Polymer supported phosphoric acids and use thereof as catalysts in the preparation of 3-indolylmethanamines

The present invention relates to the field of catalysis, more particularly to the field of organocatalysis and to polymer supported phosphoric acid catalysts. It also relates to the use of these compounds in the preparation of 3- indolylmethanamines.

BACKGROUND ART

3-indolylmethanamines, and more particularly their chiral derivatives, are useful building blocks in the preparation of biologically active natural products and drugs, such as hydro-y-carboline, gramine, aspidospermine alkaloids and pyrido[4,3-b]indole derivatives. Therefore, chiral 3-indolylmethanamines are of particular industrial interest in the preparation of pharmaceutical products or crop protecting agents.

Additionally, organocatalysis is emerging as a powerful tool for the preparation of asymmetric molecules and useful chiral building blocks. Since no metal is required for substrate activation in this particular field of catalysis, it is particularly attractive for applications in the life science industry, as it avoids the use of expensive and toxic metals. Organocatalysis are commonly robust organic small molecules, stable under air and operating under aerobic conditions. When containing chiral information, these compounds can provide high stereoselectivities in a broad range of reactions. They are usually used in rather large amounts and are difficult to recycle and isolate from the reaction product. In that sense, numerous homogeneous organocatalysis comprising a phosphoric acid moiety and useful in the preparation of 3- indolylmethanamines have been reported. Organic phosphoric acid catalysts have also been reported for other applications (e.g. asymmetric hydrogenation reactions).

In particular, Kang and co-workers reported a family of chiral organic phosphoric acids that are useful organocatalysis for the preparation of 3- indolylmethanamine derivatives by Friedel-Crafts condensation of indole derivatives onto imines formed from aldehydes. High yields and

enantioselectivities were reported for the condensation of indole derivatives onto tosylated imines formed from aromatic aldehydes catalyzed by a broad range of chiral organic phosphoric acid catalysts, when the catalyst was used in 10 mol% amount and the reaction was carried out at low temperatures (e.g. -60 °C). Furthermore, it was shown that a decrease of the catalyst loading to 2 mol% provokes a decrease in the reaction yield and selectivity, indicating a low turnover number for this family of catalysts. Additionally, an excess of the indole derivative reagent, typically five equivalents with respect to the tosylated imines, was required so as to obtain high yields and selectivity and to avoid the formation of undesired side products.

On the other hand, the use of polymer supported organocatalysts is gaining interest, so as to allow a straightforward separation of a reaction product from the catalyst in the reaction mixture. Some efforts have been reported in the state of the art to support chiral organic phosphoric acids onto polymers.

In that sense, Rueping and co-workers have reported a polymer stick prepared by co-polymerization with styrene and divinylbenzene of a binaphthyl derived chiral phosphoric acid comprising a vinylphenyl radical either on positions 3 and 3' or on positions 6 and 6' of the naphthyl rings. The prepared compounds proved to be useful catalysts in the asymmetric hydrogenation of quinolone and benzoxazine derivatives with similar activity and selectivity as their non-polymer supported counterparts. The authors are however silent about the use of these compounds in the preparation of 3-indolylmethanamine compounds and in flow process applications. The morphology of the reported catalysts, i.e. polymer sticks, is also not suitable for continuous flow

applications, as the available active surface of the catalyst is low.

Further, Zheng and co-workers have reported highly porous chiral metal- organic frameworks as catalyst for Friedel-Crafts reactions between indole compounds and imine, Particularly, the catalyst is constructed from

[Cu(carboxylate) ₄ ]secondary building units (SBUs) and chiral 3,3', 6, 6'- or 4,4',6,6'-tetra(benzoate) ligands derived from 1 ,1 '-binaphthyl-2-2'phosphonic acid. The use of these catalysts allow obtaining the opposite chirality to those afforded by the corresponding homogeneous catalyst. However, the yield and the selectivity of the resulting 3-aminomethyl-indole derivate should be enhanced (Min Zheng et al. "Cavity-induced enantioselectivity reversal in a chiral metal-organic framework Bransted acid catalyst" Chemical Science. 2012, 3, 2623-2627).

In a different approach, Bleschke and co-workers have reported a binaphthyl derived phosphoric acid substituted at the 3 and 3' position with thienyl radicals, prompt to form small oligomers, thereby forming a microporous polymer comprising a chiral phosphoric acid. This compound proved to be active in the asymmetric reduction of benzoxazine derivatives, yet giving rise to such products in moderate enantioselectivity. The catalyst proved to be recyclable, achieving a total number of turnovers lower than 80. The authors are however silent about the use of this catalyst in continuous flow processes and in the preparation of 3-indolylmethanamine compounds.

From what is described in the state of the art, there is still the need for highly active, selective and recyclable chiral organic phosphoric acid catalysts supported onto a polymer and useful in the preparation of 3- indolylmethanamine derivatives, said catalysts being further suitable for continuous flow processes. SUMMARY OF THE INVENTION

The inventors have developed a family of compounds comprising chiral phosphoric acid derivatives linked to a polymeric support through a flexible linker, said compounds being useful as highly active and selective catalysts in the preparation of 3-indolylmethanamine compounds, and having the further advantage of being easily separated from the reaction mixture, recyclable without loss of activity or selectivity and suitable for continuous flow

applications. Thus, a first aspect of the invention refers to a chiral compound of formula (I) or a salt thereof

(I)

wherein:

X is S or O;

Y is selected from the group consisting of OH and a radical of formula - NHSO2R9, wherein R ₉ is selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)haloalkyl, phenyl and phenyl substituted with one or more groups selected from the group consisting of nitro, halogen and (Ci-C6)alkyl;

Ri and R2 are each independently selected from the group consisting of (Ce- C20 aryl); (C ₅ -C2o)heteroaryl; a radical of formula Si(Rio)3 wherein R ₀ is selected form the group consisting of phenyl and phenyl substituted with one or more group selected from the group consisting of nitro, halogen, (Ci- C6)haloalkyl and (Ci-Ce)alkyl; (C6-C2o)aryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (CrC6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, phenyl, halogen and a radical of formula (II); and (C ₅ -C2o)heteroaryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, phenyl, halogen and a radical of formula (II); the radical of formula (II) is

(II) wherein B and L are each a biradical independently selected from the group consisting of (Ci-C6)alkylene, phenylene, benzylene , -CH ₂ -C6H ₄ -CH ₂ - and biphenylene ; n is 0 or 1 ;

Z is a biradical linked to L and B selected from the group consisting of -O-, - S-, -CONR11-, -SO2NR11-, -NR11CO-, -NR11SO2- and -NR11-; wherein R is selected from the group consisting of H, (Ci-C6)alkyl, phenyl and benzyl;

Pol is a polymeric support;

R3 and R ₄ are each independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen; each of the pairs R ₅ and R6, and R ₇ and Rs, together with the carbon atoms to which they are attached, form a 6-membered carbocyclic ring A and a 6- membered carbocyclic ring A' respectively, said rings being independently saturated, partially unsaturated or aromatic and being optionally substituted with one or more groups selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci- C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen, and the substituent of the position 6 and 6' of the fused ring system formed by the 6-membered ring A or the 6-membered ring A' and the adjacent phenyl ring in the compound of formula (I) is further selected from a radical of formula (II); and with the proviso that the compound of formula (I) comprises at least one radical of formula (II). A second aspect of the invention refers to a process for the preparation of the compound as defined in the first aspect of the invention, which comprises the steps of:

(i) contacting a polymeric support with a chiral compound of formula (IV)

(IV) (ii) unprotecting the alcohols on the product obtained in (i);

(iii) treating the product obtained in (ii):

with phosphorus oxychloride when in the compound of formula (I), X is O; or, alternatively,

with thiophosphoryl chloride when, in the compound of formula (I), X is S;

(iv) treating the product obtained in (iii):

with water or alternatively with an acid, when in the compound of formula (I), Y is OH; or, alternatively,

with ammonia, when in the compound of formula (I), Y is a radical of formula - NSO2R9; and optionally

(v) when in the compound of formula (I), Y is a radical of formula -NSO2R9, then the process further comprises treating the compound obtained in (iv) with a compound of formula R9SO2CI . wherein, in the compound of formula (IV):

PG is an alcohol protecting group;

R22 and R23 are independently selected from the group consisting of (C6-C20 aryl); (C ₅ -C2o)heteroaryl; a radical of formula Si(Rio)3 wherein R ₀ is selected from the group consisting of phenyl and phenyl substituted with one or more group selected from the group consisting of nitro, halogen, (Ci-C6)haloalkyl and (Ci-C6)alkyl; (C6-C2o)aryl wherein one or more of the hydrogen atoms is replaced by one or more group selected from the group consisting of (Ci- C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, phenyl, halogen and a radical of formula (IT); and (C ₅ -C2o)heteroaryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (CrC6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, phenyl, halogen and a radical of formula (IT); the radical of formula (ΙΓ) is

FG. _B / (ΙΓ) B, R ₃ and R ₄ are as defined in any of the claims 1 to 9; and wherein each of the pairs F¾ ₄ and R25, and R26 and R27, together with the carbon atoms to which they are attached, form a 6-membered carbocydic ring D and a 6-membered carbocydic ring D' respectively, said rings being independently saturated, partially unsaturated or aromatic and optionally substituted with one or more groups selected from the group consisting of (Ci-C6)alkyl, (Ci- C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci- C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen, and the

substituent of the position 6 and 6' of the fused ring system formed by the 6- membered ring D or the 6-membered ring D' and the adjacent phenyl ring in the compound of formula (IV) is further selected from a radical of formula (IT); and with the proviso that the compound of formula (IV) comprises at least one radical of formula (IT); and wherein: when in the compound of formula (I), Z is -O-, then the polymeric support comprises at least a terminal halogen group and in the compound of formula (IV), FG is hydroxyl; or, alternatively, when in the compound of formula (I), Z is -S-, then the polymeric support comprises at least a terminal halogen group and in the compound of formula (IV), FG is a -SH radical; or, alternatively, when in the compound of formula (I), Z is -CONRn-, then the polymeric support comprises at least a terminal group selected from the group consisting of carboxylic acid and carboxylic acid chloride and in the compound of formula (IV), FG is a radical of formula NHRn; or, alternatively, when in the compound of formula (I), Z is -NRnCO-, then the polymeric support comprises at least a terminal group of formula NHRn and in the compound of formula (IV), FG is a group selected from the group consisting of carboxylic acid and carboxylic acid chloride; or, alternatively, when in the compound of formula (I), Z is -SO ₂ NR _{1 1} -, then the polymeric support comprises at least a terminal sulfonyl chloride group and in the compound of formula (IV), FG is a radical of formula NHRn; or, alternatively, when in the compound of formula (I), Z is -NR ₁₁ SO ₂ -, then the polymeric support comprises at least a terminal group of formula NHRn and in the compound of formula (IV), FG is a sulfonyl chloride group; or, alternatively, when in the compound of formula (I), Z is -NRn-, then the polymeric support comprises at least a terminal halogen group and in the compound of formula (IV), FG is a radical of formula NHRn; or, alternatively, the polymeric support comprises at least a terminal group of formula NHRn and in the compound of formula (IV), FG is halogen; being R selected from the group consisting of H, (Ci-C6)alkyl, phenyl and benzyl. When used as catalysts, the compounds of the invention are particularly active and selective in the preparation of 3-indolylmethanamine compounds by Friedel-Crafts condensation of indole derivatives onto imines. The compounds of the invention can be recycled without loss of activity and selectivity and are suitable for the preparation of 3-indolylmethanamine compounds in continuous flow conditions. Flow chemistry is increasingly perceived as a replacement technology for traditional batch processing. Thus, many negative issues associated to batch processing, such as solvent waste (mainly associated to work-up), thermal risk, and problems associated to scale-up are completely avoided in flow processing.

Thus, a third aspect of the invention refers to the use of the compound according to the first aspect of the invention as a catalyst.

The catalysts of the invention can be used under continuous flow conditions, i.e. by the injection into a reactor comprising the compound of the invention of a solution of reactants.

A fourth aspect of the invention relates to a process for the preparation of a 3- indolylmethanamine of formula (XI)

(XI)

which comprises contacting a compound of formula (IX) with a compound of formula (X) in the presence of a compound of formula (I) as defined in the first aspect of the invention

(IX) (X) wherein:

R30 is selected from the group consisting of hydrogen, (CrC6)alkyl, (Ci- C6)haloalkyl, (CrC6)alkylcarbonyl, (CrC6)alkyloxycarbonyl, and benzyl;

R31 , R32, R33, R34 and R35 are independently selected from the group consisting of hydrogen, cyclic ring, (C6-C2o)aryl, (C ₅ -C2o)heteroaryl, (Ci- C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, halogen, (C6-C2o)aryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci- C6)alkyloxycarbonyl, phenyl, and halogen; and (C ₅ -C2o)heteroaryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, phenyl, and halogen;

R36 is selected from the group consisting of hydrogen; (Ci-Ce)alkyl; (Ci- C6)haloalkyl; cyclic ring; (C6-C20 aryl); (C ₅ -C2o)heteroaryl; (C6-C2o)aryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, a radical of formula -CH=NSO2R37) and halogen; and (C ₅ -C2o)heteroaryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci- C6)alkyloxycarbonyl, a radical of formula -CH=NSO2R37) and halogen; and

R37 is selected from the group consisting of (Ci-Ce)alkyl; (Ci-C6)haloalkyl; cyclic ring; benzyl; (C6-C20 aryl); (C ₅ -C2o)heteroaryl; (C6-C2o)aryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen; and (C ₅ -C2o)heteroaryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci- C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (CrC6)alkylcarbonyl, (Ci- C6)alkylcarbonyloxy, (CrC6)alkyloxycarbonyl, and halogen; being cyclic ring a saturated, or partially unsaturated, 3- to 7-membered ring, or 3- to 7-membered ring bridged or fused with one or more 5 to 12 membered ring, saturated, or partially unsaturated, or aromatic, the members of the rings being selected from C, CH, CH ₂ , O, S, N and NH; being one or more of the hydrogen atoms of the members optionally substituted by a radical selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, (Ci- C6)alkoxy, nitro, cyano, (Ci-C6)alkylcarbonyl, and (Ci-Ce) alkyloxycarbonyl.

As mentioned above, the compounds of the invention comprise a flexible linker. Unlike the catalysts reported in the prior art, the compounds of the invention allow for the preparation of 3-indolylmethanamine compounds with good yields and enantioselectivities, even at room temperature and when a minor excess of the indole reagent is used. The compounds of the invention are also more active catalysts than those described in the prior art and can be used at lower loadings under flow conditions thanks to their robustness, therefore giving rise to high turnover numbers. Without being bound to theory, it is believed that the use of a flexible linker between the polymeric support and the chiral phosphoric acid moiety allows for a more flexible spatial arrangement of the system, thus giving rise to a synergistic effect between the asymmetric induction provided by the chiral phosphoric acid moiety and the hydrophobic environment created by the polymeric support.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows the evolution over time of the conversion, represented as triangles, and enantiomeric excess, represented as squares, both expressed as percentages, of aliquots of solution taken at the outlet of a reactor comprising the compounds of the invention and fed with a solution of reagents to produce (S)-N-((1 H-indol-3-yl)(p-tolyl)methyl)-4-methylbenzenesulfonamide. Y axis is expressed in percentage and X axis represents the time, expressed in hours.

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.

The term "chiral compound" refers to a compound which contains chiral information. In the context of the invention, the compound of formula (I) is chiral when the rotation around the bond linking the two phenyl rings comprised in the compound of formula (I) is energetically demanding, to such an extent allowing for the formation of enantiomers.

In the context of the invention, a "salt of a chiral compound of formula (I)" refers to a compound of formula (I) wherein the acidic hydrogen atom born by the oxygen or nitrogen atom of the Y radical has been replaced by a metal selected from the group consisting of indium, aluminium, manganese, copper, ruthenium, rhodium, palladium, silver, lithium, sodium, potassium, rubidium, caesium, magnesium, calcium, barium, beryllium and mixtures thereof.

The term "alkyl" refers to a saturated straight or branched hydrocarbon chain which contains the number of carbon atoms specified in the description or claims. Thus, the term "(Ci-C6)alkyl" refers to a saturated straight, or branched hydrocarbon chain containing from 1 to 6 carbon atoms. Examples include the group methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, terf-butyl, n- pentyl, neo-pentyl and n-hexyl.

The term "halogen", also referred to as halo, refers to fluoro, chloro, bromo or iodo.

The term (Ci-C6)haloalkyl refers to a group resulting from the replacement of one or more hydrogen atoms from a (Ci-Ce)alkyl group with one or more, preferably from 1 to 6, halogen atoms, which can be the same or different. Examples include, among others, trifluoromethyl, fluoromethyl, 1 -chloroethyl, 2-chloroethyl, 1 -fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2- trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3- tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl, and nonafluorobutyl.

The term "(C6-C2o)aryl" as used herein, whether used alone or as part of another group, is defined as a radical derived from one of the known ring systems with 1 -4 phenyl rings, having from 6 to 20 carbon atoms wherein each one of the phenyl rings forming said ring system is isolated or, partially or totally fused.

Non-limitative examples include phenyl, naphthyl, phenantryl, anthracenyl, biphenylyl and phenylylnaphthalene.

The term "(C ₅ -C2o)heteroaryl" as used herein, whether used alone or as part of another group, is defined as a radical derived from one of the known ring systems with 1 -4 5-membered or 6-membered aromatic rings, and having from 5 to 20 atoms, each member being independently selected from the group consisting of C, O, N, NH, S and CH, and wherein each one of the rings forming said ring system is isolated or, partially or totally fused.

Non-limitative examples include pyrrolyl, furyl, thiophenyl, pyrazolyl, indolyl, benzofuryl, benzothiofuryl, quinolyl, isoquinolyl, naphtyridyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, dithiolanyl, pyridyl, , pyridazinyl, pyrimidinyl, and pyrazinyl.

In preferred embodiments of the invention, when one or more of the hydrogen atoms of (C6-C2o)aryl, or phenyl, or cyclic ring, or (C ₅ -C2o)heteroaryl is replaced by a group, then the term "one or more" refers to "from 1 to 6". In more preferred embodiments the term "one or more" refers to "from 1 to 3".

The term "(Ci-C6)alkoxy" refers to an alkyloxy group, or a (Ci-Ce)alkyl-O- radical, having from 1 to 6 carbon atoms, the alkyl moiety having the same meaning as previously defined. Examples include, among others, methoxy, ethoxy, propoxy, isopropoxy, tert-butoxy, pentoxy and hexyloxy. The term "(Ci-C6)alkylcarbonyl" refers to a saturated straight or branched alkyi chain which contains from 1 to 6 carbon atoms, where the carbon atom is appended to the alkyi chain through a carbonyl group. Examples include acetyl, 1 -oxopropyl, 1 -oxoisobutyl and 1 -oxobutyl.

The term "(Ci-C6)alkyloxycarbonyl" refers to a saturated straight or branched alkyi chain which contains from 1 to 6 carbon atoms, where the carbon atom is appended to the alkyi chain through an oxycarbonyl group (-OCO). Examples include methylcarboxy, ethylcarboxy, propylcarboxy, isopropylcarboxy, butylcarboxy, terf-butylcarboxy, pentylcarboxy, and hexylcarboxy.

The term "(CrC6)alkylcarbonyloxy" refers to a saturated straight or branched alkyi chain which contains from 1 to 6 carbon atoms, where the carbon atom is appended to the alkyi chain through an carbonyloxy group (-COO). Examples include methanoyloxy, ethanoyloxy, propanoyloxy, isopropanoyloxy, butanoyloxy, terf-butanoyloxy, pentanoyloxy, and hexanoyloxy.

The term "(Ci-C6)alkylene" refers to a diradical resulting from the removal of one hydrogen atom of (Ci-Ce)alkyl.

The term "polymeric support" is art-recognized and refers to a soluble or insoluble polymer onto which the active unit is anchored directly or through a linker. Many suitable polymeric supports are known, and include soluble polymers such as polyethylene glycols or polyvinyl alcohols, as well as insoluble polymers such as polystyrene resins. In the context of the invention, the polymeric support can be porous. Non-limitative examples of polymeric support include polystyrene, cross-linked polystyrene with for example divinylbenzene, polyacrylate, polyacrylamide, polyvinylpyrrolidinone, polysiloxane, polybutadiene, polyisoprene, polyalkane, polyoxazoline, polyether, and mixtures and co-polymers thereof.

In the context of the invention, in the compounds of formula (I) and (IV), the position 6 or 6' of a fused ring system formed by a 6-membered ring and the adjacent phenyl ring refers to the position, available for substitution, according to lUPAC rules, numbered 6 or 6' as defined below, and wherein, in the compound of formula (I), the moiety of formula O2PXY is bound at positions 2 and 2', Ri and R2 at positions 3 and 3' respectively, and R3 and R ₄ at positions 4 and 4' respectively; or, alternatively, in the compound of formula (IV), the moiety of formula OPG is bound at positions 2 and 2', F½ and F¾ at positions 3 and 3' respectively, and R3 and R ₄ at positions 4 and 4' respectively:

The term "alcohol protecting group" is known in the art, and refers to a chemical moiety or group which protects or prevents an alcohol moiety or group from participating with or interfering with one or more chemical synthetic steps and its removal restores the moiety to its original active state. The term protecting group as used herein refers to those groups intended to protect against undesirable reactions during synthetic procedures. Such protecting groups are well known to those skilled in the art. Examples of alcohol protecting groups can be found in Wuts et al., "Greene's Protective Groups in Organic Chemistry", (Wiley, 4th ed. 2007, p.16-23). Protecting groups can be removed with inter alia acid, base, fluoride ions, hydrogenation, metals such as zinc as well as by numerous other methods which are well known in the art. One of ordinary skill in the art can readily choose an appropriate protecting group to facilitate synthetic reactions according to method aspects of the present invention without engaging in undue experimentation. Further non- limitative examples of alcohol protecting groups include: tri(Ci-C6)alkylsilyl, terf-butyldiphenylsilyl (TBDPS), benzyl (Bn), tetrahydropyranyl (THP), methoxymethyl (MOM), (Ci-C ₆ )alkyl, p-methoxybenzyl (PMB), benzoyl (Bz), and acetyl (Ac). 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.

In the context of the invention, the term "yield", refers to the ratio, expressed as a percentage, of the molar amount of a 3-indolylmethanamine produced to the molar amount of compound of formula (IX) engaged in the process of preparation of the 3-indolylmethanamine. 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 .

The terms "3-indolylmethanamines" or "3-indolylmethanamine compounds" or "3-indolylmethanamine derivatives" are used interchangeably and refer to a compound comprising the moiety resulting from the removal of 1 to 9 hydrogen atoms of the compound of formula

In the context of the invention, and when referred to as a substituent, the term "cyclic ring" refers to a saturated, or partially unsaturated, 3- to 7-membered ring, or 3- to 7-membered ring bridged or fused with one or more 5 to 12 membered ring, saturated, or partially unsaturated, or aromatic, the members of the rings being selected from C, CH, CH ₂ , O, S, N and NH; being one or more of the hydrogen atoms of the members optionally substituted by a radical selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)haloalkyl, halogen, (Ci-C6)alkoxy, nitro, cyano, (Ci-C6)alkylcarbonyl, and (Ci-Ce) alkyloxycarbonyl. Non-limitative examples include cyclopentyl, cyclohexyl, cyclopropyl, cyclobutyl, piperidinyl, fluorenyl, tetrahydrofuranyl, decalinyl, pyroll idinyl , tetrahydrothiophenyl and the like.

As mentioned above, the inventors have developed polymer supported organic phosphoric acid catalysts useful in the preparation of 3- indolylmethanamine compounds. The catalysts of the invention are robust, do not deactivate easily and can be separated from the reaction mixture by, for example, filtration or centrifugation. In particular, the inventors have found that the catalysts of the invention are useful in continuous flow applications, thanks to their high activity, selectivity and robustness. In contrast with the catalysts described in the state of the art for the preparation of 3-indolylmethanamine compounds, the catalysts of the invention provide higher reactivity and enantioselectivity and can be easily recycled and regenerated without loss of activity. The anchoring of the organic phosphoric acids onto a polymeric support via a flexible linker, as described in the catalysts of the invention, surprisingly enhances the activity of the catalyst and improves the chiral induction of the process. As a result, 3-indolylmethanamine compounds can be prepared in the presence of a minor excess of the indole reagent, at lower catalyst loadings, and with higher enantiomeric excesses. Furthermore, the catalysts of the invention can be easily recycled and regenerated and are thus suitable for continuous flow applications. The compounds of formula (I) are also robust towards moisture and oxygen and can be easily handled.

In a preferred embodiment of the first aspect of the invention, X is O.

In a preferred embodiment of the first aspect of the invention, Y is selected from the group consisting of -OH and a radical of formula -NSO2R9 wherein R9 is selected from the group consisting of methyl, trifluoromethyl, phenyl and tolyl. In a more preferred embodiment, Y is -OH or -NHSO2CF3. In an even more preferred embodiment, Y is -OH.

In a preferred embodiment of the first aspect of the invention, R ₃ and R ₄ are independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano and halogen. In a more preferred embodiment, R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, trifluoromethyl, nitro, cyano and halogen. In an even more preferred embodiment, R ₃ and R ₄ are each hydrogen. In a preferred embodiment of the first aspect of the invention, Ri and R2 are each independently selected from the group consisting of (C6-C20 aryl); (C ₅ - C2o)heteroaryl; a radical of formula Si(Rio)3 wherein R10 is selected from the group consisting of phenyl and phenyl substituted with one or more group selected from the group consisting of nitro, halogen, (Ci-C6)haloalkyl and (Ci- C6)alkyl; (C6-C2o)aryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (CrC6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, phenyl, and halogen; and (C ₅ -C2o)heteroaryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, phenyl, and halogen.

In a more preferred embodiment, Ri and F¾ are each independently selected from the group consisting of phenyl, naphthyl, anthracenyl, phenantrenyl, biphenylyl, phenylylnaphthalene, furyl, pyridyl, thiophenyl, pyrrolyl, indolyl, benzofuryl, benzothiofuryl, triazolyl, pyrimidyl, quinolyl, isoquinolyl,

naphthyridyl and a radical of formula Si(Rio)3 wherein Rio is selected from the group consisting of phenyl and phenyl substituted with (Ci-C6)alkyl, and wherein the phenyl, naphthyl, anthracenyl, phenantrenyl, biphenylyl, phenylylnaphthalene, furyl, pyridyl, thiophenyl, pyrrolyl, indolyl, indenyl , benzofuryl, benzothiofuryl, triazolyl, quinolyl, isoquinolyl, naphthyridyl and pyrimidyl groups are optionally substituted with one or more groups selected from the group consisting of nitro, (Ci-C6)alkyl, (Ci-C6)haloalkyl, phenyl and halo. In another embodiment, Ri and R2 are each independently selected from the group consisting of phenyl, naphthyl, anthracenyl, phenantrenyl and a radical of formula Si(Rio)3 wherein R10 is selected from the group consisting of phenyl and phenyl substituted with (Ci-C6)alkyl, and wherein the phenyl, naphthyl, anthracenyl, phenantrenyl groups are optionally substituted with one or more groups selected from the group consisting of nitro, (Ci-C6)alkyl, (Ci-

C6)haloalkyl, phenyl and halo.

In another embodiment, Ri and R2 are each independently selected from the group consisting of phenyl, naphthyl, anthracenyl, phenantrenyl and a radical of formula Si(Rio)3 wherein R10 is selected from the group consisting of phenyl and phenyl substituted with (Ci-C6)alkyl, and wherein the phenyl, naphthyl, anthracenyl, phenantrenyl groups are optionally substituted with one or more groups selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)haloalkyl and phenyl.

In another embodiment, Ri and F¾ are each independently selected from the group consisting of phenyl, naphthyl, anthracenyl, phenantrenyl and a radical of formula Si(Rio)3 wherein Rio is selected from the group consisting of phenyl and phenyl substituted with (Ci-C6)alkyl, and wherein the phenyl, naphthyl, anthracenyl, phenantrenyl groups are optionally substituted with one to three groups selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)haloalkyl and phenyl.

In another embodiment, Ri and R2 are each independently selected from the group consisting of phenyl, naphth-2-yl, anthracen-9-yl, phenantren-9-yl and a radical of formula Si(Rio)3 wherein R10 is selected from the group consisting of phenyl and 4-tert-butylphenyl, and wherein the phenyl, naphth-2-yl, anthracen- 9-yl, phenantren-9-yl groups are optionally substituted with one or more groups selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)haloalkyl and phenyl. In an even more preferred embodiment, Ri and R2 are each

independently selected from the group consisting of phenyl, naphth-2-yl, anthracen-9-yl, phenantren-9-yl and a radical of formula Si(Rio)3 wherein R10 is selected from the group consisting of phenyl and 4-terf-butylphenyl, and wherein the phenyl group is optionally substituted with one or more groups selected from the group consisting of methyl, trifluoromethyl, iso-propyl, tert- butyl and phenyl.

In a particular embodiment, Ri and R2 are each independently selected from the group consisting of phenyl, naphth-2-yl and a radical of formula Si(Rio)3 wherein R10 is selected from the group consisting of phenyl and 4-tert- butylphenyl, and wherein the phenyl group is optionally substituted with one or more groups selected from the group consisting of methyl, trifluoromethyl, iso- propyl, terf-butyl and phenyl. More particularly, Ri and R2 are each 3,5- trifluoromethylphenyl.

In a preferred embodiment of the first aspect of the invention, Ri and R2 are the same.

In another embodiment of the first aspect of the invention, Ri and R2 are each independently selected from the group consisting of phenyl, naphthyl, anthracenyl, phenantrenyl, biphenylyl, phenylylnaphthalene, furyl, pyridyl, thiophenyl, pyrrolyl, indolyl, benzofuryl, benzothiofuryl, triazolyl, pyrimidyl, quinolyl, isoquinolyl, naphthyridyl and a radical of formula Si(Rio)3 wherein Rio is selected from the group consisting of phenyl and phenyl substituted with (CrC6)alkyl, and wherein the phenyl, naphthyl, anthracenyl, phenantrenyl, biphenylyl, phenylylnaphthalene, furyl, pyridyl, thiophenyl, pyrrolyl, indolyl, indenyl, benzofuryl, benzothiofuryl, triazolyl, quinolyl, isoquinolyl, naphthyridyl and pyrimidyl groups are optionally substituted with one or more groups selected from the group consisting of nitro, (Ci-C6)alkyl, (Ci-C6)haloalkyl, phenyl and halogen;

R3 and R ₄ are hydrogen; and

X is O. In a preferred embodiment of the first aspect of the invention, Ri and R2 are each independently selected from the group consisting of phenyl, naphthyl, anthracenyl, phenantrenyl, biphenylyl, phenylylnaphthalene, furyl, pyridyl, thiophenyl, pyrrolyl, indolyl, benzofuryl, benzothiofuryl, triazolyl, pyrimidyl, quinolyl, isoquinolyl, naphthyridyl and a radical of formula Si(Rio)3 wherein R10 is selected from the group consisting of phenyl and phenyl substituted with (Ci-C6)alkyl, and wherein the phenyl, naphthyl, anthracenyl, phenantrenyl, biphenylyl, phenylylnaphthalene, furyl, pyridyl, thiophenyl, pyrrolyl, indolyl, indenyl, benzofuryl, benzothiofuryl, triazolyl, quinolyl, isoquinolyl, naphthyridyl and pyrimidyl groups are optionally substituted with one or more groups selected from the group consisting of nitro, (Ci-C6)alkyl, (Ci-C6)haloalkyl, phenyl and halogen;

R3 and R ₄ are hydrogen;

X is O; and

In another embodiment of the first aspect of the invention, each of the pairs R ₅ and R6, and R ₇ and Rs, together with the carbon atoms to which they are attached, form a 6-membered carbocyclic ring A and a 6-membered

carbocyclic ring A' respectively, said rings being independently saturated or aromatic and optionally substituted with one or more groups selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen, and the substituent of the position 6 and 6' of the fused ring system formed by the 6-membered ring A or the 6-membered ring A' and the adjacent phenyl ring in the compound of formula (I) is further selected from a radical of formula (II), wherein the radical of formula (II) is as described above

In a further embodiment of the first aspect of the invention, the compound of formula (I) is a compound of formula (III)

(III) wherein Ri ₂ , Ri ₄ , R15, R12', RM' and R15' are independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci- C6)alkyloxycarbonyl, and halogen;

Ri, R2 _, Rs and R ₄ are as defined in the first aspect of the invention,

Ri3 and R13' are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, halogen and a radical of formula (II) as defined above; and

with the proviso that the compound of formula (III) comprises at least one radical of formula (II). The compound of formula (III) is the compound of formula (I) wherein each of the pairs R ₅ and R6, and R ₇ and Rs, together with the carbon atoms to which they are attached, form a phenyl ring A and a phenyl ring A' respectively, said rings being optionally substituted with one or more groups selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen, and the substituent at position 6 of the fused ring system formed by the phenyl ring A or the phenyl ring A' and the adjacent phenyl ring in the compound of formula (I) is further selected from a radical of formula (II), wherein the radical of formula (II) is as described above.

In a further embodiment of the first aspect of the invention, the compounds of formula (I) are selected from the group consisting of the compounds of formula (III) as defined above

wherein Ri ₂ , Ri ₄ , R15, R12', RM' and R15' are independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci- C6)alkyloxycarbonyl, and halogen; Ri and R2 are each independently selected from the group consisting of phenyl, naphthyl, anthracenyl, phenantrenyl, biphenylyl, phenylylnaphthalene, furyl, pyridyl, thiophenyl, pyrrolyl, indolyl, benzofuryl, benzothiofuryl, triazolyl, pyrimidyl, quinolyl, isoquinolyl,

naphthyridyl and a radical of formula Si(Rio)3 wherein R10 is selected from the group consisting of phenyl and phenyl substituted with (Ci-Ce)alkyl, and wherein the phenyl, naphthyl, anthracenyl, phenantrenyl, biphenylyl, phenylylnaphthalene, furyl, pyridyl, thiophenyl, pyrrolyl, indolyl, indenyl, benzofuryl, benzothiofuryl, triazolyl, quinolyl, isoquinolyl, naphthyridyl and pyrimidyl groups are optionally substituted with one or more groups selected from the group consisting of nitro, (Ci-Ce)alkyl, (Ci-C6)haloalkyl, phenyl and halogen; R13 and R13' are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, halogen and a radical of formula (II) as defined above; and with the proviso that at least one of R13 and R13' is a radical of formula (II).

In a further embodiment of the first aspect of the invention, the compound of formula (I) is a compound of formula (III) as defined above;

wherein Ri ₂ , RM, R15, R12', RM' and R15' are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci- C6)alkyloxycarbonyl, and halogen; R13 and R13' are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci- C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci- C6)alkyloxycarbonyl, halogen and a radical of formula (II) as defined above and with the proviso that one of R13 and R13' is a radical of formula (II). In a further embodiment of the first aspect of the invention, the compound of formula (I) is a compound of formula (III) as defined above;

wherein Ri ₂ , Ri ₄ , R15, R12', R14' and R15' are independently selected from the group consisting of hydrogen, methyl, methoxy, trifluoromethyl, nitro, cyano, and halogen; R13 and R13' are independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, halogen and a radical of formula (II) as defined above and with the proviso that one of R13 and R13' is a radical of formula (II).

In an even further embodiment of the first aspect of the invention, the compound of formula (I) is a compound of formula (III) as defined above;

wherein Ri ₂ , RM, R15, R12', RM' and R15' are hydrogen; R13 and R13' are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-

C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, halogen and a radical of formula (II) as defined above and with the proviso that one of R13 and R13' is a radical of formula (II). In an even further embodiment of the first aspect of the invention, the compound of formula (I) is a compound of formula (III) as defined above;

wherein Ri and R2 are the same; R12, Ri ₄ , R15, R12', R14' and R15' are hydrogen; R13 and R13' are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, halogen and a radical of formula (II) as defined above and with the proviso that one of Ri3 and R13' is a radical of formula (II).

In another embodiment of the first aspect of the invention, in the radical of formula (II), Z is a biradical linked to B and L selected from the group consisting of -O-, -S-, -NRn-, -NR11SO2- and -SO2NR11-, wherein R is as defined in the first aspect of the invention. Preferably, in the radical of formula (II), Z is a biradical linked to B and L selected from the group consisting of -O- and -SO2NR11-, wherein R is as defined in the first aspect of the invention. Even more preferably, in the radical of formula (II), Z is -O-.

In a further embodiment of the first aspect of the invention, in the radical of formula (II), B and L are each a biradical independently selected from the group consisting of methylene -CH ₂ -, ethylene -CH ₂ -CH ₂ -, phenylene -CeH -, benzylene -CH ₂ -C6H -, and -CH ₂ -C6H -CH ₂ -. In an even further embodiment, B and L are each a biradical independently selected from the group consisting of methylene -CH ₂ -, phenylene -CeH ₄ -, benzylene -CH ₂ -C6H ₄ -, and -CH ₂ -C6H ₄ - CH ₂ -. In an even further embodiment, B and L are each a biradical

independently selected from the group consisting of methylene -CH ₂ -, phenylene -CeH - and benzylene -CH ₂ -C6H -. In an even further embodiment, B and L are each a methylene biradical.

In a further embodiment of the first aspect of the invention, in the radical of formula (II), L and B are independently selected from the group consisting of the group consisting of methylene, phenylene and benzylene; and Z is selected from the group consisting of -O- and -NSO ₂ Rn-, wherein R is as defined in the first aspect of the invention .

In a particular embodiment of the first aspect of the invention, in the radical of formula (II), n is 1 . In another particular embodiment of the first aspect of the invention, in the radical of formula (II), Pol is a polymeric support comprising a polymer selected from the group consisting of polystyrene, a polyacrylate, a

polyacrylamide, a polyvinylpyrrolidinone, a polysiloxane, a polybutadiene, a polyisoprene, a polyalkane, a polyoxazoline, a polyether, mixtures and co- polymers thereof. Particularly, Pol is polystyrene, and more particularly Pol is a cross-linked polystyrene-divinylbenzene polymer. In this particular embodiment, the polymeric support is a cross-linked polystyrene- divinylbenzene polymer wherein the polymer comprises from 0.5 to 2 weight% of divinylbenzene. Such polymers are porous and are known in the art with the commercial name of Merrifield resin.

In a particular embodiment of the first aspect of the invention, the compound of formula (I) comprises from 0.01 to 5 millimoles of the moiety of formula - O ₂ PXY per gram of the compound of formula (I). More particularly, the compound of formula (I) comprises from 0.05 to 2 millimoles of the moiety of formula O ₂ PXY per gram of the compound of formula (I). Even more particularly, the compound of formula (I) comprises from 0.1 to 1 millimole of the moiety of formula O2PXY per gram of the compound of formula (I).

In a particular embodiment of the first aspect of the invention, the compound of formula (I) is selected from the group consisting of the compounds of formula (Ilia), (1Mb), (lllc), (Mid), (llle), (lllf), (lllg), (lllh) and (llli)

(nig) (lllh) (mi) wherein

R16 is a radical selected from the group consisting of hydrogen, nitro, chloro, naphth-2-yl, phenyl, 3,5-(ditrifluoromethyl)phenyl, tolyl, terf-butyl,

trifluoromethyl and isopropyl;

Ri 7 and R18 are each independently selected from the group consisting of hydrogen, methyl, isopropyl, terf-butyl, and trifluoromethyl;

Rig and R20 are each trifluoromethyl or phenyl; and

R21 is selected from the group consisting of phenyl and terf-butyl phenyl. In a more particular embodiment of the first aspect of the invention, the compound of formula (I) is selected from the group consisting of the

compounds of formula (Ilia), (lllb), (lllc), (llld), (llle), (lllf), (lllg), (lllh) and (llli), wherein Z is O.

In a more particular embodiment of the first aspect of the invention, the compound of formula (I) is selected from the group consisting of the

compounds of formula (Ilia), (lllb), (lllc), (llld), (llle), (lllf), (lllg), (lllh) and (llli), wherein Z is O and B and L are methylene.

In a more particular embodiment of the first aspect of the invention, the compound of formula (I) is selected from the group consisting of the

compounds of formula (Ilia), (lllb), (lllc), (llld), (llle), (lllf), (lllg), (lllh) and (llli), wherein Z is O; B and L are methylene and Pol is a polystyrene- divinylbenzene cross-linked polymer.

In another particular embodiment, the compound of formula (I) is a compound of formula (lllh) as defined above wherein R ₂ o is trifluoromethyl.

More particularly, the compound of formula (I) is a compound of formula (lllh) as defined above, wherein Z is -O-; B and L are methylene, and wherein R ₂ o is trifluoromethyl. Even more particularly, the compound of formula (I) is a compound of formula

(lllh) as defined above, wherein Z is -O-; B and L are methylene, R ₂ 0 is trifluoromethyl; and Pol is a polystyrene-divinylbenzene cross-linked polymer.

The beneficial contribution of the catalysts of the invention in the preparation of a 3-indolylmethanamine is an enhanced reactivity (higher turnover numbers can be achieved) in the presence of a lower excess amount of reagents (e.g. indole derivative), along with an improved enantioselectivity with respect to the catalysts of the prior art. According to the second aspect, the invention provides a process for the preparation of the catalysts of the invention. In preferred embodiments of the second aspect, in the compounds of formula (IV) used in step (i), R3 and R ₄ are as defined in any of the embodiments of the first aspect of the invention. In further preferred embodiments of the second aspect of the invention, PG is selected from the group consisting of benzyl, a radical of formula Si[(Ci- C6)alkyl] ₃ and methoxymethyl. More preferably, PG is methoxymethyl.

In a preferred embodiment of the second aspect of the invention, in the compound of formula (IV) used in step (i), F½ and F¾ are each independently selected from the group consisting of (C6-C20 aryl); (C ₅ -C2o)heteroaryl; a radical of formula Si(Rio)3 wherein R10 is selected from the group consisting of phenyl and phenyl substituted with a group selected from the group consisting of nitro, halogen, (Ci-C6)haloalkyl and (Ci-C6)alkyl; (C6-C2o)aryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, phenyl, and halogen; and (C ₅ -C2o)heteroaryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci- C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, phenyl, and halo.

In another embodiment of the second aspect of the invention, in the

compound of formula (IV) used in step (i) R22 and R23 are each independently selected from the group consisting of phenyl, naphthyl, anthracenyl, phenantrenyl and a radical of formula Si(Rio)3 wherein R10 is selected from the group consisting of phenyl and phenyl substituted with (Ci-Ce)alkyl, and wherein the phenyl, naphthyl, anthracenyl, phenantrenyl groups are optionally substituted with one or more groups selected from the group consisting of nitro, halogen, (Ci-Ce)alkyl, (Ci-Ce)haloalkyl and phenyl.

In another embodiment, R22 and R23 are each independently selected from the group consisting of phenyl, naphth-2-yl, anthracen-9-yl, phenantren-9-yl and a radical of formula Si(Rio)3 wherein R10 is selected from the group consisting of phenyl and 4-tert-butylphenyl, and wherein the phenyl group is optionally substituted with one or more groups selected from the group consisting of methyl, trifluoromethyl, iso-propyl, terf-butyl and phenyl. In a particular embodiment, F½ and F¾ are each independently selected from the group consisting of phenyl, naphth-2-yl and a radical of formula Si(Rio)3 wherein Rio is selected from the group consisting of phenyl and 4-tert- butylphenyl, and wherein the phenyl group is optionally substituted with one or more groups selected from the group consisting of methyl, trifluoromethyl, iso- propyl, terf-butyl and phenyl. More particularly, F½ and F¾ are each 3,5- trifluoromethylphenyl. In a preferred embodiment of the second aspect of the invention, F½ and F¾ are the same.

In another embodiment of the second aspect of the invention, in the

compound of formula (IV) used in step (i), each of the pairs F¾ ₄ and R25, and R26 and R27, together with the carbon atoms to which they are attached, form a 6-membered carbocyclic ring D and 6-membered carbocyclic ring D' respectively, said rings being independently saturated or aromatic and optionally substituted with one or more groups selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (CrC6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen, and the substituent at position 6 of the fused ring system formed by the 6-membered ring D or the 6-membered ring D' and the adjacent phenyl ring in the compound of formula (IV) is further selected from a radical of formula (ΙΓ) as defined in the second aspect of the invention.

In a further embodiment of the second aspect of the invention, the compound of formula (IV) used in step (i) is a compound of formula (VI)

(VI) wherein R ₃ , R ₄ , R12, Ri4, R15, R12', R14' and R15' are as defined in any embodiment of the first aspect of the invention;

R22 and R23 are as defined above; and

R28 and R29 are independently selected from the group consisting of hydrogen, (CrC6)alkyl, (Ci-C6)alkyloxy, (CrC6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, halogen and a radical of formula (ΙΓ) as defined in the second aspect of the invention; and with the proviso that the compound of formula (VI) comprises at least one radical of formula (ΙΓ).

The compound of formula (VI) is a compound of formula (IV) wherein each of the pairs R2 ₄ and R25, and R26 and R27, together with the carbon atoms to which they are attached, form a phenyl ring D and phenyl ring D' respectively, said rings being optionally substituted with one or more groups selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen, and the substituent at position 6 of the fused ring system formed by the phenyl ring D or the phenyl ring D' and the adjacent phenyl ring in the compound of formula (IV) is further selected from a radical of formula (ΙΓ) as defined in the second aspect of the invention.

In an even further embodiment of the second aspect of the invention, the compound of formula (IV) used in step (i) is a compound of formula (VI) as defined above; wherein R22 and R23 are the same; R12, Ri ₄ , R15, R12', RM' and R15' are hydrogen; R ₂ s and R29 are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, halogen and a radical of formula (Ι ) as defined above and with the proviso that one of R28 and R29 is a radical of formula (ΙΓ).

In a preferred embodiment of the second aspect of the invention, in the radical of formula (ΙΓ), FG is selected from the group consisting of the radicals of formula -OH, -SH, -NHRn , -COOH, -COCI and -SO ₂ CI; wherein R is selected from the group consisting of H, (Ci-Ce)alkyl, phenyl and benzyl.

In a further embodiment of the second aspect of the invention, the polymeric support comprises at least a terminal group selected from the group consisting of halogen, -NHRn , -COOH, -COCI and -SO ₂ CI; wherein R is selected from the group consisting of H, (Ci-C6)alkyl, phenyl and benzyl. According to the second aspect of the invention, when, in the compound of formula (I), Z is -O-, then the polymeric support used in step (i) comprises at least a terminal halogen group; and, in the compound of formula (IV), FG is hydroxyl. Similarly, when, in the compound of formula (I), Z is -S-, then the polymeric support used in step (i) comprises at least a terminal halogen group; and, in the compound of formula (IV), FG is -SH.

Similarly, when, in the compound of formula (I), Z is -CONRn-, then the polymeric support used in step (i) comprises at least a terminal group selected from the group consisting of -COOH or -COCI; and, in the compound of formula (IV), FG is -HNRn .

Similarly, when in the compound of formula (I), Z is -NRnCO-, then the polymeric support used in step (i) comprises at least a terminal group of formula -HNRn ; and, in the compound of formula (IV), FG is selected from the group consisting of -COOH or -COCI.

Similarly, when, in the compound of formula (I), Z is -SO2NR11-, then the polymeric support used in step (i) comprises at least a terminal group of formula -SO2CI; and, in the compound of formula (IV), FG is -HNRn .

Similarly, when, in the compound of formula (I), Z is -NR11SO2-, then the polymeric support used in step (i) comprises at least a terminal group of formula -HNRn ; and, in the compound of formula (IV), FG is of formula -

SO2CI .

Similarly, when, in the compound of formula (I), Z is -NRn-, then the polymeric support used in step (i) comprises at least a terminal halogen group; and, in the compound of formula (IV), FG is -HNRn ; or, alternatively, the polymeric support used in step (i) comprises at least a terminal group of formula -HNRn ; and, in the compound of formula (IV), FG is halo. In most preferred embodiments, the polymeric support comprises at least a halogen group; and, in the compound of formula (IV), FG is hydroxyl. More preferably, the halogen group is selected from the group consisting of chloride, bromide and iodide.

According to the second aspect of the invention, step (ii) of the preparation of the compound of formula (I) comprises unprotecting the alcohols in the product obtained in (i). Suitable methods to carry out this deprotection step are well known in the art and will become apparent to the skilled in the art. For instance, when PG is benzyl, a suitable deprotection method of the alcohols is catalytic hydrogenation, preferably in the presence of a palladium catalyst. Alternatively, when PG is benzoyl, a suitable deprotection method of the alcohols comprises treating the compound obtained in (i) with water, preferably in basic medium. Alternatively, when PG is a radical of formula Si[(Ci-C6)alkyl] ₃ as described above, a suitable deprotection method comprises treating the compound obtained in (i) with fluoride anions or in acidic medium. Alternatively, when OPG is an ether, such as methoxy (when PG is methyl) or methoxymethyl (when PG is methoxymethyl), a suitable deprotection method comprises treating the compound obtained in (i) in acidic medium.

According to the second aspect of the invention, step (iii) of the preparation of the compound of formula (I) comprises reacting the compound obtained in step (ii) with phosphorus oxychloride or thiophosphoryl chloride. When, in the compound of formula (I), X is O, then step (iii) of the preparation of the compound of formula (I) comprises reacting the compound obtained in step (ii) with phosphorus oxychloride. When, in the compound of formula (I), X is S, then step (iii) of the preparation of the compound of formula (I) comprises reacting the compound obtained in step (ii) with thiophosphoryl chloride.

Step (iv) of the preparation of the compound of formula (I) comprises reacting the compound obtained in step (iii) with water or ammonia. When, in the compound of formula (I), Y is OH, then step (iv) of the preparation of the compound of formula (I) comprises reacting the compound obtained in step (iii) with water. When, in the compound of formula (I), Y is a radical of formula -NSO2R9, then step (iv) of the preparation of the compound of formula (I) comprises reacting the compound obtained in step (iii) with ammonia.

Optionally, when, in the compound of formula (I), Y is a radical of formula - NSO2R9, then the preparation of the compound of formula (I) further comprises reacting the compound obtained in step (iv) with a compound of formula R ₉ SO ₂ CI.

The inventors have found that the catalysts of the invention are useful in the preparation of 3-indolylmethanamine derivatives by Friedel-Crafts

condensation of indole derivatives onto imines. In particular, the resulting performance, ease of recovery and robustness of the catalysts of the invention makes them suitable for the preparation of 3-indolylmethanamines. Thus, in a preferred embodiment of the third aspect, the compound of formula (I) is used as a catalyst in the preparation of a 3-indolylmethanamine.

In a particular embodiment of the fourth aspect of the invention, the process for the preparation of a 3-indolylmethanamine is a continuous flow process.

Being non-soluble in the reaction solvent, the compounds of the invention can be incorporated into a reactor, preferably a tubular reactor or a column, through which a solution of the reagents is pumped in, thereby allowing the catalysed reaction to occur and high turnover numbers to be reached. This is advantageous as it allows for the highly productive, continuous and non- stopping preparation of the products in high yields and enantioselectivity. Such column or reactor filled with the compound of the invention is also part of the invention. Additionally, this allows for the high-yielding and selective preparation of a large number of compounds in a reduced amount of time, by carrying out the following steps in a sequential manner:

(i) inject the solution(s) of reagents into the reactor;

(ii) collect the product at the outlet of the reactor;

(iii) wash the reactor with a solvent; and

(iv) carry out steps (i), (ii) and (iii) with different reagents than the reagents used in (i). In a particular embodiment, the fourth aspect of the invention relates to a process for the preparation of a 3-indolylmethanamine of formula (XI) wherein, in the compound of formula (X), R30 is selected from hydrogen, (Ci-C6)alkyl, and benzyl. More particularly, R ₃ o is hydrogen.

In another particular embodiment, the fourth aspect of the invention relates to a process for the preparation of a 3-indolylmethanamine of formula (XI) wherein, in the compound of formula (X), R31 , R32, R33, R34 and Rss are selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen. More particularly, R31 , R32, and R35 are hydrogen. In another particular embodiment, the fourth aspect of the invention relates to a process for the preparation of a 3-indolylmethanamine of formula (XI) wherein, in the compound of formula (IX), R37 is selected from the group consisting of (Ci-Ce)alkyl; (Ci-C6)haloalkyl; benzyl; fluorenyl; phenyl; pyridyl; phenyl substituted with one or more group selected from the group consisting of (Ci-C ₆ )alkyl, (Ci-C ₆ )alkyloxy, (Ci-C ₆ )haloalkyl, nitro, cyano, (Ci-

C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen; and pyridyl substituted with one or more group selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen. More particularly, R ₃₇ is selected from the group consisting of

(Ci-C6)alkyl, phenyl, tolyl, benzyl, fluorenyl and pyridyl.

In another particular embodiment, the fourth aspect of the invention relates to a process for the preparation of a 3-indolylmethanamine of formula (XI) wherein, in the compound of formula (IX), R36 is selected from the group consisting of (C6-C20 aryl); (C ₅ -C2o)heteroaryl; (C6-C2o)aryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, a radical of formula -CH=NSO2R3 ₇ and halogen; and (C ₅ -C2o)heteroaryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, a radical of formula and halogen; and R3 ₇ is as defined above.

In preferred embodiments of the fourth aspect of the invention, the invention relates to a process for the preparation of a 3-indolylmethanamine of formula (V), which comprises contacting a compound of formula (VII) with a compound of formula (VIII) in the presence of a compound of formula (I);

(V) (VII) (VIII) wherein:

Ar is selected from the group consisting of (C6-C20 aryl); (C ₅ -C2o)heteroaryl; (C6-C2o)aryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci- C6)haloalkyl, nitro, cyano, (CrC6)alkylcarbonyl, (CrC6)alkylcarbonyloxy, (Ci- C6)alkyloxycarbonyl, a radical of formula -CH=NSO2R and halogen; and (C ₅ - C2o)heteroaryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci- C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci- C6)alkyloxycarbonyl, a radical of formula -CH=NSO2R and halogen;

R is selected from the group consisting of phenyl, tolyl, fluorenyl, 2-pyridyl, benzyl, and terf-butyl; and

R' and R" are independently selected from the group consisting of hydrogen, (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen.

The compound of formula (VII) is a compound of formula (X) wherein R ₃₀ , R31 , R32 and R3 ₅ are hydrogen; and R33 and R3 ₄ are independently selected from the group consisting of hydrogen, (CrC6)alkyl, (Ci-C6)alkyloxy, (Ci- C6)haloalkyl, nitro, cyano, (CrC6)alkylcarbonyl, (CrC6)alkylcarbonyloxy, (Ci- C6)alkyloxycarbonyl, and halogen. The compound of formula (VIII) is a compound of formula (IX) wherein:

R36 is selected from the group consisting of (C6-C20 aryl); (C ₅ -C2o)heteroaryl; (C6-C2o)aryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-C6)alkyl, (Ci-C6)alkyloxy, (Ci- C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci- C6)alkyloxycarbonyl, a radical of formula -CH=NSO2R and halogen; and (C ₅ - C2o)heteroaryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci- C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci- C6)alkyloxycarbonyl, a radical of formula -CH=NSO2R and halogen; and

R37 is selected from the group consisting of phenyl, tolyl, fluorenyl, 2-pyridyl, benzyl, and terf-butyl.

The compound of formula (V) is a compound of formula (XI) wherein:

R30, R31 , R32 and R35 are hydrogen; and R33 and R3 ₄ are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, and halogen; R ₃ 6 is selected from the group consisting of (C6-C20 aryl); (C ₅ -C2o)heteroaryl; (C6-C2o)aryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci- C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, a radical of formula -CH=NSO2R3 ₇ and halogen; and (C ₅ -C2o)heteroaryl wherein one or more of the hydrogen atoms is replaced by a group selected from the group consisting of (Ci-Ce)alkyl, (Ci-C6)alkyloxy, (Ci-C6)haloalkyl, nitro, cyano, (Ci-

C6)alkylcarbonyl, (Ci-C6)alkylcarbonyloxy, (Ci-C6)alkyloxycarbonyl, a radical of formula -CH=NSO2R37 and halogen; and

R37 is selected from the group consisting of phenyl, tolyl, fluorenyl, 2-pyridyl, benzyl, and terf-butyl.

In more preferred embodiments of the fourth aspect of the invention, in the compound of formula (V), Ar is selected from the group consisting of phenyl, 4-chlorophenyl, 4-bromophenyl, 4-tolyl, 3-tolyl, 2-tolyl, 4-methoxyphenyl, 2- tosylforminnidatophenyl and 4-nitrophenyl.

In more preferred embodiments of the fourth aspect of the invention, in the compound of formula (V), R is selected from the group consisting of phenyl, tolyl, and 2-pyridyl.

In more preferred embodiments of the fourth aspect of the invention, in the compound of formula (V), R' and R" are each independently selected from the group consisting of hydrogen, methoxy, methyl, bromo and chloro.

In a preferred embodiment of the fourth aspect of the invention, the molar ratio of the compound of formula (X) to the compound of formula (IX) is comprised from 1 :1 to 3:1 ; more preferably from 1 :1 to 2:1 .

Using the catalysts described in the state of the art, a 3-indolylmethanamine of formula (XI) can be prepared by reacting a compound of formula (IX) with a compound of formula (X) using a molar ratio of the compound of formula (X) to the compound of formula (IX) of 5:1 . Thus, the catalysts of the invention allow decreasing the amount of excess compound of formula (X) in the preparation of a 3-indolylmethanamine without observing the formation of undesired side products.

In preferred embodiments, the preparation of a 3-indolylmethanamine of formula (XI) described above comprises contacting a compound of formula (X) with a compound of formula (IX) in the presence of the compound of formula (I) at room temperature, preferably at a temperature comprised from 10 °C to 30°C. Even when used at room temperature or at a temperature comprised from 10

°C to 30 °C, in the preparation of 3-indolylmethanamines of formula (XI), the catalysts of the invention provide high yields and enantioselectivity.

In a more preferred embodiment, the fourth aspect of the invention relates to a process for the preparation of a 3-indolylmethanamine of formula (XI) wherein the molar ratio of the compound of formula (X) to the compound of formula (IX) is comprised from 1 :1 to 3:1 ; and the process is carried out at a temperature comprised from 10 °C to 30 °C.

In preferred embodiments, the preparation of a 3-indolylmethanamine of formula (XI) described above comprises contacting a compound of formula (X) with a compound of formula (IX) in the presence of the compound of formula (I), wherein the amount of the compound of formula (I) is such that the amount of the moiety of formula Y in the compound of formula (I) is comprised from 0.5 to 10 moles per each 100 moles of compounds of formula (IX). It is advantageous since the catalysts of the invention can be used in minor amounts than the ones described in the state of the art.

In preferred embodiments, the preparation of a 3-indolylmethanamine of formula (XI) described above comprises contacting a compound of formula (X) with a compound of formula (IX) in the presence of a polar aprotic solvent. In the context of the invention, a polar aprotic solvent is polar solvent lacking of acidic hydrogen atoms able to form hydrogen bonds with the solute.

Preferably, the solvent is selected from the group consisting of

dichloromethane, dichloroethane, chloroform, toluene, N,N- dimethylformamide, tetrahydrofuran, and 1 ,4-dioxane.

Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprise" encompasses the case of "consisting of. 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 they are not intended to be limiting of the present invention. Reference signs related to drawings and placed in parentheses in a claim, are solely for attempting to increase the intelligibility of the claim, and shall not be construed as limiting the scope of the claim. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments described herein. EXAMPLES

General information Unless otherwise stated, all commercial reagents were used as received and all reactions were carried out directly under open air. Merrifield resin (1 % PS- DVB, f = 0.53 mmol of CI per gram of resin) was purchased from

Novabiochem. In each case the extent of the supporting process and the functionalization of the final resin was determined by elemental analysis. All flash chromatography was carried out using 60 mesh silica gel and dry- packed columns. NMR spectra were recorded in a Bruker Advance 400 Ultrashield NMR spectrometer for ¹ H NMR at 400 or 500 MHz, and ¹³ C at 100 or 126 MHz. The solvent employed in each case is indicated between brackets. Chemical shifts (δ) in ppm are indicated with respect to the reference used: tetramethylsilane (TMS, internal reference) in ¹ H NMR, solvent residual peak for ¹³ C NMR spectra. ATR measurements were carried out in a FT-IR Alpha spectrometer with DTGS detector, using a Bruker ATR accessory with diamond crystal. Specific rotation was determined by using a Jasco P-1030 polarimeter equipped with a sodium lamp, and a photomultiplier tube detector with a 589 nm filter, in a polarimetry cell of 100 mm length. Concentration in g/100 ml and solvent used are indicated in brackets. High resolution mass spectrometry analyses were performed in a Waters LCD PremierTM instrument operating in ESI (Electro-Spray Ionization) mode or APCI (Atmospheric-Pressure Chemical Ionization) mode. Elemental analyses were performed by MEDAC Ltd. (Surrey, UK) on a LECO CHNS 932 micro- analyzer. High performance liquid chromatography (HPLC) was performed on Agilent Technologies chromatograph (Serie1200), using Chiralcel OD-H or Chiralpak IA column and guard column. The continuous flow experiments were carried out using a Syrris Asia pump with pressurized input and backpressure regulator. The packed-bed reactor was a ¼ inch Teflon tube of 17 cm length. Conversion was monitored by real time IR spectroscopy thanks to the Mettler Toledo FlowlR.

Example 1 : Preparation of polymer supported catalyst (I I In )

Step 1 : Preparation of (R)-4-((2,2'-bis(methoxymethoxy)-[1 ,1 '-binaphthalen]-6- yl)methoxy)(terf-butyl)dimethylsilane 2

Under argon atmosphere, terf-butyldimethylchlorosilane (2.82 g, 18.16 mmol) was added to a mixture of (2,2'-bis(methoxymethoxy)-[1 ,1 '-binaphthalen]-6- yl)methanol 1 (6.12 g, 15.13 mmol, 1 was prepared as described in

Tetrahedron: Asymmetry 2001 , 12, 2589.) and imidazole (2.58 g, 37.80 mmol) in dry DMF (23 mL) at room temperature. After being stirred for 2 h, water (100 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate (3 50 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO ₄ , filtered and evaporated to give the crude product as a colorless oil . It was purified by flash chromatography on silica gel to afford the final product in quantitative yield (7.90 g, 15.13 mmol). [a] ²⁷ _D : +5.1 ° (c 1 .00, CH ₂ CI ₂ ).

IR (ATR): 2954, 2927, 2898, 2855, 1593, 1505, 1482 cm ^"1 .

HRMS (ESI+): m/z calculated for C ₃ iH ₃ 8NaO ₅ Si [M+Na] ⁺ : 541 .2381 , found 541 .2399.

Step 2: Preparation of (R)-4-terf-butyl((3,3'-dibromo-2,2'- bis(methoxymethoxy)-[1 1 '-binaphthalen]-6-yl)methoxy) dimethylsilane 3

To a solution of compound 2 (1 .09 g, 2.1 1 mmol) in anhydrous THF (8.5 mL), n-BuLi (3.16 mL, 5.06 mmol) was added dropwise at -78 °C under Ar atmosphere. The mixture was allowed to warm to 0 °C, stirred for 1 h and then cooled to -78 °C again. Then, a solution of bromine (0.33 mL, 6.32 mmol) was added dropwise and the mixture was stirred overnight at room temperature. Then, it was poured into a solution of saturated Na2SO3 (20 mL), the organic layer was separated and the aqueous phase was extracted with EtOAc (3 10 mL). The combined organic extracts were washed with brine and dried over Na2SO ₄ . The mixture was filtered and evaporated under reduced pressure. The resulting crude was purified by column chromatography on silica gel (Hexane/EtOAc 90:10) to give a light brown oil in 70% yield (1 .00 g, 1 .48 mmol).

[a] ²⁷ _D : +1 .7° (C 3.15, CH ₂ CI ₂ ).

IR (ATR): 3062, 2953, 2928, 2884, 1578, 1563, 1465, 1386, 1350 cm ^"1 .

HRMS (APCI+): m/z calculated for C3iH ₃ 6NaBr ₂ O ₅ Si [M+Na] ⁺ : 697.0591 , found 697.0598.

Step 3: Preparation of (R)-4-((3,3'-bis(3,5-bis(trifluoromethyl)ph

bis(methoxymethoxy)-[1 ,1 '-binaphthalen]-6-yl)methoxy)(terf- butyl)dimethylsilane 4

The bromo derivative 3 (3.97 g, 5.87 mmol), (3,5- bis(trifluoromethyl)phenyl)boronic acid (3.78 g, 14.67 mmol), Pd ₂ (dba) ₃ (0.16 g, 0.18 mmol), Sphos (0.29 g, 0.70 mmol) and K ₃ PO ₄ (6.23 g, 29.3 mmol) were dissolved in dry toluene (12 ml_) in a Schlenk flask under argon atmosphere. The reaction mixture was stirred overnight at 1 10 °C. Then, it was allowed to cool down to room temperature and it was filtered through a plug of celite. The filtrate was evaporated under reduced pressure to give a residue. Subsequent purification by column chromatography on silica gel (from c-Hexane to c-Hexane/EtOAc 90:10) afforded the product in 86% yield. [a] ²⁷ _D : -6.0° (C 1 .10, CH ₂ CI ₂ ).

IR (ATR): 2957, 2930, 2858, 1471 , 1378, 1278, 1 129 cm ^"1 .

HRMS (ESI+): m/z calculated for C ₄₇ H ₄₂ Fi ₂ NaO ₅ Si [M+Na] ⁺ : 965.2502, found

965.2496.

m.p.: 254-274 °C (dec).

Step 4: Preparation of (R)-4-(3,3'-bis(3,5-bis(trifluoromethyl)ph

bis(methoxymethoxy)-[1 ,1 '-binaphthalen]-6-yl)methanol 5

Compound 4 (4.70 g, 4.98 mmol) was dissolved in dry THF (28.5 mL) under argon atmosphere, a 1 M solution of Bu ₄ NF in THF (9.97 mL, 9.97 mmol) was added at 0 °C and the reaction was stirred at room temperature for 4 h. Then, water (10 mL) was added to quench the reaction, the organic layer was separated and the aqueous phase was extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine and dried over Na ₂ SO ₄ . The mixture was filtered and evaporated under reduced pressure. The resulting crude was purified by column chromatography on silica gel (from Hex: EtOAc 90:10 to Hex: EtOAc 70:30) to afford the product in 89% yield (3.63 g, 4.38 mmol).

[a] ²⁷ _D : -7.0° (c 1 .00, CH ₂ CI ₂ ).

IR (ATR): 1366, 1276, 1278, 1 123 cm ^"1 .

HRMS (ESI+): m/z calculated for C^H sNaF^Os [M+Na] ⁺ : 851 .1637, found

851 .1669.

m.p.: 96-100 °C.

Step 5 (step (i)): Preparation of (R)-4-(3,3'-bis(3,5-bis(trifluoromethyl)ph 2,2'-bis(methoxymethyloxy)-[1 ,1 '-binaphthalen]-6-yl)methoxymethyl polystyrene cross-linked with divinylbenzene at 1 % (Merrifield resin) 6

To a suspension of NaH (0.165 g, 1 .15 mmol) in dry DMF (16 mL) was added compound 5 (dissolved in 10 mL of DMF) at room temperature, under argon atmosphere. In a second flask, the polystyrene cross-linked with

divinylbenzene and functionalized with chlorine (Merrifield resin, 1 % DVB, 2.16 g, 1 .08 mmol of active chlorine) and Bu ₄ NI (0.050 g, 0.14 mmol) were suspended in dry DMF (13 mL) in order to swell the resin. Both suspensions were shaken for 1 h and the first one was then added via cannula to the resin. The reaction mixture was shaken at this temperature until Raman

spectroscopy showed complete disappearance of the chlorine band (678 cm ^-1 ). The resulting resin was filtered and washed successively with water (200 mL), water/THF 1 :1 (200 mL), THF (200 mL), THF/CH ₂ CI ₂ 1 :1 (200 mL) and CH ₂ CI ₂ (200 mL). Then it was allowed to dry overnight under vacuum at 50 °C and 2.66 g of 6 were isolated.

F elemental analysis (%): 9.08 (average of two measurements)

f. 0.39 (quantitative anchoring, f _max : 0.36 mmol _mon omer/gresin) Step 6 (step (ii)): Preparation of (R)-4-(3,3'-bis(3,5-bis(trifluoromethyl)phenyl)- 2,2'-dihydroxy-1 ,1 '-binaphthalen-6-yl)methoxymethyl polystyrene cross-linked with divinylbenzene at 1 % (Merrifield resin) 7

A mixture of compound 6 (2.66 g, 0.96 mmol) and HCI in EtOAc (2 M, 23 mL, 46 mmol) was shaken at room temperature overnight. After filtration, the resin was washed successively with EtOAc (200 mL), EtOAc/CH ₂ CI ₂ (200 mL) and CH ₂ CI ₂ (200 mL) and dried overnight under vacuum at 50 °C to afford 7 (2.50 g)-

Step 7 (step (iii) and (iv)): Preparation of (R)-4-(3,3'-bis(3,5- bis(trifluoromethyl)phenyl)-2,2'-diyl hydrogen phosphate-1 ,1 '-binaphthalen-6- yl)methoxymethyl polystyrene cross-linked with divinylbenzene at 1 %

(Merrifield resin) (lllh)a

Compound 7 (2.50 g, 0.82 mmol) was suspended in dry pyridine (14 mL) under argon atmosphere and POCI3 (0.15 mL, 1 .57 mmol) was added at room temperature. The reaction mixture was shaken for 5 h. Then, 5 mL of water were added and the resulting suspension was shaken for additional 30 min. After filtration, the resin was washed successively with 1 N aqueous HCI (300 mL), water (300 mL), THF (200 mL), stirred for 10 minutes in 2 M HCI in EtOAc, washed with 200 mL of EtOAc and CH ₂ CI ₂ (200 mL) and dried overnight under vacuum at 50 °C to afford 2.35 g of catalyst lllha.

F elemental analysis (%): 6.00 (average of 4 measurements)

f. 0.26 mmoLonomer gresin (70% of functionalization, f _max \ 0.37 mmOl _m0 nomer/gresin) Example 2: Preparation of 3-indolylmethanamine compounds of formula (V) in batch conditions

Examples 2a-2g: Preparation of (S)-/V-((1 /-/-indol-3-yl)(phenyl)methyl)-4- methylbenzenesulfonamide

General procedure: Indole (amount indicated in Table 1 ), /V-benzylidene-4- methylbenzenesulfonamide (0.07 mmol, 1 equivalent) and the compound of formula (lllh)a obtained in Example 1 (loading indicated in Table 1 ) were placed in a vial and the solvent was added (0.4 mL when the concentration was 0.16 M, or, alternatively, 0.8 mL when the concentration was 0.08 M) was added. The reaction mixture was shaken at room temperature until Thin Layer Chromatography monitoring showed complete consumption of the starting compound of formula (VIII) and for the time indicated in Table 1 . Then, the resin was filtered and the filtrate directly purified by column chromatography on silica gel (from CH ₂ CI ₂ to CH ₂ CI ₂ /EtOAc 96:4) to yield the product as a white solid.

Table 1 shows the results obtained.

Table 1

As a comparative example, Kang and co-workers reported that the same reaction, when carried out in the presence of 10 moles of compound of formula (Γ) per 100 moles of W-benzylidene-4-methylbenzenesulfonamide, and using toluene as a solvent, and wherein the molar ratio of indole to N- benzylidene-4-methylbenzenesulfonamide is 5:1 , gives rise to the formation of the 3-indolylmethanamine compound in 80% yield and 83% ee.

Examples 2a-2g show that, unlike the catalysts of the state of the art, the catalysts of the invention allow for the formation of the product in high yield and selectivity, even when a minor excess of indole is used. Example 2h: Preparation of (S)-/V-((1 H-indol-3-yl)(phenyl)methyl)-4- methylbenzenesulfonamide by catalyst recycling

W-benzylidene-4-methylbenzenesulfonamide (0.07 mmol), indole (0.1 mmol, 1 .4 equivalent) and compound of formula (lllh)a obtained in Example 1 (10 mol%) were placed in a vial and CH2CI2 (0.4 ml_, 0.16 M) was added. The reaction mixture was shaken until TLC monitoring showed complete consumption of the starting imine and for the time shown in Table 2. Then, the resin was filtered and the filtrate directly purified by column chromatography on silica gel (from CH ₂ CI ₂ to CH ₂ CI ₂ /EtOAc 96:4).

After each run, the compound (lllh)a was recovered from the filter plate and dried for 2 h under vacuum. Then, the compounds of formula (VIII) and (VII) and CH ₂ CI ₂ were again added and the same process was repeated

successively.

In total, 14 successive runs have been carried out. Table 2 shows the results obtained for each run.

a The compound of formula (lllh) was previously washed with HCI/EtOAc

Table 2

Example 2h shows that the catalysts of the invention are highly active and reusable and that high turnover numbers (around 120) can be reached upon catalyst recycling. Example 2h also shows that the catalysts of the invention can be easily reactivated via a washing with an acidic solution.

Examples 2i-2y: Preparation of various 3-indolylmethanamine compounds General Procedure A (examples 2i-2u and 2y): The compound of formula (VIII) (0.07 mmol, 1 equivalent), the compound of formula (VII) (amount indicated in Table 3) and the compound of formula (lllh)a obtained in Example 1 (loading indicated in Table 3) were placed in a vial and CH2CI2 (0.4 ml_, 0.16 M) was added. The reaction mixture was shaken at room temperature until Thin Layer Chromatography monitoring showed complete consumption of the starting compound of formula (VIII) and for the time indicated in Table 3. Then, the compound (lllh)a was filtered and the filtrate directly purified by column chromatography on silica gel (from CH2CI2 to CH ₂ Cl2/EtOAc 96:4), unless otherwise stated.

General Procedure B (examples 2v, 2w and 2x): /V-benzylidenepyridine-2- sulfonamide (0.04 mmol), compound of formula (VII) (0.05 mmol) and compound of formula (lllh)a obtained in Example 1 (loading indicated in Table 3) were placed in a vial and CH2CI2 (0.5 ml_, 0.08 M) was added. The reaction mixture was shaken at room temperature until Thin Layer Chromatography monitoring showed complete consumption of the starting compound of formula (VIII) and for the time indicated in Table 3. Then, the resin was filtered and the filtrate directly purified by column chromatography on silica gel (from CH2CI2 to CH ₂ CI ₂ /MeOH 99:1 ).

Table 3 shows the obtained results.

Amount

Amount

of (VII) yield ee

Example (VII) (VIII) of (lllh)a t (h)

in (%) (%) in mol%

equiv.

H NTs

2i 10 2.5 1.4 94 89

NTs

H

2j 10 2.5 1.4 86 87

H NTs

2k ^r ^N > J 10 1.5 1.4 81 94

Table 3 shows that the catalysts of the invention are useful in the preparation of a large number of 3-indolylmethanamine compounds and that the presence of additional functional groups does not alter significantly the performance of the catalysts of the invention.

Example 3: Preparation of 3-indolylmethanamine compounds in continuous flow conditions Example 3a: Continuous flow preparation of (S)-N-((1 H-indol-3-yl)(p- tolyl)methyl)-4-methylbenzenesulfonamide

A solution of 4-methyl-/V-(4-methylbenzylidene)benzenesulfonamide in CH ₂ CI ₂ (0.32 M) and a solution of indole (0.48 M) in CH ₂ CI ₂ were pumped through a column loaded with the catalyst (lllh)a prepared by pouring and packing the powdered compound (lllh)a into a ¼ inch Teflon tube of 17 cm length (0.36 g, f = 0.25 mmol-g ^-1 , 0.09 mmol) at a combined flow rate of 0.2 mL-min ^-1 , corresponding to a residence time of 9.3 min. The system was submitted to continuous flow operation for 6 h and the product was collected at the outlet of the reactor. Figure 1 shows the conversion of the compound of formula (VIII) and the enantiomeric excess of the compound of formula (V) as monitored every hour by collecting and analysing samples of the solution exiting of the reactor. Conversion was determined by ¹ H NMR spectroscopy and enantiomer excess was determined by chiral HPLC (Chiralcel OD-H column).

Figure 1 shows the evolution over time of the conversion of the compound of formula (VIII) and the enantiomeric excess of the compound of formula (V) produced. As it is shown in Example 3a and Figure 1 , the catalysts of the invention allow for the continuous flow production of 3-indolylmethanamine compounds in high yields and selectivity. In this Example, 3.6 g of the 3- indolylmethanamine compound were produced in 6 hours, giving rise to turnover number of 102 and a productivity of 4.3 mmol of the product per hour and gram of catalyst. Example 3b: Continuous flow preparation of 3-indolylmethanamines

A solution of a compound of formula (VIII) as shown in Table 4 in CH2CI2 (0.32 M) and a solution of a compound of formula (VII) as shown in Table 4 (0.48 M) in CH ₂ Cl2 were pumped through a column loaded with the catalyst (lllh)a prepared as described in Example 3a (0.36 g, f = 0.25 mmol-g ^-1 , 0.09 mmol) at a combined flow rate of 0.2 mL-min ^-1 , corresponding to a residence time of 9.3 min. After one hour, the column loaded with the catalyst (lllh)a was rinsed with CH2CI2 for 30 minutes and solutions of different compounds of formula (VIII) and (VII), as shown in the Table 4 were pumped through the column.

Table 4 shows the yield, enantiomeric excess and productivity, expressed in mmol of the compound of formula (V) per hour and per gram of catalyst of formula (lllh), obtained with different compounds of formula (VII) and (VIII) following the procedure described above.

Table 4

REFERENCES CITED IN THE APPLICATION -Kang et al. "Highly Enantioselective Friedel-Crafts Reaction of Indoles with Imines by a Chiral Phosphoric Acid" J. Am. Chem. Soc. 2007, 129, 1484-1485. -Rueping et al. "Synthesis and Application of Polymer-Supported Chiral Bronsted Acid Organocatalysts" Adv. Synth. Catal. 2010, 352, 281 -287. -Bleschke et al. "A Chiral Microporous Polymer Network as Asymmetric Heterogeneous Organocatalyst" Adv. Synth. Catal. 2012, 353, 3101 -3106. -Wuts et al., "Greene 's Protective Groups in Organic Chemistry", (Wiley, 4th ed. 2007, p.16-23).

-Min Zheng et al. "Cavity-induced enantioselectivity reversal in a chiral metal- organic framework Bronsted acid catalyst" Chemical Science. 2012, 3, 2623- 2627.