WO2004113351A2

WO2004113351A2 - Bifunctional amino-boron lewis acid - lewis base catalyst

Info

Publication number: WO2004113351A2
Application number: PCT/GB2004/002664
Authority: WO
Inventors: Andrew Whiting
Original assignee: University Of Durham
Priority date: 2003-06-19
Filing date: 2004-06-21
Publication date: 2004-12-29
Also published as: GB0314220D0; WO2004113351A3

Abstract

Bifunctional Lewis acid - Lewis base catalyst of Formula (I): wherein O is a C2-60 optionally heteroatom containing substituted or unsubstituted hydrocarbon scaffold comprising pendant or integral bifunctional groups LA and LB wherein LA is a pendant or integral boron or silicon Lewis acid group and LB is a pendant or integral phosphorus or nitrogen Lewis base group and its salts, N-fanctionalised derivatives, dimer or oligomer thereof; processes for the preparation thereof; novel compounds and novel intermediates; a composition comprising a catalyst or compound of the invention; a kit comprising one or more catalysts; the use thereof as catalysts in selective transformations, kits therefor and processes for selective transformation reactions catalysed thereby; screening methods to identify catalysts for specific transformations; and kits therefor.

Description

BIFUNCTIONAL CATALYSTS

The present invention relates to a class of novel bifunctional catalysts; processes for the preparation thereof; novel compounds and novel intermediates; a composition comprising a catalyst or compound of the invention; a kit comprising one or more catalysts; the use thereof as catalysts in selective transformations, kits therefor and processes for selective transformation reactions catalysed thereby; screening methods to identify catalysts for specific transformations; and kits therefor. More specifically, the invention relates to a class of novel amino-boron Lewis acid - Lewis base bifunctional catalysts adapted to selectively catalyse a wide range of selective transformations by cooperative effect of the Lewis acid and Lewis base, including the preparation of chiral compounds and complex building blocks which would be of use for both the chemical and pharmaceutical industry, prepared with high purity and using essentially waste free processes; processes for the preparation of the novel catalysts; novel compounds and novel intermediates; novel compositions; a kit comprising one or more catalysts; the use of the catalysts in selective transformations, kits therefor and processes for selective transformation reactions catalysed thereby; and screening methods to identify catalysts for specific transformations, and kits therefor.

Bifunctional catalysis is a well understood phenomenon in nature, with enzymes usually using two (or more) functional groups to accomplish selective transformations on a suitable substrate. The potential efficiency and selectivity of bifunctional catalysts is beginning to be more fully understood, especially with the development of biological mimics. Examples include hydrolytic enzyme models utilising two imidazole functions on a cyclodextrin scaffold, which is closely related to an example of bifunctionally catalysed reactions on RNA models. These developments have clearly shown that bifunctional catalysis can result in considerable rate enhancements and the introduction of selectivity in several synthetic transformations.

The mechanism of action of many biological processes, typically enzyme reactions, involve the cooperation of two or more reactive centres, but many man made catalysts just use one centre. It is now becoming clear however, that bifunctional catalysis is not merely of interest to explain or mimic biological efficiency and rate enhancement, but is a viable design principle for the development of new molecular catalysts. In recent years, there has been increased recognition of the advantages of bifunctional catalysts systems for a wide range of synthetic processes.

The majority of classical catalysts function in one of two ways; the first is that a reagent binds to a reactant thus both activating it and inducing a chiral environment which allows a second reagent to attack it in a selective fashion; the second is that two reagents simultaneously bind to the catalyst thus "intramolecularising" the reaction, which due to their proximity allows the substrates to react quickly and selectively. Whilst both strategies have been exploited very successfully in classical catalysis, multifunctional catalysts comprising both "reagents" in a single entity have been recognised as offering a number of possible advantages. Catalysts that contain both Lewis acid and Lewis basic sites could activate both reagent and substrate in a controlled environment or, more typically one reactive centre could be used to bind the substrate whilst the second active site performs the chemical transformation.

However although this looks good in theory, often bifunctional metal or organic systems do not function as intended, one of the most common reasons is the interference of a self-quenching reaction in which the Lewis acid and Lewis base combine to form a catalytically inactive adduct. Solutions to this problem in the art have included using a weak Lewis base in concert with a Lewis acid.

Examples of true bifunctional catalysis using Lewis acid - Bronsted base or certain classes of Lewis acid - Lewis base catalysts include asymmetric aldol, cyanosilylation, Strecker, allylation, epoxide ring opening reactions, and β-lactam construction. However stable amino-boronate containing compounds have not been studied in detail as potential bifunctional catalysts, even though amino-boronic acid systems have attracted interest, for example in carbohydrate recognition.

We have now surprisingly found that a novel class of bifunctional Lewis acid - Lewis base catalysts comprising a molecular scaffold supporting both a Boron or silicon Lewis acid and a phosphorus or nitrogen Lewis base function allows control of the Lewis acid-Lewis base interference and indeed allows tuning of Lewis acid and Lewis base appropriate to specific reactions which it is desired to catalyse.

The bifunctional catalysts of the invention typically comprise one Lewis acid centre to bind a substrate and a Lewis base centre to selectively deliver a stoichiometric reagent to the substrate via coordination. The catalysts typically comprise known or novel compounds which have been surprisingly found to selectively catalyse organic transformations employing two or more reactive sites on one or more substrates. Typically these reactions do not proceed at all in the presence of only one Lewis acid or Lewis base function or a mixture thereof in different entities.

Compounds comprising boron or silicon groups in the same molecule as phosphorus or nitrogen groups are known in many use areas. Specifically boron nitrogen containing compounds are known for example as sensors in sugar chemistry, however there is limited reference in the literature to their use as catalysts, and we are not aware of any reference to their use as true bimolecular catalysts.

Thus although the cooperative interaction of both a Lewis acid and Lewis base function is known in a number of limited cases, including classical examples in which the functions are on different (tandem) entities and more recent examples in which the functions are on the same very specific (bifunctional) entity, the applications are very specific in all cases and in both tandem and bifunctional examples very specific Lewis acid and Lewis base combinations are employed. The novel class of catalysts of the present invention may be useful in catalysing a range of selective transformations including asymmetric processes, as a universal class of catalysts. More specifically individual bifunctional catalysts may be selected from the novel class of catalysts, for example in which basicity and acidity are tuned by the scaffold structure, as optimal catalysts for each selective transformation which it is desired to catalyse. The novel class of catalysts are particularly useful to selectively catalyse transformations employing two or more reactive sites on one or more substrates by cooperative effect of Lewis acid and Lewis base functions. Typically these reactions do not proceed at all in the presence of only one Lewis acid or Lewis base function or a mixture thereof on separate entities. The catalysts are readily prepared and moreover provide a number of additional advantages. Accordingly in the broadest aspect of the invention there is provided a bifunctional Lewis acid - Lewis base catalyst of Formula I:

wherein jβ is ^a C_2-60 optionally heteroatom containing substituted or unsubstituted hydrocarbon scaffold comprising pendant or integral bifunctional groups LA and LB which together with the scaffold form a neutral bifunctional catalytic entity, each of LA and L_B being a catalytic function of the entity and adapted to coordinate one or more substrates, preferably one or two substrates via one or more sites, preferably via two or more sites; wherein L_A is a pendant or integral Lewis acid group LA- _AU¹ covalently attached to a C skeleton where L _' is Boron; n¹ is 2 and each X_A is same or different and is independently selected from OH, OR¹, F, Cl, Br; or n¹ is 2 or_3 and X_A is selected from OR¹, NR² ₂, SR^, and NR^OaR¹ where each R¹ is independently selected from C_1-7 alkyl or alkoxy such as methyl, ethyl, propyl, butyl, aryl, optionally halogen substituted such as CF₃ or fluoroaryl, or hydrophilic polymeric groups; and R² is selected from H or C_1-24 substituted or unsubstituted optionally heteroatom containing hydrocarbon, or two of R² form a substituted or unsubstituted cyclic aliphatic or aromatic ring; L_B is a pendant or integral Lewis base group L_B> XBΪII¹ where L_B- is selected from N and P; m¹ is zero, 1, 2 or 3 and none or 1 of X_B is selected from =O and none, 1 or 2 of X_B are independently R²; and wherein the or each R² is independently as hereinbefore defined H or C_{1- 4} substituted or unsubstituted optionally heteroatom containing hydrocarbon or one or two of R² are part of or form a substituted or unsubstituted cyclic aliphatic or aromatic ring which may contain heteroatoms selected from O, N, S; and wherein one or more optional substituents of the scaffold R³ are selected independently from groups comprising combinations of O, N, S, P, H, halo (Cl, F, Br, I) atoms or from C_1-24 substituted or unsubstituted optionally heteroatom containing hydrocarbon or any two of R³ form a cyclic ring; and its salts, N-functionalised derivatives, dimer or oligomer thereof, characterised in that L_A and L_B are not ligands for an external metal or Lewis acid.

Preferably a salt is a salt of the Lewis acid, and is BXA_'3 ^"M+ where M is a metal such as sodium and the like, and an oligomer is an oligomer of the Lewis acid such as the trimer boroxine.

Optionally in the catalyst of Formula I when L_A is B(OH)₂ and L_B is -NH- or - NCH₃- and L_B> is an imidazole nitrogen then [ _\ is not 2-phenyl benzimidazole or 2-benzyl benzimidazole in which B(OH)₂ is an ortho substituent on the phenyl or benzyl ring; or in the catalyst of Formula I when L_A is B(OH) and L_B is — N= then f~ . is not quinoline in which B(OH)₂ is in the 8-position.

Reference herein to a bifunctional catalyst is to a catalyst comprising two functional groups which are adapted to coordinate one or more substrates, preferably one or two substrates via one or more sites, preferably via two or more sites. The bifunctional catalysts of the invention provide a cooperative catalytic effect. The bifunctional catalysts enable reactions which do not proceed in the presence of only one of the two bifunctional groups or in the presence of a mixture of compounds each comprising one of the groups.

The hypothetical mode of action of the bifunctional catalyst system is shown in the following scheme, in which L_A is B(OH)₂ and L_B is NR² ₂ :

Prior art catalysts such as disclosed in US 2002/0072632 Al have a B or Si binding site and a Lewis base site for conducting the transformation, typically the B or Si binding site attaches to for example a transition metal. Such catalysts are in fact organometallic catalysts and are not truly bifunctional, and are therefore distinct from the organic bifunctional catalysts of the invention. Importantly in the catalysts of the invention L and L_B are not ligands, and the catalysts are true catalysts being regenerated in the catalysed reaction.

In the catalysts of the invention the Lewis acid B atom is attached to a C skeleton, and is maintained attached thereto throughout a catalysed reaction. This ensures that hydrolytic instability is avoided.

Reference herein to Lewis acid and Lewis base groups is to the groups as defined in the art, specifically to groups which respectively receive or donate an electron pair. Conventional acids and bases fall within this definition as do complex-forming groups. It is a feature of Lewis acid catalysed reactions and of Lewis base catalysed reactions that they are reversible. The Lewis acid - Lewis base catalysts of the invention provide reversible reactions which are advantageously reversible asymmetric reactions.

Preferably ζ ,M as hereinbefore defined comprises a core scaffold structure SCF supporting^"*^ bifunctional groups L_A and L_B as hereinbefore defined, wherein SCF is a C_2-60 optionally heteroatom containing substituted or unsubstituted hydrocarbon scaffold; optionally including spacers SPA for linking to L_A and L_B; wherein each SPA, if present, is selected independently from C_1-8 optionally heteroatom containing optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and aromatic; and wherein each of LA and L_B independently are pendant to scaffold core SCF or spacer SPA and connected thereto by one single or double bond or are integral with SCF or SPA and connected thereto by two or more single or double bonds or a combination thereof.

More preferably as hereinbefore defined is of formula F ' [SCF¹ SCF²]

wherein functional groups L_A and L_B may be on the same or different SCF moiety and wherein each of SCF¹ and SCF² is independently selected from substituted or unsubstituted C_2-58 unsaturated linear or branched aliphatic, alicyclic, or mono or multi ring aromatic such as from 1 to 6 fused 5 and/or 6 atom (hetero)aromatic ring systems, and combinations thereof, optionally including one or more heteroatoms selected from N, O, S, P, Si and / or one or more metals selected from Fe, Ru, Cr, Ni, Co⁺ , Ti, W, Mo and / or other atoms such as Pd, Al and the like and optionally one or more substituents R³ which are independently selected from OH, halo, NO₂, amino, amido, carbonyl, CN, oxo, C_1-24 alkyl or alkoxy, C_2-24 alkenyl or alkynyl, C_3- ₂₄ cycloalkyl or aryl and combinations thereof. In the case that one or both of L_A and L_B are integral with or pendant to SCF the compound of Formula I may take the formula

SCF - L_A - L_B or SCF¹ (SCF²) - L_A L_B or SCF¹ - L_A (SCF² - L_B)

Preferably each SPA, where present, is independently selected from -CH₂-, -C₂H₄-, - C₃H₆-, C₆H₅ etc. Preferably L_A is selected from BX₂, BR^! ₃, BR^Y, BR¹ Y₂, and the like wherein X, R¹ and Y are as hereinbefore defined, and preferably each XA is the same, more preferably L_A is selected from B(OH)₂, (OB _Lβ )₃, BF₂, BR¹NR².

Preferably L_B is selected from NR² ₂, PR² ₂, POR² ₂, -N=, -NR²- wherein each R² independently is as hereinbefore defined and preferably forms a hindered amine where each R² is C_3-24 substituted or unsubstituted optionally heteroatom containing hydrocarbon, or two of R² form a substituted or unsubstituted cyclic aliphatic or aromatic ring, or forms an unhindered amine where each R² is C_1-3 substituted or C_1-5 unsubstituted optionally heteroatom containing hydrocarbon. The catalyst activity may be selective to the nature of the amine hindrance, for example some catalysts have been found to be effective in catalysing particular reactions hindered amine form whilst some catalysts are effective in catalysing other reactions in unhindered form.

Preferably the or each R¹ is selected from methyl, ethyl, propyl, butyl or hydrophilic polymeric groups such as - (OCH₂CH₂)pR² where p indicates a repeating unit and is 2 to 15 or is 16 to 60 and R² is preferably H, alkyl or amino.

When R¹ is a hydrophilic polymeric group it is preferably selected from groups such as -(OCH₂CH₂)pR² where p indicates a repeating unit and is 2 to 150.

Preferably the or each R² is selected from substituted or unsubstituted, optionally heteroatom-containing, C_1-24 alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy or aryl, or two of R², optionally including L - or Lβ> form a substituted or unsubstituted 3 to 7 membered cyclic ring, wherein substituents include OH, halo, OCH , CH₃, OC₂H₅, C₂H₅, C₃H₇, C₆H₅ or hydrophilic polymeric groups such as - (OCH₂CH₂)pR² where p indicates a repeating unit and is 2 to 150 and R² is as hereinbefore defined and is preferably H, alkyl or amino.

More preferably the or each R² is selected from substituted or unsubstituted, optionally N, O, S or P containing alkyl, alkenyl or cycloalkyl such as cyanoalkyl, amino, alkoxy and the like or two of R² together with L_B which is N form a substituted or unsubstituted 5 or 6 membered cyclic ring or two of R² (two of NR²SO₂CF₃) form a substituted cyclic ring together with L_A which is B and in which one or more substituents include C_1-4 alkyl or C_6-9 aryl. In a particular advantage one or more of R² comprises a functional group which allows tuning to the required reaction conditions, for example comprises a solubilising group such as alkoxy, mono or dihydroxy alkyl or a hydrophilic polymeric group, for example comprises the polyethylene glycol mono or repeating unit -(OCH₂CH₂)pR² wherein p indicates a repeating unit and is 2 to 15 or 16 to 150 and R² is as hereinbefore defined and is preferably H, alkyl or amino.

Most preferably L_B is selected from a tertiary amine whereby there is not normally a protonating H present, such as N(CH₃)₂, N(iC₃H₇)₂, N(CH(CH₃)Ph)₂,

Preferably SCF is substituted or unsubstituted C_6-60 unsaturated or cyclic aliphatic, alicyclic, aromatic and combinations thereof, optionally including one or more heteroatoms selected from N, O, S, P, Si and / or one or more metals selected from Fe, Ru, Cr, Ni, Co⁺, Ti, W, Mo and / or other atoms such as Pd, Al and the like and optionally one or more substituents R which are independently selected from OH, halo, NO₂, amino, amido, carbonyl, CN, oxo, C_1-24 alkyl or alkoxy, C_{2- 4} alkenyl or alkynyl, C_3-24 cycloalkyl or aryl and combinations thereof. More preferably SCF comprises substituted or unsubstituted C_6-6o unsaturated aliphatic or alicyclic, or mono or multi ring aromatic, such as from 1 to 6 fused 5 and/or 6 atom (hetero)aromatic ring systems.

Most preferably SCF, or either or both SCF¹ and SCF² including as relevant a N atom from L_B, comprises C_2-10 straight chain or branched terminal or in chain aliphatic linear or branched alkyl or cycloalkyl substituted or unsubstituted molecular and macromolecular aromatic and unsaturated or electron rich 1 to 5 ring cyclic systems such as phenyl, pyrrole, imidazole, pyridine, pyrimidine, purine, hydrocarbon metal complexes such as metallocenes such as fenocenyl, ruthenocenyl, and other di and mono cyclopentadienyl, arenyl, cycloheptatrienyl and the like complexes, 4'-biphenyl, naphthalenyl, asymmetric naphthalenyl, quinoline, isoquinoline, binaphthalene, (3, 5-diphenyl)phenyl, [(3',3", 5', 5"-tetramethyl)-3, 5- diphenyl]phenyl, carbazole, benzimidazole, 4 ring systems such as steroids (6,6,6,5), macromolecules containing receptor binding sites such as cyclodextrins and other sugar containing systems and the like and oligomers and polymers thereof, preferably C_3-10 linear or branched alkyl or cycloalkyl, or a 1 to 3 fused, spiro or coordinated ring system, such as phenyl, fenocenyl, paracyclophane, benzimidazole, naphthalenyl, quinolinyl and the like.

Heteroatoms as hereinbefore refened if not otherwise defined include optionally substituted N, O, S, P, Si.

More preferably the or each of R² and R³ independently are selected from: straight or branched chain lower (C_1-5) or higher (C_6-2o) alkyl, more preferably methyl, ethyl, propyl, butyl, pentyl or hexyl, heptyl, octyl; or from C_3-20 cyclo alkyl, preferably C₃- Cι₄ cyclo alkyl; or from C_6-24 aryl, more preferably an unfused, optionally spiro 1, 2, 3, 4 or 5 ring alkyl or aryl structure; any of which are optionally substituted and/or include at least one heteroatom; or any two R² or R³ together form an optionally substituted cyclo amine wherein any heteroatom is independently selected from B, Si, O, S, P or Si as hereinbefore defined.

We have found that catalysts in which L_A ¹ is B and one or two X_A is N are stable to hydrolysis of the B-N bond but are not highly reactive despite being activating to give Lewis acidity, nevertheless where B-N is formed by a sulfonamide group eg trifluoromethylsulfonamide (Tf) and the compound is an active catalyst, this is of interest due to the steric congestion which can be used to introduce chirality. Catalysts of the invention may be rationally designed or selected by screening or the like to catalyse certain synthetic reactions. Choice of group LA may be made according to desired catalyst acidity, for example BF₂ < B(OH)₂; according to desired water stability or water compatibility, for example BF₂ < B(OH)₂. Choice of group L_B may be made according to desired catalyst chirality, for example NR² ₂ is a chiral tertiary amine group or one or both of R² is a chiral group; according to desired basicity, for example to avoid or slow down a protonation step by group L_B, tertiary amine > primary amine. Choice of scaffold SCF may similarly be made according to desired catalyst basicity, for example similarly to avoid or slow down a protonation step benzimidazole > mono N containing heterocycle; according to desired catalyst acidity, for example aromatic > saturated. Acidity, basicity and the like are a function of the interdependence of the skeleton and its bifunctional groups. Properties are conveniently measured by conventional methods such as pKa (amine basicity), isoelectric point, relative Lewis acidity of LA.

Without being limited to this theory it is thought that catalytic activity is by one of at least two mechanisms, including intramolecular chelation intermolecular coordination with polar solvents. Preferably therefore choice of scaffold SCF may be made according to catalytic activity as a function of intramolecular chelation or intermolecule coordination with polar solvents, for example rigid backbone discourages or prevents intramolecular chelation to a greater extent than a flexible backbone. We have found that it is convenient to record nmr to determine the amount of intramolecular chelation, for example using B nmr, the amount of LA L_B chelation may be determined, a shift of peak to higher field indicating donor-solvent chelation.

In a particular advantage the catalysts of the invention may be selected according to any or all of the above properties, according to the reaction which it is desired to catalyse. For example a catalyst comprising a boronic Lewis acid may proceed via a boron enolate structure in the case of the aldol condensation reaction, with activation of the aldehyde electrophile by the preformed boron enolate. In other reactions, the boron function can act directly as Lewis acid, activating an electrophile and deprotonating a proximal acidic hydrogen, resulting in reaction of the activated electrophile with the deprotonated nucleophile. Accordingly by selecting and tuning the properties of each group and of the molecule as a whole it is possible to catalyse almost any reaction whereby the catalysts of the invention may be considered to be potentially universal organic synthetic catalysts.

Preferably the scaffold stabilises and supports the bifunctional groups in manner to enable intramolecular chelation of the groups, or to enable intermolecular coordination with polar solvents to confer catalytic properties. In certain cases the scaffold prevents the bifunctional groups forming an intramolecular complex, for example provides a rigid structure, however, in other cases it is beneficial for the Lewis acid and Lewis base to stabilise each other by intramolecular chelation. This process is reversible and can assist with substrate release from the catalyst. This is distinct from prior art systems involving Lewis acid - nucleophile catalysis, which are not reversible.

In a particular advantage the catalysts of Formula I provide a variable scaffold structure which can be optimised for use in mediating a wide range of synthetic transformations in particular organic transformations. The catalysts of Formula I include both achiral and chiral variants for use in asymmetric selective transformations in particular in the synthesis of chiral products. We have suprisingly found that the catalysts of the invention catalyse reactions which showed no activity under the same conditions without the bifunctional catalyst, ie with a monofunctional catalyst or with tandem bifunctional catalysts. Without being limited to this theory it is therefore postulated that both the Lewis acid and Lewis base functions of the catalyst aι;e required to be part of the same structure and proximal to provide the molecular catalysts of the invention.

The catalysts of the invention are moreover "green" catalysts being soluble in aqueous solution, and in certain reactions, can be used without prior activation of one of the active reaction components, for example the carbonyl component can be used directly without prior generation of an enolate, such as a trimethylsilyl enolate, which is often carried out with strong bases and/or with Lewis acids. These catalysts can obviate the necessity for such additional reaction steps and achieve activation of reactants in situ. Preferably any macromolecular catalysts may be employed limited only by molecular weight allowing solubility in solvent, aided by solubilising groups or otherwise. Macromolecules may provide additional functionality such as cavities which are able to act as receptors for substrates, facilitating orientation of reactive groups, as known in the art.

Catalysts may be chiral or non chiral. Preferably a. catalyst of the invention comprises a chiral backbone for example comprises a biaryl structure, chiral scaffold or chiral Lewis acid or base function such as a chiral amine or chiral boron function. Preferably chiral catalysts are provided in enantiopure form.

In the case of multiring scaffolds, groups L_A and LB may be on the same or different rings within the scaffold. Groups on different rings may be located to allow intramolecular chelation for example in the case of structures such as fenocene and paracyclophane, or to prevent intramolecular chelation for example in the case of structures such as benzimidazole; Preferably when -N= or -NR¹- forms part of SCF, -N= or -NR¹- form part of a C_3-2o fused aromatic group or cyclic or aliphatic group.

Most preferably the catalyst is of formula la - Iu:

Most preferably L_B as hereinbefore defined is selected from -NH , -N(CH₃)₂, N(iPr)₂, -NH-, -NCH₃-, -NC₄H₉-,

wherein R is as hereinbefore defined.

Most preferably the catalyst of formula I is of formula I¹ or I¹¹

BX₂ wherein X is OH or F and R³ is H, linear or branched Cι_-8 alkyl, or a hydrophilic polymeric group as hereinbefore defined; or I II

10

wherein R is R² as hereinbefore defined, preferably isopropyl; and X is F or OH.

Preferably the bifunctional groups L_A and L_B are supported in manner to provide a desired separation and spatial organisation of functionality which facilitates catalytic activity of the catalyst of formula I.

Preferably bifunctional groups L_A and L_B are of separation of the order of 1.2 to 4 Angstrom, more preferably 1.2 to 2.3 Angstrom. This may be substantially equal to the skeletal separation of from 1 to 5, preferably 1 to 3 interatomic bonds or maybe a spatial separation which is significantly less than the skeletal separation of greater than 5 interatomic bonds depending on the orientation and conformation of the groups LA and L_B.

For example in a catalyst in which groups L_A and L_B are separated by from 1.2 to 4, preferably 2.3 Angstrom as hereinbefore defined, the intervening scaffold may comprise a linear skeleton from 1 to 5, preferably 1 to 3 interatomic bonds or may comprise a curved skeleton of 6 or more for example 8 or more interatomic bonds, wherein the skeleton winds back on itself such that the groups LA and L_B are at a lesser spatial separation than the total skeleton length. The intervening scaffold may be rigid or fixed whereby the separation of groups L_A and L_B may be constant or may vary according to phase and presence of cooperating species, such as water acid etc. In some cases the catalysts of the invention derive their powerful effect from the ability to vary their activity by changing conformation. In this regard it is thought that the catalysts of the invention provide a strong analogy with naturally occurring catalysts in particular such as enzymes.

Catalysts may be homogeneous or heterogeneous.

Preferably a homogeneous catalyst is soluble in aqueous or organic solvent, more preferably in aqueous solvent or mixed aqueous solvent systems, and may be solvated or may form intramolecular coordinations such as micelles or emulsions and the like. Catalysts of the invention are stable and may be isolated in solid form, in many cases in crystalline form. Preferably a heterogeneous catalyst is unsupported, eg powder, or attached to a solid support or a resin system, such as a porous or non-porous crosslinked or non- crosslinked hydrophilic or otherwise functionalised resin, for example Me rifield (DVB crosslinked polystyrene) or Tentagel or ArgoGel (porous polystyrene + PEG) resins, glass support, ceramic support or the like. One or more molecules of catalyst may be supported in independent manner or in manner to form bimolecules and higher coordinations.

Preferably the bifunctional catalyst is attached to a solid support or a resin system by means of a group R which is pendant to ""* or SCF or SCF or SCF as hereinbefore defined, wherein R³ is a hydrophilic polymeric group as hereinbefore defined.

Preferably a catalyst is in the form of a resin more preferably resin beads, most preferably of the order of 50-200 micron. It is an advantage that the catalysts are active without surface treatment, washing or the like for activation.

It is a particular advantage of the invention that the catalysts are readily synthesised and resolved. Bifunctional catalysts may be conceived comprising a combination of Lewis acid and Lewis base groups, but these are in many cases extremely difficult to synthesise, in some cases cannot be isolated, and may not be active. The catalyst of the invention is highly active and catalyses rapid reaction of many reaction types.

In a further aspect of the invention there is provided a composition comprising a catalytically effective amount of a catalyst of Formula I as hereinbefore defined together with suitable solvent, dilutent and the like or together with a suitable linker on a macromolecule, polymer or a solid support.

A supported catalyst may be useful in combinatorial chemistry for conducting plural parallel reaction with labelling and identification of reaction products thereby negating the need for analysis. A support is any catalyst support as known in the art or hereinbefore defined.

In a further aspect of the invention there is provided a novel compound of Formula I as hereinbefore defined with the proviso that when L_AX_AΪI¹ is B(OH)₂ and L_BX_BΠI¹ is -NH- or -NCH}- and L_B is an imidazole nitrogen then

is not 2-phenyl benzimidazole or 2-benzyl benzimidazole in which B(OH)₂ is an ortho substituent on the phenyl or benzyl ring; or in the catalyst of Formula I when LA-X_AII¹ s B(OH)₂ and L_B-X_BUI¹ is -N= then "-^ is not quinoline in which

B(OH)₂ is in the 8-ρosition; JF or ^β is not dimethyl-5-(4-iodophenyl)-dipyrrin or dimethyl-5-

(phenyl)-dipyrrin when LA is BF ; or is not o-phenyl when LB is N(C₂H₅)₂ or N(iPr)₂ of NAcCH₃ and L_A is B(OH)₂; or is not o- piperidine phenyl when LA is B(OCH₃) ; or when LA and L_B are each pendant to an intervening double bond, and LA is dialkylboron, the double bond does not include a further pendant group consisting of O, P, S andN.

In a further aspect of the invention there is provided a process for selective transformation of one or more substrates in the presence of catalyst of Formula I as hereinbefore defined or a composition or kit thereof to provide a product, with simultaneous or subsequent recovery of the catalyst. Preferably a selective transformation is reversible, more preferably reversible asymmetric. Selective transformation may be stereoselective in which case the invention includes subsequent separation of the product enantiomers. Preferably a selective transformation is suited for a combinatorial chemistry approach reacting a substrate with a plurality or reagents or cosubstrates, or reacting a plurality of substrates with one or a plurality of reagents or cosubstrates in the presence of amounts of a catalyst as hereinbefore defined. For example selective transformations may be conducted with a bead or sample of catalyst per well or pot for example in a 96 well plate. In a particular advantage of the invention the catalysts are highly active, of the level of biochemical catalysts and may be used in the order of milligrams.

A selective transformation may be any suitable reaction that may be catalysed by the catalyst of the invention, including its salts and N-dipolar adducts.

Preferably a selective transformation is selected from a condensation, eg aldol or Henry reaction, Darzens, Bayliss-Hillman, alkylation, oxidation, eg Baeyer Villiger, acylation (including Friedel-Crafts, amide, ester and acetal formation), hydrolysis (eg ester, amide and acetal hydrolysis), substitution, ring opening eg epoxide ring opening, nucleophilic addition eg cyanosilylation or Michael addition, electrophilic addition, and the like.

Preferably a selective transformation is conducted with selection of catalyst with appropriate balance of Lewis acidity of boron function versus Lewis basicity of Lewis base function. In some cases L_A and L_B coordination is desireable and facilitates catalysis whilst in some cases coordination may be undesired. Coordination is affected by separation and steric hindarance among other factors. In a particular advantage a selective transformation may be catalysed under mild aqueous or anhydrous conditions using for example an acid catalyst for aqueous transformations such as boronic acid wherein L_A as hereinbefore defined is B(OH)₂, or using a non-acid catalyst for anhydrous transformations such as boron difluoride wherein L_A as hereinbefore defined is BF₂. Solvents may be polar or non-polar.

Preferably a selective transformation comprises an aldol reaction, wherein the process comprises the transformation of an aldehyde substrate in the presence of a ketone substrate and catalyst of formula I. Preferably the catalyst is of formula I as hereinbefore defined where f j is aryl, preferably benzimidazole, more n prrpe.ffpeirraabb!ly n pbhftennyll h bnorrromnnattfie ^t&W benzimidazole of formula I¹

Different aldehydes may be used. Aryl aldehydes react to produce unsaturated methyl ketones, whereas alkyl aldehydes produce the conesponding aldol addition product. The transformation is suitably given by Scheme A or B wherein Sub indicates Substrate.

A: Sub CHO (I), aldehyde Sub CH=CH=CHO

B: Sub CHO (I), aldehyde Sub CHOHCHCH₃N0₂

In Scheme A or B aldehyde substrate is suitably optionally alkoxy or NO₂ substituted benzenaldehyde or C_1-8 alkyl or alkenyl aldehyde. Ketone substrate is suitably C_1-6 alkyl or alkenyl ketone such as acetone.

The process may be conducted in the presence of undried reagents. Suitably the reaction is conducted in aqueous ketone, for up to 25hours, and work up; or in the presence of organic solvent such as deut THF at room temperature for up to 2 weeks followed by work up; or in water at room temperature for 2 to 5 days.

Alternatively a selective transformation comprises an amide formation comprising transformation of carboxylic acid substrate in the presence of an amine substrate. Preferably the catalyst catalyses the selective transformation of an amino acid to a peptide, giving an amide. In a particular advantage this catalyst enables the generation of peptides, eliminating the need for traditional coupling reactions. Advantageously the catalyst of the invention has similar activity to peptidase in the generation of peptides.

The transformation is suitably given by Scheme C wherein Sub indicates Substrate and I indicates catalyst of formula I. Preferably the catalyst is of the formula I^π comprising a catalyst of the formula I as hereinbefore defined wherein ^ is phenyl or naphthalenyl or benzimidazole and LA is BX₂ as hereinbefore defined, pprreeffeerraabbllyy BF₂ or B(OH)₂ and LB is ortho or meta to L_A and is (CH)_0-3NR² ₂ preferably

C: Sub COOH (II) Sub CONHR⁴ ₂

In Scheme C carboxylic acid substrate is suitably optionally unsubstituted or substituted phenyl carboxylic acid such as phenyl butanoic acid or C_2-8 aliphatic carboxylic acid such as t-butanoic acid. Amine substrate is suitably benzylamine or C_1-6 alkyl or cyclic amine such as morpholine. Amide product is suitably a secondary or tertiary linear or cyclic amide where R⁴ is aryl, aralkyl, or heterocyclic such as morpholine.

The process may be conducted in the presence of undried reagents, suitably aqueous amine, for up to 24 hours, and work up; more preferably the reaction is carried out in the presence of organic solvent such as toluene at elevated temperature in the range 70 - 250C for up to 24 hours followed by work up or solvent evaporation. Catalyst is present in an amount of 1 mol % or less and transformation is quantitative. The combined use of external drying agents, such as by use of a soxlet extraction system can also be beneficial and shorten reaction times.

Catalyst of the invention is seen to catalyse transformation in the above processes and transformation is expected in a range of reactions such as hydrolysis, acylation, substitution and alkylation reactions.

Enantiopure catalyst of formula I as hereinbefore described, for example comprising chiral amines, chiral boron functions and chiral scaffolds, are useful in a series of asymmetric transformations, including kinetic resolutions and alkylation reactions and additionally in new reactions which have to date not been achieved in a catalytic asymmetric manner, i.e. haloalkoxylation and aza-Baeyer-Villiger reactions. The catalysts of the invention are true catalysts and are not consumed in the reactions which they catalyse. Preferably catalyst is regenerated by known means for example boiling to regain water, co-addition of other reagents to absorb excess acid and the like and encourage catalyst regeneration. For example regeneration of a catalyst from a Friedel-Crafts reaction in which HX is eliminated with consumption of water, boiling in water facilitates water uptake and catalyst regeneration. Alternatively in reactions producing excess acid, co-addition of stoichiometric amounts of a base such as pyridine, supported on a solid support, facilitates absorbing excess acid, whereafter the supported base can be simply separated by physical separation techniques such as filtration and the like in known manner.

Catalyst recovery is suitably 90-100%. Advantageously, catalytic performance is highly reproducible and the catalyst is readily re-used.

The catalyst of the invention may be used in any suitable form and amount. Catalytic amounts of 2.5 micromol to 2 mmol, and 0.01 to 100mol%, preferably 0.1 to 100 mol % for example 0.1 to 5 mol% or 5 to 100 mol % may be used. In a further aspect of the invention there is provided a kit comprising one or a plurality of catalysts or compounds of Formula I as hereinbefore defined adapted to catalyse one or a plurality of selective transformations as hereinbefore defined, together with one or more reagents, analytical substrates and the like for conducting the reaction(s), isolating chiral or nonchiral products and determining the products. Preferably the kit comprises a catalyst of Formula I together with a plurality of reagents and/or analytical substrates and is for use in a combinatorial catalytic transformation and screening. h a further aspect of the invention there is provided the use of a compound or catalyst of Formula I or kit thereof as hereinbefore defined in catalysing a selective transformation. A selective transformation is suitably as hereinbefore defined and ' may include asymmetric processes. The use of the compound or catalyst or kit may be of the class of catalysts of Formula I as a universal class of catalysts from which optimal catalysts for each transformation may be selected, in which basicity and acidity are tuned by the scaffold structure. Preferably a selective transformation employs two or more reactive sites on one or more substrates by cooperative effect of Lewis acid and Lewis base functions. Preferably a selective transformation does not proceed at all in the presence of only one Lewis acid or Lewis base function or a mixture thereof on separate entities. Preferably a selective transformation is reversible.

In a further aspect of the invention there is provided a method for screening one or more catalysts of Formula I as hereinbefore defined as useful catalysts for a desired selective transformation, comprising conducting a process for selective transformation with one or a plurality of catalysts of Formula I and analysing the product. In a further aspect of the invention there is provided a method for screening one or more catalysts of Formula I as hereinbefore defined as useful catalysts for any selective transformation, comprising conducting in parallel a plurality of processes for selective transformation with one or a plurality of catalysts of Formula I and analysing the product of each transformation.

Preferably the method for screening is carried out under both anhydrous conditions (eg for the BF₂ systems) and under aqueous conditions (for the acid B(OH)₂). Preferably the method comprises highly parallel reaction screening with real-time reaction monitoring, preferably using online, parallel LC-MS, in conjunction with an automated workstation system.

Preferably the screening method includes achiral reaction rate experiments, in which a comparison of the rate of the reaction between catalysed and uncatalysed transformations for processes such as amide formation and hydrolysis, ester formation and hydrolysis, epoxide ring opening, Michael additions, aldol and Henry reactions, alkylations and acylation (including Friedel-Crafts reaction) and aza- Baeyer-Villiger reactions are carried out.

Preferably the method includes screening in 3 different solvents (polar to non-polar), several different substrates (range of substitutions and reactivities), and comparing several standards (no catalyst, model Lewis acid alone, model Lewis base alone, both model Lewis acid and Lewis base) with the bifunctional catalyst-containing reaction and analytical monitoring over time, in order to show that the bifunctional catalyst is more reactive than any of the comparative reactions.

In a further aspect of the invention there is provided a screening kit for use in the screening method of the invention as hereinbefore defined comprising one or more catalysts together with one or more reagents for analysing the product of reaction.

In a further aspect of the invention there is provided a product of a catalytic reaction obtained with use of a catalyst as hereinbefore defined. In a further aspect of the invention there is provided a process for the preparation of a compound of Formula I as hereinbefore defined comprising: a) in the case that n¹ is 2 and each X_A is halogen: halogenation of a compound II: (L'AO)₃ -SCF - L_EX_BIΠ¹ to isolate the compound of Formula I : L_A'X_AΠ¹ - SCF - L_B'F₂; preferably compound II is obtained by directed metallation of a compound HI: SCF - Lβ_'Xβm¹, with a metal oxide Lv(OR⁴)₃ where R⁴ is methyl, ethyl, propyl or butyl to introduce a cyclic metal oxide precursor of the Lewis acid function; or b) in the case that n^s 2 and each XA is OH: reduction of Lewis acid ester compound IV L_B'X_BΠI -SCF - LvO₂R where O₂R is a cyclic alkyl such as - (C(CH₃) )₂ - to isolate the compound of Formula I: LA>(OH)₂ - SCF - L_B'X_BIΪI¹; preferably compound IV is obtained by directed metallation of a compound V RCOL_BX_BΠI¹, with an oxide LA>(OR⁴)₃ where R⁴ is as hereinbefore defined such as iPr to introduce an ester precursor of the Lewis acid function; or c) in the case that L_B-X_BUI¹ is integral with SCF, n¹ is 2 and each X_A is halogen: halogenation of a compound VI: Br

to isolate the compound of Formula I

preferably compound VI is commercially available or where SCF comprises a spiro biaryl structure SCF¹ - SCF² where each SCF is an aryl group Ar¹ and Ar² , is obtained by reaction of a compound VII H₂N- Ar¹ - NHC₄H₉ with a compound VIII: Br - Ar² - CO₂H to form VI: Ar^-NCnC^CHN-) - Ar² - Br; preferably compound VII is obtained from the conesponding nitroamine VIII: O₂N- Ar¹ - NHC₄H₉; which is obtained from the conesponding bromo nitro aryl IX: O₂N- Ar¹ - Br which is commercially available; or d) in the case that L_B'X_BΠI¹ is pendant to SCF, n¹ is 2 and each XA is OH: cyclisation of a compound VII:

with a compound VIII:

OCH SCF X Bτ

and reductive substitution, such as reductive amination, to generate the boronic acid and to isolate the compound of Formula I : SCF¹ (NHR) ( L_B) - SCF² L_A> XAΠ¹; preferably compounds VII and VIII are commercially available, and R may be readily interchanged by alkylbromination to give substituted amino Lewis acid Lewis base catalysts; or e) in the case that L_A'XAH' s pendant to SCF, n is 2 and each X_B is any alkyl, aryl or cycloalkyl substituent: reductive amination of a compound IX:

CO₂H

with an amine to generate the boronic acid and to isolate the compound of Formula I

SCF L_B L ; preferably compound IX and amines are commercially available, and Lewis base may be selected by selection of amine.

Alternatively a catalyst of Formula I in which X_A is halo such as F may be obtained by interconversion from a conesponding compound of Formula I in which X_A is OH by halogenation; or from the MF₃ ^" salt of compound of Formula I obtained KF and generating the product compound of Formula I in which X_A is F by reduction for example with BuLi. Depending on the nature of Lewis base and separation of Lewis base and acid groups determines whether compound of formula I is isolated directly as the dihalide or as the KF salt or LA >F₃ ^" H^1" salt, and salts may be freed in known manner to generate the neutral product.

Process a) above is preferably conducted in aqueous hydroxide such as NaOH, at pH in the range at or close to neutrality; the intermediate II is preferably obtained by reaction at temperature in the range 15 - 50C, time of 12 to 150 hours with metallation agent selected from nBuLi, or other common metallating agents, optionally in solvent such as Et₂O.

Process b) above is preferably conducted in the presence of hydrogenation agent such as NaBH₄, or borane, and solvent at temperature in the range 15 to 150C, and a sequence of base and acid treatments; the ester intermediate III is preferably obtained by reaction at temperature in the range -100 - - 50C, time of 0.5 - 5 hours with metallation agent selected from nBuLi, or other common metallating agents, optionally in solvent such as THF, and with acid or water, and with pinacol or other mono-alcohol, or diol. Process c) above is preferably conducted at temperature in the range -100 - - 50C, time of 1 - 5 hours with metallation agent selected from nBuLi, or other common metallating agents, optionally in solvent such as Et₂O, and with subsequent base and acid treatments; intermediate VI is suitably obtained by reaction of Ar¹ and Ar² in the presence of polyphosphoric acid (PPA) at temperature in the range 100 - 250C, for 3 to 7 hours followed by base treatment at pH > 7 and 0 - 10C; and by reduction using eg Pd/C and H at temperature in the range 10 to 50C and for time 1 to 5 hours; and by metallation with nBuLi at temperature in the range 50 to 100C for 6 to 15 hours.

Process d) above is preferably conducted in the presence of oxone or polyphosphoric acid in aqueous solvent, eg aqueous DMF and alkylbrommation is conducted in the presence of NaH, solvent (THF) and ether such as 15-crown-5, followed by reductive substitution with i) nBuLi, ether at reduced temperature (-78C), ii) boronic acid at reduced temperature (-78C) and iii) aqueous work up.

5 Interconversion is suitably with aqueous halogenation agent such as KHF and solvent such as methanol at temperature in the range 0-80C and for a time in the range 0.5-5 hours.

Preferably the process comprises 10 a) introducing a boroxine function by directed metallation, followed by isolation of difluoroborane directly from reaction of the boroxine with KHF₂ _as shown in Scheme a:

b) introducing a boronic acid function by directed metallation, followed by

20 trans-esterification and amide reduction requiring intermediate or product compound of Formula I (X = OH) to be soluble in acidic, basic and neutral aqueous conditions, followed by conversion to the HF salt by reaction with KHF₂. Generation of the ArBF₂ product compound of Formula I (X =F) is accomplished by reaction with tert-butyl lithium as shown in Scheme b:

25

Scheme b

,

I (X = F) The overall process b) is highly efficient and has been carried out on >10g scale, with each step being accomplished in >60 % yields; d) introducing a brominated scaffold moiety to an amine containing Lewis base scaffold moiety by substitution, using oxone, using a primary amine in the Lewis base allows substitution by any other group, for example introducing a tail suitable for anchoring to a solid substrate, and reaction with boronic acid gives the double scaffold product as shown in scheme d:

R = H, Bu

wh

e) reductive amination of a phenylcarboxylic acid boronic acid with selected amines as shown in scheme e:

where phenyl is illustrative of

Chiral product may be obtained as a racemic mixture and may subsequently be separated by methods as known in the art, such as by chiral stationary phase HPLC or by afropisomer-selective transformation with salt formation, enabling resolution. Alternatively product may be obtained as the pure or enriched enantiomer. hi a particular advantage of the invention catalysts may be isolated by any of a number of means under a number of conditions, by virtue of the bi or multifunctionality thereof. Suitably catalyst is isolated by basicity, Lewis acidity, pH or the like, typically by crystallisation from water, for example aqueous solvent or wet solvent. Alternatively catalyst may be isolated in known manner by formation of derivatives such as salts of amines and separation by crystallisation, or formation of esters such as vinyl esters and separation by chromatography. The catalysts are also suited for preparation of a range of analogues having different Lewis acid and base substituents, specifically salts, hydroxides, halides and amines.

In a further aspect of the invention there is provided a novel intermediate of formula II, III, IV, V, VI or VII as hereinbefore defined.

The invention is now illustrated in non-limiting manner with reference to the following examples and figures.

SUMMARY OF SYNTHESIS AND NMR ANALYSIS OF LEWIS ACTIVITY

We have prepared the following amino-boronic acids and amino-difluoroboranes shown in Tables 1 and 2. The completed successful syntheses have required the development of new procedures and has involved a mixture of both directed metallation, and lithium-halogen exchange and Grignard reactions in order to introduce the boronate functions into the various substrates. The catalysts prepared (Tables 1 and 2) have all required different procedures to be developed in order to be able to: 1) isolate the pure amine-boronic acid derivatives (X = OH) or in certain cases, boroxines; and 2) generate the conesponding difluoroboranes (X = F). This is a direct result of the difference in basicity of each of the nitrogen functions which requires that individually tailored reaction and isolation conditions have been required. This is exemplified by the syntheses of two catalysts, outlined in Schemes a and b. In Scheme a, it can be seen that isolation of catalyst 12 can be achieved efficiently (all yields >70%), and it is noteworthy that the difluoroborane is isolated directly from reaction of the boroxine with KHF₂. Similar reactions have been applied to the synthesis of catalysts 17 and 3,7.

Additional structures

This however, is not typical of the conversion of different amine-boronic acid derivatives. In certain cases, KF salts are obtained, in other cases, the conesponding HF salts are obtained. For example, in the case shown in Scheme 2, the boronic acid function is introduced by directed metallation, which after several steps involving trans-esterification and amide reduction (this step took considerable process development due to the ability of derivative 14 (X = OH) to be soluble in acidic, basic and neutral aqueous conditions!), can be converted to the HF salt 15 by reaction with KHF₂. Generation of the ArBF₂ derivative 16 (X =F) is accomplished by reaction with tert-butyl lithium. The overall process is highly efficient and has been carried out on >10g scale, with each step being accomplished in >60 yields. The same reaction scheme has been applied for the preparation of the conesponding fenocene catalyst 10, however, the amide reduction step is far less efficient (30 %) and results in a degree of proteo-deboronation and further process optimisation is required to improve the yield of this one step. However, an alternative asymmetric catalyst has been generated, i.e. 18, which is prepared similarly to catalyst 16, though scale up to >lg scale has yet to be carried out. Overall, we have developed several general different routes for the synthesis of different amine-boronic acids and the conesponding difluoroboranes derivatives, which can be applied to other catalysts in the general Formula I. In each case, the catalysts have been obtained in analytically pure form and have been unambiguously characterised, including by ^πB NMR (as well as ¹⁹F NMR where relevant and several X-ray structures), which in all cases clearly demonstrates the level of boron- nitrogen coordination. Hence, systems typified by 14,16 and 12 show strong intramolecular N-B chelation, but this is weak or non-existant in systems 17, 19 and 3,7. hi these systems, intermolecular coordination occurs with polar solvents instead of intramolecular chelation (this occurs in either acetonitrile or dimethylsulfoxide, both of which are used as NMR solvents). Having characterised each of the boronic acids and difluoroboranes, it was important to clarify that B-N chelation does not interfere with the ability of such systems to act as both Lewis acids and Lewis bases. To do this a series of NMR characterisation experiments were carried out on each of the bifunctional catalyst systems and these were compared with a series of standards (non-bifunctional). This consisted of the following: estimating the relative Lewis acidity of bifunctional compounds by their ability to coordinate acrolein and methacrolein using the method of R. F. Childs, D. L. Mulholland, A. Nixon, Can. J. Chem., 1982, 801; b) Idem, ibid, 1982, 809 and comparing this with M.F. de la Tone, C. Caballero, A. Whiting, Tetrahedron, 1999, 55, 8547 the contents of which are incorprated herein by reference. These NMR experiments showed a clear indication that the carbonyl function of crotonaldehyde is bound reversibly to boron.

A. SYNTHESIS OF CATALYSTS OF FORMULA I

Preparation of Compound 3 N-MethyI-2-(2-difluoroboronophenyI) benzimidazole

N-Methyl-2-(2-bromophenyl)benzimidazole

N-methylphenylene-l,2-diamine (12.0 g; 0.10 mmol), 2-bromobenzoic acid (19.9 g; 0.01 mmol) and polyphosphoric acid (60.0 g) were mixed into a paste and heated to 175 °C under argon for 4 hours. The reaction solution was then poured into ice water (ca. 400 ml) and the pH adjusted to 10-11 with ammonium hydroxide. The resulting sticky solid was then dissolved in ethanol (50 ml) and reprecipitated with dilute ammonium hydroxide at pH 10-11 to yield pale purple needles (23.7g). The

(12370), 284.0 (11940); δ_H(400 MHz, [CDC1₃]) 3.66 (3H, s, CH₃N), 7.30-7.43 (4H, m, ArH), 7.46 (IH, td, J= 7.4 and 1.4, ArH), 7.54 (dd, IH, J= 1.6 and 1.6, ArH), 7.71 (dd, IH, J= 8.0 and 0.8, ArH), 7.84 (dd, IH, J= 7.1 and 1.6, ArH); δ_c(100 MHz, [CDC1₃]) 31.1, 109.9, 120.4, 122.7, 123.2, 124.1, 127.8, 131.7, 132.4, 132.7, 133.1, 135.7, 143.0, 152.8; m/z (EI+) inter alia 288(94%, M^{+* 81}Br), 286 (96, " ⁷⁹Br), 207 (100), 206 (75) ; HRMS (EI+) C₁₄H_πN₂ ⁷⁹Br requires 286.0106, found 286.0104; C₁₄H_πN₂ ⁸¹Br requires 288.0085 found 288.0085. C₁₄H_uN₂Br requires: C, 58.56; H, 3.86; N 9.76; found C, 59.04; H, 3.87; N, 9.78.

N-MethyI-2-(2-boronophenyl)benzimidazole.

t-Butyllithium (29 ml, 1.69 M in hexanes; 48.8 mmol) and dry diethyl ether (162 ml) were placed in a flask and cooled to -72 °C. A solution of N-methyl-2-(2- bromophenyl)benzimidazole (7.0 g; 24.4 mmol in 315 ml of dry diethyl ether) was then added dropwise over 1.5 hrs. The resulting suspension was then stined for a further 2 hours at -72 °C. A solution of triisopropylborate (23.5 ml in 250 ml of dry diethyl ether) was then added dropwise over 0.5 hr. After stirring at -72 °C for further 0.5 hr the solution was allowed to warm to room temperature overnight. 5 % Aqueous sodium hydroxide (300 ml) was then added and the layers separated. The pH of the aqueous phase was then adjusted to pH 1-2 with concentrated HCl. The aqueous phase was then washed with diethyl ether (3 x 50 ml). The aqueous phase was then adjusted to pH 7-8 with 5% sodium hydroxide, saturated with salt and extracted with chloroform (3 x 100 ml). Evaporation of the solvent yielded N- methyl-2-(2-boronophenyl)benzimidazole as a cream solid (4.8 g; 78%): mp 218 dec °C; V_ma_x nujoiyc n ¹ 1734, 1596, 1532, 1491, 1433, 1370, 1325, 1296, 1279, 1256, 1239, 1174, 1135, 1118, 1063, 749; λ_max(CH3CN)/nm 208.0 (ε/dπΛnor ¹ 49610), 244.0 (15620); δ_H (400MHz [CDC1₃]) 3.16 (3H, s, CH₃N), 7.00-7.08 (IH, m, Ar-H), 7.18-7.24 (2H, m, Ar-H), 7.26-7.32 (2H, m, Ar-H), 7.38-7.48 (2H, m, Ar-H), 7.55-7.60 (IH, m, Ar-H); δ_c (100 MHz [CDC1₃]) 30.8, 109.5, 117.2, 122.2, 122.7, 124.0, 125.0, 127.9, 130.1, 131.4, 132.4, 132.6, 136.0, 137.0, 155.6; δ_B (96 MHz, [CDC1₃]) 15.5 (br s); m/z (ES+) inter alia 253 (100%, M+H), 469 ( 65%, 2M- H₂O). HRMS (ES+) C₁₄H₁₄N₂O₂ ^πB requires 253.1148, found (M+H) 253.1172.

N-Methyl-2-(2-difluoroboronophenyl)benzimidazole.

BF₂ 3 N-Methyl-2-(2-boronophenyl)benzimidazole (1.0 g; 3.9 mmol) was dissolved in methanol (5 ml) and aqueous potassium hydrogen fluoride (0.9 g; 11.7 mmol in water 5 ml) was added dropwise. This resulted in the formation of a white precipitate, further water (5 ml) was added and the resulting suspension filtered to give a mixture of two compounds. Recrystallisation from acetonitrile enabled one of the compounds to be isolated 0.198 g; 10 %;;

1575, 1550, 1489, 1333, 1299, 1263, 1193, 1173, 1120, 1097, 1059, 1021, 1005, 970, 945, 927, 831, 803, 788, 740, 753, 723; λ_max(CH3CN)/nm 196.0 (ε/dπΛnor ¹, 41530), 224.0 (12690), 244.0 (7930), 252.0 (6990), 296.0 (10460), 312.0 (12100); δ_H (400MHz [(CD₃)₂CO]) 4.41 (3H, s, CH₃), 7.47 (IH, td, J=1.2 and 7.6, Ar-H), 7.50-7.58 (2H, m, Ar-H), 7.67 (IH, d, J= 7.2, Ar-H), 7.76 (IH, dd, J= 6.4 and 2.0, Ar-H), 7.85-7.91 (IH, m, Ar-H), 8.07 (IH, d, J=6.0, Ar-H); δ_c (100MHz [(CD₃)CO₂CO]) 32.3, 113.0, 115.5, 123.9, 125.1, 126.2, 128.7, 130.5, 132.7, 133.1, 138.1; δ_B (128 MHz, [(CD₃)- ₂CO]) 6.0 (br t, J= 49.0); δ_F (188 MHz, [(CD₃CN]) -165.4- -164.8 (m); m/z (EI+) inter alia 255 (100%, M-H), 256 (27, M+); HRMS (EI+) CuHπN^B^F;, requires 256.0983, found: M^+m) 256.0983.

Preparation of Compound 7 - N-bntyl-2-(2-boronophenyl)benzimidazole l-ButyIamino-2-nitrobenzene α NHBu

4 2-Bromonitrobenzene (20.0 g; 0.099 mol) and n-butylamine (36 ml; 0.366 mol) were dissolved in DMSO (100 ml) and heated to 80°C and stined overnight. The reaction solution was then allowed to cool to room temperature before the addition of water (300 ml). The resulting solution was then extracted with DCM (3 x 150 ml). The combined extracts were then washed with brine (3 x 100 ml) and dried over MgSO₄. Filtration and evaporation of the extracts yielded the title compound as a yellow oil in quantitative yield. The product was used for the following step without further purification: V_maxfreatycm^"1 inter alia 3381, 3084, 1618, 1572, 1510, 1419, 1354, 1263, 2333, 1159, 1038, 861, 742; λ_max(EtOH)/nm 208.3 (ε/dr^mol^cm^"1 9550), 230.0 (21990), 260.8 (5580), 283.9 (7660); δ_H (400MHz [CDC1₃]) 0.97 (3H, t, J=7.2, CH₂CH₃), 1.47 (2H, sextet, J=7.4, CH₂CH₂CH₃), 1.71 (2H, quintet, J=7.3, CH₂CH₂CH₂), 3.28 (2H, m,CH₂NH), 6.60 (IH, ddd, J= 8.5, 6.8, 1.3, Ar-H), 6.83 (IH, ddd, J= 8.8, 0.8 and 0.4, Ar-H), 7.41 (IH, dddd, J= 8.8, 6.8, 1.6 and 0.8), 8.04 (IH, br s, N-H), 8.14 (IH, ddd, J= 8.4, 1.6 and 0.4); δ_c (100 MHz [CDC1₃]) 14.0, 20.5, 31.2, 42.9, 114.0, 115.2, 127.1, 131.9, 136.4, 145.9. m/z (ES+) ter alia 211 (100, M+Na), 195 (M+H); HRMS (ES+) found: (M+Na) 217.0962, C₁₄H₁₄N₂O₂B requires 217.0953.

N-Butyl-1 ,2-phenylenediamine

l-Butylamino-2-nitrobenzene (20 g; 0.10 mol) and Pd/C catalyst (2 g 10% Pd/C; 1.88 mmol) were placed in methanol and stined under hydrogen for 3 hours. The reaction was maintained at room temperature by the use of an ice-water bath. The resulting solution was the filtered through a short silica gel column to remove the catalyst. This gave a clear colourless solution which turned brown upon standing. Evaporation of the solvent gave the title compound as a viscous brown liquid, which was used for the following step without further purification, δπ (400MHz [CDC1₃]) 0.99 (3H, t, J= 7.4, CH₃CH₂), 1.48 (2H, sextet, J=7.4, CH₂CH₂CH₃), 1.68 (2H, quintet, J=7.3, CΑ₂CΗ₂CΑ2), 3.12, (2H, t, J=7, CH₂N), 3.37 (3H, br s, N-H), 6.66- 6.76 (3H, m, Ar-H), 6.85 (IH, td, J=7.4 and 1.8, Ar-H); δ_c (100 MHz [CDC1₃]) 14.3, 20.7, 32.0, 44.3, 112.0, 116.7, 118.7, 121.0, 134.3, 138.2.

2-(2-Bromophenyl)-N-butyl-liϊ-benzimidazole

N-Butyl-l,2-phenylenediamine (20 g;0.122 mol) and 2-bromobenzoic acid (26.8 g; 0.133 mol) were mixed into PPA (80 g), placed under an atmosphere of argon and heated to 180 °C for 6 hours. This resulted in the formation of a black solution which was poured into ice-water (~ 500 ml) whilst hot. The resulting water-tar mixture solution was then adjusted to alkaline pH by the addition of dilute ammonium hydroxide and further ice. The aqueous phase was then extracted with DCM (1 x 300 ml). Sodium chloride was then added to the remaining aqueous phase and the solution was further extracted with DCM (2 x 200 ml). The combined extracts were then washed with ammonium hydroxide (10%) v/v) containing a trace of ethanol and dried over MgSO₄. Evaporation of the solvent yielded a viscous black oil (28.7 g) which was purified by passing through a short dry silica gel column using diethyl ether to give 2-(2-bromophenyl)-N-butyl-lH-benzimidazole as a viscous brown oil (14.2 g; 35 %); v^filmycm^"1 3058, 2958, 2931, 2871, 1929, 1811, 1665, 1612, 1598, 1563, 1523, 1480, 1451, 1393, 1365, 1329, 1281, 1257, 1243, 1173, 1152, 1133, 1117, 1103, 1087, 1025, 1007, 949, 927, 901, 880, 766, 745; λ_max(EtOΗ)/nm 208.0 (ε/dm³mol^"1cm^"1 29590), 276.0 (5390), 284.0 (5430); δ_H (400MHz [CDC1₃]) 0.70 (3H, t, 7.2, CH₃CH₂), 1.09 (2H, sextet, J=7.4, CH₃CH₂CH₂), 1.60 (2H, quintet, J=7.5, CH₂CH₂CH₂), 3.97 (2H, t, J=7.2, CH₂Ν), 7.18-7.46 (6H, m, Ar-H), 7.64 (IH, br d, J=7.6, Ar-H), 7.74-7.80 (IH, m, Ar-H). δ_c (100 MHz [CDC1₃]) 13.7, 20.1, 31.8, 44.6, 110.4, 120.5, 122.5, 123.1, 124.1, 127.7, 131.6, 132.6, 132.7, 133.1, 134.8, 143.2, 152.4; m/z (ES+) inter alia 329 (100, M^+* + H ⁷⁹Br), 331 (96, M^+,+H ⁸¹Br); HRMS (ES+) found: 329.0634 (M+H),

C₁₇H₁₈N₂ Br requires 329.0653.

N-butyl-2-(2-boronophenyl)benzimidazoIe

2-(2-Bromophenyl)-l -butyl- lH-benzimidazole (5.1 g; 15.5 mmol) was dissolved in diethyl ether (250 ml) and cooled to -78 °C. tert-Butyllithium (1.4 M in hexanes; 22.1 ml; 31.0 mmol) was then added dropwise over 40 minutes. The solution was then cooled to -90 °C and triisopropylborate was added in a single aliquot. The solution was then stined at -90 °C for 15 min and a further 1 hr at - 78 °C before being allowed to warm to room temperature overnight. Sodium hydroxide (250 ml; 20 % w/v) was then added and the reaction solution stined for 1 hour. The resulting precipitate was then removed by filtration, and washed with small amounts of water and diethyl ether. The washes were recombined and further precipitation was promoted by partitioning the washes between sodium hydroxide (20 % w/v) and diethyl ether. The combined yield of the title compound was quantitative (4.6 g); m.ρ. 151-153 °C; v^nujoiycm^"1 inter alia 3646, 3428 br, 1616, 1520, 1396, 1377, 1368, 1330, 1283, 1258, 1200, 1174, 1134, 1106, 1059, 1026, 1010, 960, 896, 824, 745. 733, 606; (H₂O)/i]m 204.0 (ε/dπήnor ¹ 27980), 244.0 (9850), 252.0 (9170), 292.0 (11080), 312.0 (14300); δ_H (400MHz [D₂O]) 0.57 (3H, t, J= 7.4, CH₃CH₂), 1.00 (2H, sextet, J- 7.5, CHsCJ^CHz), 1.49 (2H, quintet, J=7.5, CH₂CH₂CH₂N), 3.83 (2H, t, J= 1.6, CH_ϊCHzCIfcN , 7.08-7.22 (4H, m, Ar-H), 7.29 (IH, t, J=8.0, ArH), 7.42 (IH, dd, J= 7.2 and 2.0, Ar-H), 7.53 (IH, dd, J= 6.4 and 2.4, Ar-H), 7.60 (IH, d, J= 7.2, Ar-H); δ_c (100 MHz [(CD)₃CO:D₂O 50:50]) 13.6, 20.1, 31.9, 44.7, 69.5, 111.0, 119.0, 122.5, 122.7, 125.0, 128.9, 129.2, 132.4, 133.4, 135.2, 142.1, 158.9; δ_B (128 MHz, [(CD)₃CO:D₂O 50:50]) 5.43 (br s); m/z (ES+) inter alia 317 (100, M + Na); HRMS (ES+) found: 295.1627 [M+H], C₁₇H₂₀N₂O₂B requires 295.1618.

Alternative Preparation of Compound 6 N-butvl-2-(2- boronophenvDbenzimidazole (R = Bu)

Alternative Preparation method for preparing Compound 6a - ortho- bromophenyI-(N-butyl)benzimidazole (R = H)

A solution of phenylenediamine (1.858 g, 17.2 mmol) in DMF: H₂O (30:1 v/v, 31 ml) was treated with ort^ø-bromobenzaldehyde (1.79ml, 15.5 mmol). Oxone (8.13 g, 13.2 mmol) was added, and the reaction mixture stined at RT for 8 h. The reaction mixture was slowly added to an aqueous solution of NaOH (0.04 M, 300 ml), and the resulting mixture extracted into ethyl acetate (3 x 700 ml), dried (MgsO₄) and evaporated. The dark brown oil obtained was subjected to colum chromatography (hexane : ethyl acetate, gradient elution) followed by recrystallisation (hexanes: ethyl acetate) to give ort/?o-bromophenyl-(N-butyl)benzimidazole as a pale brown powder (1.232 g, 26 %), which is identical to that reported previously. This may be converted to compound 6a as described above. Preparation of ort/to-bromophenylbenzimidazole

A solution of phenylenediamine (1.858 g, 17.2 mmol) in 30:1 DMF/H₂O (31ml) was treated with the ort zo-bromobenzaldehyde (1.79ml, 15.5 mmol). Oxone^® (8.13 g, 13.2 mmol) was added and the reaction mixture stined at RT for 8 h. The reaction mixture was added dropwise into an aqueous solution of NaOH (0.04 M, 300 ml), and the resulting mixture extracted into ethyl acetate (3 x 700 ml). After drying (MgSO₄) and evaporation, the dark brown oil was purified by silica gel chromatography (hexanes : ethyl acetate, gradient elution), followed by recrystallisation (hexanes/ ethyl acetate) to give the ørt/ισ-bromophenyl benzimidazole as a pale brown powder (1.232 g, 26 %);v_max (nujoiycm^"1 z'nter alia 3391, 3059, 2958, 1453, 1393, 1365, 1330, 1281, 1257; δ_H (400 MHz, CDC1₃) 7.28- 7.34 (3H, m, ArH), 7.42- 7.46 (1Η, m, ArH), 7.67-7.71 (3Η, m, ArH), 8.23-8.25 (1Η, m, ArH); δ_c (400 MHz, CDC1₃) 115.5, 120.4, 127.2, 128.0, 130.5, 131.2, 132.8, 134.0, 138.1, 149.8; MS (El) m/z 272 (M⁺ 99 %), 274 (M*, base peak). This may be converted to - ort ϊo-bromophenyl-(N- PEG-2 methyl )benzimidazole (R = [(CH₂)₂O]₂CH₃) by substitution with bromo PEG-2 methyl, and thereafter converted to the boronic acid product by the method as described above.

Preparation of Compound 10 iV-{[2-(difluoroborylferrocenyllmethyl}-iV V-diisopropylamine hvdrofluoride

2-(N,N-Diisopropylamido)ferroceneboronic acid

Diethylether (250 ml) and (-)-sparteine (12.9 ml; 56.0 mmol) were stined at room temperature under argon for 30 minutes. The resulting solution was then cooled to - 78 °C using a cardice/acetone bath. n-Butyllithium (35.0 ml; 1.6 M in hexanes; 56.0 mmol) was then added over 5 minutes and the resulting solution stined for a further 30 minutes. A solution of NN-diisopropyl fenocenecarboxamide* (8.77g; 28.0 mmol; in 250 ml of diethyl ether) was then added dropwise via syringe pump over 9 hours. The resulting solution was then stined at -78 °C for a further 10 hours. Trimethylborate (9.4 ml; 84.0 mmol) was then added in a single aliquot. The solution was then stined for a further 2 hrs before being allowed to warm to room temperature overnight. The reaction was then quenched with water (200 ml) and extracted with diethyl ether (3 x 100 ml). The combined extracts were then washed with brine (3 x 100 ml). Evaporation of the solvent yielded a viscous red oil. Hexane (ca. 30 ml) was then added to promote crystallisation of the desired compound as small orange needles (6.0 g, 60 %). The IR, 1H and ¹³C ΝMR data obtained was consistent with that reported in the literature. * 149-151 °C; λ_max(CH3CΝ)/nm 208.0 (ε/dnAnor ¹ 20280), 264.0 (3880); δ_B (128 MHz, [CDC1₃]) 30.5 (br s).

* M. Tsukazaki, M. Tinkl, A. Roglans, B. J. Chapell, N. J. Taylor, and V. Snieckus; J. Am. Chem. Soc. 1996, 118 (3), 685

2-[(N,N-DiisopropyIamino)methyI]ferrocenylboronic acid

2-(NN-Diisopropylamido)fenoceneboronic acid (5.34 g; 15.0 mmol) was dissolved in THF (50 ml) and borane (70 ml IM in THF) was added. The solution was then refluxed under argon for 6 days. After allowing to cool to room temperature, water (180 ml) was added dropwise and the resulting solution stined for 0.5 hr at room temperature. The reaction liquor was then extracted with diethyl ether (3 x 100 ml). The combined extracts were then back-extracted with 20% HCl(aq) (3 x 100 ml). The combined aqueous extracts were then basified with solid ΝaHCO₃. The resulting suspension was then extracted with diethyl ether (3 100 ml). The combined etheric extracts were then washed with brine (2 100 ml) and evaporated to give an orange oil. Trituration with diethyl ether resulted in the formation of an orange solid which was recrystallised from diethyl ether/hexane to give the title compound as orange needles (3.28 g; 64 %); mp 141-142 °C dec; VmxCnujoiycm * 3452, 1925, 1396, 1357, 1328, 1315, 1269, 1234, 1206, 1195, 1158, 1127, 1104, 1084, 1054, 1044, 1001, 974, 948, 889, 857, 847, 841; λ_maχ(CH₃CN)/nm 208.0 (εΛ ¹ 39990), 244.0 (4550); δ_H (400MHz [CDC1₃]) 0.98 (6H, d, J=6.8, (CH₃)₂CH), 1.12 (6H, d, J=6.4, (CH₃)₂ CH), 3.09 (2H, septet, J=6.6, 2 x (CH₃)₂ CH), 3.44 (IH, d, J=13.2, CHbN), 4.01 (IH, d, 13.2 (QfcN), 4.13 (5H, s, Fc-H), 4.24-4.30 (2H, m, Fc-H), 7.42 (IH, br s, Fc-H), 8.04 (2H, br s, B(OH)₂); δ_c (100 MHz [CDC1₃]) 18.6, 20.9, 46.0, 47.2, 69.4, 73.9, 75.0, 88.3; δ_B (128 MHz, [CDC1₃]) 32.5 (br s); m/z (ES+) ter alia 343 (M^+*,3%) 243 (100, M-CH₂N(CH(CH₃)₂)₂); C₁₇H₂₆NO₂BFe requires: C, 59.52; H, 7.64; N 4.08; found C, 59.61; H, 7.71; N, 3.97.

iV-{[2-(difluoroborylferrocenyl]methyl}-i\yV-diisopropylamine hydrofluoride

2-[(NN-diisopropylamino)methyl]fenocenylboronic acid (1.0 g; 3.0 mmol) was dissolved in methanol (25 ml) and a solution of KHF₂ (1.4 g; 17.9 mmol in 5 ml water) was added. After stirring the resulting suspension for 0.5 hr at room temperature acetone (50ml) was added and the resulting solution stined for a further 0.5 hr. The solvent was then removed under reduced pressure to yield a yellow residue, which was extracted with DCM (ca. 30 ml). Evaporation of the solvent gave the title compound as a yellow powder in quantitative yield; m.p. 176.0 °C; V_max nujoiycm^"1 3450 br, 3121, 3077, 2727, 1629, 1400, 1343, 1310, 1277, 1228, 1188, 1151, 1134, 1119, 1103, 1067, 1036, 1012, 983, 965, 951, 936, 914, 897, 866, 855, 833, 814, 763, 665; λ_max(CH3CΝ)/nm 192.0 (εΛ mol^{' 1} 49130), 204.0 (44930), 260.0 (7050); δ_H (400MHz [CDC1₃]) 1.15 (3H, d, J=6.8, CH₃CH), 1.28 (3H, d, J=6.8, CH₃CH), 1.43 (3H, d, J=6.8, CH₃CH), 1.57 (3H, d, J=6.8, CH₃CH), 3.53 (IH, septet, J=6.8, CH₃CH), 3.64-3.76 (2H, m, CH₃CH and C^N ), 4.02 (IH, s, Fc-H), 4.13 (IH, t, J=2, Fc-H), 4.19 (5H, s, Fc-H), 4.46 (IH, s, Fc-H), 4.68 (IH, dd, J-12.6 and 1.9, CH₂N), 7.46 (IH, br s, NH⁺); δ_c (100 MHz [CDC1₃]) 15.9, 18.5, 18.8, 20.4, 48.7, 51.6, 52.2, 68.2, 69.1, 70.0, 74.6; δ_B (128 MHz [CD₃CN] 4.15 (br d, J=51); δ_F (188 MHz [CD₃CN]) 132.2 (br d, J=58); m/z (ES+) ter alia M+H 368 (49%), 199 (100); HRMS (ES+) found: 368.1475 [M+H], C₁₇H₂₅NF₃FeB requires 368.1460 Preparation of Compound 12 dimethvH8-(difluoroboroyl)-naphthalen-l-yll-amine

Scheme a

l,3,5-Tris-(l-N,N-dimethylamino)-8-naphthylboroxine

NN-dimethylnapthyl-1 -amine (24.5 ml, 0.149 mol) was added to diethyl ether (450 ml) at room temperature. A 2.5 M solution of «-butyllithium in hexanes (59.6 ml, 0.149 mol) was added and the reaction was left to stir for 125 hours. The reaction mixture was cooled to -78 °C and trimethylborate (50 ml 0.48 mol) was added as rapidly as possible without raising the temperature of the reaction above -70 °C with vigorous stirring. The reaction was allowed to proceed at -78 °C for 1 hr, then allowed to warm to room temperature over 3 hr. A 5 % (w/v) solution of ΝaOH was added to the reaction (400 ml), the mixture was stined vigorously for 30 min and the white precipitate was collected by filtration, then washed with diethyl ether (2 x 100 ml) and 5 % (w/v) ΝaOH (2 x 50 ml). Residual solvent was evaporated to yield boroxine as a white powder (20.14 g, 69 %); mp > 280 °C; v_maχ(film)/cm^"1 ter alia 1452, 1254, 1204, 1116, 1056, 828, 780, 760, 665; λ_max(CH₃CΝ)/nm 220 (ε/dm³mor ¹ 12050), 288 (1580), 320 (590); δ_H(300 MHz, [CDC1₃]) 2.90 (6H, s, CH₃N), 7.25 (IH, dd, J= 7.5 and 0.9 , ArH), 7.37 (IH, t, J=8.1, ArH), 7.55-7.70 (4H, ArH); δ_c(100 MHz, [CD₃CN]) 45.3, 115.2, 124.15, 124.24, 125.1, 126.4, 126.6, 131.8, 133.6, 149.9; δ_B (96 MHz, [CDC1₃]) 19 (br); m/z (ES+) ter alia 592 (100%, MH⁺); HRMS (ES+) found 592.3101, C₃₆H₃₇B₃N₃O₃ requires 592.3114.

Preparation of dimethyl-r8-(difluoroboroyl)-naphthalen-l-yll-amine

l,3,5-Tris-(l-NN-dimethylamino)-8-naphthylboroxine (1.0 g, 1.69 mmol) was dissolved in THF (450 ml) with stirring under reflux, potassium hydrogen difluoride 1.58 g, 20.2 mmol) dissolved in water (50 ml) was added, the reaction was stined

7.6, ArH), 7.67 (IH, dt, J = 1.6 and 8.4 , ArH), 7.76 - 7.85 (3H, m, ArH); δ_c(126 MHz, [CDC1₃]) 48.1, 112.8, 125.2, 125.8, 126.5, 127.5, 129.3, 131.7, 134.2, 148.4; δ_B (128 MHz, [CDCI₃]) 9.82 (br t, J= 58 ); δ_F (470 MHz [CD₃CI3]) -148.3 (m); m/z (ES+) inter alia 243 (100 %, MHNa⁺); C₁₂H₁₂BF₂N requires C, 65.80; H, 5.52; N, 6.39; found C, 65.55; H, 5.59; N, 6.23.

Preparation of Compound 14 - N,N-Diisopropyl-2-(borono phenylmethylamine And interconversion to Compound 16 ■V,iV-Diisopropyl-2-(trifluoroboronyl)phenylmethylamine

Scheme b

,

16(X = F) 15

N,iV-DiisopropyI-2-(4,4,5,5-tetramethyl-[l,3,2]-dioxaboroIan-2-yl)-benzamide.

Scheme 11 Reagents and conditions: (i) HCl; (ii) pmacol. The boronic acid NN-diisopropyl-2-boronobenzamide (6.29g, 18.9mmol) was

10 dissolved in 60mL Et₂O. To this 40mL water was added, along with pinacol (3.55g, 18.9mmol) and HCl (9mL, IM, 9mmol), and the reaction stined under argon at ambient temperature for 72h. Reaction monitoring was done using TLC (see below). Work-up: the reaction was taken to pH9 (aq. sat. sodium carbonate), the aqueous and organic layers separated, aqueous layer extracted x3 with Et₂O, organic fractions

15 combined, dried (MgSO₄) and concentrated to afford 5.63g (90% yield) of crude product as a brown sticky solid. The product crystallised and was washed with hexane to afford 4.00g (64% yield) of white crystals: mp 108-110 °C; v_max(KCl)/cm^" ¹ 3061, 2977, 2930, 1635, 1612, 1596, 1563, 1448, 1432; δ_H (CDC1₃, 500MHz) 1.12 (6H, d, J6.5, (CH₃)₂C ), 1.32 (12H, s, 2 (CH₃)₂C), 1.58 (6H, d, J=6.5, (CH₃)₂CH), 3.51 (IH, septet, J=6.5, (CH₃)₂CH), 3.75 (IH, septet, J=6.5 , (CH₃)₂CH), 7.16 (IH, d, J 7.5, ArH), 7.32 (IH, m. ArH), 7.40 (IH, m, ArH), 7.81 (IH, d, J=7.5, ArH); δ_c (CDCI₃, 125 MHz) 20.5, 20.7, 25.1, 46.0, 51.1, 84.0, 124.8, 127.6, 130.8, 135.8,

145.2, 171.5; δ_B (CDC1₃, 96 MHz) 30.0; m/z (ES+) inter alia 330 (M-H, 61%); Calculated for C₁₉H₃₀BNO₃ m/z 331.23, found 331.23. Λf,N~Diisopropyl-2-(borono)phenylmethylamine

14

To a stined suspension of sodium borohydride (12.14 g, 320 mmol) in THF (350 ml) under argon was added chlorotrimethylsilane (81.23 ml) and the mixture heated at reflux for 2 hours. After cooling to RT, the pinacol ester (16.58 g, 23.9 mmol) was added as a suspension in THF (30 ml) and the mixture heated at reflux for 64 hours. After cooling to room temperature, the reaction mixture was quenched cautiously with MeOH (480 ml) over 30 minutes (caution: evolves H !), followed by water (50 ml). The solvent was partially evaporated, followed by the addition of saturated aqueous NH₄C1 (40 ml) and aqueous hydrochloric acid (80 ml of a 3 M solution) was added taking the aqueous layer to pH 1. Dichloromethane (250 ml) was added, followed by solid sodium carbonate was slowly added with vigorous stirring, until the aqueous layer reached pH 9 and the organic layer was separated, the aqueous layer was re-extracted with dichloromethane (2 x 100 ml), the combined organic extracts were dried (MgSO₄) and evaporated to afford the product (15.88 g, 96 %) as a mixture of boronic acid and anhydride: mp 140-142 °C; V_maxfaujoiycm^"1 znter alia 2954, 2921, 2853, 1462, 1377; δ_H(400 MHz, [CDC1₃]) 1.07-1.05 (12H, d, 7= 6.8, 2 x (CH₃)₂ CH), 3.11-3.06 (2H, septet, J 5.8, 2 x (CH₃)₂ CH), 3.78 (s, IH), 7.29-7.17 (3H, m, ArH), 7.91-7.89 (4H, m, 4 x ArH); δ_c (126 MHz, [CDC1₃]) 19.9, 47.9, 52.0,

127.3, 128.7 (br), 130.4, 131.0, 137.0, 142.2; δ_B (96 MHz, [CDC1₃]) 28.8; m/z (ES+) znter alia 236 (M+H, 55 %). iV,iV-Diisopropyl-2-(trifluoroboronyl)phenylmethylamine.

15

To boronic acid (14 g, 61 mmol) in MeOH (120 ml) was added saturated aqueous KHF₂ (20.15 g, 257.9 mmol). After 40 minutes, the precipitated product was removed by filtration, washed with cold methanol and dried. The resulting solid was recrystallised from acetonitrile to give the HF salt as a white solid (12.95 g, 82 %): mp 194-196 °C; v^nujoiycm^"1 1456, 1462, 2852, 2924, 2938, 3111; λ_max(CH₃CN)/nm 192 (s/dnAnol^{' 1}, 62950), 272 (1367) ; δ_H(400 MHz, [CD₃CN]) 8.00-7.80 (IH, br s, N-H ), 7.67 (IH, d, J = 7.2, ArH), 7.34-7.20 (3H, m, ArH), 4.38-4.36 (2H, d, J = 6.4, NCH₂), 3.61-3.58 (2H, septet, J = 6.8, CH(CH₃)₂) , 1.38-1.32 (12H, dd, / = 15.8, 6.4, 2 x CH(CH₃)₂); δ_c (100 MHz, [CD₃CN]) 133.3, 133.0, 131.5, 128.7, 127.3, 52.7, 51.7, 18.1, 17.4; δ_B (96 MHz, [CD₃CN]) δ 1.90 (q, J = 56.3 , 1 B); δ_F (376 MHz [CD₃CN]) -136.4 (m); m/z (ES+) 258 (M⁺-H, 75); C₁₃H₂₁BF₃N requires C, 60.26; H, 8.17; N, 5.41; found C, 60.25; H, 8.24; N, 5.44 %.

Alternative Reductive amination Preparation of Compound 14 - N,N- Diisopropyl-2-(borono)phenylmethylamine And analogues 14 a-c

To a 50 ml round bottomed flask under argon were added THF solvent (20 ml) 4 Angstrom activated molecular sieves (4 g), 2-formylbenzeneboronic acid (908 mg, 6 mmol) and diisopropylamine (0.854 ml, 6 mmol). The reaction was stined for 1 hour after which time sodium triacetoxyborohydride (8 g, 36 mmol) was added, the reaction was stined for a further 24 hours then, 5 % HCl (aq) (10 ml) was added the reaction was stined for 20 min. The resulting suspension was filtered through a sinter and washed through with water (50 ml) on the sinter. The filtrate THF was removed by azeofroping in vacuo. This mixture was then neutralised by the slow addition of sat NaHCO₃ (aq). The filtrate mixture was allowed to stand for 72 h then was filtered and washed with cold water (2 x 20 ml) on the filter paper to yield N,N diisopropylbenzylamine-2-boronic acid 1.00 g (71 %) as a white crystals, which was identical to that reported previously.

Analogues 14 a-c

2 % 60 % 80 %

Using the conesponding amines, in place of diisopropylamine, compounds 14 a-c were generated: tetramethylpiperidinylbenzylamine-2-boronic acid, morpholinylbenzylamine-2-boronic acid, N-α-methylbenzyl-N-methylbenzylamine- 2-boronic acid.

Example 4 CATALYTIC REACTIONS USING CATALYSTS OF THE

INVENTION

Al First general procedure for aldol reactions with acetone An aliquot (1.5 ml) of catalyst solution (0.294 g; 1 mmol in water 8 ml and acetone 5 ml) was added to each aldehyde (1 mmol) and the resulting mixture was stined at room temperature for the time stated. Water (0.5 ml) and DCM (1.0 ml) were then added and the liquor stined for 10 minutes. The phases were then separated and the aqueous layer was further extracted with DCM (1 1ml). The combined organic extracts were then passed through a small plug of silica gel and magnesium sulfate and evaporated under reduced pressure. The resulting residue was analysed by proton NMR spectroscopy.

A2 Second general procedure for aldol reactions with acetone The catalyst (7.3 mg, 2.5 μmol) was placed in a vial and an aliquot of benzaldehyde solution was added (0.5 ml of a solution containing 0.530 g in 5 ml of deuterated CH₃CN; 0.5 mmol). Deuterated THF (0.5 ml) was then added followed by acetone (184 μl; 2.5 mmol). The appropriate amount of deuterated CH₃CN and water were then added to take the total solvent volume to 2.5 ml. Each of the reaction solutions was then stined at room temperature for 10 days. Water (1.0 ml) and DCM (1.0 ml) were then added and the liquor stined for 10 minutes. The phases were then separated and the aqueous layer was further extracted with DCM (2 x 1ml). The combined organic extracts were then passed through a small plug of silica gel and magnesium sulfate. The extracts were then evaporated under reduced pressure and the resulting residue analysed by proton NMR spectroscopy.

A3 Third general procedure for the aldol reaction with acetone Benzaldehyde (5 g; 36.7 mmol), the catalyst (0.54 g; 1.8 mmol), water (33 ml) and acetone (21 ml) were placed in a reaction flask and stined for 4 days at room temperature. After which time the resulting precipitate was removed by filtration and recrystallised from diethyl ether (3.44 g; 53 %). Results are shown in Table 5 for reactions conducted in the presence of 12.5 mol% catalyst in water:acetone (60:40) solvent for 20 hours.

Table 5. Reaction of benzaldehyde was repeated with the following solvent systems:

THF:MeCN:water 0.5:1.5:0.5, catalyst 5 mol% for 10 days and gave a lower yield of ketone;

THF:MeCN:water 0.5:1.0:1.0 or 0.5:0.5:1.5, catalyst 5 mol% for 10 days and gave a higher or similar yield of racemic hydroxy ketone.

In each case there was a considerable increase in selectivity for formation of the aldol addition product 3. The most likely explanation for these observations is that the reactions are under thermodynamic control, with the catalyst assisting the reaction to reach equilibrium. Though further work on the exact mechanism operating in these reactions, these preliminary results strongly suggest that the catalyst I¹ behaves as a true catalyst, with activity not unlike that of natural type I aldolases or proline and related catalysts. In this case though, a boron enolate, rather than an iminium ion or enamine intermediate is involved, with a major advantage that the pre-activation of the carbonyl nucleophile is not required.

It is clear from these results, that both the benzimidazole and boronate units were essential for catalytic activity, since only catalyst I¹ showed any sign of reaction when compared with the benzimidazole, phenylboronic acid or a mixture of both. This demonstrates the necessity for having the cooperative effect of both an amino and boronic acid function in the same molecule to effect enolisation and hence reaction, in this case producing a mixture aldol condensation and aldol addition products, largely dependent upon the reaction polarity.

Bl First general procedure for nitro aldol with nitroethane The aldehyde (1 mmol) was placed in a vial and nitroethane (0.6 ml) was added. The catalyst (14.7 mg; 0.05 mmol) was then added followed by water (0.9 ml). The resulting biphasic reaction mixture was then stined for 3 days at room temperature. Water (0.5 ml) and DCM (1.0 ml) were then added and the liquor stined for 10 minutes. The phases were then separated and the aqueous layer was further extracted with DCM (1 1ml). The combined organic extracts were then passed through a small plug of silica gel and magnesium sulfate, and evaporated under reduced pressure. The resulting residue analysed by proton NMR spectroscopy.

B2 Second general procedure for nitro aldol with nitroethane The catalyst (7.3 mg, 2.5 μmol) was placed in a vial and an aliquot of benzaldehyde solution was added (0.5 ml of a solution containing 0.530 g in 5 ml of CD₃CN; 0.5 mmol). Deuterated THF (0.5 ml) was then added followed by nitroethane (179 μl; 2.5 mmol). The appropriate amount of CD₃CN and water were then added to take the total solvent volume to 2.5 ml. Each of the reaction solutions was then stined at room temperature for 5 days. Water (1.0 ml) and DCM (1.0 ml) were then added and the liquor stined for 10 minutes. The phases were then separated and the aqueous layer was further extracted with DCM (2 1ml). The combined organic extracts were then passed through a small plug of silica gel and magnesium sulfate, and evaporated under reduced pressure. The resulting residue analysed by proton NMR spectroscopy.

Results are shown in Table 6 Table 6.

COMPARATIVE

As comparison to illustrate the bifunctional effect, reactions A and B were repeated using as catalyst base alone (benzimidazole, no boron present) giving no reaction; acid alone (phenylboronic acid - no amine present) giving no reaction; and a mixture thereof giving no reaction.

C Example procedure for the formation of amides from phenylbutyric acid

Phenylbutyric acid (1.64 g, 10 mmol), benzylamine (0.983 ml, 3 mmol), N,N- diisopropylaminomethylphenyl boronic acid (7.1 mg, 0.03 mmol) were heated at reflux in dry toluene (40 ml) under argon, for 20 hours. The reaction mixture was filtered and then concentrated in vacuo. The residue was redissolved in DCM (60 ml), washed with 5% (w/v) HCl (100 ml), brine (100 ml), 5% (w/v) NaOH (100 ml) and brine (100 ml). The organic extracts were dried (MgSO₄) and concentrated in vacuo to give pure benzyl phenylbutyramide as a white powder (2.243 g, 98%). C Example procedure for the formation of amides from pivalic acid

Trimethylacetic acid (0.306 g, 3 mmol), benzylamine (0.33 ml, 3 mmol) and N,N- diisopropylaminomethylphenyl boronic acid (7.1 mg, 0.03 mmol) were heated at 150°C in dry ?-xylene (30 ml) under argon, for 22 hours. The reaction mixture was filtered and then concentrated in vacuo. The residue was redissolved in DCM (60 ml), washed with 5% (w/v) HCl (60 ml), 5% (w/v) NaOH (60 ml) and brine (60 ml). The organic extracts were dried (MgSO₄) and concentrated in vacuo. Silica gel chromatography (hexane:ether, 1:1, as eluant) afforded pure benzyl pivalamide as a white powder (0.45 g, 78%). Results are shown in Table 7:

Carboxylic acid conversion Product / yield

o

Ph.

XX, Ph

OH I H quant

78 %

46 %

2.2 Proof of concept: catalyst screening A series of experiments were carried out in order to probe the utility of bifunctional catalysts of the invention. These experiments involved achiral reaction rate experiments, in which a comparison of the rate of the reaction between catalysed and uncatalysed reactions for processes such as ester hydrolysis, epoxide ring opening, Michael additions, aldol and Hemy reactions, and aza-Baeyer-Villiger reactions were carried out. However, an immediate problem was encountered when trying to set up these screening reactions; for each reaction we wanted to use, 3 different solvents (polar to non-polar), several different substrates (range of substitutions and reactivities), and compare several standards (no catalyst, model Lewis acid alone, model Lewis base alone, both model Lewis acid and Lewis base) with the bifunctional catalyst-containing reaction.

We decided to screen a small number of reactions, but in more detail. This was done using reactions carried out directly in the NMR tube and using monitoring at intervals, after mixing reagents and catalysts. This type of approach was utilised because there was insufficient time, resource and suitable methods to fully develop wider ranging screening reactions. Thus, in the first instance, a single catalyst was chosen for screening, i.e. benimidazole boronic acid system 5 (R = n-Bu, X = OH) on the basis of an observation while running its ¹³C NMR in D₆-acetone, which showed clear indications of self-reaction of the solvent, producing various aldol- related products. The following experiments were therefore carried out, initially using NMR tube-based experiments: 1) excess acetone in D O solvent with catalyst 5 (R = Bu, X = OH) and different aldehydes, the results are shown in Table 5; 2) excess nitroethane in D₂O solvent with catalyst 5 (R = Bu, X = OH) and different aldehydes, the results are shown in Table 5.

For each of the reactions shown in Tables 5 and 6, conesponding reactions were carried out for comparison with: 1) phenylboronic acid as the catalyst; 2) imidazole 16 as the catalyst; and 3) both phenylboronic acid and imidazole 16 as catalysts. Most importantly, no reaction was observed under these comparison conditions, clearly showing that both the boronic acid functions and imidazole functions are required to be proximal and part of the same molecular structure in order to catalyse the aldol or Henry reactions. Hence, bifunctional catalyst 5 (R = Bu, X = OH) is a highly efficient catalyst for both the aldol reaction and Henry reaction.

These results show that amine-boronate systems have substantial potential as molecular catalysts, which are also potentially 'green' catalysts, being active in aqueous solution and not requiring the prior activation of the carbonyl component with strong bases and/or Lewis acids. Although the mechanism by which 5 (R = Bu, X = OH) operates has not been proved, we suspect that is operates according to Scheme 3 in the case of acetone and the initial C-C bond forming reaction. Similarly, with nitroethane, it is thought that catalyst 5 reacts via a boron-nitro enolate, which requires the proximal base function in order for the reaction to proceed. Despite a report by Kobayashi et al. ^u of generating boron enolates in water under catalytic conditions from silyl enol ethers and the report by Jørgensen et alX of the catalytic Hemy reaction of silyl nitronates with aldehydes, we are -unaware of catalytic behaviour similar to 5, where either acetone or nitro boron enolates are generated in situ in water, under catalytic conditions.

Further advantages and aspects of the invention are apparent from the foregoing.

Claims

1. Organic bifunctional Lewis acid - Lewis base catalyst of Formula I:

wherein \^ is a C_2-60 optionally heteroatom containing substituted or unsubstituted hydrocarbon scaffold comprising pendant or integral bifunctional groups L_A and L_B which together with the scaffold form a neutral bifunctional catalytic entity, each of L_A and L_B being a catalytic function of the entity and adapted to coordinate one or more substrates, preferably one or two substrates via one or more sites, preferably via two or more sites; wherein L_A is a pendant or integral Lewis acid group L_A XAΠ¹ covalently attached to a C skeleton where

LA' is B; n¹ is 2 and each XA is same or different and is independently selected from OH, OR¹, F, Cl, Br; or n is 2 or_3 and X_A is selected from OR¹, R¹^ SR^, and R^O^-R¹ where each R¹ is independently selected from C_1-7 alkyl or alkoxy such as methyl, ethyl, propyl, butyl, aryl, optionally halogen substituted such as CF₃ or fluoroaryl, or hydrophilic polymeric groups; and

R² is selected from H or C_{1- 4} substituted or unsubstituted optionally heteroatom containing hydrocarbon, or two of R² form a substituted or unsubstituted cyclic aliphatic or aromatic ring;

L_B is a pendant or integral Lewis base group L_B> X_BΠI¹ where L_B> is selected from N and P; m is zero, 1, 2 or 3 and none or 1 of X_B is selected from =O and none, 1 or 2 of X_B are independently R²; and wherein the or each R² is independently as hereinbefore defined H or C_1-24 substituted or unsubstituted optionally heteroatom containing hydrocarbon or one or two of R² are part of or foim a substituted or unsubstituted cyclic aliphatic or aromatic ring which may contain heteroatoms selected from O, N, S; and wherein one or more optional substituents of the scaffold R are selected independently from groups comprising combinations of O, N, S, P, H, halo (Cl, F, Br, I) atoms or from C_1-24 substituted or unsubstituted optionally heteroatom containing hydrocarbon or any two of R³ form a cyclic ring; and its salts, N-functionalised derivatives, dimer or oligomer thereof, characterised in that L_A and L_B are not ligands for an external metal or Lewis acid.

2. Bifunctional catalyst as claimed in Claim 1 wherein a salt is a salt of the Lewis acid, and is BXA_'3 ^~M+ where M is a metal such as sodium and the like, and an oligomer is an oligomer of the Lewis acid such as the trimer boroxine.

3. Bifunctional catalyst as claimed in Claim 1 or 2 wherein J is substituted by one or more groups R³ wherein R³ is selected from any OH, halo, NO₂, amino, amido, carbonyl, CN, oxo, C_1-24 alkyl or alkoxy, C_2- alkenyl or alkynyl, C_3-2 cycloalkyl or aryl and combinations thereof.

4. Bifunctional catalyst as claimed in any of Claims 1 to 3 wherein comprises a core scaffold structure SCF supporting bifunctional groups L and L_B as hereinbefore defined, wherein SCF is a C_2-6o optionally heteroatom containing substituted or unsubstituted hydrocarbon scaffold as hereinbefore defined for

0 optionally including spacers SPA for linking to L and Lβ each SPA, if present, is selected independently from C_1-8 optionally heteroatom containing optionally substituted alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and aromatic; and wherein each of L_A and L_B independently are pendant to scaffold core SCF or spacer SPA and connected thereto by one single or double bond or are integral with SCF or SPA and connected thereto by two or more single or double bonds or a combination thereof.

5. Bifiinctional catalyst of any of Claims 1 to 4 wherein ^{^} *^s °f formula I" [SCF^CF²] wherein functional groups LA and L_B may be on the same or different SCF moiety and wherein each of SCF¹ and SCF² is independently selected from a substituted or unsubstituted C _₅₈ unsaturated linear or branched aliphatic, alicyclic, or mono or multi ring aromatic such as from 1 to 6 fused 5 and/or 6 atom (hetero)aromatic ring systems, and combinations thereof, optionally including one or more heteroatoms selected from N, O, S, P, Si and / or one or more metals selected from Fe, Ru, Cr, Ni, Co⁺ , Ti, W, Mo and / or other atoms such as Pd, Al and the like and optionally one or more substituents R³ which are independently selected from OH, halo, NO₂, amino, amido, carbonyl, CN, oxo, C_1-2 alkyl or alkoxy, C_2-24 alkenyl or alkynyl, C_3- ₂ cycloalkyl or aryl and combinations thereof.

6. Bifunctional catalyst of any of Claims 1 to 5 wherein LA is selected from BXA₂, BR , BR^Y, BR}Y₂ and the like wherein X, R¹ and Y are as hereinbefore defined, and preferably each XA is the same, more preferably L_A is selected from B(OH)₂, (OB )₃, BF₂, BR^!NR².

7. Bifunctional catalyst of any of Claims 1 to 6 wherein

L_B is selected from NR² ₂, PR² ₂, POR² ₂, -N=, -NR²- wherein each R² independently is as hereinbefore defined and preferably forms a hindered amine where each R² is C_3-24 substituted or unsubstituted optionally heteroatom containing hydrocarbon, or two of R² form a substituted or unsubstituted cyclic aliphatic or aromatic ring, or forms an unhindered amine where each R² is C_1-3 substituted or C_1-5 unsubstituted optionally heteroatom containing hydrocarbon.

8. Bifunctional catalyst of any of Claims 1 to 7 wherein the or each R is selected from substituted or unsubstituted, optionally heteroatom-containing, C_1-24 alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy or aryl, or two of R², optionally including L_A> or L_B> form a substituted or unsubstituted 3 to 7 membered cyclic ring, wherein substituents include OH, halo, OCH₃, CH₃, OC₂H₅, C H₅, C₃H₇, C₆H₅ or hydrophilic polymeric groups such as - (OCH₂CH₂)pR² where p indicates a repeating unit and is 2 to 60, etc and R² is as hereinbefore defined and is preferably H, alkyl or amino.

9. Bifunctional catalyst of any of Claims 4 to 8 wherein SCF or either or both SCF¹ and SCF², including as relevant a N atom from L_B, comprises C_2-10 straight chain or branched terminal or in chain aliphatic linear or branched alkyl or cycloalkyl, substituted or unsubstituted molecular and macromolecular aromatic and unsaturated or electron rich cyclic systems such as phenyl, pynole, imidazole, pyridine, pyrimidine, purine, hydrocarbon metal complexes such as metallocenes such as fenocenyl, ruthenocenyl, and other di and mono cyclopentadienyl, arenyl, cycloheptatrienyl and the like complexes, 4'-biphenyl, naphthalenyl, asymmetric naphthalene, quinoline, isoquinoline, binaphthalene, (3, 5-diphenyl)phenyl, [(3',3", 5', 5"-tetramethyl)-3, 5-diphenyl]phenyl, carbazole, benzimidazole, 4 ring systems such as steroids (6,6,6,5), macromolecules containing receptor binding sites such as cyclodextrins and other sugar containing systems and the like and oligomers and polymers thereof, preferably C_3-1o linear or branched alkyl or cycloalkyl, or a 1 to 5, more preferably 1 to 3 fused, spiro or coordinated ring system, such as phenyl, fenocenyl, paracyclophane, benzimidazole, naphthalenyl, quinolinyl and the like.

10. Bifunctional catalyst of any of Claims 1 to 9 which is chiral or non chiral.

11. Bifunctional catalyst of formula I¹

wherein X is OH or F and R³ is H, linear or branched C_1-8 alkyl, or a hydrophilic polymeric group as hereinbefore defined, for catalysing aldol reactions; or I¹¹

wherein R is R² as hereinbefore defined, preferably C_3-8 alkyl eg isopropyl and X is F or OH, for catalysing amide formation comprising transformation of carboxylic acid substrate in the presence of an amine substrate, preferably peptide formation from amino acid.

12. Bifunctional catalyst of any of Claims 1 to 11 wherein bifunctional groups LA and L_B are of separation of the order of 1.2 to 4 Angstrom, more preferably 1.2 to 2.3 Angstrom, and the scaffold is rigid or fixed whereby the separation of groups L_A and L_B is constant or may vary according to phase and presence of cooperating species .

13. Bifunctional catalyst of any of Claims 1 to 12 which is homogeneous or heterogeneous.

14. Bifunctional catalyst of any of Claims 1 to 13 which is soluble in aqueous or organic solvent.

15. Bifunctional catalyst of any of Claims 1 to 14 which is unsupported, eg powder, or attached to a solid support or a resin system, such as a porous or non- porous crosslinked or non-crosslinked hydrophilic or otherwise functionalised resin, for example Merrifield (DVB crosslinked polystyrene) or Tentagel (porous polystyrene + PEG) resins, glass support, ceramic support or the like.

16. Bifunctional catalyst of Claim 15 which is attached to a solid support or a resin system b or SCF or SCF¹

or SCF² as hereinbefore defined, wherein R³ is a hydrophilic polymeric group as hereinbefore defined.

17. Bifunctional catalyst of any of Claims 1 to 16 which is in the form of a resin more preferably resin beads, most preferably of the order of 50-200 micron.

18. Composition comprising a catalytically effective amount of a catalyst of Formula I as hereinbefore defined in any of Claims 1 to 17 together with suitable solvent, dilutent and the like or together with a suitable linker on a macromolecule, polymer or a solid support..

19. A novel compound of Formula I as hereinbefore defined in any of Claims 1 to 18 with the proviso that when L_AXAΪI¹ is B(OH)₂ and L_BX_BΪΪI¹ is -NH- or -NCH₃- and L_B is an imidazole nitrogen then s not 2-phenyl benzimidazole or 2-

benzyl benzimidazole in which B(OH)₂ is an ortho substituent on the phenyl or benzyl ring; or in the catalyst of Formula I when L_AX_AΪI¹ is B(OH)₂ and LβXβm¹ is - N= then f^{^}\ *^{s no}* quinoline in which B(OH)₂ is in the 8-position.

20. A kit comprising one or a plurality of catalysts or compounds of Formula I as hereinbefore defined in any of Claims 1 to 19 adapted to catalyse one or a plurality of selective transformations, together with one or more reagents, analytical substrates and the like for conducting the reaction(s), isolating chiral or nonchiral products and determining the products.

21. The use of a compound or catalyst of Formula I as hereinbefore defined in any of claims 1 to 20 or kit thereof in catalysing a selective transformation.

223. Use as claimed in Claim 21 wherein a selective transformation employs two or more reactive sites on one or more substrates by cooperative effect of Lewis acid and Lewis base functions.

23. Use as claimed in Claim 21 or 22 wherein a selective transformation is reversible, preferably reversible asymmetric.

24. A process for selective transformation of one or more substrates in the presence of catalyst of Formula I or a composition or kit thereof as hereinbefore defined in any of Claims 1 to 19 to provide a product, with simultaneous or subsequent recovery of the catalyst.

25. Process as claimed in Claim 24 wherein a selective transformation is suited for a combinatorial chemistry approach reacting a substrate with a plurality or reagents or cosubstrates, or reacting a plurality of substrates with one or a plurality of reagents or cosubstrates in the presence of amounts of a catalyst as hereinbefore defined.

26. Use or process as claimed in any of Claims 21 to 25 wherein a selective transformation is selected from a condensation, eg aldol or Henry reaction, Darzens, Bayliss-Hillman, alkylation, oxidation, eg Baeyer Villiger, acylation (including Friedel-Crafts, amide, ester and acetal formation), hydrolysis (eg ester, amide and acetal hydrolysis), substitution, ring opening eg epoxide ring opening, nucleophilic addition eg cyanosilylation or Michael addition, electrophilic addition, and the like.

27. Method for screening one or more catalysts of Formula I as hereinbefore defined in any of Claims 1 to 19 as useful catalysts for a desired selective transformation, comprising conducting a process for selective transformation with one or a plurality of catalysts of Formula I and analysing the product; or comprising conducting in parallel a plurality of processes for selective transformation with one or a plurality of catalysts of Formula I and analysing the product of each transformation.

28. Method as claimed in Claim 27 which comprises highly parallel reaction screening with real-time reaction monitoring, preferably using online, parallel LC- MS, in conjunction with an automated workstation system..

29. A screening kit for use in the screening method as claimed in Claim 27 or 28 comprising one or more catalysts together with one or more reagents for analysing the product of reaction.

301. Product of a catalytic reaction obtained with use of a catalyst as hereinbefore defined in any of claims 1 to 19.

31. Process for the preparation of a catalyst of Formula I as hereinbefore defined in any of claims 1 to 19 comprising: and each X_A is halogen: halogenation of a compound II: to isolate the compound of Formula I : LAXAΠ¹ - SCF -

or b) in the case that nHs 2 and each XA is OH: reduction of Lewis acid ester compound IV LβXβm¹ -SCF - LAO₂R⁵ where O₂R⁵ is a cyclic alkyl such as - (C(CH₃)₂)₂ - to isolate the compound of Formula I: L_A(OH)₂ - SCF - LβXβm¹; or c) in the case that LβX_Bm¹ is integral with SCF, n¹ is 2 and each X_A is halogen: halogenation of a compound VI: r Br

to isolate the compound of Formula I : rSCF, -LA'XAII ;

or d) in the case that L_B-X_BUI¹ is pendant to SCF, n¹ is 2 and each X_A is OH: cyclisation of a compound VII:

with a compound VIII:

OCH- SCF² - Br and reductive substitution, such as reductive amination, to generate the boronic acid and to isolate the compound of Formula I : SCF¹ (NHR) ( L_B) - SCF² LA X_AΠ¹; or e) in the case that L X_AΠ¹ is pendant to SCF, n² is 2 and each X_B is any alkyl, aryl or cycloalkyl substituent: reductive amination of a compound IX:

with an amine to generate the boronic acid and to isolate the compound of Formula I : SCF L_B L_A; or direct introduction of L_B function onto preexisting boronic acid SCFL_A + L_B

32. . Process for the preparation of a catalyst of Formula I as claimed in any of Claims 1 to 19 in which X_A is halo such as F by interconversion from a conesponding compound of Formula I in which XA is OH by halogenation; or from the MF₃ ^" salt of compound of Formula I obtained KF and generating the product compound of Formula I in which XA is F by reduction for example with BuLi.

33. Process as claimed in Claim 31 wherein compound II is obtained by directed metallation of a compound III: SCF - L_BX_BΠI¹, with a metal oxide L_A(OR⁴)₃ where R⁴ is methyl, ethyl, propyl or butyl to introduce a cyclic metal oxide precursor of the Lewis acid function; or wherein compound IV is obtained by directed metallation of a compound V RCOLβXβm¹, with an oxide L_A(OR⁴)₃ where R⁴ is as hereinbefore defined such as iPr to introduce an ester precursor of the Lewis acid function; or wherein Ar¹ - Ar² is obtained by reaction of a compound VII H₂N- Ar¹ - NHC₄H₉ with a compound VIII: Br - Ar² - CO₂H to form VI: Ar¹(-N(nC₄H₉)C=N-) - Ar² - Br.

34. A novel intermediate of formula II, III, IV, V, VI as hereinbefore defined in Claim 31 or 33.

35. Catalyst, use, process or screening method or kit substantially as hereinbefore described in the description or examples.