mixture was passed through a Zaiput liquid-liquid separator and the yellow aqueous phase was discarded. The organic phase was collected in a receiving flask.

With the set-up described, running the flow process at 100 μΙ_ min^-1, full conversions were obtained during the first 10 h. The following three hours, a slight decrease in conversion was observed, but the conversions remained above 97%.

Conversion and enantioselectivity of the formed product were determined by ¹H NMR and HPLC analysis of periodically collected samples. Figure 2 shows the evolution over time of conversion and enantiomeric excess of the product during this experiment. An overall yield of 95% could be obtained for this reaction (8.87 g, 31.0 mmol). This experiment shows that the compound la is a suitable catalyst for continuous flow applications.

B) Flow production of a library of compounds The set-up and the way to prepare the solutions were identical to the ones previously described (example 3-A), except that a different batch of catalyst la was used (500 mg, 0.575 mmol, f = 1 .15 mmol g^"1 ) as well as different compounds of formula X and IX. The solvent channel was fed with a mixture containing aldehyde (3 equiv.), 4- nitrophenol (0.4 equiv.), nitroalkene (1 equiv.) and water (2 equiv.) in CH2CI2 (0.5 M). Each of these feed mixtures was pumped through the reactor at a flow rate of 100 μΙ_ min^-1 during 30 min. The in-line work-up and separator replicated the one described above.

After pumping each solution for 30 min, the system was rinsed by pumping CH2CI2 for 1 h and the collected sample was evaporated. The same procedure was repeated for the next 8 samples. Then, the CH₂CI₂ flow rate was reduced to 25 μΙ_ min^-1 and the system was maintained like this for 10 h. The following day, the same procedure was applied to the next 5 samples. The column was again kept with CH₂CI₂ at 25 μΙ_ min^-1 before the last experiments.

The last three members of the library were prepared following the same procedure for a longer time (4 h at 100 μΙ_ min^-1 ).

Conversion and enantioselectivity of the formed product were determined by ¹H NMR and HPLC analysis of periodically collected samples. Table 4 summarizes the results obtained for the preparation of the compounds Vllla-Vlllm following this procedure.

Table 4 shows that the same sample of catalyst can be used in one sole run for the preparation of a broad range of compounds obtainable through the Michael addition reaction.

Claims

1 .- A compound of formula I:

I

wherein:

each R† independently represent or Cyi Pi ;

each P† independently represents a polymeric support;

each R₂ independently represents halogen, Ci^alkyl, C2-4alkenyl, C2-4alkynyl, CN, NO2, -OR3 or -SR3, wherein each Ci^alkyl, C2-4alkenyl, C2-4alkynyl are optionally substituted with one or more R4;

each R₃ independently represents H or Ci^alkyl; and

each R₄ independently represents, halogen, CN, NO2, -OR3 or -SR3.

2. - The compound according to claim 1 , wherein each Ri independently represents Cyi Pi .

3. - The compound according to any of claims 1 or 2, wherein each Pi is independently selected from a polyolefin, a polyurethane, a polyamide, a polycarbonate, a polyglycol, a polysaccharide, a polyester, a polysiloxane, mixtures thereof and co-polymers thereof.

4. - The compound according to claim 3, wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polyurethane (PU), nylon, polystyrene (PS), polystyrene cross-linked with divinylbenzene, polystyrene cross-linked with 1 ,4-bis(4-vinylphenoxy)butane, polystyrene cross-linked with divinylbenzene wherein at least one phenyl ring is substituted with polyethyleneglycol , polyethylene glycol (PEG), dextran, agarose, polytetrafluoroethylene (PTFE), polyvinylidene fluoride (PVDF), polynorbornene (PNB), polycarbonate (PC), polymethylmethacrylate (PMMA) polysiloxane , mixtures thereof and co-polymers thereof.

5. - The compound according to claim 4, wherein each Pi is independently selected from polyethylene (PE), polypropylene (PP), polystyrene (PS), polyethylene glycol (PEG), polynorbornene (PNB), mixtures thereof and copolymers thereof.

6. - The compound according to claim 5, wherein each Pi is polystyrene (PS).

7.- The compound according to any of claims 1 to 6, wherein each Cyi independently represent a monocyclic or bicyclic 6- to 10-membered carbocyclic ring, wherein Cyi is aromatic, wherein Cyi is bonded to the rest of the molecule through any available C atom, and wherein Cyi is optionally substituted with one or more F½.

8.- The compound according to claim 7, wherein each Cyi is independently selected from phenyl and naphthyl, and wherein Cyi is optionally substituted with one or more F½.

9.- The compound according to claim 8, wherein each Cyi is unsubstituted phenyl.

10.- The compound according to any of claims 1 to 9, which comprises from 0.5 to 2 mmoles of pyrrolidinyl moiety per gram of compound of formula I, and preferably which comprises from 0.7 to 1 .5 mmoles of pyrrolidinyl moiety per gram of compound of formula I.

1 1 .- A process to obtain the compound of formula I as defined in any of claims 1 to 10, wherein the process comprises the reaction between one or more compounds comprising a group selected from the groups of formula FGi and Cyi-FGi and a compound of formula II:

II

wherein:

R6 is selected from the groups of formula FG2 and Cyi-FG2;

R₇ is selected from the groups of formula FG₃ and CyrFG₃;

Cyi is as described in any of claims 1 to 10;

X is halogen or -OCi-₄alkyl.

12.- Use of the compound of formula I as defined in any of claims 1 to 10, as a catalyst.

13.- The use according to claim 12, characterized in that the catalyst is used under continuous flow.

14. - The use according to any of claims 12 or 13, characterized in that the catalyst is used in a Michael addition reaction.

15. - The use according to claim 14, wherein the Michael addition reaction is selected from the addition of aldehydes to β-nitroalkenes.